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New fragility fracture recommendations emphasize coordination of care
LONDON – The European League Against Rheumatism and the European Federation of National Associations of Orthopaedics and Traumatology have joined forces to develop recommendations for the prevention and management of fragility fractures.
Such fractures are common in men and women over the age of 50 years and can lead to repeat fracture in some patients. The recommendations are unique as they are the first to consider both acute orthopedic and postfracture rheumatologic care, said Willem F. Lems, MD, PhD, of the Amsterdam Rheumatology and Immunology Centre.
At the European Congress of Rheumatology, Dr. Lems provided an overview of the draft recommendations, noting that there would be several overarching principles, one of which recognized the multidisciplinary nature of caring for someone with a fragility fracture. An important point is not who is taking care of the patient, but that the patient is given the best possible care within the multidisciplinary framework.
What constitutes optimal care of course depends on the clinical situation, notably the type of fracture and the age of the patient, and optimal care in all phases of presentation (pre-, peri- and postoperative) can have an important effect on a patient’s outcome. The prevention of subsequent fractures is a key focus, with the recommendation that all patients should be investigated systematically and those deemed at high risk for another fracture should be prescribed both pharmacologic and nonpharmacologic interventions as appropriate. Patient education is also considered important.
As for all EULAR-developed recommendations, standard procedures were followed that involved convening an expert scientific advisory committee and using the Delphi technique to come up with the most important research questions that would be used to formulate the final 10 recommendations. Four of the recommendations cover the acute care setting and six provide advice on postfracture care.
The first of the acute care recommendations looks at pre- and perioperative management of a fragility fracture and highlights that, within 24-48 hours of admission, patients should receive adequate pain and fluid management and treatment, including early surgery if appropriate. This is based on evidence that better outcomes can be achieved in terms of both morbidity and mortality if patients can be seen and managed quickly.
Another of the acute care recommendations focuses on orthogeriatric care, noting that the orthopedic surgeon and a dedicated orthogeriatric team should work together, particularly for elderly patients who have suffered a hip fracture. Key elements here are the management of and prevention of delirium, deep vein thrombosis, pressure sores, and malnutrition.
As for actual fracture treatment, a balanced approach is advised when deciding upon a surgical or nonsurgical approach, especially because this is likely to be an older population with other comorbidities. Only one in three vertebral fractures are symptomatic and only about 10% of patients will be hospitalized for pain. Analgesics, modifying activities, and bracing can be options here. Surgical options for distal radial fracture, hip fracture, and trochanteric and femoral neck fractures are included.
The fourth recommendation looks at the organization of postfracture care and the need for a systematic approach to identify those who may be at risk for subsequent fractures, starting with the suggestion that any patient older than 50 years with a recent fracture should be assessed. The fifth recommendation addresses ways to evaluate this risk, such as looking at the clinical risk factors, performing bone scans and imaging, and screening for underlying osteoporosis or metabolic disorders.
Implementation is the next step, and the sixth recommendation suggests ways these recommendations could be integrated into routine practice. Often one of the biggest barriers to effective postfracture care is the lack of patient, and sometimes clinician, awareness of the risk for a subsequent fracture. This recommendation looks at the role of a possible local fracture liaison service or facilitator to coordinate between the various members of the multidisciplinary team from secondary (orthopedic surgeons, rheumatologists, endocrinologists, and geriatricians) to primary care.
The seventh recommendation addresses rehabilitation and the need to initiate physical training and muscle strengthening as early as possible after the initial fracture, with long-term continuation of balance training and fall prevention.
The final three recommendations focus on how to educate patients about their risk factors, need for follow-up, and the duration of any pharmacologic or nonpharmacologic therapy that they may need. Nonpharmacologic options might include stopping smoking, limiting alcohol intake, as well as taking supplements such as calcium or vitamin D. There will be specific guidance on the use of calcium and vitamin D, which have both pros and cons, but the optimal dosage appears to be 1,000–1,200 mg/day for calcium and 800 IU/day for vitamin D.
Pharmacologic options to prevent subsequent fragility fractures include the bisphosphonates alendronate, risedronate, and zoledronic acid (Reclast), and also the monoclonal antibody denosumab (Prolia). These are the only drugs that have been shown to reduced the risk for vertebral, nonvertebral, and hip fractures in primary analyses. Adherence, tolerance, and regular monitoring are key, and a five-step plan is suggested to aid clinical decision making that covers case finding, risk evaluation, differential diagnosis, treatment, and follow-up.
The recommendations are being finalized and should be available for publication later this year. The recommendations task force also plans to propose a research agenda.
Dr. Lems had no relevant disclosures.
LONDON – The European League Against Rheumatism and the European Federation of National Associations of Orthopaedics and Traumatology have joined forces to develop recommendations for the prevention and management of fragility fractures.
Such fractures are common in men and women over the age of 50 years and can lead to repeat fracture in some patients. The recommendations are unique as they are the first to consider both acute orthopedic and postfracture rheumatologic care, said Willem F. Lems, MD, PhD, of the Amsterdam Rheumatology and Immunology Centre.
At the European Congress of Rheumatology, Dr. Lems provided an overview of the draft recommendations, noting that there would be several overarching principles, one of which recognized the multidisciplinary nature of caring for someone with a fragility fracture. An important point is not who is taking care of the patient, but that the patient is given the best possible care within the multidisciplinary framework.
What constitutes optimal care of course depends on the clinical situation, notably the type of fracture and the age of the patient, and optimal care in all phases of presentation (pre-, peri- and postoperative) can have an important effect on a patient’s outcome. The prevention of subsequent fractures is a key focus, with the recommendation that all patients should be investigated systematically and those deemed at high risk for another fracture should be prescribed both pharmacologic and nonpharmacologic interventions as appropriate. Patient education is also considered important.
As for all EULAR-developed recommendations, standard procedures were followed that involved convening an expert scientific advisory committee and using the Delphi technique to come up with the most important research questions that would be used to formulate the final 10 recommendations. Four of the recommendations cover the acute care setting and six provide advice on postfracture care.
The first of the acute care recommendations looks at pre- and perioperative management of a fragility fracture and highlights that, within 24-48 hours of admission, patients should receive adequate pain and fluid management and treatment, including early surgery if appropriate. This is based on evidence that better outcomes can be achieved in terms of both morbidity and mortality if patients can be seen and managed quickly.
Another of the acute care recommendations focuses on orthogeriatric care, noting that the orthopedic surgeon and a dedicated orthogeriatric team should work together, particularly for elderly patients who have suffered a hip fracture. Key elements here are the management of and prevention of delirium, deep vein thrombosis, pressure sores, and malnutrition.
As for actual fracture treatment, a balanced approach is advised when deciding upon a surgical or nonsurgical approach, especially because this is likely to be an older population with other comorbidities. Only one in three vertebral fractures are symptomatic and only about 10% of patients will be hospitalized for pain. Analgesics, modifying activities, and bracing can be options here. Surgical options for distal radial fracture, hip fracture, and trochanteric and femoral neck fractures are included.
The fourth recommendation looks at the organization of postfracture care and the need for a systematic approach to identify those who may be at risk for subsequent fractures, starting with the suggestion that any patient older than 50 years with a recent fracture should be assessed. The fifth recommendation addresses ways to evaluate this risk, such as looking at the clinical risk factors, performing bone scans and imaging, and screening for underlying osteoporosis or metabolic disorders.
Implementation is the next step, and the sixth recommendation suggests ways these recommendations could be integrated into routine practice. Often one of the biggest barriers to effective postfracture care is the lack of patient, and sometimes clinician, awareness of the risk for a subsequent fracture. This recommendation looks at the role of a possible local fracture liaison service or facilitator to coordinate between the various members of the multidisciplinary team from secondary (orthopedic surgeons, rheumatologists, endocrinologists, and geriatricians) to primary care.
The seventh recommendation addresses rehabilitation and the need to initiate physical training and muscle strengthening as early as possible after the initial fracture, with long-term continuation of balance training and fall prevention.
The final three recommendations focus on how to educate patients about their risk factors, need for follow-up, and the duration of any pharmacologic or nonpharmacologic therapy that they may need. Nonpharmacologic options might include stopping smoking, limiting alcohol intake, as well as taking supplements such as calcium or vitamin D. There will be specific guidance on the use of calcium and vitamin D, which have both pros and cons, but the optimal dosage appears to be 1,000–1,200 mg/day for calcium and 800 IU/day for vitamin D.
Pharmacologic options to prevent subsequent fragility fractures include the bisphosphonates alendronate, risedronate, and zoledronic acid (Reclast), and also the monoclonal antibody denosumab (Prolia). These are the only drugs that have been shown to reduced the risk for vertebral, nonvertebral, and hip fractures in primary analyses. Adherence, tolerance, and regular monitoring are key, and a five-step plan is suggested to aid clinical decision making that covers case finding, risk evaluation, differential diagnosis, treatment, and follow-up.
The recommendations are being finalized and should be available for publication later this year. The recommendations task force also plans to propose a research agenda.
Dr. Lems had no relevant disclosures.
LONDON – The European League Against Rheumatism and the European Federation of National Associations of Orthopaedics and Traumatology have joined forces to develop recommendations for the prevention and management of fragility fractures.
Such fractures are common in men and women over the age of 50 years and can lead to repeat fracture in some patients. The recommendations are unique as they are the first to consider both acute orthopedic and postfracture rheumatologic care, said Willem F. Lems, MD, PhD, of the Amsterdam Rheumatology and Immunology Centre.
At the European Congress of Rheumatology, Dr. Lems provided an overview of the draft recommendations, noting that there would be several overarching principles, one of which recognized the multidisciplinary nature of caring for someone with a fragility fracture. An important point is not who is taking care of the patient, but that the patient is given the best possible care within the multidisciplinary framework.
What constitutes optimal care of course depends on the clinical situation, notably the type of fracture and the age of the patient, and optimal care in all phases of presentation (pre-, peri- and postoperative) can have an important effect on a patient’s outcome. The prevention of subsequent fractures is a key focus, with the recommendation that all patients should be investigated systematically and those deemed at high risk for another fracture should be prescribed both pharmacologic and nonpharmacologic interventions as appropriate. Patient education is also considered important.
As for all EULAR-developed recommendations, standard procedures were followed that involved convening an expert scientific advisory committee and using the Delphi technique to come up with the most important research questions that would be used to formulate the final 10 recommendations. Four of the recommendations cover the acute care setting and six provide advice on postfracture care.
The first of the acute care recommendations looks at pre- and perioperative management of a fragility fracture and highlights that, within 24-48 hours of admission, patients should receive adequate pain and fluid management and treatment, including early surgery if appropriate. This is based on evidence that better outcomes can be achieved in terms of both morbidity and mortality if patients can be seen and managed quickly.
Another of the acute care recommendations focuses on orthogeriatric care, noting that the orthopedic surgeon and a dedicated orthogeriatric team should work together, particularly for elderly patients who have suffered a hip fracture. Key elements here are the management of and prevention of delirium, deep vein thrombosis, pressure sores, and malnutrition.
As for actual fracture treatment, a balanced approach is advised when deciding upon a surgical or nonsurgical approach, especially because this is likely to be an older population with other comorbidities. Only one in three vertebral fractures are symptomatic and only about 10% of patients will be hospitalized for pain. Analgesics, modifying activities, and bracing can be options here. Surgical options for distal radial fracture, hip fracture, and trochanteric and femoral neck fractures are included.
The fourth recommendation looks at the organization of postfracture care and the need for a systematic approach to identify those who may be at risk for subsequent fractures, starting with the suggestion that any patient older than 50 years with a recent fracture should be assessed. The fifth recommendation addresses ways to evaluate this risk, such as looking at the clinical risk factors, performing bone scans and imaging, and screening for underlying osteoporosis or metabolic disorders.
Implementation is the next step, and the sixth recommendation suggests ways these recommendations could be integrated into routine practice. Often one of the biggest barriers to effective postfracture care is the lack of patient, and sometimes clinician, awareness of the risk for a subsequent fracture. This recommendation looks at the role of a possible local fracture liaison service or facilitator to coordinate between the various members of the multidisciplinary team from secondary (orthopedic surgeons, rheumatologists, endocrinologists, and geriatricians) to primary care.
The seventh recommendation addresses rehabilitation and the need to initiate physical training and muscle strengthening as early as possible after the initial fracture, with long-term continuation of balance training and fall prevention.
The final three recommendations focus on how to educate patients about their risk factors, need for follow-up, and the duration of any pharmacologic or nonpharmacologic therapy that they may need. Nonpharmacologic options might include stopping smoking, limiting alcohol intake, as well as taking supplements such as calcium or vitamin D. There will be specific guidance on the use of calcium and vitamin D, which have both pros and cons, but the optimal dosage appears to be 1,000–1,200 mg/day for calcium and 800 IU/day for vitamin D.
Pharmacologic options to prevent subsequent fragility fractures include the bisphosphonates alendronate, risedronate, and zoledronic acid (Reclast), and also the monoclonal antibody denosumab (Prolia). These are the only drugs that have been shown to reduced the risk for vertebral, nonvertebral, and hip fractures in primary analyses. Adherence, tolerance, and regular monitoring are key, and a five-step plan is suggested to aid clinical decision making that covers case finding, risk evaluation, differential diagnosis, treatment, and follow-up.
The recommendations are being finalized and should be available for publication later this year. The recommendations task force also plans to propose a research agenda.
Dr. Lems had no relevant disclosures.
AT THE EULAR 2016 CONGRESS
Editorial Board Biographies
Struan H. Coleman, MD, PhD
Associate Editor for Practice Management/Economics
Dr. Coleman is a board-certified orthopedic surgeon specializing in hip preservation and sports medicine at the Hospital for Special Surgery in New York and the Vincera Institute in Philadelphia, and currently is the Head Team Physician for the New York Mets. He earned a medical degree from Columbia College of Physicians and Surgeons and holds a D.Phil in Microbiology from Oxford University in England. He completed his residency in Orthopedic Surgery and a fellowship in Sports Medicine at the Hospital for Special Surgery. Dr. Coleman focuses on the treatment of sports-related injuries of the hip, knee, and shoulder with a particular interest in hip arthroscopy and hip preservation. He has published multiple articles and book chapters, and holds numerous patents for technologies that are utilized by sports medicine physicians and surgeons.
Jack Farr II, MD
Associate Editor for Patellofemoral
Dr. Farr is a board-certified orthopedic surgeon and has a subspecialty practice in knee and cartilage restoration. He is affiliated with the OrthoIndy Hospital and Community Hospital South. He is also the Vice President of the Patellofemoral Foundation, is on the board for the International Cartilage Repair Society, holds a board position with the Cartilage Research Foundation, and holds a voluntary clinical full professorship in Orthopedic Surgery at the Indiana University Medical Center. Dr. Farr earned his medical degree from Indiana University, and completed his Orthopedic Surgery residency at Indiana University Medical Center. He was a design surgeon for a meniscal allograft transplant system and 2 knee patellofemoral osteotomy systems. He is also a member of the American Academy of Orthopaedic Surgeons (AAOS), the Arthroscopy Association of North America (AANA), and the European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA).
Kenneth Montgomery, MD
Associate Editor for Professional Sports
Dr. Montgomery is an orthopedic surgeon who is fellowship-trained in sports medicine and hand and upper extremity surgery. He is currently practicing at Tri-County Orthopedics and Sports Medicine in Morristown, New Jersey. He is also the Head Team Physician and Medical Director for the New York Jets. He served as a team orthopedist with the New York Islanders from 1997-2009, and was formerly the section chief of Sports Medicine at ProHEALTH Care Associates in Lake Success, New York. Dr. Montgomery completed his residency in Orthopedic Surgery at the Hospital for Special Surgery, and completed a Sports Medicine fellowship at Lenox Hill Hospital. He also completed a Hand and Upper Extremity fellowship at Harvard. He is one of the founders for OrthoNations, a nonprofit organization that helps educate orthopedic surgeons in developing countries. He is also one of the founding surgeons for Cayenne Medical, a medical device company specializing in sports medicine implants.
Struan H. Coleman, MD, PhD
Associate Editor for Practice Management/Economics
Dr. Coleman is a board-certified orthopedic surgeon specializing in hip preservation and sports medicine at the Hospital for Special Surgery in New York and the Vincera Institute in Philadelphia, and currently is the Head Team Physician for the New York Mets. He earned a medical degree from Columbia College of Physicians and Surgeons and holds a D.Phil in Microbiology from Oxford University in England. He completed his residency in Orthopedic Surgery and a fellowship in Sports Medicine at the Hospital for Special Surgery. Dr. Coleman focuses on the treatment of sports-related injuries of the hip, knee, and shoulder with a particular interest in hip arthroscopy and hip preservation. He has published multiple articles and book chapters, and holds numerous patents for technologies that are utilized by sports medicine physicians and surgeons.
Jack Farr II, MD
Associate Editor for Patellofemoral
Dr. Farr is a board-certified orthopedic surgeon and has a subspecialty practice in knee and cartilage restoration. He is affiliated with the OrthoIndy Hospital and Community Hospital South. He is also the Vice President of the Patellofemoral Foundation, is on the board for the International Cartilage Repair Society, holds a board position with the Cartilage Research Foundation, and holds a voluntary clinical full professorship in Orthopedic Surgery at the Indiana University Medical Center. Dr. Farr earned his medical degree from Indiana University, and completed his Orthopedic Surgery residency at Indiana University Medical Center. He was a design surgeon for a meniscal allograft transplant system and 2 knee patellofemoral osteotomy systems. He is also a member of the American Academy of Orthopaedic Surgeons (AAOS), the Arthroscopy Association of North America (AANA), and the European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA).
Kenneth Montgomery, MD
Associate Editor for Professional Sports
Dr. Montgomery is an orthopedic surgeon who is fellowship-trained in sports medicine and hand and upper extremity surgery. He is currently practicing at Tri-County Orthopedics and Sports Medicine in Morristown, New Jersey. He is also the Head Team Physician and Medical Director for the New York Jets. He served as a team orthopedist with the New York Islanders from 1997-2009, and was formerly the section chief of Sports Medicine at ProHEALTH Care Associates in Lake Success, New York. Dr. Montgomery completed his residency in Orthopedic Surgery at the Hospital for Special Surgery, and completed a Sports Medicine fellowship at Lenox Hill Hospital. He also completed a Hand and Upper Extremity fellowship at Harvard. He is one of the founders for OrthoNations, a nonprofit organization that helps educate orthopedic surgeons in developing countries. He is also one of the founding surgeons for Cayenne Medical, a medical device company specializing in sports medicine implants.
Struan H. Coleman, MD, PhD
Associate Editor for Practice Management/Economics
Dr. Coleman is a board-certified orthopedic surgeon specializing in hip preservation and sports medicine at the Hospital for Special Surgery in New York and the Vincera Institute in Philadelphia, and currently is the Head Team Physician for the New York Mets. He earned a medical degree from Columbia College of Physicians and Surgeons and holds a D.Phil in Microbiology from Oxford University in England. He completed his residency in Orthopedic Surgery and a fellowship in Sports Medicine at the Hospital for Special Surgery. Dr. Coleman focuses on the treatment of sports-related injuries of the hip, knee, and shoulder with a particular interest in hip arthroscopy and hip preservation. He has published multiple articles and book chapters, and holds numerous patents for technologies that are utilized by sports medicine physicians and surgeons.
Jack Farr II, MD
Associate Editor for Patellofemoral
Dr. Farr is a board-certified orthopedic surgeon and has a subspecialty practice in knee and cartilage restoration. He is affiliated with the OrthoIndy Hospital and Community Hospital South. He is also the Vice President of the Patellofemoral Foundation, is on the board for the International Cartilage Repair Society, holds a board position with the Cartilage Research Foundation, and holds a voluntary clinical full professorship in Orthopedic Surgery at the Indiana University Medical Center. Dr. Farr earned his medical degree from Indiana University, and completed his Orthopedic Surgery residency at Indiana University Medical Center. He was a design surgeon for a meniscal allograft transplant system and 2 knee patellofemoral osteotomy systems. He is also a member of the American Academy of Orthopaedic Surgeons (AAOS), the Arthroscopy Association of North America (AANA), and the European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA).
Kenneth Montgomery, MD
Associate Editor for Professional Sports
Dr. Montgomery is an orthopedic surgeon who is fellowship-trained in sports medicine and hand and upper extremity surgery. He is currently practicing at Tri-County Orthopedics and Sports Medicine in Morristown, New Jersey. He is also the Head Team Physician and Medical Director for the New York Jets. He served as a team orthopedist with the New York Islanders from 1997-2009, and was formerly the section chief of Sports Medicine at ProHEALTH Care Associates in Lake Success, New York. Dr. Montgomery completed his residency in Orthopedic Surgery at the Hospital for Special Surgery, and completed a Sports Medicine fellowship at Lenox Hill Hospital. He also completed a Hand and Upper Extremity fellowship at Harvard. He is one of the founders for OrthoNations, a nonprofit organization that helps educate orthopedic surgeons in developing countries. He is also one of the founding surgeons for Cayenne Medical, a medical device company specializing in sports medicine implants.
Engineered Bone Graft
Exactech
Optecure+ccc
(http://www.exac.com/products/biologics/optecure-optecure-ccc)
Autogenous bone graft remains the standard for augmenting the surgical care of severe fractures, promoting spinal fusion, filling bone voids, and treating nonunions. However, lingering problems with donor site morbidity, volume limitation, increased operative time, and increased case complexity have led to the growing use of bone graft substitutes.1 These alternatives include allograft bone, demineralized bone matrix, calcium sulfate and calcium phosphate, bioglass, growth factors (rhBMP-2, rhBMP-7, rhPDGF, and PRP [platelet-rich plasma]), collagen matrix, and new cellular-based compounds using mesenchymal stem cells. Since each individual class of bone substitute falls short of the optimal blend of osteoconduction, osteoinduction, and osteogenesis, novel composite grafts have been developed to combine the convenience, durability, and flexibility of synthetic grafts with the biologic activity of native bone.
Optecure+ccc (Exactech) is an engineered composite bone graft that contains demineralized bone mixed with gamma irradiated cortical cancellous chips in an absorbable synthetic hydrogel matrix (Figure). When mixed with saline, blood, autogenous bone, bone marrow aspirate, or PRP, it becomes a surprisingly robust and malleable 3-dimensional matrix that allows easy bone void filling with excellent osteoconductive and osteoinductive characteristics. Each individual lot is tested for sterility and endotoxin levels to confirm safety as well as in vivo testing in athymic mice to confirm osteoinductive potential. Optecure+ccc has been successfully used to augment healing when combined with bone marrow aspirate in minimally invasive spine fusion surgery.2
Surgical pearl: I treat a large number of bicycle injuries on Nantucket; many are quite serious. I have found Optecure+ccc to be particularly useful during locked volar plating of severe distal radius wrist fractures as a way to restore and support radial length when autogenous bone access is limited. In this application, Optecure’s ability to expand and mold into a functional bone scaffold is critical to create a stable, stress-resistant fracture construct.
After exposure of the comminuted fracture line of the distal radius, gentle axial traction is applied and a small osteotome or freer is used to carefully wedge open the cortex to allow metaphyseal window access. The Optecure+ccc is mixed with either blood or bone marrow aspirate to reach a “grape nuts cereal”-like consistency and then carefully packed into the metaphyseal window to backfill the void. Multiplanar fluoroscopy is used to monitor graft placement and gradual joint line restoration. Traction is then released after the void is filled sufficiently to support the provisional reduction. Additional grafting with standard Optecure without bone chips can be used to fill more difficult-to-access areas. Both forms of Optecure are resistant to diluent migration, giving them good intraoperative behavior. Excess graft can be easily wiped away from the fracture site prior to plate application.
After elevation and restoration of the joint line, the locking volar plate is then affixed, wrist alignment confirmed fluoroscopically, and the procedure completed. The result is a well-filled void and an improved fracture construct. While Optecure+ccc has proven its battle readiness in wrist fracture surgery, I have also found it very helpful in reconstructing complex proximal humerus and clavicle fractures. Its unique combination of intraoperative versatility and durability provides a welcome edge in challenging cases.
1. Rodgers WB, Gerber EJ, Patterson JR. Fusion after minimally disruptive anterior lumbar interbody fusion: analysis of extreme lateral interbody fusion by computed tomography. SAS J. 2010;4(2):63-66.
2. Sasso RC, LeHuec JC, Shaffrey C; Spine Interbody Research Group. Iliac crest bone graft donor site pain after anterior lumbar interbody fusion: a prospective patient satisfaction outcome assessment. J Spinal Disord Tech. 2005;18 Suppl:S77-S81.
Exactech
Optecure+ccc
(http://www.exac.com/products/biologics/optecure-optecure-ccc)
Autogenous bone graft remains the standard for augmenting the surgical care of severe fractures, promoting spinal fusion, filling bone voids, and treating nonunions. However, lingering problems with donor site morbidity, volume limitation, increased operative time, and increased case complexity have led to the growing use of bone graft substitutes.1 These alternatives include allograft bone, demineralized bone matrix, calcium sulfate and calcium phosphate, bioglass, growth factors (rhBMP-2, rhBMP-7, rhPDGF, and PRP [platelet-rich plasma]), collagen matrix, and new cellular-based compounds using mesenchymal stem cells. Since each individual class of bone substitute falls short of the optimal blend of osteoconduction, osteoinduction, and osteogenesis, novel composite grafts have been developed to combine the convenience, durability, and flexibility of synthetic grafts with the biologic activity of native bone.
Optecure+ccc (Exactech) is an engineered composite bone graft that contains demineralized bone mixed with gamma irradiated cortical cancellous chips in an absorbable synthetic hydrogel matrix (Figure). When mixed with saline, blood, autogenous bone, bone marrow aspirate, or PRP, it becomes a surprisingly robust and malleable 3-dimensional matrix that allows easy bone void filling with excellent osteoconductive and osteoinductive characteristics. Each individual lot is tested for sterility and endotoxin levels to confirm safety as well as in vivo testing in athymic mice to confirm osteoinductive potential. Optecure+ccc has been successfully used to augment healing when combined with bone marrow aspirate in minimally invasive spine fusion surgery.2
Surgical pearl: I treat a large number of bicycle injuries on Nantucket; many are quite serious. I have found Optecure+ccc to be particularly useful during locked volar plating of severe distal radius wrist fractures as a way to restore and support radial length when autogenous bone access is limited. In this application, Optecure’s ability to expand and mold into a functional bone scaffold is critical to create a stable, stress-resistant fracture construct.
After exposure of the comminuted fracture line of the distal radius, gentle axial traction is applied and a small osteotome or freer is used to carefully wedge open the cortex to allow metaphyseal window access. The Optecure+ccc is mixed with either blood or bone marrow aspirate to reach a “grape nuts cereal”-like consistency and then carefully packed into the metaphyseal window to backfill the void. Multiplanar fluoroscopy is used to monitor graft placement and gradual joint line restoration. Traction is then released after the void is filled sufficiently to support the provisional reduction. Additional grafting with standard Optecure without bone chips can be used to fill more difficult-to-access areas. Both forms of Optecure are resistant to diluent migration, giving them good intraoperative behavior. Excess graft can be easily wiped away from the fracture site prior to plate application.
After elevation and restoration of the joint line, the locking volar plate is then affixed, wrist alignment confirmed fluoroscopically, and the procedure completed. The result is a well-filled void and an improved fracture construct. While Optecure+ccc has proven its battle readiness in wrist fracture surgery, I have also found it very helpful in reconstructing complex proximal humerus and clavicle fractures. Its unique combination of intraoperative versatility and durability provides a welcome edge in challenging cases.
Exactech
Optecure+ccc
(http://www.exac.com/products/biologics/optecure-optecure-ccc)
Autogenous bone graft remains the standard for augmenting the surgical care of severe fractures, promoting spinal fusion, filling bone voids, and treating nonunions. However, lingering problems with donor site morbidity, volume limitation, increased operative time, and increased case complexity have led to the growing use of bone graft substitutes.1 These alternatives include allograft bone, demineralized bone matrix, calcium sulfate and calcium phosphate, bioglass, growth factors (rhBMP-2, rhBMP-7, rhPDGF, and PRP [platelet-rich plasma]), collagen matrix, and new cellular-based compounds using mesenchymal stem cells. Since each individual class of bone substitute falls short of the optimal blend of osteoconduction, osteoinduction, and osteogenesis, novel composite grafts have been developed to combine the convenience, durability, and flexibility of synthetic grafts with the biologic activity of native bone.
Optecure+ccc (Exactech) is an engineered composite bone graft that contains demineralized bone mixed with gamma irradiated cortical cancellous chips in an absorbable synthetic hydrogel matrix (Figure). When mixed with saline, blood, autogenous bone, bone marrow aspirate, or PRP, it becomes a surprisingly robust and malleable 3-dimensional matrix that allows easy bone void filling with excellent osteoconductive and osteoinductive characteristics. Each individual lot is tested for sterility and endotoxin levels to confirm safety as well as in vivo testing in athymic mice to confirm osteoinductive potential. Optecure+ccc has been successfully used to augment healing when combined with bone marrow aspirate in minimally invasive spine fusion surgery.2
Surgical pearl: I treat a large number of bicycle injuries on Nantucket; many are quite serious. I have found Optecure+ccc to be particularly useful during locked volar plating of severe distal radius wrist fractures as a way to restore and support radial length when autogenous bone access is limited. In this application, Optecure’s ability to expand and mold into a functional bone scaffold is critical to create a stable, stress-resistant fracture construct.
After exposure of the comminuted fracture line of the distal radius, gentle axial traction is applied and a small osteotome or freer is used to carefully wedge open the cortex to allow metaphyseal window access. The Optecure+ccc is mixed with either blood or bone marrow aspirate to reach a “grape nuts cereal”-like consistency and then carefully packed into the metaphyseal window to backfill the void. Multiplanar fluoroscopy is used to monitor graft placement and gradual joint line restoration. Traction is then released after the void is filled sufficiently to support the provisional reduction. Additional grafting with standard Optecure without bone chips can be used to fill more difficult-to-access areas. Both forms of Optecure are resistant to diluent migration, giving them good intraoperative behavior. Excess graft can be easily wiped away from the fracture site prior to plate application.
After elevation and restoration of the joint line, the locking volar plate is then affixed, wrist alignment confirmed fluoroscopically, and the procedure completed. The result is a well-filled void and an improved fracture construct. While Optecure+ccc has proven its battle readiness in wrist fracture surgery, I have also found it very helpful in reconstructing complex proximal humerus and clavicle fractures. Its unique combination of intraoperative versatility and durability provides a welcome edge in challenging cases.
1. Rodgers WB, Gerber EJ, Patterson JR. Fusion after minimally disruptive anterior lumbar interbody fusion: analysis of extreme lateral interbody fusion by computed tomography. SAS J. 2010;4(2):63-66.
2. Sasso RC, LeHuec JC, Shaffrey C; Spine Interbody Research Group. Iliac crest bone graft donor site pain after anterior lumbar interbody fusion: a prospective patient satisfaction outcome assessment. J Spinal Disord Tech. 2005;18 Suppl:S77-S81.
1. Rodgers WB, Gerber EJ, Patterson JR. Fusion after minimally disruptive anterior lumbar interbody fusion: analysis of extreme lateral interbody fusion by computed tomography. SAS J. 2010;4(2):63-66.
2. Sasso RC, LeHuec JC, Shaffrey C; Spine Interbody Research Group. Iliac crest bone graft donor site pain after anterior lumbar interbody fusion: a prospective patient satisfaction outcome assessment. J Spinal Disord Tech. 2005;18 Suppl:S77-S81.
The Arthroscopic Superior Capsular Reconstruction
Rotator cuff tears are very common, and 250,000 to 500,000 rotator cuff repairs are performed in the United States each year.1,2 In most cases, a complete repair of even large or massive tears can be achieved. However, a subset of patients exist in whom the glenohumeral joint has minimal degenerative changes and the rotator cuff tendon is either irreparable or very poor quality and unlikely to heal (ie, failed previous cuff repair). Some authors have advocated for reverse shoulder arthroplasty (RSA) in these patients despite the lack of glenohumeral arthritis. However, due to the permanent destruction of the glenohumeral articular surfaces, complication rates, and concerns about implant longevity with RSA, we believe the superior capsular reconstruction (SCR) is a viable alternative in patients in whom joint preservation is appropriate based on age limitations and/or activity requirements.3
The SCR was first described by Mihata and colleagues4 as a means to reconstruct the superior capsule in shoulders with large, irreparable posterosuperior rotator cuff tears. Originally described using a fascia lata autograft, our technique has been adapted to incorporate a dermal allograft, which limits donor site morbidity and operative time. In most cases, the dermal allograft is fixed to the normal anatomic attachments of the superior glenoid just medial to the superior labrum, laterally to the greater tuberosity, and posteriorly with side-to-side sutures to the remaining rotator cuff. If there is a robust band of “comma” tissue anteriorly, we fix the anterior margin of the dermal graft to this with side-to-side sutures. The comma tissue represents the medial sling of the biceps tendon and connects the upper subscapularis tendon to the anterior supraspinatus. In most cases, this tissue is intact after repair of the subscapularis tendon.
Technique
The patient is positioned in either the lateral decubitus or beach chair position. The arm is positioned in 20° to 30° of abduction and 20° to 30° of forward flexion. A diagnostic arthroscopy is performed through a posterior glenohumeral viewing portal. The subscapularis is visualized and repaired if torn. A biceps tenodesis is performed in most cases, as there is often a tear of the subscapularis, tear or instability of the biceps tendon, and/or a compromised attachment of the biceps root.
Attention is turned to the subacromial space. Posterior viewing and lateral working portals are established. A 10-mm flexible cannula (PassPort; Arthrex) is placed in the lateral portal to aid with suture management and graft passage. A limited subacromial decompression is performed that preserves the coracoacromial arch. The rotator cuff is carefully dissected and freed from the internal deltoid fascia. The scapular spine is identified to visualize the raphé between the supraspinatus and infraspinatus. The infraspinatus is mobilized and repaired as much as possible.
If we think that the tear might be reparable by gaining added excursion from a posterior interval slide, or if it is clearly not reparable but the remaining rim of rotator cuff obscures clear visualization of the superior glenoid, we perform a posterior interval slide. If the additional excursion that is achieved by the posterior slide is adequate for a complete repair, we proceed with the repair. However, if the tear is not reparable even after the posterior interval slide, we have found that the exposure and preparation of the superior glenoid is greatly improved after the posterior slide. After fixation of the dermal graft, we typically perform a partial side-to-side repair of the supraspinatus to the infraspinatus over the top of the graft.
The bone beds of the greater tuberosity and just medial to the superior glenoid labrum are prepared with a shaver and motorized burr. Two anchors (3.0-mm BioComposite SutureTak; Arthrex) are placed in the superior glenoid neck at about the 10 o’clock and 2 o’clock positions approximately 5 mm medial to the superior labrum. Note: the placement medial to the labrum is chosen because this is the normal origin of the superior capsule and because of the angle of approach, these percutaneous portals are often more medial than typical portals for placing anchors during SLAP (superior labral anterior to posterior) repair. Next, 2 threaded anchors (4.75-mm BioComposite SwiveLock; Arthrex) preloaded with suture tape are placed in the greater tuberosity along the articular margin (Figure 1). However, if a biceps tenodesis with an interference screw is placed at the top of the bicipital groove, this anchor preloaded with suture tape can also serve as the anteromedial anchor in the greater tuberosity footprint. The distances between all 4 anchors are carefully measured with a calibrated probe (Figures 2A-2D).
We use a 3.0-mm acellular dermal allograft (ArthroFlex; Arthrex) to reconstruct the superior capsule. The positions of the 4 anchors are carefully marked on the dermal allograft. We routinely add an additional 5 mm of tissue to the medial, anterior, and posterior margins to decrease the risk of suture cut out. An additional 10 mm of tissue is added laterally to cover the greater tuberosity. The final contoured graft is typically trapezoidal in shape.
The sutures from the 4 anchors are then sequentially retrieved through the lateral cannula. The sutures from the greater tuberosity anchors are passed through their respective holes in the graft. However, the suture limbs from each of the glenoid anchors are individually passed 2 mm anterior and 2 mm posterior to their respective marks on the graft with an antegrade suture passer (Figure 3). It is important to have an assistant apply tension to each of the sutures after they are passed through the graft to decrease the chance of crossing and tangling the sutures.
The eyelets of the medial anchors are utilized as pulleys to deliver the dermal allograft into the shoulder. One suture limb from each of the glenoid anchors is tied to the other over a switching stick (Figure 4A). The 2 remaining (untied) suture limbs are then pulled, which introduces the graft to the orifice of the cannula (Figure 4B). A tissue grasper is then used to fold the dermal allograft along its long axis and introduce the graft into the joint (Figure 4C). Once the medial portion of the graft is positioned onto the superior glenoid the 2 remaining (untied) suture limbs are tied to each other as a static knot in the subacromial space (Figure 4D).
The redundancy in the suture tapes can be removed by sequentially sliding a retriever down each suture and tensioning the suture as the nose of the instrument pushes the dermal graft down to the tuberosity bone bed. The suture tapes are crisscrossed and secured laterally with 2 additional knotless threaded anchors (Figure 5). One may also place cinch stitches at the anterolateral and posterolateral corners of the graft that are incorporated into the lateral anchors. These sutures can be useful for pulling the graft back out of the subacromial space in the event of any suture tangles, and can be used for controlling the lateral aspect of the graft during lateral anchor placement.
At this point in the procedure, additional glenoid anchors can be placed both anterior and posterior to the superior glenoid anchors if additional glenoid fixation is desired. Finally, 2 to 3 side-to-side sutures are placed posteriorly attaching the anterior aspect of the infraspinatus to the posterior aspect of the dermal allograft (Figures 6A-6C). If rotator interval tissue (comma tissue) is present, anterior side-to-side sutures may be placed. However, we do not recommend placing anterior side-to-side sutures directly from the dermal allograft to the subscapularis as this may deform the graft, over- constrain the shoulder, and restrict motion.
Discussion
Reconstruction of the superior capsule has been shown to restore the normal restraint to superior translation of the humeral head and reestablish a stable fulcrum at the glenohumeral joint.5 It should be mentioned that we do not perform the SCR in patients with advanced glenohumeral arthritis. The short-term results of this novel procedure have been encouraging, including our own series of patients, in which most patients have had a significant reduction in pain, improvement in function, and very few complications (P. J. Denard, MD, S. S. Burkhart, MD, P. C. Brady, MD, J. Tokish, MD, C. R. Adams, MD, unpublished data, May 2016).
The early success of this procedure suggests that a robust superior capsule is necessary, in addition to functional muscle-tendon units, to restore the stable fulcrum and force couples that are necessary for normal shoulder function. Perhaps we have not paid enough attention to the integrity of the superior capsule in the past. In cases of revision cuff repair, we pay special attention to the quality of the capsular layer deep to the cuff tendon. If the capsule is poor quality, we sometimes reconstruct the capsule with a dermal allograft (SCR) and then do a rotator cuff repair (partial or complete) over the top of the SCR to maintain the normal anatomic deep to superficial layering of the capsule and rotator cuff.
We are very conservative with our postoperative rehabilitation program after a SCR. We know that the rate of stiffness with a conservative program after an arthroscopic rotator cuff repair, even in the revision setting, is very low.6 Furthermore, both basic science on healing of soft tissue to bone and radiographic analysis of healing after postoperative rotator cuff repairs support a slow rehabilitation program.7,8 A canine model specifically evaluating acellular dermal allografts in the shoulder suggests that these grafts undergo significant remodeling and become weaker before they get stronger.9 We would rather err on the side of healing of the SCR with potentially a slight increase in the rate of shoulder stiffness than to regain early motion at the expense of graft failure. Therefore, we have the patient wear a sling with no shoulder motion for 6 weeks. Passive motion is started at 6 weeks postoperative and strengthening is delayed until 12 to 16 weeks postoperative.
1. Orr SB, Chainani A, Hippensteel KJ, et al. Aligned multilayered electrospun scaffolds for rotator cuff tendon tissue engineering. Acta Biomater. 2015;24:117-126.
2. Austin L, Black EM, Lombardi NJ, Pepe MD, Lazarus M. Arthroscopic transosseous rotator cuff repair. A prospective study on cost savings, surgical time, and outcomes. Ortho J Sports Med. 2015;3(2 Suppl). doi:10.1177/2325967115S00156.
3. Denard PJ, Lädermann A, Jiwani AZ, Burkhart SS. Functional outcome after arthroscopic repair of massive rotator cuff tears in individuals with pseudoparalysis. Arthroscopy. 2012;28(9):1214-1219.
4. Mihata T, Lee TQ, Watanabe C, et al. Clinical results of arthroscopic superior capsule reconstruction for irreparable rotator cuff tears. Arthroscopy. 2013;29(3):459-470.
5. Mihata T, McGarry MH, Pirolo JM, Kinoshita M, Lee TQ. Superior capsule reconstruction to restore superior stability in irreparable rotator cuff tears: a biomechanical cadaveric study. Am J Sports Med. 2012;40(10):2248-2255.
6. Huberty DP, Schoolfield JD, Brady PC, Vadala AP, Arrigoni P, Burkhart SS. Incidence and treatment of postoperative stiffness following arthroscopic rotator cuff repair. Arthroscopy. 2009;25(8):880-890.
7. Sonnabend DH, Howlett CR, Young AA. Histological evaluation of repair of the rotator cuff in a primate model. J Bone Joint Surg Br. 2010;92(4):586-594.
8. Lee BG, Cho NS, Rhee YG. Effect of two rehabilitation protocols on range of motion and healing rates after arthroscopic rotator cuff repair: aggressive versus limited early passive exercises. Arthroscopy. 2012;28(1):34-42.
9. Adams JE, Zobitz ME, Reach JS Jr, An KN, Steinmann SP. Rotator cuff repair using an acellular dermal matrix graft: an in vivo study in a canine model. Arthroscopy. 2006;22(7):700-709.
Rotator cuff tears are very common, and 250,000 to 500,000 rotator cuff repairs are performed in the United States each year.1,2 In most cases, a complete repair of even large or massive tears can be achieved. However, a subset of patients exist in whom the glenohumeral joint has minimal degenerative changes and the rotator cuff tendon is either irreparable or very poor quality and unlikely to heal (ie, failed previous cuff repair). Some authors have advocated for reverse shoulder arthroplasty (RSA) in these patients despite the lack of glenohumeral arthritis. However, due to the permanent destruction of the glenohumeral articular surfaces, complication rates, and concerns about implant longevity with RSA, we believe the superior capsular reconstruction (SCR) is a viable alternative in patients in whom joint preservation is appropriate based on age limitations and/or activity requirements.3
The SCR was first described by Mihata and colleagues4 as a means to reconstruct the superior capsule in shoulders with large, irreparable posterosuperior rotator cuff tears. Originally described using a fascia lata autograft, our technique has been adapted to incorporate a dermal allograft, which limits donor site morbidity and operative time. In most cases, the dermal allograft is fixed to the normal anatomic attachments of the superior glenoid just medial to the superior labrum, laterally to the greater tuberosity, and posteriorly with side-to-side sutures to the remaining rotator cuff. If there is a robust band of “comma” tissue anteriorly, we fix the anterior margin of the dermal graft to this with side-to-side sutures. The comma tissue represents the medial sling of the biceps tendon and connects the upper subscapularis tendon to the anterior supraspinatus. In most cases, this tissue is intact after repair of the subscapularis tendon.
Technique
The patient is positioned in either the lateral decubitus or beach chair position. The arm is positioned in 20° to 30° of abduction and 20° to 30° of forward flexion. A diagnostic arthroscopy is performed through a posterior glenohumeral viewing portal. The subscapularis is visualized and repaired if torn. A biceps tenodesis is performed in most cases, as there is often a tear of the subscapularis, tear or instability of the biceps tendon, and/or a compromised attachment of the biceps root.
Attention is turned to the subacromial space. Posterior viewing and lateral working portals are established. A 10-mm flexible cannula (PassPort; Arthrex) is placed in the lateral portal to aid with suture management and graft passage. A limited subacromial decompression is performed that preserves the coracoacromial arch. The rotator cuff is carefully dissected and freed from the internal deltoid fascia. The scapular spine is identified to visualize the raphé between the supraspinatus and infraspinatus. The infraspinatus is mobilized and repaired as much as possible.
If we think that the tear might be reparable by gaining added excursion from a posterior interval slide, or if it is clearly not reparable but the remaining rim of rotator cuff obscures clear visualization of the superior glenoid, we perform a posterior interval slide. If the additional excursion that is achieved by the posterior slide is adequate for a complete repair, we proceed with the repair. However, if the tear is not reparable even after the posterior interval slide, we have found that the exposure and preparation of the superior glenoid is greatly improved after the posterior slide. After fixation of the dermal graft, we typically perform a partial side-to-side repair of the supraspinatus to the infraspinatus over the top of the graft.
The bone beds of the greater tuberosity and just medial to the superior glenoid labrum are prepared with a shaver and motorized burr. Two anchors (3.0-mm BioComposite SutureTak; Arthrex) are placed in the superior glenoid neck at about the 10 o’clock and 2 o’clock positions approximately 5 mm medial to the superior labrum. Note: the placement medial to the labrum is chosen because this is the normal origin of the superior capsule and because of the angle of approach, these percutaneous portals are often more medial than typical portals for placing anchors during SLAP (superior labral anterior to posterior) repair. Next, 2 threaded anchors (4.75-mm BioComposite SwiveLock; Arthrex) preloaded with suture tape are placed in the greater tuberosity along the articular margin (Figure 1). However, if a biceps tenodesis with an interference screw is placed at the top of the bicipital groove, this anchor preloaded with suture tape can also serve as the anteromedial anchor in the greater tuberosity footprint. The distances between all 4 anchors are carefully measured with a calibrated probe (Figures 2A-2D).
We use a 3.0-mm acellular dermal allograft (ArthroFlex; Arthrex) to reconstruct the superior capsule. The positions of the 4 anchors are carefully marked on the dermal allograft. We routinely add an additional 5 mm of tissue to the medial, anterior, and posterior margins to decrease the risk of suture cut out. An additional 10 mm of tissue is added laterally to cover the greater tuberosity. The final contoured graft is typically trapezoidal in shape.
The sutures from the 4 anchors are then sequentially retrieved through the lateral cannula. The sutures from the greater tuberosity anchors are passed through their respective holes in the graft. However, the suture limbs from each of the glenoid anchors are individually passed 2 mm anterior and 2 mm posterior to their respective marks on the graft with an antegrade suture passer (Figure 3). It is important to have an assistant apply tension to each of the sutures after they are passed through the graft to decrease the chance of crossing and tangling the sutures.
The eyelets of the medial anchors are utilized as pulleys to deliver the dermal allograft into the shoulder. One suture limb from each of the glenoid anchors is tied to the other over a switching stick (Figure 4A). The 2 remaining (untied) suture limbs are then pulled, which introduces the graft to the orifice of the cannula (Figure 4B). A tissue grasper is then used to fold the dermal allograft along its long axis and introduce the graft into the joint (Figure 4C). Once the medial portion of the graft is positioned onto the superior glenoid the 2 remaining (untied) suture limbs are tied to each other as a static knot in the subacromial space (Figure 4D).
The redundancy in the suture tapes can be removed by sequentially sliding a retriever down each suture and tensioning the suture as the nose of the instrument pushes the dermal graft down to the tuberosity bone bed. The suture tapes are crisscrossed and secured laterally with 2 additional knotless threaded anchors (Figure 5). One may also place cinch stitches at the anterolateral and posterolateral corners of the graft that are incorporated into the lateral anchors. These sutures can be useful for pulling the graft back out of the subacromial space in the event of any suture tangles, and can be used for controlling the lateral aspect of the graft during lateral anchor placement.
At this point in the procedure, additional glenoid anchors can be placed both anterior and posterior to the superior glenoid anchors if additional glenoid fixation is desired. Finally, 2 to 3 side-to-side sutures are placed posteriorly attaching the anterior aspect of the infraspinatus to the posterior aspect of the dermal allograft (Figures 6A-6C). If rotator interval tissue (comma tissue) is present, anterior side-to-side sutures may be placed. However, we do not recommend placing anterior side-to-side sutures directly from the dermal allograft to the subscapularis as this may deform the graft, over- constrain the shoulder, and restrict motion.
Discussion
Reconstruction of the superior capsule has been shown to restore the normal restraint to superior translation of the humeral head and reestablish a stable fulcrum at the glenohumeral joint.5 It should be mentioned that we do not perform the SCR in patients with advanced glenohumeral arthritis. The short-term results of this novel procedure have been encouraging, including our own series of patients, in which most patients have had a significant reduction in pain, improvement in function, and very few complications (P. J. Denard, MD, S. S. Burkhart, MD, P. C. Brady, MD, J. Tokish, MD, C. R. Adams, MD, unpublished data, May 2016).
The early success of this procedure suggests that a robust superior capsule is necessary, in addition to functional muscle-tendon units, to restore the stable fulcrum and force couples that are necessary for normal shoulder function. Perhaps we have not paid enough attention to the integrity of the superior capsule in the past. In cases of revision cuff repair, we pay special attention to the quality of the capsular layer deep to the cuff tendon. If the capsule is poor quality, we sometimes reconstruct the capsule with a dermal allograft (SCR) and then do a rotator cuff repair (partial or complete) over the top of the SCR to maintain the normal anatomic deep to superficial layering of the capsule and rotator cuff.
We are very conservative with our postoperative rehabilitation program after a SCR. We know that the rate of stiffness with a conservative program after an arthroscopic rotator cuff repair, even in the revision setting, is very low.6 Furthermore, both basic science on healing of soft tissue to bone and radiographic analysis of healing after postoperative rotator cuff repairs support a slow rehabilitation program.7,8 A canine model specifically evaluating acellular dermal allografts in the shoulder suggests that these grafts undergo significant remodeling and become weaker before they get stronger.9 We would rather err on the side of healing of the SCR with potentially a slight increase in the rate of shoulder stiffness than to regain early motion at the expense of graft failure. Therefore, we have the patient wear a sling with no shoulder motion for 6 weeks. Passive motion is started at 6 weeks postoperative and strengthening is delayed until 12 to 16 weeks postoperative.
