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 colleagues^59,60 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 colleagues^59,60 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 colleagues^59,60 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.

Higher implicit racial bias among non-black oncologists was associated with aspects of their interactions and care of non-black patients, investigators report.

In a study of 18 non-black oncologists and 112 black patients, oncologists who were higher in implicit racial bias had shorter interactions with the black patients, and those interactions were rated less supportive by observers and patients. Higher implicit bias was also associated with more patient difficulty remembering contents of the interaction, Louis A. Penner, Ph.D., of Karmanos Cancer Institute, Detroit, and his associates reported (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.66.3658).

©Alexander Raths/Fotolia.com

“We acknowledge it is unlikely racial bias alone [that] is the major source of the well-documented, widespread racial disparities in cancer treatment. Factors such as patient socioeconomic status, limited access to high-quality health care, and patients’ health-related attitudes also contribute to racial disparities in cancer treatment. However, our data suggest that oncologist implicit racial bias may uniquely contribute to these disparities and should be further explored,” wrote Dr. Penner and his associates.

For the study, oncologists completed the Implicit Association Test that measured implicit racial bias prior to professional interaction. Patients also completed a baseline questionnaire prior to their appointment with an oncologist. Patients and physicians then had an appointment to discuss initial treatment for a current cancer. Patient questionnaires measuring perception of oncologist, the interaction, and recommended treatments, and physician questionnaires measuring patient participation were completed following the appointment. In addition, 96 of 112 appointments were videotaped and reviewed by four – two black and two white – researchers to assess various aspects of the physician-patient interaction.

Bivariate multilevel models revealed that higher implicit racial bias among oncologists was significantly associated to shorter appointment times (P = .02) and decreased use of supportive communication (P less than .01 when controlling for physician age). Implicit racial bias was not significantly correlated to talk-time ratio (P = .27) nor to the extent to which oncologists involved their patients in treatment decisions (P = .22).

Higher implicit racial bias was associated with patients experiencing greater difficulty remembering conversation contents (P less than .01) and patients perceiving the conversation as being less patient-centered (P = .01). Higher implicit racial bias was not significantly correlated to patient’s perception of treatment plans discussed (P = .19), post-visit distress (P = .57), or trust in their oncologist (P = .08).

This study was funded by the National Cancer Institute and the research advisory committee of the Southeast Michigan Partners Against Cancer. Eleven investigators had no relevant disclosures to report. The three other investigators reported serving in advisory roles for, receiving financial compensation or honoraria from, or participating in the speakers bureau of multiple companies.

[email protected]

On Twitter @jessnicolecraig

Higher implicit racial bias among non-black oncologists was associated with aspects of their interactions and care of non-black patients, investigators report.

In a study of 18 non-black oncologists and 112 black patients, oncologists who were higher in implicit racial bias had shorter interactions with the black patients, and those interactions were rated less supportive by observers and patients. Higher implicit bias was also associated with more patient difficulty remembering contents of the interaction, Louis A. Penner, Ph.D., of Karmanos Cancer Institute, Detroit, and his associates reported (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.66.3658).

©Alexander Raths/Fotolia.com

“We acknowledge it is unlikely racial bias alone [that] is the major source of the well-documented, widespread racial disparities in cancer treatment. Factors such as patient socioeconomic status, limited access to high-quality health care, and patients’ health-related attitudes also contribute to racial disparities in cancer treatment. However, our data suggest that oncologist implicit racial bias may uniquely contribute to these disparities and should be further explored,” wrote Dr. Penner and his associates.

For the study, oncologists completed the Implicit Association Test that measured implicit racial bias prior to professional interaction. Patients also completed a baseline questionnaire prior to their appointment with an oncologist. Patients and physicians then had an appointment to discuss initial treatment for a current cancer. Patient questionnaires measuring perception of oncologist, the interaction, and recommended treatments, and physician questionnaires measuring patient participation were completed following the appointment. In addition, 96 of 112 appointments were videotaped and reviewed by four – two black and two white – researchers to assess various aspects of the physician-patient interaction.

Bivariate multilevel models revealed that higher implicit racial bias among oncologists was significantly associated to shorter appointment times (P = .02) and decreased use of supportive communication (P less than .01 when controlling for physician age). Implicit racial bias was not significantly correlated to talk-time ratio (P = .27) nor to the extent to which oncologists involved their patients in treatment decisions (P = .22).

Higher implicit racial bias was associated with patients experiencing greater difficulty remembering conversation contents (P less than .01) and patients perceiving the conversation as being less patient-centered (P = .01). Higher implicit racial bias was not significantly correlated to patient’s perception of treatment plans discussed (P = .19), post-visit distress (P = .57), or trust in their oncologist (P = .08).

This study was funded by the National Cancer Institute and the research advisory committee of the Southeast Michigan Partners Against Cancer. Eleven investigators had no relevant disclosures to report. The three other investigators reported serving in advisory roles for, receiving financial compensation or honoraria from, or participating in the speakers bureau of multiple companies.

[email protected]

On Twitter @jessnicolecraig

Higher implicit racial bias among non-black oncologists was associated with aspects of their interactions and care of non-black patients, investigators report.

In a study of 18 non-black oncologists and 112 black patients, oncologists who were higher in implicit racial bias had shorter interactions with the black patients, and those interactions were rated less supportive by observers and patients. Higher implicit bias was also associated with more patient difficulty remembering contents of the interaction, Louis A. Penner, Ph.D., of Karmanos Cancer Institute, Detroit, and his associates reported (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.66.3658).

©Alexander Raths/Fotolia.com

“We acknowledge it is unlikely racial bias alone [that] is the major source of the well-documented, widespread racial disparities in cancer treatment. Factors such as patient socioeconomic status, limited access to high-quality health care, and patients’ health-related attitudes also contribute to racial disparities in cancer treatment. However, our data suggest that oncologist implicit racial bias may uniquely contribute to these disparities and should be further explored,” wrote Dr. Penner and his associates.

For the study, oncologists completed the Implicit Association Test that measured implicit racial bias prior to professional interaction. Patients also completed a baseline questionnaire prior to their appointment with an oncologist. Patients and physicians then had an appointment to discuss initial treatment for a current cancer. Patient questionnaires measuring perception of oncologist, the interaction, and recommended treatments, and physician questionnaires measuring patient participation were completed following the appointment. In addition, 96 of 112 appointments were videotaped and reviewed by four – two black and two white – researchers to assess various aspects of the physician-patient interaction.

