Clinical Review

In this Update, I discuss important new study results regarding the cardiovascular safety of hormone therapy (HT) in early menopausal women. In addition, I review survey data that reveal a huge number of US women are using compounded HT preparations, which have unproven efficacy and safety.

Earlier initiation is better: ELITE trial provides strong support for the estrogen timing hypothesis
_{Hodis HN, Mack WJ, Henderson VW, et al; for the ELITE Research Group. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221-1231.}

_{Keaney JF, Solomon G. Postmenopausal hormone therapy and atherosclerosis--time is of the essence [editorial]. N Engl J Med. 2016;374(13):1279-1280.}

A substantial amount of published data, including from the Women's Health Initiative (WHI), supports the timing hypothesis, which proposes that HT slows the progression of atherosclerosis among recently menopausal women but has a neutral or adverse effect among women who are a decade or more past menopause onset.¹ To directly test this hypothesis, Hodis and colleagues randomly assigned healthy postmenopausal women (<6 years or ≥10 years past menopause) without cardiovascular disease (CVD) to oral estradiol 1 mg or placebo. Women with a uterus also were randomly assigned to receive either vaginal progesterone gel or placebo gel. The primary outcome was the rate of change in carotid artery intima-media thickness (CIMT), which was assessed at baseline and each 6 months of the study. (An earlier report had noted that baseline CIMT correlated well with CVD risk factors.²) Coronary artery atherosclerosis, a secondary outcome, was assessed at study completion using computed tomography (CT).

Details of the study
Among the 643 participants in the Early versus Late Intervention Trial with Estradiol (ELITE), the median years since menopause and the median age at enrollment were 3.5 and 55.4, respectively, in the early postmenopause group and 14.3 and 63.6, respectively, in the late postmenopause group.  

Among the younger women, after a median of 5 years of study medications, the estradiol group had less progression of CIMT than the placebo group (P = .008). By contrast, in the older group, rates of CIMT progression were similar in the HT and placebo groups (P = .29). The relationship between estrogen and CIMT progression differed significantly between the younger and older groups (P = .007). Use of progesterone did not change these trends. Coronary artery CT parameters did not differ significantly between the placebo and HT groups in the age group or in the time-since-menopause group.

What this evidence means for practice
In an editorial accompanying the published results of the ELITE trial, Keaney and Solomon concluded that, although estrogen had a favorable effect on atherosclerosis in early menopause, it would be premature to recommend HT for prevention of cardiovascular events. I agree with them, but I also would like to note that the use of HT for the treatment of menopausal symptoms has plummeted since the initial WHI findings in 2002, with infrequent HT use even among symptomatic women in early menopause.³ (And I refer you to the special inset featuring JoAnn E. Manson, MD, DrPH) The takeaway message is that this important new clinical trial provides additional reassurance regarding the cardiovascular safety of HT when initiated by recently menopausal women to treat bothersome vasomotor symptoms. This message represents welcome news for women with bothersome menopausal symptoms considering use of HT.

A word about the vaginal progesterone gel used in the ELITE trial in relation to clinical practice: Given the need for vaginal placement of progesterone gel, potential messiness, and high cost, few clinicians may prescribe this formulation, and few women probably would choose to use it. As an alternative, micronized progesterone 100-mg capsules are less expensive and well accepted by most patients. These capsules are formulated with peanut oil. Because they may cause women to feel drowsy, the capsules should be taken at bedtime. In women with an intact uterus who are taking oral estradiol 1-mg tablets, one appropriate progestogen regimen for endometrial suppression is a 100-mg micronized progesterone capsule each night, continuously.

WHI, ELITE and the timing hypothesis:
New evidence on HT in early menopause is reassuring

 

Q&A with JoAnn E. Manson, MD, DrPH
In this interview, Dr. JoAnn Manson discusses the reassuring results of recent hormone therapy (HT) trials in early versus later postmenopausal women, examines these outcomes in the context of the Women's Health Initiative (WHI) trial and ELITE trial, and debunks an enduring common misconception about the WHI.

Q You have said for several years that there has been a misconception about the WHI trial. What is that misconception, and what has been its impact on clinicians, women, and the use of HT?
A The WHI HT trial has been largely misunderstood. It was designed to address the balance of benefits and risks of long-term HT for the prevention of chronic disease in postmenopausal women across a broad range of ages (average age 63).^1,2 It was not intended to evaluate the clinical role of HT for managing menopausal symptoms in young and early menopausal women.³ Overall, the WHI study findings have been inappropriately extrapolated to women in their 40s and early 50s who report distressing hot flashes, night sweats, and other menopausal symptoms, and they are often used as a reason to deny therapy when in fact many of these women would be appropriate candidates for HT.

There is increasing evidence that younger women in early menopause who are taking HT have a lower risk of adverse outcomes and lower absolute risks of disease than older women.^2,3 In younger, early menopausal women with bothersome hot flashes, night sweats, or other menopausal symptoms and who have no contraindications to HT, the benefits of treatment are likely to outweigh the risks, and these patients derive quality-of-life benefits from treatment.

Q How do the results of the recent ELITE (Early versus Late Intervention Trial with Estradiol) trial build on cardiovascular safety, in particular, of HT and when HT is optimally initiated?
A The ELITE trial directly tested the "timing hypothesis" and the role of HT in slowing the progression of atherosclerosis in early menopause (defined as within 6 years of menopause onset) compared with the effect in women in later menopause (defined as at least 10 yearspast menopause).⁴ The investigators used carotid artery intima-media thickness (CIMT) as a surrogate end point. In this trial, 643 women were randomly assigned according to whether they were in early or later menopause to receive either placebo or estradiol 1 mg daily; women with a uterus also received progesterone 45 mg as a 4% vaginal gel or matching placebo gel. The median duration of intervention was 5 years.
 
The ELITE study results provide support for the "critical window hypothesis" in that the estradiol-treated younger women closer to onset of menopause had slowing of atherosclerosis compared with the placebo group, while the older women more distant from menopause did not have slowing of atherosclerosis with estradiol.
 
The ELITE trial was not large enough, however, to assess clinical end points--rates of heart attack, stroke, or other cardiovascular events. So it remains unclear whether the findings for the surrogate end point of CIMT would translate into a reduced risk of clinical events in the younger women. Nevertheless, ELITE does provide more reassurance about the use of HT in early menopause and supports the possibility that the overall results of the WHI among women enrolled at an average age of 63 years may not apply directly to younger women in early menopause.

Q What impact on clinical practice do you anticipate as a result of the ELITE trial results?
A The findings provide further support for the timing hypothesis and offer additional reassurance regarding the safety  of HT in early menopause for management of menopausal symptoms. However, the trial does not provide conclusive evidence to support recommendations to use HT for the express purpose of preventing cardiovascular disease (CVD), even if HT is started in early menopause. Using a surrogate end point for atherosclerosis (CIMT) is not the same as looking at clinical events. There are many biologic pathways for heart attacks, strokes, and other cardiovascular events. In addition to atherosclerosis, for example, there is thrombosis, clotting, thrombo-occlusion within a blood vessel, and plaque rupture. Again, we do not know whether the CIMT-based results would translate directly into a reduction in clinical heart attacks and stroke.

The main takeaway point from the ELITE trial results is further reassurance for use of HT for management of menopausal symptoms in early menopause, but not for long-term chronic disease prevention at any age.

Q Another recent study, published in the Journal of Clinical Endocrinology and Metabolism, addresses HT and the timing hypothesis but in this instance relating to glucose tolerance.⁵ What did these study authors find? 
A This study by Pereira and colleagues is very interesting and suggests that the window of opportunity for initiating estrogen therapy may apply not only to coronary events but also to glucose tolerance, insulin sensitivity, and diabetes risk.⁵

The authors investigated the effects of short-term high-dose transdermal estradiol on the insulin-mediated glucose disposal rate (GDR), which is a measure of insulin-stimulated glucose uptake. Participants in this randomized, crossover, placebo-controlled study included 22 women who were in early menopause (6 years or less since final menses) and 24 women who were in later menopause (10 years or longer since final menses). All of the women were naïve to hormone therapy, and baseline GDR did not differ between groups. After 1 week of treatment with transdermal estradiol (a high dose of 150 μg) or placebo, the participants' GDR was measured via a hyperinsulinemic-euglycemic clamp.
 
The investigators found that in the younger women, estradiol had a favorable effect on insulin sensitivity and GDR, whereas in the older women, there was no evidence of a favorable effect and, in fact, there was a signal for risk and more adverse findings in this group.

Several studies in the WHI also looked at glucose tolerance and at the risk of being diagnosed with diabetes. While the results of the WHI estrogen-alone trial revealed a reduction in diabetes and favorable effects across age groups, in the WHI estrogen-plus-progestin trial we did see a signal that the results for diabetes may have been more favorable in the younger than in the older women, somewhat consistent with the findings of Pereira and colleagues.^2,5
Overall this issue requires more research, but the Pereira study provides further support for the possibility that estrogen's metabolic effects may vary by age and time since menopause, and there is evidence that the estrogen receptors may be more functional and more sensitive in early rather than later menopause. These findings are very interesting and consistent with the overall hypothesis about the importance of age and time since menopause in relation to estrogen action. Again, they offer further support for use of HT for managing bothersome menopausal symptoms in early menopause, but they should not be interpreted as endorsing the use of HT to prevent either diabetes or CVD, due to the potential for other risks.

Q Where would you like to see future research conducted regarding the timing hypothesis?
A I would like to see more research on the role of oral versus transdermal estrogen in relation to insulin sensitivity, diabetes risk, and CVD risk, and more research on the role of estrogen dose, different types of progestogens, and the benefits and risks of novel formulations, including selective estrogen receptor modulators and tissue selective estrogen complexes.
 

 

---

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women's Health at Harvard Medical School and Chief of the Division of Preventive Medicine at Brigham and Women's Hospital, Boston, Massachusetts. She is a past President of the North American Menopause Society (NAMS) and a NAMS Certified Menopause Practitioner.

The author reports no financial relationships relevant to this article.

 

---

References

 

1. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
2. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013(13);310:1353-1368.
3. Manson JE, Kaunitz AM. Menopause management-- getting clinical care back on track. N Engl J Med. 2016;374(19):803-806.
4. Hodis HN, Mack WJ, Henderson VW, et al; ELITE Research Group. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221-1231.
5. Pereira RI, Casey BA, Swibas TA, Erickson CB, Wolfe P, Van Pelt RE. Timing of estradiol treatment after menopause may determine benefit or harm to insulin action. J Clin Endocrinol Metab. 2015;100(12):4456-4462.

FDA-approved HT is preferable to compounded HT formulations
_{Pinkerton JV, Santoro N. Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women. Menopause. 2015;22(9):926-936.}

_{Pinkerton JV, Constantine GD. Compounded non-FDA-approved menopausal hormone therapy prescriptions have increased: results of a pharmacy survey. Menopause. 2016;23(4):359-367.}

_{Gass ML, Stuenkel CA, Utian WH, LaCroix A, Liu JH, Shifren JL.; North American Menopause Society (NAMS) Advisory Panel consisting of representatives of NAMS Board of Trustees and other experts in women's health. Use of compounded hormone therapy in the United States: report of The North American Menopause Society Survey. Menopause. 2015;22(12):1276-1284.}

Consider how you would manage this clinical scenario: During a well-woman visit, your 54-year-old patient mentions that, after seeing an advertisement on television, she visited a clinic that sells compounded hormones. There, she underwent some testing and received an estrogen-testosterone implant and a progesterone cream that she applies to her skin each night to treat her menopausal symptoms. Now what?

The use of HT for menopausal symptoms declined considerably following the 2002 publication of the initial findings from the WHI, and its use remains low.⁴ Symptomatic menopausal women often find that their physicians are reluctant to consider prescribing treatment for menopausal symptoms because of safety concerns regarding HT use. Further, confusion about HT safety has opened the door to the increasing use of compounded bioidentical HT formulations, which are not approved by the US Food and Drug Administration (FDA).³ Since the publication of my 2015 Update on menopause (OBG Manag. 2015;27(6):37−40,42−43), several reports have addressed the use of "custom compounded" bioidentical menopausal HT in US women.

Millions use compounded HT for menopausal symptoms
A recent study by Pinkerton and Santoro that analyzed data from 2 national surveys suggested that as many as 2.5 million US women currently use non−FDA-approved custom-compounded HT. The authors also found that more than three-quarters of women using compounded HT are unaware that these medications, which include oral, topical, injectable, and implantable (pellet) formulations, are not FDA approved. In a study by Pinkerton and Constantine, total annual sales of compounded HT were estimated at approximately $1.5 billion. The dramatic growth in the use of compounded HT appears to have stemmed from celebrity endorsements, aggressive and unregulated marketing, and beliefs about the safety of "natural" hormones.⁵

Spurious laboratory testing. Women seeking care from physicians and clinics that provide compounded HT are often advised to undergo saliva and serum testing to determine hormone levels. Many women are unaware, however, that saliva testing does not correlate with serum levels of hormones. Further, in contrast with conditions such as thyroid disease and diabetes, routine laboratory testing is neither indicated nor helpful in the management of menopausal symptoms.⁶ Of note, insurance companies often do not reimburse for the cost of saliva hormone testing or for non-FDA-approved hormones.⁵

Inadequate endometrial protection. Topical progesterone cream, which is not absorbed in sufficient quantities to generate therapeutic effects, is often prescribed by practitioners who sell bioidentical compounded hormones to their patients.7 According to a report by the North American Menopause Society, several cases of endometrial cancer have been reported among women using compounded HT. These cases may reflect use of systemic estrogen without adequate progesterone protection, as could occur when topical progesterone cream is prescribed to women with an intact uterus using systemic estrogen therapy. 

What this evidence means for practice
Clinicians should be alert to the growing prevalence of use of compounded HT and should educate themselves and their patients about the differences between non−FDA-approved HT and FDA-approved HT. Further, women interested in using "natural," "bioidentical," or "custom compounded" HT should be aware that FDA-approved estradiol (oral, transdermal, and vaginal) and progesterone (oral and vaginal) formulations are available.

Because the FDA does not test custom compounded hormones for efficacy or safety and the standardization and purity of these products are uncertain, the American College of Obstetricians and Gynecologists has stated that FDA-approved HT is preferred for management of menopausal symptoms.⁸ Similarly, the North American Menopause Society does not recommend the use of compounded HT for treatment of menopausal symptoms unless a patient is allergic to ingredients contained in FDA-approved HT formulations.⁹

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update, I discuss important new study results regarding the cardiovascular safety of hormone therapy (HT) in early menopausal women. In addition, I review survey data that reveal a huge number of US women are using compounded HT preparations, which have unproven efficacy and safety.

Earlier initiation is better: ELITE trial provides strong support for the estrogen timing hypothesis
_{Hodis HN, Mack WJ, Henderson VW, et al; for the ELITE Research Group. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221-1231.}

_{Keaney JF, Solomon G. Postmenopausal hormone therapy and atherosclerosis--time is of the essence [editorial]. N Engl J Med. 2016;374(13):1279-1280.}

A substantial amount of published data, including from the Women's Health Initiative (WHI), supports the timing hypothesis, which proposes that HT slows the progression of atherosclerosis among recently menopausal women but has a neutral or adverse effect among women who are a decade or more past menopause onset.¹ To directly test this hypothesis, Hodis and colleagues randomly assigned healthy postmenopausal women (<6 years or ≥10 years past menopause) without cardiovascular disease (CVD) to oral estradiol 1 mg or placebo. Women with a uterus also were randomly assigned to receive either vaginal progesterone gel or placebo gel. The primary outcome was the rate of change in carotid artery intima-media thickness (CIMT), which was assessed at baseline and each 6 months of the study. (An earlier report had noted that baseline CIMT correlated well with CVD risk factors.²) Coronary artery atherosclerosis, a secondary outcome, was assessed at study completion using computed tomography (CT).

Details of the study
Among the 643 participants in the Early versus Late Intervention Trial with Estradiol (ELITE), the median years since menopause and the median age at enrollment were 3.5 and 55.4, respectively, in the early postmenopause group and 14.3 and 63.6, respectively, in the late postmenopause group.  

Among the younger women, after a median of 5 years of study medications, the estradiol group had less progression of CIMT than the placebo group (P = .008). By contrast, in the older group, rates of CIMT progression were similar in the HT and placebo groups (P = .29). The relationship between estrogen and CIMT progression differed significantly between the younger and older groups (P = .007). Use of progesterone did not change these trends. Coronary artery CT parameters did not differ significantly between the placebo and HT groups in the age group or in the time-since-menopause group.

What this evidence means for practice
In an editorial accompanying the published results of the ELITE trial, Keaney and Solomon concluded that, although estrogen had a favorable effect on atherosclerosis in early menopause, it would be premature to recommend HT for prevention of cardiovascular events. I agree with them, but I also would like to note that the use of HT for the treatment of menopausal symptoms has plummeted since the initial WHI findings in 2002, with infrequent HT use even among symptomatic women in early menopause.³ (And I refer you to the special inset featuring JoAnn E. Manson, MD, DrPH) The takeaway message is that this important new clinical trial provides additional reassurance regarding the cardiovascular safety of HT when initiated by recently menopausal women to treat bothersome vasomotor symptoms. This message represents welcome news for women with bothersome menopausal symptoms considering use of HT.

A word about the vaginal progesterone gel used in the ELITE trial in relation to clinical practice: Given the need for vaginal placement of progesterone gel, potential messiness, and high cost, few clinicians may prescribe this formulation, and few women probably would choose to use it. As an alternative, micronized progesterone 100-mg capsules are less expensive and well accepted by most patients. These capsules are formulated with peanut oil. Because they may cause women to feel drowsy, the capsules should be taken at bedtime. In women with an intact uterus who are taking oral estradiol 1-mg tablets, one appropriate progestogen regimen for endometrial suppression is a 100-mg micronized progesterone capsule each night, continuously.

WHI, ELITE and the timing hypothesis:
New evidence on HT in early menopause is reassuring

 

Q&A with JoAnn E. Manson, MD, DrPH
In this interview, Dr. JoAnn Manson discusses the reassuring results of recent hormone therapy (HT) trials in early versus later postmenopausal women, examines these outcomes in the context of the Women's Health Initiative (WHI) trial and ELITE trial, and debunks an enduring common misconception about the WHI.

Q You have said for several years that there has been a misconception about the WHI trial. What is that misconception, and what has been its impact on clinicians, women, and the use of HT?
A The WHI HT trial has been largely misunderstood. It was designed to address the balance of benefits and risks of long-term HT for the prevention of chronic disease in postmenopausal women across a broad range of ages (average age 63).^1,2 It was not intended to evaluate the clinical role of HT for managing menopausal symptoms in young and early menopausal women.³ Overall, the WHI study findings have been inappropriately extrapolated to women in their 40s and early 50s who report distressing hot flashes, night sweats, and other menopausal symptoms, and they are often used as a reason to deny therapy when in fact many of these women would be appropriate candidates for HT.