Rotator cuff tears are very common, and 250,000 to 500,000 rotator cuff repairs are performed in the United States each year.1,2 In most cases, a complete repair of even large or massive tears can be achieved. However, a subset of patients exist in whom the glenohumeral joint has minimal degenerative changes and the rotator cuff tendon is either irreparable or very poor quality and unlikely to heal (ie, failed previous cuff repair). Some authors have advocated for reverse shoulder arthroplasty (RSA) in these patients despite the lack of glenohumeral arthritis. However, due to the permanent destruction of the glenohumeral articular surfaces, complication rates, and concerns about implant longevity with RSA, we believe the superior capsular reconstruction (SCR) is a viable alternative in patients in whom joint preservation is appropriate based on age limitations and/or activity requirements.3
The SCR was first described by Mihata and colleagues4 as a means to reconstruct the superior capsule in shoulders with large, irreparable posterosuperior rotator cuff tears. Originally described using a fascia lata autograft, our technique has been adapted to incorporate a dermal allograft, which limits donor site morbidity and operative time. In most cases, the dermal allograft is fixed to the normal anatomic attachments of the superior glenoid just medial to the superior labrum, laterally to the greater tuberosity, and posteriorly with side-to-side sutures to the remaining rotator cuff. If there is a robust band of “comma” tissue anteriorly, we fix the anterior margin of the dermal graft to this with side-to-side sutures. The comma tissue represents the medial sling of the biceps tendon and connects the upper subscapularis tendon to the anterior supraspinatus. In most cases, this tissue is intact after repair of the subscapularis tendon.
Technique
The patient is positioned in either the lateral decubitus or beach chair position. The arm is positioned in 20° to 30° of abduction and 20° to 30° of forward flexion. A diagnostic arthroscopy is performed through a posterior glenohumeral viewing portal. The subscapularis is visualized and repaired if torn. A biceps tenodesis is performed in most cases, as there is often a tear of the subscapularis, tear or instability of the biceps tendon, and/or a compromised attachment of the biceps root.
Attention is turned to the subacromial space. Posterior viewing and lateral working portals are established. A 10-mm flexible cannula (PassPort; Arthrex) is placed in the lateral portal to aid with suture management and graft passage. A limited subacromial decompression is performed that preserves the coracoacromial arch. The rotator cuff is carefully dissected and freed from the internal deltoid fascia. The scapular spine is identified to visualize the raphé between the supraspinatus and infraspinatus. The infraspinatus is mobilized and repaired as much as possible.
If we think that the tear might be reparable by gaining added excursion from a posterior interval slide, or if it is clearly not reparable but the remaining rim of rotator cuff obscures clear visualization of the superior glenoid, we perform a posterior interval slide. If the additional excursion that is achieved by the posterior slide is adequate for a complete repair, we proceed with the repair. However, if the tear is not reparable even after the posterior interval slide, we have found that the exposure and preparation of the superior glenoid is greatly improved after the posterior slide. After fixation of the dermal graft, we typically perform a partial side-to-side repair of the supraspinatus to the infraspinatus over the top of the graft.
The bone beds of the greater tuberosity and just medial to the superior glenoid labrum are prepared with a shaver and motorized burr. Two anchors (3.0-mm BioComposite SutureTak; Arthrex) are placed in the superior glenoid neck at about the 10 o’clock and 2 o’clock positions approximately 5 mm medial to the superior labrum. Note: the placement medial to the labrum is chosen because this is the normal origin of the superior capsule and because of the angle of approach, these percutaneous portals are often more medial than typical portals for placing anchors during SLAP (superior labral anterior to posterior) repair. Next, 2 threaded anchors (4.75-mm BioComposite SwiveLock; Arthrex) preloaded with suture tape are placed in the greater tuberosity along the articular margin (Figure 1). However, if a biceps tenodesis with an interference screw is placed at the top of the bicipital groove, this anchor preloaded with suture tape can also serve as the anteromedial anchor in the greater tuberosity footprint. The distances between all 4 anchors are carefully measured with a calibrated probe (Figures 2A-2D).
We use a 3.0-mm acellular dermal allograft (ArthroFlex; Arthrex) to reconstruct the superior capsule. The positions of the 4 anchors are carefully marked on the dermal allograft. We routinely add an additional 5 mm of tissue to the medial, anterior, and posterior margins to decrease the risk of suture cut out. An additional 10 mm of tissue is added laterally to cover the greater tuberosity. The final contoured graft is typically trapezoidal in shape.
The sutures from the 4 anchors are then sequentially retrieved through the lateral cannula. The sutures from the greater tuberosity anchors are passed through their respective holes in the graft. However, the suture limbs from each of the glenoid anchors are individually passed 2 mm anterior and 2 mm posterior to their respective marks on the graft with an antegrade suture passer (Figure 3). It is important to have an assistant apply tension to each of the sutures after they are passed through the graft to decrease the chance of crossing and tangling the sutures.
The eyelets of the medial anchors are utilized as pulleys to deliver the dermal allograft into the shoulder. One suture limb from each of the glenoid anchors is tied to the other over a switching stick (Figure 4A). The 2 remaining (untied) suture limbs are then pulled, which introduces the graft to the orifice of the cannula (Figure 4B). A tissue grasper is then used to fold the dermal allograft along its long axis and introduce the graft into the joint (Figure 4C). Once the medial portion of the graft is positioned onto the superior glenoid the 2 remaining (untied) suture limbs are tied to each other as a static knot in the subacromial space (Figure 4D).
The redundancy in the suture tapes can be removed by sequentially sliding a retriever down each suture and tensioning the suture as the nose of the instrument pushes the dermal graft down to the tuberosity bone bed. The suture tapes are crisscrossed and secured laterally with 2 additional knotless threaded anchors (Figure 5). One may also place cinch stitches at the anterolateral and posterolateral corners of the graft that are incorporated into the lateral anchors. These sutures can be useful for pulling the graft back out of the subacromial space in the event of any suture tangles, and can be used for controlling the lateral aspect of the graft during lateral anchor placement.
At this point in the procedure, additional glenoid anchors can be placed both anterior and posterior to the superior glenoid anchors if additional glenoid fixation is desired. Finally, 2 to 3 side-to-side sutures are placed posteriorly attaching the anterior aspect of the infraspinatus to the posterior aspect of the dermal allograft (Figures 6A-6C). If rotator interval tissue (comma tissue) is present, anterior side-to-side sutures may be placed. However, we do not recommend placing anterior side-to-side sutures directly from the dermal allograft to the subscapularis as this may deform the graft, over- constrain the shoulder, and restrict motion.
Discussion
Reconstruction of the superior capsule has been shown to restore the normal restraint to superior translation of the humeral head and reestablish a stable fulcrum at the glenohumeral joint.5 It should be mentioned that we do not perform the SCR in patients with advanced glenohumeral arthritis. The short-term results of this novel procedure have been encouraging, including our own series of patients, in which most patients have had a significant reduction in pain, improvement in function, and very few complications (P. J. Denard, MD, S. S. Burkhart, MD, P. C. Brady, MD, J. Tokish, MD, C. R. Adams, MD, unpublished data, May 2016).
The early success of this procedure suggests that a robust superior capsule is necessary, in addition to functional muscle-tendon units, to restore the stable fulcrum and force couples that are necessary for normal shoulder function. Perhaps we have not paid enough attention to the integrity of the superior capsule in the past. In cases of revision cuff repair, we pay special attention to the quality of the capsular layer deep to the cuff tendon. If the capsule is poor quality, we sometimes reconstruct the capsule with a dermal allograft (SCR) and then do a rotator cuff repair (partial or complete) over the top of the SCR to maintain the normal anatomic deep to superficial layering of the capsule and rotator cuff.
We are very conservative with our postoperative rehabilitation program after a SCR. We know that the rate of stiffness with a conservative program after an arthroscopic rotator cuff repair, even in the revision setting, is very low.6 Furthermore, both basic science on healing of soft tissue to bone and radiographic analysis of healing after postoperative rotator cuff repairs support a slow rehabilitation program.7,8 A canine model specifically evaluating acellular dermal allografts in the shoulder suggests that these grafts undergo significant remodeling and become weaker before they get stronger.9 We would rather err on the side of healing of the SCR with potentially a slight increase in the rate of shoulder stiffness than to regain early motion at the expense of graft failure. Therefore, we have the patient wear a sling with no shoulder motion for 6 weeks. Passive motion is started at 6 weeks postoperative and strengthening is delayed until 12 to 16 weeks postoperative.
1. Orr SB, Chainani A, Hippensteel KJ, et al. Aligned multilayered electrospun scaffolds for rotator cuff tendon tissue engineering. Acta Biomater. 2015;24:117-126.
2. Austin L, Black EM, Lombardi NJ, Pepe MD, Lazarus M. Arthroscopic transosseous rotator cuff repair. A prospective study on cost savings, surgical time, and outcomes. Ortho J Sports Med. 2015;3(2 Suppl). doi:10.1177/2325967115S00156.
3. Denard PJ, Lädermann A, Jiwani AZ, Burkhart SS. Functional outcome after arthroscopic repair of massive rotator cuff tears in individuals with pseudoparalysis. Arthroscopy. 2012;28(9):1214-1219.
4. Mihata T, Lee TQ, Watanabe C, et al. Clinical results of arthroscopic superior capsule reconstruction for irreparable rotator cuff tears. Arthroscopy. 2013;29(3):459-470.
5. Mihata T, McGarry MH, Pirolo JM, Kinoshita M, Lee TQ. Superior capsule reconstruction to restore superior stability in irreparable rotator cuff tears: a biomechanical cadaveric study. Am J Sports Med. 2012;40(10):2248-2255.
6. Huberty DP, Schoolfield JD, Brady PC, Vadala AP, Arrigoni P, Burkhart SS. Incidence and treatment of postoperative stiffness following arthroscopic rotator cuff repair. Arthroscopy. 2009;25(8):880-890.
7. Sonnabend DH, Howlett CR, Young AA. Histological evaluation of repair of the rotator cuff in a primate model. J Bone Joint Surg Br. 2010;92(4):586-594.
8. Lee BG, Cho NS, Rhee YG. Effect of two rehabilitation protocols on range of motion and healing rates after arthroscopic rotator cuff repair: aggressive versus limited early passive exercises. Arthroscopy. 2012;28(1):34-42.
9. Adams JE, Zobitz ME, Reach JS Jr, An KN, Steinmann SP. Rotator cuff repair using an acellular dermal matrix graft: an in vivo study in a canine model. Arthroscopy. 2006;22(7):700-709.
1. Orr SB, Chainani A, Hippensteel KJ, et al. Aligned multilayered electrospun scaffolds for rotator cuff tendon tissue engineering. Acta Biomater. 2015;24:117-126.
2. Austin L, Black EM, Lombardi NJ, Pepe MD, Lazarus M. Arthroscopic transosseous rotator cuff repair. A prospective study on cost savings, surgical time, and outcomes. Ortho J Sports Med. 2015;3(2 Suppl). doi:10.1177/2325967115S00156.
3. Denard PJ, Lädermann A, Jiwani AZ, Burkhart SS. Functional outcome after arthroscopic repair of massive rotator cuff tears in individuals with pseudoparalysis. Arthroscopy. 2012;28(9):1214-1219.
4. Mihata T, Lee TQ, Watanabe C, et al. Clinical results of arthroscopic superior capsule reconstruction for irreparable rotator cuff tears. Arthroscopy. 2013;29(3):459-470.
5. Mihata T, McGarry MH, Pirolo JM, Kinoshita M, Lee TQ. Superior capsule reconstruction to restore superior stability in irreparable rotator cuff tears: a biomechanical cadaveric study. Am J Sports Med. 2012;40(10):2248-2255.
6. Huberty DP, Schoolfield JD, Brady PC, Vadala AP, Arrigoni P, Burkhart SS. Incidence and treatment of postoperative stiffness following arthroscopic rotator cuff repair. Arthroscopy. 2009;25(8):880-890.
7. Sonnabend DH, Howlett CR, Young AA. Histological evaluation of repair of the rotator cuff in a primate model. J Bone Joint Surg Br. 2010;92(4):586-594.
8. Lee BG, Cho NS, Rhee YG. Effect of two rehabilitation protocols on range of motion and healing rates after arthroscopic rotator cuff repair: aggressive versus limited early passive exercises. Arthroscopy. 2012;28(1):34-42.
9. Adams JE, Zobitz ME, Reach JS Jr, An KN, Steinmann SP. Rotator cuff repair using an acellular dermal matrix graft: an in vivo study in a canine model. Arthroscopy. 2006;22(7):700-709.
Don’t Forget the Pulses! Aortoiliac Peripheral Artery Disease Masquerading as Lumbar Radiculopathy—A Report of 3 Cases
Lumbar radiculopathy is a common problem encountered by orthopedic surgeons, and typically presents with lower back or buttock pain radiating down the leg.1 While the most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis, the differential diagnosis for lower extremity pain is broad and can be musculoskeletal, vascular, neurologic, or inflammatory in nature.1,2 Differentiating between orthopedic, neurologic, and vascular causes of leg pain, such as peripheral artery disease (PAD), can sometimes be challenging. This is especially true in aortoiliac PAD, which can present with hip, buttock, and thigh pain. Dorsalis pedis pulses can be palpable due to collateral circulation. A careful history and physical examination is crucial to the correct diagnosis. The history should clearly document the nature of the pain, details of walking impairment, and the alleviating effects of standing still or positional changes. A complete neurovascular examination should include observations regarding the skin, hair, and nails, examination of dorsal pedis, popliteal, and femoral pulses in comparison to the contralateral side, and documentation of dural tension signs. Misdiagnoses can send the patient down a path of unnecessary tests, unindicated procedures, and ultimately, a delay in definitive diagnosis and treatment.1
To our knowledge, this is the first report on a series of patients with thigh pain initially diagnosed as radiculopathy who underwent unproductive diagnostic tests and procedures, and ultimately were given delayed diagnoses of aortoiliac PAD. The patients provided written informed consent for print and electronic publication of these case reports.
Case 1
An 81-year-old woman with a medical history notable for hypertension, hyperlipidemia, and stroke initially presented to an outside orthopedic institution with complaints of several months of lower back and right hip, thigh, and leg pain when walking. She did not report any history of night pain, weakness, or numbness. Examination at the time was notable for painful back extension, 4/5 hip flexion strength on the right compared to 5/5 on the left, but symmetric reflexes and negative dural tension signs. X-rays showed multilevel degenerative disc disease of the lumbar spine, and magnetic resonance imaging (MRI) showed a small L3/4 disc protrusion causing impingement of the L4 nerve root.
A transforaminal epidural steroid injection at the L4 level was performed with minimal resolution of symptoms. Several months later, right-sided intra-articular facet injections were performed at the L4/5 and L5/S1 levels, again with minimal relief of symptoms. At this point, the patient was sent for further physical therapy.
Over a year after symptom onset, the patient presented to our institution and was evaluated by a vascular surgeon. Physical examination was notable for 1+ femoral artery and dorsal pedis pulses on the right side, compared to 2+ on the left. An aortoiliac duplex ultrasound showed severe significant stenosis of the right common iliac artery (>75%).
The patient underwent a right common iliac artery angioplasty and stenting (Figures 1A, 1B), which resolved her symptoms.
Case 2
A 65-year-old man, who is a former smoker with a medical history notable for hyperlipidemia and coronary artery disease status post myocardial infarction, presented with a long history of right leg pain. He underwent a L5/S1 anterior posterior fusion at an outside institution and did well for about 5 years after the procedure (Figures 2A, 2B). The pain returned and he underwent several years of physical therapy, epidural steroid injections, and implantation of a spinal cord stimulator with no improvement. He reported right leg pain with minimal back pain, primarily in the thigh and not radiating to the feet and toes. The pain limited him from walking more than 1 block. On examination, strength was 5/5 bilaterally. Pulse examination was notable for lack of dorsalis pedis/posterior tibial pulses bilaterally. He had no bowel or bladder dysfunction.
Computed tomography myelogram showed a moderate amount of stenosis at L3/4 and L4/5. He was sent for evaluation by a vascular surgeon. Arterial duplex ultrasound showed significant stenosis of the right common iliac artery.
Angioplasty was attempted but vascular surgery was unable to cross the lesion (Figures 3A, 3B), and the patient ultimately had a femoral-femoral bypass, which resolved his leg pain.
Case 3
A 78-year-old woman, nonsmoker, presented with a 1-year history of left buttock and thigh pain exacerbated by ambulation. Ambulation was limited to 2 blocks. The patient was being worked up for spinal and hip etiologies of pain at an outside hospital. MRI revealed a mild posterior disc herniation at L3/4 and L4/5 and moderate narrowing of the spinal canal. She underwent 2 epidural steroid injections with no improvement. The patient’s relative, a physician, suggested that the patient receive a vascular surgery consultation, and the patient ultimately presented to our institution for evaluation by vascular surgery.
The physical examination was significant for a 1+ dorsal pedis pulse on the left compared to 2+ on the right. Moreover, the patient only demonstrated trace L femoral pulse compared to the right. Strength was 5/5 bilaterally.
The patient was taken to the operating room for angioplasty and stenting of the left common iliac artery (Figures 4A, 4B). This provided immediate symptom relief, and she has remained asymptomatic.
Discussion
Lumbar radiculopathy is a common diagnosis encountered by orthopedic surgeons. Although the diagnosis can appear to be straightforward in a patient presenting with lower back and leg pain, the etiology of lower back and leg pain can be extremely varied, and can be musculoskeletal, neurologic, vascular, rheumatologic, or oncologic in origin.1 In particular, differentiating between radiculopathy and vascular claudication can sometimes be challenging.
The 2 most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis.1 Lumbar disc herniation results from tear in the annulus of the intervertebral disc, resulting in herniation of disc material into the spinal canal causing compression and irritation of spinal nerve roots.1 Spinal stenosis is narrowing of the spinal canal that produces compression of neural elements before they exit the neural foramen.3 Adult degenerative spinal stenosis is most often caused by osteophytes from the facet joints or hypertrophy of the ligamentum flavum, and can be broadly categorized into central spinal stenosis or lateral spinal stenosis.
PAD is defined as progressive stenosis or occlusion, or aneurysmal dilation of noncoronary arteries.2 When PAD affects the vessels of the lower extremities, the symptoms typically manifest as intermittent claudication, which is exercise-induced ischemic pain in the lower extremity that is relieved by rest.2 As the disease progresses, symptoms can progress to rest pain, ulceration, and, eventually, gangrene. The most common cause of PAD is atherosclerosis, and the risk factors include smoking, hypertension, diabetes, and hyperlipidemia. The prevalence of PAD rises sharply with age, starting from <3% in ages less than 60 years to >20% in ages 75 years and older.4
A detailed and pertinent history from the patient provides important information for differentiating radiculopathy and neurogenic claudication from vascular claudication. Patients with lumbar radiculopathy typically report pain in the lower back radiating down the leg past the knee in a dermatomal distribution. The pain often begins soon if not immediately after activity, but often takes time for relief onset after rest. Positional changes in the back such as flexion can provide relief.2 Patients with neurogenic claudication from central spinal stenosis can present with bilateral thigh pain from prolonged standing and activity that is alleviated with flexion or stooping.3 Patients may admit to a positive “shopping cart sign,” with increased walking comfort stooped forward with hands on a shopping cart.
In contrast, patients with vascular claudication often report pain in the calf, thigh, or hip, but rarely in the foot. The location of pain varies with area of stenosis; generally, patients with superficial femoral artery occlusion present with calf claudication, while patients with aortoiliac disease present with buttock and thigh pain. The pain typically occurs after a very reproducible length of walking, and is relieved by cessation of walking, often even if the patient remains standing. Back positioning should have no effect on the pain.2-5
Physical examination should begin with observation of the patient’s gait and posture, which may be hunched over in the setting of spinal stenosis. Examination of the patient’s skin may show loss of hair, shiny skin, or atrophic changes suggestive of vascular disease (Figure 5).1 Prior to proceeding to a spine examination, palpating the trochanteric bursa and testing for hip range of motion is important to rule out intra-articular hip pathology and trochanteric bursitis as common causes of pain in the area. Patients with radiculopathy may show sensory disturbances in a dermatomal distribution, muscular weakness at the corresponding spinal level, and decreased deep tendon reflexes. The straight leg raise test can elicit signs of nerve root tension. A careful examination of bilateral lower extremity pulses at the dorsal pedis, popliteal, and femoral levels can help identify any asymmetric or decreased pulses that would indicate peripheral vascular disease. With chronic aortoiliac disease, it is important to check for femoral pulses, given the dorsal pedis pulse can be present due to collateral circulation. And finally, the ankle brachial index (ABI), measured as the ratio of the systolic pressure at the ankle divided by the systolic pressure at the arm, is a good screening test for PAD.6 A normal ABI is >1.
A thorough history and physical examination can elicit important information that is helpful in evaluating orthopedic patients, especially to differentiate between spinal and vascular causes of leg pain. This can help avoid misdiagnoses, which result in unnecessary tests, procedures, and wasted time. Don’t forget the pulses!
1. Grimm BD, Blessinger BJ, Darden BV, Brigham CD, Kneisl JS, Laxer EB. Mimickers of lumbar radiculopathy. J Am Acad Orthop Surg. 2015;23(1):7-17.
2. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA Guidelines for the Management of Patients with Peripheral Arterial Disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Associations for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease)--summary of recommendations. J Vasc Interv Radiol. 2006;17(9):1383-1397.
3. Spivak JM. Degenerative lumbar spinal stenosis. J Bone Joint Surg Am. 1998;80(7):1053-1066.
4. Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71(3):510-515.
5. Ouriel K. Peripheral arterial disease. Lancet. 2001;358(9289):1257-1264.
6. Jeon CH, Han SH, Chung NS, Hyun HS. The validity of ankle-brachial index for the differential diagnosis of peripheral arterial disease and lumbar spinal stenosis in patients with atypical claudication. Eur Spine J. 2012;21(6):1165-1170.
Lumbar radiculopathy is a common problem encountered by orthopedic surgeons, and typically presents with lower back or buttock pain radiating down the leg.1 While the most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis, the differential diagnosis for lower extremity pain is broad and can be musculoskeletal, vascular, neurologic, or inflammatory in nature.1,2 Differentiating between orthopedic, neurologic, and vascular causes of leg pain, such as peripheral artery disease (PAD), can sometimes be challenging. This is especially true in aortoiliac PAD, which can present with hip, buttock, and thigh pain. Dorsalis pedis pulses can be palpable due to collateral circulation. A careful history and physical examination is crucial to the correct diagnosis. The history should clearly document the nature of the pain, details of walking impairment, and the alleviating effects of standing still or positional changes. A complete neurovascular examination should include observations regarding the skin, hair, and nails, examination of dorsal pedis, popliteal, and femoral pulses in comparison to the contralateral side, and documentation of dural tension signs. Misdiagnoses can send the patient down a path of unnecessary tests, unindicated procedures, and ultimately, a delay in definitive diagnosis and treatment.1
To our knowledge, this is the first report on a series of patients with thigh pain initially diagnosed as radiculopathy who underwent unproductive diagnostic tests and procedures, and ultimately were given delayed diagnoses of aortoiliac PAD. The patients provided written informed consent for print and electronic publication of these case reports.
Case 1
An 81-year-old woman with a medical history notable for hypertension, hyperlipidemia, and stroke initially presented to an outside orthopedic institution with complaints of several months of lower back and right hip, thigh, and leg pain when walking. She did not report any history of night pain, weakness, or numbness. Examination at the time was notable for painful back extension, 4/5 hip flexion strength on the right compared to 5/5 on the left, but symmetric reflexes and negative dural tension signs. X-rays showed multilevel degenerative disc disease of the lumbar spine, and magnetic resonance imaging (MRI) showed a small L3/4 disc protrusion causing impingement of the L4 nerve root.
A transforaminal epidural steroid injection at the L4 level was performed with minimal resolution of symptoms. Several months later, right-sided intra-articular facet injections were performed at the L4/5 and L5/S1 levels, again with minimal relief of symptoms. At this point, the patient was sent for further physical therapy.
Over a year after symptom onset, the patient presented to our institution and was evaluated by a vascular surgeon. Physical examination was notable for 1+ femoral artery and dorsal pedis pulses on the right side, compared to 2+ on the left. An aortoiliac duplex ultrasound showed severe significant stenosis of the right common iliac artery (>75%).
The patient underwent a right common iliac artery angioplasty and stenting (Figures 1A, 1B), which resolved her symptoms.
Case 2
A 65-year-old man, who is a former smoker with a medical history notable for hyperlipidemia and coronary artery disease status post myocardial infarction, presented with a long history of right leg pain. He underwent a L5/S1 anterior posterior fusion at an outside institution and did well for about 5 years after the procedure (Figures 2A, 2B). The pain returned and he underwent several years of physical therapy, epidural steroid injections, and implantation of a spinal cord stimulator with no improvement. He reported right leg pain with minimal back pain, primarily in the thigh and not radiating to the feet and toes. The pain limited him from walking more than 1 block. On examination, strength was 5/5 bilaterally. Pulse examination was notable for lack of dorsalis pedis/posterior tibial pulses bilaterally. He had no bowel or bladder dysfunction.
Computed tomography myelogram showed a moderate amount of stenosis at L3/4 and L4/5. He was sent for evaluation by a vascular surgeon. Arterial duplex ultrasound showed significant stenosis of the right common iliac artery.
Angioplasty was attempted but vascular surgery was unable to cross the lesion (Figures 3A, 3B), and the patient ultimately had a femoral-femoral bypass, which resolved his leg pain.
Case 3
A 78-year-old woman, nonsmoker, presented with a 1-year history of left buttock and thigh pain exacerbated by ambulation. Ambulation was limited to 2 blocks. The patient was being worked up for spinal and hip etiologies of pain at an outside hospital. MRI revealed a mild posterior disc herniation at L3/4 and L4/5 and moderate narrowing of the spinal canal. She underwent 2 epidural steroid injections with no improvement. The patient’s relative, a physician, suggested that the patient receive a vascular surgery consultation, and the patient ultimately presented to our institution for evaluation by vascular surgery.
The physical examination was significant for a 1+ dorsal pedis pulse on the left compared to 2+ on the right. Moreover, the patient only demonstrated trace L femoral pulse compared to the right. Strength was 5/5 bilaterally.
The patient was taken to the operating room for angioplasty and stenting of the left common iliac artery (Figures 4A, 4B). This provided immediate symptom relief, and she has remained asymptomatic.
Discussion
Lumbar radiculopathy is a common diagnosis encountered by orthopedic surgeons. Although the diagnosis can appear to be straightforward in a patient presenting with lower back and leg pain, the etiology of lower back and leg pain can be extremely varied, and can be musculoskeletal, neurologic, vascular, rheumatologic, or oncologic in origin.1 In particular, differentiating between radiculopathy and vascular claudication can sometimes be challenging.
The 2 most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis.1 Lumbar disc herniation results from tear in the annulus of the intervertebral disc, resulting in herniation of disc material into the spinal canal causing compression and irritation of spinal nerve roots.1 Spinal stenosis is narrowing of the spinal canal that produces compression of neural elements before they exit the neural foramen.3 Adult degenerative spinal stenosis is most often caused by osteophytes from the facet joints or hypertrophy of the ligamentum flavum, and can be broadly categorized into central spinal stenosis or lateral spinal stenosis.
PAD is defined as progressive stenosis or occlusion, or aneurysmal dilation of noncoronary arteries.2 When PAD affects the vessels of the lower extremities, the symptoms typically manifest as intermittent claudication, which is exercise-induced ischemic pain in the lower extremity that is relieved by rest.2 As the disease progresses, symptoms can progress to rest pain, ulceration, and, eventually, gangrene. The most common cause of PAD is atherosclerosis, and the risk factors include smoking, hypertension, diabetes, and hyperlipidemia. The prevalence of PAD rises sharply with age, starting from <3% in ages less than 60 years to >20% in ages 75 years and older.4
A detailed and pertinent history from the patient provides important information for differentiating radiculopathy and neurogenic claudication from vascular claudication. Patients with lumbar radiculopathy typically report pain in the lower back radiating down the leg past the knee in a dermatomal distribution. The pain often begins soon if not immediately after activity, but often takes time for relief onset after rest. Positional changes in the back such as flexion can provide relief.2 Patients with neurogenic claudication from central spinal stenosis can present with bilateral thigh pain from prolonged standing and activity that is alleviated with flexion or stooping.3 Patients may admit to a positive “shopping cart sign,” with increased walking comfort stooped forward with hands on a shopping cart.
In contrast, patients with vascular claudication often report pain in the calf, thigh, or hip, but rarely in the foot. The location of pain varies with area of stenosis; generally, patients with superficial femoral artery occlusion present with calf claudication, while patients with aortoiliac disease present with buttock and thigh pain. The pain typically occurs after a very reproducible length of walking, and is relieved by cessation of walking, often even if the patient remains standing. Back positioning should have no effect on the pain.2-5
Physical examination should begin with observation of the patient’s gait and posture, which may be hunched over in the setting of spinal stenosis. Examination of the patient’s skin may show loss of hair, shiny skin, or atrophic changes suggestive of vascular disease (Figure 5).1 Prior to proceeding to a spine examination, palpating the trochanteric bursa and testing for hip range of motion is important to rule out intra-articular hip pathology and trochanteric bursitis as common causes of pain in the area. Patients with radiculopathy may show sensory disturbances in a dermatomal distribution, muscular weakness at the corresponding spinal level, and decreased deep tendon reflexes. The straight leg raise test can elicit signs of nerve root tension. A careful examination of bilateral lower extremity pulses at the dorsal pedis, popliteal, and femoral levels can help identify any asymmetric or decreased pulses that would indicate peripheral vascular disease. With chronic aortoiliac disease, it is important to check for femoral pulses, given the dorsal pedis pulse can be present due to collateral circulation. And finally, the ankle brachial index (ABI), measured as the ratio of the systolic pressure at the ankle divided by the systolic pressure at the arm, is a good screening test for PAD.6 A normal ABI is >1.
A thorough history and physical examination can elicit important information that is helpful in evaluating orthopedic patients, especially to differentiate between spinal and vascular causes of leg pain. This can help avoid misdiagnoses, which result in unnecessary tests, procedures, and wasted time. Don’t forget the pulses!
Lumbar radiculopathy is a common problem encountered by orthopedic surgeons, and typically presents with lower back or buttock pain radiating down the leg.1 While the most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis, the differential diagnosis for lower extremity pain is broad and can be musculoskeletal, vascular, neurologic, or inflammatory in nature.1,2 Differentiating between orthopedic, neurologic, and vascular causes of leg pain, such as peripheral artery disease (PAD), can sometimes be challenging. This is especially true in aortoiliac PAD, which can present with hip, buttock, and thigh pain. Dorsalis pedis pulses can be palpable due to collateral circulation. A careful history and physical examination is crucial to the correct diagnosis. The history should clearly document the nature of the pain, details of walking impairment, and the alleviating effects of standing still or positional changes. A complete neurovascular examination should include observations regarding the skin, hair, and nails, examination of dorsal pedis, popliteal, and femoral pulses in comparison to the contralateral side, and documentation of dural tension signs. Misdiagnoses can send the patient down a path of unnecessary tests, unindicated procedures, and ultimately, a delay in definitive diagnosis and treatment.1
To our knowledge, this is the first report on a series of patients with thigh pain initially diagnosed as radiculopathy who underwent unproductive diagnostic tests and procedures, and ultimately were given delayed diagnoses of aortoiliac PAD. The patients provided written informed consent for print and electronic publication of these case reports.
Case 1
An 81-year-old woman with a medical history notable for hypertension, hyperlipidemia, and stroke initially presented to an outside orthopedic institution with complaints of several months of lower back and right hip, thigh, and leg pain when walking. She did not report any history of night pain, weakness, or numbness. Examination at the time was notable for painful back extension, 4/5 hip flexion strength on the right compared to 5/5 on the left, but symmetric reflexes and negative dural tension signs. X-rays showed multilevel degenerative disc disease of the lumbar spine, and magnetic resonance imaging (MRI) showed a small L3/4 disc protrusion causing impingement of the L4 nerve root.
A transforaminal epidural steroid injection at the L4 level was performed with minimal resolution of symptoms. Several months later, right-sided intra-articular facet injections were performed at the L4/5 and L5/S1 levels, again with minimal relief of symptoms. At this point, the patient was sent for further physical therapy.
Over a year after symptom onset, the patient presented to our institution and was evaluated by a vascular surgeon. Physical examination was notable for 1+ femoral artery and dorsal pedis pulses on the right side, compared to 2+ on the left. An aortoiliac duplex ultrasound showed severe significant stenosis of the right common iliac artery (>75%).
The patient underwent a right common iliac artery angioplasty and stenting (Figures 1A, 1B), which resolved her symptoms.
Case 2
A 65-year-old man, who is a former smoker with a medical history notable for hyperlipidemia and coronary artery disease status post myocardial infarction, presented with a long history of right leg pain. He underwent a L5/S1 anterior posterior fusion at an outside institution and did well for about 5 years after the procedure (Figures 2A, 2B). The pain returned and he underwent several years of physical therapy, epidural steroid injections, and implantation of a spinal cord stimulator with no improvement. He reported right leg pain with minimal back pain, primarily in the thigh and not radiating to the feet and toes. The pain limited him from walking more than 1 block. On examination, strength was 5/5 bilaterally. Pulse examination was notable for lack of dorsalis pedis/posterior tibial pulses bilaterally. He had no bowel or bladder dysfunction.
Computed tomography myelogram showed a moderate amount of stenosis at L3/4 and L4/5. He was sent for evaluation by a vascular surgeon. Arterial duplex ultrasound showed significant stenosis of the right common iliac artery.
Angioplasty was attempted but vascular surgery was unable to cross the lesion (Figures 3A, 3B), and the patient ultimately had a femoral-femoral bypass, which resolved his leg pain.
Case 3
A 78-year-old woman, nonsmoker, presented with a 1-year history of left buttock and thigh pain exacerbated by ambulation. Ambulation was limited to 2 blocks. The patient was being worked up for spinal and hip etiologies of pain at an outside hospital. MRI revealed a mild posterior disc herniation at L3/4 and L4/5 and moderate narrowing of the spinal canal. She underwent 2 epidural steroid injections with no improvement. The patient’s relative, a physician, suggested that the patient receive a vascular surgery consultation, and the patient ultimately presented to our institution for evaluation by vascular surgery.
The physical examination was significant for a 1+ dorsal pedis pulse on the left compared to 2+ on the right. Moreover, the patient only demonstrated trace L femoral pulse compared to the right. Strength was 5/5 bilaterally.
The patient was taken to the operating room for angioplasty and stenting of the left common iliac artery (Figures 4A, 4B). This provided immediate symptom relief, and she has remained asymptomatic.
Discussion
Lumbar radiculopathy is a common diagnosis encountered by orthopedic surgeons. Although the diagnosis can appear to be straightforward in a patient presenting with lower back and leg pain, the etiology of lower back and leg pain can be extremely varied, and can be musculoskeletal, neurologic, vascular, rheumatologic, or oncologic in origin.1 In particular, differentiating between radiculopathy and vascular claudication can sometimes be challenging.
The 2 most common causes of lumbar radiculopathy are lumbar disc herniation and spinal stenosis.1 Lumbar disc herniation results from tear in the annulus of the intervertebral disc, resulting in herniation of disc material into the spinal canal causing compression and irritation of spinal nerve roots.1 Spinal stenosis is narrowing of the spinal canal that produces compression of neural elements before they exit the neural foramen.3 Adult degenerative spinal stenosis is most often caused by osteophytes from the facet joints or hypertrophy of the ligamentum flavum, and can be broadly categorized into central spinal stenosis or lateral spinal stenosis.
PAD is defined as progressive stenosis or occlusion, or aneurysmal dilation of noncoronary arteries.2 When PAD affects the vessels of the lower extremities, the symptoms typically manifest as intermittent claudication, which is exercise-induced ischemic pain in the lower extremity that is relieved by rest.2 As the disease progresses, symptoms can progress to rest pain, ulceration, and, eventually, gangrene. The most common cause of PAD is atherosclerosis, and the risk factors include smoking, hypertension, diabetes, and hyperlipidemia. The prevalence of PAD rises sharply with age, starting from <3% in ages less than 60 years to >20% in ages 75 years and older.4
A detailed and pertinent history from the patient provides important information for differentiating radiculopathy and neurogenic claudication from vascular claudication. Patients with lumbar radiculopathy typically report pain in the lower back radiating down the leg past the knee in a dermatomal distribution. The pain often begins soon if not immediately after activity, but often takes time for relief onset after rest. Positional changes in the back such as flexion can provide relief.2 Patients with neurogenic claudication from central spinal stenosis can present with bilateral thigh pain from prolonged standing and activity that is alleviated with flexion or stooping.3 Patients may admit to a positive “shopping cart sign,” with increased walking comfort stooped forward with hands on a shopping cart.
In contrast, patients with vascular claudication often report pain in the calf, thigh, or hip, but rarely in the foot. The location of pain varies with area of stenosis; generally, patients with superficial femoral artery occlusion present with calf claudication, while patients with aortoiliac disease present with buttock and thigh pain. The pain typically occurs after a very reproducible length of walking, and is relieved by cessation of walking, often even if the patient remains standing. Back positioning should have no effect on the pain.2-5
Physical examination should begin with observation of the patient’s gait and posture, which may be hunched over in the setting of spinal stenosis. Examination of the patient’s skin may show loss of hair, shiny skin, or atrophic changes suggestive of vascular disease (Figure 5).1 Prior to proceeding to a spine examination, palpating the trochanteric bursa and testing for hip range of motion is important to rule out intra-articular hip pathology and trochanteric bursitis as common causes of pain in the area. Patients with radiculopathy may show sensory disturbances in a dermatomal distribution, muscular weakness at the corresponding spinal level, and decreased deep tendon reflexes. The straight leg raise test can elicit signs of nerve root tension. A careful examination of bilateral lower extremity pulses at the dorsal pedis, popliteal, and femoral levels can help identify any asymmetric or decreased pulses that would indicate peripheral vascular disease. With chronic aortoiliac disease, it is important to check for femoral pulses, given the dorsal pedis pulse can be present due to collateral circulation. And finally, the ankle brachial index (ABI), measured as the ratio of the systolic pressure at the ankle divided by the systolic pressure at the arm, is a good screening test for PAD.6 A normal ABI is >1.
A thorough history and physical examination can elicit important information that is helpful in evaluating orthopedic patients, especially to differentiate between spinal and vascular causes of leg pain. This can help avoid misdiagnoses, which result in unnecessary tests, procedures, and wasted time. Don’t forget the pulses!
1. Grimm BD, Blessinger BJ, Darden BV, Brigham CD, Kneisl JS, Laxer EB. Mimickers of lumbar radiculopathy. J Am Acad Orthop Surg. 2015;23(1):7-17.
2. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA Guidelines for the Management of Patients with Peripheral Arterial Disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Associations for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease)--summary of recommendations. J Vasc Interv Radiol. 2006;17(9):1383-1397.
3. Spivak JM. Degenerative lumbar spinal stenosis. J Bone Joint Surg Am. 1998;80(7):1053-1066.
4. Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71(3):510-515.
5. Ouriel K. Peripheral arterial disease. Lancet. 2001;358(9289):1257-1264.
6. Jeon CH, Han SH, Chung NS, Hyun HS. The validity of ankle-brachial index for the differential diagnosis of peripheral arterial disease and lumbar spinal stenosis in patients with atypical claudication. Eur Spine J. 2012;21(6):1165-1170.
1. Grimm BD, Blessinger BJ, Darden BV, Brigham CD, Kneisl JS, Laxer EB. Mimickers of lumbar radiculopathy. J Am Acad Orthop Surg. 2015;23(1):7-17.
2. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA Guidelines for the Management of Patients with Peripheral Arterial Disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Associations for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease)--summary of recommendations. J Vasc Interv Radiol. 2006;17(9):1383-1397.
3. Spivak JM. Degenerative lumbar spinal stenosis. J Bone Joint Surg Am. 1998;80(7):1053-1066.
4. Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71(3):510-515.
5. Ouriel K. Peripheral arterial disease. Lancet. 2001;358(9289):1257-1264.
6. Jeon CH, Han SH, Chung NS, Hyun HS. The validity of ankle-brachial index for the differential diagnosis of peripheral arterial disease and lumbar spinal stenosis in patients with atypical claudication. Eur Spine J. 2012;21(6):1165-1170.
Efficacy of Unloader Bracing in Reducing Symptoms of Knee Osteoarthritis
Knee osteoarthritis (OA) is a progressive, degenerative joint disease characterized by pain and dysfunction. OA is a leading cause of disability in middle-aged and older adults,1 affecting an estimated 27 million Americans.2 With the continued aging of the baby boomer population and rising obesity rates, the incidence of OA is estimated to increase by 40% by 2025.3 The clinical and economic burdens of OA on our society—medical costs and workdays lost—are significant and will continue to be a problem for years to come.4
Total knee arthroplasty (TKA) is an option for severe end-stage OA. Most patients with mild to moderate OA follow nonsurgical strategies in an attempt to avoid invasive procedures. As there is no established cure, initial treatment of knee OA is geared toward alleviating pain and improving function. A multimodal approach is typically used and recommended.5,6 Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and narcotic analgesics are commonly prescribed. NSAIDs can be effective7 but have well-known cardiovascular, renal, and gastrointestinal risks. If possible, narcotic analgesics should be avoided because of the risk of addiction and the problems associated with dependence. Intra-articular injections of corticosteroids or hyaluronic acid (viscosupplementation) are often recommended to reduce pain associated with arthritis. Braces designed to “off-load” the more diseased medial or lateral compartment of the knee have also been used in an effort to provide symptomatic relief. These low-risk, noninvasive unloader braces have increasingly been advanced as a conservative treatment modality for knee OA,6,8-10despite modest evidence and lack of appropriately powered randomized controlled trials.11 As more research on the efficacy of these braces is needed, we conducted a study to determine whether an unloader brace is an acceptable and valid treatment modality for knee OA.
Patients and Methods
This was a prospective, randomized, controlled trial of patients with symptomatic, predominantly unicompartmental OA involving the medial compartment of the knee. The study protocol was approved by the Institutional Review Board at Baptist Hospital in Pensacola, Florida. Patients were excluded if they had a rheumatologic disorder other than OA; a history of knee surgery other than a routine arthroscopic procedure; any soft-tissue, neurologic, or vascular compromise preventing long-term brace use; or obesity preventing effective or comfortable brace use. It is generally felt that unloader bracing may not be effective for patients with severe contractures or significant knee deformity; therefore, those lacking more than 10° of extension or 20° of flexion, or those who had a varus deformity of more than 8° of varus, were not offered enrollment.
Ideal sizes for the proposed study groups were determined through power analysis using standard deviations from prior similar investigations. The target was 30 patients per group.
Patients gave informed consent to the work. A computer-generated randomization schedule was used to randomize patients either to receive a medial unloader brace (Fusion OA; Breg, Inc) or not to receive a brace. Patients in these brace and control groups were allowed to continue their standard conservative OA treatment modalities, including NSAID use, home exercises, and joint supplement use. Patients were restricted from receiving any injection therapy or narcotic pain medication in an effort to isolate the effects of bracing on relief of pain and other symptoms.
All patients were examined by an orthopedic surgeon or fellowship-trained primary care sports medicine specialist. Age, sex, height, and weight data were recorded. Body mass index was calculated. Anteroposterior, lateral, flexion weight-bearing, and long-leg standing radiographs were obtained. Two orthopedic surgeons blindly graded OA12 and calculated knee varus angles.13 Values were averaged, and intraobserver reliability and interobserver reliability were calculated.
Prospective subjective outcomes were evaluated with the Knee Injury and Osteoarthritis Outcome Score (KOOS), administered on study entry and at 4, 8, 16, and 24 weeks during the study. The KOOS has 5 subscales: Pain, Symptoms, Function in Daily Living, Function in Sport and Recreation, and Knee-Related Quality of Life. Each subscale is scored separately. Items are rated 0 (extreme problems) to 100 (no problems). Patients were also asked to complete a weekly diary, which included visual analog scale (VAS) ratings of pain, NSAID use, sleep, and activity level. VAS items were rated 1 (extreme problems) to 100 (no problems). For brace-group patients, hours of brace use per day were recorded. Patients were required to use the brace for a minimum of 4 hours per day.
KOOS and VAS data were analyzed with repeated-measures analysis of variance. Significance level was set at P < .05.
Results
Of the 50 patients randomized, 31 (16 brace, 15 control) completed the study. Of the 19 dropouts, 10 were in the brace group (4 dropped out because of brace discomfort) and 9 in the control group (5 dropped out because of significant pain and the desire for more aggressive treatment with injections). The target patient numbers based on the power analysis were not achieved because of patient enrollment difficulties resulting from the strict criteria established in the study design.
The brace group consisted of 8 men and 8 women. Braces were worn an average of 6.7 hours per day. The control group consisted of 8 men and 7 women. The groups were not significantly different in age, height, weight, body mass index, measured varus knee angle, or arthritis grade (Table 1).
Radiographs were assessed by 2 orthopedic surgeons. Varus angle measurements showed high interobserver reliability (.904, P = .03) and high intraobserver reliability (.969, P = .05); arthritis grades showed low interobserver reliability (.469, P = .59) and high intraobserver reliability (.810, P = .001).
KOOS results showed that, compared with control patients, brace patients had significantly less pain (P < .001), fewer arthritis symptoms (P = .007), better ability to engage in activities of daily living (ADLs) (P = .008), and better total knee function (P = .004) (Figures 1-4). The groups did not differ in ability to engage in sport and recreation (P = .402) or in knee-related quality of life (P = .718), but each parameter showed a trend to be better in the brace group. There was no effect of time in any KOOS subscale. Confidence intervals for these data are listed in Table 2.
VAS results showed that, compared with control patients, brace patients had significantly less pain throughout the day (P = .021) and better activity levels (P = .035) (Figures 5, 6). The groups did not differ in ability to sleep (P = .117) or NSAID use (P = .138), but each parameter showed a trend to be better in the brace group. There was no effect of time in either VAS.
Discussion
We conducted this study to determine the efficacy of a medial unloader brace in reducing the pain and symptoms associated with varus knee OA.
Although TKA is an option for patients with significant end-stage knee OA, mild OA and moderate OA typically are managed with nonoperative modalities. These modalities can be effective and may delay or eliminate the need for surgery, which poses a small but definite risk. Delaying surgery, especially in younger, active patients, has the potential to reduce the number of wear-related revision surgeries.14
Braces designed to off-load the more diseased medial or lateral compartment of the knee have been used in an effort to provide relief from symptomatic OA. There is a lack of appropriately powered, randomized controlled studies on the efficacy of these braces. With the evidence being inconclusive, the American Academy of Orthopaedic Surgeons is unable to recommend for or against use of a brace in medial unicompartmental OA.11 More research on the efficacy of these braces is needed. In the present study, we asked 2 questions: Does use of an unloader brace lessen the pain associated with knee OA? Is the unloader brace an acceptable and valid treatment modality for knee OA?
The 2 clinical outcome tools used in this study showed significant improvement in pain in brace patients compared with control patients. KOOS results showed reduced pain and arthritis symptoms. VAS results showed less pain experienced throughout the day. Pain reduction is probably the most important benefit of any nonoperative modality for knee OA. Pain typically is the driving force and the major indication for TKA. Other investigators have found pain reduced with use of unloader braces, but few long-term prospective randomized trials have been conducted. Ramsey and colleagues15 compared a neutral stabilizing brace with a medial unloading brace and found that both helped reduce pain and functional disability. This led to discussion about the 2 major potential mechanisms for symptom relief. One theory holds that bracing unloads the diseased portion of the joint and thereby helps improve symptoms.16-18 According to the other theory, bracing stabilizes the knee, reducing muscle cocontractions and joint compression.15,19,20 Draganich and colleagues21 found that both off-the-shelf and adjustable unloader braces reduced pain. In a short-term (8-week) study, Barnes and colleagues22 found substantial improvement in knee pain with use of an unloader brace. In one of the larger, better designed, prospective studies, Brouwer and colleagues23 found borderline but significant improvements in pain. Larsen and colleagues,24 in another short-term study, found no improvement in pain but did report improved activity levels with use of a medial unloader brace.
In addition to demonstrating pain reduction, our results showed that, compared with control patients, brace patients had fewer arthritis symptoms, better ability to engage in ADLs, and increased activity levels. Other studies have identified additional benefits of bracing for knee arthritis. Larsen and colleagues24 found that valgus bracing for medial compartment knee OA improved walking and sit-to-stand activities. Although pain relief results were modest, Brouwer and colleagues23 found significantly better knee function and longer walking distances for patients who used a medial unloader brace. Hewett and colleagues25 found that pain, ADLs, and walking distance were all improved after 9 weeks of brace wear.
Our study had a few limitations. Although injections and narcotic pain medications were not allowed, NSAIDs, home exercises, and other modalities were permitted. We did not think it was reasonable to eliminate every nonoperative modality during the 6-month study period. Therefore, it is possible that some of the study population’s improvements are attributable to these other modalities, which were not rigidly controlled.
Patient enrollment was difficult because of the strict inclusion and exclusion criteria used. The result was a smaller than anticipated patient population. Although there were many excellent study candidates, most declined enrollment when they learned they could be randomized to the control group. These patients were not willing to forgo injections or bracing for 6 months. We thought it was important to maintain our study design because it allowed us to evaluate the true effect of brace use while eliminating confounding variables. Nearly equal numbers of brace and control patients dropped out of the study. The majority of control group dropouts wanted more treatment options, indicating that NSAIDs and exercises alone were not controlling patients’ symptoms. This finding supports recommendations for a multimodal approach to treatment. As expected, some patients dropped out because their brace was uncomfortable—an important finding that should be considered when counseling patients about treatment options for OA.