Bivariate multilevel models revealed that higher implicit racial bias among oncologists was significantly associated to shorter appointment times (P = .02) and decreased use of supportive communication (P less than .01 when controlling for physician age). Implicit racial bias was not significantly correlated to talk-time ratio (P = .27) nor to the extent to which oncologists involved their patients in treatment decisions (P = .22).

Higher implicit racial bias was associated with patients experiencing greater difficulty remembering conversation contents (P less than .01) and patients perceiving the conversation as being less patient-centered (P = .01). Higher implicit racial bias was not significantly correlated to patient’s perception of treatment plans discussed (P = .19), post-visit distress (P = .57), or trust in their oncologist (P = .08).

This study was funded by the National Cancer Institute and the research advisory committee of the Southeast Michigan Partners Against Cancer. Eleven investigators had no relevant disclosures to report. The three other investigators reported serving in advisory roles for, receiving financial compensation or honoraria from, or participating in the speakers bureau of multiple companies.

[email protected]

On Twitter @jessnicolecraig

The 2 cardinal properties of stem cells are the ability to self-renew and the ability to differentiate into distinctive end-stage cell types. The work of Caplan¹ captured our early attention, with cells cultured from bone marrow differentiating into a number of different cell types of orthopedic interest. Our latest attention has been captured by the additional abilities of these cells to mobilize, monitor, and interact with their surrounding environment.^2-4 In response to their environment, stem cells are able to release a broad spectrum of macromolecules with trophic, chemotactic, and immunomodulatory potential, which allows them to participate in injury response, tissue healing, and tissue regeneration.⁴ These cells are innate to the body’s monitoring, maintenance, repair, and stress response systems.^2,4-11 Basic science and animal studies have illustrated the potential of cells with stem potential regardless of their environment/source of harvest.

Where Can We Get Stem Cells?

Cells with stem properties are present in many environmental niches, including the bone marrow, peripheral circulatory system, adipose tissue, synovial tissue, muscle tissue, and tendon tissue.^12-15 A number of cell types with stem properties populate the bone marrow niche, including hematopoietic stem/progenitor cells (HSPC), perivascular stromal cells (PSC), endothelial stem cells (ESC), and immature cells with qualities like embryonal stem cells termed very small embryonal-like stem cells (VESL).^12,15-19 All of these cells have stem properties and have been shown to differentiate to tissues of orthopedic interest.The interplay, interaction, and potential of these cell types is complex and incompletely understood.^12,15-19 When bone marrow is aspirated for culturing purposes, it is unclear which cell line produces the plastic-adherent multipotent cells grown in culture, which are often referred to as mesenchymal stem cells (MSCs). Researches propose that HSPC and/or VESL circulate peripherally in small numbers but leave the bone marrow in certain mobilization instances and are important for the monitoring and maintenance of the majority of tissues in our bodies.^5,16 Current clinical utilization of these cell types by the orthopedic community primarily utilizes point-of-care bone marrow aspiration and concentration, while the hematology oncology community mobilizes cells from the bone marrow to the blood stream with pharmaceutical agents and harvests cells via apheresis. Bone marrow aspiration produces variable numbers of stem cells, with studies ranging from 1 stem cell per mL of tissue collected to 300,000 stem cells per mL of tissue collected.20Mobilization and apheresis can produce large volumes of peripheral blood-derived cells with 600,000 HSPC per mL and 2.32 million PSC per mL of tissue collected.²¹

In adipose tissue, cells adherent to the abluminal side of blood vessels known as pericytes also carry stem qualities. Aspiration and processing of adipose tissue can access these stem cells, producing a product often referred to as stromal vascular fraction (SVF). Processing of lipoaspirate to create stromal vascular fraction requires mechanical or enzymatic processing. This also produces variable numbers of stem cells, with quantitative studies ranging from 5000 to 1.5 million stem cells per mL of tissue collected.²⁰ Similar to adipose-derived stem cells, synovial-derived and muscle-derived stem cells also require mechanical or enzymatic processing. For applications where it is believed that a large number of cells is necessary, investigators often utilize culturing techniques for all sources with the exception of mobilization and apheresis harvest. As clinicians, 3 challenges have proven more important than which cell type to utilize: 1) patient-care logistics regarding collection and application; 2) the undefined dose-response curve regarding stem cell treatments; and 3) evolving government/community regulation.

Regulation of Stem Cell Therapies

The regulation of stem cell technologies is a double-edged sword for development. While loose regulation encourages clinical application and experimentation, patient safety and efficacy concerns are raised, and a technology’s worth is not proven before clinical application. Tight regulation temporarily hampers progress, yet ensures the proof of safety and efficacy prior to widespread implementation. Within the United States, the Food and Drug Administration (FDA) has tightened regulation, established precedent, and intervened in the ability of clinicians to utilize stem cell therapies in humans, through “warning letters,” “untitled letters,” and industry guidance documents.^22-30

The FDA categorizes stem cell therapies as human cells, tissues, and cellular- and tissue-based products (HCT/Ps). Section 361 of the Public Health Safety (PHS) Act established and outlined the authority of the FDA to regulate low-risk HCT/Ps in order to prevent the introduction, transmission, and spread of communicable disease. Section 361 provided standards for safety without requiring preclinical development. The FDA established 4 principles to determine the risk of HCT/Ps: the extent of manipulation involved in manufacture, the metabolic activity/autologous nature of the product, whether the product represents a tissue combined with another product, and whether the product is utilized in a fashion homologous with its original function (Figure 1). If a product/therapy meets requirements around all 4 of these principles, then it is deemed a low-risk product and regulated under Section 361 alone. If a product/therapy does not meet requirements around all 4 of these principles, then the FDA regulates the product/therapy under additional codes including Section 351 of the PHS Act. Section 351 outlines a developmental process including preclinical animal trials, phased clinical study, and premarket review by the FDA prior to offering the product/treatment in clinical practice. The developmental process requires investigators and/or industry developers to initiate an Investigational New Drug (IND) program whose end goal is to present data from all developmental study and obtain a Biologic License Application (BLA) approval to market the product.^22-23 To establish safety and efficacy, the traditional IND program involves a preclinical animal study, a small pilot human study (Phase I), a small initial randomized controlled trial (Phase II), followed by a large multicenter randomized controlled trial (Phase III) (Figure 2). The FDA has recognized little to no stem cell treatments as products regulated by Section 361 alone. Additionally, the FDA has established precedent regarding allograft stem cells, cells obtained from fat harvest, amniotic/placental products, and cultured cells, suggesting that these products are not low risk and require an IND pathway outlined in Section 351.^24-30

Bone Marrow Aspiration

Surprisingly, the FDA has not moved to regulate the point-of-care use of bone marrow aspirate or platelet-rich plasma and has labeled these as “not HCTPs.” The stem cell concentration of bone marrow aspirate is technique-dependent, declines with age, and has been found to be an important factor for clinical benefit.³¹ While it is possible to aspirate from multiple sites, posterior iliac crest harvest produces the highest stem cell yield.^32-34 Hernigou and colleagues^35-36 have outlined safe zones for trocar placement and illustrated that strong aspiration with small-volume syringes, 10-mL syringes, optimizes stem cell harvest. Additionally, studies by Hernigou and colleagues^31,37-38 involving tibial nonunion, avascular necrosis of the femur, and augmentation of rotator cuff repair are guideposts to clinicians utilizing bone marrow aspirate.