There is increasing evidence that younger women in early menopause who are taking HT have a lower risk of adverse outcomes and lower absolute risks of disease than older women.^2,3 In younger, early menopausal women with bothersome hot flashes, night sweats, or other menopausal symptoms and who have no contraindications to HT, the benefits of treatment are likely to outweigh the risks, and these patients derive quality-of-life benefits from treatment.

Q How do the results of the recent ELITE (Early versus Late Intervention Trial with Estradiol) trial build on cardiovascular safety, in particular, of HT and when HT is optimally initiated?
A The ELITE trial directly tested the "timing hypothesis" and the role of HT in slowing the progression of atherosclerosis in early menopause (defined as within 6 years of menopause onset) compared with the effect in women in later menopause (defined as at least 10 yearspast menopause).⁴ The investigators used carotid artery intima-media thickness (CIMT) as a surrogate end point. In this trial, 643 women were randomly assigned according to whether they were in early or later menopause to receive either placebo or estradiol 1 mg daily; women with a uterus also received progesterone 45 mg as a 4% vaginal gel or matching placebo gel. The median duration of intervention was 5 years.
 
The ELITE study results provide support for the "critical window hypothesis" in that the estradiol-treated younger women closer to onset of menopause had slowing of atherosclerosis compared with the placebo group, while the older women more distant from menopause did not have slowing of atherosclerosis with estradiol.
 
The ELITE trial was not large enough, however, to assess clinical end points--rates of heart attack, stroke, or other cardiovascular events. So it remains unclear whether the findings for the surrogate end point of CIMT would translate into a reduced risk of clinical events in the younger women. Nevertheless, ELITE does provide more reassurance about the use of HT in early menopause and supports the possibility that the overall results of the WHI among women enrolled at an average age of 63 years may not apply directly to younger women in early menopause.

Q What impact on clinical practice do you anticipate as a result of the ELITE trial results?
A The findings provide further support for the timing hypothesis and offer additional reassurance regarding the safety  of HT in early menopause for management of menopausal symptoms. However, the trial does not provide conclusive evidence to support recommendations to use HT for the express purpose of preventing cardiovascular disease (CVD), even if HT is started in early menopause. Using a surrogate end point for atherosclerosis (CIMT) is not the same as looking at clinical events. There are many biologic pathways for heart attacks, strokes, and other cardiovascular events. In addition to atherosclerosis, for example, there is thrombosis, clotting, thrombo-occlusion within a blood vessel, and plaque rupture. Again, we do not know whether the CIMT-based results would translate directly into a reduction in clinical heart attacks and stroke.

The main takeaway point from the ELITE trial results is further reassurance for use of HT for management of menopausal symptoms in early menopause, but not for long-term chronic disease prevention at any age.

Q Another recent study, published in the Journal of Clinical Endocrinology and Metabolism, addresses HT and the timing hypothesis but in this instance relating to glucose tolerance.⁵ What did these study authors find? 
A This study by Pereira and colleagues is very interesting and suggests that the window of opportunity for initiating estrogen therapy may apply not only to coronary events but also to glucose tolerance, insulin sensitivity, and diabetes risk.⁵

The authors investigated the effects of short-term high-dose transdermal estradiol on the insulin-mediated glucose disposal rate (GDR), which is a measure of insulin-stimulated glucose uptake. Participants in this randomized, crossover, placebo-controlled study included 22 women who were in early menopause (6 years or less since final menses) and 24 women who were in later menopause (10 years or longer since final menses). All of the women were naïve to hormone therapy, and baseline GDR did not differ between groups. After 1 week of treatment with transdermal estradiol (a high dose of 150 μg) or placebo, the participants' GDR was measured via a hyperinsulinemic-euglycemic clamp.
 
The investigators found that in the younger women, estradiol had a favorable effect on insulin sensitivity and GDR, whereas in the older women, there was no evidence of a favorable effect and, in fact, there was a signal for risk and more adverse findings in this group.

Several studies in the WHI also looked at glucose tolerance and at the risk of being diagnosed with diabetes. While the results of the WHI estrogen-alone trial revealed a reduction in diabetes and favorable effects across age groups, in the WHI estrogen-plus-progestin trial we did see a signal that the results for diabetes may have been more favorable in the younger than in the older women, somewhat consistent with the findings of Pereira and colleagues.^2,5
Overall this issue requires more research, but the Pereira study provides further support for the possibility that estrogen's metabolic effects may vary by age and time since menopause, and there is evidence that the estrogen receptors may be more functional and more sensitive in early rather than later menopause. These findings are very interesting and consistent with the overall hypothesis about the importance of age and time since menopause in relation to estrogen action. Again, they offer further support for use of HT for managing bothersome menopausal symptoms in early menopause, but they should not be interpreted as endorsing the use of HT to prevent either diabetes or CVD, due to the potential for other risks.

Q Where would you like to see future research conducted regarding the timing hypothesis?
A I would like to see more research on the role of oral versus transdermal estrogen in relation to insulin sensitivity, diabetes risk, and CVD risk, and more research on the role of estrogen dose, different types of progestogens, and the benefits and risks of novel formulations, including selective estrogen receptor modulators and tissue selective estrogen complexes.
 

 

---

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women's Health at Harvard Medical School and Chief of the Division of Preventive Medicine at Brigham and Women's Hospital, Boston, Massachusetts. She is a past President of the North American Menopause Society (NAMS) and a NAMS Certified Menopause Practitioner.

The author reports no financial relationships relevant to this article.

 

---

References

 

1. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
2. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013(13);310:1353-1368.
3. Manson JE, Kaunitz AM. Menopause management-- getting clinical care back on track. N Engl J Med. 2016;374(19):803-806.
4. Hodis HN, Mack WJ, Henderson VW, et al; ELITE Research Group. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221-1231.
5. Pereira RI, Casey BA, Swibas TA, Erickson CB, Wolfe P, Van Pelt RE. Timing of estradiol treatment after menopause may determine benefit or harm to insulin action. J Clin Endocrinol Metab. 2015;100(12):4456-4462.

FDA-approved HT is preferable to compounded HT formulations
_{Pinkerton JV, Santoro N. Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women. Menopause. 2015;22(9):926-936.}

_{Pinkerton JV, Constantine GD. Compounded non-FDA-approved menopausal hormone therapy prescriptions have increased: results of a pharmacy survey. Menopause. 2016;23(4):359-367.}

_{Gass ML, Stuenkel CA, Utian WH, LaCroix A, Liu JH, Shifren JL.; North American Menopause Society (NAMS) Advisory Panel consisting of representatives of NAMS Board of Trustees and other experts in women's health. Use of compounded hormone therapy in the United States: report of The North American Menopause Society Survey. Menopause. 2015;22(12):1276-1284.}

Consider how you would manage this clinical scenario: During a well-woman visit, your 54-year-old patient mentions that, after seeing an advertisement on television, she visited a clinic that sells compounded hormones. There, she underwent some testing and received an estrogen-testosterone implant and a progesterone cream that she applies to her skin each night to treat her menopausal symptoms. Now what?

The use of HT for menopausal symptoms declined considerably following the 2002 publication of the initial findings from the WHI, and its use remains low.⁴ Symptomatic menopausal women often find that their physicians are reluctant to consider prescribing treatment for menopausal symptoms because of safety concerns regarding HT use. Further, confusion about HT safety has opened the door to the increasing use of compounded bioidentical HT formulations, which are not approved by the US Food and Drug Administration (FDA).³ Since the publication of my 2015 Update on menopause (OBG Manag. 2015;27(6):37−40,42−43), several reports have addressed the use of "custom compounded" bioidentical menopausal HT in US women.

Millions use compounded HT for menopausal symptoms
A recent study by Pinkerton and Santoro that analyzed data from 2 national surveys suggested that as many as 2.5 million US women currently use non−FDA-approved custom-compounded HT. The authors also found that more than three-quarters of women using compounded HT are unaware that these medications, which include oral, topical, injectable, and implantable (pellet) formulations, are not FDA approved. In a study by Pinkerton and Constantine, total annual sales of compounded HT were estimated at approximately $1.5 billion. The dramatic growth in the use of compounded HT appears to have stemmed from celebrity endorsements, aggressive and unregulated marketing, and beliefs about the safety of "natural" hormones.⁵

Spurious laboratory testing. Women seeking care from physicians and clinics that provide compounded HT are often advised to undergo saliva and serum testing to determine hormone levels. Many women are unaware, however, that saliva testing does not correlate with serum levels of hormones. Further, in contrast with conditions such as thyroid disease and diabetes, routine laboratory testing is neither indicated nor helpful in the management of menopausal symptoms.⁶ Of note, insurance companies often do not reimburse for the cost of saliva hormone testing or for non-FDA-approved hormones.⁵

Inadequate endometrial protection. Topical progesterone cream, which is not absorbed in sufficient quantities to generate therapeutic effects, is often prescribed by practitioners who sell bioidentical compounded hormones to their patients.7 According to a report by the North American Menopause Society, several cases of endometrial cancer have been reported among women using compounded HT. These cases may reflect use of systemic estrogen without adequate progesterone protection, as could occur when topical progesterone cream is prescribed to women with an intact uterus using systemic estrogen therapy. 

What this evidence means for practice
Clinicians should be alert to the growing prevalence of use of compounded HT and should educate themselves and their patients about the differences between non−FDA-approved HT and FDA-approved HT. Further, women interested in using "natural," "bioidentical," or "custom compounded" HT should be aware that FDA-approved estradiol (oral, transdermal, and vaginal) and progesterone (oral and vaginal) formulations are available.

Because the FDA does not test custom compounded hormones for efficacy or safety and the standardization and purity of these products are uncertain, the American College of Obstetricians and Gynecologists has stated that FDA-approved HT is preferred for management of menopausal symptoms.⁸ Similarly, the North American Menopause Society does not recommend the use of compounded HT for treatment of menopausal symptoms unless a patient is allergic to ingredients contained in FDA-approved HT formulations.⁹

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update, I discuss important new study results regarding the cardiovascular safety of hormone therapy (HT) in early menopausal women. In addition, I review survey data that reveal a huge number of US women are using compounded HT preparations, which have unproven efficacy and safety.

Earlier initiation is better: ELITE trial provides strong support for the estrogen timing hypothesis
_{Hodis HN, Mack WJ, Henderson VW, et al; for the ELITE Research Group. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221-1231.}

_{Keaney JF, Solomon G. Postmenopausal hormone therapy and atherosclerosis--time is of the essence [editorial]. N Engl J Med. 2016;374(13):1279-1280.}

A substantial amount of published data, including from the Women's Health Initiative (WHI), supports the timing hypothesis, which proposes that HT slows the progression of atherosclerosis among recently menopausal women but has a neutral or adverse effect among women who are a decade or more past menopause onset.¹ To directly test this hypothesis, Hodis and colleagues randomly assigned healthy postmenopausal women (<6 years or ≥10 years past menopause) without cardiovascular disease (CVD) to oral estradiol 1 mg or placebo. Women with a uterus also were randomly assigned to receive either vaginal progesterone gel or placebo gel. The primary outcome was the rate of change in carotid artery intima-media thickness (CIMT), which was assessed at baseline and each 6 months of the study. (An earlier report had noted that baseline CIMT correlated well with CVD risk factors.²) Coronary artery atherosclerosis, a secondary outcome, was assessed at study completion using computed tomography (CT).

Details of the study
Among the 643 participants in the Early versus Late Intervention Trial with Estradiol (ELITE), the median years since menopause and the median age at enrollment were 3.5 and 55.4, respectively, in the early postmenopause group and 14.3 and 63.6, respectively, in the late postmenopause group.  

Among the younger women, after a median of 5 years of study medications, the estradiol group had less progression of CIMT than the placebo group (P = .008). By contrast, in the older group, rates of CIMT progression were similar in the HT and placebo groups (P = .29). The relationship between estrogen and CIMT progression differed significantly between the younger and older groups (P = .007). Use of progesterone did not change these trends. Coronary artery CT parameters did not differ significantly between the placebo and HT groups in the age group or in the time-since-menopause group.

What this evidence means for practice
In an editorial accompanying the published results of the ELITE trial, Keaney and Solomon concluded that, although estrogen had a favorable effect on atherosclerosis in early menopause, it would be premature to recommend HT for prevention of cardiovascular events. I agree with them, but I also would like to note that the use of HT for the treatment of menopausal symptoms has plummeted since the initial WHI findings in 2002, with infrequent HT use even among symptomatic women in early menopause.³ (And I refer you to the special inset featuring JoAnn E. Manson, MD, DrPH) The takeaway message is that this important new clinical trial provides additional reassurance regarding the cardiovascular safety of HT when initiated by recently menopausal women to treat bothersome vasomotor symptoms. This message represents welcome news for women with bothersome menopausal symptoms considering use of HT.

A word about the vaginal progesterone gel used in the ELITE trial in relation to clinical practice: Given the need for vaginal placement of progesterone gel, potential messiness, and high cost, few clinicians may prescribe this formulation, and few women probably would choose to use it. As an alternative, micronized progesterone 100-mg capsules are less expensive and well accepted by most patients. These capsules are formulated with peanut oil. Because they may cause women to feel drowsy, the capsules should be taken at bedtime. In women with an intact uterus who are taking oral estradiol 1-mg tablets, one appropriate progestogen regimen for endometrial suppression is a 100-mg micronized progesterone capsule each night, continuously.

WHI, ELITE and the timing hypothesis:
New evidence on HT in early menopause is reassuring

 

Q&A with JoAnn E. Manson, MD, DrPH
In this interview, Dr. JoAnn Manson discusses the reassuring results of recent hormone therapy (HT) trials in early versus later postmenopausal women, examines these outcomes in the context of the Women's Health Initiative (WHI) trial and ELITE trial, and debunks an enduring common misconception about the WHI.

Q You have said for several years that there has been a misconception about the WHI trial. What is that misconception, and what has been its impact on clinicians, women, and the use of HT?
A The WHI HT trial has been largely misunderstood. It was designed to address the balance of benefits and risks of long-term HT for the prevention of chronic disease in postmenopausal women across a broad range of ages (average age 63).^1,2 It was not intended to evaluate the clinical role of HT for managing menopausal symptoms in young and early menopausal women.³ Overall, the WHI study findings have been inappropriately extrapolated to women in their 40s and early 50s who report distressing hot flashes, night sweats, and other menopausal symptoms, and they are often used as a reason to deny therapy when in fact many of these women would be appropriate candidates for HT.

There is increasing evidence that younger women in early menopause who are taking HT have a lower risk of adverse outcomes and lower absolute risks of disease than older women.^2,3 In younger, early menopausal women with bothersome hot flashes, night sweats, or other menopausal symptoms and who have no contraindications to HT, the benefits of treatment are likely to outweigh the risks, and these patients derive quality-of-life benefits from treatment.

Q How do the results of the recent ELITE (Early versus Late Intervention Trial with Estradiol) trial build on cardiovascular safety, in particular, of HT and when HT is optimally initiated?
A The ELITE trial directly tested the "timing hypothesis" and the role of HT in slowing the progression of atherosclerosis in early menopause (defined as within 6 years of menopause onset) compared with the effect in women in later menopause (defined as at least 10 yearspast menopause).⁴ The investigators used carotid artery intima-media thickness (CIMT) as a surrogate end point. In this trial, 643 women were randomly assigned according to whether they were in early or later menopause to receive either placebo or estradiol 1 mg daily; women with a uterus also received progesterone 45 mg as a 4% vaginal gel or matching placebo gel. The median duration of intervention was 5 years.
 
The ELITE study results provide support for the "critical window hypothesis" in that the estradiol-treated younger women closer to onset of menopause had slowing of atherosclerosis compared with the placebo group, while the older women more distant from menopause did not have slowing of atherosclerosis with estradiol.
 
The ELITE trial was not large enough, however, to assess clinical end points--rates of heart attack, stroke, or other cardiovascular events. So it remains unclear whether the findings for the surrogate end point of CIMT would translate into a reduced risk of clinical events in the younger women. Nevertheless, ELITE does provide more reassurance about the use of HT in early menopause and supports the possibility that the overall results of the WHI among women enrolled at an average age of 63 years may not apply directly to younger women in early menopause.

Q What impact on clinical practice do you anticipate as a result of the ELITE trial results?
A The findings provide further support for the timing hypothesis and offer additional reassurance regarding the safety  of HT in early menopause for management of menopausal symptoms. However, the trial does not provide conclusive evidence to support recommendations to use HT for the express purpose of preventing cardiovascular disease (CVD), even if HT is started in early menopause. Using a surrogate end point for atherosclerosis (CIMT) is not the same as looking at clinical events. There are many biologic pathways for heart attacks, strokes, and other cardiovascular events. In addition to atherosclerosis, for example, there is thrombosis, clotting, thrombo-occlusion within a blood vessel, and plaque rupture. Again, we do not know whether the CIMT-based results would translate directly into a reduction in clinical heart attacks and stroke.

The main takeaway point from the ELITE trial results is further reassurance for use of HT for management of menopausal symptoms in early menopause, but not for long-term chronic disease prevention at any age.

Q Another recent study, published in the Journal of Clinical Endocrinology and Metabolism, addresses HT and the timing hypothesis but in this instance relating to glucose tolerance.⁵ What did these study authors find? 
A This study by Pereira and colleagues is very interesting and suggests that the window of opportunity for initiating estrogen therapy may apply not only to coronary events but also to glucose tolerance, insulin sensitivity, and diabetes risk.⁵

The authors investigated the effects of short-term high-dose transdermal estradiol on the insulin-mediated glucose disposal rate (GDR), which is a measure of insulin-stimulated glucose uptake. Participants in this randomized, crossover, placebo-controlled study included 22 women who were in early menopause (6 years or less since final menses) and 24 women who were in later menopause (10 years or longer since final menses). All of the women were naïve to hormone therapy, and baseline GDR did not differ between groups. After 1 week of treatment with transdermal estradiol (a high dose of 150 μg) or placebo, the participants' GDR was measured via a hyperinsulinemic-euglycemic clamp.
 
The investigators found that in the younger women, estradiol had a favorable effect on insulin sensitivity and GDR, whereas in the older women, there was no evidence of a favorable effect and, in fact, there was a signal for risk and more adverse findings in this group.