Not all patients are candidates for braces. Braces can be irritating and uncomfortable for obese patients and patients with skin or vascular issues. Some patients find braces inconvenient. As discussed, a multimodal OA treatment approach is encouraged, but not every mode fits every patient. Physician and patient should thoroughly discuss the benefits and potential problems of brace use before prescribing. Our study results showed trends toward better improvements for brace patients (compared with control patients) in quality of life, ability to engage in sport and recreation, ability to sleep, and need for NSAIDs. Had we enrolled more patients, we might have found statistical significance for these trends. Despite the challenges with patient enrollment and study population size, the data make clear that unloader braces can benefit appropriate patients.
Our findings support use of a medial unloader brace as an acceptable and valid treatment modality for mild and moderate knee OA. The medial unloader brace should be considered a reasonable alternative, as part of a multimodal approach, to more invasive options, such as TKA.
1. Michaud C, McKenna M, Begg S, et al. The burden of disease and injury in the United States 1996. Popul Health Metr. 2006;4:11.
2. Lawrence RC, Felson DT, Helmick CG, et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58(1):26-35.
3. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81(9):646-656.
4. London NJ, Miller LE, Block JE. Clinical and economic consequences of the treatment gap in knee osteoarthritis management. Med Hypotheses. 2011;76(6):887-892.
5. Hochberg MC, Altman RD, April KT, et al; American College of Rheumatology. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):465-474.
6. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22(3):363-388.
7. Gallelli L, Galasso O, Falcone D, et al. The effects of nonsteroidal anti-inflammatory drugs on clinical outcomes, synovial fluid cytokine concentration and signal transduction pathways in knee osteoarthritis. A randomized open label trial. Osteoarthritis Cartilage. 2013;21(9):1400-1408.
8. Pollo FE, Jackson RW. Knee bracing for unicompartmental osteoarthritis. J Am Acad Orthop Surg. 2006;14(1):5-11.
9. Ramsey DK, Russell ME. Unloader braces for medial compartment knee osteoarthritis: implications on mediating progression. Sports Health. 2009;1(5):416-426.
10. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16(2):137-162.
11. Richmond J, Hunter D, Irrgang J, et al; American Academy of Orthopaedic Surgeons. American Academy of Orthopaedic Surgeons clinical practice guideline on the treatment of osteoarthritis (OA) of the knee. J Bone Joint Surg Am. 2010;92(4):990-993.
12. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16(4):494-502.
13. Dugdale TW, Noyes FR, Styer D. Preoperative planning for high tibial osteotomy. The effect of lateral tibiofemoral separation and tibiofemoral length. Clin Orthop Relat Res. 1992;(274):248-264.
14. Weinstein AM, Rome BN, Reichmann WM, et al. Estimating the burden of total knee replacement in the United States. J Bone Joint Surg Am. 2013;95(5):385-392.
15. Ramsey DK, Briem K, Axe MJ, Snyder-Mackler L. A mechanical theory for the effectiveness of bracing for medial compartment osteoarthritis of the knee. J Bone Joint Surg Am. 2007;89(11):2398-2407.
16. Haim A, Wolf A, Rubin G, Genis Y, Khoury M, Rozen N. Effect of center of pressure modulation on knee adduction moment in medial compartment knee osteoarthritis. J Orthop Res. 2011;29(11):1668-1674.
17. Pollo FE, Otis JC, Backus SI, Warren RF, Wickiewicz TL. Reduction of medial compartment loads with valgus bracing of the osteoarthritic knee. Am J Sports Med. 2002;30(3):414-421.
18. Shelburne KB, Torry MR, Steadman JR, Pandy MG. Effects of foot orthoses and valgus bracing on the knee adduction moment and medial joint load during gait. Clin Biomech. 2008;23(6):814-821.
19. Lewek MD, Ramsey DK, Snyder-Mackler L, Rudolph KS. Knee stabilization in patients with medial compartment knee osteoarthritis. Arthritis Rheum. 2005;52(9):2845-2853.
20. Lewek MD, Rudolph KS, Snyder-Mackler L. Control of frontal plane knee laxity during gait in patients with medial compartment knee osteoarthritis. Osteoarthritis Cartilage. 2004;12(9):745-751.
21. Draganich L, Reider B, Rimington T, Piotrowski G, Mallik K, Nasson S. The effectiveness of self-adjustable custom and off-the-shelf bracing in the treatment of varus gonarthrosis. J Bone Joint Surg Am. 2006;88(12):2645-2652.
22. Barnes CL, Cawley PW, Hederman B. Effect of CounterForce brace on symptomatic relief in a group of patients with symptomatic unicompartmental osteoarthritis: a prospective 2-year investigation. Am J Orthop. 2002;31(7):396-401.
23. Brouwer RW, van Raaij TM, Verhaar JA, Coene LN, Bierma-Zeinstra SM. Brace treatment for osteoarthritis of the knee: a prospective randomized multi-centre trial. Osteoarthritis Cartilage. 2006;14(8):777-783.
24. Larsen BL, Jacofsky MC, Brown JA, Jacofsky DJ. Valgus bracing affords short-term treatment solution across walking and sit-to-stand activities. J Arthroplasty. 2013;28(5):792-797.
25. Hewett TE, Noyes FR, Barber-Westin SD, Heckmann TP. Decrease in knee joint pain and increase in function in patients with medial compartment arthrosis: a prospective analysis of valgus bracing. Orthopedics. 1998;21(2):131-138.
Knee osteoarthritis (OA) is a progressive, degenerative joint disease characterized by pain and dysfunction. OA is a leading cause of disability in middle-aged and older adults,1 affecting an estimated 27 million Americans.2 With the continued aging of the baby boomer population and rising obesity rates, the incidence of OA is estimated to increase by 40% by 2025.3 The clinical and economic burdens of OA on our society—medical costs and workdays lost—are significant and will continue to be a problem for years to come.4
Total knee arthroplasty (TKA) is an option for severe end-stage OA. Most patients with mild to moderate OA follow nonsurgical strategies in an attempt to avoid invasive procedures. As there is no established cure, initial treatment of knee OA is geared toward alleviating pain and improving function. A multimodal approach is typically used and recommended.5,6 Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and narcotic analgesics are commonly prescribed. NSAIDs can be effective7 but have well-known cardiovascular, renal, and gastrointestinal risks. If possible, narcotic analgesics should be avoided because of the risk of addiction and the problems associated with dependence. Intra-articular injections of corticosteroids or hyaluronic acid (viscosupplementation) are often recommended to reduce pain associated with arthritis. Braces designed to “off-load” the more diseased medial or lateral compartment of the knee have also been used in an effort to provide symptomatic relief. These low-risk, noninvasive unloader braces have increasingly been advanced as a conservative treatment modality for knee OA,6,8-10despite modest evidence and lack of appropriately powered randomized controlled trials.11 As more research on the efficacy of these braces is needed, we conducted a study to determine whether an unloader brace is an acceptable and valid treatment modality for knee OA.
Patients and Methods
This was a prospective, randomized, controlled trial of patients with symptomatic, predominantly unicompartmental OA involving the medial compartment of the knee. The study protocol was approved by the Institutional Review Board at Baptist Hospital in Pensacola, Florida. Patients were excluded if they had a rheumatologic disorder other than OA; a history of knee surgery other than a routine arthroscopic procedure; any soft-tissue, neurologic, or vascular compromise preventing long-term brace use; or obesity preventing effective or comfortable brace use. It is generally felt that unloader bracing may not be effective for patients with severe contractures or significant knee deformity; therefore, those lacking more than 10° of extension or 20° of flexion, or those who had a varus deformity of more than 8° of varus, were not offered enrollment.
Ideal sizes for the proposed study groups were determined through power analysis using standard deviations from prior similar investigations. The target was 30 patients per group.
Patients gave informed consent to the work. A computer-generated randomization schedule was used to randomize patients either to receive a medial unloader brace (Fusion OA; Breg, Inc) or not to receive a brace. Patients in these brace and control groups were allowed to continue their standard conservative OA treatment modalities, including NSAID use, home exercises, and joint supplement use. Patients were restricted from receiving any injection therapy or narcotic pain medication in an effort to isolate the effects of bracing on relief of pain and other symptoms.
All patients were examined by an orthopedic surgeon or fellowship-trained primary care sports medicine specialist. Age, sex, height, and weight data were recorded. Body mass index was calculated. Anteroposterior, lateral, flexion weight-bearing, and long-leg standing radiographs were obtained. Two orthopedic surgeons blindly graded OA12 and calculated knee varus angles.13 Values were averaged, and intraobserver reliability and interobserver reliability were calculated.
Prospective subjective outcomes were evaluated with the Knee Injury and Osteoarthritis Outcome Score (KOOS), administered on study entry and at 4, 8, 16, and 24 weeks during the study. The KOOS has 5 subscales: Pain, Symptoms, Function in Daily Living, Function in Sport and Recreation, and Knee-Related Quality of Life. Each subscale is scored separately. Items are rated 0 (extreme problems) to 100 (no problems). Patients were also asked to complete a weekly diary, which included visual analog scale (VAS) ratings of pain, NSAID use, sleep, and activity level. VAS items were rated 1 (extreme problems) to 100 (no problems). For brace-group patients, hours of brace use per day were recorded. Patients were required to use the brace for a minimum of 4 hours per day.
KOOS and VAS data were analyzed with repeated-measures analysis of variance. Significance level was set at P < .05.
Results
Of the 50 patients randomized, 31 (16 brace, 15 control) completed the study. Of the 19 dropouts, 10 were in the brace group (4 dropped out because of brace discomfort) and 9 in the control group (5 dropped out because of significant pain and the desire for more aggressive treatment with injections). The target patient numbers based on the power analysis were not achieved because of patient enrollment difficulties resulting from the strict criteria established in the study design.
The brace group consisted of 8 men and 8 women. Braces were worn an average of 6.7 hours per day. The control group consisted of 8 men and 7 women. The groups were not significantly different in age, height, weight, body mass index, measured varus knee angle, or arthritis grade (Table 1).
Radiographs were assessed by 2 orthopedic surgeons. Varus angle measurements showed high interobserver reliability (.904, P = .03) and high intraobserver reliability (.969, P = .05); arthritis grades showed low interobserver reliability (.469, P = .59) and high intraobserver reliability (.810, P = .001).
KOOS results showed that, compared with control patients, brace patients had significantly less pain (P < .001), fewer arthritis symptoms (P = .007), better ability to engage in activities of daily living (ADLs) (P = .008), and better total knee function (P = .004) (Figures 1-4). The groups did not differ in ability to engage in sport and recreation (P = .402) or in knee-related quality of life (P = .718), but each parameter showed a trend to be better in the brace group. There was no effect of time in any KOOS subscale. Confidence intervals for these data are listed in Table 2.
VAS results showed that, compared with control patients, brace patients had significantly less pain throughout the day (P = .021) and better activity levels (P = .035) (Figures 5, 6). The groups did not differ in ability to sleep (P = .117) or NSAID use (P = .138), but each parameter showed a trend to be better in the brace group. There was no effect of time in either VAS.
Discussion
We conducted this study to determine the efficacy of a medial unloader brace in reducing the pain and symptoms associated with varus knee OA.
Although TKA is an option for patients with significant end-stage knee OA, mild OA and moderate OA typically are managed with nonoperative modalities. These modalities can be effective and may delay or eliminate the need for surgery, which poses a small but definite risk. Delaying surgery, especially in younger, active patients, has the potential to reduce the number of wear-related revision surgeries.14
Braces designed to off-load the more diseased medial or lateral compartment of the knee have been used in an effort to provide relief from symptomatic OA. There is a lack of appropriately powered, randomized controlled studies on the efficacy of these braces. With the evidence being inconclusive, the American Academy of Orthopaedic Surgeons is unable to recommend for or against use of a brace in medial unicompartmental OA.11 More research on the efficacy of these braces is needed. In the present study, we asked 2 questions: Does use of an unloader brace lessen the pain associated with knee OA? Is the unloader brace an acceptable and valid treatment modality for knee OA?
The 2 clinical outcome tools used in this study showed significant improvement in pain in brace patients compared with control patients. KOOS results showed reduced pain and arthritis symptoms. VAS results showed less pain experienced throughout the day. Pain reduction is probably the most important benefit of any nonoperative modality for knee OA. Pain typically is the driving force and the major indication for TKA. Other investigators have found pain reduced with use of unloader braces, but few long-term prospective randomized trials have been conducted. Ramsey and colleagues15 compared a neutral stabilizing brace with a medial unloading brace and found that both helped reduce pain and functional disability. This led to discussion about the 2 major potential mechanisms for symptom relief. One theory holds that bracing unloads the diseased portion of the joint and thereby helps improve symptoms.16-18 According to the other theory, bracing stabilizes the knee, reducing muscle cocontractions and joint compression.15,19,20 Draganich and colleagues21 found that both off-the-shelf and adjustable unloader braces reduced pain. In a short-term (8-week) study, Barnes and colleagues22 found substantial improvement in knee pain with use of an unloader brace. In one of the larger, better designed, prospective studies, Brouwer and colleagues23 found borderline but significant improvements in pain. Larsen and colleagues,24 in another short-term study, found no improvement in pain but did report improved activity levels with use of a medial unloader brace.
In addition to demonstrating pain reduction, our results showed that, compared with control patients, brace patients had fewer arthritis symptoms, better ability to engage in ADLs, and increased activity levels. Other studies have identified additional benefits of bracing for knee arthritis. Larsen and colleagues24 found that valgus bracing for medial compartment knee OA improved walking and sit-to-stand activities. Although pain relief results were modest, Brouwer and colleagues23 found significantly better knee function and longer walking distances for patients who used a medial unloader brace. Hewett and colleagues25 found that pain, ADLs, and walking distance were all improved after 9 weeks of brace wear.
Our study had a few limitations. Although injections and narcotic pain medications were not allowed, NSAIDs, home exercises, and other modalities were permitted. We did not think it was reasonable to eliminate every nonoperative modality during the 6-month study period. Therefore, it is possible that some of the study population’s improvements are attributable to these other modalities, which were not rigidly controlled.
Patient enrollment was difficult because of the strict inclusion and exclusion criteria used. The result was a smaller than anticipated patient population. Although there were many excellent study candidates, most declined enrollment when they learned they could be randomized to the control group. These patients were not willing to forgo injections or bracing for 6 months. We thought it was important to maintain our study design because it allowed us to evaluate the true effect of brace use while eliminating confounding variables. Nearly equal numbers of brace and control patients dropped out of the study. The majority of control group dropouts wanted more treatment options, indicating that NSAIDs and exercises alone were not controlling patients’ symptoms. This finding supports recommendations for a multimodal approach to treatment. As expected, some patients dropped out because their brace was uncomfortable—an important finding that should be considered when counseling patients about treatment options for OA.
Not all patients are candidates for braces. Braces can be irritating and uncomfortable for obese patients and patients with skin or vascular issues. Some patients find braces inconvenient. As discussed, a multimodal OA treatment approach is encouraged, but not every mode fits every patient. Physician and patient should thoroughly discuss the benefits and potential problems of brace use before prescribing. Our study results showed trends toward better improvements for brace patients (compared with control patients) in quality of life, ability to engage in sport and recreation, ability to sleep, and need for NSAIDs. Had we enrolled more patients, we might have found statistical significance for these trends. Despite the challenges with patient enrollment and study population size, the data make clear that unloader braces can benefit appropriate patients.
Our findings support use of a medial unloader brace as an acceptable and valid treatment modality for mild and moderate knee OA. The medial unloader brace should be considered a reasonable alternative, as part of a multimodal approach, to more invasive options, such as TKA.
Knee osteoarthritis (OA) is a progressive, degenerative joint disease characterized by pain and dysfunction. OA is a leading cause of disability in middle-aged and older adults,1 affecting an estimated 27 million Americans.2 With the continued aging of the baby boomer population and rising obesity rates, the incidence of OA is estimated to increase by 40% by 2025.3 The clinical and economic burdens of OA on our society—medical costs and workdays lost—are significant and will continue to be a problem for years to come.4
Total knee arthroplasty (TKA) is an option for severe end-stage OA. Most patients with mild to moderate OA follow nonsurgical strategies in an attempt to avoid invasive procedures. As there is no established cure, initial treatment of knee OA is geared toward alleviating pain and improving function. A multimodal approach is typically used and recommended.5,6 Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and narcotic analgesics are commonly prescribed. NSAIDs can be effective7 but have well-known cardiovascular, renal, and gastrointestinal risks. If possible, narcotic analgesics should be avoided because of the risk of addiction and the problems associated with dependence. Intra-articular injections of corticosteroids or hyaluronic acid (viscosupplementation) are often recommended to reduce pain associated with arthritis. Braces designed to “off-load” the more diseased medial or lateral compartment of the knee have also been used in an effort to provide symptomatic relief. These low-risk, noninvasive unloader braces have increasingly been advanced as a conservative treatment modality for knee OA,6,8-10despite modest evidence and lack of appropriately powered randomized controlled trials.11 As more research on the efficacy of these braces is needed, we conducted a study to determine whether an unloader brace is an acceptable and valid treatment modality for knee OA.
Patients and Methods
This was a prospective, randomized, controlled trial of patients with symptomatic, predominantly unicompartmental OA involving the medial compartment of the knee. The study protocol was approved by the Institutional Review Board at Baptist Hospital in Pensacola, Florida. Patients were excluded if they had a rheumatologic disorder other than OA; a history of knee surgery other than a routine arthroscopic procedure; any soft-tissue, neurologic, or vascular compromise preventing long-term brace use; or obesity preventing effective or comfortable brace use. It is generally felt that unloader bracing may not be effective for patients with severe contractures or significant knee deformity; therefore, those lacking more than 10° of extension or 20° of flexion, or those who had a varus deformity of more than 8° of varus, were not offered enrollment.
Ideal sizes for the proposed study groups were determined through power analysis using standard deviations from prior similar investigations. The target was 30 patients per group.
Patients gave informed consent to the work. A computer-generated randomization schedule was used to randomize patients either to receive a medial unloader brace (Fusion OA; Breg, Inc) or not to receive a brace. Patients in these brace and control groups were allowed to continue their standard conservative OA treatment modalities, including NSAID use, home exercises, and joint supplement use. Patients were restricted from receiving any injection therapy or narcotic pain medication in an effort to isolate the effects of bracing on relief of pain and other symptoms.
All patients were examined by an orthopedic surgeon or fellowship-trained primary care sports medicine specialist. Age, sex, height, and weight data were recorded. Body mass index was calculated. Anteroposterior, lateral, flexion weight-bearing, and long-leg standing radiographs were obtained. Two orthopedic surgeons blindly graded OA12 and calculated knee varus angles.13 Values were averaged, and intraobserver reliability and interobserver reliability were calculated.
Prospective subjective outcomes were evaluated with the Knee Injury and Osteoarthritis Outcome Score (KOOS), administered on study entry and at 4, 8, 16, and 24 weeks during the study. The KOOS has 5 subscales: Pain, Symptoms, Function in Daily Living, Function in Sport and Recreation, and Knee-Related Quality of Life. Each subscale is scored separately. Items are rated 0 (extreme problems) to 100 (no problems). Patients were also asked to complete a weekly diary, which included visual analog scale (VAS) ratings of pain, NSAID use, sleep, and activity level. VAS items were rated 1 (extreme problems) to 100 (no problems). For brace-group patients, hours of brace use per day were recorded. Patients were required to use the brace for a minimum of 4 hours per day.
KOOS and VAS data were analyzed with repeated-measures analysis of variance. Significance level was set at P < .05.
Results
Of the 50 patients randomized, 31 (16 brace, 15 control) completed the study. Of the 19 dropouts, 10 were in the brace group (4 dropped out because of brace discomfort) and 9 in the control group (5 dropped out because of significant pain and the desire for more aggressive treatment with injections). The target patient numbers based on the power analysis were not achieved because of patient enrollment difficulties resulting from the strict criteria established in the study design.
The brace group consisted of 8 men and 8 women. Braces were worn an average of 6.7 hours per day. The control group consisted of 8 men and 7 women. The groups were not significantly different in age, height, weight, body mass index, measured varus knee angle, or arthritis grade (Table 1).
Radiographs were assessed by 2 orthopedic surgeons. Varus angle measurements showed high interobserver reliability (.904, P = .03) and high intraobserver reliability (.969, P = .05); arthritis grades showed low interobserver reliability (.469, P = .59) and high intraobserver reliability (.810, P = .001).
KOOS results showed that, compared with control patients, brace patients had significantly less pain (P < .001), fewer arthritis symptoms (P = .007), better ability to engage in activities of daily living (ADLs) (P = .008), and better total knee function (P = .004) (Figures 1-4). The groups did not differ in ability to engage in sport and recreation (P = .402) or in knee-related quality of life (P = .718), but each parameter showed a trend to be better in the brace group. There was no effect of time in any KOOS subscale. Confidence intervals for these data are listed in Table 2.
VAS results showed that, compared with control patients, brace patients had significantly less pain throughout the day (P = .021) and better activity levels (P = .035) (Figures 5, 6). The groups did not differ in ability to sleep (P = .117) or NSAID use (P = .138), but each parameter showed a trend to be better in the brace group. There was no effect of time in either VAS.
Discussion
We conducted this study to determine the efficacy of a medial unloader brace in reducing the pain and symptoms associated with varus knee OA.
Although TKA is an option for patients with significant end-stage knee OA, mild OA and moderate OA typically are managed with nonoperative modalities. These modalities can be effective and may delay or eliminate the need for surgery, which poses a small but definite risk. Delaying surgery, especially in younger, active patients, has the potential to reduce the number of wear-related revision surgeries.14
Braces designed to off-load the more diseased medial or lateral compartment of the knee have been used in an effort to provide relief from symptomatic OA. There is a lack of appropriately powered, randomized controlled studies on the efficacy of these braces. With the evidence being inconclusive, the American Academy of Orthopaedic Surgeons is unable to recommend for or against use of a brace in medial unicompartmental OA.11 More research on the efficacy of these braces is needed. In the present study, we asked 2 questions: Does use of an unloader brace lessen the pain associated with knee OA? Is the unloader brace an acceptable and valid treatment modality for knee OA?
The 2 clinical outcome tools used in this study showed significant improvement in pain in brace patients compared with control patients. KOOS results showed reduced pain and arthritis symptoms. VAS results showed less pain experienced throughout the day. Pain reduction is probably the most important benefit of any nonoperative modality for knee OA. Pain typically is the driving force and the major indication for TKA. Other investigators have found pain reduced with use of unloader braces, but few long-term prospective randomized trials have been conducted. Ramsey and colleagues15 compared a neutral stabilizing brace with a medial unloading brace and found that both helped reduce pain and functional disability. This led to discussion about the 2 major potential mechanisms for symptom relief. One theory holds that bracing unloads the diseased portion of the joint and thereby helps improve symptoms.16-18 According to the other theory, bracing stabilizes the knee, reducing muscle cocontractions and joint compression.15,19,20 Draganich and colleagues21 found that both off-the-shelf and adjustable unloader braces reduced pain. In a short-term (8-week) study, Barnes and colleagues22 found substantial improvement in knee pain with use of an unloader brace. In one of the larger, better designed, prospective studies, Brouwer and colleagues23 found borderline but significant improvements in pain. Larsen and colleagues,24 in another short-term study, found no improvement in pain but did report improved activity levels with use of a medial unloader brace.
In addition to demonstrating pain reduction, our results showed that, compared with control patients, brace patients had fewer arthritis symptoms, better ability to engage in ADLs, and increased activity levels. Other studies have identified additional benefits of bracing for knee arthritis. Larsen and colleagues24 found that valgus bracing for medial compartment knee OA improved walking and sit-to-stand activities. Although pain relief results were modest, Brouwer and colleagues23 found significantly better knee function and longer walking distances for patients who used a medial unloader brace. Hewett and colleagues25 found that pain, ADLs, and walking distance were all improved after 9 weeks of brace wear.
Our study had a few limitations. Although injections and narcotic pain medications were not allowed, NSAIDs, home exercises, and other modalities were permitted. We did not think it was reasonable to eliminate every nonoperative modality during the 6-month study period. Therefore, it is possible that some of the study population’s improvements are attributable to these other modalities, which were not rigidly controlled.
Patient enrollment was difficult because of the strict inclusion and exclusion criteria used. The result was a smaller than anticipated patient population. Although there were many excellent study candidates, most declined enrollment when they learned they could be randomized to the control group. These patients were not willing to forgo injections or bracing for 6 months. We thought it was important to maintain our study design because it allowed us to evaluate the true effect of brace use while eliminating confounding variables. Nearly equal numbers of brace and control patients dropped out of the study. The majority of control group dropouts wanted more treatment options, indicating that NSAIDs and exercises alone were not controlling patients’ symptoms. This finding supports recommendations for a multimodal approach to treatment. As expected, some patients dropped out because their brace was uncomfortable—an important finding that should be considered when counseling patients about treatment options for OA.
Not all patients are candidates for braces. Braces can be irritating and uncomfortable for obese patients and patients with skin or vascular issues. Some patients find braces inconvenient. As discussed, a multimodal OA treatment approach is encouraged, but not every mode fits every patient. Physician and patient should thoroughly discuss the benefits and potential problems of brace use before prescribing. Our study results showed trends toward better improvements for brace patients (compared with control patients) in quality of life, ability to engage in sport and recreation, ability to sleep, and need for NSAIDs. Had we enrolled more patients, we might have found statistical significance for these trends. Despite the challenges with patient enrollment and study population size, the data make clear that unloader braces can benefit appropriate patients.
Our findings support use of a medial unloader brace as an acceptable and valid treatment modality for mild and moderate knee OA. The medial unloader brace should be considered a reasonable alternative, as part of a multimodal approach, to more invasive options, such as TKA.
1. Michaud C, McKenna M, Begg S, et al. The burden of disease and injury in the United States 1996. Popul Health Metr. 2006;4:11.
2. Lawrence RC, Felson DT, Helmick CG, et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58(1):26-35.
3. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81(9):646-656.
4. London NJ, Miller LE, Block JE. Clinical and economic consequences of the treatment gap in knee osteoarthritis management. Med Hypotheses. 2011;76(6):887-892.
5. Hochberg MC, Altman RD, April KT, et al; American College of Rheumatology. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):465-474.
6. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22(3):363-388.
7. Gallelli L, Galasso O, Falcone D, et al. The effects of nonsteroidal anti-inflammatory drugs on clinical outcomes, synovial fluid cytokine concentration and signal transduction pathways in knee osteoarthritis. A randomized open label trial. Osteoarthritis Cartilage. 2013;21(9):1400-1408.
8. Pollo FE, Jackson RW. Knee bracing for unicompartmental osteoarthritis. J Am Acad Orthop Surg. 2006;14(1):5-11.
9. Ramsey DK, Russell ME. Unloader braces for medial compartment knee osteoarthritis: implications on mediating progression. Sports Health. 2009;1(5):416-426.
10. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16(2):137-162.
11. Richmond J, Hunter D, Irrgang J, et al; American Academy of Orthopaedic Surgeons. American Academy of Orthopaedic Surgeons clinical practice guideline on the treatment of osteoarthritis (OA) of the knee. J Bone Joint Surg Am. 2010;92(4):990-993.
12. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16(4):494-502.
13. Dugdale TW, Noyes FR, Styer D. Preoperative planning for high tibial osteotomy. The effect of lateral tibiofemoral separation and tibiofemoral length. Clin Orthop Relat Res. 1992;(274):248-264.
14. Weinstein AM, Rome BN, Reichmann WM, et al. Estimating the burden of total knee replacement in the United States. J Bone Joint Surg Am. 2013;95(5):385-392.
15. Ramsey DK, Briem K, Axe MJ, Snyder-Mackler L. A mechanical theory for the effectiveness of bracing for medial compartment osteoarthritis of the knee. J Bone Joint Surg Am. 2007;89(11):2398-2407.
16. Haim A, Wolf A, Rubin G, Genis Y, Khoury M, Rozen N. Effect of center of pressure modulation on knee adduction moment in medial compartment knee osteoarthritis. J Orthop Res. 2011;29(11):1668-1674.
17. Pollo FE, Otis JC, Backus SI, Warren RF, Wickiewicz TL. Reduction of medial compartment loads with valgus bracing of the osteoarthritic knee. Am J Sports Med. 2002;30(3):414-421.
18. Shelburne KB, Torry MR, Steadman JR, Pandy MG. Effects of foot orthoses and valgus bracing on the knee adduction moment and medial joint load during gait. Clin Biomech. 2008;23(6):814-821.
19. Lewek MD, Ramsey DK, Snyder-Mackler L, Rudolph KS. Knee stabilization in patients with medial compartment knee osteoarthritis. Arthritis Rheum. 2005;52(9):2845-2853.
20. Lewek MD, Rudolph KS, Snyder-Mackler L. Control of frontal plane knee laxity during gait in patients with medial compartment knee osteoarthritis. Osteoarthritis Cartilage. 2004;12(9):745-751.
21. Draganich L, Reider B, Rimington T, Piotrowski G, Mallik K, Nasson S. The effectiveness of self-adjustable custom and off-the-shelf bracing in the treatment of varus gonarthrosis. J Bone Joint Surg Am. 2006;88(12):2645-2652.
22. Barnes CL, Cawley PW, Hederman B. Effect of CounterForce brace on symptomatic relief in a group of patients with symptomatic unicompartmental osteoarthritis: a prospective 2-year investigation. Am J Orthop. 2002;31(7):396-401.
23. Brouwer RW, van Raaij TM, Verhaar JA, Coene LN, Bierma-Zeinstra SM. Brace treatment for osteoarthritis of the knee: a prospective randomized multi-centre trial. Osteoarthritis Cartilage. 2006;14(8):777-783.
24. Larsen BL, Jacofsky MC, Brown JA, Jacofsky DJ. Valgus bracing affords short-term treatment solution across walking and sit-to-stand activities. J Arthroplasty. 2013;28(5):792-797.
25. Hewett TE, Noyes FR, Barber-Westin SD, Heckmann TP. Decrease in knee joint pain and increase in function in patients with medial compartment arthrosis: a prospective analysis of valgus bracing. Orthopedics. 1998;21(2):131-138.
1. Michaud C, McKenna M, Begg S, et al. The burden of disease and injury in the United States 1996. Popul Health Metr. 2006;4:11.
2. Lawrence RC, Felson DT, Helmick CG, et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58(1):26-35.
3. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81(9):646-656.
4. London NJ, Miller LE, Block JE. Clinical and economic consequences of the treatment gap in knee osteoarthritis management. Med Hypotheses. 2011;76(6):887-892.
5. Hochberg MC, Altman RD, April KT, et al; American College of Rheumatology. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):465-474.
6. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22(3):363-388.
7. Gallelli L, Galasso O, Falcone D, et al. The effects of nonsteroidal anti-inflammatory drugs on clinical outcomes, synovial fluid cytokine concentration and signal transduction pathways in knee osteoarthritis. A randomized open label trial. Osteoarthritis Cartilage. 2013;21(9):1400-1408.
8. Pollo FE, Jackson RW. Knee bracing for unicompartmental osteoarthritis. J Am Acad Orthop Surg. 2006;14(1):5-11.
9. Ramsey DK, Russell ME. Unloader braces for medial compartment knee osteoarthritis: implications on mediating progression. Sports Health. 2009;1(5):416-426.
10. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16(2):137-162.
11. Richmond J, Hunter D, Irrgang J, et al; American Academy of Orthopaedic Surgeons. American Academy of Orthopaedic Surgeons clinical practice guideline on the treatment of osteoarthritis (OA) of the knee. J Bone Joint Surg Am. 2010;92(4):990-993.
12. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16(4):494-502.
13. Dugdale TW, Noyes FR, Styer D. Preoperative planning for high tibial osteotomy. The effect of lateral tibiofemoral separation and tibiofemoral length. Clin Orthop Relat Res. 1992;(274):248-264.
14. Weinstein AM, Rome BN, Reichmann WM, et al. Estimating the burden of total knee replacement in the United States. J Bone Joint Surg Am. 2013;95(5):385-392.
15. Ramsey DK, Briem K, Axe MJ, Snyder-Mackler L. A mechanical theory for the effectiveness of bracing for medial compartment osteoarthritis of the knee. J Bone Joint Surg Am. 2007;89(11):2398-2407.
16. Haim A, Wolf A, Rubin G, Genis Y, Khoury M, Rozen N. Effect of center of pressure modulation on knee adduction moment in medial compartment knee osteoarthritis. J Orthop Res. 2011;29(11):1668-1674.
17. Pollo FE, Otis JC, Backus SI, Warren RF, Wickiewicz TL. Reduction of medial compartment loads with valgus bracing of the osteoarthritic knee. Am J Sports Med. 2002;30(3):414-421.
18. Shelburne KB, Torry MR, Steadman JR, Pandy MG. Effects of foot orthoses and valgus bracing on the knee adduction moment and medial joint load during gait. Clin Biomech. 2008;23(6):814-821.
19. Lewek MD, Ramsey DK, Snyder-Mackler L, Rudolph KS. Knee stabilization in patients with medial compartment knee osteoarthritis. Arthritis Rheum. 2005;52(9):2845-2853.
20. Lewek MD, Rudolph KS, Snyder-Mackler L. Control of frontal plane knee laxity during gait in patients with medial compartment knee osteoarthritis. Osteoarthritis Cartilage. 2004;12(9):745-751.
21. Draganich L, Reider B, Rimington T, Piotrowski G, Mallik K, Nasson S. The effectiveness of self-adjustable custom and off-the-shelf bracing in the treatment of varus gonarthrosis. J Bone Joint Surg Am. 2006;88(12):2645-2652.
22. Barnes CL, Cawley PW, Hederman B. Effect of CounterForce brace on symptomatic relief in a group of patients with symptomatic unicompartmental osteoarthritis: a prospective 2-year investigation. Am J Orthop. 2002;31(7):396-401.
23. Brouwer RW, van Raaij TM, Verhaar JA, Coene LN, Bierma-Zeinstra SM. Brace treatment for osteoarthritis of the knee: a prospective randomized multi-centre trial. Osteoarthritis Cartilage. 2006;14(8):777-783.
24. Larsen BL, Jacofsky MC, Brown JA, Jacofsky DJ. Valgus bracing affords short-term treatment solution across walking and sit-to-stand activities. J Arthroplasty. 2013;28(5):792-797.
25. Hewett TE, Noyes FR, Barber-Westin SD, Heckmann TP. Decrease in knee joint pain and increase in function in patients with medial compartment arthrosis: a prospective analysis of valgus bracing. Orthopedics. 1998;21(2):131-138.
Platelet-Rich Plasma Can Be Used to Successfully Treat Elbow Ulnar Collateral Ligament Insufficiency in High-Level Throwers
For overhead athletes, elbow ulnar collateral ligament (UCL) insufficiency is a potential career-ending injury. Baseball players with UCL insufficiency typically complain of medial-sided elbow pain that affects their ability to throw. Loss of velocity, loss of control, difficulty warming up, and pain while throwing are all symptoms of UCL injury.
Classically, nonoperative treatment of UCL injuries involves activity modification, use of anti-inflammatory medication, and a structured physical therapy program. Asymptomatic players can return to throwing after a structured interval throwing program. Rettig and colleagues1 found a 42% rate of success in conservatively treating UCL injuries in throwing athletes. UCL reconstruction is reserved for players with complete tears of the UCL or with partial tears after failed conservative treatment. Several techniques have been used to reconstruct the ligament, but successful outcomes depend on a long rehabilitation process. According to most published series, 85% to 90% of athletes who had UCL reconstruction returned to their previous level of play, but it took, on average, 9 to 12 months.2,3 This prolonged recovery period is one reason that some older professional baseball players, as well as casual high school and college players, elect to forgo surgery.
Over the past few years, platelet-rich plasma (PRP) has garnered attention as a bridge between conservative treatment and surgery. PRP refers to a sample of autologous blood that contains a platelet concentration higher than baseline levels. This sample often has a 3 to 5 times increase in growth factor concentration.4-6 Initial studies focused on its ability to successfully treat lateral epicondylitis.7-9 More recent clinical work has shown that PRP can potentially enhance healing after anterior cruciate ligament reconstruction,10-14 rotator cuff repair,15-17 and subacromial decompression.11,18-23 If PRP could be used to successfully treat UCL insufficiency that is refractory to conservative treatment, then year-long recovery periods could be avoided. This could potentially prolong certain athletes’ careers or, at the very least, allow them to return to play much sooner. In the present case series, we hypothesized that PRP injections could be used to successfully treat partial UCL tears in high-level throwing athletes, obviating the need for surgery and its associated prolonged recovery period.
Materials and Methods
Institutional Review Board approval was obtained for this retrospective study of 44 baseball players treated with PRP injections for partial-thickness UCL tears.
Patients provided written informed consent. They were diagnosed with UCL insufficiency by physical examination, and findings were confirmed by magnetic resonance imaging (MRI). After diagnosis, all throwers underwent a trial of conservative treatment that included rest, activity modification, use of anti-inflammatory medication, and physical therapy followed by an attempt to return to throwing using an interval throwing program.
Study inclusion criteria were physical examinations and MRI results consistent with UCL insufficiency, and failure of the conservative treatment plan described.
Patients were injected using the Autologous Conditioned Plasma system (Arthrex). PRP solutions were prepared according to manufacturer guidelines. After the elbow was prepared sterilely, the UCL was injected at the location of the tear. Typically, 3 mL of PRP was injected into the elbow. Sixteen patients had 1 injection, 6 had 2, and 22 had 3. Repeat injections were considered for recalcitrant pain after 3 weeks.
After injection, patients used acetaminophen and ice for pain control. Anti-inflammatory medications were avoided for a minimum of 2 weeks after injection. Typical postinjection therapy protocol consisted of rest followed by progressive stretching and strengthening for about 4 to 6 weeks before the start of an interval throwing program. Although there is no well-defined postinjection recovery protocol, as a general rule rest was prescribed for the first 2 weeks, followed by a progressive stretching and strengthening program for the next month. Patients who were asymptomatic subjectively and clinically—negative moving valgus stress test, negative milking maneuver, no pain with valgus stress—were started on an interval throwing program.
Final follow-up involved a physical examination. Results were classified according to a modified version of the Conway Scale12,24-26: excellent (return to preinjury level of competition or performance), good (return to play at a lower level of competition or performance or, specifically for baseball players, ability to throw in daily batting practice), fair (able to play recreationally), and poor (unable to return to previous sport at any level).
By final follow-up, all patients had completed their postoperative rehabilitation protocol, and all had at least tried to return to their previous activities. No patients were lost to follow-up.
Results
Of the 44 baseball players, 6 were professional, 14 were in college, and 24 were in high school. There were 36 pitchers and 8 position players. Mean age was 17.3 years (range, 16-28 years). All patients were available for follow-up after injection (mean, 11 months). Fifteen of the 44 players had an excellent outcome (34%), 17 had a good outcome, 2 had a fair outcome, and 10 had a poor outcome. After injection, 4 (67%) of the 6 professional baseball players returned to professional play. Five (36%) of the 14 college players had an excellent outcome, and 4 (17%) of the 24 high school players had an excellent outcome. Of the 8 position players, 4 had an excellent outcome, 3 had a good outcome, and 1 had a poor outcome.
Before treatment, all patients had medial-sided elbow pain over the UCL inhibiting their ability to throw. Mean duration of symptoms before injection was 8.8 months (range, 1-36 months). There was no correlation between symptom duration and any outcome measure. On MRI, 29 patients showed partial tears: 22 proximally based and 7 distally based. The other 15 patients had diffuse signal without partial tear. All 7 patients with distally based partial tears and 3 of the patients with proximally based partial tears had a poor outcome. Overall, there were 6 excellent, 7 good, and 2 fair outcomes in the partial-tear group. In the patients with diffuse signal without partial tear, there were 9 excellent and 10 good outcomes.
Mean time from injection to return to throwing was 5 weeks, and mean time to return to competition was 12 weeks (range, 5-24 weeks). The 1 player who returned at 5 weeks was a professional relief pitcher whose team was in the playoffs. He has now pitched for an additional 2 baseball seasons without elbow difficulty.
There were no injection-related complications.
Discussion
To our knowledge, this is the first report documenting successful PRP treatment of UCL insufficiency. In this study, 73% of players who had failed a course of conservative treatment had good to excellent outcomes with PRP injection.
Data on successful nonoperative treatment of UCL injuries are limited. Rettig and colleagues1 treated 31 throwing athletes’ UCL injuries with a supervised rehabilitation program. Treatment included rest, use of anti-inflammatory medication, progressive strengthening, and an interval throwing program. Only 41% of the athletes returned to their previous level of play, and it took, on average, 24.5 weeks. There was no significant difference in age or in duration or acuity of symptoms between those who returned to play and those whose conservative treatment failed.
Surgical reconstruction of UCL injuries has been very successful, with upward of 90% of athletes returning to previous level of play.3,27The procedure, however, is not without associated complications, including retear of the ligament, stiffness, ulnar nerve injury, and fracture.27-29 In addition, even when successful, the procedure requires that athletes take 9 to 12 months to recover before returning to competition at their previous level.
Savoie and colleagues,30 in their recent study on UCL repairs, highlighted an important fact that is often overlooked when reviewing the literature on UCL tears. Most of the literature on these injuries focuses on college and professional baseball players in whom ligament damage is often extensive, precluding repair. In contrast to prior reports, Savoie and colleagues30 found excellent results in 93% of their young athletes who underwent UCL repair. It is possible that their results can be attributed to the fact that many of their athletes had tears isolated to one area of the ligament, as opposed to generalized ligament incompetence. Our improved results vis-à-vis other reports on conservative management may be attributable to the same phenomenon.
PRP has garnered much attention in the literature and media because of its potential to enhance healing of tendons and ligaments; in some cases, it can obviate the need for surgery. After failure of other nonoperative measures in 15 patients with elbow epicondylitis, Mishra and Pavelko8 treated each patient with a single PRP injection. They prepared the PRP using the GPS III system (Biomet). At final follow-up, 93% improvement was seen. Clearly, their experiment had design flaws: It was nonblinded, and 3 of the 5 patients in the control group treated with bupivacaine injection withdrew from the experiment. Despite its shortcomings, their study became the impetus for several other studies.
A larger, double-blinded, randomized controlled trial comparing PRP and cortisone injections for lateral epicondylitis in 100 patients is under way, and preliminary results have been published.9 A minimum of 6 months after injection, patients who received PRP showed more improvement in visual analog scale (VAS) pain scores and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire scores. In another large, double-blinded, randomized controlled trial, patients with chronic lateral epicondylitis had significant improvements in VAS pain scores and DASH scores relative to patients injected with corticosteroids with a 2-year follow-up.31 Similarly, Thanasas and colleagues32 found significantly reduced VAS pain scores in patients injected with PRP versus autologous whole blood. Another study demonstrated improved tendon morphology using ultrasound imaging 6 months after PRP injection.33
Contrary to these positive results, Krogh and colleagues34 found that a single injection of PRP or glucocorticoid was not significantly superior to a saline injection for reducing pain and disability over a 3-month period in patients with lateral epicondylitis. Their study, however, had major flaws. Its original design called for a 12-month follow-up, but there was massive dropout in all 3 treatment arms, necessitating reporting of only 3-month data. In addition, 60% of the patients in the glucocorticoid group were not naïve to this treatment, so definitive conclusions about the efficacy of glucocorticoids could not be made.
In the present study, we successfully treated partial ligament tears with PRP injections. Sixty-seven percent of our baseball players returned to play at a mean of 4 months, much earlier than the 9 to 12 months typically required after ligament reconstruction. Many athletes, such as high school baseball players or aging veteran professional baseball players, do not have the luxury of 12 months for recovery. Therefore, this select group of patients clearly has a limited window of opportunity to return to play. In fact, these patients might be ideal candidates for PRP injections for UCL injuries. Return-to-play rates, however, differed significantly among professional players and nonprofessional players. The difference may be attributable to professional players’ conditioning, quality of physical therapy, extrinsic motivation, and other intangible factors. Four (67%) of our 6 professional baseball players returned to professional play after injection, whereas only 36% of college players and 17% of high school players had excellent outcomes.
Limitations
The present study had several weaknesses, several of which are inherent to PRP studies conducted so far. It was not a prospective, randomized controlled trial. It is important to note that PRP treatment in diseased tissue may have some drawbacks, as its success depends on the ability of healing tissue to use concentrated growth factors and cytokines to proliferate.35 Thus, a chronically injured ligament with depleted active cells may have a diminished response to PRP. Another limitation of this study is that we evaluated outcomes based on return to play using the Conway Scale, which is well reported but not validated. Despite the potential weaknesses of this outcome scale, it has become the benchmark for measuring the success of outcomes of UCL reconstruction. Furthermore, we did not measure patients’ satisfaction with the treatment. Players who could not return to their preinjury level of play may have considered the treatment a failure regardless of their ability to continue throwing. Last, MRI was not repeated to document ligament healing. We did not routinely perform a second MRI because we thought it would not affect treatment. Several series have found a high incidence of abnormal signal in baseball players’ UCLs. In this group of patients, the most important outcome is return to previous level of competition.
This study raised several questions. Is one PRP brand better than another? Should more than 1 injection be given? What is the ideal postinjection protocol? Clearly, larger, prospective, randomized controlled studies are needed to truly elucidate the potential role of PRP in the treatment algorithm for UCL injury. Nevertheless, in certain cases in which traditional conservative measures have failed and patients do not have the luxury of rehabilitating for 9 to 12 months after surgery, PRP may be a viable treatment option.
Conclusion
In this study, use of PRP in the treatment of UCL insufficiency produced outcomes much better than earlier reported outcomes of conservative treatment of these injuries. PRP injections may be particularly beneficial in young athletes who have sustained acute damage to an isolated part of the ligament and in athletes unwilling or unable to undergo the extended rehabilitation required after surgical reconstruction of the ligament.
1. Rettig AC, Sherrill C, Snead DS, Mendler JC, Mieling P. Nonoperative treatment of ulnar collateral ligament injuries in throwing athletes. Am J Sports Med. 2001;29(1):15-17.
2. Eygendaal D, Rahussen FT, Diercks RL. Biomechanics of the elbow joint in tennis players and relation to pathology. Br J Sports Med. 2007;41(11):820-823.
3. Bowers AL, Dines JS, Dines DM, Altchek DW. Elbow medial ulnar collateral ligament reconstruction: clinical relevance and the docking technique. J Shoulder Elbow Surg. 2010;19(2):110-117.
5. Kibler WB. Biomechanical analysis of the shoulder during tennis activities. Clin Sports Med. 1995;14(1):79-85.
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8. Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006;34(11):1774-1778.
9. Mishra A, Woodall J Jr, Vieira A. Treatment of tendon and muscle using platelet-rich plasma. Clin Sports Med. 2009;28(1):113-125.
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11. Xie X, Wu H, Zhao S, Xie G, Huangfu X, Zhao J. The effect of platelet-rich plasma on patterns of gene expression in a dog model of anterior cruciate ligament reconstruction. J Surg Res. 2013;180(1):80-88.
12. Pluim BM, Staal JB, Windler GE, Jayanthi N. Tennis injuries: occurrence, aetiology, and prevention. Br J Sports Med. 2006;40(5):415-423.
13. Xie X, Zhao S, Wu H, et al. Platelet-rich plasma enhances autograft revascularization and reinnervation in a dog model of anterior cruciate ligament reconstruction. J Surg Res. 2013;183(1):214-222.
14. Lopez-Vidriero E, Goulding KA, Simon DA, Sanchez M, Johnson DH. The use of platelet-rich plasma in arthroscopy and sports medicine: optimizing the healing environment. Arthroscopy. 2010;26(2):269-278.
15. Jo CH, Shin JS, Shin WH, Lee SY, Yoon KS, Shin S. Platelet-rich plasma for arthroscopic repair of medium to large rotator cuff tears: a randomized controlled trial. Am J Sports Med. 2015;43(9):2102-2110.
16. Jo CH, Shin JS, Lee YG, et al. Platelet-rich plasma for arthroscopic repair of large to massive rotator cuff tears: a randomized, single-blinded, parallel-group trial. Am J Sports Med. 2013;41(10):2240-2248.
17. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet-rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518-528.
18. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518-528.
19. Barber FA, Hrnack SA, Snyder SJ, Hapa O. Rotator cuff repair healing influenced by platelet-rich plasma construct augmentation. Arthroscopy. 2011;27(8):1029-1035.
20. Jo CH, Kim JE, Yoon KS, et al. Does platelet-rich plasma accelerate recovery after rotator cuff repair? A prospective cohort study. Am J Sports Med. 2011;39(10):2082-2090.
21. Jo CH, Kim JE, Yoon KS, Shin S. Platelet-rich plasma stimulates cell proliferation and enhances matrix gene expression and synthesis in tenocytes from human rotator cuff tendons with degenerative tears. Am J Sports Med. 2012;40(5):1035-1045.
22. Chahal J, Van Thiel GS, Mall N, et al. The role of platelet-rich plasma in arthroscopic rotator cuff repair: a systematic review with quantitative synthesis. Arthroscopy. 2012;28(11):1718-1727.
23. Mei-Dan O, Carmont MR. The role of platelet-rich plasma in rotator cuff repair. Sports Med Arthrosc Rev. 2011;19(3):244-250.
24. Dines JS, ElAttrache NS, Conway JE, Smith W, Ahmad CS. Clinical outcomes of the DANE TJ technique to treat ulnar collateral ligament insufficiency of the elbow. Am J Sports Med. 2007;35(12):2039-2044.
25. Hutchinson MR, Laprade RF, Burnett QM 2nd, Moss R, Terpstra J. Injury surveillance at the USTA boys’ tennis championships: a 6-yr study. Med Sci Sports Exerc. 1995;27(6):826-830.
26. Winge S, Jørgensen U, Nielsen A. Epidemiology of injuries in Danish championship tennis. Int J Sports Med. 1989;10(5):368-371.