Amniotic Stem Cell Technologies and Adipose-Derived Stem Cells

While some argue that there is regulatory confusion around amniotic/placental-derived tissues and adipose-derived products, the FDA has clearly established precedent establishing these as products requiring Section 351 development.^26-29 Companies are marketing products derived from perinatal byproducts, yet there are multiple FDA letters suggesting that these are not products regulated solely under PHS Act 361 because they do not meet the criteria of homologous use and are not autologous.^28-29 Use of these products places risk upon the clinician and the patient. Some argue that adipose-derived stem cell products are 361 products. While the FDA has approved devices for the mechanical processing of lipoaspirate, they have established precedent suggesting that they consider orthopedic applications nonhomologous and any processing that “alters the original relevant characteristics of adipose tissue relating to the tissue’s utility for reconstruction, repair, or replacement” as more than minimal manipulation.^26,27 The FDA originally planned an open forum for discussion with clinicians and industry for April 2016. This open forum was delayed due to the volume of interest, and a workshop has been planned for Fall 2016.

Future Regulation of Stem Cell Technologies

While many countries have mirrored the FDA with tight regulatory mechanisms, a few countries have established modern regulatory mechanisms aimed at the promotion of conscientious development, including South Korea, Japan, and England. For example, in 2014 Japan labeled stem cell technologies as “regenerative medicine products,” setting them apart from pharmaceuticals, and implemented a new approval system allowing early observed commercialization with reimbursement after less stringent safety and efficacy milestones.²²The observed commercialization lowers time and financial hurdles for development while still requiring the proof of the technology’s worth. Countries that have effected change have positioned themselves to be pioneers in this emerging field.

In March 2016, the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act of 2016 (S. 2689 / H.R. 4762) was introduced into the United States Congress. This bipartisan, bicameral legislation was introduced, read twice, and referred to subcommittee. Its goal is to reduce barriers and accelerate development of biologic therapies while keeping the frame work set forth under Sections 351 and 361 of the PHS Act.³⁹ Similar to the pathway in Japan, the REGROW Act would establish a conditional approval pathway that would ensure products are safe and effective while also evolving the regulatory pathway towards progress (Figure 3). Development would still require an IND application after preclinical animal study. However, after safety was established with human Phase I data and preliminary evidence of efficacy with Phase II data, patients could be treated with the investigational therapies and reimbursement collected for a limited period of time (5 years) prior to a large Phase III human clinical trial. Patients treated with the new therapy would be monitored closely. All results would be reported to the FDA in a BLA. This change in legislation would lower but not remove regulatory hurdles necessary for development.

Conclusion

The future of stem cell treatments hinges upon the creation of new favorable regulatory mechanisms that will promote clinical application while ensuring that safety and efficacy milestones are reached. Clinical researchers require freedom to develop these technologies while protecting patients and ensuring the validity of treatments. The coordination of research and regulatory affairs on a global level is necessary focusing on the harmonization of guidelines, regulations, and mechanisms for simultaneous adoption in different countries. The global orthopedic community has made strides regarding the science of stem cell technologies; it is time for us to initiate progressive change regarding regulation so that we can determine what is effective clinically.

The 2 cardinal properties of stem cells are the ability to self-renew and the ability to differentiate into distinctive end-stage cell types. The work of Caplan¹ captured our early attention, with cells cultured from bone marrow differentiating into a number of different cell types of orthopedic interest. Our latest attention has been captured by the additional abilities of these cells to mobilize, monitor, and interact with their surrounding environment.^2-4 In response to their environment, stem cells are able to release a broad spectrum of macromolecules with trophic, chemotactic, and immunomodulatory potential, which allows them to participate in injury response, tissue healing, and tissue regeneration.⁴ These cells are innate to the body’s monitoring, maintenance, repair, and stress response systems.^2,4-11 Basic science and animal studies have illustrated the potential of cells with stem potential regardless of their environment/source of harvest.

Where Can We Get Stem Cells?

Cells with stem properties are present in many environmental niches, including the bone marrow, peripheral circulatory system, adipose tissue, synovial tissue, muscle tissue, and tendon tissue.^12-15 A number of cell types with stem properties populate the bone marrow niche, including hematopoietic stem/progenitor cells (HSPC), perivascular stromal cells (PSC), endothelial stem cells (ESC), and immature cells with qualities like embryonal stem cells termed very small embryonal-like stem cells (VESL).^12,15-19 All of these cells have stem properties and have been shown to differentiate to tissues of orthopedic interest.The interplay, interaction, and potential of these cell types is complex and incompletely understood.^12,15-19 When bone marrow is aspirated for culturing purposes, it is unclear which cell line produces the plastic-adherent multipotent cells grown in culture, which are often referred to as mesenchymal stem cells (MSCs). Researches propose that HSPC and/or VESL circulate peripherally in small numbers but leave the bone marrow in certain mobilization instances and are important for the monitoring and maintenance of the majority of tissues in our bodies.^5,16 Current clinical utilization of these cell types by the orthopedic community primarily utilizes point-of-care bone marrow aspiration and concentration, while the hematology oncology community mobilizes cells from the bone marrow to the blood stream with pharmaceutical agents and harvests cells via apheresis. Bone marrow aspiration produces variable numbers of stem cells, with studies ranging from 1 stem cell per mL of tissue collected to 300,000 stem cells per mL of tissue collected.20Mobilization and apheresis can produce large volumes of peripheral blood-derived cells with 600,000 HSPC per mL and 2.32 million PSC per mL of tissue collected.²¹

In adipose tissue, cells adherent to the abluminal side of blood vessels known as pericytes also carry stem qualities. Aspiration and processing of adipose tissue can access these stem cells, producing a product often referred to as stromal vascular fraction (SVF). Processing of lipoaspirate to create stromal vascular fraction requires mechanical or enzymatic processing. This also produces variable numbers of stem cells, with quantitative studies ranging from 5000 to 1.5 million stem cells per mL of tissue collected.²⁰ Similar to adipose-derived stem cells, synovial-derived and muscle-derived stem cells also require mechanical or enzymatic processing. For applications where it is believed that a large number of cells is necessary, investigators often utilize culturing techniques for all sources with the exception of mobilization and apheresis harvest. As clinicians, 3 challenges have proven more important than which cell type to utilize: 1) patient-care logistics regarding collection and application; 2) the undefined dose-response curve regarding stem cell treatments; and 3) evolving government/community regulation.