Several studies in the WHI also looked at glucose tolerance and at the risk of being diagnosed with diabetes. While the results of the WHI estrogen-alone trial revealed a reduction in diabetes and favorable effects across age groups, in the WHI estrogen-plus-progestin trial we did see a signal that the results for diabetes may have been more favorable in the younger than in the older women, somewhat consistent with the findings of Pereira and colleagues.^2,5
Overall this issue requires more research, but the Pereira study provides further support for the possibility that estrogen's metabolic effects may vary by age and time since menopause, and there is evidence that the estrogen receptors may be more functional and more sensitive in early rather than later menopause. These findings are very interesting and consistent with the overall hypothesis about the importance of age and time since menopause in relation to estrogen action. Again, they offer further support for use of HT for managing bothersome menopausal symptoms in early menopause, but they should not be interpreted as endorsing the use of HT to prevent either diabetes or CVD, due to the potential for other risks.

Q Where would you like to see future research conducted regarding the timing hypothesis?
A I would like to see more research on the role of oral versus transdermal estrogen in relation to insulin sensitivity, diabetes risk, and CVD risk, and more research on the role of estrogen dose, different types of progestogens, and the benefits and risks of novel formulations, including selective estrogen receptor modulators and tissue selective estrogen complexes.
 

 

---

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women's Health at Harvard Medical School and Chief of the Division of Preventive Medicine at Brigham and Women's Hospital, Boston, Massachusetts. She is a past President of the North American Menopause Society (NAMS) and a NAMS Certified Menopause Practitioner.

The author reports no financial relationships relevant to this article.

 

---

References

 

1. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
2. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013(13);310:1353-1368.
3. Manson JE, Kaunitz AM. Menopause management-- getting clinical care back on track. N Engl J Med. 2016;374(19):803-806.
4. Hodis HN, Mack WJ, Henderson VW, et al; ELITE Research Group. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221-1231.
5. Pereira RI, Casey BA, Swibas TA, Erickson CB, Wolfe P, Van Pelt RE. Timing of estradiol treatment after menopause may determine benefit or harm to insulin action. J Clin Endocrinol Metab. 2015;100(12):4456-4462.

FDA-approved HT is preferable to compounded HT formulations
_{Pinkerton JV, Santoro N. Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women. Menopause. 2015;22(9):926-936.}

_{Pinkerton JV, Constantine GD. Compounded non-FDA-approved menopausal hormone therapy prescriptions have increased: results of a pharmacy survey. Menopause. 2016;23(4):359-367.}

_{Gass ML, Stuenkel CA, Utian WH, LaCroix A, Liu JH, Shifren JL.; North American Menopause Society (NAMS) Advisory Panel consisting of representatives of NAMS Board of Trustees and other experts in women's health. Use of compounded hormone therapy in the United States: report of The North American Menopause Society Survey. Menopause. 2015;22(12):1276-1284.}

Consider how you would manage this clinical scenario: During a well-woman visit, your 54-year-old patient mentions that, after seeing an advertisement on television, she visited a clinic that sells compounded hormones. There, she underwent some testing and received an estrogen-testosterone implant and a progesterone cream that she applies to her skin each night to treat her menopausal symptoms. Now what?

The use of HT for menopausal symptoms declined considerably following the 2002 publication of the initial findings from the WHI, and its use remains low.⁴ Symptomatic menopausal women often find that their physicians are reluctant to consider prescribing treatment for menopausal symptoms because of safety concerns regarding HT use. Further, confusion about HT safety has opened the door to the increasing use of compounded bioidentical HT formulations, which are not approved by the US Food and Drug Administration (FDA).³ Since the publication of my 2015 Update on menopause (OBG Manag. 2015;27(6):37−40,42−43), several reports have addressed the use of "custom compounded" bioidentical menopausal HT in US women.

Millions use compounded HT for menopausal symptoms
A recent study by Pinkerton and Santoro that analyzed data from 2 national surveys suggested that as many as 2.5 million US women currently use non−FDA-approved custom-compounded HT. The authors also found that more than three-quarters of women using compounded HT are unaware that these medications, which include oral, topical, injectable, and implantable (pellet) formulations, are not FDA approved. In a study by Pinkerton and Constantine, total annual sales of compounded HT were estimated at approximately $1.5 billion. The dramatic growth in the use of compounded HT appears to have stemmed from celebrity endorsements, aggressive and unregulated marketing, and beliefs about the safety of "natural" hormones.⁵

Spurious laboratory testing. Women seeking care from physicians and clinics that provide compounded HT are often advised to undergo saliva and serum testing to determine hormone levels. Many women are unaware, however, that saliva testing does not correlate with serum levels of hormones. Further, in contrast with conditions such as thyroid disease and diabetes, routine laboratory testing is neither indicated nor helpful in the management of menopausal symptoms.⁶ Of note, insurance companies often do not reimburse for the cost of saliva hormone testing or for non-FDA-approved hormones.⁵

Inadequate endometrial protection. Topical progesterone cream, which is not absorbed in sufficient quantities to generate therapeutic effects, is often prescribed by practitioners who sell bioidentical compounded hormones to their patients.7 According to a report by the North American Menopause Society, several cases of endometrial cancer have been reported among women using compounded HT. These cases may reflect use of systemic estrogen without adequate progesterone protection, as could occur when topical progesterone cream is prescribed to women with an intact uterus using systemic estrogen therapy. 

What this evidence means for practice
Clinicians should be alert to the growing prevalence of use of compounded HT and should educate themselves and their patients about the differences between non−FDA-approved HT and FDA-approved HT. Further, women interested in using "natural," "bioidentical," or "custom compounded" HT should be aware that FDA-approved estradiol (oral, transdermal, and vaginal) and progesterone (oral and vaginal) formulations are available.

Because the FDA does not test custom compounded hormones for efficacy or safety and the standardization and purity of these products are uncertain, the American College of Obstetricians and Gynecologists has stated that FDA-approved HT is preferred for management of menopausal symptoms.⁸ Similarly, the North American Menopause Society does not recommend the use of compounded HT for treatment of menopausal symptoms unless a patient is allergic to ingredients contained in FDA-approved HT formulations.⁹

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Patient may benefit from treatment for dyspareuniaA 54-year-old woman has been in your care for more than 15 years. Three years ago, at her well-woman examination, she was not yet having symptoms of menopause. Now, during her current examination, she reports hot flashes, which she says are not bothersome. In passing, she also says, “I don’t want to take hormone therapy,” but then is not overly conversational or responsive to your questions. She does mention having had 3 urinary tract infections over the past 8 months. On physical examination, you note mildly atrophied vaginal tissue.

Your patient does not bring up any sexual concerns, and so far you have not directly asked about sexual health. However, the time remaining in this visit is limited, and your patient, whose daughter is sitting in the waiting area, seems anxious to finish and leave. Still, you want to broach the subject of your patient’s sexual health. What are your best options?

We learned a lot about women’s perceptions regarding their sexual health in the 2008 Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking study (PRESIDE). Approximately 43% of 31,581 questionnaire respondents reported dysfunction in sexual desire, arousal, or orgasm.¹ Results also showed that 11.5% of the respondents with any of these types of female sexual dysfunction (FSD) were distressed about it. For clinicians, knowing who these women are is key in recognizing and treating FSD.

Important to the opening case, in PRESIDE, Shifren and colleagues found that women in their midlife years (aged 45 to 64) had the highest rate of any distressing sexual problem: 14.8%. Younger women (aged 18 to 44 years) had a rate of 10.8%; older women (aged 65 years or older) had a rate of 8.9%.¹

The most prevalent FSD was hypoactive sexual desire disorder,¹ which in 2013 was renamed sexual interest and arousal disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.² As with any distressing FSD, reports of being distressed about low sexual desire were highest for midlife women (12.3%) relative to younger (8.9%) and older (7.4%) women.¹

Unfortunately, decreased desire can have a ripple effect that goes well beyond a patient’s sexual health. A less-than-satisfying sex life can have a significant negative impact on self-image, possibly leading to depression or overall mood instability, which in turn can put undue strain on personal relationships.^1,3 A patient’s entire quality of life can be affected negatively.

With so much at stake, it is important for physicians to take a more active role in addressing the sexual health of their patients. Emphasizing wellness can help reduce the stigma of sexual dysfunction, break the silence, and open up patient–physician communication.⁴ There is also much to be gained by helping patients realize that having positive and respectful relationships is protective for health, including sexual health.⁴ Likewise, patients benefit from acknowledging that sexual health is an element of overall health and contributes to it.⁴

Toward these ends, more discussion with patients is needed. According to a 2008 national study, although 63% of US ObGyns surveyed indicated that they routinely asked their patients about sexual activity, only 40% asked about sexual problems, and only 29% asked patients if their sex lives were satisfying.⁵

Without communication, information is missed, and clinicians easily can overlook their patients’ sexual dysfunction and need for intervention. For midlife women, who are disproportionately affected by dysfunction relative to younger and older women, and for whom the rate of menopausal symptoms increases over the transition years, the results of going undiagnosed and untreated can be especially troubling. As reported in one study, for example, the rate of bothersome vulvovaginal atrophy, which can be a source of sexual dysfunction, increased from less than 5% at premenopause to almost 50% at 3 years postmenopause.⁶ What is standing in our way, however, and how can we overcome the hurdles to an open-door approach and meaningful conversation?

Obstacles to taking a sexual historyInitiating a sexual history can be like opening Pandora’s box. How do clinicians deal with the problems that come out? Some clinicians worry about embarrassing a patient with the first few questions about sexual health. Male gynecologists may feel awkward asking a patient about sex—particularly an older, midlife patient. The problem with not starting the conversation is that the midlife patient is often the one in the most distress, and the one most in need of treatment. Only by having the sexual health discussion can clinicians identify any issues and begin to address them.

Icebreakers to jump-start the conversation
Asking open-ended questions works best. Here are some options for starting a conversation with a midlife patient:

Such tools as checklists are often needed to bridge the wide communication gap between patients and physicians. Of the 255 women who reported experiencing dyspareunia in the Revealing Vaginal Effects at Midlife (REVEAL) study, almost half (44%) indicated that they had not spoken with their health care clinician about it.⁷ Another 44% had spoken about the problem but on their own initiative. In only 10% of cases had a physician started the conversation.

Clinicians can and should do better. Many of us have known our patients for years—given them their annual examinations, delivered their babies, performed their surgeries, become familiar with their bodies and intimate medical histories. We are uniquely qualified to start conversations on sexual health. A clinician who examines tissues and sees a decrease in vaginal caliber and pallor must say something. In some cases, the vagina is dry, but the patient has not been having lubrication problems. In other cases, a more serious condition might be involved. The important thing is to open up a conversation and talk about treatments.

CASE Continued
As today’s office visit wraps up and your patient begins moving for the door, you say, “Your hot flashes aren’t bothering you, but some women start experiencing certain sexual problems around this time in life. Have you noticed any issues?”

“Well, I have been having more burning during intercourse,” your patient responds.

On hearing this, you say, “That’s very important, Mrs. X, and I am glad you told me about it. I would like to discuss your concern a bit more, so let’s make another appointment to do just that.”

At the next visit, as part of the discussion, you give your patient a 15-minute sexual status examination.

Sexual status examination
Performing this examination helps clinicians see patterns in both sexual behavior and sexual health, which in turn can make it easier to recognize any dysfunction that might subsequently develop. The key to this process is establishing trust with the patient and having her feel comfortable with the discussion.

The patient remains fully clothed during this 15-minute session, which takes place with guarantees of nonjudgmental listening, confidentiality, privacy, and no interruptions. With the topic of sex being so personal, it should be emphasized that she is simply giving the clinician information, as she does on other health-related matters.

Establish her sexual status. Begin by asking the patient to describe her most recent or typical sexual encounter, including details such as day, time, location, type of activity, thoughts and feelings, and responses.

Potential issues can become apparent immediately. A patient may not have had a sexual encounter recently, or ever. Another may want sex, or more sex, but sees obstacles or lack of opportunity. Each of these is an issue to be explored, if the patient allows.

A patient can be sexually active in a number of ways, as the definition varies among population groups (race and age) and individuals. Sex is not only intercourse or oral sex—it is also kissing, touching, and hugging. Some people have an expansive view of what it is to be sexually active. When the patient mentions an encounter, ask what day, what time, where (at home, in a hotel room, at the office), and what type of activity (foreplay, oral sex, manual stimulation, intercourse, and position). Following up, ask what the patient was thinking or feeling about the encounter. For example, were there distracting thoughts or feelings of guilt? How did the patient and her partner respond during the encounter?

Assess for sexual dysfunction. After assessing the patient’s sexual status, turn to dysfunction. Arousal, pain, orgasm, and satisfaction are 4 areas of interest. Did the patient have difficulty becoming aroused? Was there a problem with lubrication? Did she have an orgasm? Was sex painful? How did she feel in terms of overall satisfaction?

In general, patients are comfortable speaking about sexual function and health. Having this talk can help identify a pattern, which can be discussed further during another visit. Such a follow-up would not take long—a level 3 visit should suffice.

Differential diagnosis. Consider the effects of current medications.^8,9 The psychiatric illnesses and general health factors that may affect sexual function should be considered as well (FIGURE 2).^10–22

When is it important to refer?
There are many reasons to refer a patient to another physician, including:

• a recommended treatment is not working
• abuse is suspected
• the patient shows symptoms of depression, anxiety, or another psychiatric condition
• a chronic, generalized (vs situational) disorder may be involved
• physical pain issues must be addressed
• you simply do not feel comfortable with a particular problem or patient.

Given the range of potential issues associated with sexual function, it is important to be able to provide the patient with expert assistance from a multidisciplinary team of specialists. This team can include psychologists, psychiatrists, counselors, sex educators, and, for pain issues, pelvic floor specialists and pelvic floor physical therapists. These colleagues are thoroughly familiar with the kinds of issues that can arise, and can offer alternative and adjunctive therapies.

Referrals also can be made for the latest nonpharmacologic and FDA-approved pharmacologic treatment options. Specialists tend to be familiar with these options, some of which are available only recently.

It is important to ask patients about sexual function and, if necessary, give them access to the best treatment options.

CASE Resolved
During the sexual status examination, your patient describes her most recent sexual encounter with her husband. She is frustrated with her lack of sexual response and describes a dry, tearing sensation during intercourse. You recommend first-line treatment with vaginal lubricants, preferably iso-osmolar aqueous− or silicone/dimethicone−based lubricants during intercourse. You also can discuss topical estrogen therapy via estradiol cream, conjugated equine estrogen cream, estradiol tablets in the vagina, or the estrogen ring. She is reassured that topical estrogen use will not pose significant risk for cancer, stroke, heart disease, or blood clot and that progesterone treatment is not necessary.

For patients who are particularly concerned about vaginal estrogen use, 2 or 3 times weekly use of a vaginal moisturizer could be an alternative for genitourinary symptoms and dyspareunia.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Patient may benefit from treatment for dyspareuniaA 54-year-old woman has been in your care for more than 15 years. Three years ago, at her well-woman examination, she was not yet having symptoms of menopause. Now, during her current examination, she reports hot flashes, which she says are not bothersome. In passing, she also says, “I don’t want to take hormone therapy,” but then is not overly conversational or responsive to your questions. She does mention having had 3 urinary tract infections over the past 8 months. On physical examination, you note mildly atrophied vaginal tissue.

Your patient does not bring up any sexual concerns, and so far you have not directly asked about sexual health. However, the time remaining in this visit is limited, and your patient, whose daughter is sitting in the waiting area, seems anxious to finish and leave. Still, you want to broach the subject of your patient’s sexual health. What are your best options?

We learned a lot about women’s perceptions regarding their sexual health in the 2008 Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking study (PRESIDE). Approximately 43% of 31,581 questionnaire respondents reported dysfunction in sexual desire, arousal, or orgasm.¹ Results also showed that 11.5% of the respondents with any of these types of female sexual dysfunction (FSD) were distressed about it. For clinicians, knowing who these women are is key in recognizing and treating FSD.

Important to the opening case, in PRESIDE, Shifren and colleagues found that women in their midlife years (aged 45 to 64) had the highest rate of any distressing sexual problem: 14.8%. Younger women (aged 18 to 44 years) had a rate of 10.8%; older women (aged 65 years or older) had a rate of 8.9%.¹

The most prevalent FSD was hypoactive sexual desire disorder,¹ which in 2013 was renamed sexual interest and arousal disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.² As with any distressing FSD, reports of being distressed about low sexual desire were highest for midlife women (12.3%) relative to younger (8.9%) and older (7.4%) women.¹

Unfortunately, decreased desire can have a ripple effect that goes well beyond a patient’s sexual health. A less-than-satisfying sex life can have a significant negative impact on self-image, possibly leading to depression or overall mood instability, which in turn can put undue strain on personal relationships.^1,3 A patient’s entire quality of life can be affected negatively.

With so much at stake, it is important for physicians to take a more active role in addressing the sexual health of their patients. Emphasizing wellness can help reduce the stigma of sexual dysfunction, break the silence, and open up patient–physician communication.⁴ There is also much to be gained by helping patients realize that having positive and respectful relationships is protective for health, including sexual health.⁴ Likewise, patients benefit from acknowledging that sexual health is an element of overall health and contributes to it.⁴

Toward these ends, more discussion with patients is needed. According to a 2008 national study, although 63% of US ObGyns surveyed indicated that they routinely asked their patients about sexual activity, only 40% asked about sexual problems, and only 29% asked patients if their sex lives were satisfying.⁵

Without communication, information is missed, and clinicians easily can overlook their patients’ sexual dysfunction and need for intervention. For midlife women, who are disproportionately affected by dysfunction relative to younger and older women, and for whom the rate of menopausal symptoms increases over the transition years, the results of going undiagnosed and untreated can be especially troubling. As reported in one study, for example, the rate of bothersome vulvovaginal atrophy, which can be a source of sexual dysfunction, increased from less than 5% at premenopause to almost 50% at 3 years postmenopause.⁶ What is standing in our way, however, and how can we overcome the hurdles to an open-door approach and meaningful conversation?

Obstacles to taking a sexual historyInitiating a sexual history can be like opening Pandora’s box. How do clinicians deal with the problems that come out? Some clinicians worry about embarrassing a patient with the first few questions about sexual health. Male gynecologists may feel awkward asking a patient about sex—particularly an older, midlife patient. The problem with not starting the conversation is that the midlife patient is often the one in the most distress, and the one most in need of treatment. Only by having the sexual health discussion can clinicians identify any issues and begin to address them.

Icebreakers to jump-start the conversation
Asking open-ended questions works best. Here are some options for starting a conversation with a midlife patient:

Such tools as checklists are often needed to bridge the wide communication gap between patients and physicians. Of the 255 women who reported experiencing dyspareunia in the Revealing Vaginal Effects at Midlife (REVEAL) study, almost half (44%) indicated that they had not spoken with their health care clinician about it.⁷ Another 44% had spoken about the problem but on their own initiative. In only 10% of cases had a physician started the conversation.