27. Safran MR, Hutchinson MR, Moss R, Albrandt J. A comparison of injuries in elite boys and girls tennis players. Paper presented at: 9th Annual Meeting of the Society of Tennis Medicine and Science; March 1999; Indian Wells, CA.
28. Cain EL, Andrews JR, Dugas JR, et al. Outcome of ulnar collateral ligament reconstruction of the elbow in 1281 athletes: results in 743 athletes with minimum 2-year follow-up. Am J Sports Med. 2010;38(12):2426-2434.
29. Dines JS, Yocum LA, Frank JB, ElAttrache NS, Gambardella RA, Jobe FW. Revision surgery for failed elbow medial collateral ligament reconstruction. Am J Sports Med. 2008;36(6):1061-1065.
30. Savoie FH, Trenhaile SW, Roberts J, Field LD, Ramsey JR. Primary repair of ulnar collateral ligament injuries of the elbow in young athletes: a case series of injuries to the proximal and distal ends of the ligament. Am J Sports Med. 2008;36(6):1066-1072.
31. Gosens T, Peerbooms JC, van Laar W, Oudsten den BL. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. Am J Sports Med. 2011;39(6):1200-1208.
32. Thanasas C, Papadimitriou G, Charalambidis C, Paraskevopoulos I, Papanikolaou A. Platelet-rich plasma versus autologous whole blood for the treatment of chronic lateral elbow epicondylitis: a randomized controlled clinical trial. Am J Sports Med. 2011;39(10):2130-2134.
33. Chaudhury S, La Lama de M, Adler RS, et al. Platelet-rich plasma for the treatment of lateral epicondylitis: sonographic assessment of tendon morphology and vascularity (pilot study). Skeletal Radiol. 2013;42(1):91-97.
34. Krogh TP, Fredberg U, Stengaard-Pedersen K, Christensen R, Jensen P, Ellingsen T. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med. 2013;41(3):625-635.
35. Anz AW, Hackel JG, Nilssen EC, Andrews JR. Application of biologics in the treatment of the rotator cuff, meniscus, cartilage, and osteoarthritis. J Am Acad Orthop Surg. 2014;22(2):68-79.
For overhead athletes, elbow ulnar collateral ligament (UCL) insufficiency is a potential career-ending injury. Baseball players with UCL insufficiency typically complain of medial-sided elbow pain that affects their ability to throw. Loss of velocity, loss of control, difficulty warming up, and pain while throwing are all symptoms of UCL injury.
Classically, nonoperative treatment of UCL injuries involves activity modification, use of anti-inflammatory medication, and a structured physical therapy program. Asymptomatic players can return to throwing after a structured interval throwing program. Rettig and colleagues1 found a 42% rate of success in conservatively treating UCL injuries in throwing athletes. UCL reconstruction is reserved for players with complete tears of the UCL or with partial tears after failed conservative treatment. Several techniques have been used to reconstruct the ligament, but successful outcomes depend on a long rehabilitation process. According to most published series, 85% to 90% of athletes who had UCL reconstruction returned to their previous level of play, but it took, on average, 9 to 12 months.2,3 This prolonged recovery period is one reason that some older professional baseball players, as well as casual high school and college players, elect to forgo surgery.
Over the past few years, platelet-rich plasma (PRP) has garnered attention as a bridge between conservative treatment and surgery. PRP refers to a sample of autologous blood that contains a platelet concentration higher than baseline levels. This sample often has a 3 to 5 times increase in growth factor concentration.4-6 Initial studies focused on its ability to successfully treat lateral epicondylitis.7-9 More recent clinical work has shown that PRP can potentially enhance healing after anterior cruciate ligament reconstruction,10-14 rotator cuff repair,15-17 and subacromial decompression.11,18-23 If PRP could be used to successfully treat UCL insufficiency that is refractory to conservative treatment, then year-long recovery periods could be avoided. This could potentially prolong certain athletes’ careers or, at the very least, allow them to return to play much sooner. In the present case series, we hypothesized that PRP injections could be used to successfully treat partial UCL tears in high-level throwing athletes, obviating the need for surgery and its associated prolonged recovery period.
Materials and Methods
Institutional Review Board approval was obtained for this retrospective study of 44 baseball players treated with PRP injections for partial-thickness UCL tears.
Patients provided written informed consent. They were diagnosed with UCL insufficiency by physical examination, and findings were confirmed by magnetic resonance imaging (MRI). After diagnosis, all throwers underwent a trial of conservative treatment that included rest, activity modification, use of anti-inflammatory medication, and physical therapy followed by an attempt to return to throwing using an interval throwing program.
Study inclusion criteria were physical examinations and MRI results consistent with UCL insufficiency, and failure of the conservative treatment plan described.
Patients were injected using the Autologous Conditioned Plasma system (Arthrex). PRP solutions were prepared according to manufacturer guidelines. After the elbow was prepared sterilely, the UCL was injected at the location of the tear. Typically, 3 mL of PRP was injected into the elbow. Sixteen patients had 1 injection, 6 had 2, and 22 had 3. Repeat injections were considered for recalcitrant pain after 3 weeks.
After injection, patients used acetaminophen and ice for pain control. Anti-inflammatory medications were avoided for a minimum of 2 weeks after injection. Typical postinjection therapy protocol consisted of rest followed by progressive stretching and strengthening for about 4 to 6 weeks before the start of an interval throwing program. Although there is no well-defined postinjection recovery protocol, as a general rule rest was prescribed for the first 2 weeks, followed by a progressive stretching and strengthening program for the next month. Patients who were asymptomatic subjectively and clinically—negative moving valgus stress test, negative milking maneuver, no pain with valgus stress—were started on an interval throwing program.
Final follow-up involved a physical examination. Results were classified according to a modified version of the Conway Scale12,24-26: excellent (return to preinjury level of competition or performance), good (return to play at a lower level of competition or performance or, specifically for baseball players, ability to throw in daily batting practice), fair (able to play recreationally), and poor (unable to return to previous sport at any level).
By final follow-up, all patients had completed their postoperative rehabilitation protocol, and all had at least tried to return to their previous activities. No patients were lost to follow-up.
Results
Of the 44 baseball players, 6 were professional, 14 were in college, and 24 were in high school. There were 36 pitchers and 8 position players. Mean age was 17.3 years (range, 16-28 years). All patients were available for follow-up after injection (mean, 11 months). Fifteen of the 44 players had an excellent outcome (34%), 17 had a good outcome, 2 had a fair outcome, and 10 had a poor outcome. After injection, 4 (67%) of the 6 professional baseball players returned to professional play. Five (36%) of the 14 college players had an excellent outcome, and 4 (17%) of the 24 high school players had an excellent outcome. Of the 8 position players, 4 had an excellent outcome, 3 had a good outcome, and 1 had a poor outcome.
Before treatment, all patients had medial-sided elbow pain over the UCL inhibiting their ability to throw. Mean duration of symptoms before injection was 8.8 months (range, 1-36 months). There was no correlation between symptom duration and any outcome measure. On MRI, 29 patients showed partial tears: 22 proximally based and 7 distally based. The other 15 patients had diffuse signal without partial tear. All 7 patients with distally based partial tears and 3 of the patients with proximally based partial tears had a poor outcome. Overall, there were 6 excellent, 7 good, and 2 fair outcomes in the partial-tear group. In the patients with diffuse signal without partial tear, there were 9 excellent and 10 good outcomes.
Mean time from injection to return to throwing was 5 weeks, and mean time to return to competition was 12 weeks (range, 5-24 weeks). The 1 player who returned at 5 weeks was a professional relief pitcher whose team was in the playoffs. He has now pitched for an additional 2 baseball seasons without elbow difficulty.
There were no injection-related complications.
Discussion
To our knowledge, this is the first report documenting successful PRP treatment of UCL insufficiency. In this study, 73% of players who had failed a course of conservative treatment had good to excellent outcomes with PRP injection.
Data on successful nonoperative treatment of UCL injuries are limited. Rettig and colleagues1 treated 31 throwing athletes’ UCL injuries with a supervised rehabilitation program. Treatment included rest, use of anti-inflammatory medication, progressive strengthening, and an interval throwing program. Only 41% of the athletes returned to their previous level of play, and it took, on average, 24.5 weeks. There was no significant difference in age or in duration or acuity of symptoms between those who returned to play and those whose conservative treatment failed.
Surgical reconstruction of UCL injuries has been very successful, with upward of 90% of athletes returning to previous level of play.3,27The procedure, however, is not without associated complications, including retear of the ligament, stiffness, ulnar nerve injury, and fracture.27-29 In addition, even when successful, the procedure requires that athletes take 9 to 12 months to recover before returning to competition at their previous level.
Savoie and colleagues,30 in their recent study on UCL repairs, highlighted an important fact that is often overlooked when reviewing the literature on UCL tears. Most of the literature on these injuries focuses on college and professional baseball players in whom ligament damage is often extensive, precluding repair. In contrast to prior reports, Savoie and colleagues30 found excellent results in 93% of their young athletes who underwent UCL repair. It is possible that their results can be attributed to the fact that many of their athletes had tears isolated to one area of the ligament, as opposed to generalized ligament incompetence. Our improved results vis-à-vis other reports on conservative management may be attributable to the same phenomenon.
PRP has garnered much attention in the literature and media because of its potential to enhance healing of tendons and ligaments; in some cases, it can obviate the need for surgery. After failure of other nonoperative measures in 15 patients with elbow epicondylitis, Mishra and Pavelko8 treated each patient with a single PRP injection. They prepared the PRP using the GPS III system (Biomet). At final follow-up, 93% improvement was seen. Clearly, their experiment had design flaws: It was nonblinded, and 3 of the 5 patients in the control group treated with bupivacaine injection withdrew from the experiment. Despite its shortcomings, their study became the impetus for several other studies.
A larger, double-blinded, randomized controlled trial comparing PRP and cortisone injections for lateral epicondylitis in 100 patients is under way, and preliminary results have been published.9 A minimum of 6 months after injection, patients who received PRP showed more improvement in visual analog scale (VAS) pain scores and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire scores. In another large, double-blinded, randomized controlled trial, patients with chronic lateral epicondylitis had significant improvements in VAS pain scores and DASH scores relative to patients injected with corticosteroids with a 2-year follow-up.31 Similarly, Thanasas and colleagues32 found significantly reduced VAS pain scores in patients injected with PRP versus autologous whole blood. Another study demonstrated improved tendon morphology using ultrasound imaging 6 months after PRP injection.33
Contrary to these positive results, Krogh and colleagues34 found that a single injection of PRP or glucocorticoid was not significantly superior to a saline injection for reducing pain and disability over a 3-month period in patients with lateral epicondylitis. Their study, however, had major flaws. Its original design called for a 12-month follow-up, but there was massive dropout in all 3 treatment arms, necessitating reporting of only 3-month data. In addition, 60% of the patients in the glucocorticoid group were not naïve to this treatment, so definitive conclusions about the efficacy of glucocorticoids could not be made.
In the present study, we successfully treated partial ligament tears with PRP injections. Sixty-seven percent of our baseball players returned to play at a mean of 4 months, much earlier than the 9 to 12 months typically required after ligament reconstruction. Many athletes, such as high school baseball players or aging veteran professional baseball players, do not have the luxury of 12 months for recovery. Therefore, this select group of patients clearly has a limited window of opportunity to return to play. In fact, these patients might be ideal candidates for PRP injections for UCL injuries. Return-to-play rates, however, differed significantly among professional players and nonprofessional players. The difference may be attributable to professional players’ conditioning, quality of physical therapy, extrinsic motivation, and other intangible factors. Four (67%) of our 6 professional baseball players returned to professional play after injection, whereas only 36% of college players and 17% of high school players had excellent outcomes.
Limitations
The present study had several weaknesses, several of which are inherent to PRP studies conducted so far. It was not a prospective, randomized controlled trial. It is important to note that PRP treatment in diseased tissue may have some drawbacks, as its success depends on the ability of healing tissue to use concentrated growth factors and cytokines to proliferate.35 Thus, a chronically injured ligament with depleted active cells may have a diminished response to PRP. Another limitation of this study is that we evaluated outcomes based on return to play using the Conway Scale, which is well reported but not validated. Despite the potential weaknesses of this outcome scale, it has become the benchmark for measuring the success of outcomes of UCL reconstruction. Furthermore, we did not measure patients’ satisfaction with the treatment. Players who could not return to their preinjury level of play may have considered the treatment a failure regardless of their ability to continue throwing. Last, MRI was not repeated to document ligament healing. We did not routinely perform a second MRI because we thought it would not affect treatment. Several series have found a high incidence of abnormal signal in baseball players’ UCLs. In this group of patients, the most important outcome is return to previous level of competition.
This study raised several questions. Is one PRP brand better than another? Should more than 1 injection be given? What is the ideal postinjection protocol? Clearly, larger, prospective, randomized controlled studies are needed to truly elucidate the potential role of PRP in the treatment algorithm for UCL injury. Nevertheless, in certain cases in which traditional conservative measures have failed and patients do not have the luxury of rehabilitating for 9 to 12 months after surgery, PRP may be a viable treatment option.
Conclusion
In this study, use of PRP in the treatment of UCL insufficiency produced outcomes much better than earlier reported outcomes of conservative treatment of these injuries. PRP injections may be particularly beneficial in young athletes who have sustained acute damage to an isolated part of the ligament and in athletes unwilling or unable to undergo the extended rehabilitation required after surgical reconstruction of the ligament.
For overhead athletes, elbow ulnar collateral ligament (UCL) insufficiency is a potential career-ending injury. Baseball players with UCL insufficiency typically complain of medial-sided elbow pain that affects their ability to throw. Loss of velocity, loss of control, difficulty warming up, and pain while throwing are all symptoms of UCL injury.
Classically, nonoperative treatment of UCL injuries involves activity modification, use of anti-inflammatory medication, and a structured physical therapy program. Asymptomatic players can return to throwing after a structured interval throwing program. Rettig and colleagues1 found a 42% rate of success in conservatively treating UCL injuries in throwing athletes. UCL reconstruction is reserved for players with complete tears of the UCL or with partial tears after failed conservative treatment. Several techniques have been used to reconstruct the ligament, but successful outcomes depend on a long rehabilitation process. According to most published series, 85% to 90% of athletes who had UCL reconstruction returned to their previous level of play, but it took, on average, 9 to 12 months.2,3 This prolonged recovery period is one reason that some older professional baseball players, as well as casual high school and college players, elect to forgo surgery.
Over the past few years, platelet-rich plasma (PRP) has garnered attention as a bridge between conservative treatment and surgery. PRP refers to a sample of autologous blood that contains a platelet concentration higher than baseline levels. This sample often has a 3 to 5 times increase in growth factor concentration.4-6 Initial studies focused on its ability to successfully treat lateral epicondylitis.7-9 More recent clinical work has shown that PRP can potentially enhance healing after anterior cruciate ligament reconstruction,10-14 rotator cuff repair,15-17 and subacromial decompression.11,18-23 If PRP could be used to successfully treat UCL insufficiency that is refractory to conservative treatment, then year-long recovery periods could be avoided. This could potentially prolong certain athletes’ careers or, at the very least, allow them to return to play much sooner. In the present case series, we hypothesized that PRP injections could be used to successfully treat partial UCL tears in high-level throwing athletes, obviating the need for surgery and its associated prolonged recovery period.
Materials and Methods
Institutional Review Board approval was obtained for this retrospective study of 44 baseball players treated with PRP injections for partial-thickness UCL tears.
Patients provided written informed consent. They were diagnosed with UCL insufficiency by physical examination, and findings were confirmed by magnetic resonance imaging (MRI). After diagnosis, all throwers underwent a trial of conservative treatment that included rest, activity modification, use of anti-inflammatory medication, and physical therapy followed by an attempt to return to throwing using an interval throwing program.
Study inclusion criteria were physical examinations and MRI results consistent with UCL insufficiency, and failure of the conservative treatment plan described.
Patients were injected using the Autologous Conditioned Plasma system (Arthrex). PRP solutions were prepared according to manufacturer guidelines. After the elbow was prepared sterilely, the UCL was injected at the location of the tear. Typically, 3 mL of PRP was injected into the elbow. Sixteen patients had 1 injection, 6 had 2, and 22 had 3. Repeat injections were considered for recalcitrant pain after 3 weeks.
After injection, patients used acetaminophen and ice for pain control. Anti-inflammatory medications were avoided for a minimum of 2 weeks after injection. Typical postinjection therapy protocol consisted of rest followed by progressive stretching and strengthening for about 4 to 6 weeks before the start of an interval throwing program. Although there is no well-defined postinjection recovery protocol, as a general rule rest was prescribed for the first 2 weeks, followed by a progressive stretching and strengthening program for the next month. Patients who were asymptomatic subjectively and clinically—negative moving valgus stress test, negative milking maneuver, no pain with valgus stress—were started on an interval throwing program.
Final follow-up involved a physical examination. Results were classified according to a modified version of the Conway Scale12,24-26: excellent (return to preinjury level of competition or performance), good (return to play at a lower level of competition or performance or, specifically for baseball players, ability to throw in daily batting practice), fair (able to play recreationally), and poor (unable to return to previous sport at any level).
By final follow-up, all patients had completed their postoperative rehabilitation protocol, and all had at least tried to return to their previous activities. No patients were lost to follow-up.
Results
Of the 44 baseball players, 6 were professional, 14 were in college, and 24 were in high school. There were 36 pitchers and 8 position players. Mean age was 17.3 years (range, 16-28 years). All patients were available for follow-up after injection (mean, 11 months). Fifteen of the 44 players had an excellent outcome (34%), 17 had a good outcome, 2 had a fair outcome, and 10 had a poor outcome. After injection, 4 (67%) of the 6 professional baseball players returned to professional play. Five (36%) of the 14 college players had an excellent outcome, and 4 (17%) of the 24 high school players had an excellent outcome. Of the 8 position players, 4 had an excellent outcome, 3 had a good outcome, and 1 had a poor outcome.
Before treatment, all patients had medial-sided elbow pain over the UCL inhibiting their ability to throw. Mean duration of symptoms before injection was 8.8 months (range, 1-36 months). There was no correlation between symptom duration and any outcome measure. On MRI, 29 patients showed partial tears: 22 proximally based and 7 distally based. The other 15 patients had diffuse signal without partial tear. All 7 patients with distally based partial tears and 3 of the patients with proximally based partial tears had a poor outcome. Overall, there were 6 excellent, 7 good, and 2 fair outcomes in the partial-tear group. In the patients with diffuse signal without partial tear, there were 9 excellent and 10 good outcomes.
Mean time from injection to return to throwing was 5 weeks, and mean time to return to competition was 12 weeks (range, 5-24 weeks). The 1 player who returned at 5 weeks was a professional relief pitcher whose team was in the playoffs. He has now pitched for an additional 2 baseball seasons without elbow difficulty.
There were no injection-related complications.
Discussion
To our knowledge, this is the first report documenting successful PRP treatment of UCL insufficiency. In this study, 73% of players who had failed a course of conservative treatment had good to excellent outcomes with PRP injection.
Data on successful nonoperative treatment of UCL injuries are limited. Rettig and colleagues1 treated 31 throwing athletes’ UCL injuries with a supervised rehabilitation program. Treatment included rest, use of anti-inflammatory medication, progressive strengthening, and an interval throwing program. Only 41% of the athletes returned to their previous level of play, and it took, on average, 24.5 weeks. There was no significant difference in age or in duration or acuity of symptoms between those who returned to play and those whose conservative treatment failed.
Surgical reconstruction of UCL injuries has been very successful, with upward of 90% of athletes returning to previous level of play.3,27The procedure, however, is not without associated complications, including retear of the ligament, stiffness, ulnar nerve injury, and fracture.27-29 In addition, even when successful, the procedure requires that athletes take 9 to 12 months to recover before returning to competition at their previous level.
Savoie and colleagues,30 in their recent study on UCL repairs, highlighted an important fact that is often overlooked when reviewing the literature on UCL tears. Most of the literature on these injuries focuses on college and professional baseball players in whom ligament damage is often extensive, precluding repair. In contrast to prior reports, Savoie and colleagues30 found excellent results in 93% of their young athletes who underwent UCL repair. It is possible that their results can be attributed to the fact that many of their athletes had tears isolated to one area of the ligament, as opposed to generalized ligament incompetence. Our improved results vis-à-vis other reports on conservative management may be attributable to the same phenomenon.
PRP has garnered much attention in the literature and media because of its potential to enhance healing of tendons and ligaments; in some cases, it can obviate the need for surgery. After failure of other nonoperative measures in 15 patients with elbow epicondylitis, Mishra and Pavelko8 treated each patient with a single PRP injection. They prepared the PRP using the GPS III system (Biomet). At final follow-up, 93% improvement was seen. Clearly, their experiment had design flaws: It was nonblinded, and 3 of the 5 patients in the control group treated with bupivacaine injection withdrew from the experiment. Despite its shortcomings, their study became the impetus for several other studies.
A larger, double-blinded, randomized controlled trial comparing PRP and cortisone injections for lateral epicondylitis in 100 patients is under way, and preliminary results have been published.9 A minimum of 6 months after injection, patients who received PRP showed more improvement in visual analog scale (VAS) pain scores and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire scores. In another large, double-blinded, randomized controlled trial, patients with chronic lateral epicondylitis had significant improvements in VAS pain scores and DASH scores relative to patients injected with corticosteroids with a 2-year follow-up.31 Similarly, Thanasas and colleagues32 found significantly reduced VAS pain scores in patients injected with PRP versus autologous whole blood. Another study demonstrated improved tendon morphology using ultrasound imaging 6 months after PRP injection.33
Contrary to these positive results, Krogh and colleagues34 found that a single injection of PRP or glucocorticoid was not significantly superior to a saline injection for reducing pain and disability over a 3-month period in patients with lateral epicondylitis. Their study, however, had major flaws. Its original design called for a 12-month follow-up, but there was massive dropout in all 3 treatment arms, necessitating reporting of only 3-month data. In addition, 60% of the patients in the glucocorticoid group were not naïve to this treatment, so definitive conclusions about the efficacy of glucocorticoids could not be made.
In the present study, we successfully treated partial ligament tears with PRP injections. Sixty-seven percent of our baseball players returned to play at a mean of 4 months, much earlier than the 9 to 12 months typically required after ligament reconstruction. Many athletes, such as high school baseball players or aging veteran professional baseball players, do not have the luxury of 12 months for recovery. Therefore, this select group of patients clearly has a limited window of opportunity to return to play. In fact, these patients might be ideal candidates for PRP injections for UCL injuries. Return-to-play rates, however, differed significantly among professional players and nonprofessional players. The difference may be attributable to professional players’ conditioning, quality of physical therapy, extrinsic motivation, and other intangible factors. Four (67%) of our 6 professional baseball players returned to professional play after injection, whereas only 36% of college players and 17% of high school players had excellent outcomes.
Limitations
The present study had several weaknesses, several of which are inherent to PRP studies conducted so far. It was not a prospective, randomized controlled trial. It is important to note that PRP treatment in diseased tissue may have some drawbacks, as its success depends on the ability of healing tissue to use concentrated growth factors and cytokines to proliferate.35 Thus, a chronically injured ligament with depleted active cells may have a diminished response to PRP. Another limitation of this study is that we evaluated outcomes based on return to play using the Conway Scale, which is well reported but not validated. Despite the potential weaknesses of this outcome scale, it has become the benchmark for measuring the success of outcomes of UCL reconstruction. Furthermore, we did not measure patients’ satisfaction with the treatment. Players who could not return to their preinjury level of play may have considered the treatment a failure regardless of their ability to continue throwing. Last, MRI was not repeated to document ligament healing. We did not routinely perform a second MRI because we thought it would not affect treatment. Several series have found a high incidence of abnormal signal in baseball players’ UCLs. In this group of patients, the most important outcome is return to previous level of competition.
This study raised several questions. Is one PRP brand better than another? Should more than 1 injection be given? What is the ideal postinjection protocol? Clearly, larger, prospective, randomized controlled studies are needed to truly elucidate the potential role of PRP in the treatment algorithm for UCL injury. Nevertheless, in certain cases in which traditional conservative measures have failed and patients do not have the luxury of rehabilitating for 9 to 12 months after surgery, PRP may be a viable treatment option.
Conclusion
In this study, use of PRP in the treatment of UCL insufficiency produced outcomes much better than earlier reported outcomes of conservative treatment of these injuries. PRP injections may be particularly beneficial in young athletes who have sustained acute damage to an isolated part of the ligament and in athletes unwilling or unable to undergo the extended rehabilitation required after surgical reconstruction of the ligament.
1. Rettig AC, Sherrill C, Snead DS, Mendler JC, Mieling P. Nonoperative treatment of ulnar collateral ligament injuries in throwing athletes. Am J Sports Med. 2001;29(1):15-17.
2. Eygendaal D, Rahussen FT, Diercks RL. Biomechanics of the elbow joint in tennis players and relation to pathology. Br J Sports Med. 2007;41(11):820-823.
3. Bowers AL, Dines JS, Dines DM, Altchek DW. Elbow medial ulnar collateral ligament reconstruction: clinical relevance and the docking technique. J Shoulder Elbow Surg. 2010;19(2):110-117.
5. Kibler WB. Biomechanical analysis of the shoulder during tennis activities. Clin Sports Med. 1995;14(1):79-85.
5. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg. 2004;62(4):489-496.
6. Marx RE. Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant Dent. 2001;10(4):225-228.
7. Elliott B, Fleisig G, Nicholls R, Escamilia R. Technique effects on upper limb loading in the tennis serve. J Sci Med Sport. 2003;6(1):76-87.
8. Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006;34(11):1774-1778.
9. Mishra A, Woodall J Jr, Vieira A. Treatment of tendon and muscle using platelet-rich plasma. Clin Sports Med. 2009;28(1):113-125.
10. Kovacs MS. Applied physiology of tennis performance. Br J Sports Med. 2006;40(5):381-386.
11. Xie X, Wu H, Zhao S, Xie G, Huangfu X, Zhao J. The effect of platelet-rich plasma on patterns of gene expression in a dog model of anterior cruciate ligament reconstruction. J Surg Res. 2013;180(1):80-88.
12. Pluim BM, Staal JB, Windler GE, Jayanthi N. Tennis injuries: occurrence, aetiology, and prevention. Br J Sports Med. 2006;40(5):415-423.
13. Xie X, Zhao S, Wu H, et al. Platelet-rich plasma enhances autograft revascularization and reinnervation in a dog model of anterior cruciate ligament reconstruction. J Surg Res. 2013;183(1):214-222.
14. Lopez-Vidriero E, Goulding KA, Simon DA, Sanchez M, Johnson DH. The use of platelet-rich plasma in arthroscopy and sports medicine: optimizing the healing environment. Arthroscopy. 2010;26(2):269-278.
15. Jo CH, Shin JS, Shin WH, Lee SY, Yoon KS, Shin S. Platelet-rich plasma for arthroscopic repair of medium to large rotator cuff tears: a randomized controlled trial. Am J Sports Med. 2015;43(9):2102-2110.
16. Jo CH, Shin JS, Lee YG, et al. Platelet-rich plasma for arthroscopic repair of large to massive rotator cuff tears: a randomized, single-blinded, parallel-group trial. Am J Sports Med. 2013;41(10):2240-2248.
17. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet-rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518-528.
18. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518-528.
19. Barber FA, Hrnack SA, Snyder SJ, Hapa O. Rotator cuff repair healing influenced by platelet-rich plasma construct augmentation. Arthroscopy. 2011;27(8):1029-1035.
20. Jo CH, Kim JE, Yoon KS, et al. Does platelet-rich plasma accelerate recovery after rotator cuff repair? A prospective cohort study. Am J Sports Med. 2011;39(10):2082-2090.
21. Jo CH, Kim JE, Yoon KS, Shin S. Platelet-rich plasma stimulates cell proliferation and enhances matrix gene expression and synthesis in tenocytes from human rotator cuff tendons with degenerative tears. Am J Sports Med. 2012;40(5):1035-1045.
22. Chahal J, Van Thiel GS, Mall N, et al. The role of platelet-rich plasma in arthroscopic rotator cuff repair: a systematic review with quantitative synthesis. Arthroscopy. 2012;28(11):1718-1727.
23. Mei-Dan O, Carmont MR. The role of platelet-rich plasma in rotator cuff repair. Sports Med Arthrosc Rev. 2011;19(3):244-250.
24. Dines JS, ElAttrache NS, Conway JE, Smith W, Ahmad CS. Clinical outcomes of the DANE TJ technique to treat ulnar collateral ligament insufficiency of the elbow. Am J Sports Med. 2007;35(12):2039-2044.
25. Hutchinson MR, Laprade RF, Burnett QM 2nd, Moss R, Terpstra J. Injury surveillance at the USTA boys’ tennis championships: a 6-yr study. Med Sci Sports Exerc. 1995;27(6):826-830.
26. Winge S, Jørgensen U, Nielsen A. Epidemiology of injuries in Danish championship tennis. Int J Sports Med. 1989;10(5):368-371.
27. Safran MR, Hutchinson MR, Moss R, Albrandt J. A comparison of injuries in elite boys and girls tennis players. Paper presented at: 9th Annual Meeting of the Society of Tennis Medicine and Science; March 1999; Indian Wells, CA.
28. Cain EL, Andrews JR, Dugas JR, et al. Outcome of ulnar collateral ligament reconstruction of the elbow in 1281 athletes: results in 743 athletes with minimum 2-year follow-up. Am J Sports Med. 2010;38(12):2426-2434.
29. Dines JS, Yocum LA, Frank JB, ElAttrache NS, Gambardella RA, Jobe FW. Revision surgery for failed elbow medial collateral ligament reconstruction. Am J Sports Med. 2008;36(6):1061-1065.
30. Savoie FH, Trenhaile SW, Roberts J, Field LD, Ramsey JR. Primary repair of ulnar collateral ligament injuries of the elbow in young athletes: a case series of injuries to the proximal and distal ends of the ligament. Am J Sports Med. 2008;36(6):1066-1072.
31. Gosens T, Peerbooms JC, van Laar W, Oudsten den BL. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. Am J Sports Med. 2011;39(6):1200-1208.
32. Thanasas C, Papadimitriou G, Charalambidis C, Paraskevopoulos I, Papanikolaou A. Platelet-rich plasma versus autologous whole blood for the treatment of chronic lateral elbow epicondylitis: a randomized controlled clinical trial. Am J Sports Med. 2011;39(10):2130-2134.
33. Chaudhury S, La Lama de M, Adler RS, et al. Platelet-rich plasma for the treatment of lateral epicondylitis: sonographic assessment of tendon morphology and vascularity (pilot study). Skeletal Radiol. 2013;42(1):91-97.
34. Krogh TP, Fredberg U, Stengaard-Pedersen K, Christensen R, Jensen P, Ellingsen T. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med. 2013;41(3):625-635.
35. Anz AW, Hackel JG, Nilssen EC, Andrews JR. Application of biologics in the treatment of the rotator cuff, meniscus, cartilage, and osteoarthritis. J Am Acad Orthop Surg. 2014;22(2):68-79.
1. Rettig AC, Sherrill C, Snead DS, Mendler JC, Mieling P. Nonoperative treatment of ulnar collateral ligament injuries in throwing athletes. Am J Sports Med. 2001;29(1):15-17.
2. Eygendaal D, Rahussen FT, Diercks RL. Biomechanics of the elbow joint in tennis players and relation to pathology. Br J Sports Med. 2007;41(11):820-823.
3. Bowers AL, Dines JS, Dines DM, Altchek DW. Elbow medial ulnar collateral ligament reconstruction: clinical relevance and the docking technique. J Shoulder Elbow Surg. 2010;19(2):110-117.
5. Kibler WB. Biomechanical analysis of the shoulder during tennis activities. Clin Sports Med. 1995;14(1):79-85.
5. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg. 2004;62(4):489-496.
6. Marx RE. Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant Dent. 2001;10(4):225-228.
7. Elliott B, Fleisig G, Nicholls R, Escamilia R. Technique effects on upper limb loading in the tennis serve. J Sci Med Sport. 2003;6(1):76-87.
8. Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006;34(11):1774-1778.
9. Mishra A, Woodall J Jr, Vieira A. Treatment of tendon and muscle using platelet-rich plasma. Clin Sports Med. 2009;28(1):113-125.
10. Kovacs MS. Applied physiology of tennis performance. Br J Sports Med. 2006;40(5):381-386.
11. Xie X, Wu H, Zhao S, Xie G, Huangfu X, Zhao J. The effect of platelet-rich plasma on patterns of gene expression in a dog model of anterior cruciate ligament reconstruction. J Surg Res. 2013;180(1):80-88.
12. Pluim BM, Staal JB, Windler GE, Jayanthi N. Tennis injuries: occurrence, aetiology, and prevention. Br J Sports Med. 2006;40(5):415-423.
13. Xie X, Zhao S, Wu H, et al. Platelet-rich plasma enhances autograft revascularization and reinnervation in a dog model of anterior cruciate ligament reconstruction. J Surg Res. 2013;183(1):214-222.
14. Lopez-Vidriero E, Goulding KA, Simon DA, Sanchez M, Johnson DH. The use of platelet-rich plasma in arthroscopy and sports medicine: optimizing the healing environment. Arthroscopy. 2010;26(2):269-278.
15. Jo CH, Shin JS, Shin WH, Lee SY, Yoon KS, Shin S. Platelet-rich plasma for arthroscopic repair of medium to large rotator cuff tears: a randomized controlled trial. Am J Sports Med. 2015;43(9):2102-2110.
16. Jo CH, Shin JS, Lee YG, et al. Platelet-rich plasma for arthroscopic repair of large to massive rotator cuff tears: a randomized, single-blinded, parallel-group trial. Am J Sports Med. 2013;41(10):2240-2248.
17. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet-rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518-528.
18. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518-528.
19. Barber FA, Hrnack SA, Snyder SJ, Hapa O. Rotator cuff repair healing influenced by platelet-rich plasma construct augmentation. Arthroscopy. 2011;27(8):1029-1035.
20. Jo CH, Kim JE, Yoon KS, et al. Does platelet-rich plasma accelerate recovery after rotator cuff repair? A prospective cohort study. Am J Sports Med. 2011;39(10):2082-2090.
21. Jo CH, Kim JE, Yoon KS, Shin S. Platelet-rich plasma stimulates cell proliferation and enhances matrix gene expression and synthesis in tenocytes from human rotator cuff tendons with degenerative tears. Am J Sports Med. 2012;40(5):1035-1045.
22. Chahal J, Van Thiel GS, Mall N, et al. The role of platelet-rich plasma in arthroscopic rotator cuff repair: a systematic review with quantitative synthesis. Arthroscopy. 2012;28(11):1718-1727.
23. Mei-Dan O, Carmont MR. The role of platelet-rich plasma in rotator cuff repair. Sports Med Arthrosc Rev. 2011;19(3):244-250.
24. Dines JS, ElAttrache NS, Conway JE, Smith W, Ahmad CS. Clinical outcomes of the DANE TJ technique to treat ulnar collateral ligament insufficiency of the elbow. Am J Sports Med. 2007;35(12):2039-2044.
25. Hutchinson MR, Laprade RF, Burnett QM 2nd, Moss R, Terpstra J. Injury surveillance at the USTA boys’ tennis championships: a 6-yr study. Med Sci Sports Exerc. 1995;27(6):826-830.
26. Winge S, Jørgensen U, Nielsen A. Epidemiology of injuries in Danish championship tennis. Int J Sports Med. 1989;10(5):368-371.
27. Safran MR, Hutchinson MR, Moss R, Albrandt J. A comparison of injuries in elite boys and girls tennis players. Paper presented at: 9th Annual Meeting of the Society of Tennis Medicine and Science; March 1999; Indian Wells, CA.
28. Cain EL, Andrews JR, Dugas JR, et al. Outcome of ulnar collateral ligament reconstruction of the elbow in 1281 athletes: results in 743 athletes with minimum 2-year follow-up. Am J Sports Med. 2010;38(12):2426-2434.
29. Dines JS, Yocum LA, Frank JB, ElAttrache NS, Gambardella RA, Jobe FW. Revision surgery for failed elbow medial collateral ligament reconstruction. Am J Sports Med. 2008;36(6):1061-1065.
30. Savoie FH, Trenhaile SW, Roberts J, Field LD, Ramsey JR. Primary repair of ulnar collateral ligament injuries of the elbow in young athletes: a case series of injuries to the proximal and distal ends of the ligament. Am J Sports Med. 2008;36(6):1066-1072.
31. Gosens T, Peerbooms JC, van Laar W, Oudsten den BL. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. Am J Sports Med. 2011;39(6):1200-1208.
32. Thanasas C, Papadimitriou G, Charalambidis C, Paraskevopoulos I, Papanikolaou A. Platelet-rich plasma versus autologous whole blood for the treatment of chronic lateral elbow epicondylitis: a randomized controlled clinical trial. Am J Sports Med. 2011;39(10):2130-2134.
33. Chaudhury S, La Lama de M, Adler RS, et al. Platelet-rich plasma for the treatment of lateral epicondylitis: sonographic assessment of tendon morphology and vascularity (pilot study). Skeletal Radiol. 2013;42(1):91-97.
34. Krogh TP, Fredberg U, Stengaard-Pedersen K, Christensen R, Jensen P, Ellingsen T. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med. 2013;41(3):625-635.
35. Anz AW, Hackel JG, Nilssen EC, Andrews JR. Application of biologics in the treatment of the rotator cuff, meniscus, cartilage, and osteoarthritis. J Am Acad Orthop Surg. 2014;22(2):68-79.
Acellular Dermal Matrix in Rotator Cuff Surgery
Rotator cuff repairs (RCRs) can be challenging due to poor tendon quality and the inability of tendon to heal to bone. Smoking, age over 63 years, fatty infiltration, and massive cuff tears are all factors implicated in increased failure rates.1-3 Tears >3 cm have a structural failure rate ranging from 11% to 95% in the literature.1-5 Massive tears (tears >5 cm or involving 2 or more tendons) are even more complex and have failure rates of 20% to 90%.5,6 The weakest link in the RCR construct is the suture-tendon interface, and suture pullout through the tendon is thought to be the most common method of failure.6 The purpose of this review is to examine whether literature supports the use of acellular dermal matrices (ADMs) in rotator cuff surgery.
The high rate of structural failures after RCR has led surgeons to seek means to augment repairs and new means of reconstruction for irreparable tears. Freeze dried allograft tendons have been used historically with mixed results, including reports of complete graft failures and foreign body reaction.7-10 Porcine intestinal submucosal membrane “patches” gained popularity due to off-the- shelf availability of the graft. However, these were found to have poor outcomes with early graft rejection and intense inflammatory reaction.11,12 Recently, ADMs have gained significant interest due to favorable biomechanical properties and clinical outcomes.13-19
An ADM is an allograft composed of mostly type I collagen that is processed to remove donor cells while preserving the extracellular matrix. There are several commercially available ADMs with different methods of processing and sterilization, as well as handling characteristics.20,21 In vivo studies have demonstrated that removing the cellular components allows infiltration of native cellular agents, such as fibroblasts, vascular tissue, and tenocytes, while causing minimal host inflammatory reaction.21-23 In addition, superior suture pullout strength has been demonstrated by multiple benchtop and preclinical studies.23,24 Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.
Emerging Evidence
Multiple biomechanical studies have evaluated ADMs in RC models.24-28 Barber and colleagues24 demonstrated that ADM had significantly higher loads to failure (229 N) than porcine skin (128 N), bovine skin (76 N), and porcine small intestine submucosa (32 N) (P < .001). In another study, Barber and colleagues25 subsequently demonstrated, in a cadaver RC tear model, an increase in mean failure strength in augmented repairs with ADM (325 N) compared to cadaveric controls (273 N) (P = .047).
A subsequent study by Barber and Aziz-Jacobo26 compared ADMs to a control model of allograft RC. The ADMs had significantly higher tensile modulus (P < .001) and higher suture retention measure by a single-pull destructive test of a simple vertical stitch (P < .05) than the RC allograft. The ultimate load to failure of the ADM model was higher than the RC allograft control (523±154 N vs 208±115 N); however, this difference did not reach statistical significance.26 Beitzel and colleagues27 evaluated ADM augmentation in a cadaver RC model and found a statistically significant increase in load to failure in ADM augmented repairs vs nonaugmented controls, (575.8 N vs 348.9 N, P = .025). Ely and colleagues28 also demonstrated that repairs augmented with ADM had a higher load to failure (643 N vs 551 N) and less gap formation (2.2 mm vs 2.8 mm) compared to controls, although this difference was not statistically significant.
These biomechanical studies have been translated to clinical findings. A level II, prospective, randomized controlled study by Barber and colleagues29 evaluated 42 patients with >3 cm, 2-tendon RCTs repaired arthroscopically.Twenty-two patients were randomized to single-row arthroscopic repair, and 20 patients to single-row arthroscopic repair augmented by ADM by an onlay technique (Figure 1) as described by Labbé.30 At average follow-up of 24 months, 85% of the augmented repairs were intact on magnetic resonance imaging (MRI) at follow-up, compared to 40% in the control group (P < .05). Agrawal31 retrospectively reviewed 14 patients with either RCTs >3 cm or recurrent RCT (may be <3 cm) that were arthroscopically repaired with a double-row technique with ADM augmentation. Postoperative MRI obtained at average of 16.8 months revealed 85.7% of repairs to be intact, with 14.3% having recurrent tears of <1 cm. Rotini and colleagues32 evaluated a smaller subset of 5 patients with large/massive primary cuff tears, arthroscopically repaired with double-row technique and ADM augmentation. Follow-up MRI at an average of 1 year demonstrated 3 intact repairs, 1 partial recurrence, and 1 complete recurrence. These clinical studies demonstrate that RCRs augmented with ADM have a much higher rate of structural integrity on postoperative imaging compared to what has been previously reported in the literature.1-6
Although an “off-label” indication, the use of ADM in massive RC tears has been described with good clinical results.14,17,19,33 The ADM is used to bridge the gap by suturing it to the edge of the retracted tendon and anchoring it to the tuberosity (Figures 2A-2E). Improvement in pain, function, and active range of motion can be achieved. Burkhead and colleagues14 obtained postoperative MRIs at average follow-up of 1.2 years and found only 3 of 11 repairs with evidence of re-tear, all noted to be smaller than preoperative tears. Gupta and colleagues17 obtained postoperative ultrasounds in 24 patients at average 3 years and showed 76% of tears to be fully intact, with the remaining 24% having only a partial tear, and 0% with full re-tears. Venouziou and colleagues19 evaluated 14 patients with minimum 18-month follow-up and Kokkalis and colleagues33 evaluated 21 patients with a 29-month follow-up; both described successful clinical outcomes but did not provide postoperative imaging evaluation. Multiple studies have adapted this technique to a fully arthroscopic method and have had similarly positive results clinically and with MRI.13,16,18,34,35 Bond and colleagues13 reported 16 cases with massive irreparable tears repaired arthroscopically with ADM to span the tendon gap. At an average follow-up of 26.8 months, 75% had good or excellent clinical results, and at an average of 1 year postoperatively 13 of 16 cases had an intact repair on gadolinium enhanced MRI.13 These studies suggest that ADM can be used for bridging massive irreparable RC tears with good clinical and radiographic outcomes.
Superior capsule reconstruction is a biomechanically proven concept that has been described in previous studies.36,37 In the original technique, autologous tensor fascia lata (TFL) is anchored from the glenoid margin to the greater tuberosity footprint to restore the superior stability of the glenohumeral joint, without altering the native glenohumeral contact forces.38 This concept has gained popularity in the United States, but with the use of an ADM instead of harvesting TFL (Figures 3A, 3B). However, there are no published biomechanical or clinical studies with the use of ADM in superior capsular reconstruction.
Conclusion
The use of ADM is an emerging solution for augmenting primary RCRs and the treatment of irreparable RC tears. The biomechanical and clinical studies summarized support the use of ADM in RC surgery. Further randomized studies are needed to add to the growing evidence on the use of ADMs.
1. Green A. Chronic massive rotator cuff tears: evaluation and management. J Am Acad Orthop Surg. 2003;11(5):321-331.
2. Boileau P, Brassart N, Watkinson DJ, Carles M, Hatzidakis AM, Krishnan SG. Arthroscopic repair of full-thickness tears of the supraspinatus: does the tendon really heal? J Bone Joint Surg Am. 2005;87(6):1229-1240.
3. Iannotti JP, Deutsch A, Green A, et al. Time to failure after rotator cuff repair: a prospective imaging study. J Bone Joint Surg Am. 2013;95(11):965-971.
4. Karas EH, Iannotti JP. Failed repair of the rotator cuff: evaluation and treatment of complications. Instr Course Lect. 1998;47:87-95.
5. Burkhart SS. Biomechanics of rotator cuff repair: converting the ritual to a science. Instr Course Lect. 1998;47:43-50.
6. Derwin KA, Badylak SF, Steinmann SP, Iannotti JP. Extracellular matrix scaffold devices for rotator cuff repair. J Shoulder Elbow Surg. 2010;19:467-476.
7. Neviaser JS, Neviaser RJ, Neviaser TJ. The repair of chronic massive ruptures of the rotator cuff of the shoulder by use of a freeze-dried rotator cuff. J Bone Joint Surg Am. 1978;60(5):681-684.
8. Ito J, Morioka T. Surgical treatment for large and massive tears of the rotator cuff. Int Orthop. 2003;27(4):228-231.
9. Nasca RJ. The use of freeze-dried allografts in the management of global rotator cuff tears. Clin Orthop Related Res. 1988;228:218-226.
10. Moore DR, Cain EL, Schwartz ML, Clancy WG Jr. Allograft reconstruction for massive, irreparable rotator cuff tears. Am J Sports Med. 2006;34(3):392-396.
11. Walton JR, Bowman NK, Khatib Y, Linklater J, Murrell GA. Restore orthobiologic implant: not recommended for augmentation of rotator cuff repairs. J Bone Joint Surg Am. 2007;89(4):786-791.
12. Iannotti JP, Codsi MJ, Kwon YW, Derwin K, Ciccone J, Brems JJ. Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88(6):1238-1244.
13. Bond JL, Dopirak RM, Higgins J, Burns J, Snyder SJ. Arthroscopic replacement of massive, irreparable rotator cuff tears using a GraftJacket allograft: technique and preliminary results. Arthroscopy. 2008;24(4):403-409.
14. Burkhead WZ Jr, Schiffern SC, Krishnan SG. Use of Graft Jacket as an augmentation for massive rotator cuff tears. Semin Arthoplasty. 2007;18(1):11-18.
15. Dehler T, Pennings AL, ElMaraghy AW. Dermal allograft reconstruction of a chronic pectoralis major tear. J Shoulder Elbow Surg. 2013;22(10):e18-e22.
16. Dopirak R, Bond JL, Snyder SJ. Arthroscopic total rotator cuff replacement with an acellular dermal allograft matrix. Int J Shoulder Surg. 2007;1(1):7-15.
17. Gupta AK, Hug K, Berkoff DJ, et al. Dermal tissue allograft for the repair of massive irreparable rotator cuff tears. Am J Sports Med. 2012;40(1):141-147.
18. Modi A, Singh HP, Pandey R, Armstrong A. Management of irreparable rotator cuff tears with the GraftJacket allograft as an interpositional graft. Shoulder Elbow. 2013;5(3):188-194.
19. Venouziou AI, Kokkalis ZT, Sotereanos DG. Human dermal allograft interposition for the reconstruction of massive irreparable rotator cuff tears. Am J Orthop. 2013;42(2):63-70.
20. Acevedo DC, Shore B, Mirzayan R. Orthopedic applications of acellular human dermal allograft for shoulder and elbow surgery. Orthop Clin North Am. 2015;46(3):377-388.
21. Beniker D, McQuillan D, Livesey S, et al. The use of acellular dermal matrix as a scaffold for periosteum replacement. Orthopedics. 2003;26(5 Suppl):s591-s596.
22. Smith RD, Carr A, Dakin SG, Snelling SJ, Yapp C, Hakimi O. The response of tenocytes to commercial scaffolds used for rotator cuff repair. Eur Cell Mater. 2016;31:107-118.
23. Adams JE, Zobitz ME, Reach JS Jr, An KN, Steinmann SP. Rotator cuff repair using an acellular dermal matrix graft: an in vivo study in a canine model. Arthroscopy. 2006;22(7):700-709.
24. Barber FA, Herbert MA, Coons DA. Tendon augmentation grafts: biomechanical failure loads and failure patterns. Arthroscopy. 2006;22(5):534-538.
25. Barber FA, Herbert MA, Boothby MH. Ultimate tensile failure loads of a human dermal allograft rotator cuff augmentation. Arthroscopy. 2008;24(1):20-24.
26. Barber AF, Aziz-Jacobo J. Biomechanical testing of commercially available soft-tissue augmentation materials. Arthroscopy. 2009;25(11):1233-1239.
27. Beitzel K, Chowaniec DM, McCarthy MB, et al. Stability of double-row rotator cuff repair is not adversely affected by scaffold interposition between tendon and bone. Am J Sports Med. 2012;40(5):1148-1154.
28. Ely EE, Figueroa NM, Gilot GJ. Biomechanical analysis of rotator cuff repairs with extraccellular matrix graft augmentation. Orthopedics. 2014;37(9):608-614.
29. Barber AF, Burns JP, Deutsch A, Labbé MR, Litchfield RB. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. 2012;28(1):8-15.
30. Labbé MR. Arthroscopic technique for patch augmentation of rotator cuff repairs. Arthroscopy. 2006;22(1):1136.e1-e6.
31. Agrawal V. Healing rates for challenging rotator cuff tears utilizing an acellular human dermal reinforcement graft. Int J Shoulder Surg. 2012;6(2):36-44.
32. Rotini R, Marinelli A, Guerra E, et al. Human dermal matrix scaffold augmentation for large and massive rotator cuff repairs: preliminary clinical and MRI results at 1-year follow-up. Musculoskelet Surg. 2011;95 Suppl 1:S13-S23.