Regulation of Stem Cell Therapies

The regulation of stem cell technologies is a double-edged sword for development. While loose regulation encourages clinical application and experimentation, patient safety and efficacy concerns are raised, and a technology’s worth is not proven before clinical application. Tight regulation temporarily hampers progress, yet ensures the proof of safety and efficacy prior to widespread implementation. Within the United States, the Food and Drug Administration (FDA) has tightened regulation, established precedent, and intervened in the ability of clinicians to utilize stem cell therapies in humans, through “warning letters,” “untitled letters,” and industry guidance documents.^22-30

The FDA categorizes stem cell therapies as human cells, tissues, and cellular- and tissue-based products (HCT/Ps). Section 361 of the Public Health Safety (PHS) Act established and outlined the authority of the FDA to regulate low-risk HCT/Ps in order to prevent the introduction, transmission, and spread of communicable disease. Section 361 provided standards for safety without requiring preclinical development. The FDA established 4 principles to determine the risk of HCT/Ps: the extent of manipulation involved in manufacture, the metabolic activity/autologous nature of the product, whether the product represents a tissue combined with another product, and whether the product is utilized in a fashion homologous with its original function (Figure 1). If a product/therapy meets requirements around all 4 of these principles, then it is deemed a low-risk product and regulated under Section 361 alone. If a product/therapy does not meet requirements around all 4 of these principles, then the FDA regulates the product/therapy under additional codes including Section 351 of the PHS Act. Section 351 outlines a developmental process including preclinical animal trials, phased clinical study, and premarket review by the FDA prior to offering the product/treatment in clinical practice. The developmental process requires investigators and/or industry developers to initiate an Investigational New Drug (IND) program whose end goal is to present data from all developmental study and obtain a Biologic License Application (BLA) approval to market the product.^22-23 To establish safety and efficacy, the traditional IND program involves a preclinical animal study, a small pilot human study (Phase I), a small initial randomized controlled trial (Phase II), followed by a large multicenter randomized controlled trial (Phase III) (Figure 2). The FDA has recognized little to no stem cell treatments as products regulated by Section 361 alone. Additionally, the FDA has established precedent regarding allograft stem cells, cells obtained from fat harvest, amniotic/placental products, and cultured cells, suggesting that these products are not low risk and require an IND pathway outlined in Section 351.^24-30

Bone Marrow Aspiration

Surprisingly, the FDA has not moved to regulate the point-of-care use of bone marrow aspirate or platelet-rich plasma and has labeled these as “not HCTPs.” The stem cell concentration of bone marrow aspirate is technique-dependent, declines with age, and has been found to be an important factor for clinical benefit.³¹ While it is possible to aspirate from multiple sites, posterior iliac crest harvest produces the highest stem cell yield.^32-34 Hernigou and colleagues^35-36 have outlined safe zones for trocar placement and illustrated that strong aspiration with small-volume syringes, 10-mL syringes, optimizes stem cell harvest. Additionally, studies by Hernigou and colleagues^31,37-38 involving tibial nonunion, avascular necrosis of the femur, and augmentation of rotator cuff repair are guideposts to clinicians utilizing bone marrow aspirate.

Amniotic Stem Cell Technologies and Adipose-Derived Stem Cells

While some argue that there is regulatory confusion around amniotic/placental-derived tissues and adipose-derived products, the FDA has clearly established precedent establishing these as products requiring Section 351 development.^26-29 Companies are marketing products derived from perinatal byproducts, yet there are multiple FDA letters suggesting that these are not products regulated solely under PHS Act 361 because they do not meet the criteria of homologous use and are not autologous.^28-29 Use of these products places risk upon the clinician and the patient. Some argue that adipose-derived stem cell products are 361 products. While the FDA has approved devices for the mechanical processing of lipoaspirate, they have established precedent suggesting that they consider orthopedic applications nonhomologous and any processing that “alters the original relevant characteristics of adipose tissue relating to the tissue’s utility for reconstruction, repair, or replacement” as more than minimal manipulation.^26,27 The FDA originally planned an open forum for discussion with clinicians and industry for April 2016. This open forum was delayed due to the volume of interest, and a workshop has been planned for Fall 2016.

Future Regulation of Stem Cell Technologies

While many countries have mirrored the FDA with tight regulatory mechanisms, a few countries have established modern regulatory mechanisms aimed at the promotion of conscientious development, including South Korea, Japan, and England. For example, in 2014 Japan labeled stem cell technologies as “regenerative medicine products,” setting them apart from pharmaceuticals, and implemented a new approval system allowing early observed commercialization with reimbursement after less stringent safety and efficacy milestones.²²The observed commercialization lowers time and financial hurdles for development while still requiring the proof of the technology’s worth. Countries that have effected change have positioned themselves to be pioneers in this emerging field.

In March 2016, the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act of 2016 (S. 2689 / H.R. 4762) was introduced into the United States Congress. This bipartisan, bicameral legislation was introduced, read twice, and referred to subcommittee. Its goal is to reduce barriers and accelerate development of biologic therapies while keeping the frame work set forth under Sections 351 and 361 of the PHS Act.³⁹ Similar to the pathway in Japan, the REGROW Act would establish a conditional approval pathway that would ensure products are safe and effective while also evolving the regulatory pathway towards progress (Figure 3). Development would still require an IND application after preclinical animal study. However, after safety was established with human Phase I data and preliminary evidence of efficacy with Phase II data, patients could be treated with the investigational therapies and reimbursement collected for a limited period of time (5 years) prior to a large Phase III human clinical trial. Patients treated with the new therapy would be monitored closely. All results would be reported to the FDA in a BLA. This change in legislation would lower but not remove regulatory hurdles necessary for development.