Clinicians can and should do better. Many of us have known our patients for years—given them their annual examinations, delivered their babies, performed their surgeries, become familiar with their bodies and intimate medical histories. We are uniquely qualified to start conversations on sexual health. A clinician who examines tissues and sees a decrease in vaginal caliber and pallor must say something. In some cases, the vagina is dry, but the patient has not been having lubrication problems. In other cases, a more serious condition might be involved. The important thing is to open up a conversation and talk about treatments.

CASE Continued
As today’s office visit wraps up and your patient begins moving for the door, you say, “Your hot flashes aren’t bothering you, but some women start experiencing certain sexual problems around this time in life. Have you noticed any issues?”

“Well, I have been having more burning during intercourse,” your patient responds.

On hearing this, you say, “That’s very important, Mrs. X, and I am glad you told me about it. I would like to discuss your concern a bit more, so let’s make another appointment to do just that.”

At the next visit, as part of the discussion, you give your patient a 15-minute sexual status examination.

Sexual status examination
Performing this examination helps clinicians see patterns in both sexual behavior and sexual health, which in turn can make it easier to recognize any dysfunction that might subsequently develop. The key to this process is establishing trust with the patient and having her feel comfortable with the discussion.

The patient remains fully clothed during this 15-minute session, which takes place with guarantees of nonjudgmental listening, confidentiality, privacy, and no interruptions. With the topic of sex being so personal, it should be emphasized that she is simply giving the clinician information, as she does on other health-related matters.

Establish her sexual status. Begin by asking the patient to describe her most recent or typical sexual encounter, including details such as day, time, location, type of activity, thoughts and feelings, and responses.

Potential issues can become apparent immediately. A patient may not have had a sexual encounter recently, or ever. Another may want sex, or more sex, but sees obstacles or lack of opportunity. Each of these is an issue to be explored, if the patient allows.

A patient can be sexually active in a number of ways, as the definition varies among population groups (race and age) and individuals. Sex is not only intercourse or oral sex—it is also kissing, touching, and hugging. Some people have an expansive view of what it is to be sexually active. When the patient mentions an encounter, ask what day, what time, where (at home, in a hotel room, at the office), and what type of activity (foreplay, oral sex, manual stimulation, intercourse, and position). Following up, ask what the patient was thinking or feeling about the encounter. For example, were there distracting thoughts or feelings of guilt? How did the patient and her partner respond during the encounter?

Assess for sexual dysfunction. After assessing the patient’s sexual status, turn to dysfunction. Arousal, pain, orgasm, and satisfaction are 4 areas of interest. Did the patient have difficulty becoming aroused? Was there a problem with lubrication? Did she have an orgasm? Was sex painful? How did she feel in terms of overall satisfaction?

In general, patients are comfortable speaking about sexual function and health. Having this talk can help identify a pattern, which can be discussed further during another visit. Such a follow-up would not take long—a level 3 visit should suffice.

Differential diagnosis. Consider the effects of current medications.^8,9 The psychiatric illnesses and general health factors that may affect sexual function should be considered as well (FIGURE 2).^10–22

When is it important to refer?
There are many reasons to refer a patient to another physician, including:

• a recommended treatment is not working
• abuse is suspected
• the patient shows symptoms of depression, anxiety, or another psychiatric condition
• a chronic, generalized (vs situational) disorder may be involved
• physical pain issues must be addressed
• you simply do not feel comfortable with a particular problem or patient.

Given the range of potential issues associated with sexual function, it is important to be able to provide the patient with expert assistance from a multidisciplinary team of specialists. This team can include psychologists, psychiatrists, counselors, sex educators, and, for pain issues, pelvic floor specialists and pelvic floor physical therapists. These colleagues are thoroughly familiar with the kinds of issues that can arise, and can offer alternative and adjunctive therapies.

Referrals also can be made for the latest nonpharmacologic and FDA-approved pharmacologic treatment options. Specialists tend to be familiar with these options, some of which are available only recently.

It is important to ask patients about sexual function and, if necessary, give them access to the best treatment options.

CASE Resolved
During the sexual status examination, your patient describes her most recent sexual encounter with her husband. She is frustrated with her lack of sexual response and describes a dry, tearing sensation during intercourse. You recommend first-line treatment with vaginal lubricants, preferably iso-osmolar aqueous− or silicone/dimethicone−based lubricants during intercourse. You also can discuss topical estrogen therapy via estradiol cream, conjugated equine estrogen cream, estradiol tablets in the vagina, or the estrogen ring. She is reassured that topical estrogen use will not pose significant risk for cancer, stroke, heart disease, or blood clot and that progesterone treatment is not necessary.

For patients who are particularly concerned about vaginal estrogen use, 2 or 3 times weekly use of a vaginal moisturizer could be an alternative for genitourinary symptoms and dyspareunia.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Patient may benefit from treatment for dyspareuniaA 54-year-old woman has been in your care for more than 15 years. Three years ago, at her well-woman examination, she was not yet having symptoms of menopause. Now, during her current examination, she reports hot flashes, which she says are not bothersome. In passing, she also says, “I don’t want to take hormone therapy,” but then is not overly conversational or responsive to your questions. She does mention having had 3 urinary tract infections over the past 8 months. On physical examination, you note mildly atrophied vaginal tissue.

Your patient does not bring up any sexual concerns, and so far you have not directly asked about sexual health. However, the time remaining in this visit is limited, and your patient, whose daughter is sitting in the waiting area, seems anxious to finish and leave. Still, you want to broach the subject of your patient’s sexual health. What are your best options?

We learned a lot about women’s perceptions regarding their sexual health in the 2008 Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking study (PRESIDE). Approximately 43% of 31,581 questionnaire respondents reported dysfunction in sexual desire, arousal, or orgasm.¹ Results also showed that 11.5% of the respondents with any of these types of female sexual dysfunction (FSD) were distressed about it. For clinicians, knowing who these women are is key in recognizing and treating FSD.

Important to the opening case, in PRESIDE, Shifren and colleagues found that women in their midlife years (aged 45 to 64) had the highest rate of any distressing sexual problem: 14.8%. Younger women (aged 18 to 44 years) had a rate of 10.8%; older women (aged 65 years or older) had a rate of 8.9%.¹

The most prevalent FSD was hypoactive sexual desire disorder,¹ which in 2013 was renamed sexual interest and arousal disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.² As with any distressing FSD, reports of being distressed about low sexual desire were highest for midlife women (12.3%) relative to younger (8.9%) and older (7.4%) women.¹

Unfortunately, decreased desire can have a ripple effect that goes well beyond a patient’s sexual health. A less-than-satisfying sex life can have a significant negative impact on self-image, possibly leading to depression or overall mood instability, which in turn can put undue strain on personal relationships.^1,3 A patient’s entire quality of life can be affected negatively.

With so much at stake, it is important for physicians to take a more active role in addressing the sexual health of their patients. Emphasizing wellness can help reduce the stigma of sexual dysfunction, break the silence, and open up patient–physician communication.⁴ There is also much to be gained by helping patients realize that having positive and respectful relationships is protective for health, including sexual health.⁴ Likewise, patients benefit from acknowledging that sexual health is an element of overall health and contributes to it.⁴

Toward these ends, more discussion with patients is needed. According to a 2008 national study, although 63% of US ObGyns surveyed indicated that they routinely asked their patients about sexual activity, only 40% asked about sexual problems, and only 29% asked patients if their sex lives were satisfying.⁵

Without communication, information is missed, and clinicians easily can overlook their patients’ sexual dysfunction and need for intervention. For midlife women, who are disproportionately affected by dysfunction relative to younger and older women, and for whom the rate of menopausal symptoms increases over the transition years, the results of going undiagnosed and untreated can be especially troubling. As reported in one study, for example, the rate of bothersome vulvovaginal atrophy, which can be a source of sexual dysfunction, increased from less than 5% at premenopause to almost 50% at 3 years postmenopause.⁶ What is standing in our way, however, and how can we overcome the hurdles to an open-door approach and meaningful conversation?

Obstacles to taking a sexual historyInitiating a sexual history can be like opening Pandora’s box. How do clinicians deal with the problems that come out? Some clinicians worry about embarrassing a patient with the first few questions about sexual health. Male gynecologists may feel awkward asking a patient about sex—particularly an older, midlife patient. The problem with not starting the conversation is that the midlife patient is often the one in the most distress, and the one most in need of treatment. Only by having the sexual health discussion can clinicians identify any issues and begin to address them.

Icebreakers to jump-start the conversation
Asking open-ended questions works best. Here are some options for starting a conversation with a midlife patient:

Such tools as checklists are often needed to bridge the wide communication gap between patients and physicians. Of the 255 women who reported experiencing dyspareunia in the Revealing Vaginal Effects at Midlife (REVEAL) study, almost half (44%) indicated that they had not spoken with their health care clinician about it.⁷ Another 44% had spoken about the problem but on their own initiative. In only 10% of cases had a physician started the conversation.

Clinicians can and should do better. Many of us have known our patients for years—given them their annual examinations, delivered their babies, performed their surgeries, become familiar with their bodies and intimate medical histories. We are uniquely qualified to start conversations on sexual health. A clinician who examines tissues and sees a decrease in vaginal caliber and pallor must say something. In some cases, the vagina is dry, but the patient has not been having lubrication problems. In other cases, a more serious condition might be involved. The important thing is to open up a conversation and talk about treatments.

CASE Continued
As today’s office visit wraps up and your patient begins moving for the door, you say, “Your hot flashes aren’t bothering you, but some women start experiencing certain sexual problems around this time in life. Have you noticed any issues?”

“Well, I have been having more burning during intercourse,” your patient responds.

On hearing this, you say, “That’s very important, Mrs. X, and I am glad you told me about it. I would like to discuss your concern a bit more, so let’s make another appointment to do just that.”

At the next visit, as part of the discussion, you give your patient a 15-minute sexual status examination.

Sexual status examination
Performing this examination helps clinicians see patterns in both sexual behavior and sexual health, which in turn can make it easier to recognize any dysfunction that might subsequently develop. The key to this process is establishing trust with the patient and having her feel comfortable with the discussion.

The patient remains fully clothed during this 15-minute session, which takes place with guarantees of nonjudgmental listening, confidentiality, privacy, and no interruptions. With the topic of sex being so personal, it should be emphasized that she is simply giving the clinician information, as she does on other health-related matters.

Establish her sexual status. Begin by asking the patient to describe her most recent or typical sexual encounter, including details such as day, time, location, type of activity, thoughts and feelings, and responses.

Potential issues can become apparent immediately. A patient may not have had a sexual encounter recently, or ever. Another may want sex, or more sex, but sees obstacles or lack of opportunity. Each of these is an issue to be explored, if the patient allows.

A patient can be sexually active in a number of ways, as the definition varies among population groups (race and age) and individuals. Sex is not only intercourse or oral sex—it is also kissing, touching, and hugging. Some people have an expansive view of what it is to be sexually active. When the patient mentions an encounter, ask what day, what time, where (at home, in a hotel room, at the office), and what type of activity (foreplay, oral sex, manual stimulation, intercourse, and position). Following up, ask what the patient was thinking or feeling about the encounter. For example, were there distracting thoughts or feelings of guilt? How did the patient and her partner respond during the encounter?

Assess for sexual dysfunction. After assessing the patient’s sexual status, turn to dysfunction. Arousal, pain, orgasm, and satisfaction are 4 areas of interest. Did the patient have difficulty becoming aroused? Was there a problem with lubrication? Did she have an orgasm? Was sex painful? How did she feel in terms of overall satisfaction?

In general, patients are comfortable speaking about sexual function and health. Having this talk can help identify a pattern, which can be discussed further during another visit. Such a follow-up would not take long—a level 3 visit should suffice.

Differential diagnosis. Consider the effects of current medications.^8,9 The psychiatric illnesses and general health factors that may affect sexual function should be considered as well (FIGURE 2).^10–22

When is it important to refer?
There are many reasons to refer a patient to another physician, including:

• a recommended treatment is not working
• abuse is suspected
• the patient shows symptoms of depression, anxiety, or another psychiatric condition
• a chronic, generalized (vs situational) disorder may be involved
• physical pain issues must be addressed
• you simply do not feel comfortable with a particular problem or patient.

Given the range of potential issues associated with sexual function, it is important to be able to provide the patient with expert assistance from a multidisciplinary team of specialists. This team can include psychologists, psychiatrists, counselors, sex educators, and, for pain issues, pelvic floor specialists and pelvic floor physical therapists. These colleagues are thoroughly familiar with the kinds of issues that can arise, and can offer alternative and adjunctive therapies.

Referrals also can be made for the latest nonpharmacologic and FDA-approved pharmacologic treatment options. Specialists tend to be familiar with these options, some of which are available only recently.

It is important to ask patients about sexual function and, if necessary, give them access to the best treatment options.

CASE Resolved
During the sexual status examination, your patient describes her most recent sexual encounter with her husband. She is frustrated with her lack of sexual response and describes a dry, tearing sensation during intercourse. You recommend first-line treatment with vaginal lubricants, preferably iso-osmolar aqueous− or silicone/dimethicone−based lubricants during intercourse. You also can discuss topical estrogen therapy via estradiol cream, conjugated equine estrogen cream, estradiol tablets in the vagina, or the estrogen ring. She is reassured that topical estrogen use will not pose significant risk for cancer, stroke, heart disease, or blood clot and that progesterone treatment is not necessary.

For patients who are particularly concerned about vaginal estrogen use, 2 or 3 times weekly use of a vaginal moisturizer could be an alternative for genitourinary symptoms and dyspareunia.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Rotator cuff repairs (RCRs) can be challenging due to poor tendon quality and the inability of tendon to heal to bone. Smoking, age over 63 years, fatty infiltration, and massive cuff tears are all factors implicated in increased failure rates.^1-3 Tears >3 cm have a structural failure rate ranging from 11% to 95% in the literature.^1-5 Massive tears (tears >5 cm or involving 2 or more tendons) are even more complex and have failure rates of 20% to 90%.^5,6 The weakest link in the RCR construct is the suture-tendon interface, and suture pullout through the tendon is thought to be the most common method of failure.⁶ The purpose of this review is to examine whether literature supports the use of acellular dermal matrices (ADMs) in rotator cuff surgery.

The high rate of structural failures after RCR has led surgeons to seek means to augment repairs and new means of reconstruction for irreparable tears. Freeze dried allograft tendons have been used historically with mixed results, including reports of complete graft failures and foreign body reaction.^7-10 Porcine intestinal submucosal membrane “patches” gained popularity due to off-the- shelf availability of the graft. However, these were found to have poor outcomes with early graft rejection and intense inflammatory reaction.^11,12 Recently, ADMs have gained significant interest due to favorable biomechanical properties and clinical outcomes.^13-19

An ADM is an allograft composed of mostly type I collagen that is processed to remove donor cells while preserving the extracellular matrix. There are several commercially available ADMs with different methods of processing and sterilization, as well as handling characteristics.^20,21 In vivo studies have demonstrated that removing the cellular components allows infiltration of native cellular agents, such as fibroblasts, vascular tissue, and tenocytes, while causing minimal host inflammatory reaction.^21-23 In addition, superior suture pullout strength has been demonstrated by multiple benchtop and preclinical studies.^23,24 Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.

Emerging Evidence

Multiple biomechanical studies have evaluated ADMs in RC models.^24-28 Barber and colleagues²⁴ demonstrated that ADM had significantly higher loads to failure (229 N) than porcine skin (128 N), bovine skin (76 N), and porcine small intestine submucosa (32 N) (P < .001). In another study, Barber and colleagues²⁵ subsequently demonstrated, in a cadaver RC tear model, an increase in mean failure strength in augmented repairs with ADM (325 N) compared to cadaveric controls (273 N) (P = .047).

A subsequent study by Barber and Aziz-Jacobo²⁶ compared ADMs to a control model of allograft RC. The ADMs had significantly higher tensile modulus (P < .001) and higher suture retention measure by a single-pull destructive test of a simple vertical stitch (P < .05) than the RC allograft. The ultimate load to failure of the ADM model was higher than the RC allograft control (523±154 N vs 208±115 N); however, this difference did not reach statistical significance.²⁶ Beitzel and colleagues²⁷ evaluated ADM augmentation in a cadaver RC model and found a statistically significant increase in load to failure in ADM augmented repairs vs nonaugmented controls, (575.8 N vs 348.9 N, P = .025). Ely and colleagues²⁸ also demonstrated that repairs augmented with ADM had a higher load to failure (643 N vs 551 N) and less gap formation (2.2 mm vs 2.8 mm) compared to controls, although this difference was not statistically significant.

These biomechanical studies have been translated to clinical findings. A level II, prospective, randomized controlled study by Barber and colleagues²⁹ evaluated 42 patients with >3 cm, 2-tendon RCTs repaired arthroscopically.Twenty-two patients were randomized to single-row arthroscopic repair, and 20 patients to single-row arthroscopic repair augmented by ADM by an onlay technique (Figure 1) as described by Labbé.³⁰ At average follow-up of 24 months, 85% of the augmented repairs were intact on magnetic resonance imaging (MRI) at follow-up, compared to 40% in the control group (P < .05). Agrawal³¹ retrospectively reviewed 14 patients with either RCTs >3 cm or recurrent RCT (may be <3 cm) that were arthroscopically repaired with a double-row technique with ADM augmentation. Postoperative MRI obtained at average of 16.8 months revealed 85.7% of repairs to be intact, with 14.3% having recurrent tears of <1 cm. Rotini and colleagues³² evaluated a smaller subset of 5 patients with large/massive primary cuff tears, arthroscopically repaired with double-row technique and ADM augmentation. Follow-up MRI at an average of 1 year demonstrated 3 intact repairs, 1 partial recurrence, and 1 complete recurrence. These clinical studies demonstrate that RCRs augmented with ADM have a much higher rate of structural integrity on postoperative imaging compared to what has been previously reported in the literature.^1-6

Although an “off-label” indication, the use of ADM in massive RC tears has been described with good clinical results.^14,17,19,33 The ADM is used to bridge the gap by suturing it to the edge of the retracted tendon and anchoring it to the tuberosity (Figures 2A-2E). Improvement in pain, function, and active range of motion can be achieved. Burkhead and colleagues¹⁴ obtained postoperative MRIs at average follow-up of 1.2 years and found only 3 of 11 repairs with evidence of re-tear, all noted to be smaller than preoperative tears. Gupta and colleagues¹⁷ obtained postoperative ultrasounds in 24 patients at average 3 years and showed 76% of tears to be fully intact, with the remaining 24% having only a partial tear, and 0% with full re-tears. Venouziou and colleagues¹⁹ evaluated 14 patients with minimum 18-month follow-up and Kokkalis and colleagues³³ evaluated 21 patients with a 29-month follow-up; both described successful clinical outcomes but did not provide postoperative imaging evaluation. Multiple studies have adapted this technique to a fully arthroscopic method and have had similarly positive results clinically and with MRI.^{13,16,18,34,35} Bond and colleagues¹³ reported 16 cases with massive irreparable tears repaired arthroscopically with ADM to span the tendon gap. At an average follow-up of 26.8 months, 75% had good or excellent clinical results, and at an average of 1 year postoperatively 13 of 16 cases had an intact repair on gadolinium enhanced MRI.¹³ These studies suggest that ADM can be used for bridging massive irreparable RC tears with good clinical and radiographic outcomes.