33. Kokkalis ZT, Mavrogenis AF, Scarlat M, et al. Human dermal allograft for massive rotator cuff tears. Orthopedics. 2014;37(12):e1108-e1116.
34. Wong I, Burns J, Snyder S. Arthroscopic GraftJacket repair of rotator cuff tears. J Shoulder Elbow Surg. 2010;19(2 Suppl):104-109.
35. Snyder SJ, Bond JL. Technique for arthroscopic replacement of severely damaged rotator cuff using “GraftJacket” allograft. Oper Tech Sports Med. 2007;15(2):86-94.
36. Mihata T, McGarry MH, Pirolo JM, Kinoshita M, Lee TQ. Superior capsule reconstruction to restore superior stability in irreparable rotator cuff tears: a biomechanical cadaveric study. Am J Sports Med. 2012;40(10):2248-2255.
37. Mihata T, McGarry MH, Kahn T, Goldberg I, Neo M, Lee TQ. Biomechanical role of capsular continuity in superior capsule reconstruction for irreparable tears of the supraspinatus tendon. Am J Sports Med. 2016;44(6):1423-1430.
38. Mihata T, Lee TQ, Watanabe C, et al. Clinical results of arthroscopic superior capsule reconstruction for irreparable rotator cuff tears. Arthroscopy. 2013;29(3):459-470.
Rotator cuff repairs (RCRs) can be challenging due to poor tendon quality and the inability of tendon to heal to bone. Smoking, age over 63 years, fatty infiltration, and massive cuff tears are all factors implicated in increased failure rates.1-3 Tears >3 cm have a structural failure rate ranging from 11% to 95% in the literature.1-5 Massive tears (tears >5 cm or involving 2 or more tendons) are even more complex and have failure rates of 20% to 90%.5,6 The weakest link in the RCR construct is the suture-tendon interface, and suture pullout through the tendon is thought to be the most common method of failure.6 The purpose of this review is to examine whether literature supports the use of acellular dermal matrices (ADMs) in rotator cuff surgery.
The high rate of structural failures after RCR has led surgeons to seek means to augment repairs and new means of reconstruction for irreparable tears. Freeze dried allograft tendons have been used historically with mixed results, including reports of complete graft failures and foreign body reaction.7-10 Porcine intestinal submucosal membrane “patches” gained popularity due to off-the- shelf availability of the graft. However, these were found to have poor outcomes with early graft rejection and intense inflammatory reaction.11,12 Recently, ADMs have gained significant interest due to favorable biomechanical properties and clinical outcomes.13-19
An ADM is an allograft composed of mostly type I collagen that is processed to remove donor cells while preserving the extracellular matrix. There are several commercially available ADMs with different methods of processing and sterilization, as well as handling characteristics.20,21 In vivo studies have demonstrated that removing the cellular components allows infiltration of native cellular agents, such as fibroblasts, vascular tissue, and tenocytes, while causing minimal host inflammatory reaction.21-23 In addition, superior suture pullout strength has been demonstrated by multiple benchtop and preclinical studies.23,24 Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.
Emerging Evidence
Multiple biomechanical studies have evaluated ADMs in RC models.24-28 Barber and colleagues24 demonstrated that ADM had significantly higher loads to failure (229 N) than porcine skin (128 N), bovine skin (76 N), and porcine small intestine submucosa (32 N) (P < .001). In another study, Barber and colleagues25 subsequently demonstrated, in a cadaver RC tear model, an increase in mean failure strength in augmented repairs with ADM (325 N) compared to cadaveric controls (273 N) (P = .047).
A subsequent study by Barber and Aziz-Jacobo26 compared ADMs to a control model of allograft RC. The ADMs had significantly higher tensile modulus (P < .001) and higher suture retention measure by a single-pull destructive test of a simple vertical stitch (P < .05) than the RC allograft. The ultimate load to failure of the ADM model was higher than the RC allograft control (523±154 N vs 208±115 N); however, this difference did not reach statistical significance.26 Beitzel and colleagues27 evaluated ADM augmentation in a cadaver RC model and found a statistically significant increase in load to failure in ADM augmented repairs vs nonaugmented controls, (575.8 N vs 348.9 N, P = .025). Ely and colleagues28 also demonstrated that repairs augmented with ADM had a higher load to failure (643 N vs 551 N) and less gap formation (2.2 mm vs 2.8 mm) compared to controls, although this difference was not statistically significant.
These biomechanical studies have been translated to clinical findings. A level II, prospective, randomized controlled study by Barber and colleagues29 evaluated 42 patients with >3 cm, 2-tendon RCTs repaired arthroscopically.Twenty-two patients were randomized to single-row arthroscopic repair, and 20 patients to single-row arthroscopic repair augmented by ADM by an onlay technique (Figure 1) as described by Labbé.30 At average follow-up of 24 months, 85% of the augmented repairs were intact on magnetic resonance imaging (MRI) at follow-up, compared to 40% in the control group (P < .05). Agrawal31 retrospectively reviewed 14 patients with either RCTs >3 cm or recurrent RCT (may be <3 cm) that were arthroscopically repaired with a double-row technique with ADM augmentation. Postoperative MRI obtained at average of 16.8 months revealed 85.7% of repairs to be intact, with 14.3% having recurrent tears of <1 cm. Rotini and colleagues32 evaluated a smaller subset of 5 patients with large/massive primary cuff tears, arthroscopically repaired with double-row technique and ADM augmentation. Follow-up MRI at an average of 1 year demonstrated 3 intact repairs, 1 partial recurrence, and 1 complete recurrence. These clinical studies demonstrate that RCRs augmented with ADM have a much higher rate of structural integrity on postoperative imaging compared to what has been previously reported in the literature.1-6
Although an “off-label” indication, the use of ADM in massive RC tears has been described with good clinical results.14,17,19,33 The ADM is used to bridge the gap by suturing it to the edge of the retracted tendon and anchoring it to the tuberosity (Figures 2A-2E). Improvement in pain, function, and active range of motion can be achieved. Burkhead and colleagues14 obtained postoperative MRIs at average follow-up of 1.2 years and found only 3 of 11 repairs with evidence of re-tear, all noted to be smaller than preoperative tears. Gupta and colleagues17 obtained postoperative ultrasounds in 24 patients at average 3 years and showed 76% of tears to be fully intact, with the remaining 24% having only a partial tear, and 0% with full re-tears. Venouziou and colleagues19 evaluated 14 patients with minimum 18-month follow-up and Kokkalis and colleagues33 evaluated 21 patients with a 29-month follow-up; both described successful clinical outcomes but did not provide postoperative imaging evaluation. Multiple studies have adapted this technique to a fully arthroscopic method and have had similarly positive results clinically and with MRI.13,16,18,34,35 Bond and colleagues13 reported 16 cases with massive irreparable tears repaired arthroscopically with ADM to span the tendon gap. At an average follow-up of 26.8 months, 75% had good or excellent clinical results, and at an average of 1 year postoperatively 13 of 16 cases had an intact repair on gadolinium enhanced MRI.13 These studies suggest that ADM can be used for bridging massive irreparable RC tears with good clinical and radiographic outcomes.
Superior capsule reconstruction is a biomechanically proven concept that has been described in previous studies.36,37 In the original technique, autologous tensor fascia lata (TFL) is anchored from the glenoid margin to the greater tuberosity footprint to restore the superior stability of the glenohumeral joint, without altering the native glenohumeral contact forces.38 This concept has gained popularity in the United States, but with the use of an ADM instead of harvesting TFL (Figures 3A, 3B). However, there are no published biomechanical or clinical studies with the use of ADM in superior capsular reconstruction.
Conclusion
The use of ADM is an emerging solution for augmenting primary RCRs and the treatment of irreparable RC tears. The biomechanical and clinical studies summarized support the use of ADM in RC surgery. Further randomized studies are needed to add to the growing evidence on the use of ADMs.
Rotator cuff repairs (RCRs) can be challenging due to poor tendon quality and the inability of tendon to heal to bone. Smoking, age over 63 years, fatty infiltration, and massive cuff tears are all factors implicated in increased failure rates.1-3 Tears >3 cm have a structural failure rate ranging from 11% to 95% in the literature.1-5 Massive tears (tears >5 cm or involving 2 or more tendons) are even more complex and have failure rates of 20% to 90%.5,6 The weakest link in the RCR construct is the suture-tendon interface, and suture pullout through the tendon is thought to be the most common method of failure.6 The purpose of this review is to examine whether literature supports the use of acellular dermal matrices (ADMs) in rotator cuff surgery.
The high rate of structural failures after RCR has led surgeons to seek means to augment repairs and new means of reconstruction for irreparable tears. Freeze dried allograft tendons have been used historically with mixed results, including reports of complete graft failures and foreign body reaction.7-10 Porcine intestinal submucosal membrane “patches” gained popularity due to off-the- shelf availability of the graft. However, these were found to have poor outcomes with early graft rejection and intense inflammatory reaction.11,12 Recently, ADMs have gained significant interest due to favorable biomechanical properties and clinical outcomes.13-19
An ADM is an allograft composed of mostly type I collagen that is processed to remove donor cells while preserving the extracellular matrix. There are several commercially available ADMs with different methods of processing and sterilization, as well as handling characteristics.20,21 In vivo studies have demonstrated that removing the cellular components allows infiltration of native cellular agents, such as fibroblasts, vascular tissue, and tenocytes, while causing minimal host inflammatory reaction.21-23 In addition, superior suture pullout strength has been demonstrated by multiple benchtop and preclinical studies.23,24 Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.
Emerging Evidence
Multiple biomechanical studies have evaluated ADMs in RC models.24-28 Barber and colleagues24 demonstrated that ADM had significantly higher loads to failure (229 N) than porcine skin (128 N), bovine skin (76 N), and porcine small intestine submucosa (32 N) (P < .001). In another study, Barber and colleagues25 subsequently demonstrated, in a cadaver RC tear model, an increase in mean failure strength in augmented repairs with ADM (325 N) compared to cadaveric controls (273 N) (P = .047).
A subsequent study by Barber and Aziz-Jacobo26 compared ADMs to a control model of allograft RC. The ADMs had significantly higher tensile modulus (P < .001) and higher suture retention measure by a single-pull destructive test of a simple vertical stitch (P < .05) than the RC allograft. The ultimate load to failure of the ADM model was higher than the RC allograft control (523±154 N vs 208±115 N); however, this difference did not reach statistical significance.26 Beitzel and colleagues27 evaluated ADM augmentation in a cadaver RC model and found a statistically significant increase in load to failure in ADM augmented repairs vs nonaugmented controls, (575.8 N vs 348.9 N, P = .025). Ely and colleagues28 also demonstrated that repairs augmented with ADM had a higher load to failure (643 N vs 551 N) and less gap formation (2.2 mm vs 2.8 mm) compared to controls, although this difference was not statistically significant.
These biomechanical studies have been translated to clinical findings. A level II, prospective, randomized controlled study by Barber and colleagues29 evaluated 42 patients with >3 cm, 2-tendon RCTs repaired arthroscopically.Twenty-two patients were randomized to single-row arthroscopic repair, and 20 patients to single-row arthroscopic repair augmented by ADM by an onlay technique (Figure 1) as described by Labbé.30 At average follow-up of 24 months, 85% of the augmented repairs were intact on magnetic resonance imaging (MRI) at follow-up, compared to 40% in the control group (P < .05). Agrawal31 retrospectively reviewed 14 patients with either RCTs >3 cm or recurrent RCT (may be <3 cm) that were arthroscopically repaired with a double-row technique with ADM augmentation. Postoperative MRI obtained at average of 16.8 months revealed 85.7% of repairs to be intact, with 14.3% having recurrent tears of <1 cm. Rotini and colleagues32 evaluated a smaller subset of 5 patients with large/massive primary cuff tears, arthroscopically repaired with double-row technique and ADM augmentation. Follow-up MRI at an average of 1 year demonstrated 3 intact repairs, 1 partial recurrence, and 1 complete recurrence. These clinical studies demonstrate that RCRs augmented with ADM have a much higher rate of structural integrity on postoperative imaging compared to what has been previously reported in the literature.1-6
Although an “off-label” indication, the use of ADM in massive RC tears has been described with good clinical results.14,17,19,33 The ADM is used to bridge the gap by suturing it to the edge of the retracted tendon and anchoring it to the tuberosity (Figures 2A-2E). Improvement in pain, function, and active range of motion can be achieved. Burkhead and colleagues14 obtained postoperative MRIs at average follow-up of 1.2 years and found only 3 of 11 repairs with evidence of re-tear, all noted to be smaller than preoperative tears. Gupta and colleagues17 obtained postoperative ultrasounds in 24 patients at average 3 years and showed 76% of tears to be fully intact, with the remaining 24% having only a partial tear, and 0% with full re-tears. Venouziou and colleagues19 evaluated 14 patients with minimum 18-month follow-up and Kokkalis and colleagues33 evaluated 21 patients with a 29-month follow-up; both described successful clinical outcomes but did not provide postoperative imaging evaluation. Multiple studies have adapted this technique to a fully arthroscopic method and have had similarly positive results clinically and with MRI.13,16,18,34,35 Bond and colleagues13 reported 16 cases with massive irreparable tears repaired arthroscopically with ADM to span the tendon gap. At an average follow-up of 26.8 months, 75% had good or excellent clinical results, and at an average of 1 year postoperatively 13 of 16 cases had an intact repair on gadolinium enhanced MRI.13 These studies suggest that ADM can be used for bridging massive irreparable RC tears with good clinical and radiographic outcomes.
Superior capsule reconstruction is a biomechanically proven concept that has been described in previous studies.36,37 In the original technique, autologous tensor fascia lata (TFL) is anchored from the glenoid margin to the greater tuberosity footprint to restore the superior stability of the glenohumeral joint, without altering the native glenohumeral contact forces.38 This concept has gained popularity in the United States, but with the use of an ADM instead of harvesting TFL (Figures 3A, 3B). However, there are no published biomechanical or clinical studies with the use of ADM in superior capsular reconstruction.
Conclusion
The use of ADM is an emerging solution for augmenting primary RCRs and the treatment of irreparable RC tears. The biomechanical and clinical studies summarized support the use of ADM in RC surgery. Further randomized studies are needed to add to the growing evidence on the use of ADMs.
1. Green A. Chronic massive rotator cuff tears: evaluation and management. J Am Acad Orthop Surg. 2003;11(5):321-331.
2. Boileau P, Brassart N, Watkinson DJ, Carles M, Hatzidakis AM, Krishnan SG. Arthroscopic repair of full-thickness tears of the supraspinatus: does the tendon really heal? J Bone Joint Surg Am. 2005;87(6):1229-1240.
3. Iannotti JP, Deutsch A, Green A, et al. Time to failure after rotator cuff repair: a prospective imaging study. J Bone Joint Surg Am. 2013;95(11):965-971.
4. Karas EH, Iannotti JP. Failed repair of the rotator cuff: evaluation and treatment of complications. Instr Course Lect. 1998;47:87-95.
5. Burkhart SS. Biomechanics of rotator cuff repair: converting the ritual to a science. Instr Course Lect. 1998;47:43-50.
6. Derwin KA, Badylak SF, Steinmann SP, Iannotti JP. Extracellular matrix scaffold devices for rotator cuff repair. J Shoulder Elbow Surg. 2010;19:467-476.
7. Neviaser JS, Neviaser RJ, Neviaser TJ. The repair of chronic massive ruptures of the rotator cuff of the shoulder by use of a freeze-dried rotator cuff. J Bone Joint Surg Am. 1978;60(5):681-684.
8. Ito J, Morioka T. Surgical treatment for large and massive tears of the rotator cuff. Int Orthop. 2003;27(4):228-231.
9. Nasca RJ. The use of freeze-dried allografts in the management of global rotator cuff tears. Clin Orthop Related Res. 1988;228:218-226.
10. Moore DR, Cain EL, Schwartz ML, Clancy WG Jr. Allograft reconstruction for massive, irreparable rotator cuff tears. Am J Sports Med. 2006;34(3):392-396.
11. Walton JR, Bowman NK, Khatib Y, Linklater J, Murrell GA. Restore orthobiologic implant: not recommended for augmentation of rotator cuff repairs. J Bone Joint Surg Am. 2007;89(4):786-791.
12. Iannotti JP, Codsi MJ, Kwon YW, Derwin K, Ciccone J, Brems JJ. Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88(6):1238-1244.
13. Bond JL, Dopirak RM, Higgins J, Burns J, Snyder SJ. Arthroscopic replacement of massive, irreparable rotator cuff tears using a GraftJacket allograft: technique and preliminary results. Arthroscopy. 2008;24(4):403-409.
14. Burkhead WZ Jr, Schiffern SC, Krishnan SG. Use of Graft Jacket as an augmentation for massive rotator cuff tears. Semin Arthoplasty. 2007;18(1):11-18.
15. Dehler T, Pennings AL, ElMaraghy AW. Dermal allograft reconstruction of a chronic pectoralis major tear. J Shoulder Elbow Surg. 2013;22(10):e18-e22.
16. Dopirak R, Bond JL, Snyder SJ. Arthroscopic total rotator cuff replacement with an acellular dermal allograft matrix. Int J Shoulder Surg. 2007;1(1):7-15.
17. Gupta AK, Hug K, Berkoff DJ, et al. Dermal tissue allograft for the repair of massive irreparable rotator cuff tears. Am J Sports Med. 2012;40(1):141-147.
18. Modi A, Singh HP, Pandey R, Armstrong A. Management of irreparable rotator cuff tears with the GraftJacket allograft as an interpositional graft. Shoulder Elbow. 2013;5(3):188-194.
19. Venouziou AI, Kokkalis ZT, Sotereanos DG. Human dermal allograft interposition for the reconstruction of massive irreparable rotator cuff tears. Am J Orthop. 2013;42(2):63-70.
20. Acevedo DC, Shore B, Mirzayan R. Orthopedic applications of acellular human dermal allograft for shoulder and elbow surgery. Orthop Clin North Am. 2015;46(3):377-388.
21. Beniker D, McQuillan D, Livesey S, et al. The use of acellular dermal matrix as a scaffold for periosteum replacement. Orthopedics. 2003;26(5 Suppl):s591-s596.
22. Smith RD, Carr A, Dakin SG, Snelling SJ, Yapp C, Hakimi O. The response of tenocytes to commercial scaffolds used for rotator cuff repair. Eur Cell Mater. 2016;31:107-118.
23. Adams JE, Zobitz ME, Reach JS Jr, An KN, Steinmann SP. Rotator cuff repair using an acellular dermal matrix graft: an in vivo study in a canine model. Arthroscopy. 2006;22(7):700-709.
24. Barber FA, Herbert MA, Coons DA. Tendon augmentation grafts: biomechanical failure loads and failure patterns. Arthroscopy. 2006;22(5):534-538.
25. Barber FA, Herbert MA, Boothby MH. Ultimate tensile failure loads of a human dermal allograft rotator cuff augmentation. Arthroscopy. 2008;24(1):20-24.
26. Barber AF, Aziz-Jacobo J. Biomechanical testing of commercially available soft-tissue augmentation materials. Arthroscopy. 2009;25(11):1233-1239.
27. Beitzel K, Chowaniec DM, McCarthy MB, et al. Stability of double-row rotator cuff repair is not adversely affected by scaffold interposition between tendon and bone. Am J Sports Med. 2012;40(5):1148-1154.
28. Ely EE, Figueroa NM, Gilot GJ. Biomechanical analysis of rotator cuff repairs with extraccellular matrix graft augmentation. Orthopedics. 2014;37(9):608-614.
29. Barber AF, Burns JP, Deutsch A, Labbé MR, Litchfield RB. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. 2012;28(1):8-15.
30. Labbé MR. Arthroscopic technique for patch augmentation of rotator cuff repairs. Arthroscopy. 2006;22(1):1136.e1-e6.
31. Agrawal V. Healing rates for challenging rotator cuff tears utilizing an acellular human dermal reinforcement graft. Int J Shoulder Surg. 2012;6(2):36-44.
32. Rotini R, Marinelli A, Guerra E, et al. Human dermal matrix scaffold augmentation for large and massive rotator cuff repairs: preliminary clinical and MRI results at 1-year follow-up. Musculoskelet Surg. 2011;95 Suppl 1:S13-S23.
33. Kokkalis ZT, Mavrogenis AF, Scarlat M, et al. Human dermal allograft for massive rotator cuff tears. Orthopedics. 2014;37(12):e1108-e1116.
34. Wong I, Burns J, Snyder S. Arthroscopic GraftJacket repair of rotator cuff tears. J Shoulder Elbow Surg. 2010;19(2 Suppl):104-109.
35. Snyder SJ, Bond JL. Technique for arthroscopic replacement of severely damaged rotator cuff using “GraftJacket” allograft. Oper Tech Sports Med. 2007;15(2):86-94.
36. Mihata T, McGarry MH, Pirolo JM, Kinoshita M, Lee TQ. Superior capsule reconstruction to restore superior stability in irreparable rotator cuff tears: a biomechanical cadaveric study. Am J Sports Med. 2012;40(10):2248-2255.
37. Mihata T, McGarry MH, Kahn T, Goldberg I, Neo M, Lee TQ. Biomechanical role of capsular continuity in superior capsule reconstruction for irreparable tears of the supraspinatus tendon. Am J Sports Med. 2016;44(6):1423-1430.
38. Mihata T, Lee TQ, Watanabe C, et al. Clinical results of arthroscopic superior capsule reconstruction for irreparable rotator cuff tears. Arthroscopy. 2013;29(3):459-470.
1. Green A. Chronic massive rotator cuff tears: evaluation and management. J Am Acad Orthop Surg. 2003;11(5):321-331.
2. Boileau P, Brassart N, Watkinson DJ, Carles M, Hatzidakis AM, Krishnan SG. Arthroscopic repair of full-thickness tears of the supraspinatus: does the tendon really heal? J Bone Joint Surg Am. 2005;87(6):1229-1240.
3. Iannotti JP, Deutsch A, Green A, et al. Time to failure after rotator cuff repair: a prospective imaging study. J Bone Joint Surg Am. 2013;95(11):965-971.
4. Karas EH, Iannotti JP. Failed repair of the rotator cuff: evaluation and treatment of complications. Instr Course Lect. 1998;47:87-95.
5. Burkhart SS. Biomechanics of rotator cuff repair: converting the ritual to a science. Instr Course Lect. 1998;47:43-50.
6. Derwin KA, Badylak SF, Steinmann SP, Iannotti JP. Extracellular matrix scaffold devices for rotator cuff repair. J Shoulder Elbow Surg. 2010;19:467-476.
7. Neviaser JS, Neviaser RJ, Neviaser TJ. The repair of chronic massive ruptures of the rotator cuff of the shoulder by use of a freeze-dried rotator cuff. J Bone Joint Surg Am. 1978;60(5):681-684.
8. Ito J, Morioka T. Surgical treatment for large and massive tears of the rotator cuff. Int Orthop. 2003;27(4):228-231.
9. Nasca RJ. The use of freeze-dried allografts in the management of global rotator cuff tears. Clin Orthop Related Res. 1988;228:218-226.
10. Moore DR, Cain EL, Schwartz ML, Clancy WG Jr. Allograft reconstruction for massive, irreparable rotator cuff tears. Am J Sports Med. 2006;34(3):392-396.
11. Walton JR, Bowman NK, Khatib Y, Linklater J, Murrell GA. Restore orthobiologic implant: not recommended for augmentation of rotator cuff repairs. J Bone Joint Surg Am. 2007;89(4):786-791.
12. Iannotti JP, Codsi MJ, Kwon YW, Derwin K, Ciccone J, Brems JJ. Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88(6):1238-1244.
13. Bond JL, Dopirak RM, Higgins J, Burns J, Snyder SJ. Arthroscopic replacement of massive, irreparable rotator cuff tears using a GraftJacket allograft: technique and preliminary results. Arthroscopy. 2008;24(4):403-409.
14. Burkhead WZ Jr, Schiffern SC, Krishnan SG. Use of Graft Jacket as an augmentation for massive rotator cuff tears. Semin Arthoplasty. 2007;18(1):11-18.
15. Dehler T, Pennings AL, ElMaraghy AW. Dermal allograft reconstruction of a chronic pectoralis major tear. J Shoulder Elbow Surg. 2013;22(10):e18-e22.
16. Dopirak R, Bond JL, Snyder SJ. Arthroscopic total rotator cuff replacement with an acellular dermal allograft matrix. Int J Shoulder Surg. 2007;1(1):7-15.
17. Gupta AK, Hug K, Berkoff DJ, et al. Dermal tissue allograft for the repair of massive irreparable rotator cuff tears. Am J Sports Med. 2012;40(1):141-147.
18. Modi A, Singh HP, Pandey R, Armstrong A. Management of irreparable rotator cuff tears with the GraftJacket allograft as an interpositional graft. Shoulder Elbow. 2013;5(3):188-194.
19. Venouziou AI, Kokkalis ZT, Sotereanos DG. Human dermal allograft interposition for the reconstruction of massive irreparable rotator cuff tears. Am J Orthop. 2013;42(2):63-70.
20. Acevedo DC, Shore B, Mirzayan R. Orthopedic applications of acellular human dermal allograft for shoulder and elbow surgery. Orthop Clin North Am. 2015;46(3):377-388.
21. Beniker D, McQuillan D, Livesey S, et al. The use of acellular dermal matrix as a scaffold for periosteum replacement. Orthopedics. 2003;26(5 Suppl):s591-s596.
22. Smith RD, Carr A, Dakin SG, Snelling SJ, Yapp C, Hakimi O. The response of tenocytes to commercial scaffolds used for rotator cuff repair. Eur Cell Mater. 2016;31:107-118.
23. Adams JE, Zobitz ME, Reach JS Jr, An KN, Steinmann SP. Rotator cuff repair using an acellular dermal matrix graft: an in vivo study in a canine model. Arthroscopy. 2006;22(7):700-709.
24. Barber FA, Herbert MA, Coons DA. Tendon augmentation grafts: biomechanical failure loads and failure patterns. Arthroscopy. 2006;22(5):534-538.
25. Barber FA, Herbert MA, Boothby MH. Ultimate tensile failure loads of a human dermal allograft rotator cuff augmentation. Arthroscopy. 2008;24(1):20-24.
26. Barber AF, Aziz-Jacobo J. Biomechanical testing of commercially available soft-tissue augmentation materials. Arthroscopy. 2009;25(11):1233-1239.
27. Beitzel K, Chowaniec DM, McCarthy MB, et al. Stability of double-row rotator cuff repair is not adversely affected by scaffold interposition between tendon and bone. Am J Sports Med. 2012;40(5):1148-1154.
28. Ely EE, Figueroa NM, Gilot GJ. Biomechanical analysis of rotator cuff repairs with extraccellular matrix graft augmentation. Orthopedics. 2014;37(9):608-614.
29. Barber AF, Burns JP, Deutsch A, Labbé MR, Litchfield RB. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy. 2012;28(1):8-15.
30. Labbé MR. Arthroscopic technique for patch augmentation of rotator cuff repairs. Arthroscopy. 2006;22(1):1136.e1-e6.
31. Agrawal V. Healing rates for challenging rotator cuff tears utilizing an acellular human dermal reinforcement graft. Int J Shoulder Surg. 2012;6(2):36-44.
32. Rotini R, Marinelli A, Guerra E, et al. Human dermal matrix scaffold augmentation for large and massive rotator cuff repairs: preliminary clinical and MRI results at 1-year follow-up. Musculoskelet Surg. 2011;95 Suppl 1:S13-S23.
33. Kokkalis ZT, Mavrogenis AF, Scarlat M, et al. Human dermal allograft for massive rotator cuff tears. Orthopedics. 2014;37(12):e1108-e1116.
34. Wong I, Burns J, Snyder S. Arthroscopic GraftJacket repair of rotator cuff tears. J Shoulder Elbow Surg. 2010;19(2 Suppl):104-109.
35. Snyder SJ, Bond JL. Technique for arthroscopic replacement of severely damaged rotator cuff using “GraftJacket” allograft. Oper Tech Sports Med. 2007;15(2):86-94.
36. Mihata T, McGarry MH, Pirolo JM, Kinoshita M, Lee TQ. Superior capsule reconstruction to restore superior stability in irreparable rotator cuff tears: a biomechanical cadaveric study. Am J Sports Med. 2012;40(10):2248-2255.
37. Mihata T, McGarry MH, Kahn T, Goldberg I, Neo M, Lee TQ. Biomechanical role of capsular continuity in superior capsule reconstruction for irreparable tears of the supraspinatus tendon. Am J Sports Med. 2016;44(6):1423-1430.
38. Mihata T, Lee TQ, Watanabe C, et al. Clinical results of arthroscopic superior capsule reconstruction for irreparable rotator cuff tears. Arthroscopy. 2013;29(3):459-470.
Platelet-Rich Plasma (PRP) in Orthopedic Sports Medicine
Platelet-rich plasma (PRP) is a refined product of autologous blood with a platelet concentration greater than that of whole blood. It is prepared via plasmapheresis utilizing a 2-stage centrifugation process and more than 40 commercially available systems are marketed to concentrate whole blood to PRP.1 It is rich in biologic factors (growth factors, cytokines, proteins, cellular components) essential to the body’s response to injury. For this reason, it was first used in oromaxillofacial surgery in the 1950s, but its effects on the musculoskeletal system have yet to be clearly elucidated.2 However, this lack of clarity has not deterred its widespread use among orthopedic surgeons. In this review, we aim to delineate the current understanding of PRP and its proven effectiveness in the treatment of rotator cuff tears, knee osteoarthritis, ulnar collateral ligament (UCL) tears, lateral epicondylitis, hamstring injuries, and Achilles tendinopathy.
Rotator Cuff Tears
Rotator cuff tears are one of the most common etiologies for shoulder pain and disability. The incidence continues to increase with the active aging population.3 Rotator cuff tears treated with arthroscopic repair have exhibited satisfactory pain relief and functional outcomes.4-7 Despite advances in fixation techniques, the quality and speed of tendon-to-bone healing remains unpredictable, with repaired tendons exhibiting inferior mechanical properties that are susceptible to re-tear.8-10
Numerous studies have investigated PRP application during arthroscopic rotator cuff repair (RCR) in an attempt to enhance and accelerate the repair process.11-15 However, wide variability exists among protocols of how and when PRP is utilized to augment the repair. Warth and colleagues16 performed a meta-analysis of 11 Level I/II studies evaluating RCR with PRP augmentation. With regards to clinical outcome scores, they found no significant difference in pre- and postoperative American Shoulder and Elbow Surgeons (ASES), Constant, Disability of the Arm, Shoulder and Hand (DASH), or visual analog scale (VAS) pain scores between those patients with or without PRP augmentation. However, they did note a significant increase in Constant scores when PRP was delivered to the tendon-bone interface rather than over the surface of the repair site. There was no significant difference in structural outcomes (evaluated by magnetic resonance imaging [MRI] re-tear rates) between those RCRs with and without PRP augmentation, except in those tears >3 cm in anterior-posterior length using double-row technique, with the PRP group exhibiting a significantly decreased re-tear rate (25.9% vs 57.1%).16 Zhao and colleagues17 reported similar results in a meta-analysis of 8 randomized controlled trials, exhibiting no significant differences in clinical outcome scores or re-tear rates after RCR with and without PRP augmentation. Overall, most studies have failed to demonstrate a significant benefit with regards to re-tear rates or shoulder-specific outcomes with the addition of PRP during arthroscopic RCR.
Knee Osteoarthritis
Osteoarthritis is the most common musculoskeletal disorder, with an estimated prevalence of 10% of the world’s population age 60 years and older.18 The knee is commonly symptomatic, resulting in pain, disability, and significant healthcare costs. Novel biologic, nonoperative therapies, including intra-articular viscosupplementation and PRP injections, have been proposed to treat the early stages of osteoarthritis to provide symptomatic relief and delay surgical intervention.
A multitude of studies have been performed investigating the effects of PRP on knee osteoarthritis, revealing mixed results.19-22 Campbell and colleagues23 published a 2015 systematic review of 3 overlapping meta-analyses comparing the outcomes of intra-articular injection of PRP vs control (hyaluronic acid [HA] or placebo) in 3278 knees. They reported a significant improvement in patient outcome scores for the PRP group when compared to control from 2 to 12 months after injection, but due to significant differences within the included studies, the ideal number of injections or time intervals between injections remains unclear. Meheux and colleagues24 reported a 2016 systematic review including 6 studies (817 knees) comparing PRP and HA injections. They demonstrated significantly better improvements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores with PRP vs HA injections at 3 and 12 months postinjection. Similarly, Smith25 conducted a Food and Drug Administration-sanctioned, randomized, double-blind, placebo-controlled clinical trial investigating the effects of intra-articular leukocyte-poor autologous conditioned plasma (ACP) in 30 patients. He reported an improvement in the ACP treatment group WOMAC scores by 78% compared to 7% improvement in the placebo group after 12 months. Despite the heterogeneity amongst studies, the majority of published data suggests better symptomatic relief in patients with early knee degenerative changes, and use of PRP may be considered in this population.
Ulnar Collateral Ligament Injuries
The anterior band of the UCL of the elbow provides stability to valgus stress. Overhead, high-velocity throwing athletes may cause repetitive injury to the UCL, resulting in partial or complete tears of the ligament. This may result in medial elbow pain, as well as decreased throwing velocity and accuracy. Athletes with complete UCL tears have few nonoperative treatment options and generally, operative treatment with UCL reconstruction is recommended for those athletes desiring to return to sport. However, it remains unclear how to definitively treat athletes with partial UCL tears. Recently, there has been an interest in treating these injuries with PRP in conjunction with physical therapy to facilitate a more predictable outcome.
Podesta and colleagues26 published a case series of 34 athletes with MRI-diagnosed partial UCL tears who underwent ultrasound-guided UCL injections and physical therapy. At an average follow-up of 70 weeks, they reported an average return to play (RTP) of 12 weeks, with significant improvements in Kerlan-Jobe Orthopaedic Clinic (KJOC) and DASH outcome scores, and decreased dynamic ulnohumeral joint widening to valgus stress on ultrasound. Most athletes (30/34) returned to their previous level of play, and 1 patient underwent subsequent UCL reconstruction. This study demonstrates that PRP may be used in conjunction with physical therapy and an interval throwing program for the treatment of partial UCL tears, but without a comparison control group, more studies are necessary to delineate the role of PRP in this population.
Lateral Elbow Epicondylitis
Lateral elbow epicondylitis, also known as “tennis elbow,” is thought to be caused by repetitive wrist extension and is more likely to present in patients with various comorbidities such as rotator cuff pathology or a history of smoking.27-29 The condition typically presents as radiating pain centered about the lateral epicondyle. Annual incidence ranges from 0.34% to 3%, with the most recent large-scale, population-based study estimating that nearly 1 million individuals in the United States develop lateral elbow epicondylitis each year.30 For the majority of patients, symptoms resolve after 6 to 12 months of various nonoperative or minimally invasive treatments.31-33 Those who develop chronic symptoms (>12 months) may benefit from surgical intervention.34 The use of PRP has become a contentious topic of debate in treating lateral epicondylitis. Its use and efficacy have been empirically examined and compared among more traditional treatments.35-37
In a small case-series of 6 patients, contrast-enhanced ultrasound imaging was utilized to demonstrate that PRP injection therapy may induce vascularization of the myotendinous junction of the common extensor tendon up to 6 months following injection.38 These physiologic changes may precede observable clinical improvements. Brklijac and colleagues39 prospectively followed 34 patients who had refractory symptoms despite conservative treatment and elected to undergo injection with PRP. At a mean follow-up of 26 weeks, 88.2% of the patients demonstrated improvements on their Oxford Elbow Score (OES). While potentially promising, case series lack large sample sizes, longitudinal analysis, and adequate control groups for comparative analyses of treatments, thereby increasing the likelihood of unintended selection bias.
Randomized controlled trials have demonstrated no difference between PRP and corticosteroid (CS) injection treatments in the short term for symptomatic lateral elbow epicondylitis. At 15 days, 1 month, and 6 months postinjection, no significant difference was found between PRP and CS injections in dynamometer strength measurements nor patient outcome scores (VAS, DASH, OES, and Mayo Clinic Performance Index for Elbow [MMCPIE]).40,41 In fact, multiple randomized controlled trials have demonstrated PRP to be less effective at 1 and 3 months compared to CS injections, as assessed by the Patient Rated Tennis-Elbow Evaluation (PRTEE) questionnaire, VAS, MMCPIE, and Nirschl scores.42,43 One mid-term, multi-center randomized controlled trial published by Mishra and colleagues44 compared PRP injections to an active control group, demonstrating a significant improvement in VAS pain scores at 24 weeks, but no difference in the PRTEE outcome. The available evidence indicates PRP injection therapy remains limited in utility for treatment of lateral epicondylitis, particularly in the short term when compared to CS injections. In the midterm to long term, PRP therapy may provide some benefit, but ultimately, well-designed prospective randomized controlled trials are needed to delineate the effects of PRP versus the natural course of tendon healing and symptom resolution.
Hamstring Injuries
Acute hamstring injuries are common across all levels and types of sport, particularly those in which sprinting or running is involved. While there is no consensus within the literature on how RTP after hamstring injury should be managed or defined, most injuries seem to resolve around 3 to 6 weeks.45 The proximal myotendinous junction of the long head of the biceps femoris and semitendinosus are commonly associated with significant pain and edema after acute hamstring injury.46 The amount of edema resulting from grade 1 and 2 hamstring injuries has been found to correlate (minimally) with time to RTP in elite athletes.47 PRP injection near the proximal myotendinous hamstring origin has been theorized to help speed the recovery process after acute hamstring injury. To date, the literature demonstrates mixed and limited benefit of PRP injection therapy for acute hamstring injury.
Few studies have shown improvements of PRP therapy over typical nonoperative management (rest, physical therapy, nonsteroidal anti-inflammatory drugs) in acute hamstring injury, but the results must be interpreted carefully.48,49 Wetzel and colleagues48 retrospectively reviewed 17 patients with acute hamstring injury, 12 of whom failed typical management and received PRP injection at the hamstring origin. This group demonstrated significant improvements in their VAS and Nirschl scores at follow-up, whereas the 5 patients who did not receive the injection did not. However, this study exhibited significant limitations inherent to a retrospective review with a small sample size. Hamid and colleagues49 conducted a randomized controlled trial of 24 athletes with diagnosed grade 2a acute hamstring injuries, comparing autologous PRP therapy combined with a rehabilitation program versus rehabilitation program alone. RTP, changes in pain severity (Brief Pain Injury-Short Form [BPI-SF] questions 2-6), and pain interference (BPI-SF questions 9A-9G) scores over time were examined. Athletes in the PRP group exhibited no difference in outcomes scores, but returned to play sooner than controls (26.7 vs 42.5 days).
Mejia and Bradley50 have reported their experience in treating 12 National Football League (NFL) players with acute MRI grade 1 or 2 hamstring injuries with a series of PRP injections at the site of injury. They found a 1-game difference in earlier RTP when compared to the predicted RTP based on MRI grading. Similarly, Hamid and colleagues49 performed a randomized control trial published in 2014, reporting an earlier RTP (26.7 vs 42.5 days) when comparing single PRP injection vs rehabilitation alone in 28 patients diagnosed with acute ultrasound grade 2 hamstring injuries. On the contrary, a small case-control study of NFL players and a retrospective cohort study of athletes with severe hamstring injuries demonstrated no difference in RTP when PRP injected patients were compared with controls.51,52 Larger randomized controlled trials have demonstrated comparable results, including a study of 90 professional athletes in whom a single PRP injection did not decrease RTP or lessen the risk of re-injury at 2 and 6 months.53 In another large multicenter randomized controlled trial examining 80 competitive and recreational athletes, PRP did not accelerate RTP, lessen the risk of 2-month or 1-year re-injury rate, or improve secondary measures of MRI parameters, subjective patient satisfaction, or the hamstring outcome score.54 Although further study is warranted, available evidence suggests limited utility of PRP injection in the treatment of acute hamstring injuries.
Achilles Tendinopathy
Noninsertional Achilles tendinopathy is a common source of pain for both recreational and competitive athletes. Typically thought of as an overuse syndrome, Achilles tendinopathy may result in significant pain and swelling, often at the site of its tenuous blood supply, approximately 2 to 7 cm proximal to its insertion.55 Conservative management frequently begins with rest, activity/shoe modification, physical therapy, and eccentric loading exercises.56 For those whom conservative management has failed to reduce symptoms after 6 months, more invasive treatment options may be considered. Peritendinous PRP injection has become an alternative approach in treating Achilles tendinopathy refractory to conservative treatment.
In the few randomized controlled trials published, the data demonstrates no significant improvements in clinical outcomes from PRP injection for Achilles tendinopathy. Kearney and colleagues57 conducted a pilot study of 20 patients randomized into PRP injection or eccentric loading program for mid-substance Achilles tendinopathy, in which Victorian Institute of Sports Assessment (VISA-A), EuroQol 5 dimensions questionnaire (EQ-5D), and complications associated with the injection were recorded at 6 weeks, 3 months, and 6 months. Although this was a pilot study with a small sample size, no significant difference was found between groups across these time periods. Similarly, de Vos and colleagues58,59 conducted a double-blind randomized controlled trial of 54 patients with chronic mid-substance Achilles tendinopathy and randomized them into eccentric exercise therapy with either a PRP injection or a saline injected placebo groups. VISA-A scores were recorded and imaging parameters assessing tendon structure by ultrasonographic tissue characterization and color Doppler ultrasonography were taken with follow-up at 6, 12, and 24 weeks. VISA-A scores improved significantly in both groups after 24 weeks, but the difference was not statistically significant between groups. In addition, tendon structure and neovascularization (exhibited by color Doppler ultrasonography) improved in both groups, with no significant difference between groups. The current literature does not support the use of PRP in treatment of Achilles tendinopathy, as it has failed to reveal additional benefits over conventional treatment alone. Future prospective, well-designed randomized controlled trials with large sample sizes will need to be conducted to ultimately conclude whether or not PRP deserves a role in the treatment of Achilles tendinopathy.
Summary
In theory, the use of PRP within orthopedic surgery makes a great deal of sense to accelerate and augment the healing process of the aforementioned musculoskeletal injuries. However, the vast majority of published literature is Level III and IV evidence. Future research may provide the missing critical information of optimal growth factor, platelet, and leukocyte concentrations necessary for the desired effect, as well as the appropriate delivery method and timing of PRP application in different target tissues. Evidence-based guidelines to direct the use of PRP will benefit from more homogenous, repeatable, and randomized controlled trials.
1. Hsu WK, Mishra A, Rodeo SR, et al. Platelet-rich plasma in orthopaedic applications: evidence-based recommendations for treatment. J Am Acad Orthop Surg. 2013;21(12):739-748.
2. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg. 2004;62(4):489-496.
3. Jo CH, Kim JE, Yoon KS, et al. Does platelet-rich plasma accelerate recovery after rotator cuff repair? A prospective cohort study. Am J Sports Med. 2011;39(10):2082-2090.
4. Burkhart SS, Danaceau SM, Pearce CE Jr. Arthroscopic rotator cuff repair: Analysis of results by tear size and by repair technique-margin convergence versus direct tendon-to-bone repair. Arthroscopy. 2001;17(9):905-912.
5. Severud EL, Ruotolo C, Abbott DD, Nottage WM. All-arthroscopic versus mini-open rotator cuff repair: A long-term retrospective outcome comparison. Arthroscopy. 2003;19(3):234-238.
6. Huang R, Wang S, Wang Y, Qin X, Sun Y. Systematic review of all-arthroscopic versus mini-open repair of rotator cuff tears: a meta-analysis. Sci Rep. 2016;6:22857.
7. Watson EM, Sonnabend DH. Outcome of rotator cuff repair. J Shoulder Elbow Surg. 2002;11(3):201-211.
8. Butler DL, Juncosa N, Dressler MR. Functional efficacy of tendon repair processes. Annu Rev Biomed Eng. 2004;6:303-329.
9. Galatz LM, Ball CM, Teefey SA, Middleton WD, Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears. J Bone Joint Surg Am. 2004;86-A(2):219-224.
10. Lafosse L, Brozska R, Toussaint B, Gobezie R. The outcome and structural integrity of arthroscopic rotator cuff repair with use of the double-row suture anchor technique. J Bone Joint Surg Am. 2007;89(7):1533-1541.
11. Castricini R, Longo UG, De Benedetto M, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med. 2011;39(2):258-265.
12. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518-528.
13. Weber SC, Kauffman JI, Parise C, Weber SJ, Katz SD. Platelet-rich fibrin matrix in the management of arthroscopic repair of the rotator cuff: a prospective, randomized, double-blinded study. Am J Sports Med. 2013;41(2):263-270.
14. Gumina S, Campagna V, Ferrazza G, et al. Use of platelet-leukocyte membrane in arthroscopic repair of large rotator cuff tears: a prospective randomized study. J Bone Joint Surg Am. 2012;94(15):1345-1352.
15. Rodeo SA, Delos D, Williams RJ, Adler RS, Pearle A, Warren RF. The effect of platelet-rich fibrin matrix on rotator cuff tendon healing: a prospective, randomized clinical study. Am J Sports Med. 2012;40(6):1234-1241.
16. Warth RJ, Dornan GJ, James EW, Horan MP, Millett PJ. Clinical and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears with and without platelet-rich product supplementation: a meta-analysis and meta-regression. Arthroscopy. 2015;31(2):306-320.
17. Zhao JG, Zhao L, Jiang YX, Wang ZL, Wang J, Zhang P. Platelet-rich plasma in arthroscopic rotator cuff repair: a meta-analysis of randomized controlled trials. Arthroscopy. 2015;31(1):125-135.
18. Glyn-Jones S, Palmer AJ, Agricola R, et al. Osteoarthritis. Lancet. 2015;386(9991):376-387.
19. Cerza F, Carni S, Carcangiu A, et al. Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis. Am J Sports Med. 2012;40(12):2822-2827.
20. Filardo G, Kon E, Di Martino A, et al. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord. 2012;13:229.
21. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med. 2013;41(2):356-364.
22. Sanchez M, Fiz N, Azofra J, et al. A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy. 2012;28(8):1070-1078.
23. Campbell KA, Saltzman BM, Mascarenhas R, et al. Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? A systematic review of overlapping meta-analyses. Arthroscopy. 2015;31(11):2213-2221.
24. Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: A systematic review. Arthroscopy. 2016;32(3):495-505.
25. Smith PA. Intra-articular autologous conditioned plasma injections provide safe and efficacious treatment for knee osteoarthritis: An FDA-sanctioned, randomized, double-blind, placebo-controlled clinical trial. Am J Sports Med. 2016;44(4):884-891.
26. Podesta L, Crow SA, Volkmer D, Bert T, Yocum LA. Treatment of partial ulnar collateral ligament tears in the elbow with platelet-rich plasma. Am J Sports Med. 2013;41(7):1689-1694.
27. Herquelot E, Gueguen A, Roquelaure Y, et al. Work-related risk factors for incidence of lateral epicondylitis in a large working population. Scand J Work Environ Health. 2013;39(6):578-588.
28. Titchener AG, Fakis A, Tambe AA, Smith C, Hubbard RB, Clark DI. Risk factors in lateral epicondylitis (tennis elbow): a case-control study. J Hand Surg Eur Vol. 2013;38(2):159-164.
29. Gruchow HW, Pelletier D. An epidemiologic study of tennis elbow. Incidence, recurrence, and effectiveness of prevention strategies. Am J Sports Med. 1979;7(4):234-238.
30. Sanders TL Jr, Maradit Kremers H, Bryan AJ, Ransom JE, Smith J, Morrey BF. The epidemiology and health care burden of tennis elbow: a population-based study. Am J Sports Med. 2015;43(5):1066-1071.
31. Coonrad RW, Hooper WR. Tennis elbow: its course, natural history, conservative and surgical management. J Bone Joint Surg Am. 1973;55(6):1177-1182.
32. Taylor SA, Hannafin JA. Evaluation and management of elbow tendinopathy. Sports Health. 2012;4(5):384-393.
33. Sims SE, Miller K, Elfar JC, Hammert WC. Non-surgical treatment of lateral epicondylitis: a systematic review of randomized controlled trials. Hand (NY). 2014;9(4):419-446.
34. Brummel J, Baker CL 3rd, Hopkins R, Baker CL Jr. Epicondylitis: lateral. Sports Med Arthrosc. 2014;22(3):e1-e6.
35. de Vos RJ, Windt J, Weir A. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br J Sports Med. 2014;48(12):952-956.
36. Ahmad Z, Brooks R, Kang SN, et al. The effect of platelet-rich plasma on clinical outcomes in lateral epicondylitis. Arthroscopy. 2013;29(11):1851-1862.
37. Arirachakaran A, Sukthuayat A, Sisayanarane T, Laoratanavoraphong S, Kanchanatawan W, Kongtharvonskul J. Platelet-rich plasma versus autologous blood versus steroid injection in lateral epicondylitis: systematic review and network meta-analysis. J Orthop Traumatol. 2016;17(2):101-112.
38. Chaudhury S, de La Lama M, Adler RS, et al. Platelet-rich plasma for the treatment of lateral epicondylitis: sonographic assessment of tendon morphology and vascularity (pilot study). Skeletal Radiol. 2013;42(1):91-97.
39. Brkljac M, Kumar S, Kalloo D, Hirehal K. The effect of platelet-rich plasma injection on lateral epicondylitis following failed conservative management. J Orthop. 2015;12(Suppl 2):S166-S170.
40. Yadav R, Kothari SY, Borah D. Comparison of local injection of platelet rich plasma and corticosteroids in the treatment of lateral epicondylitis of humerus. J Clin Diagn Res. 2015;9(7):RC05-RC07.
41. Gautam VK, Verma S, Batra S, Bhatnagar N, Arora S. Platelet-rich plasma versus corticosteroid injection for recalcitrant lateral epicondylitis: clinical and ultrasonographic evaluation. J Orthop Surg (Hong Kong). 2015;23(1):1-5.