Conclusion

The future of stem cell treatments hinges upon the creation of new favorable regulatory mechanisms that will promote clinical application while ensuring that safety and efficacy milestones are reached. Clinical researchers require freedom to develop these technologies while protecting patients and ensuring the validity of treatments. The coordination of research and regulatory affairs on a global level is necessary focusing on the harmonization of guidelines, regulations, and mechanisms for simultaneous adoption in different countries. The global orthopedic community has made strides regarding the science of stem cell technologies; it is time for us to initiate progressive change regarding regulation so that we can determine what is effective clinically.

The 2 cardinal properties of stem cells are the ability to self-renew and the ability to differentiate into distinctive end-stage cell types. The work of Caplan¹ captured our early attention, with cells cultured from bone marrow differentiating into a number of different cell types of orthopedic interest. Our latest attention has been captured by the additional abilities of these cells to mobilize, monitor, and interact with their surrounding environment.^2-4 In response to their environment, stem cells are able to release a broad spectrum of macromolecules with trophic, chemotactic, and immunomodulatory potential, which allows them to participate in injury response, tissue healing, and tissue regeneration.⁴ These cells are innate to the body’s monitoring, maintenance, repair, and stress response systems.^2,4-11 Basic science and animal studies have illustrated the potential of cells with stem potential regardless of their environment/source of harvest.

Where Can We Get Stem Cells?

Cells with stem properties are present in many environmental niches, including the bone marrow, peripheral circulatory system, adipose tissue, synovial tissue, muscle tissue, and tendon tissue.^12-15 A number of cell types with stem properties populate the bone marrow niche, including hematopoietic stem/progenitor cells (HSPC), perivascular stromal cells (PSC), endothelial stem cells (ESC), and immature cells with qualities like embryonal stem cells termed very small embryonal-like stem cells (VESL).^12,15-19 All of these cells have stem properties and have been shown to differentiate to tissues of orthopedic interest.The interplay, interaction, and potential of these cell types is complex and incompletely understood.^12,15-19 When bone marrow is aspirated for culturing purposes, it is unclear which cell line produces the plastic-adherent multipotent cells grown in culture, which are often referred to as mesenchymal stem cells (MSCs). Researches propose that HSPC and/or VESL circulate peripherally in small numbers but leave the bone marrow in certain mobilization instances and are important for the monitoring and maintenance of the majority of tissues in our bodies.^5,16 Current clinical utilization of these cell types by the orthopedic community primarily utilizes point-of-care bone marrow aspiration and concentration, while the hematology oncology community mobilizes cells from the bone marrow to the blood stream with pharmaceutical agents and harvests cells via apheresis. Bone marrow aspiration produces variable numbers of stem cells, with studies ranging from 1 stem cell per mL of tissue collected to 300,000 stem cells per mL of tissue collected.20Mobilization and apheresis can produce large volumes of peripheral blood-derived cells with 600,000 HSPC per mL and 2.32 million PSC per mL of tissue collected.²¹

In adipose tissue, cells adherent to the abluminal side of blood vessels known as pericytes also carry stem qualities. Aspiration and processing of adipose tissue can access these stem cells, producing a product often referred to as stromal vascular fraction (SVF). Processing of lipoaspirate to create stromal vascular fraction requires mechanical or enzymatic processing. This also produces variable numbers of stem cells, with quantitative studies ranging from 5000 to 1.5 million stem cells per mL of tissue collected.²⁰ Similar to adipose-derived stem cells, synovial-derived and muscle-derived stem cells also require mechanical or enzymatic processing. For applications where it is believed that a large number of cells is necessary, investigators often utilize culturing techniques for all sources with the exception of mobilization and apheresis harvest. As clinicians, 3 challenges have proven more important than which cell type to utilize: 1) patient-care logistics regarding collection and application; 2) the undefined dose-response curve regarding stem cell treatments; and 3) evolving government/community regulation.

Regulation of Stem Cell Therapies

The regulation of stem cell technologies is a double-edged sword for development. While loose regulation encourages clinical application and experimentation, patient safety and efficacy concerns are raised, and a technology’s worth is not proven before clinical application. Tight regulation temporarily hampers progress, yet ensures the proof of safety and efficacy prior to widespread implementation. Within the United States, the Food and Drug Administration (FDA) has tightened regulation, established precedent, and intervened in the ability of clinicians to utilize stem cell therapies in humans, through “warning letters,” “untitled letters,” and industry guidance documents.^22-30

The FDA categorizes stem cell therapies as human cells, tissues, and cellular- and tissue-based products (HCT/Ps). Section 361 of the Public Health Safety (PHS) Act established and outlined the authority of the FDA to regulate low-risk HCT/Ps in order to prevent the introduction, transmission, and spread of communicable disease. Section 361 provided standards for safety without requiring preclinical development. The FDA established 4 principles to determine the risk of HCT/Ps: the extent of manipulation involved in manufacture, the metabolic activity/autologous nature of the product, whether the product represents a tissue combined with another product, and whether the product is utilized in a fashion homologous with its original function (Figure 1). If a product/therapy meets requirements around all 4 of these principles, then it is deemed a low-risk product and regulated under Section 361 alone. If a product/therapy does not meet requirements around all 4 of these principles, then the FDA regulates the product/therapy under additional codes including Section 351 of the PHS Act. Section 351 outlines a developmental process including preclinical animal trials, phased clinical study, and premarket review by the FDA prior to offering the product/treatment in clinical practice. The developmental process requires investigators and/or industry developers to initiate an Investigational New Drug (IND) program whose end goal is to present data from all developmental study and obtain a Biologic License Application (BLA) approval to market the product.^22-23 To establish safety and efficacy, the traditional IND program involves a preclinical animal study, a small pilot human study (Phase I), a small initial randomized controlled trial (Phase II), followed by a large multicenter randomized controlled trial (Phase III) (Figure 2). The FDA has recognized little to no stem cell treatments as products regulated by Section 361 alone. Additionally, the FDA has established precedent regarding allograft stem cells, cells obtained from fat harvest, amniotic/placental products, and cultured cells, suggesting that these products are not low risk and require an IND pathway outlined in Section 351.^24-30

Bone Marrow Aspiration

Surprisingly, the FDA has not moved to regulate the point-of-care use of bone marrow aspirate or platelet-rich plasma and has labeled these as “not HCTPs.” The stem cell concentration of bone marrow aspirate is technique-dependent, declines with age, and has been found to be an important factor for clinical benefit.³¹ While it is possible to aspirate from multiple sites, posterior iliac crest harvest produces the highest stem cell yield.^32-34 Hernigou and colleagues^35-36 have outlined safe zones for trocar placement and illustrated that strong aspiration with small-volume syringes, 10-mL syringes, optimizes stem cell harvest. Additionally, studies by Hernigou and colleagues^31,37-38 involving tibial nonunion, avascular necrosis of the femur, and augmentation of rotator cuff repair are guideposts to clinicians utilizing bone marrow aspirate.