Superior capsule reconstruction is a biomechanically proven concept that has been described in previous studies.^36,37 In the original technique, autologous tensor fascia lata (TFL) is anchored from the glenoid margin to the greater tuberosity footprint to restore the superior stability of the glenohumeral joint, without altering the native glenohumeral contact forces.³⁸ This concept has gained popularity in the United States, but with the use of an ADM instead of harvesting TFL (Figures 3A, 3B). However, there are no published biomechanical or clinical studies with the use of ADM in superior capsular reconstruction.

Conclusion

The use of ADM is an emerging solution for augmenting primary RCRs and the treatment of irreparable RC tears. The biomechanical and clinical studies summarized support the use of ADM in RC surgery. Further randomized studies are needed to add to the growing evidence on the use of ADMs.

Rotator cuff repairs (RCRs) can be challenging due to poor tendon quality and the inability of tendon to heal to bone. Smoking, age over 63 years, fatty infiltration, and massive cuff tears are all factors implicated in increased failure rates.^1-3 Tears >3 cm have a structural failure rate ranging from 11% to 95% in the literature.^1-5 Massive tears (tears >5 cm or involving 2 or more tendons) are even more complex and have failure rates of 20% to 90%.^5,6 The weakest link in the RCR construct is the suture-tendon interface, and suture pullout through the tendon is thought to be the most common method of failure.⁶ The purpose of this review is to examine whether literature supports the use of acellular dermal matrices (ADMs) in rotator cuff surgery.

The high rate of structural failures after RCR has led surgeons to seek means to augment repairs and new means of reconstruction for irreparable tears. Freeze dried allograft tendons have been used historically with mixed results, including reports of complete graft failures and foreign body reaction.^7-10 Porcine intestinal submucosal membrane “patches” gained popularity due to off-the- shelf availability of the graft. However, these were found to have poor outcomes with early graft rejection and intense inflammatory reaction.^11,12 Recently, ADMs have gained significant interest due to favorable biomechanical properties and clinical outcomes.^13-19

An ADM is an allograft composed of mostly type I collagen that is processed to remove donor cells while preserving the extracellular matrix. There are several commercially available ADMs with different methods of processing and sterilization, as well as handling characteristics.^20,21 In vivo studies have demonstrated that removing the cellular components allows infiltration of native cellular agents, such as fibroblasts, vascular tissue, and tenocytes, while causing minimal host inflammatory reaction.^21-23 In addition, superior suture pullout strength has been demonstrated by multiple benchtop and preclinical studies.^23,24 Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.

Emerging Evidence

Multiple biomechanical studies have evaluated ADMs in RC models.^24-28 Barber and colleagues²⁴ demonstrated that ADM had significantly higher loads to failure (229 N) than porcine skin (128 N), bovine skin (76 N), and porcine small intestine submucosa (32 N) (P < .001). In another study, Barber and colleagues²⁵ subsequently demonstrated, in a cadaver RC tear model, an increase in mean failure strength in augmented repairs with ADM (325 N) compared to cadaveric controls (273 N) (P = .047).

A subsequent study by Barber and Aziz-Jacobo²⁶ compared ADMs to a control model of allograft RC. The ADMs had significantly higher tensile modulus (P < .001) and higher suture retention measure by a single-pull destructive test of a simple vertical stitch (P < .05) than the RC allograft. The ultimate load to failure of the ADM model was higher than the RC allograft control (523±154 N vs 208±115 N); however, this difference did not reach statistical significance.²⁶ Beitzel and colleagues²⁷ evaluated ADM augmentation in a cadaver RC model and found a statistically significant increase in load to failure in ADM augmented repairs vs nonaugmented controls, (575.8 N vs 348.9 N, P = .025). Ely and colleagues²⁸ also demonstrated that repairs augmented with ADM had a higher load to failure (643 N vs 551 N) and less gap formation (2.2 mm vs 2.8 mm) compared to controls, although this difference was not statistically significant.

These biomechanical studies have been translated to clinical findings. A level II, prospective, randomized controlled study by Barber and colleagues²⁹ evaluated 42 patients with >3 cm, 2-tendon RCTs repaired arthroscopically.Twenty-two patients were randomized to single-row arthroscopic repair, and 20 patients to single-row arthroscopic repair augmented by ADM by an onlay technique (Figure 1) as described by Labbé.³⁰ At average follow-up of 24 months, 85% of the augmented repairs were intact on magnetic resonance imaging (MRI) at follow-up, compared to 40% in the control group (P < .05). Agrawal³¹ retrospectively reviewed 14 patients with either RCTs >3 cm or recurrent RCT (may be <3 cm) that were arthroscopically repaired with a double-row technique with ADM augmentation. Postoperative MRI obtained at average of 16.8 months revealed 85.7% of repairs to be intact, with 14.3% having recurrent tears of <1 cm. Rotini and colleagues³² evaluated a smaller subset of 5 patients with large/massive primary cuff tears, arthroscopically repaired with double-row technique and ADM augmentation. Follow-up MRI at an average of 1 year demonstrated 3 intact repairs, 1 partial recurrence, and 1 complete recurrence. These clinical studies demonstrate that RCRs augmented with ADM have a much higher rate of structural integrity on postoperative imaging compared to what has been previously reported in the literature.^1-6

Although an “off-label” indication, the use of ADM in massive RC tears has been described with good clinical results.^14,17,19,33 The ADM is used to bridge the gap by suturing it to the edge of the retracted tendon and anchoring it to the tuberosity (Figures 2A-2E). Improvement in pain, function, and active range of motion can be achieved. Burkhead and colleagues¹⁴ obtained postoperative MRIs at average follow-up of 1.2 years and found only 3 of 11 repairs with evidence of re-tear, all noted to be smaller than preoperative tears. Gupta and colleagues¹⁷ obtained postoperative ultrasounds in 24 patients at average 3 years and showed 76% of tears to be fully intact, with the remaining 24% having only a partial tear, and 0% with full re-tears. Venouziou and colleagues¹⁹ evaluated 14 patients with minimum 18-month follow-up and Kokkalis and colleagues³³ evaluated 21 patients with a 29-month follow-up; both described successful clinical outcomes but did not provide postoperative imaging evaluation. Multiple studies have adapted this technique to a fully arthroscopic method and have had similarly positive results clinically and with MRI.^{13,16,18,34,35} Bond and colleagues¹³ reported 16 cases with massive irreparable tears repaired arthroscopically with ADM to span the tendon gap. At an average follow-up of 26.8 months, 75% had good or excellent clinical results, and at an average of 1 year postoperatively 13 of 16 cases had an intact repair on gadolinium enhanced MRI.¹³ These studies suggest that ADM can be used for bridging massive irreparable RC tears with good clinical and radiographic outcomes.

Superior capsule reconstruction is a biomechanically proven concept that has been described in previous studies.^36,37 In the original technique, autologous tensor fascia lata (TFL) is anchored from the glenoid margin to the greater tuberosity footprint to restore the superior stability of the glenohumeral joint, without altering the native glenohumeral contact forces.³⁸ This concept has gained popularity in the United States, but with the use of an ADM instead of harvesting TFL (Figures 3A, 3B). However, there are no published biomechanical or clinical studies with the use of ADM in superior capsular reconstruction.

Conclusion

The use of ADM is an emerging solution for augmenting primary RCRs and the treatment of irreparable RC tears. The biomechanical and clinical studies summarized support the use of ADM in RC surgery. Further randomized studies are needed to add to the growing evidence on the use of ADMs.

Rotator cuff repairs (RCRs) can be challenging due to poor tendon quality and the inability of tendon to heal to bone. Smoking, age over 63 years, fatty infiltration, and massive cuff tears are all factors implicated in increased failure rates.^1-3 Tears >3 cm have a structural failure rate ranging from 11% to 95% in the literature.^1-5 Massive tears (tears >5 cm or involving 2 or more tendons) are even more complex and have failure rates of 20% to 90%.^5,6 The weakest link in the RCR construct is the suture-tendon interface, and suture pullout through the tendon is thought to be the most common method of failure.⁶ The purpose of this review is to examine whether literature supports the use of acellular dermal matrices (ADMs) in rotator cuff surgery.

The high rate of structural failures after RCR has led surgeons to seek means to augment repairs and new means of reconstruction for irreparable tears. Freeze dried allograft tendons have been used historically with mixed results, including reports of complete graft failures and foreign body reaction.^7-10 Porcine intestinal submucosal membrane “patches” gained popularity due to off-the- shelf availability of the graft. However, these were found to have poor outcomes with early graft rejection and intense inflammatory reaction.^11,12 Recently, ADMs have gained significant interest due to favorable biomechanical properties and clinical outcomes.^13-19

An ADM is an allograft composed of mostly type I collagen that is processed to remove donor cells while preserving the extracellular matrix. There are several commercially available ADMs with different methods of processing and sterilization, as well as handling characteristics.^20,21 In vivo studies have demonstrated that removing the cellular components allows infiltration of native cellular agents, such as fibroblasts, vascular tissue, and tenocytes, while causing minimal host inflammatory reaction.^21-23 In addition, superior suture pullout strength has been demonstrated by multiple benchtop and preclinical studies.^23,24 Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.

Emerging Evidence

Multiple biomechanical studies have evaluated ADMs in RC models.^24-28 Barber and colleagues²⁴ demonstrated that ADM had significantly higher loads to failure (229 N) than porcine skin (128 N), bovine skin (76 N), and porcine small intestine submucosa (32 N) (P < .001). In another study, Barber and colleagues²⁵ subsequently demonstrated, in a cadaver RC tear model, an increase in mean failure strength in augmented repairs with ADM (325 N) compared to cadaveric controls (273 N) (P = .047).

A subsequent study by Barber and Aziz-Jacobo²⁶ compared ADMs to a control model of allograft RC. The ADMs had significantly higher tensile modulus (P < .001) and higher suture retention measure by a single-pull destructive test of a simple vertical stitch (P < .05) than the RC allograft. The ultimate load to failure of the ADM model was higher than the RC allograft control (523±154 N vs 208±115 N); however, this difference did not reach statistical significance.²⁶ Beitzel and colleagues²⁷ evaluated ADM augmentation in a cadaver RC model and found a statistically significant increase in load to failure in ADM augmented repairs vs nonaugmented controls, (575.8 N vs 348.9 N, P = .025). Ely and colleagues²⁸ also demonstrated that repairs augmented with ADM had a higher load to failure (643 N vs 551 N) and less gap formation (2.2 mm vs 2.8 mm) compared to controls, although this difference was not statistically significant.

These biomechanical studies have been translated to clinical findings. A level II, prospective, randomized controlled study by Barber and colleagues²⁹ evaluated 42 patients with >3 cm, 2-tendon RCTs repaired arthroscopically.Twenty-two patients were randomized to single-row arthroscopic repair, and 20 patients to single-row arthroscopic repair augmented by ADM by an onlay technique (Figure 1) as described by Labbé.³⁰ At average follow-up of 24 months, 85% of the augmented repairs were intact on magnetic resonance imaging (MRI) at follow-up, compared to 40% in the control group (P < .05). Agrawal³¹ retrospectively reviewed 14 patients with either RCTs >3 cm or recurrent RCT (may be <3 cm) that were arthroscopically repaired with a double-row technique with ADM augmentation. Postoperative MRI obtained at average of 16.8 months revealed 85.7% of repairs to be intact, with 14.3% having recurrent tears of <1 cm. Rotini and colleagues³² evaluated a smaller subset of 5 patients with large/massive primary cuff tears, arthroscopically repaired with double-row technique and ADM augmentation. Follow-up MRI at an average of 1 year demonstrated 3 intact repairs, 1 partial recurrence, and 1 complete recurrence. These clinical studies demonstrate that RCRs augmented with ADM have a much higher rate of structural integrity on postoperative imaging compared to what has been previously reported in the literature.^1-6

Although an “off-label” indication, the use of ADM in massive RC tears has been described with good clinical results.^14,17,19,33 The ADM is used to bridge the gap by suturing it to the edge of the retracted tendon and anchoring it to the tuberosity (Figures 2A-2E). Improvement in pain, function, and active range of motion can be achieved. Burkhead and colleagues¹⁴ obtained postoperative MRIs at average follow-up of 1.2 years and found only 3 of 11 repairs with evidence of re-tear, all noted to be smaller than preoperative tears. Gupta and colleagues¹⁷ obtained postoperative ultrasounds in 24 patients at average 3 years and showed 76% of tears to be fully intact, with the remaining 24% having only a partial tear, and 0% with full re-tears. Venouziou and colleagues¹⁹ evaluated 14 patients with minimum 18-month follow-up and Kokkalis and colleagues³³ evaluated 21 patients with a 29-month follow-up; both described successful clinical outcomes but did not provide postoperative imaging evaluation. Multiple studies have adapted this technique to a fully arthroscopic method and have had similarly positive results clinically and with MRI.^{13,16,18,34,35} Bond and colleagues¹³ reported 16 cases with massive irreparable tears repaired arthroscopically with ADM to span the tendon gap. At an average follow-up of 26.8 months, 75% had good or excellent clinical results, and at an average of 1 year postoperatively 13 of 16 cases had an intact repair on gadolinium enhanced MRI.¹³ These studies suggest that ADM can be used for bridging massive irreparable RC tears with good clinical and radiographic outcomes.

Superior capsule reconstruction is a biomechanically proven concept that has been described in previous studies.^36,37 In the original technique, autologous tensor fascia lata (TFL) is anchored from the glenoid margin to the greater tuberosity footprint to restore the superior stability of the glenohumeral joint, without altering the native glenohumeral contact forces.³⁸ This concept has gained popularity in the United States, but with the use of an ADM instead of harvesting TFL (Figures 3A, 3B). However, there are no published biomechanical or clinical studies with the use of ADM in superior capsular reconstruction.

Conclusion

The use of ADM is an emerging solution for augmenting primary RCRs and the treatment of irreparable RC tears. The biomechanical and clinical studies summarized support the use of ADM in RC surgery. Further randomized studies are needed to add to the growing evidence on the use of ADMs.

Platelet-rich plasma (PRP) is a refined product of autologous blood with a platelet concentration greater than that of whole blood. It is prepared via plasmapheresis utilizing a 2-stage centrifugation process and more than 40 commercially available systems are marketed to concentrate whole blood to PRP.¹ It is rich in biologic factors (growth factors, cytokines, proteins, cellular components) essential to the body’s response to injury. For this reason, it was first used in oromaxillofacial surgery in the 1950s, but its effects on the musculoskeletal system have yet to be clearly elucidated.² However, this lack of clarity has not deterred its widespread use among orthopedic surgeons. In this review, we aim to delineate the current understanding of PRP and its proven effectiveness in the treatment of rotator cuff tears, knee osteoarthritis, ulnar collateral ligament (UCL) tears, lateral epicondylitis, hamstring injuries, and Achilles tendinopathy.

Rotator Cuff Tears

Rotator cuff tears are one of the most common etiologies for shoulder pain and disability. The incidence continues to increase with the active aging population.³ Rotator cuff tears treated with arthroscopic repair have exhibited satisfactory pain relief and functional outcomes.^4-7 Despite advances in fixation techniques, the quality and speed of tendon-to-bone healing remains unpredictable, with repaired tendons exhibiting inferior mechanical properties that are susceptible to re-tear.^8-10

Numerous studies have investigated PRP application during arthroscopic rotator cuff repair (RCR) in an attempt to enhance and accelerate the repair process.^11-15 However, wide variability exists among protocols of how and when PRP is utilized to augment the repair. Warth and colleagues¹⁶ performed a meta-analysis of 11 Level I/II studies evaluating RCR with PRP augmentation. With regards to clinical outcome scores, they found no significant difference in pre- and postoperative American Shoulder and Elbow Surgeons (ASES), Constant, Disability of the Arm, Shoulder and Hand (DASH), or visual analog scale (VAS) pain scores between those patients with or without PRP augmentation. However, they did note a significant increase in Constant scores when PRP was delivered to the tendon-bone interface rather than over the surface of the repair site. There was no significant difference in structural outcomes (evaluated by magnetic resonance imaging [MRI] re-tear rates) between those RCRs with and without PRP augmentation, except in those tears >3 cm in anterior-posterior length using double-row technique, with the PRP group exhibiting a significantly decreased re-tear rate (25.9% vs 57.1%).¹⁶ Zhao and colleagues¹⁷ reported similar results in a meta-analysis of 8 randomized controlled trials, exhibiting no significant differences in clinical outcome scores or re-tear rates after RCR with and without PRP augmentation. Overall, most studies have failed to demonstrate a significant benefit with regards to re-tear rates or shoulder-specific outcomes with the addition of PRP during arthroscopic RCR.

Knee Osteoarthritis

Osteoarthritis is the most common musculoskeletal disorder, with an estimated prevalence of 10% of the world’s population age 60 years and older.¹⁸ The knee is commonly symptomatic, resulting in pain, disability, and significant healthcare costs. Novel biologic, nonoperative therapies, including intra-articular viscosupplementation and PRP injections, have been proposed to treat the early stages of osteoarthritis to provide symptomatic relief and delay surgical intervention.

A multitude of studies have been performed investigating the effects of PRP on knee osteoarthritis, revealing mixed results.^19-22 Campbell and colleagues²³ published a 2015 systematic review of 3 overlapping meta-analyses comparing the outcomes of intra-articular injection of PRP vs control (hyaluronic acid [HA] or placebo) in 3278 knees. They reported a significant improvement in patient outcome scores for the PRP group when compared to control from 2 to 12 months after injection, but due to significant differences within the included studies, the ideal number of injections or time intervals between injections remains unclear. Meheux and colleagues²⁴ reported a 2016 systematic review including 6 studies (817 knees) comparing PRP and HA injections. They demonstrated significantly better improvements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores with PRP vs HA injections at 3 and 12 months postinjection. Similarly, Smith²⁵ conducted a Food and Drug Administration-sanctioned, randomized, double-blind, placebo-controlled clinical trial investigating the effects of intra-articular leukocyte-poor autologous conditioned plasma (ACP) in 30 patients. He reported an improvement in the ACP treatment group WOMAC scores by 78% compared to 7% improvement in the placebo group after 12 months. Despite the heterogeneity amongst studies, the majority of published data suggests better symptomatic relief in patients with early knee degenerative changes, and use of PRP may be considered in this population.