42. Krogh TP, Fredberg U, Stengaard-Pedersen K, Christensen R, Jensen P, Ellingsen T. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med. 2013;41(3):625-635.
43. Behera P, Dhillon M, Aggarwal S, Marwaha N, Prakash M. Leukocyte-poor platelet-rich plasma versus bupivacaine for recalcitrant lateral epicondylar tendinopathy. J Orthop Surg (Hong Kong). 2015;23(1):6-10.
44. Mishra AK, Skrepnik NV, Edwards SG, et al. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med. 2014;42(2):463-471.
45. van der Horst N, van de Hoef S, Reurink G, Huisstede B, Backx F. Return to play after hamstring injuries: a qualitative systematic review of definitions and criteria. Sports Med. 2016;46(6):899-912.
46. Crema MD, Guermazi A, Tol JL, Niu J, Hamilton B, Roemer FW. Acute hamstring injury in football players: Association between anatomical location and extent of injury-A large single-center MRI report. J Sci Med Sport. 2016;19(4):317-322.
47. Ekstrand J, Lee JC, Healy JC. MRI findings and return to play in football: a prospective analysis of 255 hamstring injuries in the UEFA Elite Club Injury Study. Br J Sports Med. 2016;50(12):738-743.
48. Wetzel RJ, Patel RM, Terry MA. Platelet-rich plasma as an effective treatment for proximal hamstring injuries. Orthopedics. 2013;36(1):e64-e70.
49. Hamid A, Mohamed Ali MR, Yusof A, George J, Lee LP. Platelet-rich plasma injections for the treatment of hamstring injuries: a randomized controlled trial. Am J Sports Med. 2014;42(10):2410-2418.
50. Mejia HA, Bradley JP. The effects of platelet-rich plasma on muscle: basic science and clinical application. Operative Techniques in Sports Medicine. 2011;19(3):149-153.
51. Guillodo Y, Madouas G, Simon T, Le Dauphin H, Saraux A. Platelet-rich plasma (PRP) treatment of sports-related severe acute hamstring injuries. Muscles Ligaments Tendons J. 2015;5(4):284-288.
52. Rettig AC, Meyer S, Bhadra AK. Platelet-rich plasma in addition to rehabilitation for acute hamstring injuries in NFL players: Clinical effects and time to return to play. Orthop J Sports Med. 2013;1(1):2325967113494354.
53. Hamilton B, Tol JL, Almusa E, et al. Platelet-rich plasma does not enhance return to play in hamstring injuries: a randomised controlled trial. Br J Sports Med. 2015;49(14):943-950.
54. Reurink G, Goudswaard GJ, Moen MH, et al. Rationale, secondary outcome scores and 1-year follow-up of a randomised trial of platelet-rich plasma injections in acute hamstring muscle injury: the Dutch Hamstring Injection Therapy study. Br J Sports Med. 2015;49(18):1206-1212.
55. Kujala UM, Sarna S, Kaprio J. Cumulative incidence of achilles tendon rupture and tendinopathy in male former elite athletes. Clin J Sport Med. 2005;15(3):133-135.
56. Alfredson H. Clinical commentary of the evolution of the treatment for chronic painful mid-portion Achilles tendinopathy. Braz J Phys Ther. 2015;19(5):429-432.
57. Kearney RS, Parsons N, Costa ML. Achilles tendinopathy management: A pilot randomised controlled trial comparing platelet-rich plasma injection with an eccentric loading programme. Bone Joint Res. 2013;2(10):227-232.
58. de Vos RJ, Weir A, Tol JL, Verhaar JA, Weinans H, van Schie HT. No effects of PRP on ultrasonographic tendon structure and neovascularisation in chronic midportion Achilles tendinopathy. Br J Sports Med. 2011;45(5):387-392.
59. de Vos RJ, Weir A, van Schie HT, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA. 2010;303(2):144-149.
Platelet-rich plasma (PRP) is a refined product of autologous blood with a platelet concentration greater than that of whole blood. It is prepared via plasmapheresis utilizing a 2-stage centrifugation process and more than 40 commercially available systems are marketed to concentrate whole blood to PRP.1 It is rich in biologic factors (growth factors, cytokines, proteins, cellular components) essential to the body’s response to injury. For this reason, it was first used in oromaxillofacial surgery in the 1950s, but its effects on the musculoskeletal system have yet to be clearly elucidated.2 However, this lack of clarity has not deterred its widespread use among orthopedic surgeons. In this review, we aim to delineate the current understanding of PRP and its proven effectiveness in the treatment of rotator cuff tears, knee osteoarthritis, ulnar collateral ligament (UCL) tears, lateral epicondylitis, hamstring injuries, and Achilles tendinopathy.
Rotator Cuff Tears
Rotator cuff tears are one of the most common etiologies for shoulder pain and disability. The incidence continues to increase with the active aging population.3 Rotator cuff tears treated with arthroscopic repair have exhibited satisfactory pain relief and functional outcomes.4-7 Despite advances in fixation techniques, the quality and speed of tendon-to-bone healing remains unpredictable, with repaired tendons exhibiting inferior mechanical properties that are susceptible to re-tear.8-10
Numerous studies have investigated PRP application during arthroscopic rotator cuff repair (RCR) in an attempt to enhance and accelerate the repair process.11-15 However, wide variability exists among protocols of how and when PRP is utilized to augment the repair. Warth and colleagues16 performed a meta-analysis of 11 Level I/II studies evaluating RCR with PRP augmentation. With regards to clinical outcome scores, they found no significant difference in pre- and postoperative American Shoulder and Elbow Surgeons (ASES), Constant, Disability of the Arm, Shoulder and Hand (DASH), or visual analog scale (VAS) pain scores between those patients with or without PRP augmentation. However, they did note a significant increase in Constant scores when PRP was delivered to the tendon-bone interface rather than over the surface of the repair site. There was no significant difference in structural outcomes (evaluated by magnetic resonance imaging [MRI] re-tear rates) between those RCRs with and without PRP augmentation, except in those tears >3 cm in anterior-posterior length using double-row technique, with the PRP group exhibiting a significantly decreased re-tear rate (25.9% vs 57.1%).16 Zhao and colleagues17 reported similar results in a meta-analysis of 8 randomized controlled trials, exhibiting no significant differences in clinical outcome scores or re-tear rates after RCR with and without PRP augmentation. Overall, most studies have failed to demonstrate a significant benefit with regards to re-tear rates or shoulder-specific outcomes with the addition of PRP during arthroscopic RCR.
Knee Osteoarthritis
Osteoarthritis is the most common musculoskeletal disorder, with an estimated prevalence of 10% of the world’s population age 60 years and older.18 The knee is commonly symptomatic, resulting in pain, disability, and significant healthcare costs. Novel biologic, nonoperative therapies, including intra-articular viscosupplementation and PRP injections, have been proposed to treat the early stages of osteoarthritis to provide symptomatic relief and delay surgical intervention.
A multitude of studies have been performed investigating the effects of PRP on knee osteoarthritis, revealing mixed results.19-22 Campbell and colleagues23 published a 2015 systematic review of 3 overlapping meta-analyses comparing the outcomes of intra-articular injection of PRP vs control (hyaluronic acid [HA] or placebo) in 3278 knees. They reported a significant improvement in patient outcome scores for the PRP group when compared to control from 2 to 12 months after injection, but due to significant differences within the included studies, the ideal number of injections or time intervals between injections remains unclear. Meheux and colleagues24 reported a 2016 systematic review including 6 studies (817 knees) comparing PRP and HA injections. They demonstrated significantly better improvements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores with PRP vs HA injections at 3 and 12 months postinjection. Similarly, Smith25 conducted a Food and Drug Administration-sanctioned, randomized, double-blind, placebo-controlled clinical trial investigating the effects of intra-articular leukocyte-poor autologous conditioned plasma (ACP) in 30 patients. He reported an improvement in the ACP treatment group WOMAC scores by 78% compared to 7% improvement in the placebo group after 12 months. Despite the heterogeneity amongst studies, the majority of published data suggests better symptomatic relief in patients with early knee degenerative changes, and use of PRP may be considered in this population.
Ulnar Collateral Ligament Injuries
The anterior band of the UCL of the elbow provides stability to valgus stress. Overhead, high-velocity throwing athletes may cause repetitive injury to the UCL, resulting in partial or complete tears of the ligament. This may result in medial elbow pain, as well as decreased throwing velocity and accuracy. Athletes with complete UCL tears have few nonoperative treatment options and generally, operative treatment with UCL reconstruction is recommended for those athletes desiring to return to sport. However, it remains unclear how to definitively treat athletes with partial UCL tears. Recently, there has been an interest in treating these injuries with PRP in conjunction with physical therapy to facilitate a more predictable outcome.
Podesta and colleagues26 published a case series of 34 athletes with MRI-diagnosed partial UCL tears who underwent ultrasound-guided UCL injections and physical therapy. At an average follow-up of 70 weeks, they reported an average return to play (RTP) of 12 weeks, with significant improvements in Kerlan-Jobe Orthopaedic Clinic (KJOC) and DASH outcome scores, and decreased dynamic ulnohumeral joint widening to valgus stress on ultrasound. Most athletes (30/34) returned to their previous level of play, and 1 patient underwent subsequent UCL reconstruction. This study demonstrates that PRP may be used in conjunction with physical therapy and an interval throwing program for the treatment of partial UCL tears, but without a comparison control group, more studies are necessary to delineate the role of PRP in this population.
Lateral Elbow Epicondylitis
Lateral elbow epicondylitis, also known as “tennis elbow,” is thought to be caused by repetitive wrist extension and is more likely to present in patients with various comorbidities such as rotator cuff pathology or a history of smoking.27-29 The condition typically presents as radiating pain centered about the lateral epicondyle. Annual incidence ranges from 0.34% to 3%, with the most recent large-scale, population-based study estimating that nearly 1 million individuals in the United States develop lateral elbow epicondylitis each year.30 For the majority of patients, symptoms resolve after 6 to 12 months of various nonoperative or minimally invasive treatments.31-33 Those who develop chronic symptoms (>12 months) may benefit from surgical intervention.34 The use of PRP has become a contentious topic of debate in treating lateral epicondylitis. Its use and efficacy have been empirically examined and compared among more traditional treatments.35-37
In a small case-series of 6 patients, contrast-enhanced ultrasound imaging was utilized to demonstrate that PRP injection therapy may induce vascularization of the myotendinous junction of the common extensor tendon up to 6 months following injection.38 These physiologic changes may precede observable clinical improvements. Brklijac and colleagues39 prospectively followed 34 patients who had refractory symptoms despite conservative treatment and elected to undergo injection with PRP. At a mean follow-up of 26 weeks, 88.2% of the patients demonstrated improvements on their Oxford Elbow Score (OES). While potentially promising, case series lack large sample sizes, longitudinal analysis, and adequate control groups for comparative analyses of treatments, thereby increasing the likelihood of unintended selection bias.
Randomized controlled trials have demonstrated no difference between PRP and corticosteroid (CS) injection treatments in the short term for symptomatic lateral elbow epicondylitis. At 15 days, 1 month, and 6 months postinjection, no significant difference was found between PRP and CS injections in dynamometer strength measurements nor patient outcome scores (VAS, DASH, OES, and Mayo Clinic Performance Index for Elbow [MMCPIE]).40,41 In fact, multiple randomized controlled trials have demonstrated PRP to be less effective at 1 and 3 months compared to CS injections, as assessed by the Patient Rated Tennis-Elbow Evaluation (PRTEE) questionnaire, VAS, MMCPIE, and Nirschl scores.42,43 One mid-term, multi-center randomized controlled trial published by Mishra and colleagues44 compared PRP injections to an active control group, demonstrating a significant improvement in VAS pain scores at 24 weeks, but no difference in the PRTEE outcome. The available evidence indicates PRP injection therapy remains limited in utility for treatment of lateral epicondylitis, particularly in the short term when compared to CS injections. In the midterm to long term, PRP therapy may provide some benefit, but ultimately, well-designed prospective randomized controlled trials are needed to delineate the effects of PRP versus the natural course of tendon healing and symptom resolution.
Hamstring Injuries
Acute hamstring injuries are common across all levels and types of sport, particularly those in which sprinting or running is involved. While there is no consensus within the literature on how RTP after hamstring injury should be managed or defined, most injuries seem to resolve around 3 to 6 weeks.45 The proximal myotendinous junction of the long head of the biceps femoris and semitendinosus are commonly associated with significant pain and edema after acute hamstring injury.46 The amount of edema resulting from grade 1 and 2 hamstring injuries has been found to correlate (minimally) with time to RTP in elite athletes.47 PRP injection near the proximal myotendinous hamstring origin has been theorized to help speed the recovery process after acute hamstring injury. To date, the literature demonstrates mixed and limited benefit of PRP injection therapy for acute hamstring injury.
Few studies have shown improvements of PRP therapy over typical nonoperative management (rest, physical therapy, nonsteroidal anti-inflammatory drugs) in acute hamstring injury, but the results must be interpreted carefully.48,49 Wetzel and colleagues48 retrospectively reviewed 17 patients with acute hamstring injury, 12 of whom failed typical management and received PRP injection at the hamstring origin. This group demonstrated significant improvements in their VAS and Nirschl scores at follow-up, whereas the 5 patients who did not receive the injection did not. However, this study exhibited significant limitations inherent to a retrospective review with a small sample size. Hamid and colleagues49 conducted a randomized controlled trial of 24 athletes with diagnosed grade 2a acute hamstring injuries, comparing autologous PRP therapy combined with a rehabilitation program versus rehabilitation program alone. RTP, changes in pain severity (Brief Pain Injury-Short Form [BPI-SF] questions 2-6), and pain interference (BPI-SF questions 9A-9G) scores over time were examined. Athletes in the PRP group exhibited no difference in outcomes scores, but returned to play sooner than controls (26.7 vs 42.5 days).
Mejia and Bradley50 have reported their experience in treating 12 National Football League (NFL) players with acute MRI grade 1 or 2 hamstring injuries with a series of PRP injections at the site of injury. They found a 1-game difference in earlier RTP when compared to the predicted RTP based on MRI grading. Similarly, Hamid and colleagues49 performed a randomized control trial published in 2014, reporting an earlier RTP (26.7 vs 42.5 days) when comparing single PRP injection vs rehabilitation alone in 28 patients diagnosed with acute ultrasound grade 2 hamstring injuries. On the contrary, a small case-control study of NFL players and a retrospective cohort study of athletes with severe hamstring injuries demonstrated no difference in RTP when PRP injected patients were compared with controls.51,52 Larger randomized controlled trials have demonstrated comparable results, including a study of 90 professional athletes in whom a single PRP injection did not decrease RTP or lessen the risk of re-injury at 2 and 6 months.53 In another large multicenter randomized controlled trial examining 80 competitive and recreational athletes, PRP did not accelerate RTP, lessen the risk of 2-month or 1-year re-injury rate, or improve secondary measures of MRI parameters, subjective patient satisfaction, or the hamstring outcome score.54 Although further study is warranted, available evidence suggests limited utility of PRP injection in the treatment of acute hamstring injuries.
Achilles Tendinopathy
Noninsertional Achilles tendinopathy is a common source of pain for both recreational and competitive athletes. Typically thought of as an overuse syndrome, Achilles tendinopathy may result in significant pain and swelling, often at the site of its tenuous blood supply, approximately 2 to 7 cm proximal to its insertion.55 Conservative management frequently begins with rest, activity/shoe modification, physical therapy, and eccentric loading exercises.56 For those whom conservative management has failed to reduce symptoms after 6 months, more invasive treatment options may be considered. Peritendinous PRP injection has become an alternative approach in treating Achilles tendinopathy refractory to conservative treatment.
In the few randomized controlled trials published, the data demonstrates no significant improvements in clinical outcomes from PRP injection for Achilles tendinopathy. Kearney and colleagues57 conducted a pilot study of 20 patients randomized into PRP injection or eccentric loading program for mid-substance Achilles tendinopathy, in which Victorian Institute of Sports Assessment (VISA-A), EuroQol 5 dimensions questionnaire (EQ-5D), and complications associated with the injection were recorded at 6 weeks, 3 months, and 6 months. Although this was a pilot study with a small sample size, no significant difference was found between groups across these time periods. Similarly, de Vos and colleagues58,59 conducted a double-blind randomized controlled trial of 54 patients with chronic mid-substance Achilles tendinopathy and randomized them into eccentric exercise therapy with either a PRP injection or a saline injected placebo groups. VISA-A scores were recorded and imaging parameters assessing tendon structure by ultrasonographic tissue characterization and color Doppler ultrasonography were taken with follow-up at 6, 12, and 24 weeks. VISA-A scores improved significantly in both groups after 24 weeks, but the difference was not statistically significant between groups. In addition, tendon structure and neovascularization (exhibited by color Doppler ultrasonography) improved in both groups, with no significant difference between groups. The current literature does not support the use of PRP in treatment of Achilles tendinopathy, as it has failed to reveal additional benefits over conventional treatment alone. Future prospective, well-designed randomized controlled trials with large sample sizes will need to be conducted to ultimately conclude whether or not PRP deserves a role in the treatment of Achilles tendinopathy.
Summary
In theory, the use of PRP within orthopedic surgery makes a great deal of sense to accelerate and augment the healing process of the aforementioned musculoskeletal injuries. However, the vast majority of published literature is Level III and IV evidence. Future research may provide the missing critical information of optimal growth factor, platelet, and leukocyte concentrations necessary for the desired effect, as well as the appropriate delivery method and timing of PRP application in different target tissues. Evidence-based guidelines to direct the use of PRP will benefit from more homogenous, repeatable, and randomized controlled trials.
Platelet-rich plasma (PRP) is a refined product of autologous blood with a platelet concentration greater than that of whole blood. It is prepared via plasmapheresis utilizing a 2-stage centrifugation process and more than 40 commercially available systems are marketed to concentrate whole blood to PRP.1 It is rich in biologic factors (growth factors, cytokines, proteins, cellular components) essential to the body’s response to injury. For this reason, it was first used in oromaxillofacial surgery in the 1950s, but its effects on the musculoskeletal system have yet to be clearly elucidated.2 However, this lack of clarity has not deterred its widespread use among orthopedic surgeons. In this review, we aim to delineate the current understanding of PRP and its proven effectiveness in the treatment of rotator cuff tears, knee osteoarthritis, ulnar collateral ligament (UCL) tears, lateral epicondylitis, hamstring injuries, and Achilles tendinopathy.
Rotator Cuff Tears
Rotator cuff tears are one of the most common etiologies for shoulder pain and disability. The incidence continues to increase with the active aging population.3 Rotator cuff tears treated with arthroscopic repair have exhibited satisfactory pain relief and functional outcomes.4-7 Despite advances in fixation techniques, the quality and speed of tendon-to-bone healing remains unpredictable, with repaired tendons exhibiting inferior mechanical properties that are susceptible to re-tear.8-10
Numerous studies have investigated PRP application during arthroscopic rotator cuff repair (RCR) in an attempt to enhance and accelerate the repair process.11-15 However, wide variability exists among protocols of how and when PRP is utilized to augment the repair. Warth and colleagues16 performed a meta-analysis of 11 Level I/II studies evaluating RCR with PRP augmentation. With regards to clinical outcome scores, they found no significant difference in pre- and postoperative American Shoulder and Elbow Surgeons (ASES), Constant, Disability of the Arm, Shoulder and Hand (DASH), or visual analog scale (VAS) pain scores between those patients with or without PRP augmentation. However, they did note a significant increase in Constant scores when PRP was delivered to the tendon-bone interface rather than over the surface of the repair site. There was no significant difference in structural outcomes (evaluated by magnetic resonance imaging [MRI] re-tear rates) between those RCRs with and without PRP augmentation, except in those tears >3 cm in anterior-posterior length using double-row technique, with the PRP group exhibiting a significantly decreased re-tear rate (25.9% vs 57.1%).16 Zhao and colleagues17 reported similar results in a meta-analysis of 8 randomized controlled trials, exhibiting no significant differences in clinical outcome scores or re-tear rates after RCR with and without PRP augmentation. Overall, most studies have failed to demonstrate a significant benefit with regards to re-tear rates or shoulder-specific outcomes with the addition of PRP during arthroscopic RCR.
Knee Osteoarthritis
Osteoarthritis is the most common musculoskeletal disorder, with an estimated prevalence of 10% of the world’s population age 60 years and older.18 The knee is commonly symptomatic, resulting in pain, disability, and significant healthcare costs. Novel biologic, nonoperative therapies, including intra-articular viscosupplementation and PRP injections, have been proposed to treat the early stages of osteoarthritis to provide symptomatic relief and delay surgical intervention.
A multitude of studies have been performed investigating the effects of PRP on knee osteoarthritis, revealing mixed results.19-22 Campbell and colleagues23 published a 2015 systematic review of 3 overlapping meta-analyses comparing the outcomes of intra-articular injection of PRP vs control (hyaluronic acid [HA] or placebo) in 3278 knees. They reported a significant improvement in patient outcome scores for the PRP group when compared to control from 2 to 12 months after injection, but due to significant differences within the included studies, the ideal number of injections or time intervals between injections remains unclear. Meheux and colleagues24 reported a 2016 systematic review including 6 studies (817 knees) comparing PRP and HA injections. They demonstrated significantly better improvements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores with PRP vs HA injections at 3 and 12 months postinjection. Similarly, Smith25 conducted a Food and Drug Administration-sanctioned, randomized, double-blind, placebo-controlled clinical trial investigating the effects of intra-articular leukocyte-poor autologous conditioned plasma (ACP) in 30 patients. He reported an improvement in the ACP treatment group WOMAC scores by 78% compared to 7% improvement in the placebo group after 12 months. Despite the heterogeneity amongst studies, the majority of published data suggests better symptomatic relief in patients with early knee degenerative changes, and use of PRP may be considered in this population.
Ulnar Collateral Ligament Injuries
The anterior band of the UCL of the elbow provides stability to valgus stress. Overhead, high-velocity throwing athletes may cause repetitive injury to the UCL, resulting in partial or complete tears of the ligament. This may result in medial elbow pain, as well as decreased throwing velocity and accuracy. Athletes with complete UCL tears have few nonoperative treatment options and generally, operative treatment with UCL reconstruction is recommended for those athletes desiring to return to sport. However, it remains unclear how to definitively treat athletes with partial UCL tears. Recently, there has been an interest in treating these injuries with PRP in conjunction with physical therapy to facilitate a more predictable outcome.
Podesta and colleagues26 published a case series of 34 athletes with MRI-diagnosed partial UCL tears who underwent ultrasound-guided UCL injections and physical therapy. At an average follow-up of 70 weeks, they reported an average return to play (RTP) of 12 weeks, with significant improvements in Kerlan-Jobe Orthopaedic Clinic (KJOC) and DASH outcome scores, and decreased dynamic ulnohumeral joint widening to valgus stress on ultrasound. Most athletes (30/34) returned to their previous level of play, and 1 patient underwent subsequent UCL reconstruction. This study demonstrates that PRP may be used in conjunction with physical therapy and an interval throwing program for the treatment of partial UCL tears, but without a comparison control group, more studies are necessary to delineate the role of PRP in this population.
Lateral Elbow Epicondylitis
Lateral elbow epicondylitis, also known as “tennis elbow,” is thought to be caused by repetitive wrist extension and is more likely to present in patients with various comorbidities such as rotator cuff pathology or a history of smoking.27-29 The condition typically presents as radiating pain centered about the lateral epicondyle. Annual incidence ranges from 0.34% to 3%, with the most recent large-scale, population-based study estimating that nearly 1 million individuals in the United States develop lateral elbow epicondylitis each year.30 For the majority of patients, symptoms resolve after 6 to 12 months of various nonoperative or minimally invasive treatments.31-33 Those who develop chronic symptoms (>12 months) may benefit from surgical intervention.34 The use of PRP has become a contentious topic of debate in treating lateral epicondylitis. Its use and efficacy have been empirically examined and compared among more traditional treatments.35-37
In a small case-series of 6 patients, contrast-enhanced ultrasound imaging was utilized to demonstrate that PRP injection therapy may induce vascularization of the myotendinous junction of the common extensor tendon up to 6 months following injection.38 These physiologic changes may precede observable clinical improvements. Brklijac and colleagues39 prospectively followed 34 patients who had refractory symptoms despite conservative treatment and elected to undergo injection with PRP. At a mean follow-up of 26 weeks, 88.2% of the patients demonstrated improvements on their Oxford Elbow Score (OES). While potentially promising, case series lack large sample sizes, longitudinal analysis, and adequate control groups for comparative analyses of treatments, thereby increasing the likelihood of unintended selection bias.
Randomized controlled trials have demonstrated no difference between PRP and corticosteroid (CS) injection treatments in the short term for symptomatic lateral elbow epicondylitis. At 15 days, 1 month, and 6 months postinjection, no significant difference was found between PRP and CS injections in dynamometer strength measurements nor patient outcome scores (VAS, DASH, OES, and Mayo Clinic Performance Index for Elbow [MMCPIE]).40,41 In fact, multiple randomized controlled trials have demonstrated PRP to be less effective at 1 and 3 months compared to CS injections, as assessed by the Patient Rated Tennis-Elbow Evaluation (PRTEE) questionnaire, VAS, MMCPIE, and Nirschl scores.42,43 One mid-term, multi-center randomized controlled trial published by Mishra and colleagues44 compared PRP injections to an active control group, demonstrating a significant improvement in VAS pain scores at 24 weeks, but no difference in the PRTEE outcome. The available evidence indicates PRP injection therapy remains limited in utility for treatment of lateral epicondylitis, particularly in the short term when compared to CS injections. In the midterm to long term, PRP therapy may provide some benefit, but ultimately, well-designed prospective randomized controlled trials are needed to delineate the effects of PRP versus the natural course of tendon healing and symptom resolution.
Hamstring Injuries
Acute hamstring injuries are common across all levels and types of sport, particularly those in which sprinting or running is involved. While there is no consensus within the literature on how RTP after hamstring injury should be managed or defined, most injuries seem to resolve around 3 to 6 weeks.45 The proximal myotendinous junction of the long head of the biceps femoris and semitendinosus are commonly associated with significant pain and edema after acute hamstring injury.46 The amount of edema resulting from grade 1 and 2 hamstring injuries has been found to correlate (minimally) with time to RTP in elite athletes.47 PRP injection near the proximal myotendinous hamstring origin has been theorized to help speed the recovery process after acute hamstring injury. To date, the literature demonstrates mixed and limited benefit of PRP injection therapy for acute hamstring injury.
Few studies have shown improvements of PRP therapy over typical nonoperative management (rest, physical therapy, nonsteroidal anti-inflammatory drugs) in acute hamstring injury, but the results must be interpreted carefully.48,49 Wetzel and colleagues48 retrospectively reviewed 17 patients with acute hamstring injury, 12 of whom failed typical management and received PRP injection at the hamstring origin. This group demonstrated significant improvements in their VAS and Nirschl scores at follow-up, whereas the 5 patients who did not receive the injection did not. However, this study exhibited significant limitations inherent to a retrospective review with a small sample size. Hamid and colleagues49 conducted a randomized controlled trial of 24 athletes with diagnosed grade 2a acute hamstring injuries, comparing autologous PRP therapy combined with a rehabilitation program versus rehabilitation program alone. RTP, changes in pain severity (Brief Pain Injury-Short Form [BPI-SF] questions 2-6), and pain interference (BPI-SF questions 9A-9G) scores over time were examined. Athletes in the PRP group exhibited no difference in outcomes scores, but returned to play sooner than controls (26.7 vs 42.5 days).
Mejia and Bradley50 have reported their experience in treating 12 National Football League (NFL) players with acute MRI grade 1 or 2 hamstring injuries with a series of PRP injections at the site of injury. They found a 1-game difference in earlier RTP when compared to the predicted RTP based on MRI grading. Similarly, Hamid and colleagues49 performed a randomized control trial published in 2014, reporting an earlier RTP (26.7 vs 42.5 days) when comparing single PRP injection vs rehabilitation alone in 28 patients diagnosed with acute ultrasound grade 2 hamstring injuries. On the contrary, a small case-control study of NFL players and a retrospective cohort study of athletes with severe hamstring injuries demonstrated no difference in RTP when PRP injected patients were compared with controls.51,52 Larger randomized controlled trials have demonstrated comparable results, including a study of 90 professional athletes in whom a single PRP injection did not decrease RTP or lessen the risk of re-injury at 2 and 6 months.53 In another large multicenter randomized controlled trial examining 80 competitive and recreational athletes, PRP did not accelerate RTP, lessen the risk of 2-month or 1-year re-injury rate, or improve secondary measures of MRI parameters, subjective patient satisfaction, or the hamstring outcome score.54 Although further study is warranted, available evidence suggests limited utility of PRP injection in the treatment of acute hamstring injuries.
Achilles Tendinopathy
Noninsertional Achilles tendinopathy is a common source of pain for both recreational and competitive athletes. Typically thought of as an overuse syndrome, Achilles tendinopathy may result in significant pain and swelling, often at the site of its tenuous blood supply, approximately 2 to 7 cm proximal to its insertion.55 Conservative management frequently begins with rest, activity/shoe modification, physical therapy, and eccentric loading exercises.56 For those whom conservative management has failed to reduce symptoms after 6 months, more invasive treatment options may be considered. Peritendinous PRP injection has become an alternative approach in treating Achilles tendinopathy refractory to conservative treatment.
In the few randomized controlled trials published, the data demonstrates no significant improvements in clinical outcomes from PRP injection for Achilles tendinopathy. Kearney and colleagues57 conducted a pilot study of 20 patients randomized into PRP injection or eccentric loading program for mid-substance Achilles tendinopathy, in which Victorian Institute of Sports Assessment (VISA-A), EuroQol 5 dimensions questionnaire (EQ-5D), and complications associated with the injection were recorded at 6 weeks, 3 months, and 6 months. Although this was a pilot study with a small sample size, no significant difference was found between groups across these time periods. Similarly, de Vos and colleagues58,59 conducted a double-blind randomized controlled trial of 54 patients with chronic mid-substance Achilles tendinopathy and randomized them into eccentric exercise therapy with either a PRP injection or a saline injected placebo groups. VISA-A scores were recorded and imaging parameters assessing tendon structure by ultrasonographic tissue characterization and color Doppler ultrasonography were taken with follow-up at 6, 12, and 24 weeks. VISA-A scores improved significantly in both groups after 24 weeks, but the difference was not statistically significant between groups. In addition, tendon structure and neovascularization (exhibited by color Doppler ultrasonography) improved in both groups, with no significant difference between groups. The current literature does not support the use of PRP in treatment of Achilles tendinopathy, as it has failed to reveal additional benefits over conventional treatment alone. Future prospective, well-designed randomized controlled trials with large sample sizes will need to be conducted to ultimately conclude whether or not PRP deserves a role in the treatment of Achilles tendinopathy.
Summary
In theory, the use of PRP within orthopedic surgery makes a great deal of sense to accelerate and augment the healing process of the aforementioned musculoskeletal injuries. However, the vast majority of published literature is Level III and IV evidence. Future research may provide the missing critical information of optimal growth factor, platelet, and leukocyte concentrations necessary for the desired effect, as well as the appropriate delivery method and timing of PRP application in different target tissues. Evidence-based guidelines to direct the use of PRP will benefit from more homogenous, repeatable, and randomized controlled trials.
1. Hsu WK, Mishra A, Rodeo SR, et al. Platelet-rich plasma in orthopaedic applications: evidence-based recommendations for treatment. J Am Acad Orthop Surg. 2013;21(12):739-748.
2. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg. 2004;62(4):489-496.
3. Jo CH, Kim JE, Yoon KS, et al. Does platelet-rich plasma accelerate recovery after rotator cuff repair? A prospective cohort study. Am J Sports Med. 2011;39(10):2082-2090.
4. Burkhart SS, Danaceau SM, Pearce CE Jr. Arthroscopic rotator cuff repair: Analysis of results by tear size and by repair technique-margin convergence versus direct tendon-to-bone repair. Arthroscopy. 2001;17(9):905-912.
5. Severud EL, Ruotolo C, Abbott DD, Nottage WM. All-arthroscopic versus mini-open rotator cuff repair: A long-term retrospective outcome comparison. Arthroscopy. 2003;19(3):234-238.
6. Huang R, Wang S, Wang Y, Qin X, Sun Y. Systematic review of all-arthroscopic versus mini-open repair of rotator cuff tears: a meta-analysis. Sci Rep. 2016;6:22857.
7. Watson EM, Sonnabend DH. Outcome of rotator cuff repair. J Shoulder Elbow Surg. 2002;11(3):201-211.
8. Butler DL, Juncosa N, Dressler MR. Functional efficacy of tendon repair processes. Annu Rev Biomed Eng. 2004;6:303-329.
9. Galatz LM, Ball CM, Teefey SA, Middleton WD, Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears. J Bone Joint Surg Am. 2004;86-A(2):219-224.
10. Lafosse L, Brozska R, Toussaint B, Gobezie R. The outcome and structural integrity of arthroscopic rotator cuff repair with use of the double-row suture anchor technique. J Bone Joint Surg Am. 2007;89(7):1533-1541.
11. Castricini R, Longo UG, De Benedetto M, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med. 2011;39(2):258-265.
12. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518-528.
13. Weber SC, Kauffman JI, Parise C, Weber SJ, Katz SD. Platelet-rich fibrin matrix in the management of arthroscopic repair of the rotator cuff: a prospective, randomized, double-blinded study. Am J Sports Med. 2013;41(2):263-270.
14. Gumina S, Campagna V, Ferrazza G, et al. Use of platelet-leukocyte membrane in arthroscopic repair of large rotator cuff tears: a prospective randomized study. J Bone Joint Surg Am. 2012;94(15):1345-1352.
15. Rodeo SA, Delos D, Williams RJ, Adler RS, Pearle A, Warren RF. The effect of platelet-rich fibrin matrix on rotator cuff tendon healing: a prospective, randomized clinical study. Am J Sports Med. 2012;40(6):1234-1241.
16. Warth RJ, Dornan GJ, James EW, Horan MP, Millett PJ. Clinical and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears with and without platelet-rich product supplementation: a meta-analysis and meta-regression. Arthroscopy. 2015;31(2):306-320.
17. Zhao JG, Zhao L, Jiang YX, Wang ZL, Wang J, Zhang P. Platelet-rich plasma in arthroscopic rotator cuff repair: a meta-analysis of randomized controlled trials. Arthroscopy. 2015;31(1):125-135.
18. Glyn-Jones S, Palmer AJ, Agricola R, et al. Osteoarthritis. Lancet. 2015;386(9991):376-387.
19. Cerza F, Carni S, Carcangiu A, et al. Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis. Am J Sports Med. 2012;40(12):2822-2827.
20. Filardo G, Kon E, Di Martino A, et al. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord. 2012;13:229.
21. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med. 2013;41(2):356-364.
22. Sanchez M, Fiz N, Azofra J, et al. A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy. 2012;28(8):1070-1078.
23. Campbell KA, Saltzman BM, Mascarenhas R, et al. Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? A systematic review of overlapping meta-analyses. Arthroscopy. 2015;31(11):2213-2221.
24. Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: A systematic review. Arthroscopy. 2016;32(3):495-505.
25. Smith PA. Intra-articular autologous conditioned plasma injections provide safe and efficacious treatment for knee osteoarthritis: An FDA-sanctioned, randomized, double-blind, placebo-controlled clinical trial. Am J Sports Med. 2016;44(4):884-891.
26. Podesta L, Crow SA, Volkmer D, Bert T, Yocum LA. Treatment of partial ulnar collateral ligament tears in the elbow with platelet-rich plasma. Am J Sports Med. 2013;41(7):1689-1694.
27. Herquelot E, Gueguen A, Roquelaure Y, et al. Work-related risk factors for incidence of lateral epicondylitis in a large working population. Scand J Work Environ Health. 2013;39(6):578-588.
28. Titchener AG, Fakis A, Tambe AA, Smith C, Hubbard RB, Clark DI. Risk factors in lateral epicondylitis (tennis elbow): a case-control study. J Hand Surg Eur Vol. 2013;38(2):159-164.
29. Gruchow HW, Pelletier D. An epidemiologic study of tennis elbow. Incidence, recurrence, and effectiveness of prevention strategies. Am J Sports Med. 1979;7(4):234-238.
30. Sanders TL Jr, Maradit Kremers H, Bryan AJ, Ransom JE, Smith J, Morrey BF. The epidemiology and health care burden of tennis elbow: a population-based study. Am J Sports Med. 2015;43(5):1066-1071.
31. Coonrad RW, Hooper WR. Tennis elbow: its course, natural history, conservative and surgical management. J Bone Joint Surg Am. 1973;55(6):1177-1182.
32. Taylor SA, Hannafin JA. Evaluation and management of elbow tendinopathy. Sports Health. 2012;4(5):384-393.
33. Sims SE, Miller K, Elfar JC, Hammert WC. Non-surgical treatment of lateral epicondylitis: a systematic review of randomized controlled trials. Hand (NY). 2014;9(4):419-446.
34. Brummel J, Baker CL 3rd, Hopkins R, Baker CL Jr. Epicondylitis: lateral. Sports Med Arthrosc. 2014;22(3):e1-e6.
35. de Vos RJ, Windt J, Weir A. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br J Sports Med. 2014;48(12):952-956.
36. Ahmad Z, Brooks R, Kang SN, et al. The effect of platelet-rich plasma on clinical outcomes in lateral epicondylitis. Arthroscopy. 2013;29(11):1851-1862.
37. Arirachakaran A, Sukthuayat A, Sisayanarane T, Laoratanavoraphong S, Kanchanatawan W, Kongtharvonskul J. Platelet-rich plasma versus autologous blood versus steroid injection in lateral epicondylitis: systematic review and network meta-analysis. J Orthop Traumatol. 2016;17(2):101-112.
38. Chaudhury S, de La Lama M, Adler RS, et al. Platelet-rich plasma for the treatment of lateral epicondylitis: sonographic assessment of tendon morphology and vascularity (pilot study). Skeletal Radiol. 2013;42(1):91-97.
39. Brkljac M, Kumar S, Kalloo D, Hirehal K. The effect of platelet-rich plasma injection on lateral epicondylitis following failed conservative management. J Orthop. 2015;12(Suppl 2):S166-S170.
40. Yadav R, Kothari SY, Borah D. Comparison of local injection of platelet rich plasma and corticosteroids in the treatment of lateral epicondylitis of humerus. J Clin Diagn Res. 2015;9(7):RC05-RC07.
41. Gautam VK, Verma S, Batra S, Bhatnagar N, Arora S. Platelet-rich plasma versus corticosteroid injection for recalcitrant lateral epicondylitis: clinical and ultrasonographic evaluation. J Orthop Surg (Hong Kong). 2015;23(1):1-5.
42. Krogh TP, Fredberg U, Stengaard-Pedersen K, Christensen R, Jensen P, Ellingsen T. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med. 2013;41(3):625-635.
43. Behera P, Dhillon M, Aggarwal S, Marwaha N, Prakash M. Leukocyte-poor platelet-rich plasma versus bupivacaine for recalcitrant lateral epicondylar tendinopathy. J Orthop Surg (Hong Kong). 2015;23(1):6-10.
44. Mishra AK, Skrepnik NV, Edwards SG, et al. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med. 2014;42(2):463-471.
45. van der Horst N, van de Hoef S, Reurink G, Huisstede B, Backx F. Return to play after hamstring injuries: a qualitative systematic review of definitions and criteria. Sports Med. 2016;46(6):899-912.
46. Crema MD, Guermazi A, Tol JL, Niu J, Hamilton B, Roemer FW. Acute hamstring injury in football players: Association between anatomical location and extent of injury-A large single-center MRI report. J Sci Med Sport. 2016;19(4):317-322.
47. Ekstrand J, Lee JC, Healy JC. MRI findings and return to play in football: a prospective analysis of 255 hamstring injuries in the UEFA Elite Club Injury Study. Br J Sports Med. 2016;50(12):738-743.
48. Wetzel RJ, Patel RM, Terry MA. Platelet-rich plasma as an effective treatment for proximal hamstring injuries. Orthopedics. 2013;36(1):e64-e70.
49. Hamid A, Mohamed Ali MR, Yusof A, George J, Lee LP. Platelet-rich plasma injections for the treatment of hamstring injuries: a randomized controlled trial. Am J Sports Med. 2014;42(10):2410-2418.
50. Mejia HA, Bradley JP. The effects of platelet-rich plasma on muscle: basic science and clinical application. Operative Techniques in Sports Medicine. 2011;19(3):149-153.
51. Guillodo Y, Madouas G, Simon T, Le Dauphin H, Saraux A. Platelet-rich plasma (PRP) treatment of sports-related severe acute hamstring injuries. Muscles Ligaments Tendons J. 2015;5(4):284-288.
52. Rettig AC, Meyer S, Bhadra AK. Platelet-rich plasma in addition to rehabilitation for acute hamstring injuries in NFL players: Clinical effects and time to return to play. Orthop J Sports Med. 2013;1(1):2325967113494354.
53. Hamilton B, Tol JL, Almusa E, et al. Platelet-rich plasma does not enhance return to play in hamstring injuries: a randomised controlled trial. Br J Sports Med. 2015;49(14):943-950.
54. Reurink G, Goudswaard GJ, Moen MH, et al. Rationale, secondary outcome scores and 1-year follow-up of a randomised trial of platelet-rich plasma injections in acute hamstring muscle injury: the Dutch Hamstring Injection Therapy study. Br J Sports Med. 2015;49(18):1206-1212.
55. Kujala UM, Sarna S, Kaprio J. Cumulative incidence of achilles tendon rupture and tendinopathy in male former elite athletes. Clin J Sport Med. 2005;15(3):133-135.
56. Alfredson H. Clinical commentary of the evolution of the treatment for chronic painful mid-portion Achilles tendinopathy. Braz J Phys Ther. 2015;19(5):429-432.
57. Kearney RS, Parsons N, Costa ML. Achilles tendinopathy management: A pilot randomised controlled trial comparing platelet-rich plasma injection with an eccentric loading programme. Bone Joint Res. 2013;2(10):227-232.
58. de Vos RJ, Weir A, Tol JL, Verhaar JA, Weinans H, van Schie HT. No effects of PRP on ultrasonographic tendon structure and neovascularisation in chronic midportion Achilles tendinopathy. Br J Sports Med. 2011;45(5):387-392.
59. de Vos RJ, Weir A, van Schie HT, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA. 2010;303(2):144-149.
1. Hsu WK, Mishra A, Rodeo SR, et al. Platelet-rich plasma in orthopaedic applications: evidence-based recommendations for treatment. J Am Acad Orthop Surg. 2013;21(12):739-748.
2. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg. 2004;62(4):489-496.
3. Jo CH, Kim JE, Yoon KS, et al. Does platelet-rich plasma accelerate recovery after rotator cuff repair? A prospective cohort study. Am J Sports Med. 2011;39(10):2082-2090.
4. Burkhart SS, Danaceau SM, Pearce CE Jr. Arthroscopic rotator cuff repair: Analysis of results by tear size and by repair technique-margin convergence versus direct tendon-to-bone repair. Arthroscopy. 2001;17(9):905-912.
5. Severud EL, Ruotolo C, Abbott DD, Nottage WM. All-arthroscopic versus mini-open rotator cuff repair: A long-term retrospective outcome comparison. Arthroscopy. 2003;19(3):234-238.
6. Huang R, Wang S, Wang Y, Qin X, Sun Y. Systematic review of all-arthroscopic versus mini-open repair of rotator cuff tears: a meta-analysis. Sci Rep. 2016;6:22857.
7. Watson EM, Sonnabend DH. Outcome of rotator cuff repair. J Shoulder Elbow Surg. 2002;11(3):201-211.
8. Butler DL, Juncosa N, Dressler MR. Functional efficacy of tendon repair processes. Annu Rev Biomed Eng. 2004;6:303-329.
9. Galatz LM, Ball CM, Teefey SA, Middleton WD, Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears. J Bone Joint Surg Am. 2004;86-A(2):219-224.
10. Lafosse L, Brozska R, Toussaint B, Gobezie R. The outcome and structural integrity of arthroscopic rotator cuff repair with use of the double-row suture anchor technique. J Bone Joint Surg Am. 2007;89(7):1533-1541.
11. Castricini R, Longo UG, De Benedetto M, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med. 2011;39(2):258-265.
12. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518-528.
13. Weber SC, Kauffman JI, Parise C, Weber SJ, Katz SD. Platelet-rich fibrin matrix in the management of arthroscopic repair of the rotator cuff: a prospective, randomized, double-blinded study. Am J Sports Med. 2013;41(2):263-270.
14. Gumina S, Campagna V, Ferrazza G, et al. Use of platelet-leukocyte membrane in arthroscopic repair of large rotator cuff tears: a prospective randomized study. J Bone Joint Surg Am. 2012;94(15):1345-1352.
15. Rodeo SA, Delos D, Williams RJ, Adler RS, Pearle A, Warren RF. The effect of platelet-rich fibrin matrix on rotator cuff tendon healing: a prospective, randomized clinical study. Am J Sports Med. 2012;40(6):1234-1241.
16. Warth RJ, Dornan GJ, James EW, Horan MP, Millett PJ. Clinical and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears with and without platelet-rich product supplementation: a meta-analysis and meta-regression. Arthroscopy. 2015;31(2):306-320.
17. Zhao JG, Zhao L, Jiang YX, Wang ZL, Wang J, Zhang P. Platelet-rich plasma in arthroscopic rotator cuff repair: a meta-analysis of randomized controlled trials. Arthroscopy. 2015;31(1):125-135.
18. Glyn-Jones S, Palmer AJ, Agricola R, et al. Osteoarthritis. Lancet. 2015;386(9991):376-387.
19. Cerza F, Carni S, Carcangiu A, et al. Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis. Am J Sports Med. 2012;40(12):2822-2827.
20. Filardo G, Kon E, Di Martino A, et al. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord. 2012;13:229.
21. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med. 2013;41(2):356-364.
22. Sanchez M, Fiz N, Azofra J, et al. A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy. 2012;28(8):1070-1078.
23. Campbell KA, Saltzman BM, Mascarenhas R, et al. Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? A systematic review of overlapping meta-analyses. Arthroscopy. 2015;31(11):2213-2221.
24. Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: A systematic review. Arthroscopy. 2016;32(3):495-505.
25. Smith PA. Intra-articular autologous conditioned plasma injections provide safe and efficacious treatment for knee osteoarthritis: An FDA-sanctioned, randomized, double-blind, placebo-controlled clinical trial. Am J Sports Med. 2016;44(4):884-891.
26. Podesta L, Crow SA, Volkmer D, Bert T, Yocum LA. Treatment of partial ulnar collateral ligament tears in the elbow with platelet-rich plasma. Am J Sports Med. 2013;41(7):1689-1694.
27. Herquelot E, Gueguen A, Roquelaure Y, et al. Work-related risk factors for incidence of lateral epicondylitis in a large working population. Scand J Work Environ Health. 2013;39(6):578-588.
28. Titchener AG, Fakis A, Tambe AA, Smith C, Hubbard RB, Clark DI. Risk factors in lateral epicondylitis (tennis elbow): a case-control study. J Hand Surg Eur Vol. 2013;38(2):159-164.
29. Gruchow HW, Pelletier D. An epidemiologic study of tennis elbow. Incidence, recurrence, and effectiveness of prevention strategies. Am J Sports Med. 1979;7(4):234-238.
30. Sanders TL Jr, Maradit Kremers H, Bryan AJ, Ransom JE, Smith J, Morrey BF. The epidemiology and health care burden of tennis elbow: a population-based study. Am J Sports Med. 2015;43(5):1066-1071.
31. Coonrad RW, Hooper WR. Tennis elbow: its course, natural history, conservative and surgical management. J Bone Joint Surg Am. 1973;55(6):1177-1182.
32. Taylor SA, Hannafin JA. Evaluation and management of elbow tendinopathy. Sports Health. 2012;4(5):384-393.
33. Sims SE, Miller K, Elfar JC, Hammert WC. Non-surgical treatment of lateral epicondylitis: a systematic review of randomized controlled trials. Hand (NY). 2014;9(4):419-446.
34. Brummel J, Baker CL 3rd, Hopkins R, Baker CL Jr. Epicondylitis: lateral. Sports Med Arthrosc. 2014;22(3):e1-e6.
35. de Vos RJ, Windt J, Weir A. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br J Sports Med. 2014;48(12):952-956.
36. Ahmad Z, Brooks R, Kang SN, et al. The effect of platelet-rich plasma on clinical outcomes in lateral epicondylitis. Arthroscopy. 2013;29(11):1851-1862.
37. Arirachakaran A, Sukthuayat A, Sisayanarane T, Laoratanavoraphong S, Kanchanatawan W, Kongtharvonskul J. Platelet-rich plasma versus autologous blood versus steroid injection in lateral epicondylitis: systematic review and network meta-analysis. J Orthop Traumatol. 2016;17(2):101-112.
38. Chaudhury S, de La Lama M, Adler RS, et al. Platelet-rich plasma for the treatment of lateral epicondylitis: sonographic assessment of tendon morphology and vascularity (pilot study). Skeletal Radiol. 2013;42(1):91-97.
39. Brkljac M, Kumar S, Kalloo D, Hirehal K. The effect of platelet-rich plasma injection on lateral epicondylitis following failed conservative management. J Orthop. 2015;12(Suppl 2):S166-S170.
40. Yadav R, Kothari SY, Borah D. Comparison of local injection of platelet rich plasma and corticosteroids in the treatment of lateral epicondylitis of humerus. J Clin Diagn Res. 2015;9(7):RC05-RC07.
41. Gautam VK, Verma S, Batra S, Bhatnagar N, Arora S. Platelet-rich plasma versus corticosteroid injection for recalcitrant lateral epicondylitis: clinical and ultrasonographic evaluation. J Orthop Surg (Hong Kong). 2015;23(1):1-5.
42. Krogh TP, Fredberg U, Stengaard-Pedersen K, Christensen R, Jensen P, Ellingsen T. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med. 2013;41(3):625-635.