Amniotic Stem Cell Technologies and Adipose-Derived Stem Cells

While some argue that there is regulatory confusion around amniotic/placental-derived tissues and adipose-derived products, the FDA has clearly established precedent establishing these as products requiring Section 351 development.^26-29 Companies are marketing products derived from perinatal byproducts, yet there are multiple FDA letters suggesting that these are not products regulated solely under PHS Act 361 because they do not meet the criteria of homologous use and are not autologous.^28-29 Use of these products places risk upon the clinician and the patient. Some argue that adipose-derived stem cell products are 361 products. While the FDA has approved devices for the mechanical processing of lipoaspirate, they have established precedent suggesting that they consider orthopedic applications nonhomologous and any processing that “alters the original relevant characteristics of adipose tissue relating to the tissue’s utility for reconstruction, repair, or replacement” as more than minimal manipulation.^26,27 The FDA originally planned an open forum for discussion with clinicians and industry for April 2016. This open forum was delayed due to the volume of interest, and a workshop has been planned for Fall 2016.

Future Regulation of Stem Cell Technologies

While many countries have mirrored the FDA with tight regulatory mechanisms, a few countries have established modern regulatory mechanisms aimed at the promotion of conscientious development, including South Korea, Japan, and England. For example, in 2014 Japan labeled stem cell technologies as “regenerative medicine products,” setting them apart from pharmaceuticals, and implemented a new approval system allowing early observed commercialization with reimbursement after less stringent safety and efficacy milestones.²²The observed commercialization lowers time and financial hurdles for development while still requiring the proof of the technology’s worth. Countries that have effected change have positioned themselves to be pioneers in this emerging field.

In March 2016, the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act of 2016 (S. 2689 / H.R. 4762) was introduced into the United States Congress. This bipartisan, bicameral legislation was introduced, read twice, and referred to subcommittee. Its goal is to reduce barriers and accelerate development of biologic therapies while keeping the frame work set forth under Sections 351 and 361 of the PHS Act.³⁹ Similar to the pathway in Japan, the REGROW Act would establish a conditional approval pathway that would ensure products are safe and effective while also evolving the regulatory pathway towards progress (Figure 3). Development would still require an IND application after preclinical animal study. However, after safety was established with human Phase I data and preliminary evidence of efficacy with Phase II data, patients could be treated with the investigational therapies and reimbursement collected for a limited period of time (5 years) prior to a large Phase III human clinical trial. Patients treated with the new therapy would be monitored closely. All results would be reported to the FDA in a BLA. This change in legislation would lower but not remove regulatory hurdles necessary for development.

Conclusion

The future of stem cell treatments hinges upon the creation of new favorable regulatory mechanisms that will promote clinical application while ensuring that safety and efficacy milestones are reached. Clinical researchers require freedom to develop these technologies while protecting patients and ensuring the validity of treatments. The coordination of research and regulatory affairs on a global level is necessary focusing on the harmonization of guidelines, regulations, and mechanisms for simultaneous adoption in different countries. The global orthopedic community has made strides regarding the science of stem cell technologies; it is time for us to initiate progressive change regarding regulation so that we can determine what is effective clinically.

Yes. Physicians taking care of patients who have hypertension and resistant hypertension should be aware of the possible diagnosis of obstructive sleep apnea (OSA) and offer in-laboratory polysomnography or home sleep testing if appropriate. Large, long-term observational studies have shown higher incidence rates of hypertension in people with untreated OSA than in those who underwent treatment for it with continuous positive airway pressure (CPAP). Read more on how OSA and hypertension are linked in this article from Cleveland Clinic Journal of Medicine, available at: http://www.ccjm.org/current-issue/issue-single-view/should-i-suspect-obstructive-sleep-apnea-if-a-patient-has-hard-to-control-hypertension/b8ddb92518fe3517d3e073b1eacb89c2.html.

Yes. Physicians taking care of patients who have hypertension and resistant hypertension should be aware of the possible diagnosis of obstructive sleep apnea (OSA) and offer in-laboratory polysomnography or home sleep testing if appropriate. Large, long-term observational studies have shown higher incidence rates of hypertension in people with untreated OSA than in those who underwent treatment for it with continuous positive airway pressure (CPAP). Read more on how OSA and hypertension are linked in this article from Cleveland Clinic Journal of Medicine, available at: http://www.ccjm.org/current-issue/issue-single-view/should-i-suspect-obstructive-sleep-apnea-if-a-patient-has-hard-to-control-hypertension/b8ddb92518fe3517d3e073b1eacb89c2.html.

Yes. Physicians taking care of patients who have hypertension and resistant hypertension should be aware of the possible diagnosis of obstructive sleep apnea (OSA) and offer in-laboratory polysomnography or home sleep testing if appropriate. Large, long-term observational studies have shown higher incidence rates of hypertension in people with untreated OSA than in those who underwent treatment for it with continuous positive airway pressure (CPAP). Read more on how OSA and hypertension are linked in this article from Cleveland Clinic Journal of Medicine, available at: http://www.ccjm.org/current-issue/issue-single-view/should-i-suspect-obstructive-sleep-apnea-if-a-patient-has-hard-to-control-hypertension/b8ddb92518fe3517d3e073b1eacb89c2.html.

Substituting a less-expensive hepatitis C core antigen test into the standard 2-step process for diagnosing active hepatitis C virus (HCV) infection could streamline and cut the cost of HCV detection, according to the results of a study published in Annals of Internal Medicine. Dr. J. Morgan Freiman, of the Boston Medical Center, and her colleagues, performed a meta-analysis to determine the sensitivity and specificity associated with each of the 5 HCV core antigen tests. To find out which tests performed best, go to Family Practice News: http://www.familypracticenews.com/specialty-focus/infectious-diseases/single-article-page/new-hcv-test-approach-could-cut-costs-streamline-diagnosis/8d117e35547c3068dfb553f396ff7ed7.html.

Substituting a less-expensive hepatitis C core antigen test into the standard 2-step process for diagnosing active hepatitis C virus (HCV) infection could streamline and cut the cost of HCV detection, according to the results of a study published in Annals of Internal Medicine. Dr. J. Morgan Freiman, of the Boston Medical Center, and her colleagues, performed a meta-analysis to determine the sensitivity and specificity associated with each of the 5 HCV core antigen tests. To find out which tests performed best, go to Family Practice News: http://www.familypracticenews.com/specialty-focus/infectious-diseases/single-article-page/new-hcv-test-approach-could-cut-costs-streamline-diagnosis/8d117e35547c3068dfb553f396ff7ed7.html.