Ulnar Collateral Ligament Injuries

The anterior band of the UCL of the elbow provides stability to valgus stress. Overhead, high-velocity throwing athletes may cause repetitive injury to the UCL, resulting in partial or complete tears of the ligament. This may result in medial elbow pain, as well as decreased throwing velocity and accuracy. Athletes with complete UCL tears have few nonoperative treatment options and generally, operative treatment with UCL reconstruction is recommended for those athletes desiring to return to sport. However, it remains unclear how to definitively treat athletes with partial UCL tears. Recently, there has been an interest in treating these injuries with PRP in conjunction with physical therapy to facilitate a more predictable outcome.

Podesta and colleagues²⁶ published a case series of 34 athletes with MRI-diagnosed partial UCL tears who underwent ultrasound-guided UCL injections and physical therapy. At an average follow-up of 70 weeks, they reported an average return to play (RTP) of 12 weeks, with significant improvements in Kerlan-Jobe Orthopaedic Clinic (KJOC) and DASH outcome scores, and decreased dynamic ulnohumeral joint widening to valgus stress on ultrasound. Most athletes (30/34) returned to their previous level of play, and 1 patient underwent subsequent UCL reconstruction. This study demonstrates that PRP may be used in conjunction with physical therapy and an interval throwing program for the treatment of partial UCL tears, but without a comparison control group, more studies are necessary to delineate the role of PRP in this population.

Lateral Elbow Epicondylitis

Lateral elbow epicondylitis, also known as “tennis elbow,” is thought to be caused by repetitive wrist extension and is more likely to present in patients with various comorbidities such as rotator cuff pathology or a history of smoking.^27-29 The condition typically presents as radiating pain centered about the lateral epicondyle. Annual incidence ranges from 0.34% to 3%, with the most recent large-scale, population-based study estimating that nearly 1 million individuals in the United States develop lateral elbow epicondylitis each year.³⁰ For the majority of patients, symptoms resolve after 6 to 12 months of various nonoperative or minimally invasive treatments.^31-33 Those who develop chronic symptoms (>12 months) may benefit from surgical intervention.³⁴ The use of PRP has become a contentious topic of debate in treating lateral epicondylitis. Its use and efficacy have been empirically examined and compared among more traditional treatments.^35-37

In a small case-series of 6 patients, contrast-enhanced ultrasound imaging was utilized to demonstrate that PRP injection therapy may induce vascularization of the myotendinous junction of the common extensor tendon up to 6 months following injection.³⁸ These physiologic changes may precede observable clinical improvements. Brklijac and colleagues³⁹ prospectively followed 34 patients who had refractory symptoms despite conservative treatment and elected to undergo injection with PRP. At a mean follow-up of 26 weeks, 88.2% of the patients demonstrated improvements on their Oxford Elbow Score (OES). While potentially promising, case series lack large sample sizes, longitudinal analysis, and adequate control groups for comparative analyses of treatments, thereby increasing the likelihood of unintended selection bias.

Randomized controlled trials have demonstrated no difference between PRP and corticosteroid (CS) injection treatments in the short term for symptomatic lateral elbow epicondylitis. At 15 days, 1 month, and 6 months postinjection, no significant difference was found between PRP and CS injections in dynamometer strength measurements nor patient outcome scores (VAS, DASH, OES, and Mayo Clinic Performance Index for Elbow [MMCPIE]).^40,41 In fact, multiple randomized controlled trials have demonstrated PRP to be less effective at 1 and 3 months compared to CS injections, as assessed by the Patient Rated Tennis-Elbow Evaluation (PRTEE) questionnaire, VAS, MMCPIE, and Nirschl scores.^42,43 One mid-term, multi-center randomized controlled trial published by Mishra and colleagues⁴⁴ compared PRP injections to an active control group, demonstrating a significant improvement in VAS pain scores at 24 weeks, but no difference in the PRTEE outcome. The available evidence indicates PRP injection therapy remains limited in utility for treatment of lateral epicondylitis, particularly in the short term when compared to CS injections. In the midterm to long term, PRP therapy may provide some benefit, but ultimately, well-designed prospective randomized controlled trials are needed to delineate the effects of PRP versus the natural course of tendon healing and symptom resolution.

Hamstring Injuries

Acute hamstring injuries are common across all levels and types of sport, particularly those in which sprinting or running is involved. While there is no consensus within the literature on how RTP after hamstring injury should be managed or defined, most injuries seem to resolve around 3 to 6 weeks.⁴⁵ The proximal myotendinous junction of the long head of the biceps femoris and semitendinosus are commonly associated with significant pain and edema after acute hamstring injury.⁴⁶ The amount of edema resulting from grade 1 and 2 hamstring injuries has been found to correlate (minimally) with time to RTP in elite athletes.⁴⁷ PRP injection near the proximal myotendinous hamstring origin has been theorized to help speed the recovery process after acute hamstring injury. To date, the literature demonstrates mixed and limited benefit of PRP injection therapy for acute hamstring injury.

Few studies have shown improvements of PRP therapy over typical nonoperative management (rest, physical therapy, nonsteroidal anti-inflammatory drugs) in acute hamstring injury, but the results must be interpreted carefully.^48,49 Wetzel and colleagues⁴⁸ retrospectively reviewed 17 patients with acute hamstring injury, 12 of whom failed typical management and received PRP injection at the hamstring origin. This group demonstrated significant improvements in their VAS and Nirschl scores at follow-up, whereas the 5 patients who did not receive the injection did not. However, this study exhibited significant limitations inherent to a retrospective review with a small sample size. Hamid and colleagues⁴⁹ conducted a randomized controlled trial of 24 athletes with diagnosed grade 2a acute hamstring injuries, comparing autologous PRP therapy combined with a rehabilitation program versus rehabilitation program alone. RTP, changes in pain severity (Brief Pain Injury-Short Form [BPI-SF] questions 2-6), and pain interference (BPI-SF questions 9A-9G) scores over time were examined. Athletes in the PRP group exhibited no difference in outcomes scores, but returned to play sooner than controls (26.7 vs 42.5 days).

Mejia and Bradley⁵⁰ have reported their experience in treating 12 National Football League (NFL) players with acute MRI grade 1 or 2 hamstring injuries with a series of PRP injections at the site of injury. They found a 1-game difference in earlier RTP when compared to the predicted RTP based on MRI grading. Similarly, Hamid and colleagues⁴⁹ performed a randomized control trial published in 2014, reporting an earlier RTP (26.7 vs 42.5 days) when comparing single PRP injection vs rehabilitation alone in 28 patients diagnosed with acute ultrasound grade 2 hamstring injuries. On the contrary, a small case-control study of NFL players and a retrospective cohort study of athletes with severe hamstring injuries demonstrated no difference in RTP when PRP injected patients were compared with controls.^51,52 Larger randomized controlled trials have demonstrated comparable results, including a study of 90 professional athletes in whom a single PRP injection did not decrease RTP or lessen the risk of re-injury at 2 and 6 months.⁵³ In another large multicenter randomized controlled trial examining 80 competitive and recreational athletes, PRP did not accelerate RTP, lessen the risk of 2-month or 1-year re-injury rate, or improve secondary measures of MRI parameters, subjective patient satisfaction, or the hamstring outcome score.⁵⁴ Although further study is warranted, available evidence suggests limited utility of PRP injection in the treatment of acute hamstring injuries.

Achilles Tendinopathy

Noninsertional Achilles tendinopathy is a common source of pain for both recreational and competitive athletes. Typically thought of as an overuse syndrome, Achilles tendinopathy may result in significant pain and swelling, often at the site of its tenuous blood supply, approximately 2 to 7 cm proximal to its insertion.⁵⁵ Conservative management frequently begins with rest, activity/shoe modification, physical therapy, and eccentric loading exercises.⁵⁶ For those whom conservative management has failed to reduce symptoms after 6 months, more invasive treatment options may be considered. Peritendinous PRP injection has become an alternative approach in treating Achilles tendinopathy refractory to conservative treatment.

In the few randomized controlled trials published, the data demonstrates no significant improvements in clinical outcomes from PRP injection for Achilles tendinopathy. Kearney and colleagues⁵⁷ conducted a pilot study of 20 patients randomized into PRP injection or eccentric loading program for mid-substance Achilles tendinopathy, in which Victorian Institute of Sports Assessment (VISA-A), EuroQol 5 dimensions questionnaire (EQ-5D), and complications associated with the injection were recorded at 6 weeks, 3 months, and 6 months. Although this was a pilot study with a small sample size, no significant difference was found between groups across these time periods. Similarly, de Vos and colleagues^58,59 conducted a double-blind randomized controlled trial of 54 patients with chronic mid-substance Achilles tendinopathy and randomized them into eccentric exercise therapy with either a PRP injection or a saline injected placebo groups. VISA-A scores were recorded and imaging parameters assessing tendon structure by ultrasonographic tissue characterization and color Doppler ultrasonography were taken with follow-up at 6, 12, and 24 weeks. VISA-A scores improved significantly in both groups after 24 weeks, but the difference was not statistically significant between groups. In addition, tendon structure and neovascularization (exhibited by color Doppler ultrasonography) improved in both groups, with no significant difference between groups. The current literature does not support the use of PRP in treatment of Achilles tendinopathy, as it has failed to reveal additional benefits over conventional treatment alone. Future prospective, well-designed randomized controlled trials with large sample sizes will need to be conducted to ultimately conclude whether or not PRP deserves a role in the treatment of Achilles tendinopathy.

Summary

In theory, the use of PRP within orthopedic surgery makes a great deal of sense to accelerate and augment the healing process of the aforementioned musculoskeletal injuries. However, the vast majority of published literature is Level III and IV evidence. Future research may provide the missing critical information of optimal growth factor, platelet, and leukocyte concentrations necessary for the desired effect, as well as the appropriate delivery method and timing of PRP application in different target tissues. Evidence-based guidelines to direct the use of PRP will benefit from more homogenous, repeatable, and randomized controlled trials.

Platelet-rich plasma (PRP) is a refined product of autologous blood with a platelet concentration greater than that of whole blood. It is prepared via plasmapheresis utilizing a 2-stage centrifugation process and more than 40 commercially available systems are marketed to concentrate whole blood to PRP.¹ It is rich in biologic factors (growth factors, cytokines, proteins, cellular components) essential to the body’s response to injury. For this reason, it was first used in oromaxillofacial surgery in the 1950s, but its effects on the musculoskeletal system have yet to be clearly elucidated.² However, this lack of clarity has not deterred its widespread use among orthopedic surgeons. In this review, we aim to delineate the current understanding of PRP and its proven effectiveness in the treatment of rotator cuff tears, knee osteoarthritis, ulnar collateral ligament (UCL) tears, lateral epicondylitis, hamstring injuries, and Achilles tendinopathy.

Rotator Cuff Tears

Rotator cuff tears are one of the most common etiologies for shoulder pain and disability. The incidence continues to increase with the active aging population.³ Rotator cuff tears treated with arthroscopic repair have exhibited satisfactory pain relief and functional outcomes.^4-7 Despite advances in fixation techniques, the quality and speed of tendon-to-bone healing remains unpredictable, with repaired tendons exhibiting inferior mechanical properties that are susceptible to re-tear.^8-10

Numerous studies have investigated PRP application during arthroscopic rotator cuff repair (RCR) in an attempt to enhance and accelerate the repair process.^11-15 However, wide variability exists among protocols of how and when PRP is utilized to augment the repair. Warth and colleagues¹⁶ performed a meta-analysis of 11 Level I/II studies evaluating RCR with PRP augmentation. With regards to clinical outcome scores, they found no significant difference in pre- and postoperative American Shoulder and Elbow Surgeons (ASES), Constant, Disability of the Arm, Shoulder and Hand (DASH), or visual analog scale (VAS) pain scores between those patients with or without PRP augmentation. However, they did note a significant increase in Constant scores when PRP was delivered to the tendon-bone interface rather than over the surface of the repair site. There was no significant difference in structural outcomes (evaluated by magnetic resonance imaging [MRI] re-tear rates) between those RCRs with and without PRP augmentation, except in those tears >3 cm in anterior-posterior length using double-row technique, with the PRP group exhibiting a significantly decreased re-tear rate (25.9% vs 57.1%).¹⁶ Zhao and colleagues¹⁷ reported similar results in a meta-analysis of 8 randomized controlled trials, exhibiting no significant differences in clinical outcome scores or re-tear rates after RCR with and without PRP augmentation. Overall, most studies have failed to demonstrate a significant benefit with regards to re-tear rates or shoulder-specific outcomes with the addition of PRP during arthroscopic RCR.

Knee Osteoarthritis

Osteoarthritis is the most common musculoskeletal disorder, with an estimated prevalence of 10% of the world’s population age 60 years and older.¹⁸ The knee is commonly symptomatic, resulting in pain, disability, and significant healthcare costs. Novel biologic, nonoperative therapies, including intra-articular viscosupplementation and PRP injections, have been proposed to treat the early stages of osteoarthritis to provide symptomatic relief and delay surgical intervention.

A multitude of studies have been performed investigating the effects of PRP on knee osteoarthritis, revealing mixed results.^19-22 Campbell and colleagues²³ published a 2015 systematic review of 3 overlapping meta-analyses comparing the outcomes of intra-articular injection of PRP vs control (hyaluronic acid [HA] or placebo) in 3278 knees. They reported a significant improvement in patient outcome scores for the PRP group when compared to control from 2 to 12 months after injection, but due to significant differences within the included studies, the ideal number of injections or time intervals between injections remains unclear. Meheux and colleagues²⁴ reported a 2016 systematic review including 6 studies (817 knees) comparing PRP and HA injections. They demonstrated significantly better improvements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores with PRP vs HA injections at 3 and 12 months postinjection. Similarly, Smith²⁵ conducted a Food and Drug Administration-sanctioned, randomized, double-blind, placebo-controlled clinical trial investigating the effects of intra-articular leukocyte-poor autologous conditioned plasma (ACP) in 30 patients. He reported an improvement in the ACP treatment group WOMAC scores by 78% compared to 7% improvement in the placebo group after 12 months. Despite the heterogeneity amongst studies, the majority of published data suggests better symptomatic relief in patients with early knee degenerative changes, and use of PRP may be considered in this population.

Ulnar Collateral Ligament Injuries

The anterior band of the UCL of the elbow provides stability to valgus stress. Overhead, high-velocity throwing athletes may cause repetitive injury to the UCL, resulting in partial or complete tears of the ligament. This may result in medial elbow pain, as well as decreased throwing velocity and accuracy. Athletes with complete UCL tears have few nonoperative treatment options and generally, operative treatment with UCL reconstruction is recommended for those athletes desiring to return to sport. However, it remains unclear how to definitively treat athletes with partial UCL tears. Recently, there has been an interest in treating these injuries with PRP in conjunction with physical therapy to facilitate a more predictable outcome.

Podesta and colleagues²⁶ published a case series of 34 athletes with MRI-diagnosed partial UCL tears who underwent ultrasound-guided UCL injections and physical therapy. At an average follow-up of 70 weeks, they reported an average return to play (RTP) of 12 weeks, with significant improvements in Kerlan-Jobe Orthopaedic Clinic (KJOC) and DASH outcome scores, and decreased dynamic ulnohumeral joint widening to valgus stress on ultrasound. Most athletes (30/34) returned to their previous level of play, and 1 patient underwent subsequent UCL reconstruction. This study demonstrates that PRP may be used in conjunction with physical therapy and an interval throwing program for the treatment of partial UCL tears, but without a comparison control group, more studies are necessary to delineate the role of PRP in this population.

Lateral Elbow Epicondylitis

Lateral elbow epicondylitis, also known as “tennis elbow,” is thought to be caused by repetitive wrist extension and is more likely to present in patients with various comorbidities such as rotator cuff pathology or a history of smoking.^27-29 The condition typically presents as radiating pain centered about the lateral epicondyle. Annual incidence ranges from 0.34% to 3%, with the most recent large-scale, population-based study estimating that nearly 1 million individuals in the United States develop lateral elbow epicondylitis each year.³⁰ For the majority of patients, symptoms resolve after 6 to 12 months of various nonoperative or minimally invasive treatments.^31-33 Those who develop chronic symptoms (>12 months) may benefit from surgical intervention.³⁴ The use of PRP has become a contentious topic of debate in treating lateral epicondylitis. Its use and efficacy have been empirically examined and compared among more traditional treatments.^35-37

In a small case-series of 6 patients, contrast-enhanced ultrasound imaging was utilized to demonstrate that PRP injection therapy may induce vascularization of the myotendinous junction of the common extensor tendon up to 6 months following injection.³⁸ These physiologic changes may precede observable clinical improvements. Brklijac and colleagues³⁹ prospectively followed 34 patients who had refractory symptoms despite conservative treatment and elected to undergo injection with PRP. At a mean follow-up of 26 weeks, 88.2% of the patients demonstrated improvements on their Oxford Elbow Score (OES). While potentially promising, case series lack large sample sizes, longitudinal analysis, and adequate control groups for comparative analyses of treatments, thereby increasing the likelihood of unintended selection bias.

Randomized controlled trials have demonstrated no difference between PRP and corticosteroid (CS) injection treatments in the short term for symptomatic lateral elbow epicondylitis. At 15 days, 1 month, and 6 months postinjection, no significant difference was found between PRP and CS injections in dynamometer strength measurements nor patient outcome scores (VAS, DASH, OES, and Mayo Clinic Performance Index for Elbow [MMCPIE]).^40,41 In fact, multiple randomized controlled trials have demonstrated PRP to be less effective at 1 and 3 months compared to CS injections, as assessed by the Patient Rated Tennis-Elbow Evaluation (PRTEE) questionnaire, VAS, MMCPIE, and Nirschl scores.^42,43 One mid-term, multi-center randomized controlled trial published by Mishra and colleagues⁴⁴ compared PRP injections to an active control group, demonstrating a significant improvement in VAS pain scores at 24 weeks, but no difference in the PRTEE outcome. The available evidence indicates PRP injection therapy remains limited in utility for treatment of lateral epicondylitis, particularly in the short term when compared to CS injections. In the midterm to long term, PRP therapy may provide some benefit, but ultimately, well-designed prospective randomized controlled trials are needed to delineate the effects of PRP versus the natural course of tendon healing and symptom resolution.