43. Behera P, Dhillon M, Aggarwal S, Marwaha N, Prakash M. Leukocyte-poor platelet-rich plasma versus bupivacaine for recalcitrant lateral epicondylar tendinopathy. J Orthop Surg (Hong Kong). 2015;23(1):6-10.
44. Mishra AK, Skrepnik NV, Edwards SG, et al. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med. 2014;42(2):463-471.
45. van der Horst N, van de Hoef S, Reurink G, Huisstede B, Backx F. Return to play after hamstring injuries: a qualitative systematic review of definitions and criteria. Sports Med. 2016;46(6):899-912.
46. Crema MD, Guermazi A, Tol JL, Niu J, Hamilton B, Roemer FW. Acute hamstring injury in football players: Association between anatomical location and extent of injury-A large single-center MRI report. J Sci Med Sport. 2016;19(4):317-322.
47. Ekstrand J, Lee JC, Healy JC. MRI findings and return to play in football: a prospective analysis of 255 hamstring injuries in the UEFA Elite Club Injury Study. Br J Sports Med. 2016;50(12):738-743.
48. Wetzel RJ, Patel RM, Terry MA. Platelet-rich plasma as an effective treatment for proximal hamstring injuries. Orthopedics. 2013;36(1):e64-e70.
49. Hamid A, Mohamed Ali MR, Yusof A, George J, Lee LP. Platelet-rich plasma injections for the treatment of hamstring injuries: a randomized controlled trial. Am J Sports Med. 2014;42(10):2410-2418.
50. Mejia HA, Bradley JP. The effects of platelet-rich plasma on muscle: basic science and clinical application. Operative Techniques in Sports Medicine. 2011;19(3):149-153.
51. Guillodo Y, Madouas G, Simon T, Le Dauphin H, Saraux A. Platelet-rich plasma (PRP) treatment of sports-related severe acute hamstring injuries. Muscles Ligaments Tendons J. 2015;5(4):284-288.
52. Rettig AC, Meyer S, Bhadra AK. Platelet-rich plasma in addition to rehabilitation for acute hamstring injuries in NFL players: Clinical effects and time to return to play. Orthop J Sports Med. 2013;1(1):2325967113494354.
53. Hamilton B, Tol JL, Almusa E, et al. Platelet-rich plasma does not enhance return to play in hamstring injuries: a randomised controlled trial. Br J Sports Med. 2015;49(14):943-950.
54. Reurink G, Goudswaard GJ, Moen MH, et al. Rationale, secondary outcome scores and 1-year follow-up of a randomised trial of platelet-rich plasma injections in acute hamstring muscle injury: the Dutch Hamstring Injection Therapy study. Br J Sports Med. 2015;49(18):1206-1212.
55. Kujala UM, Sarna S, Kaprio J. Cumulative incidence of achilles tendon rupture and tendinopathy in male former elite athletes. Clin J Sport Med. 2005;15(3):133-135.
56. Alfredson H. Clinical commentary of the evolution of the treatment for chronic painful mid-portion Achilles tendinopathy. Braz J Phys Ther. 2015;19(5):429-432.
57. Kearney RS, Parsons N, Costa ML. Achilles tendinopathy management: A pilot randomised controlled trial comparing platelet-rich plasma injection with an eccentric loading programme. Bone Joint Res. 2013;2(10):227-232.
58. de Vos RJ, Weir A, Tol JL, Verhaar JA, Weinans H, van Schie HT. No effects of PRP on ultrasonographic tendon structure and neovascularisation in chronic midportion Achilles tendinopathy. Br J Sports Med. 2011;45(5):387-392.
59. de Vos RJ, Weir A, van Schie HT, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA. 2010;303(2):144-149.
Stem Cells in Orthopedics: A Comprehensive Guide for the General Orthopedist
Biologic use in orthopedics is a continuously evolving field that complements technical, anatomic, and biomechanical advancements in orthopedics. Biologic agents are receiving increasing attention for their use in augmenting healing of muscles, tendons, ligaments, and osseous structures. As biologic augmentation strategies become increasingly utilized in bony and soft-tissue injuries, research on stem cell use in orthopedics continues to increase. Stem cell-based therapies for the repair or regeneration of muscle and tendon represent a promising technology going forward for numerous diseases.1
Stem cells by definition are undifferentiated cells that have 4 main characteristics: (1) mobilization during angiogenesis, (2) differentiation into specialized cell types, (3) proliferation and regeneration, and (4) release of immune regulators and growth factors.2 Mesenchymal stem cells (MSCs) have garnered the most attention in the field of surgery due to their ability to differentiate into the tissues of interest for the surgeon.3 This includes both bone marrow-derived mesenchymal stem cells (bm-MSCs) and adipose-derived mesenchymal stem cells (a-MSCs). These multipotent stem cells in adults originate from mesenchymal tissues, including bone marrow, tendon, adipose, and muscle tissue.4 They are attractive for clinical use because of their multipotent potential and relative ease of growth in culture.5 They also exert a paracrine effect to modulate and control inflammation, stimulate endogenous cell repair and proliferation, inhibit apoptosis, and improve blood flow through secretion of chemokines, cytokines, and growth factors.6,7
Questions exist regarding the best way to administer stem cells, whether systematic administration is possible for these cells to localize to the tissue in need, or more likely if direct application to the pathologic area is necessary.8,9 A number of sources, purification process, and modes of delivery are available, but the most effective means of preparation and administration are still under investigation. The goal of this review is to illustrate the current state of knowledge surrounding stem cell therapy in orthopedics with a focus on osteoarthritis, tendinopathy, articular cartilage, and enhancement of surgical procedures.
Important Considerations
Common stem cell isolates include embryonic, induced pluripotent, and mesenchymal formulations (Table 1). MSCs can be obtained from multiple sites, including but not limited to the adult bone marrow, adipose, muscular, or tendinous tissues, and their use has been highlighted in the study of numerous orthopedic and nonorthopedic pathologies over the course of the last decade. Research on the use of embryonic stem cells in medical therapy with human implications has received substantial attention, with many ethical concerns by those opposed, and the existence of a potential risk of malignant alterations.8,10 Amniotic-derived stem cells can be isolated from amniotic fluid, umbilical cord blood, or the placenta and thus do not harbor the same social constraints as the aforementioned embryonic cells; however, they do not harbor the same magnitude of multi-differentiation potential, either.4
Adult MSCs are more locally available and easy to obtain for treatment when compared with embryonic and fetal stem cells, and the former has a lower immunogenicity, which allows allogeneic use.11 Safety has been preliminarily demonstrated in use thus far; Centeno and colleagues12 found no neoplastic tissue generation at the site of stem cell injection after 3 years postinjection for a cohort of patients who were treated with autologous bm-MSCs for various pathologies. Self-limited pain and swelling are the most commonly reported adverse events after use.13 However, long-term data are lacking in many instances to definitively suggest the absence of possible complications.
Basic Science
Stem cell research encompasses a wide range of rapidly developing treatment strategies that are applicable to virtually every field of medicine. In general, stem cells can be classified as embryonic stem cells (ESCs), induced pluripotent stem (iPS) cells, or adult-derived MSCs. ESCs are embryonic cells derived typically from fetal tissue, whereas iPS cells are dedifferentiated from adult tissue, thus avoiding many of the ethical and legal challenges imposed by research with ESCs. However, oncogenic and lingering politico-legal concerns with introducing dedifferentiated ESCs or iPS cells into healthy tissue necessitate the development, isolation, and expansion of multi- but not pluripotent stem cell lines.14 To date, the most advantageous and widely utilized from any perspective are MSCs, which can further differentiate into cartilage, tendon, muscle, and bony tissue.7,15,16
MSCs are defined by their ability to demonstrate in vitro differentiation into osteoblasts, adipocytes, or chondroblasts, adhere to plastic, express CD105, CD73, and CD90, and not express CD43, CD23, CD14 or CD11b, CD79 or CD19, or HLA-DR.17 Porada and Almeida-Porada18 have outlined 6 reasons highlighting the advantages of MSCs: 1) ease of isolation, 2) high differentiation capabilities, 3) strong colony expansion without differentiation loss, 4) immunosuppression following transplantation, 5) powerful anti-inflammatory properties, and 6) their ability to localize to damaged tissue. The anti-inflammatory properties of MSCs are particularly important as they promote allo- and xenotransplantation from donor tissues.19,20 MSCs can be isolated from numerous sources, including but not limited to bone marrow, periosteum, adipocyte, and muscle.21-23 Interestingly, the source tissue used to isolate MSCs can affect differentiation capabilities, colony size, and growth rate (Table 2).24 Advantages of a-MSCs include high prevalence and ease of harvest; however, several animal studies have shown inferior results when compared to bm-MSCs.25-27 More research is needed to determine the ideal source material for MSCs, which will likely depend in part on the procedure for which they are employed.27
Following harvesting, isolation, and expansion, MSC delivery methods for treatments typically consist of either cell-based or tissue engineering approaches. Cell-based techniques involve the injection of MSCs into damaged tissues. Purely cell-based therapy has shown success in limited clinical trials involving knee osteoarthritis, cartilage repair, and meniscal repair.28-30 However, additional studies with longer follow-up are required to validate these preliminary findings. Tissue engineering approaches involve the construction of a 3-dimensional scaffold seeded with MSCs that is later surgically implanted. While promising in theory, limited and often conflicting data exist regarding the efficacy of tissue-engineered MSC implantation.31-32 Suboptimal scaffold vascularity is a major limitation to scaffold design, which may be alleviated in part with the advent of 3-dimensional printing and the ability to more precisely alter scaffold architecture.14,33 Additional limitations include ensuring MSC purity and differentiation potential following harvesting and expansion. At present, the use of tissue engineering with MSCs is promising but it remains a nascent technology with additional preclinical studies required to confirm implant efficacy and safety.
Clinical Entities
Osteoarthritis
MSC therapies have emerged as promising treatment strategies in the setting of early osteoarthritis (OA). In addition to their regenerative potential, MSCs demonstrate potent anti-inflammatory properties, increasing their attractiveness as biologic agents in the setting of OA.34 Over the past decade, multiple human trials have been published demonstrating the efficacy of MSC injections into patients with OA.35,36 In a study evaluating a-MSC injection into elderly patients (age >65 years) with knee OA, Koh and colleagues29 found that 88% demonstrated improved cartilage status at 2-year follow-up, while no patient underwent a total knee arthroplasty during this time period. In another study investigating patients with unicompartmental knee OA with varus alignment undergoing high tibial osteotomy and microfracture, Wong and colleagues37 reported improved clinical, patient-reported, and magnetic resonance imaging (MRI)-based outcomes in a group receiving a preoperative MSC injection compared to a control group. Further, in a recent randomized control trial of patients with knee osteoarthritis, Vega and colleagues38 reported improved cartilage and quality of life outcomes at 1 year following MSC injection compared to a control group receiving a hyaluronic acid injection. In addition to knee OA, studies have also reported improvement in ankle OA following MSC injection.39 While promising, many of the preliminary clinical studies evaluating the efficacy of MSC therapies in the treatment of OA are hindered by small patient populations and short-term follow-up. Additional large-scale, randomized studies are required and many are ongoing presently in hopes of validating these preliminary findings.36
Tendinopathy
The quality of repaired tissue in primary tendon-to-tendon and tendon-to-bone healing has long been a topic of great interest.40 The healing potential of tendons is inferior to that of other bony and connective tissues,41 with tendon healing typically resulting in a biomechanically and histologically inferior structure to the native tissue.42 As such, this has been a particularly salient opportunity for stem cell use with hopes of recapitulating a more normal tendon or tendon enthesis following injury. In addition to the acute injury, there is great interest in the application of stem cells to chronic states of injury such as tendinopathy.
In equine models, the effect of autologous bm-MSCs treatment on tendinopathy of the superficial digital flexor tendon has been studied. Godwin and colleagues43 evaluated 141 race horses with spontaneous superficial digital flexor tendinopathy treated in this manner, and reported a reinjury percentage in these treated horses of just 27.4%, which compared favorably to historical controls and alternative therapeutics. Machova Urdzikova and colleagues44 injected MSCs at Achilles tendinopathy locations to augment nonoperative healing in 40 rats, and identified more native histological organization and improved vascularization in comparison to control rat specimens. Oshita and colleagues45 reported histologic improvement of tendinopathy findings in 8 rats receiving a-MSCs at the location of induced Achilles tendinopathy that was significantly superior to a control cohort. Bm-MSCs were used by Yuksel and colleagues46 in comparison with platelet-rich plasma (PRP) for treatment of Achilles tendon ruptures created surgically in rat models. They demonstrated successful effects with its use in terms of recovery for the tendon’s histopathologic, immunohistochemical, and biomechanical properties, related to significantly greater levels of anti-inflammatory cytokines. However, these aforementioned findings have not been uniform across the literature—other authors have reported findings that MSC transplantation alone did not repair Achilles tendon injury with such high levels of success.47
Human treatment of tendinopathies with stem cells has been scarcely studied to date. Pascual-Garrido and colleagues48 evaluated 8 patients with refractory patellar tendinopathy treated with injection of autologous bm-MSCs and reported successful results at 2- to 5-year follow-up, with significant improvements in patient-reported outcome measures for 100% of patients. Seven of 8 (87.5%) noted that they would undergo the procedure again.
Articular Cartilage Injury
Chondral injury is a particularly important subject given the limited potential of chondrocytes to replicate or migrate to the site of pathology.49 Stem cell use in this setting assists with programmed growth factor release and alteration of the anatomic microenvironment to facilitate regeneration and repair of the chondral surface. Autologous stem cell use through microfracture provides a perforation into the bone marrow and a subsequent fibrin clot formation containing platelets, growth factors, vascular elements, and MSCs.50 A similar concept to PRP is currently being explored with bm-MSCs. Isolated bm-MSCs are commonly referred to as bone marrow aspirate or bone marrow aspirate concentrate (BMAC). Commercially available systems are now available to aid in the harvesting and implementation of BMAC. One of the more promising avenues for BMAC implementation is in articular cartilage repair or regeneration due to chondrogenic potential of BMAC when used in isolation or when combined with microfracture, chondrocyte transfer, or collagen scaffolds.19,51 Synovial-derived stem cells as an additional source for stem cell use has demonstrated excellent chondrogenic potential in animal studies with full-thickness lesion healing and native-appearing cartilage histologically.52 Incorporation of a-MSCs into scaffolds for surgical implantation has demonstrated success in repairing full-thickness chondral defects with continuous joint surface and extracellular proteins, surface markers, and gene products similar to the native cartilage in animal models.53,54 In light of the promising basic science and animal studies, clinical studies have begun to emerge.55-57
Fortier and colleagues58 found MRI and histologic evidence of full-thickness chondral repair and increased integration with neighboring cartilage when BMAC was concurrently used at the time of microfracture in an equine model. Fortier and colleagues58 also demonstrated greater healing in equine models with acute full-thickness cartilage defects treated by microfracture with MSCs than without delivery of MSCs. Kim and colleagues59,60 similarly reported superiority in clinical outcomes for patients with osteochondral lesions of the talus treated with marrow stimulation and MSC injection than by the former in isolation.
In humans, stem cell use for chondral repair has additionally proven promising. A systematic review of the literature suggested good to excellent overall outcomes for the treatment of moderate focal chondral defects with BMAC with or without scaffolds and microfracture with inclusion of 8 total publications.61 This review included Gobbi and colleagues,62 who prospectively treated 15 patients with a mean focal chondral defect size of 9.2 cm2 about the knee. Use of BMAC covered with a collagen I/III matrix produced significant improvements in patient-reported outcome scores and MRI demonstrated complete hyaline-like cartilage coverage in 80%, with second-look arthroscopy demonstrating normal to nearly normal tissue. Gobbi and colleagues55 also found evidence for superiority of chondral defects treated with BMAC compared to matrix-induced autologous chondrocyte implantation (MACI) for patellofemoral lesions in 37 patients (MRI showed complete filling of defects in 81% of BMAC-treated patients vs 76% of MACI-treated patients).
Meniscal Repair
Clinical application of MSCs in the treatment of meniscal pathology is evolving as well. ASCs have been added to modify the biomechanical environment of avascular zone meniscal tears at the time of suture repair in a rabbit, and have demonstrated increased healing rates in small and larger lesions, although the effect lessens with delay in repair.63 Angele and colleagues64 treated meniscal defects in a rabbit model with scaffolds with bm-MSCs compared with empty scaffolds or control cohorts and found a higher proportion of menisci with healed meniscus-like fibrocartilage when MSCs were utilized.
In humans, Vangsness and colleagues30 treated knees with partial medial meniscectomy with allogeneic stem cells and reported an increase in meniscal volume and decrease in pain in those patients when compared to a cohort of knees treated with hyaluronic acid. Despite promising early results, additional clinical studies are necessary to determine the external validity and broad applicability of stem cell use in meniscal repair.
Rotator Cuff Repair
The number of local resident stem cells at the site of rotator cuff tear has been shown to decrease with tear size, chronicity, and degree of fatty infiltration, suggesting that those with the greatest need for a good reparative environment are those least equipped to heal.65 The need for improvement in this domain is related to the still relatively high re-tear rate after rotator cuff repair despite improvements in instrumentation and surgical technique.66 The native fibrocartilaginous transition zone between the humerus and the rotator cuff becomes a fibrovascular scar tissue after rupture and repair with poorer material properties than the native tissue.67 Thus, a-MSCs have been evaluated in this setting to determine if the biomechanical and histological properties of the repair may improve.68
In rat models, Valencia Mora and colleagues68 reported on the application of a-MSCs in a rat rotator cuff repair model compared to an untreated group. They found no differences between those treated rats and those without a-MSCs use in terms of biomechanical properties of the tendon-to-bone healing, but those with stem cell use had less inflammation shown histologically (diminished presence of edema and neutrophils) at 2- and 4-week time points, which the authors suggested may lead to a more elastic repair and less scar at the bone-tendon healing site. Oh and colleagues1 evaluated the use of a-MSCs in a rabbit subscapularis tear model, and reported significantly reduced fatty infiltration at the site of chronic rotator cuff tear after repair with its application at the repair site; while the load-to-failure was higher in those rabbits with ASCs administration, it was short of reaching statistical significance. Yokoya and colleagues69 demonstrated regeneration of rotator cuff tendon-to-bone insertional site anatomy and in the belly of the cuff tendon in a rabbit model with MSCs applied at the operative site. However, Gulotta and colleagues70 did not see the same improvement in their similar study in the rat model; these authors failed to see improvement in structure, strength, or composition of the tendinous attachment site despite addition of MSCs.
Clinical studies on augmented rotator cuff repair have also found mixed results. MSCs for this purpose have been cultivated from arthroscopic bone marrow aspiration of the proximal humerus71 and subacromial bursa72 with successful and reproducibly high concentrations of stem cells. Hernigou and colleagues73 found a significant improvement in rate of healing (87% intact cuffs vs 44% in the control group) and repair surface tendon integrity (via ultrasound and MRI) for patients at a minimum of 10 years after rotator cuff repair with MSC injection at the time of surgery. The authors found a direct correlation in these outcomes with the number of MSCs injected at the time of repair. Ellera Gomes and colleagues74 injected bm-MSCs obtained from the iliac crest into the tendinous repair site in 14 consecutive patients with full-thickness rotator cuff tears treated by transosseous sutures via a mini-open approach. MRI demonstrated integrity of the repair site in all patients at more than 1-year follow-up.
Achilles Tendon Repair
The goal with stem cell use in Achilles repair is to accelerate the healing and rehabilitation. Several animal studies have demonstrated improved mechanical properties and collagen composition of tendon repairs augmented with stem cells, including Achilles tendon repair in a rat model. Adams and colleagues75 compared suture alone (36 tendons) to suture plus stem cell concentrate injection (36 tendons) and stem cell loaded suture (36 tendons) in Achilles tendon repair with rat models. The suture-alone cohort had lower ultimate failure loads at 14 days after surgery, indicating biomechanical superiority with stem cell augmentation means. Transplantation of hypoxic MSCs at the time of Achilles tendon repair may be a promising option for superior biomechanical failure loads and histologic findings as per recent rat model findings by Huang and colleagues.76 Yao and colleagues77 demonstrated increased strength of suture repair for Achilles repair in rat models at early time points when using MSC-coated suture in comparison to standard suture, and suggested that the addition of stem cells may improve early mechanical properties during the tendon repair process. A-MSC addition to PRP has provided significantly increased tensile strength to rabbit models with Achilles tendon repair as well.78
In evaluation of stem cell use for this purpose with humans, Stein and colleagues79 reviewed 28 sports-related Achilles tendon ruptures in 27 patients treated with open repair and BMAC injection. At a mean follow-up of 29.7 months, the authors reported no re-ruptures, with 92% return to sport at 5.9 months, and excellent clinical outcomes. This small cohort study found no adverse outcomes related to the BMAC addition, and thus proposed further study of the efficacy of stem cell treatment for Achilles tendon repair.
Anterior Cruciate Ligament Reconstruction
Bm-MSCs genetically modified with bone morphogenetic protein 2 (BMP2) and basic fibroblast growth factor (bFGF) have shown great promise in improvement of the formation of mechanically sound tendon-bone interface in anterior cruciate ligament (ACL) reconstruction.80 Similar to the other surgical procedures mentioned in this review, animal studies have successfully evaluated the augmentation of osteointegration of tendon to bone in the setting of ACL reconstruction. Jang and colleagues3 investigated the use of nonautologous transplantation of human umbilical cord blood-derived MSCs in a rabbit ACL reconstruction model. The authors demonstrated a lack of immune rejection, and enhanced tendon-bone healing with broad fibrocartilage formation at the transition zone (similar to the native ACL) and decreased femoral and tibial tunnel widening as compared to a control cohort at 12-weeks after surgery. In a rat model, Kanaya and colleagues81 reported improved histological scores and slight improvements in biomechanical integrity of partially transected rat ACLs treated with intra-articular MSC injection. Stem cell use in the form of suture-supporting scaffolds seeded with MSCs has been evaluated in a total ACL transection rabbit model; the authors of this report demonstrated total ACL regeneration in one-third of samples treated with this augmentation option, in comparison to complete failure in all suture and scaffold alone groups.82
The use of autologous MSCs in ACL healing remains limited to preclinical research and small case series of patients. One human trial by Silva and colleagues83 evaluated the graft-to-bone site of healing in ACL reconstruction for 20 patients who received an intraoperative infiltration of their graft with adult bm-MSCs. MRI and histologic analysis showed no difference in comparison to control groups, but the authors’ conclusion proposed that the number of stem cells injected might have been too minimal to show a clinical effect.
Other Applications
Although outside the scope of this article, stem cells have demonstrated efficacy in the treatment of a number of osseous clinical entities. This includes the treatment of fracture nonunion, augmentation of spinal fusion, and assistance in the treatment of osteonecrosis.84
Summary
As a scientific community, our understanding of the use of stem cells, their nuances, and their indications has expanded dramatically over the last several years. Stem cell treatment has particularly infiltrated the world of operative and nonoperative sports medicine, given in part the active patient population seeking greater levels of improvement.85 Stem cell therapy offers a potentially effective therapy for a multitude of pathologies because of these cells’ anti-inflammatory, immunoregulatory, angiogenic, and paracrine effects.86 It thus remains a very dynamic option in the study of musculoskeletal tissue regeneration. While the potential exists for stem cell use in daily surgery practices, it is still premature to predict whether this can be expected.
The ideal stem cell sources (including allogeneic or autologous), preparation, cell number, timing, and means of application continue to be evaluated, as well as those advantageous pathologies that can benefit from the technology. In order to better answer these pertinent questions, we need to make sure we have a safe, economic, and ethically acceptable means for stem cell translational research efforts. More high-level studies with standardized protocols need to be performed. It is necessary to improve national and international collaboration in research, as well as collaboration with governing bodies, to attempt to further scientific advancement in this field of research.49 Further study on embryonic stem cell use may be valuable as well, pending governmental approval. Finally, more dedicated research efforts must be placed on the utility of adjuncts with stem cell use, including PRP and scaffolds, which may increase protection, nutritional support, and mechanical stimulation of the administered stem cells.
1. Oh JH, Chung SW, Kim SH, Chung JY, Kim JY. 2013 Neer Award: Effect of the adipose-derived stem cell for the improvement of fatty degeneration and rotator cuff healing in rabbit model. J Shoulder Elb Surg. 2014;23(4):445-455.
2. Caplan AI, Correa D. PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs. J Orthop Res. 2011;29(12):1795-1803.
3. Jang KM, Lim HC, Jung WY, Moon SW, Wang JH. Efficacy and safety of human umbilical cord blood-derived mesenchymal stem cells in anterior cruciate ligament reconstruction of a rabbit model: new strategy to enhance tendon graft healing. Arthroscopy. 2015;31(8):1530-1539.
4. Muttini A, Salini V, Valbonetti L, Abate M. Stem cell therapy of tendinopathies: suggestions from veterinary medicine. Muscles Ligaments Tendons J. 2012;2(3):187-192.
5. Xia P, Wang X, Lin Q, Li X. Efficacy of mesenchymal stem cells injection for the management of knee osteoarthritis: a systematic review and meta-analysis. Int Orthop. 2015;39(12):2363-2372.
6. Veronesi F, Giavaresi G, Tschon M, Borsari V, Nicoli Aldini N, Fini M. Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem Cells Dev. 2013;22(2):181-192.
7. Caplan AI. Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Eng. 2005;11(7-8):1198-1211.
8. Hirzinger C, Tauber M, Korntner S, et al. ACL injuries and stem cell therapy. Arch Orthop Trauma Surg. 2014;134(11):1573-1578.
9. Becerra P, Valdés Vázquez MA, Dudhia J, et al. Distribution of injected technetium(99m)-labeled mesenchymal stem cells in horses with naturally occurring tendinopathy. J Orthop Res. 2013;31(7):1096-1102.
10. Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. J Exp Clin Cancer Res. 2011;30:9.
11. García-Gómez I, Elvira G, Zapata AG, et al. Mesenchymal stem cells: biological properties and clinical applications. Expert Opin Biol Ther. 2010;10(10):1453-1468.
12. Centeno CJ, Schultz JR, Cheever M, et al. Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2011;6(4):368-378.
13. Centeno CJ, Al-Sayegh H, Freeman MD, Smith J, Murrell WD, Bubnov R. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. Int Orthop. 2016 Mar 30. [Epub ahead of print]
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26. Vidal MA, Robinson SO, Lopez MJ, et al. Comparison of chondrogenic potential in equine mesenchymal stromal cells derived from adipose tissue and bone marrow. Vet Surg. 2008;37(8):713-724.
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28. Hogan MV, Walker GN, Cui LR, Fu FH, Huard J. The role of stem cells and tissue engineering in orthopaedic sports medicine: current evidence and future directions. Arthroscopy. 2015;31(5):1017-1021.
29. Koh YG, Choi YJ, Kwon SK, Kim YS, Yeo JE. Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2015;23(5):1308-1316.
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31. Goodrich LR, Chen AC, Werpy NM, et al. Addition of mesenchymal stem cells to autologous platelet-enhanced fibrin scaffolds in chondral defects: does it enhance repair? J Bone Joint Surg Am. 2016;98(1):23-34.
32. Kim YS, Choi YJ, Suh DS, et al. Mesenchymal stem cell implantation in osteoarthritic knees: is fibrin glue effective as a scaffold? Am J Sports Med. 2015;43(1):176-185.
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34. Pers YM, Ruiz M, Noël D, Jorgensen C. Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives. Osteoarthritis Cartilage. 2015;23(11):2027-2035.
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37. Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy. 2013;29(12):2020-2028.
38. Vega A, Martín-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99(8):1681-1690.
39. Kim YS, Lee M, Koh YG. Additional mesenchymal stem cell injection improves the outcomes of marrow stimulation combined with supramalleolar osteotomy in varus ankle osteoarthritis: short-term clinical results with second-look arthroscopic evaluation. J Exp Orthop. 2016;3(1):12.
40. Kraus TM, Imhoff FB, Reinert J, et al. Stem cells and bFGF in tendon healing: Effects of lentiviral gene transfer and long-term follow-up in a rat Achilles tendon defect model. BMC Musculoskelet Disord. 2016;17(1):148.
41. Thomopoulos S, Parks WC, Rifkin DB, Derwin KA. Mechanisms of tendon injury and repair. J Orthop Res. 2015;33(6):832-839.
42. Müller SA, Todorov A, Heisterbach PE, Martin I, Majewski M. Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. Knee Surg Sports Traumatol Arthrosc. 2015;23(7):2097-3105.
43. Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RK. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44(1):25-32.
44. Machova Urdzikova L, Sedlacek R, Suchy T, et al. Human multipotent mesenchymal stem cells improve healing after collagenase tendon injury in the rat. Biomed Eng Online. 2014;13:42.
45. Oshita T, Tobita M, Tajima S, Mizuno H. Adipose-derived stem cells improve collagenase-induced tendinopathy in a rat model. Am J Sports Med. 2016 Apr 11. [Epub ahead of print]
46. Yuksel S, Guleç MA, Gultekin MZ, et al. Comparison of the early-period effects of bone marrow-derived mesenchymal stem cells and platelet-rich plasma on achilles tendon ruptures in rats. Connect Tissue Res. 2016 May 18. [Epub ahead of print]
47. Chen L, Liu JP, Tang KL, et al. Tendon derived stem cells promote platelet-rich plasma healing in collagenase-induced rat achilles tendinopathy. Cell Physiol Biochem. 2014;34(6):2153-2168.
48. Pascual-Garrido C, Rolón A, Makino A. Treatment of chronic patellar tendinopathy with autologous bone marrow stem cells: a 5-year-followup. Stem Cells Int. 2012;2012:953510.
49. Zlotnicki JP, Geeslin AG, Murray IR, et al. Biologic treatments for sports injuries ii think tank-current concepts, future research, and barriers to advancement, part 3: articular cartilage. Orthop J Sports Med. 2016;4(4):2325967116642433.
50. McCormack RA, Shreve M, Strauss EJ. Biologic augmentation in rotator cuff repair--should we do it, who should get it, and has it worked? Bull Hosp Jt Dis (2013). 2014;72(1):89-96.
51. Mosna F, Sensebé L, Krampera M. Human bone marrow and adipose tissue mesenchymal stem cells: a user’s guide. Stem Cells Dev. 2010;19(10):1449-1470.
52. Nakamura T, Sekiya I, Muneta T, et al. Arthroscopic, histological and MRI analyses of cartilage repair after a minimally invasive method of transplantation of allogeneic synovial mesenchymal stromal cells into cartilage defects in pigs. Cytotherapy. 2012;14(3):327-338.
53. Dragoo JL, Carlson G, McCormick F, et al. Healing full-thickness cartilage defects using adipose-derived stem cells. Tissue Eng. 2007;13(7):1615-1621.
54. Masuoka K, Asazuma T, Hattori H, et al. Tissue engineering of articular cartilage with autologous cultured adipose tissue-derived stromal cells using atelocollagen honeycomb-shaped scaffold with a membrane sealing in rabbits. J Biomed Mater Res B Appl Biomater. 2006 79(1):25-34.
55. Gobbi A, Karnatzikos G, Sankineani SR. One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee. Am J Sports Med. 2014;42(3):648-657.
56. Kim JD, Lee GW, Jung GH, et al. Clinical outcome of autologous bone marrow aspirates concentrate (BMAC) injection in degenerative arthritis of the knee. Eur J Orthop Surg Traumatol. 2014;24(8):1505-1511.
57. Krych AJ, Nawabi DH, Farshad-Amacker NA, et al. Bone marrow concentrate improves early cartilage phase maturation of a scaffold plug in the knee: a comparative magnetic resonance imaging analysis to platelet-rich plasma and control. Am J Sports Med. 2016;44(1):91-98.
58. Fortier LA, Potter HG, Rickey EJ, et al. Concentrated bone marrow aspirate improves full-thickness cartilage repair compared with microfracture in the equine model. J Bone Joint Surg Am. 2010;92(10):1927-1937.
59. Kim YS, Park EH, Kim YC, Koh YG. Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus. Am J Sports Med. 2013;41(5):1090-1099.
60. Kim YS, Lee HJ, Choi YJ, Kim YI, Koh YG. Does an injection of a stromal vascular fraction containing adipose-derived mesenchymal stem cells influence the outcomes of marrow stimulation in osteochondral lesions of the talus? A clinical and magnetic resonance imaging study. Am J Sports Med. 2014;42(10):2424-2434.
61. Chahla J, Dean CS, Moatshe G, Pascual-Garrido C, Serra Cruz R, LaPrade RF. Concentrated bone marrow aspirate for the treatment of chondral injuries and osteoarthritis of the knee: a systematic review of outcomes. Orthop J Sports Med. 2016;4(1):2325967115625481.
62. Gobbi A, Karnatzikos G, Scotti C, Mahajan V, Mazzucco L, Grigolo B. One-step cartilage repair with bone marrow aspirate concentrated cells and collagen matrix in full-thickness knee cartilage lesions: results at 2-year follow-up. Cartilage. 2011;2(3):286-299.
63. Ruiz-Ibán MÁ, Díaz-Heredia J, García-Gómez I, Gonzalez-Lizán F, Elías-Martín E, Abraira V. The effect of the addition of adipose-derived mesenchymal stem cells to a meniscal repair in the avascular zone: an experimental study in rabbits. Arthroscopy. 2011;27(12):1688-1696.
64. Angele P, Johnstone B, Kujat R, et al. Stem cell based tissue engineering for meniscus repair. J Biomed Mater Res A. 2008;85(2):445-455.
65. Hernigou P, Merouse G, Duffiet P, Chevalier N, Rouard H. Reduced levels of mesenchymal stem cells at the tendon-bone interface tuberosity in patients with symptomatic rotator cuff tear. Int Orthop. 2015;39(6):1219-1225.
66. Goutallier D, Postel JM, Gleyze P, Leguilloux P, Van Driessche S. Influence of cuff muscle fatty degeneration on anatomic and functional outcomes after simple suture of full-thickness tears. J Shoulder Elbow Surg. 2003;12(6):550-554.
67. Kovacevic D, Rodeo SA. Biological augmentation of rotator cuff tendon repair. Clin Orthop Relat Res. 2008;466(3):622-633.
68. Valencia Mora M, Antuña Antuña S, García Arranz M, Carrascal MT, Barco R. Application of adipose tissue-derived stem cells in a rat rotator cuff repair model. Injury. 2014;45 Suppl 4:S22-S27.
69. Yokoya S, Mochizuki Y, Natsu K, Omae H, Nagata Y, Ochi M. Rotator cuff regeneration using a bioabsorbable material with bone marrow-derived mesenchymal stem cells in a rabbit model. Am J Sports Med. 2012;40(6):1259-1268.
70. Gulotta LV, Kovacevic D, Ehteshami JR, Dagher E, Packer JD, Rodeo SA. Application of bone marrow-derived mesenchymal stem cells in a rotator cuff repair model. Am J Sports Med. 2009;37(11):2126-2133.
71. Beitzel K, McCarthy MB, Cote MP, et al. Comparison of mesenchymal stem cells (osteoprogenitors) harvested from proximal humerus and distal femur during arthroscopic surgery. Arthroscopy. 2013;29(2):301-308.
72. Utsunomiya H, Uchida S, Sekiya I, Sakai A, Moridera K, Nakamura T. Isolation and characterization of human mesenchymal stem cells derived from shoulder tissues involved in rotator cuff tears. Am J Sports Med. 2013;41(3):657-668.
73. Hernigou P, Flouzat Lachaniette CH, Delambre J, et al. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop. 2014;38(9):1811-1818.
74. Ellera Gomes JL, da Silva RC, Silla LM, Abreu MR, Pellanda R. Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells. Knee Surg Sports Traumatol Arthrosc. 2012;20(2):373-377.
75. Adams SB Jr, Thorpe MA, Parks BG, Aghazarian G, Allen E, Schon LC. Stem cell-bearing suture improves Achilles tendon healing in a rat model. Foot Ankle Int. 2014;35(3):293-299.
76. Huang TF, Yew TL, Chiang ER, et al. Mesenchymal stem cells from a hypoxic culture improve and engraft Achilles tendon repair. Am J Sports Med. 2013;41(5):1117-1125.
77. Yao J, Woon CY, Behn A, et al. The effect of suture coated with mesenchymal stem cells and bioactive substrate on tendon repair strength in a rat model. J Hand Surg Am. 2012;37(8):1639-1645.
78. Uysal CA, Tobita M, Hyakusoku H, Mizuno H. Adipose-derived stem cells enhance primary tendon repair: biomechanical and immunohistochemical evaluation. J Plast Reconstr Aesthet Surg. 2012;65(12):1712-1719.
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Biologic use in orthopedics is a continuously evolving field that complements technical, anatomic, and biomechanical advancements in orthopedics. Biologic agents are receiving increasing attention for their use in augmenting healing of muscles, tendons, ligaments, and osseous structures. As biologic augmentation strategies become increasingly utilized in bony and soft-tissue injuries, research on stem cell use in orthopedics continues to increase. Stem cell-based therapies for the repair or regeneration of muscle and tendon represent a promising technology going forward for numerous diseases.1
Stem cells by definition are undifferentiated cells that have 4 main characteristics: (1) mobilization during angiogenesis, (2) differentiation into specialized cell types, (3) proliferation and regeneration, and (4) release of immune regulators and growth factors.2 Mesenchymal stem cells (MSCs) have garnered the most attention in the field of surgery due to their ability to differentiate into the tissues of interest for the surgeon.3 This includes both bone marrow-derived mesenchymal stem cells (bm-MSCs) and adipose-derived mesenchymal stem cells (a-MSCs). These multipotent stem cells in adults originate from mesenchymal tissues, including bone marrow, tendon, adipose, and muscle tissue.4 They are attractive for clinical use because of their multipotent potential and relative ease of growth in culture.5 They also exert a paracrine effect to modulate and control inflammation, stimulate endogenous cell repair and proliferation, inhibit apoptosis, and improve blood flow through secretion of chemokines, cytokines, and growth factors.6,7
Questions exist regarding the best way to administer stem cells, whether systematic administration is possible for these cells to localize to the tissue in need, or more likely if direct application to the pathologic area is necessary.8,9 A number of sources, purification process, and modes of delivery are available, but the most effective means of preparation and administration are still under investigation. The goal of this review is to illustrate the current state of knowledge surrounding stem cell therapy in orthopedics with a focus on osteoarthritis, tendinopathy, articular cartilage, and enhancement of surgical procedures.
Important Considerations
Common stem cell isolates include embryonic, induced pluripotent, and mesenchymal formulations (Table 1). MSCs can be obtained from multiple sites, including but not limited to the adult bone marrow, adipose, muscular, or tendinous tissues, and their use has been highlighted in the study of numerous orthopedic and nonorthopedic pathologies over the course of the last decade. Research on the use of embryonic stem cells in medical therapy with human implications has received substantial attention, with many ethical concerns by those opposed, and the existence of a potential risk of malignant alterations.8,10 Amniotic-derived stem cells can be isolated from amniotic fluid, umbilical cord blood, or the placenta and thus do not harbor the same social constraints as the aforementioned embryonic cells; however, they do not harbor the same magnitude of multi-differentiation potential, either.4
Adult MSCs are more locally available and easy to obtain for treatment when compared with embryonic and fetal stem cells, and the former has a lower immunogenicity, which allows allogeneic use.11 Safety has been preliminarily demonstrated in use thus far; Centeno and colleagues12 found no neoplastic tissue generation at the site of stem cell injection after 3 years postinjection for a cohort of patients who were treated with autologous bm-MSCs for various pathologies. Self-limited pain and swelling are the most commonly reported adverse events after use.13 However, long-term data are lacking in many instances to definitively suggest the absence of possible complications.
Basic Science
Stem cell research encompasses a wide range of rapidly developing treatment strategies that are applicable to virtually every field of medicine. In general, stem cells can be classified as embryonic stem cells (ESCs), induced pluripotent stem (iPS) cells, or adult-derived MSCs. ESCs are embryonic cells derived typically from fetal tissue, whereas iPS cells are dedifferentiated from adult tissue, thus avoiding many of the ethical and legal challenges imposed by research with ESCs. However, oncogenic and lingering politico-legal concerns with introducing dedifferentiated ESCs or iPS cells into healthy tissue necessitate the development, isolation, and expansion of multi- but not pluripotent stem cell lines.14 To date, the most advantageous and widely utilized from any perspective are MSCs, which can further differentiate into cartilage, tendon, muscle, and bony tissue.7,15,16
MSCs are defined by their ability to demonstrate in vitro differentiation into osteoblasts, adipocytes, or chondroblasts, adhere to plastic, express CD105, CD73, and CD90, and not express CD43, CD23, CD14 or CD11b, CD79 or CD19, or HLA-DR.17 Porada and Almeida-Porada18 have outlined 6 reasons highlighting the advantages of MSCs: 1) ease of isolation, 2) high differentiation capabilities, 3) strong colony expansion without differentiation loss, 4) immunosuppression following transplantation, 5) powerful anti-inflammatory properties, and 6) their ability to localize to damaged tissue. The anti-inflammatory properties of MSCs are particularly important as they promote allo- and xenotransplantation from donor tissues.19,20 MSCs can be isolated from numerous sources, including but not limited to bone marrow, periosteum, adipocyte, and muscle.21-23 Interestingly, the source tissue used to isolate MSCs can affect differentiation capabilities, colony size, and growth rate (Table 2).24 Advantages of a-MSCs include high prevalence and ease of harvest; however, several animal studies have shown inferior results when compared to bm-MSCs.25-27 More research is needed to determine the ideal source material for MSCs, which will likely depend in part on the procedure for which they are employed.27
Following harvesting, isolation, and expansion, MSC delivery methods for treatments typically consist of either cell-based or tissue engineering approaches. Cell-based techniques involve the injection of MSCs into damaged tissues. Purely cell-based therapy has shown success in limited clinical trials involving knee osteoarthritis, cartilage repair, and meniscal repair.28-30 However, additional studies with longer follow-up are required to validate these preliminary findings. Tissue engineering approaches involve the construction of a 3-dimensional scaffold seeded with MSCs that is later surgically implanted. While promising in theory, limited and often conflicting data exist regarding the efficacy of tissue-engineered MSC implantation.31-32 Suboptimal scaffold vascularity is a major limitation to scaffold design, which may be alleviated in part with the advent of 3-dimensional printing and the ability to more precisely alter scaffold architecture.14,33 Additional limitations include ensuring MSC purity and differentiation potential following harvesting and expansion. At present, the use of tissue engineering with MSCs is promising but it remains a nascent technology with additional preclinical studies required to confirm implant efficacy and safety.
Clinical Entities
Osteoarthritis
MSC therapies have emerged as promising treatment strategies in the setting of early osteoarthritis (OA). In addition to their regenerative potential, MSCs demonstrate potent anti-inflammatory properties, increasing their attractiveness as biologic agents in the setting of OA.34 Over the past decade, multiple human trials have been published demonstrating the efficacy of MSC injections into patients with OA.35,36 In a study evaluating a-MSC injection into elderly patients (age >65 years) with knee OA, Koh and colleagues29 found that 88% demonstrated improved cartilage status at 2-year follow-up, while no patient underwent a total knee arthroplasty during this time period. In another study investigating patients with unicompartmental knee OA with varus alignment undergoing high tibial osteotomy and microfracture, Wong and colleagues37 reported improved clinical, patient-reported, and magnetic resonance imaging (MRI)-based outcomes in a group receiving a preoperative MSC injection compared to a control group. Further, in a recent randomized control trial of patients with knee osteoarthritis, Vega and colleagues38 reported improved cartilage and quality of life outcomes at 1 year following MSC injection compared to a control group receiving a hyaluronic acid injection. In addition to knee OA, studies have also reported improvement in ankle OA following MSC injection.39 While promising, many of the preliminary clinical studies evaluating the efficacy of MSC therapies in the treatment of OA are hindered by small patient populations and short-term follow-up. Additional large-scale, randomized studies are required and many are ongoing presently in hopes of validating these preliminary findings.36
Tendinopathy
The quality of repaired tissue in primary tendon-to-tendon and tendon-to-bone healing has long been a topic of great interest.40 The healing potential of tendons is inferior to that of other bony and connective tissues,41 with tendon healing typically resulting in a biomechanically and histologically inferior structure to the native tissue.42 As such, this has been a particularly salient opportunity for stem cell use with hopes of recapitulating a more normal tendon or tendon enthesis following injury. In addition to the acute injury, there is great interest in the application of stem cells to chronic states of injury such as tendinopathy.
In equine models, the effect of autologous bm-MSCs treatment on tendinopathy of the superficial digital flexor tendon has been studied. Godwin and colleagues43 evaluated 141 race horses with spontaneous superficial digital flexor tendinopathy treated in this manner, and reported a reinjury percentage in these treated horses of just 27.4%, which compared favorably to historical controls and alternative therapeutics. Machova Urdzikova and colleagues44 injected MSCs at Achilles tendinopathy locations to augment nonoperative healing in 40 rats, and identified more native histological organization and improved vascularization in comparison to control rat specimens. Oshita and colleagues45 reported histologic improvement of tendinopathy findings in 8 rats receiving a-MSCs at the location of induced Achilles tendinopathy that was significantly superior to a control cohort. Bm-MSCs were used by Yuksel and colleagues46 in comparison with platelet-rich plasma (PRP) for treatment of Achilles tendon ruptures created surgically in rat models. They demonstrated successful effects with its use in terms of recovery for the tendon’s histopathologic, immunohistochemical, and biomechanical properties, related to significantly greater levels of anti-inflammatory cytokines. However, these aforementioned findings have not been uniform across the literature—other authors have reported findings that MSC transplantation alone did not repair Achilles tendon injury with such high levels of success.47
Human treatment of tendinopathies with stem cells has been scarcely studied to date. Pascual-Garrido and colleagues48 evaluated 8 patients with refractory patellar tendinopathy treated with injection of autologous bm-MSCs and reported successful results at 2- to 5-year follow-up, with significant improvements in patient-reported outcome measures for 100% of patients. Seven of 8 (87.5%) noted that they would undergo the procedure again.
Articular Cartilage Injury
Chondral injury is a particularly important subject given the limited potential of chondrocytes to replicate or migrate to the site of pathology.49 Stem cell use in this setting assists with programmed growth factor release and alteration of the anatomic microenvironment to facilitate regeneration and repair of the chondral surface. Autologous stem cell use through microfracture provides a perforation into the bone marrow and a subsequent fibrin clot formation containing platelets, growth factors, vascular elements, and MSCs.50 A similar concept to PRP is currently being explored with bm-MSCs. Isolated bm-MSCs are commonly referred to as bone marrow aspirate or bone marrow aspirate concentrate (BMAC). Commercially available systems are now available to aid in the harvesting and implementation of BMAC. One of the more promising avenues for BMAC implementation is in articular cartilage repair or regeneration due to chondrogenic potential of BMAC when used in isolation or when combined with microfracture, chondrocyte transfer, or collagen scaffolds.19,51 Synovial-derived stem cells as an additional source for stem cell use has demonstrated excellent chondrogenic potential in animal studies with full-thickness lesion healing and native-appearing cartilage histologically.52 Incorporation of a-MSCs into scaffolds for surgical implantation has demonstrated success in repairing full-thickness chondral defects with continuous joint surface and extracellular proteins, surface markers, and gene products similar to the native cartilage in animal models.53,54 In light of the promising basic science and animal studies, clinical studies have begun to emerge.55-57
Fortier and colleagues58 found MRI and histologic evidence of full-thickness chondral repair and increased integration with neighboring cartilage when BMAC was concurrently used at the time of microfracture in an equine model. Fortier and colleagues58 also demonstrated greater healing in equine models with acute full-thickness cartilage defects treated by microfracture with MSCs than without delivery of MSCs. Kim and colleagues59,60 similarly reported superiority in clinical outcomes for patients with osteochondral lesions of the talus treated with marrow stimulation and MSC injection than by the former in isolation.
In humans, stem cell use for chondral repair has additionally proven promising. A systematic review of the literature suggested good to excellent overall outcomes for the treatment of moderate focal chondral defects with BMAC with or without scaffolds and microfracture with inclusion of 8 total publications.61 This review included Gobbi and colleagues,62 who prospectively treated 15 patients with a mean focal chondral defect size of 9.2 cm2 about the knee. Use of BMAC covered with a collagen I/III matrix produced significant improvements in patient-reported outcome scores and MRI demonstrated complete hyaline-like cartilage coverage in 80%, with second-look arthroscopy demonstrating normal to nearly normal tissue. Gobbi and colleagues55 also found evidence for superiority of chondral defects treated with BMAC compared to matrix-induced autologous chondrocyte implantation (MACI) for patellofemoral lesions in 37 patients (MRI showed complete filling of defects in 81% of BMAC-treated patients vs 76% of MACI-treated patients).
Meniscal Repair
Clinical application of MSCs in the treatment of meniscal pathology is evolving as well. ASCs have been added to modify the biomechanical environment of avascular zone meniscal tears at the time of suture repair in a rabbit, and have demonstrated increased healing rates in small and larger lesions, although the effect lessens with delay in repair.63 Angele and colleagues64 treated meniscal defects in a rabbit model with scaffolds with bm-MSCs compared with empty scaffolds or control cohorts and found a higher proportion of menisci with healed meniscus-like fibrocartilage when MSCs were utilized.
In humans, Vangsness and colleagues30 treated knees with partial medial meniscectomy with allogeneic stem cells and reported an increase in meniscal volume and decrease in pain in those patients when compared to a cohort of knees treated with hyaluronic acid. Despite promising early results, additional clinical studies are necessary to determine the external validity and broad applicability of stem cell use in meniscal repair.