Substituting a less-expensive hepatitis C core antigen test into the standard 2-step process for diagnosing active hepatitis C virus (HCV) infection could streamline and cut the cost of HCV detection, according to the results of a study published in Annals of Internal Medicine. Dr. J. Morgan Freiman, of the Boston Medical Center, and her colleagues, performed a meta-analysis to determine the sensitivity and specificity associated with each of the 5 HCV core antigen tests. To find out which tests performed best, go to Family Practice News: http://www.familypracticenews.com/specialty-focus/infectious-diseases/single-article-page/new-hcv-test-approach-could-cut-costs-streamline-diagnosis/8d117e35547c3068dfb553f396ff7ed7.html.

A meta-analysis of 20 randomized controlled studies involving more than 4000 heart failure patients confirmed that an exercise training intervention run for at least 3 weeks produces a statistically significant relative reduction in all-cause mortality of 18%, according to Oriana Ciani, PhD, a health technology researcher at the University of Exeter (England). The individual patient data meta-analysis also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization during at least 6 months of follow-up to the exercise programs. Learn more about the findings at Cardiology News, available at: http://www.ecardiologynews.com/specialty-focus/heart-failure/single-article-page/exercise-training-cuts-heart-failure-mortality/c94d2f9c4abf4eea8381de3290883eea.html.

A meta-analysis of 20 randomized controlled studies involving more than 4000 heart failure patients confirmed that an exercise training intervention run for at least 3 weeks produces a statistically significant relative reduction in all-cause mortality of 18%, according to Oriana Ciani, PhD, a health technology researcher at the University of Exeter (England). The individual patient data meta-analysis also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization during at least 6 months of follow-up to the exercise programs. Learn more about the findings at Cardiology News, available at: http://www.ecardiologynews.com/specialty-focus/heart-failure/single-article-page/exercise-training-cuts-heart-failure-mortality/c94d2f9c4abf4eea8381de3290883eea.html.

A meta-analysis of 20 randomized controlled studies involving more than 4000 heart failure patients confirmed that an exercise training intervention run for at least 3 weeks produces a statistically significant relative reduction in all-cause mortality of 18%, according to Oriana Ciani, PhD, a health technology researcher at the University of Exeter (England). The individual patient data meta-analysis also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization during at least 6 months of follow-up to the exercise programs. Learn more about the findings at Cardiology News, available at: http://www.ecardiologynews.com/specialty-focus/heart-failure/single-article-page/exercise-training-cuts-heart-failure-mortality/c94d2f9c4abf4eea8381de3290883eea.html.

Glucose self-monitoring not only yields valuable information on which to base diabetes treatment, it also helps motivate patients and keeps them engaged in and adherent to their care. However, choosing the most appropriate meters and supplies from the plethora available can be challenging. Working together, healthcare providers and certified diabetes educators can ensure that people with diabetes are getting the most out of self-monitoring process. To find out who should monitor blood glucose and how often, and the advances in and limitations of current devices, go to Cleveland Clinic Journal of Medicine: http://www.ccjm.org/past-issues/past-issue-single-view/self-monitoring-of-blood-glucose-advice-for-providers-and-patients/a077c938c36233cb5bb87ccf89270041.html.

Glucose self-monitoring not only yields valuable information on which to base diabetes treatment, it also helps motivate patients and keeps them engaged in and adherent to their care. However, choosing the most appropriate meters and supplies from the plethora available can be challenging. Working together, healthcare providers and certified diabetes educators can ensure that people with diabetes are getting the most out of self-monitoring process. To find out who should monitor blood glucose and how often, and the advances in and limitations of current devices, go to Cleveland Clinic Journal of Medicine: http://www.ccjm.org/past-issues/past-issue-single-view/self-monitoring-of-blood-glucose-advice-for-providers-and-patients/a077c938c36233cb5bb87ccf89270041.html.

Glucose self-monitoring not only yields valuable information on which to base diabetes treatment, it also helps motivate patients and keeps them engaged in and adherent to their care. However, choosing the most appropriate meters and supplies from the plethora available can be challenging. Working together, healthcare providers and certified diabetes educators can ensure that people with diabetes are getting the most out of self-monitoring process. To find out who should monitor blood glucose and how often, and the advances in and limitations of current devices, go to Cleveland Clinic Journal of Medicine: http://www.ccjm.org/past-issues/past-issue-single-view/self-monitoring-of-blood-glucose-advice-for-providers-and-patients/a077c938c36233cb5bb87ccf89270041.html.

The sun has finally set on Kobe Bryant’s magnificent career. After all the tributes and tearful goodbyes, he has finally played his last game and become a part of basketball history. Ever since his field trip to Germany for interleukin-1 receptor antagonist protein (IRAP) treatments to his knee, and his subsequent return to high-level play, I’ve been under siege in the office by patients who “want what Kobe had.” I’ve had to explain, time and time again, that IRAP treatment is not available in the United States and that platelet-rich plasma (PRP) is the closest alternative treatment, convince them that PRP may be even better, and then let them know that it’s considered experimental and not covered by insurance.

In the last issue, we discussed the future of orthopedics, which in my opinion will rely heavily on the biologic therapies now considered experimental. In this issue, we will look into our crystal balls and imagine what that future might look like. To do so, we should first consider what we hope to accomplish through the incorporation of biologic therapies.

The regeneration of articular cartilage, acceleration of fracture and tissue healing, and faster incorporation of tendon grafts to bone have long been considered the Holy Grail of Orthopedics. In his best seller, The Da Vinci Code, Dan Brown makes a compelling argument that the Holy Grail, the chalice thought to have held the blood of Christ, was in fact a mistranslated reference to his living descendants. Whenever I have a visitor or student in the operating room, I focus the scope on the synovial capillaries so they can see the individual red blood cells passing single-file through the vessels on their way to supply cells with the nutrients they need.

Perhaps, like in The Da Vinci Code, the solution to our greatest biologic challenges lies in the blood, already there, just waiting to be unlocked.

PRP has been utilized for everything from tendinopathy to arthropathy, with varied results in the literature. The lack of standardization of PRP preparations, which vary in inclusion of white cells and absolute platelet count, confounds these results even further. In this issue, we review its use in sports medicine and knee arthritis, taking a closer look at partial ulnar collateral ligament tears in baseball players.

In “Tips of the Trade,” we present a technique for “superior capsular reconstruction” that provides a novel solution for patients with pseudoparalysis from massive rotator cuff tears with little other options beside reverse total shoulder arthroplasty.