Hamstring Injuries

Acute hamstring injuries are common across all levels and types of sport, particularly those in which sprinting or running is involved. While there is no consensus within the literature on how RTP after hamstring injury should be managed or defined, most injuries seem to resolve around 3 to 6 weeks.⁴⁵ The proximal myotendinous junction of the long head of the biceps femoris and semitendinosus are commonly associated with significant pain and edema after acute hamstring injury.⁴⁶ The amount of edema resulting from grade 1 and 2 hamstring injuries has been found to correlate (minimally) with time to RTP in elite athletes.⁴⁷ PRP injection near the proximal myotendinous hamstring origin has been theorized to help speed the recovery process after acute hamstring injury. To date, the literature demonstrates mixed and limited benefit of PRP injection therapy for acute hamstring injury.

Few studies have shown improvements of PRP therapy over typical nonoperative management (rest, physical therapy, nonsteroidal anti-inflammatory drugs) in acute hamstring injury, but the results must be interpreted carefully.^48,49 Wetzel and colleagues⁴⁸ retrospectively reviewed 17 patients with acute hamstring injury, 12 of whom failed typical management and received PRP injection at the hamstring origin. This group demonstrated significant improvements in their VAS and Nirschl scores at follow-up, whereas the 5 patients who did not receive the injection did not. However, this study exhibited significant limitations inherent to a retrospective review with a small sample size. Hamid and colleagues⁴⁹ conducted a randomized controlled trial of 24 athletes with diagnosed grade 2a acute hamstring injuries, comparing autologous PRP therapy combined with a rehabilitation program versus rehabilitation program alone. RTP, changes in pain severity (Brief Pain Injury-Short Form [BPI-SF] questions 2-6), and pain interference (BPI-SF questions 9A-9G) scores over time were examined. Athletes in the PRP group exhibited no difference in outcomes scores, but returned to play sooner than controls (26.7 vs 42.5 days).

Mejia and Bradley⁵⁰ have reported their experience in treating 12 National Football League (NFL) players with acute MRI grade 1 or 2 hamstring injuries with a series of PRP injections at the site of injury. They found a 1-game difference in earlier RTP when compared to the predicted RTP based on MRI grading. Similarly, Hamid and colleagues⁴⁹ performed a randomized control trial published in 2014, reporting an earlier RTP (26.7 vs 42.5 days) when comparing single PRP injection vs rehabilitation alone in 28 patients diagnosed with acute ultrasound grade 2 hamstring injuries. On the contrary, a small case-control study of NFL players and a retrospective cohort study of athletes with severe hamstring injuries demonstrated no difference in RTP when PRP injected patients were compared with controls.^51,52 Larger randomized controlled trials have demonstrated comparable results, including a study of 90 professional athletes in whom a single PRP injection did not decrease RTP or lessen the risk of re-injury at 2 and 6 months.⁵³ In another large multicenter randomized controlled trial examining 80 competitive and recreational athletes, PRP did not accelerate RTP, lessen the risk of 2-month or 1-year re-injury rate, or improve secondary measures of MRI parameters, subjective patient satisfaction, or the hamstring outcome score.⁵⁴ Although further study is warranted, available evidence suggests limited utility of PRP injection in the treatment of acute hamstring injuries.

Achilles Tendinopathy

Noninsertional Achilles tendinopathy is a common source of pain for both recreational and competitive athletes. Typically thought of as an overuse syndrome, Achilles tendinopathy may result in significant pain and swelling, often at the site of its tenuous blood supply, approximately 2 to 7 cm proximal to its insertion.⁵⁵ Conservative management frequently begins with rest, activity/shoe modification, physical therapy, and eccentric loading exercises.⁵⁶ For those whom conservative management has failed to reduce symptoms after 6 months, more invasive treatment options may be considered. Peritendinous PRP injection has become an alternative approach in treating Achilles tendinopathy refractory to conservative treatment.

In the few randomized controlled trials published, the data demonstrates no significant improvements in clinical outcomes from PRP injection for Achilles tendinopathy. Kearney and colleagues⁵⁷ conducted a pilot study of 20 patients randomized into PRP injection or eccentric loading program for mid-substance Achilles tendinopathy, in which Victorian Institute of Sports Assessment (VISA-A), EuroQol 5 dimensions questionnaire (EQ-5D), and complications associated with the injection were recorded at 6 weeks, 3 months, and 6 months. Although this was a pilot study with a small sample size, no significant difference was found between groups across these time periods. Similarly, de Vos and colleagues^58,59 conducted a double-blind randomized controlled trial of 54 patients with chronic mid-substance Achilles tendinopathy and randomized them into eccentric exercise therapy with either a PRP injection or a saline injected placebo groups. VISA-A scores were recorded and imaging parameters assessing tendon structure by ultrasonographic tissue characterization and color Doppler ultrasonography were taken with follow-up at 6, 12, and 24 weeks. VISA-A scores improved significantly in both groups after 24 weeks, but the difference was not statistically significant between groups. In addition, tendon structure and neovascularization (exhibited by color Doppler ultrasonography) improved in both groups, with no significant difference between groups. The current literature does not support the use of PRP in treatment of Achilles tendinopathy, as it has failed to reveal additional benefits over conventional treatment alone. Future prospective, well-designed randomized controlled trials with large sample sizes will need to be conducted to ultimately conclude whether or not PRP deserves a role in the treatment of Achilles tendinopathy.

Summary

In theory, the use of PRP within orthopedic surgery makes a great deal of sense to accelerate and augment the healing process of the aforementioned musculoskeletal injuries. However, the vast majority of published literature is Level III and IV evidence. Future research may provide the missing critical information of optimal growth factor, platelet, and leukocyte concentrations necessary for the desired effect, as well as the appropriate delivery method and timing of PRP application in different target tissues. Evidence-based guidelines to direct the use of PRP will benefit from more homogenous, repeatable, and randomized controlled trials.

Platelet-rich plasma (PRP) is a refined product of autologous blood with a platelet concentration greater than that of whole blood. It is prepared via plasmapheresis utilizing a 2-stage centrifugation process and more than 40 commercially available systems are marketed to concentrate whole blood to PRP.¹ It is rich in biologic factors (growth factors, cytokines, proteins, cellular components) essential to the body’s response to injury. For this reason, it was first used in oromaxillofacial surgery in the 1950s, but its effects on the musculoskeletal system have yet to be clearly elucidated.² However, this lack of clarity has not deterred its widespread use among orthopedic surgeons. In this review, we aim to delineate the current understanding of PRP and its proven effectiveness in the treatment of rotator cuff tears, knee osteoarthritis, ulnar collateral ligament (UCL) tears, lateral epicondylitis, hamstring injuries, and Achilles tendinopathy.

Rotator Cuff Tears

Rotator cuff tears are one of the most common etiologies for shoulder pain and disability. The incidence continues to increase with the active aging population.³ Rotator cuff tears treated with arthroscopic repair have exhibited satisfactory pain relief and functional outcomes.^4-7 Despite advances in fixation techniques, the quality and speed of tendon-to-bone healing remains unpredictable, with repaired tendons exhibiting inferior mechanical properties that are susceptible to re-tear.^8-10

Numerous studies have investigated PRP application during arthroscopic rotator cuff repair (RCR) in an attempt to enhance and accelerate the repair process.^11-15 However, wide variability exists among protocols of how and when PRP is utilized to augment the repair. Warth and colleagues¹⁶ performed a meta-analysis of 11 Level I/II studies evaluating RCR with PRP augmentation. With regards to clinical outcome scores, they found no significant difference in pre- and postoperative American Shoulder and Elbow Surgeons (ASES), Constant, Disability of the Arm, Shoulder and Hand (DASH), or visual analog scale (VAS) pain scores between those patients with or without PRP augmentation. However, they did note a significant increase in Constant scores when PRP was delivered to the tendon-bone interface rather than over the surface of the repair site. There was no significant difference in structural outcomes (evaluated by magnetic resonance imaging [MRI] re-tear rates) between those RCRs with and without PRP augmentation, except in those tears >3 cm in anterior-posterior length using double-row technique, with the PRP group exhibiting a significantly decreased re-tear rate (25.9% vs 57.1%).¹⁶ Zhao and colleagues¹⁷ reported similar results in a meta-analysis of 8 randomized controlled trials, exhibiting no significant differences in clinical outcome scores or re-tear rates after RCR with and without PRP augmentation. Overall, most studies have failed to demonstrate a significant benefit with regards to re-tear rates or shoulder-specific outcomes with the addition of PRP during arthroscopic RCR.

Knee Osteoarthritis

Osteoarthritis is the most common musculoskeletal disorder, with an estimated prevalence of 10% of the world’s population age 60 years and older.¹⁸ The knee is commonly symptomatic, resulting in pain, disability, and significant healthcare costs. Novel biologic, nonoperative therapies, including intra-articular viscosupplementation and PRP injections, have been proposed to treat the early stages of osteoarthritis to provide symptomatic relief and delay surgical intervention.

A multitude of studies have been performed investigating the effects of PRP on knee osteoarthritis, revealing mixed results.^19-22 Campbell and colleagues²³ published a 2015 systematic review of 3 overlapping meta-analyses comparing the outcomes of intra-articular injection of PRP vs control (hyaluronic acid [HA] or placebo) in 3278 knees. They reported a significant improvement in patient outcome scores for the PRP group when compared to control from 2 to 12 months after injection, but due to significant differences within the included studies, the ideal number of injections or time intervals between injections remains unclear. Meheux and colleagues²⁴ reported a 2016 systematic review including 6 studies (817 knees) comparing PRP and HA injections. They demonstrated significantly better improvements in Western Ontario and McMaster Universities Arthritis Index (WOMAC) outcome scores with PRP vs HA injections at 3 and 12 months postinjection. Similarly, Smith²⁵ conducted a Food and Drug Administration-sanctioned, randomized, double-blind, placebo-controlled clinical trial investigating the effects of intra-articular leukocyte-poor autologous conditioned plasma (ACP) in 30 patients. He reported an improvement in the ACP treatment group WOMAC scores by 78% compared to 7% improvement in the placebo group after 12 months. Despite the heterogeneity amongst studies, the majority of published data suggests better symptomatic relief in patients with early knee degenerative changes, and use of PRP may be considered in this population.

Ulnar Collateral Ligament Injuries

The anterior band of the UCL of the elbow provides stability to valgus stress. Overhead, high-velocity throwing athletes may cause repetitive injury to the UCL, resulting in partial or complete tears of the ligament. This may result in medial elbow pain, as well as decreased throwing velocity and accuracy. Athletes with complete UCL tears have few nonoperative treatment options and generally, operative treatment with UCL reconstruction is recommended for those athletes desiring to return to sport. However, it remains unclear how to definitively treat athletes with partial UCL tears. Recently, there has been an interest in treating these injuries with PRP in conjunction with physical therapy to facilitate a more predictable outcome.

Podesta and colleagues²⁶ published a case series of 34 athletes with MRI-diagnosed partial UCL tears who underwent ultrasound-guided UCL injections and physical therapy. At an average follow-up of 70 weeks, they reported an average return to play (RTP) of 12 weeks, with significant improvements in Kerlan-Jobe Orthopaedic Clinic (KJOC) and DASH outcome scores, and decreased dynamic ulnohumeral joint widening to valgus stress on ultrasound. Most athletes (30/34) returned to their previous level of play, and 1 patient underwent subsequent UCL reconstruction. This study demonstrates that PRP may be used in conjunction with physical therapy and an interval throwing program for the treatment of partial UCL tears, but without a comparison control group, more studies are necessary to delineate the role of PRP in this population.

Lateral Elbow Epicondylitis

Lateral elbow epicondylitis, also known as “tennis elbow,” is thought to be caused by repetitive wrist extension and is more likely to present in patients with various comorbidities such as rotator cuff pathology or a history of smoking.^27-29 The condition typically presents as radiating pain centered about the lateral epicondyle. Annual incidence ranges from 0.34% to 3%, with the most recent large-scale, population-based study estimating that nearly 1 million individuals in the United States develop lateral elbow epicondylitis each year.³⁰ For the majority of patients, symptoms resolve after 6 to 12 months of various nonoperative or minimally invasive treatments.^31-33 Those who develop chronic symptoms (>12 months) may benefit from surgical intervention.³⁴ The use of PRP has become a contentious topic of debate in treating lateral epicondylitis. Its use and efficacy have been empirically examined and compared among more traditional treatments.^35-37

In a small case-series of 6 patients, contrast-enhanced ultrasound imaging was utilized to demonstrate that PRP injection therapy may induce vascularization of the myotendinous junction of the common extensor tendon up to 6 months following injection.³⁸ These physiologic changes may precede observable clinical improvements. Brklijac and colleagues³⁹ prospectively followed 34 patients who had refractory symptoms despite conservative treatment and elected to undergo injection with PRP. At a mean follow-up of 26 weeks, 88.2% of the patients demonstrated improvements on their Oxford Elbow Score (OES). While potentially promising, case series lack large sample sizes, longitudinal analysis, and adequate control groups for comparative analyses of treatments, thereby increasing the likelihood of unintended selection bias.

Randomized controlled trials have demonstrated no difference between PRP and corticosteroid (CS) injection treatments in the short term for symptomatic lateral elbow epicondylitis. At 15 days, 1 month, and 6 months postinjection, no significant difference was found between PRP and CS injections in dynamometer strength measurements nor patient outcome scores (VAS, DASH, OES, and Mayo Clinic Performance Index for Elbow [MMCPIE]).^40,41 In fact, multiple randomized controlled trials have demonstrated PRP to be less effective at 1 and 3 months compared to CS injections, as assessed by the Patient Rated Tennis-Elbow Evaluation (PRTEE) questionnaire, VAS, MMCPIE, and Nirschl scores.^42,43 One mid-term, multi-center randomized controlled trial published by Mishra and colleagues⁴⁴ compared PRP injections to an active control group, demonstrating a significant improvement in VAS pain scores at 24 weeks, but no difference in the PRTEE outcome. The available evidence indicates PRP injection therapy remains limited in utility for treatment of lateral epicondylitis, particularly in the short term when compared to CS injections. In the midterm to long term, PRP therapy may provide some benefit, but ultimately, well-designed prospective randomized controlled trials are needed to delineate the effects of PRP versus the natural course of tendon healing and symptom resolution.

Hamstring Injuries

Acute hamstring injuries are common across all levels and types of sport, particularly those in which sprinting or running is involved. While there is no consensus within the literature on how RTP after hamstring injury should be managed or defined, most injuries seem to resolve around 3 to 6 weeks.⁴⁵ The proximal myotendinous junction of the long head of the biceps femoris and semitendinosus are commonly associated with significant pain and edema after acute hamstring injury.⁴⁶ The amount of edema resulting from grade 1 and 2 hamstring injuries has been found to correlate (minimally) with time to RTP in elite athletes.⁴⁷ PRP injection near the proximal myotendinous hamstring origin has been theorized to help speed the recovery process after acute hamstring injury. To date, the literature demonstrates mixed and limited benefit of PRP injection therapy for acute hamstring injury.

Few studies have shown improvements of PRP therapy over typical nonoperative management (rest, physical therapy, nonsteroidal anti-inflammatory drugs) in acute hamstring injury, but the results must be interpreted carefully.^48,49 Wetzel and colleagues⁴⁸ retrospectively reviewed 17 patients with acute hamstring injury, 12 of whom failed typical management and received PRP injection at the hamstring origin. This group demonstrated significant improvements in their VAS and Nirschl scores at follow-up, whereas the 5 patients who did not receive the injection did not. However, this study exhibited significant limitations inherent to a retrospective review with a small sample size. Hamid and colleagues⁴⁹ conducted a randomized controlled trial of 24 athletes with diagnosed grade 2a acute hamstring injuries, comparing autologous PRP therapy combined with a rehabilitation program versus rehabilitation program alone. RTP, changes in pain severity (Brief Pain Injury-Short Form [BPI-SF] questions 2-6), and pain interference (BPI-SF questions 9A-9G) scores over time were examined. Athletes in the PRP group exhibited no difference in outcomes scores, but returned to play sooner than controls (26.7 vs 42.5 days).

Mejia and Bradley⁵⁰ have reported their experience in treating 12 National Football League (NFL) players with acute MRI grade 1 or 2 hamstring injuries with a series of PRP injections at the site of injury. They found a 1-game difference in earlier RTP when compared to the predicted RTP based on MRI grading. Similarly, Hamid and colleagues⁴⁹ performed a randomized control trial published in 2014, reporting an earlier RTP (26.7 vs 42.5 days) when comparing single PRP injection vs rehabilitation alone in 28 patients diagnosed with acute ultrasound grade 2 hamstring injuries. On the contrary, a small case-control study of NFL players and a retrospective cohort study of athletes with severe hamstring injuries demonstrated no difference in RTP when PRP injected patients were compared with controls.^51,52 Larger randomized controlled trials have demonstrated comparable results, including a study of 90 professional athletes in whom a single PRP injection did not decrease RTP or lessen the risk of re-injury at 2 and 6 months.⁵³ In another large multicenter randomized controlled trial examining 80 competitive and recreational athletes, PRP did not accelerate RTP, lessen the risk of 2-month or 1-year re-injury rate, or improve secondary measures of MRI parameters, subjective patient satisfaction, or the hamstring outcome score.⁵⁴ Although further study is warranted, available evidence suggests limited utility of PRP injection in the treatment of acute hamstring injuries.

Achilles Tendinopathy

Noninsertional Achilles tendinopathy is a common source of pain for both recreational and competitive athletes. Typically thought of as an overuse syndrome, Achilles tendinopathy may result in significant pain and swelling, often at the site of its tenuous blood supply, approximately 2 to 7 cm proximal to its insertion.⁵⁵ Conservative management frequently begins with rest, activity/shoe modification, physical therapy, and eccentric loading exercises.⁵⁶ For those whom conservative management has failed to reduce symptoms after 6 months, more invasive treatment options may be considered. Peritendinous PRP injection has become an alternative approach in treating Achilles tendinopathy refractory to conservative treatment.