Rotator Cuff Repair
The number of local resident stem cells at the site of rotator cuff tear has been shown to decrease with tear size, chronicity, and degree of fatty infiltration, suggesting that those with the greatest need for a good reparative environment are those least equipped to heal.65 The need for improvement in this domain is related to the still relatively high re-tear rate after rotator cuff repair despite improvements in instrumentation and surgical technique.66 The native fibrocartilaginous transition zone between the humerus and the rotator cuff becomes a fibrovascular scar tissue after rupture and repair with poorer material properties than the native tissue.67 Thus, a-MSCs have been evaluated in this setting to determine if the biomechanical and histological properties of the repair may improve.68
In rat models, Valencia Mora and colleagues68 reported on the application of a-MSCs in a rat rotator cuff repair model compared to an untreated group. They found no differences between those treated rats and those without a-MSCs use in terms of biomechanical properties of the tendon-to-bone healing, but those with stem cell use had less inflammation shown histologically (diminished presence of edema and neutrophils) at 2- and 4-week time points, which the authors suggested may lead to a more elastic repair and less scar at the bone-tendon healing site. Oh and colleagues1 evaluated the use of a-MSCs in a rabbit subscapularis tear model, and reported significantly reduced fatty infiltration at the site of chronic rotator cuff tear after repair with its application at the repair site; while the load-to-failure was higher in those rabbits with ASCs administration, it was short of reaching statistical significance. Yokoya and colleagues69 demonstrated regeneration of rotator cuff tendon-to-bone insertional site anatomy and in the belly of the cuff tendon in a rabbit model with MSCs applied at the operative site. However, Gulotta and colleagues70 did not see the same improvement in their similar study in the rat model; these authors failed to see improvement in structure, strength, or composition of the tendinous attachment site despite addition of MSCs.
Clinical studies on augmented rotator cuff repair have also found mixed results. MSCs for this purpose have been cultivated from arthroscopic bone marrow aspiration of the proximal humerus71 and subacromial bursa72 with successful and reproducibly high concentrations of stem cells. Hernigou and colleagues73 found a significant improvement in rate of healing (87% intact cuffs vs 44% in the control group) and repair surface tendon integrity (via ultrasound and MRI) for patients at a minimum of 10 years after rotator cuff repair with MSC injection at the time of surgery. The authors found a direct correlation in these outcomes with the number of MSCs injected at the time of repair. Ellera Gomes and colleagues74 injected bm-MSCs obtained from the iliac crest into the tendinous repair site in 14 consecutive patients with full-thickness rotator cuff tears treated by transosseous sutures via a mini-open approach. MRI demonstrated integrity of the repair site in all patients at more than 1-year follow-up.
Achilles Tendon Repair
The goal with stem cell use in Achilles repair is to accelerate the healing and rehabilitation. Several animal studies have demonstrated improved mechanical properties and collagen composition of tendon repairs augmented with stem cells, including Achilles tendon repair in a rat model. Adams and colleagues75 compared suture alone (36 tendons) to suture plus stem cell concentrate injection (36 tendons) and stem cell loaded suture (36 tendons) in Achilles tendon repair with rat models. The suture-alone cohort had lower ultimate failure loads at 14 days after surgery, indicating biomechanical superiority with stem cell augmentation means. Transplantation of hypoxic MSCs at the time of Achilles tendon repair may be a promising option for superior biomechanical failure loads and histologic findings as per recent rat model findings by Huang and colleagues.76 Yao and colleagues77 demonstrated increased strength of suture repair for Achilles repair in rat models at early time points when using MSC-coated suture in comparison to standard suture, and suggested that the addition of stem cells may improve early mechanical properties during the tendon repair process. A-MSC addition to PRP has provided significantly increased tensile strength to rabbit models with Achilles tendon repair as well.78
In evaluation of stem cell use for this purpose with humans, Stein and colleagues79 reviewed 28 sports-related Achilles tendon ruptures in 27 patients treated with open repair and BMAC injection. At a mean follow-up of 29.7 months, the authors reported no re-ruptures, with 92% return to sport at 5.9 months, and excellent clinical outcomes. This small cohort study found no adverse outcomes related to the BMAC addition, and thus proposed further study of the efficacy of stem cell treatment for Achilles tendon repair.
Anterior Cruciate Ligament Reconstruction
Bm-MSCs genetically modified with bone morphogenetic protein 2 (BMP2) and basic fibroblast growth factor (bFGF) have shown great promise in improvement of the formation of mechanically sound tendon-bone interface in anterior cruciate ligament (ACL) reconstruction.80 Similar to the other surgical procedures mentioned in this review, animal studies have successfully evaluated the augmentation of osteointegration of tendon to bone in the setting of ACL reconstruction. Jang and colleagues3 investigated the use of nonautologous transplantation of human umbilical cord blood-derived MSCs in a rabbit ACL reconstruction model. The authors demonstrated a lack of immune rejection, and enhanced tendon-bone healing with broad fibrocartilage formation at the transition zone (similar to the native ACL) and decreased femoral and tibial tunnel widening as compared to a control cohort at 12-weeks after surgery. In a rat model, Kanaya and colleagues81 reported improved histological scores and slight improvements in biomechanical integrity of partially transected rat ACLs treated with intra-articular MSC injection. Stem cell use in the form of suture-supporting scaffolds seeded with MSCs has been evaluated in a total ACL transection rabbit model; the authors of this report demonstrated total ACL regeneration in one-third of samples treated with this augmentation option, in comparison to complete failure in all suture and scaffold alone groups.82
The use of autologous MSCs in ACL healing remains limited to preclinical research and small case series of patients. One human trial by Silva and colleagues83 evaluated the graft-to-bone site of healing in ACL reconstruction for 20 patients who received an intraoperative infiltration of their graft with adult bm-MSCs. MRI and histologic analysis showed no difference in comparison to control groups, but the authors’ conclusion proposed that the number of stem cells injected might have been too minimal to show a clinical effect.
Other Applications
Although outside the scope of this article, stem cells have demonstrated efficacy in the treatment of a number of osseous clinical entities. This includes the treatment of fracture nonunion, augmentation of spinal fusion, and assistance in the treatment of osteonecrosis.84
Summary
As a scientific community, our understanding of the use of stem cells, their nuances, and their indications has expanded dramatically over the last several years. Stem cell treatment has particularly infiltrated the world of operative and nonoperative sports medicine, given in part the active patient population seeking greater levels of improvement.85 Stem cell therapy offers a potentially effective therapy for a multitude of pathologies because of these cells’ anti-inflammatory, immunoregulatory, angiogenic, and paracrine effects.86 It thus remains a very dynamic option in the study of musculoskeletal tissue regeneration. While the potential exists for stem cell use in daily surgery practices, it is still premature to predict whether this can be expected.
The ideal stem cell sources (including allogeneic or autologous), preparation, cell number, timing, and means of application continue to be evaluated, as well as those advantageous pathologies that can benefit from the technology. In order to better answer these pertinent questions, we need to make sure we have a safe, economic, and ethically acceptable means for stem cell translational research efforts. More high-level studies with standardized protocols need to be performed. It is necessary to improve national and international collaboration in research, as well as collaboration with governing bodies, to attempt to further scientific advancement in this field of research.49 Further study on embryonic stem cell use may be valuable as well, pending governmental approval. Finally, more dedicated research efforts must be placed on the utility of adjuncts with stem cell use, including PRP and scaffolds, which may increase protection, nutritional support, and mechanical stimulation of the administered stem cells.
Biologic use in orthopedics is a continuously evolving field that complements technical, anatomic, and biomechanical advancements in orthopedics. Biologic agents are receiving increasing attention for their use in augmenting healing of muscles, tendons, ligaments, and osseous structures. As biologic augmentation strategies become increasingly utilized in bony and soft-tissue injuries, research on stem cell use in orthopedics continues to increase. Stem cell-based therapies for the repair or regeneration of muscle and tendon represent a promising technology going forward for numerous diseases.1
Stem cells by definition are undifferentiated cells that have 4 main characteristics: (1) mobilization during angiogenesis, (2) differentiation into specialized cell types, (3) proliferation and regeneration, and (4) release of immune regulators and growth factors.2 Mesenchymal stem cells (MSCs) have garnered the most attention in the field of surgery due to their ability to differentiate into the tissues of interest for the surgeon.3 This includes both bone marrow-derived mesenchymal stem cells (bm-MSCs) and adipose-derived mesenchymal stem cells (a-MSCs). These multipotent stem cells in adults originate from mesenchymal tissues, including bone marrow, tendon, adipose, and muscle tissue.4 They are attractive for clinical use because of their multipotent potential and relative ease of growth in culture.5 They also exert a paracrine effect to modulate and control inflammation, stimulate endogenous cell repair and proliferation, inhibit apoptosis, and improve blood flow through secretion of chemokines, cytokines, and growth factors.6,7
Questions exist regarding the best way to administer stem cells, whether systematic administration is possible for these cells to localize to the tissue in need, or more likely if direct application to the pathologic area is necessary.8,9 A number of sources, purification process, and modes of delivery are available, but the most effective means of preparation and administration are still under investigation. The goal of this review is to illustrate the current state of knowledge surrounding stem cell therapy in orthopedics with a focus on osteoarthritis, tendinopathy, articular cartilage, and enhancement of surgical procedures.
Important Considerations
Common stem cell isolates include embryonic, induced pluripotent, and mesenchymal formulations (Table 1). MSCs can be obtained from multiple sites, including but not limited to the adult bone marrow, adipose, muscular, or tendinous tissues, and their use has been highlighted in the study of numerous orthopedic and nonorthopedic pathologies over the course of the last decade. Research on the use of embryonic stem cells in medical therapy with human implications has received substantial attention, with many ethical concerns by those opposed, and the existence of a potential risk of malignant alterations.8,10 Amniotic-derived stem cells can be isolated from amniotic fluid, umbilical cord blood, or the placenta and thus do not harbor the same social constraints as the aforementioned embryonic cells; however, they do not harbor the same magnitude of multi-differentiation potential, either.4
Adult MSCs are more locally available and easy to obtain for treatment when compared with embryonic and fetal stem cells, and the former has a lower immunogenicity, which allows allogeneic use.11 Safety has been preliminarily demonstrated in use thus far; Centeno and colleagues12 found no neoplastic tissue generation at the site of stem cell injection after 3 years postinjection for a cohort of patients who were treated with autologous bm-MSCs for various pathologies. Self-limited pain and swelling are the most commonly reported adverse events after use.13 However, long-term data are lacking in many instances to definitively suggest the absence of possible complications.
Basic Science
Stem cell research encompasses a wide range of rapidly developing treatment strategies that are applicable to virtually every field of medicine. In general, stem cells can be classified as embryonic stem cells (ESCs), induced pluripotent stem (iPS) cells, or adult-derived MSCs. ESCs are embryonic cells derived typically from fetal tissue, whereas iPS cells are dedifferentiated from adult tissue, thus avoiding many of the ethical and legal challenges imposed by research with ESCs. However, oncogenic and lingering politico-legal concerns with introducing dedifferentiated ESCs or iPS cells into healthy tissue necessitate the development, isolation, and expansion of multi- but not pluripotent stem cell lines.14 To date, the most advantageous and widely utilized from any perspective are MSCs, which can further differentiate into cartilage, tendon, muscle, and bony tissue.7,15,16
MSCs are defined by their ability to demonstrate in vitro differentiation into osteoblasts, adipocytes, or chondroblasts, adhere to plastic, express CD105, CD73, and CD90, and not express CD43, CD23, CD14 or CD11b, CD79 or CD19, or HLA-DR.17 Porada and Almeida-Porada18 have outlined 6 reasons highlighting the advantages of MSCs: 1) ease of isolation, 2) high differentiation capabilities, 3) strong colony expansion without differentiation loss, 4) immunosuppression following transplantation, 5) powerful anti-inflammatory properties, and 6) their ability to localize to damaged tissue. The anti-inflammatory properties of MSCs are particularly important as they promote allo- and xenotransplantation from donor tissues.19,20 MSCs can be isolated from numerous sources, including but not limited to bone marrow, periosteum, adipocyte, and muscle.21-23 Interestingly, the source tissue used to isolate MSCs can affect differentiation capabilities, colony size, and growth rate (Table 2).24 Advantages of a-MSCs include high prevalence and ease of harvest; however, several animal studies have shown inferior results when compared to bm-MSCs.25-27 More research is needed to determine the ideal source material for MSCs, which will likely depend in part on the procedure for which they are employed.27
Following harvesting, isolation, and expansion, MSC delivery methods for treatments typically consist of either cell-based or tissue engineering approaches. Cell-based techniques involve the injection of MSCs into damaged tissues. Purely cell-based therapy has shown success in limited clinical trials involving knee osteoarthritis, cartilage repair, and meniscal repair.28-30 However, additional studies with longer follow-up are required to validate these preliminary findings. Tissue engineering approaches involve the construction of a 3-dimensional scaffold seeded with MSCs that is later surgically implanted. While promising in theory, limited and often conflicting data exist regarding the efficacy of tissue-engineered MSC implantation.31-32 Suboptimal scaffold vascularity is a major limitation to scaffold design, which may be alleviated in part with the advent of 3-dimensional printing and the ability to more precisely alter scaffold architecture.14,33 Additional limitations include ensuring MSC purity and differentiation potential following harvesting and expansion. At present, the use of tissue engineering with MSCs is promising but it remains a nascent technology with additional preclinical studies required to confirm implant efficacy and safety.
Clinical Entities
Osteoarthritis
MSC therapies have emerged as promising treatment strategies in the setting of early osteoarthritis (OA). In addition to their regenerative potential, MSCs demonstrate potent anti-inflammatory properties, increasing their attractiveness as biologic agents in the setting of OA.34 Over the past decade, multiple human trials have been published demonstrating the efficacy of MSC injections into patients with OA.35,36 In a study evaluating a-MSC injection into elderly patients (age >65 years) with knee OA, Koh and colleagues29 found that 88% demonstrated improved cartilage status at 2-year follow-up, while no patient underwent a total knee arthroplasty during this time period. In another study investigating patients with unicompartmental knee OA with varus alignment undergoing high tibial osteotomy and microfracture, Wong and colleagues37 reported improved clinical, patient-reported, and magnetic resonance imaging (MRI)-based outcomes in a group receiving a preoperative MSC injection compared to a control group. Further, in a recent randomized control trial of patients with knee osteoarthritis, Vega and colleagues38 reported improved cartilage and quality of life outcomes at 1 year following MSC injection compared to a control group receiving a hyaluronic acid injection. In addition to knee OA, studies have also reported improvement in ankle OA following MSC injection.39 While promising, many of the preliminary clinical studies evaluating the efficacy of MSC therapies in the treatment of OA are hindered by small patient populations and short-term follow-up. Additional large-scale, randomized studies are required and many are ongoing presently in hopes of validating these preliminary findings.36
Tendinopathy
The quality of repaired tissue in primary tendon-to-tendon and tendon-to-bone healing has long been a topic of great interest.40 The healing potential of tendons is inferior to that of other bony and connective tissues,41 with tendon healing typically resulting in a biomechanically and histologically inferior structure to the native tissue.42 As such, this has been a particularly salient opportunity for stem cell use with hopes of recapitulating a more normal tendon or tendon enthesis following injury. In addition to the acute injury, there is great interest in the application of stem cells to chronic states of injury such as tendinopathy.
In equine models, the effect of autologous bm-MSCs treatment on tendinopathy of the superficial digital flexor tendon has been studied. Godwin and colleagues43 evaluated 141 race horses with spontaneous superficial digital flexor tendinopathy treated in this manner, and reported a reinjury percentage in these treated horses of just 27.4%, which compared favorably to historical controls and alternative therapeutics. Machova Urdzikova and colleagues44 injected MSCs at Achilles tendinopathy locations to augment nonoperative healing in 40 rats, and identified more native histological organization and improved vascularization in comparison to control rat specimens. Oshita and colleagues45 reported histologic improvement of tendinopathy findings in 8 rats receiving a-MSCs at the location of induced Achilles tendinopathy that was significantly superior to a control cohort. Bm-MSCs were used by Yuksel and colleagues46 in comparison with platelet-rich plasma (PRP) for treatment of Achilles tendon ruptures created surgically in rat models. They demonstrated successful effects with its use in terms of recovery for the tendon’s histopathologic, immunohistochemical, and biomechanical properties, related to significantly greater levels of anti-inflammatory cytokines. However, these aforementioned findings have not been uniform across the literature—other authors have reported findings that MSC transplantation alone did not repair Achilles tendon injury with such high levels of success.47
Human treatment of tendinopathies with stem cells has been scarcely studied to date. Pascual-Garrido and colleagues48 evaluated 8 patients with refractory patellar tendinopathy treated with injection of autologous bm-MSCs and reported successful results at 2- to 5-year follow-up, with significant improvements in patient-reported outcome measures for 100% of patients. Seven of 8 (87.5%) noted that they would undergo the procedure again.
Articular Cartilage Injury
Chondral injury is a particularly important subject given the limited potential of chondrocytes to replicate or migrate to the site of pathology.49 Stem cell use in this setting assists with programmed growth factor release and alteration of the anatomic microenvironment to facilitate regeneration and repair of the chondral surface. Autologous stem cell use through microfracture provides a perforation into the bone marrow and a subsequent fibrin clot formation containing platelets, growth factors, vascular elements, and MSCs.50 A similar concept to PRP is currently being explored with bm-MSCs. Isolated bm-MSCs are commonly referred to as bone marrow aspirate or bone marrow aspirate concentrate (BMAC). Commercially available systems are now available to aid in the harvesting and implementation of BMAC. One of the more promising avenues for BMAC implementation is in articular cartilage repair or regeneration due to chondrogenic potential of BMAC when used in isolation or when combined with microfracture, chondrocyte transfer, or collagen scaffolds.19,51 Synovial-derived stem cells as an additional source for stem cell use has demonstrated excellent chondrogenic potential in animal studies with full-thickness lesion healing and native-appearing cartilage histologically.52 Incorporation of a-MSCs into scaffolds for surgical implantation has demonstrated success in repairing full-thickness chondral defects with continuous joint surface and extracellular proteins, surface markers, and gene products similar to the native cartilage in animal models.53,54 In light of the promising basic science and animal studies, clinical studies have begun to emerge.55-57
Fortier and colleagues58 found MRI and histologic evidence of full-thickness chondral repair and increased integration with neighboring cartilage when BMAC was concurrently used at the time of microfracture in an equine model. Fortier and colleagues58 also demonstrated greater healing in equine models with acute full-thickness cartilage defects treated by microfracture with MSCs than without delivery of MSCs. Kim and colleagues59,60 similarly reported superiority in clinical outcomes for patients with osteochondral lesions of the talus treated with marrow stimulation and MSC injection than by the former in isolation.
In humans, stem cell use for chondral repair has additionally proven promising. A systematic review of the literature suggested good to excellent overall outcomes for the treatment of moderate focal chondral defects with BMAC with or without scaffolds and microfracture with inclusion of 8 total publications.61 This review included Gobbi and colleagues,62 who prospectively treated 15 patients with a mean focal chondral defect size of 9.2 cm2 about the knee. Use of BMAC covered with a collagen I/III matrix produced significant improvements in patient-reported outcome scores and MRI demonstrated complete hyaline-like cartilage coverage in 80%, with second-look arthroscopy demonstrating normal to nearly normal tissue. Gobbi and colleagues55 also found evidence for superiority of chondral defects treated with BMAC compared to matrix-induced autologous chondrocyte implantation (MACI) for patellofemoral lesions in 37 patients (MRI showed complete filling of defects in 81% of BMAC-treated patients vs 76% of MACI-treated patients).
Meniscal Repair
Clinical application of MSCs in the treatment of meniscal pathology is evolving as well. ASCs have been added to modify the biomechanical environment of avascular zone meniscal tears at the time of suture repair in a rabbit, and have demonstrated increased healing rates in small and larger lesions, although the effect lessens with delay in repair.63 Angele and colleagues64 treated meniscal defects in a rabbit model with scaffolds with bm-MSCs compared with empty scaffolds or control cohorts and found a higher proportion of menisci with healed meniscus-like fibrocartilage when MSCs were utilized.
In humans, Vangsness and colleagues30 treated knees with partial medial meniscectomy with allogeneic stem cells and reported an increase in meniscal volume and decrease in pain in those patients when compared to a cohort of knees treated with hyaluronic acid. Despite promising early results, additional clinical studies are necessary to determine the external validity and broad applicability of stem cell use in meniscal repair.
Rotator Cuff Repair
The number of local resident stem cells at the site of rotator cuff tear has been shown to decrease with tear size, chronicity, and degree of fatty infiltration, suggesting that those with the greatest need for a good reparative environment are those least equipped to heal.65 The need for improvement in this domain is related to the still relatively high re-tear rate after rotator cuff repair despite improvements in instrumentation and surgical technique.66 The native fibrocartilaginous transition zone between the humerus and the rotator cuff becomes a fibrovascular scar tissue after rupture and repair with poorer material properties than the native tissue.67 Thus, a-MSCs have been evaluated in this setting to determine if the biomechanical and histological properties of the repair may improve.68
In rat models, Valencia Mora and colleagues68 reported on the application of a-MSCs in a rat rotator cuff repair model compared to an untreated group. They found no differences between those treated rats and those without a-MSCs use in terms of biomechanical properties of the tendon-to-bone healing, but those with stem cell use had less inflammation shown histologically (diminished presence of edema and neutrophils) at 2- and 4-week time points, which the authors suggested may lead to a more elastic repair and less scar at the bone-tendon healing site. Oh and colleagues1 evaluated the use of a-MSCs in a rabbit subscapularis tear model, and reported significantly reduced fatty infiltration at the site of chronic rotator cuff tear after repair with its application at the repair site; while the load-to-failure was higher in those rabbits with ASCs administration, it was short of reaching statistical significance. Yokoya and colleagues69 demonstrated regeneration of rotator cuff tendon-to-bone insertional site anatomy and in the belly of the cuff tendon in a rabbit model with MSCs applied at the operative site. However, Gulotta and colleagues70 did not see the same improvement in their similar study in the rat model; these authors failed to see improvement in structure, strength, or composition of the tendinous attachment site despite addition of MSCs.
Clinical studies on augmented rotator cuff repair have also found mixed results. MSCs for this purpose have been cultivated from arthroscopic bone marrow aspiration of the proximal humerus71 and subacromial bursa72 with successful and reproducibly high concentrations of stem cells. Hernigou and colleagues73 found a significant improvement in rate of healing (87% intact cuffs vs 44% in the control group) and repair surface tendon integrity (via ultrasound and MRI) for patients at a minimum of 10 years after rotator cuff repair with MSC injection at the time of surgery. The authors found a direct correlation in these outcomes with the number of MSCs injected at the time of repair. Ellera Gomes and colleagues74 injected bm-MSCs obtained from the iliac crest into the tendinous repair site in 14 consecutive patients with full-thickness rotator cuff tears treated by transosseous sutures via a mini-open approach. MRI demonstrated integrity of the repair site in all patients at more than 1-year follow-up.
Achilles Tendon Repair
The goal with stem cell use in Achilles repair is to accelerate the healing and rehabilitation. Several animal studies have demonstrated improved mechanical properties and collagen composition of tendon repairs augmented with stem cells, including Achilles tendon repair in a rat model. Adams and colleagues75 compared suture alone (36 tendons) to suture plus stem cell concentrate injection (36 tendons) and stem cell loaded suture (36 tendons) in Achilles tendon repair with rat models. The suture-alone cohort had lower ultimate failure loads at 14 days after surgery, indicating biomechanical superiority with stem cell augmentation means. Transplantation of hypoxic MSCs at the time of Achilles tendon repair may be a promising option for superior biomechanical failure loads and histologic findings as per recent rat model findings by Huang and colleagues.76 Yao and colleagues77 demonstrated increased strength of suture repair for Achilles repair in rat models at early time points when using MSC-coated suture in comparison to standard suture, and suggested that the addition of stem cells may improve early mechanical properties during the tendon repair process. A-MSC addition to PRP has provided significantly increased tensile strength to rabbit models with Achilles tendon repair as well.78
In evaluation of stem cell use for this purpose with humans, Stein and colleagues79 reviewed 28 sports-related Achilles tendon ruptures in 27 patients treated with open repair and BMAC injection. At a mean follow-up of 29.7 months, the authors reported no re-ruptures, with 92% return to sport at 5.9 months, and excellent clinical outcomes. This small cohort study found no adverse outcomes related to the BMAC addition, and thus proposed further study of the efficacy of stem cell treatment for Achilles tendon repair.
Anterior Cruciate Ligament Reconstruction
Bm-MSCs genetically modified with bone morphogenetic protein 2 (BMP2) and basic fibroblast growth factor (bFGF) have shown great promise in improvement of the formation of mechanically sound tendon-bone interface in anterior cruciate ligament (ACL) reconstruction.80 Similar to the other surgical procedures mentioned in this review, animal studies have successfully evaluated the augmentation of osteointegration of tendon to bone in the setting of ACL reconstruction. Jang and colleagues3 investigated the use of nonautologous transplantation of human umbilical cord blood-derived MSCs in a rabbit ACL reconstruction model. The authors demonstrated a lack of immune rejection, and enhanced tendon-bone healing with broad fibrocartilage formation at the transition zone (similar to the native ACL) and decreased femoral and tibial tunnel widening as compared to a control cohort at 12-weeks after surgery. In a rat model, Kanaya and colleagues81 reported improved histological scores and slight improvements in biomechanical integrity of partially transected rat ACLs treated with intra-articular MSC injection. Stem cell use in the form of suture-supporting scaffolds seeded with MSCs has been evaluated in a total ACL transection rabbit model; the authors of this report demonstrated total ACL regeneration in one-third of samples treated with this augmentation option, in comparison to complete failure in all suture and scaffold alone groups.82
The use of autologous MSCs in ACL healing remains limited to preclinical research and small case series of patients. One human trial by Silva and colleagues83 evaluated the graft-to-bone site of healing in ACL reconstruction for 20 patients who received an intraoperative infiltration of their graft with adult bm-MSCs. MRI and histologic analysis showed no difference in comparison to control groups, but the authors’ conclusion proposed that the number of stem cells injected might have been too minimal to show a clinical effect.
Other Applications
Although outside the scope of this article, stem cells have demonstrated efficacy in the treatment of a number of osseous clinical entities. This includes the treatment of fracture nonunion, augmentation of spinal fusion, and assistance in the treatment of osteonecrosis.84
Summary
As a scientific community, our understanding of the use of stem cells, their nuances, and their indications has expanded dramatically over the last several years. Stem cell treatment has particularly infiltrated the world of operative and nonoperative sports medicine, given in part the active patient population seeking greater levels of improvement.85 Stem cell therapy offers a potentially effective therapy for a multitude of pathologies because of these cells’ anti-inflammatory, immunoregulatory, angiogenic, and paracrine effects.86 It thus remains a very dynamic option in the study of musculoskeletal tissue regeneration. While the potential exists for stem cell use in daily surgery practices, it is still premature to predict whether this can be expected.
The ideal stem cell sources (including allogeneic or autologous), preparation, cell number, timing, and means of application continue to be evaluated, as well as those advantageous pathologies that can benefit from the technology. In order to better answer these pertinent questions, we need to make sure we have a safe, economic, and ethically acceptable means for stem cell translational research efforts. More high-level studies with standardized protocols need to be performed. It is necessary to improve national and international collaboration in research, as well as collaboration with governing bodies, to attempt to further scientific advancement in this field of research.49 Further study on embryonic stem cell use may be valuable as well, pending governmental approval. Finally, more dedicated research efforts must be placed on the utility of adjuncts with stem cell use, including PRP and scaffolds, which may increase protection, nutritional support, and mechanical stimulation of the administered stem cells.
1. Oh JH, Chung SW, Kim SH, Chung JY, Kim JY. 2013 Neer Award: Effect of the adipose-derived stem cell for the improvement of fatty degeneration and rotator cuff healing in rabbit model. J Shoulder Elb Surg. 2014;23(4):445-455.
2. Caplan AI, Correa D. PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs. J Orthop Res. 2011;29(12):1795-1803.
3. Jang KM, Lim HC, Jung WY, Moon SW, Wang JH. Efficacy and safety of human umbilical cord blood-derived mesenchymal stem cells in anterior cruciate ligament reconstruction of a rabbit model: new strategy to enhance tendon graft healing. Arthroscopy. 2015;31(8):1530-1539.
4. Muttini A, Salini V, Valbonetti L, Abate M. Stem cell therapy of tendinopathies: suggestions from veterinary medicine. Muscles Ligaments Tendons J. 2012;2(3):187-192.
5. Xia P, Wang X, Lin Q, Li X. Efficacy of mesenchymal stem cells injection for the management of knee osteoarthritis: a systematic review and meta-analysis. Int Orthop. 2015;39(12):2363-2372.
6. Veronesi F, Giavaresi G, Tschon M, Borsari V, Nicoli Aldini N, Fini M. Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem Cells Dev. 2013;22(2):181-192.
7. Caplan AI. Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Eng. 2005;11(7-8):1198-1211.
8. Hirzinger C, Tauber M, Korntner S, et al. ACL injuries and stem cell therapy. Arch Orthop Trauma Surg. 2014;134(11):1573-1578.
9. Becerra P, Valdés Vázquez MA, Dudhia J, et al. Distribution of injected technetium(99m)-labeled mesenchymal stem cells in horses with naturally occurring tendinopathy. J Orthop Res. 2013;31(7):1096-1102.
10. Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. J Exp Clin Cancer Res. 2011;30:9.
11. García-Gómez I, Elvira G, Zapata AG, et al. Mesenchymal stem cells: biological properties and clinical applications. Expert Opin Biol Ther. 2010;10(10):1453-1468.
12. Centeno CJ, Schultz JR, Cheever M, et al. Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2011;6(4):368-378.
13. Centeno CJ, Al-Sayegh H, Freeman MD, Smith J, Murrell WD, Bubnov R. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. Int Orthop. 2016 Mar 30. [Epub ahead of print]
14. Schmitt A, van Griensven M, Imhoff AB, Buchmann S. Application of stem cells in orthopedics. Stem Cells Int. 2012;2012:394962.
15. Tuan RS, Boland G, Tuli R. Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther. 2003;5(1):32-45.
16. Anz AW, Hackel JG, Nilssen EC, Andrews JR. Application of biologics in the treatment of the rotator cuff, meniscus, cartilage, and osteoarthritis. J Am Acad Orthop Surg. 2014;22(2):68-79.
17. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317.
18. Porada CD, Almeida-Porada G. Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. Adv Drug Deliv Rev. 2010;62(12):1156-1566.
19. Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. 2013;21(8):1717-1729.
20. Liechty KW, MacKenzie TC, Shaaban AF, et al. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med. 2000;6(11):1282-1286.
21. Hung SC, Chen NJ, Hsieh SL, Li H, Ma HL, Lo WH. Isolation and characterization of size-sieved stem cells from human bone marrow. Stem Cells. 2002;20(3):249-258.
22. De Bari C, Dell’Accio F, Vanlauwe J, et al. Mesenchymal multipotency of adult human periosteal cells demonstrated by single-cell lineage analysis. Arthritis Rheum. 2006;54(4):1209-1221.
23. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279-4295.
24. Mafi R, Hindocha S, Mafi P, Griffin M, Khan WS. Sources of adult mesenchymal stem cells applicable for musculoskeletal applications - a systematic review of the literature. Open Orthop J. 2011;5 Suppl 2:242-248.
25. Frisbie DD, Kisiday JD, Kawcak CE, Werpy NM, McIlwraith CW. Evaluation of adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis. J Orthop Res. 2009;27(12):1675-1680.
26. Vidal MA, Robinson SO, Lopez MJ, et al. Comparison of chondrogenic potential in equine mesenchymal stromal cells derived from adipose tissue and bone marrow. Vet Surg. 2008;37(8):713-724.
27. Yoshimura H, Muneta T, Nimura A, Yokoyama A, Koga H, Sekiya I. Comparison of rat mesenchymal stem cells derived from bone marrow, synovium, periosteum, adipose tissue, and muscle. Cell Tissue Res. 2007;327(3):449-462.
28. Hogan MV, Walker GN, Cui LR, Fu FH, Huard J. The role of stem cells and tissue engineering in orthopaedic sports medicine: current evidence and future directions. Arthroscopy. 2015;31(5):1017-1021.
29. Koh YG, Choi YJ, Kwon SK, Kim YS, Yeo JE. Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2015;23(5):1308-1316.
30. Vangsness CT Jr, Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. 2014;96(2):90-98.
31. Goodrich LR, Chen AC, Werpy NM, et al. Addition of mesenchymal stem cells to autologous platelet-enhanced fibrin scaffolds in chondral defects: does it enhance repair? J Bone Joint Surg Am. 2016;98(1):23-34.
32. Kim YS, Choi YJ, Suh DS, et al. Mesenchymal stem cell implantation in osteoarthritic knees: is fibrin glue effective as a scaffold? Am J Sports Med. 2015;43(1):176-185.
33. Steinert AF, Rackwitz L, Gilbert F, Nöth U, Tuan RS. Concise review: the clinical application of mesenchymal stem cells for musculoskeletal regeneration: current status and perspectives. Stem Cells Transl Med. 2012;1(3):237-247.
34. Pers YM, Ruiz M, Noël D, Jorgensen C. Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives. Osteoarthritis Cartilage. 2015;23(11):2027-2035.
35. Mamidi MK, Das AK, Zakaria Z, Bhonde R. Mesenchymal stromal cells for cartilage repair in osteoarthritis. Osteoarthritis Cartilage. 2016 Mar 10. [Epub ahead of print]
36. Wyles CC, Houdek MT, Behfar A, Sierra RJ. Mesenchymal stem cell therapy for osteoarthritis: current perspectives. Stem Cells Cloning. 2015;8:117-124.
37. Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy. 2013;29(12):2020-2028.
38. Vega A, Martín-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99(8):1681-1690.
39. Kim YS, Lee M, Koh YG. Additional mesenchymal stem cell injection improves the outcomes of marrow stimulation combined with supramalleolar osteotomy in varus ankle osteoarthritis: short-term clinical results with second-look arthroscopic evaluation. J Exp Orthop. 2016;3(1):12.
40. Kraus TM, Imhoff FB, Reinert J, et al. Stem cells and bFGF in tendon healing: Effects of lentiviral gene transfer and long-term follow-up in a rat Achilles tendon defect model. BMC Musculoskelet Disord. 2016;17(1):148.
41. Thomopoulos S, Parks WC, Rifkin DB, Derwin KA. Mechanisms of tendon injury and repair. J Orthop Res. 2015;33(6):832-839.
42. Müller SA, Todorov A, Heisterbach PE, Martin I, Majewski M. Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. Knee Surg Sports Traumatol Arthrosc. 2015;23(7):2097-3105.
43. Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RK. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44(1):25-32.
44. Machova Urdzikova L, Sedlacek R, Suchy T, et al. Human multipotent mesenchymal stem cells improve healing after collagenase tendon injury in the rat. Biomed Eng Online. 2014;13:42.
45. Oshita T, Tobita M, Tajima S, Mizuno H. Adipose-derived stem cells improve collagenase-induced tendinopathy in a rat model. Am J Sports Med. 2016 Apr 11. [Epub ahead of print]
46. Yuksel S, Guleç MA, Gultekin MZ, et al. Comparison of the early-period effects of bone marrow-derived mesenchymal stem cells and platelet-rich plasma on achilles tendon ruptures in rats. Connect Tissue Res. 2016 May 18. [Epub ahead of print]
47. Chen L, Liu JP, Tang KL, et al. Tendon derived stem cells promote platelet-rich plasma healing in collagenase-induced rat achilles tendinopathy. Cell Physiol Biochem. 2014;34(6):2153-2168.
48. Pascual-Garrido C, Rolón A, Makino A. Treatment of chronic patellar tendinopathy with autologous bone marrow stem cells: a 5-year-followup. Stem Cells Int. 2012;2012:953510.
49. Zlotnicki JP, Geeslin AG, Murray IR, et al. Biologic treatments for sports injuries ii think tank-current concepts, future research, and barriers to advancement, part 3: articular cartilage. Orthop J Sports Med. 2016;4(4):2325967116642433.
50. McCormack RA, Shreve M, Strauss EJ. Biologic augmentation in rotator cuff repair--should we do it, who should get it, and has it worked? Bull Hosp Jt Dis (2013). 2014;72(1):89-96.
51. Mosna F, Sensebé L, Krampera M. Human bone marrow and adipose tissue mesenchymal stem cells: a user’s guide. Stem Cells Dev. 2010;19(10):1449-1470.
52. Nakamura T, Sekiya I, Muneta T, et al. Arthroscopic, histological and MRI analyses of cartilage repair after a minimally invasive method of transplantation of allogeneic synovial mesenchymal stromal cells into cartilage defects in pigs. Cytotherapy. 2012;14(3):327-338.
53. Dragoo JL, Carlson G, McCormick F, et al. Healing full-thickness cartilage defects using adipose-derived stem cells. Tissue Eng. 2007;13(7):1615-1621.
54. Masuoka K, Asazuma T, Hattori H, et al. Tissue engineering of articular cartilage with autologous cultured adipose tissue-derived stromal cells using atelocollagen honeycomb-shaped scaffold with a membrane sealing in rabbits. J Biomed Mater Res B Appl Biomater. 2006 79(1):25-34.
55. Gobbi A, Karnatzikos G, Sankineani SR. One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee. Am J Sports Med. 2014;42(3):648-657.
56. Kim JD, Lee GW, Jung GH, et al. Clinical outcome of autologous bone marrow aspirates concentrate (BMAC) injection in degenerative arthritis of the knee. Eur J Orthop Surg Traumatol. 2014;24(8):1505-1511.
57. Krych AJ, Nawabi DH, Farshad-Amacker NA, et al. Bone marrow concentrate improves early cartilage phase maturation of a scaffold plug in the knee: a comparative magnetic resonance imaging analysis to platelet-rich plasma and control. Am J Sports Med. 2016;44(1):91-98.
58. Fortier LA, Potter HG, Rickey EJ, et al. Concentrated bone marrow aspirate improves full-thickness cartilage repair compared with microfracture in the equine model. J Bone Joint Surg Am. 2010;92(10):1927-1937.
59. Kim YS, Park EH, Kim YC, Koh YG. Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus. Am J Sports Med. 2013;41(5):1090-1099.
60. Kim YS, Lee HJ, Choi YJ, Kim YI, Koh YG. Does an injection of a stromal vascular fraction containing adipose-derived mesenchymal stem cells influence the outcomes of marrow stimulation in osteochondral lesions of the talus? A clinical and magnetic resonance imaging study. Am J Sports Med. 2014;42(10):2424-2434.
61. Chahla J, Dean CS, Moatshe G, Pascual-Garrido C, Serra Cruz R, LaPrade RF. Concentrated bone marrow aspirate for the treatment of chondral injuries and osteoarthritis of the knee: a systematic review of outcomes. Orthop J Sports Med. 2016;4(1):2325967115625481.
62. Gobbi A, Karnatzikos G, Scotti C, Mahajan V, Mazzucco L, Grigolo B. One-step cartilage repair with bone marrow aspirate concentrated cells and collagen matrix in full-thickness knee cartilage lesions: results at 2-year follow-up. Cartilage. 2011;2(3):286-299.
63. Ruiz-Ibán MÁ, Díaz-Heredia J, García-Gómez I, Gonzalez-Lizán F, Elías-Martín E, Abraira V. The effect of the addition of adipose-derived mesenchymal stem cells to a meniscal repair in the avascular zone: an experimental study in rabbits. Arthroscopy. 2011;27(12):1688-1696.
64. Angele P, Johnstone B, Kujat R, et al. Stem cell based tissue engineering for meniscus repair. J Biomed Mater Res A. 2008;85(2):445-455.
65. Hernigou P, Merouse G, Duffiet P, Chevalier N, Rouard H. Reduced levels of mesenchymal stem cells at the tendon-bone interface tuberosity in patients with symptomatic rotator cuff tear. Int Orthop. 2015;39(6):1219-1225.
66. Goutallier D, Postel JM, Gleyze P, Leguilloux P, Van Driessche S. Influence of cuff muscle fatty degeneration on anatomic and functional outcomes after simple suture of full-thickness tears. J Shoulder Elbow Surg. 2003;12(6):550-554.
67. Kovacevic D, Rodeo SA. Biological augmentation of rotator cuff tendon repair. Clin Orthop Relat Res. 2008;466(3):622-633.
68. Valencia Mora M, Antuña Antuña S, García Arranz M, Carrascal MT, Barco R. Application of adipose tissue-derived stem cells in a rat rotator cuff repair model. Injury. 2014;45 Suppl 4:S22-S27.
69. Yokoya S, Mochizuki Y, Natsu K, Omae H, Nagata Y, Ochi M. Rotator cuff regeneration using a bioabsorbable material with bone marrow-derived mesenchymal stem cells in a rabbit model. Am J Sports Med. 2012;40(6):1259-1268.
70. Gulotta LV, Kovacevic D, Ehteshami JR, Dagher E, Packer JD, Rodeo SA. Application of bone marrow-derived mesenchymal stem cells in a rotator cuff repair model. Am J Sports Med. 2009;37(11):2126-2133.
71. Beitzel K, McCarthy MB, Cote MP, et al. Comparison of mesenchymal stem cells (osteoprogenitors) harvested from proximal humerus and distal femur during arthroscopic surgery. Arthroscopy. 2013;29(2):301-308.
72. Utsunomiya H, Uchida S, Sekiya I, Sakai A, Moridera K, Nakamura T. Isolation and characterization of human mesenchymal stem cells derived from shoulder tissues involved in rotator cuff tears. Am J Sports Med. 2013;41(3):657-668.
73. Hernigou P, Flouzat Lachaniette CH, Delambre J, et al. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop. 2014;38(9):1811-1818.
74. Ellera Gomes JL, da Silva RC, Silla LM, Abreu MR, Pellanda R. Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells. Knee Surg Sports Traumatol Arthrosc. 2012;20(2):373-377.
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1. Oh JH, Chung SW, Kim SH, Chung JY, Kim JY. 2013 Neer Award: Effect of the adipose-derived stem cell for the improvement of fatty degeneration and rotator cuff healing in rabbit model. J Shoulder Elb Surg. 2014;23(4):445-455.
2. Caplan AI, Correa D. PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs. J Orthop Res. 2011;29(12):1795-1803.
3. Jang KM, Lim HC, Jung WY, Moon SW, Wang JH. Efficacy and safety of human umbilical cord blood-derived mesenchymal stem cells in anterior cruciate ligament reconstruction of a rabbit model: new strategy to enhance tendon graft healing. Arthroscopy. 2015;31(8):1530-1539.
4. Muttini A, Salini V, Valbonetti L, Abate M. Stem cell therapy of tendinopathies: suggestions from veterinary medicine. Muscles Ligaments Tendons J. 2012;2(3):187-192.
5. Xia P, Wang X, Lin Q, Li X. Efficacy of mesenchymal stem cells injection for the management of knee osteoarthritis: a systematic review and meta-analysis. Int Orthop. 2015;39(12):2363-2372.
6. Veronesi F, Giavaresi G, Tschon M, Borsari V, Nicoli Aldini N, Fini M. Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem Cells Dev. 2013;22(2):181-192.
7. Caplan AI. Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Eng. 2005;11(7-8):1198-1211.
8. Hirzinger C, Tauber M, Korntner S, et al. ACL injuries and stem cell therapy. Arch Orthop Trauma Surg. 2014;134(11):1573-1578.
9. Becerra P, Valdés Vázquez MA, Dudhia J, et al. Distribution of injected technetium(99m)-labeled mesenchymal stem cells in horses with naturally occurring tendinopathy. J Orthop Res. 2013;31(7):1096-1102.
10. Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. J Exp Clin Cancer Res. 2011;30:9.
11. García-Gómez I, Elvira G, Zapata AG, et al. Mesenchymal stem cells: biological properties and clinical applications. Expert Opin Biol Ther. 2010;10(10):1453-1468.
12. Centeno CJ, Schultz JR, Cheever M, et al. Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2011;6(4):368-378.
13. Centeno CJ, Al-Sayegh H, Freeman MD, Smith J, Murrell WD, Bubnov R. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. Int Orthop. 2016 Mar 30. [Epub ahead of print]
14. Schmitt A, van Griensven M, Imhoff AB, Buchmann S. Application of stem cells in orthopedics. Stem Cells Int. 2012;2012:394962.
15. Tuan RS, Boland G, Tuli R. Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther. 2003;5(1):32-45.
16. Anz AW, Hackel JG, Nilssen EC, Andrews JR. Application of biologics in the treatment of the rotator cuff, meniscus, cartilage, and osteoarthritis. J Am Acad Orthop Surg. 2014;22(2):68-79.
17. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317.
18. Porada CD, Almeida-Porada G. Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. Adv Drug Deliv Rev. 2010;62(12):1156-1566.
19. Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. 2013;21(8):1717-1729.
20. Liechty KW, MacKenzie TC, Shaaban AF, et al. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med. 2000;6(11):1282-1286.
21. Hung SC, Chen NJ, Hsieh SL, Li H, Ma HL, Lo WH. Isolation and characterization of size-sieved stem cells from human bone marrow. Stem Cells. 2002;20(3):249-258.
22. De Bari C, Dell’Accio F, Vanlauwe J, et al. Mesenchymal multipotency of adult human periosteal cells demonstrated by single-cell lineage analysis. Arthritis Rheum. 2006;54(4):1209-1221.
23. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279-4295.
24. Mafi R, Hindocha S, Mafi P, Griffin M, Khan WS. Sources of adult mesenchymal stem cells applicable for musculoskeletal applications - a systematic review of the literature. Open Orthop J. 2011;5 Suppl 2:242-248.
25. Frisbie DD, Kisiday JD, Kawcak CE, Werpy NM, McIlwraith CW. Evaluation of adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis. J Orthop Res. 2009;27(12):1675-1680.
26. Vidal MA, Robinson SO, Lopez MJ, et al. Comparison of chondrogenic potential in equine mesenchymal stromal cells derived from adipose tissue and bone marrow. Vet Surg. 2008;37(8):713-724.
27. Yoshimura H, Muneta T, Nimura A, Yokoyama A, Koga H, Sekiya I. Comparison of rat mesenchymal stem cells derived from bone marrow, synovium, periosteum, adipose tissue, and muscle. Cell Tissue Res. 2007;327(3):449-462.
28. Hogan MV, Walker GN, Cui LR, Fu FH, Huard J. The role of stem cells and tissue engineering in orthopaedic sports medicine: current evidence and future directions. Arthroscopy. 2015;31(5):1017-1021.
29. Koh YG, Choi YJ, Kwon SK, Kim YS, Yeo JE. Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2015;23(5):1308-1316.
30. Vangsness CT Jr, Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. 2014;96(2):90-98.
31. Goodrich LR, Chen AC, Werpy NM, et al. Addition of mesenchymal stem cells to autologous platelet-enhanced fibrin scaffolds in chondral defects: does it enhance repair? J Bone Joint Surg Am. 2016;98(1):23-34.
32. Kim YS, Choi YJ, Suh DS, et al. Mesenchymal stem cell implantation in osteoarthritic knees: is fibrin glue effective as a scaffold? Am J Sports Med. 2015;43(1):176-185.
33. Steinert AF, Rackwitz L, Gilbert F, Nöth U, Tuan RS. Concise review: the clinical application of mesenchymal stem cells for musculoskeletal regeneration: current status and perspectives. Stem Cells Transl Med. 2012;1(3):237-247.
34. Pers YM, Ruiz M, Noël D, Jorgensen C. Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives. Osteoarthritis Cartilage. 2015;23(11):2027-2035.
35. Mamidi MK, Das AK, Zakaria Z, Bhonde R. Mesenchymal stromal cells for cartilage repair in osteoarthritis. Osteoarthritis Cartilage. 2016 Mar 10. [Epub ahead of print]
36. Wyles CC, Houdek MT, Behfar A, Sierra RJ. Mesenchymal stem cell therapy for osteoarthritis: current perspectives. Stem Cells Cloning. 2015;8:117-124.
37. Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy. 2013;29(12):2020-2028.
38. Vega A, Martín-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99(8):1681-1690.
39. Kim YS, Lee M, Koh YG. Additional mesenchymal stem cell injection improves the outcomes of marrow stimulation combined with supramalleolar osteotomy in varus ankle osteoarthritis: short-term clinical results with second-look arthroscopic evaluation. J Exp Orthop. 2016;3(1):12.
40. Kraus TM, Imhoff FB, Reinert J, et al. Stem cells and bFGF in tendon healing: Effects of lentiviral gene transfer and long-term follow-up in a rat Achilles tendon defect model. BMC Musculoskelet Disord. 2016;17(1):148.
41. Thomopoulos S, Parks WC, Rifkin DB, Derwin KA. Mechanisms of tendon injury and repair. J Orthop Res. 2015;33(6):832-839.
42. Müller SA, Todorov A, Heisterbach PE, Martin I, Majewski M. Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. Knee Surg Sports Traumatol Arthrosc. 2015;23(7):2097-3105.
43. Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RK. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44(1):25-32.
44. Machova Urdzikova L, Sedlacek R, Suchy T, et al. Human multipotent mesenchymal stem cells improve healing after collagenase tendon injury in the rat. Biomed Eng Online. 2014;13:42.
45. Oshita T, Tobita M, Tajima S, Mizuno H. Adipose-derived stem cells improve collagenase-induced tendinopathy in a rat model. Am J Sports Med. 2016 Apr 11. [Epub ahead of print]
46. Yuksel S, Guleç MA, Gultekin MZ, et al. Comparison of the early-period effects of bone marrow-derived mesenchymal stem cells and platelet-rich plasma on achilles tendon ruptures in rats. Connect Tissue Res. 2016 May 18. [Epub ahead of print]
47. Chen L, Liu JP, Tang KL, et al. Tendon derived stem cells promote platelet-rich plasma healing in collagenase-induced rat achilles tendinopathy. Cell Physiol Biochem. 2014;34(6):2153-2168.
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49. Zlotnicki JP, Geeslin AG, Murray IR, et al. Biologic treatments for sports injuries ii think tank-current concepts, future research, and barriers to advancement, part 3: articular cartilage. Orthop J Sports Med. 2016;4(4):2325967116642433.
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