The one absolute statement I can make regarding biologics is that we currently have more questions than answers, and every hypothesis we prove simply begets more questions. More randomized controlled studies are needed in virtually every aspect of biologics, and we should all consider taking part. While the solutions our patients crave may not arrive during our careers, or even our lifetimes, the groundwork we do now will set the stage for future generations to enjoy biologically enhanced outcomes.

The sun has finally set on Kobe Bryant’s magnificent career. After all the tributes and tearful goodbyes, he has finally played his last game and become a part of basketball history. Ever since his field trip to Germany for interleukin-1 receptor antagonist protein (IRAP) treatments to his knee, and his subsequent return to high-level play, I’ve been under siege in the office by patients who “want what Kobe had.” I’ve had to explain, time and time again, that IRAP treatment is not available in the United States and that platelet-rich plasma (PRP) is the closest alternative treatment, convince them that PRP may be even better, and then let them know that it’s considered experimental and not covered by insurance.

In the last issue, we discussed the future of orthopedics, which in my opinion will rely heavily on the biologic therapies now considered experimental. In this issue, we will look into our crystal balls and imagine what that future might look like. To do so, we should first consider what we hope to accomplish through the incorporation of biologic therapies.

The regeneration of articular cartilage, acceleration of fracture and tissue healing, and faster incorporation of tendon grafts to bone have long been considered the Holy Grail of Orthopedics. In his best seller, The Da Vinci Code, Dan Brown makes a compelling argument that the Holy Grail, the chalice thought to have held the blood of Christ, was in fact a mistranslated reference to his living descendants. Whenever I have a visitor or student in the operating room, I focus the scope on the synovial capillaries so they can see the individual red blood cells passing single-file through the vessels on their way to supply cells with the nutrients they need.

Perhaps, like in The Da Vinci Code, the solution to our greatest biologic challenges lies in the blood, already there, just waiting to be unlocked.

PRP has been utilized for everything from tendinopathy to arthropathy, with varied results in the literature. The lack of standardization of PRP preparations, which vary in inclusion of white cells and absolute platelet count, confounds these results even further. In this issue, we review its use in sports medicine and knee arthritis, taking a closer look at partial ulnar collateral ligament tears in baseball players.

In “Tips of the Trade,” we present a technique for “superior capsular reconstruction” that provides a novel solution for patients with pseudoparalysis from massive rotator cuff tears with little other options beside reverse total shoulder arthroplasty.

The one absolute statement I can make regarding biologics is that we currently have more questions than answers, and every hypothesis we prove simply begets more questions. More randomized controlled studies are needed in virtually every aspect of biologics, and we should all consider taking part. While the solutions our patients crave may not arrive during our careers, or even our lifetimes, the groundwork we do now will set the stage for future generations to enjoy biologically enhanced outcomes.

The sun has finally set on Kobe Bryant’s magnificent career. After all the tributes and tearful goodbyes, he has finally played his last game and become a part of basketball history. Ever since his field trip to Germany for interleukin-1 receptor antagonist protein (IRAP) treatments to his knee, and his subsequent return to high-level play, I’ve been under siege in the office by patients who “want what Kobe had.” I’ve had to explain, time and time again, that IRAP treatment is not available in the United States and that platelet-rich plasma (PRP) is the closest alternative treatment, convince them that PRP may be even better, and then let them know that it’s considered experimental and not covered by insurance.

In the last issue, we discussed the future of orthopedics, which in my opinion will rely heavily on the biologic therapies now considered experimental. In this issue, we will look into our crystal balls and imagine what that future might look like. To do so, we should first consider what we hope to accomplish through the incorporation of biologic therapies.

The regeneration of articular cartilage, acceleration of fracture and tissue healing, and faster incorporation of tendon grafts to bone have long been considered the Holy Grail of Orthopedics. In his best seller, The Da Vinci Code, Dan Brown makes a compelling argument that the Holy Grail, the chalice thought to have held the blood of Christ, was in fact a mistranslated reference to his living descendants. Whenever I have a visitor or student in the operating room, I focus the scope on the synovial capillaries so they can see the individual red blood cells passing single-file through the vessels on their way to supply cells with the nutrients they need.

Perhaps, like in The Da Vinci Code, the solution to our greatest biologic challenges lies in the blood, already there, just waiting to be unlocked.

PRP has been utilized for everything from tendinopathy to arthropathy, with varied results in the literature. The lack of standardization of PRP preparations, which vary in inclusion of white cells and absolute platelet count, confounds these results even further. In this issue, we review its use in sports medicine and knee arthritis, taking a closer look at partial ulnar collateral ligament tears in baseball players.

In “Tips of the Trade,” we present a technique for “superior capsular reconstruction” that provides a novel solution for patients with pseudoparalysis from massive rotator cuff tears with little other options beside reverse total shoulder arthroplasty.

The one absolute statement I can make regarding biologics is that we currently have more questions than answers, and every hypothesis we prove simply begets more questions. More randomized controlled studies are needed in virtually every aspect of biologics, and we should all consider taking part. While the solutions our patients crave may not arrive during our careers, or even our lifetimes, the groundwork we do now will set the stage for future generations to enjoy biologically enhanced outcomes.

In contrast to stable chronic obstructive pulmonary disease (COPD), acute exacerbations of COPD pose special management challenges and can significantly increase the risks of morbidity and death as well as the cost of care. This review from Cleveland Clinic Journal of Medicine, available at http://www.ccjm.org/topics/pulmonary/single-article-page/treating-and-preventing-acute-exacerbations-of-copd/8265d5ff355c3a17c96fa34564ea7465.html, provides the latest information on the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

In contrast to stable chronic obstructive pulmonary disease (COPD), acute exacerbations of COPD pose special management challenges and can significantly increase the risks of morbidity and death as well as the cost of care. This review from Cleveland Clinic Journal of Medicine, available at http://www.ccjm.org/topics/pulmonary/single-article-page/treating-and-preventing-acute-exacerbations-of-copd/8265d5ff355c3a17c96fa34564ea7465.html, provides the latest information on the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

In contrast to stable chronic obstructive pulmonary disease (COPD), acute exacerbations of COPD pose special management challenges and can significantly increase the risks of morbidity and death as well as the cost of care. This review from Cleveland Clinic Journal of Medicine, available at http://www.ccjm.org/topics/pulmonary/single-article-page/treating-and-preventing-acute-exacerbations-of-copd/8265d5ff355c3a17c96fa34564ea7465.html, provides the latest information on the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.