In the few randomized controlled trials published, the data demonstrates no significant improvements in clinical outcomes from PRP injection for Achilles tendinopathy. Kearney and colleagues⁵⁷ conducted a pilot study of 20 patients randomized into PRP injection or eccentric loading program for mid-substance Achilles tendinopathy, in which Victorian Institute of Sports Assessment (VISA-A), EuroQol 5 dimensions questionnaire (EQ-5D), and complications associated with the injection were recorded at 6 weeks, 3 months, and 6 months. Although this was a pilot study with a small sample size, no significant difference was found between groups across these time periods. Similarly, de Vos and colleagues^58,59 conducted a double-blind randomized controlled trial of 54 patients with chronic mid-substance Achilles tendinopathy and randomized them into eccentric exercise therapy with either a PRP injection or a saline injected placebo groups. VISA-A scores were recorded and imaging parameters assessing tendon structure by ultrasonographic tissue characterization and color Doppler ultrasonography were taken with follow-up at 6, 12, and 24 weeks. VISA-A scores improved significantly in both groups after 24 weeks, but the difference was not statistically significant between groups. In addition, tendon structure and neovascularization (exhibited by color Doppler ultrasonography) improved in both groups, with no significant difference between groups. The current literature does not support the use of PRP in treatment of Achilles tendinopathy, as it has failed to reveal additional benefits over conventional treatment alone. Future prospective, well-designed randomized controlled trials with large sample sizes will need to be conducted to ultimately conclude whether or not PRP deserves a role in the treatment of Achilles tendinopathy.

Summary

In theory, the use of PRP within orthopedic surgery makes a great deal of sense to accelerate and augment the healing process of the aforementioned musculoskeletal injuries. However, the vast majority of published literature is Level III and IV evidence. Future research may provide the missing critical information of optimal growth factor, platelet, and leukocyte concentrations necessary for the desired effect, as well as the appropriate delivery method and timing of PRP application in different target tissues. Evidence-based guidelines to direct the use of PRP will benefit from more homogenous, repeatable, and randomized controlled trials.

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.

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.

IN THIS ARTICLE

• Conditions associated with increased risk for case disease
• Outcome for the case patient
• Differential diagnosis

A 78-year-old white man with chronic lymphocytic leukemia is admitted to the hospital with worsening cough, shortness of breath, and fever. His medical history is significant for pneumonia caused by Pneumocystis jirovecii in the past year. In the weeks preceding hospital admission, the patient developed an erythematous rash over his trunk (see photographs).

During the man’s hospital stay, this eruption becomes increasingly pruritic and spreads to his proximal extremities. His pulmonary symptoms improve slightly following the initiation of broad-spectrum antibiotic therapy (piperacillin/tazobactam and vancomycin), but CT performed one week after admission reveals worsening pulmonary disease (see image). The radiologist’s differential diagnosis includes neoplasm, fungal infection, Kaposi sarcoma, and autoimmune disease.

A. The patient's back shows a distribution of lesions, with areas of excoriation caused by scratching.	B. A close-up reveals erythematous papules and keratotic papules.

Suspecting that the progressive rash is related to the systemic process, the provider orders a punch biopsy in an effort to reach a diagnosis with minimally invasive studies. When the patient’s clinical status further declines, he undergoes video-assisted thoracoscopic surgery to obtain an excisional biopsy of one of the pulmonary nodules. Subsequent analysis reveals fungal organisms consistent with histoplasmosis. Interestingly, in the histologic review of the skin biopsy, focal acantholytic dyskeratosis—suggestive of Grover disease—is identified.

Continue for discussion >>

DISCUSSION
Grover disease (GD), also known as transient acantholytic dermatosis, is a skin condition of uncertain pathophysiology. Its clinical presentation can be difficult to distinguish from other dermopathies.^1,2

Incidence
GD most commonly appears in fair-skinned persons of late middle age, with men affected at two to three times the rate seen in women.^1,2 Although GD has been documented in patients ranging in age from 4 to 100, this dermopathy is rare in younger patients.^1-3 Persons with a prior history of atopic dermatitis, contact dermatitis, or xerosis cutis are at increased risk for GD—likely due to an increased dermatologic sensitivity to irritants resulting from the aforementioned disorders.^1,4 Risk for GD is also elevated in patients with chronic medical conditions, immunodeficiency, febrile illnesses, or malignancies (see Table 1).^2-5

The true incidence of GD is not known; biopsy-proven GD is uncommon, and specific data on the incidence and prevalence of the condition are lacking. Swiss researchers who reviewed more than 30,000 skin biopsies in the late 1990s noted only 24 diagnosed cases of GD, and similar findings have been reported in the United States.^1,6 However, the variable presentation and often mild nature of GD may result in cases of misdiagnosis, lack of diagnosis, or empiric treatment in the absence of a formal diagnosis.⁷

Causative factors
Although the pathophysiology of GD is uncertain, the most likely cause is an occlusion of the eccrine glands.³ This is followed by acantholysis, or separation of keratinocytes within the epidermis, which in turn leads to the development of vesicular lesions.

Though diagnosed most often in the winter, GD has also been associated with exposure to sunlight, heat, xerosis, and diaphoresis.^1,3 Hospitalized or bedridden patients are at risk for occlusion of the eccrine glands and thus for GD. Use of certain therapies, including sulfadoxine/pyrimethamine (an antimalarial treatment), ionizing radiation, and interleukin-4, may also be precursors for the condition.²

Other exacerbating factors have been suggested, but reports are largely limited to case studies and other anecdotal publications.² Concrete data regarding the etiology and pathophysiology of GD are still relatively scarce.

Clinical presentation
Patients with GD present with pruritic dermatitis on the trunk and proximal extremities, most classically on the anterior chest and mid back.^2,3 The severity of the rash does not necessarily correlate to the degree of pruritus. Some patients report only mild pruritus, while others experience debilitating discomfort and pain. In most cases, erythematous and violaceous papules and vesicles appear first, followed by keratotic erosions.³

GD is a self-limited disorder that often resolves within a few weeks, although some cases will persist for several months.^3,5 Severity and duration of symptoms appear to be correlated with increasing age; elderly patients experience worse pruritus for longer periods than do younger patients.²

Although the condition is sometimes referred to as transient acantholytic dermatosis, there are three typical presentations of GD: transient eruptive, persistent pruritic, and chronic asymptomatic.⁴ Transient eruptive GD presents suddenly, with intense pruritus, and tends to subside over several weeks. Persistent pruritic disease generally causes a milder pruritus, with symptoms that last for several months and are not well controlled by medication. Chronic asymptomatic GD can be difficult to treat medically, yet this form of the disease typically causes little to no irritation and requires minimal therapeutic intervention.⁴

Systemic symptoms of GD have not been observed. Pruritus and rash are the main features in most affected patients. However, pruritic papulovesicular eruptions are commonly seen in other conditions with similar characteristics (see Table 2,^3,4), and GD is comparatively rare. While clinical appearance alone may suggest a diagnosis of GD, further testing may be needed to eliminate other conditions from the differential.

Treatment and prognosis
In the absence of randomized therapeutic trials for GD, there are no strict guidelines for treatment. When irritation, inflammation, and pruritus become bothersome, several interventions may be considered. The first step may consist of efforts to modify aggravating factors, such as dry skin, occlusion, excess heat, and rapid temperature changes. Indeed, for mild cases of GD, this may be all that is required.

The firstline pharmacotherapy for GD is medium- to high-potency topical corticosteroids, which reduce inflammation and pruritus in approximately half of affected patients.^3,6,8 Topical emollients and oral antihistamines can also provide symptom relief. Vitamin D analogues are considered secondline therapy, and retinoids (both topical and systemic) have also been shown to reduce GD severity.^3,4,8

Severe, refractory cases may require more aggressive systemic therapy with corticosteroids or retinoids. For pruritic relief, several weeks of oral corticosteroids may be necessary—and GD may rebound after treatment ceases.^3,4 Therefore, oral corticosteroids should only be considered for severe or persistent cases, since the systemic adverse effects (eg, immunosuppression, weight gain, dysglycemia) of these drugs may outweigh the benefits in patients with GD. Other interventions, including phototherapy and immunosuppressive drugs (eg, etanercept) have also demonstrated benefit in select patients.^4,9,10

The self-limited nature of GD, along with its lack of systemic symptoms, is associated with a generally benign course of disease and no long-term sequelae.^3,5

Continue to outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
This case involved an immunocompromised patient with systemic symptoms, vasculitic cutaneous lesions, and significant pulmonary disease. The differential diagnosis was extensive, and diagnosis based on clinical grounds alone was extremely challenging. In these circumstances, diagnostic testing was essential to reach a final diagnosis.

In this case, the skin biopsy yielded a diagnosis of GD, and the rash was found to be unrelated to the patient’s systemic and pulmonary symptoms. The providers were then able to focus on the diagnosis of histoplasmosis, with only minimal intervention for the patient’s GD (ie, oral diphenhydramine prn for pruritus).

CONCLUSION
In many cases of GD, skin biopsy can guide providers when the history and physical examination do not yield a clear diagnosis. The histopathology of affected tissue can provide invaluable information about an underlying disease process, particularly in complex cases such as this patient’s. Skin biopsy provides a minimally invasive opportunity to obtain a diagnosis in patients with a condition that affects multiple organ systems, and its use should be considered in disease processes with cutaneous manifestations.

REFERENCES
1. Scheinfeld N, Mones J. Seasonal variation of transient acantholytic dyskeratosis (Grover’s disease). J Am Acad Dermatol. 2006;55(2): 263-268.
2. Parsons JM. Transient acantholytic dermatosis (Grover’s disease): a global perspective. J Am Acad Dermatol. 1996;35(5 part 1):653-666.
3. Weaver J, Bergfeld WF. Grover disease (transient acantholytic dermatosis). Arch Pathol Lab Med. 2009;133(9):1490-1494.
4. Quirk CJ, Heenan PJ. Grover’s disease: 34 years on. Australas J Dermatol. 2004;45(2):83-86.
5. Ippoliti G, Paulli M, Lucioni M, et al. Grover’s disease after heart transplantation: a case report. Case Rep Transplant. 2012;2012:126592.
6. Streit M, Paredes BE, Braathen LR, Brand CU. Transitory acantholytic dermatosis (Grover’s disease): an analysis of the clinical spectrum based on 21 histologically assessed cases [in German]. Hautarzt. 2000;51:244-249.
7. Joshi R, Taneja A. Grover’s disease with acrosyringeal acantholysis: a rare histological presentation of an uncommon disease. Indian J Dermatol. 2014;59(6):621-623.
8. Riemann H, High WA. Grover’s disease (transient and persistent acantholytic dermatosis). UpToDate. 2015. www.uptodate.com/contents/grovers-disease-transient-and-persistent-acantholytic-dermatosis. Accessed June 4, 2016.
9. Breuckmann F, Appelhans C, Altmeyer P, Kreuter A. Medium-dose ultraviolet A1 phototherapy in transient acantholytic dermatosis (Grover’s disease). J Am Acad Dermatol. 2005;52(1):169-170.
10. Norman R, Chau V. Use of etanercept in treating pruritus and preventing new lesions in Grover disease. J Am Acad Dermatol. 2011;64(4):796-798.

IN THIS ARTICLE

• Conditions associated with increased risk for case disease
• Outcome for the case patient
• Differential diagnosis

A 78-year-old white man with chronic lymphocytic leukemia is admitted to the hospital with worsening cough, shortness of breath, and fever. His medical history is significant for pneumonia caused by Pneumocystis jirovecii in the past year. In the weeks preceding hospital admission, the patient developed an erythematous rash over his trunk (see photographs).

During the man’s hospital stay, this eruption becomes increasingly pruritic and spreads to his proximal extremities. His pulmonary symptoms improve slightly following the initiation of broad-spectrum antibiotic therapy (piperacillin/tazobactam and vancomycin), but CT performed one week after admission reveals worsening pulmonary disease (see image). The radiologist’s differential diagnosis includes neoplasm, fungal infection, Kaposi sarcoma, and autoimmune disease.

A. The patient's back shows a distribution of lesions, with areas of excoriation caused by scratching.	B. A close-up reveals erythematous papules and keratotic papules.

Suspecting that the progressive rash is related to the systemic process, the provider orders a punch biopsy in an effort to reach a diagnosis with minimally invasive studies. When the patient’s clinical status further declines, he undergoes video-assisted thoracoscopic surgery to obtain an excisional biopsy of one of the pulmonary nodules. Subsequent analysis reveals fungal organisms consistent with histoplasmosis. Interestingly, in the histologic review of the skin biopsy, focal acantholytic dyskeratosis—suggestive of Grover disease—is identified.

Continue for discussion >>

DISCUSSION
Grover disease (GD), also known as transient acantholytic dermatosis, is a skin condition of uncertain pathophysiology. Its clinical presentation can be difficult to distinguish from other dermopathies.^1,2

Incidence
GD most commonly appears in fair-skinned persons of late middle age, with men affected at two to three times the rate seen in women.^1,2 Although GD has been documented in patients ranging in age from 4 to 100, this dermopathy is rare in younger patients.^1-3 Persons with a prior history of atopic dermatitis, contact dermatitis, or xerosis cutis are at increased risk for GD—likely due to an increased dermatologic sensitivity to irritants resulting from the aforementioned disorders.^1,4 Risk for GD is also elevated in patients with chronic medical conditions, immunodeficiency, febrile illnesses, or malignancies (see Table 1).^2-5

The true incidence of GD is not known; biopsy-proven GD is uncommon, and specific data on the incidence and prevalence of the condition are lacking. Swiss researchers who reviewed more than 30,000 skin biopsies in the late 1990s noted only 24 diagnosed cases of GD, and similar findings have been reported in the United States.^1,6 However, the variable presentation and often mild nature of GD may result in cases of misdiagnosis, lack of diagnosis, or empiric treatment in the absence of a formal diagnosis.⁷

Causative factors
Although the pathophysiology of GD is uncertain, the most likely cause is an occlusion of the eccrine glands.³ This is followed by acantholysis, or separation of keratinocytes within the epidermis, which in turn leads to the development of vesicular lesions.

Though diagnosed most often in the winter, GD has also been associated with exposure to sunlight, heat, xerosis, and diaphoresis.^1,3 Hospitalized or bedridden patients are at risk for occlusion of the eccrine glands and thus for GD. Use of certain therapies, including sulfadoxine/pyrimethamine (an antimalarial treatment), ionizing radiation, and interleukin-4, may also be precursors for the condition.²

Other exacerbating factors have been suggested, but reports are largely limited to case studies and other anecdotal publications.² Concrete data regarding the etiology and pathophysiology of GD are still relatively scarce.

Clinical presentation
Patients with GD present with pruritic dermatitis on the trunk and proximal extremities, most classically on the anterior chest and mid back.^2,3 The severity of the rash does not necessarily correlate to the degree of pruritus. Some patients report only mild pruritus, while others experience debilitating discomfort and pain. In most cases, erythematous and violaceous papules and vesicles appear first, followed by keratotic erosions.³

GD is a self-limited disorder that often resolves within a few weeks, although some cases will persist for several months.^3,5 Severity and duration of symptoms appear to be correlated with increasing age; elderly patients experience worse pruritus for longer periods than do younger patients.²

Although the condition is sometimes referred to as transient acantholytic dermatosis, there are three typical presentations of GD: transient eruptive, persistent pruritic, and chronic asymptomatic.⁴ Transient eruptive GD presents suddenly, with intense pruritus, and tends to subside over several weeks. Persistent pruritic disease generally causes a milder pruritus, with symptoms that last for several months and are not well controlled by medication. Chronic asymptomatic GD can be difficult to treat medically, yet this form of the disease typically causes little to no irritation and requires minimal therapeutic intervention.⁴

Systemic symptoms of GD have not been observed. Pruritus and rash are the main features in most affected patients. However, pruritic papulovesicular eruptions are commonly seen in other conditions with similar characteristics (see Table 2,^3,4), and GD is comparatively rare. While clinical appearance alone may suggest a diagnosis of GD, further testing may be needed to eliminate other conditions from the differential.

Treatment and prognosis
In the absence of randomized therapeutic trials for GD, there are no strict guidelines for treatment. When irritation, inflammation, and pruritus become bothersome, several interventions may be considered. The first step may consist of efforts to modify aggravating factors, such as dry skin, occlusion, excess heat, and rapid temperature changes. Indeed, for mild cases of GD, this may be all that is required.

The firstline pharmacotherapy for GD is medium- to high-potency topical corticosteroids, which reduce inflammation and pruritus in approximately half of affected patients.^3,6,8 Topical emollients and oral antihistamines can also provide symptom relief. Vitamin D analogues are considered secondline therapy, and retinoids (both topical and systemic) have also been shown to reduce GD severity.^3,4,8

Severe, refractory cases may require more aggressive systemic therapy with corticosteroids or retinoids. For pruritic relief, several weeks of oral corticosteroids may be necessary—and GD may rebound after treatment ceases.^3,4 Therefore, oral corticosteroids should only be considered for severe or persistent cases, since the systemic adverse effects (eg, immunosuppression, weight gain, dysglycemia) of these drugs may outweigh the benefits in patients with GD. Other interventions, including phototherapy and immunosuppressive drugs (eg, etanercept) have also demonstrated benefit in select patients.^4,9,10

The self-limited nature of GD, along with its lack of systemic symptoms, is associated with a generally benign course of disease and no long-term sequelae.^3,5

Continue to outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
This case involved an immunocompromised patient with systemic symptoms, vasculitic cutaneous lesions, and significant pulmonary disease. The differential diagnosis was extensive, and diagnosis based on clinical grounds alone was extremely challenging. In these circumstances, diagnostic testing was essential to reach a final diagnosis.

In this case, the skin biopsy yielded a diagnosis of GD, and the rash was found to be unrelated to the patient’s systemic and pulmonary symptoms. The providers were then able to focus on the diagnosis of histoplasmosis, with only minimal intervention for the patient’s GD (ie, oral diphenhydramine prn for pruritus).

CONCLUSION
In many cases of GD, skin biopsy can guide providers when the history and physical examination do not yield a clear diagnosis. The histopathology of affected tissue can provide invaluable information about an underlying disease process, particularly in complex cases such as this patient’s. Skin biopsy provides a minimally invasive opportunity to obtain a diagnosis in patients with a condition that affects multiple organ systems, and its use should be considered in disease processes with cutaneous manifestations.

REFERENCES
1. Scheinfeld N, Mones J. Seasonal variation of transient acantholytic dyskeratosis (Grover’s disease). J Am Acad Dermatol. 2006;55(2): 263-268.
2. Parsons JM. Transient acantholytic dermatosis (Grover’s disease): a global perspective. J Am Acad Dermatol. 1996;35(5 part 1):653-666.
3. Weaver J, Bergfeld WF. Grover disease (transient acantholytic dermatosis). Arch Pathol Lab Med. 2009;133(9):1490-1494.
4. Quirk CJ, Heenan PJ. Grover’s disease: 34 years on. Australas J Dermatol. 2004;45(2):83-86.
5. Ippoliti G, Paulli M, Lucioni M, et al. Grover’s disease after heart transplantation: a case report. Case Rep Transplant. 2012;2012:126592.
6. Streit M, Paredes BE, Braathen LR, Brand CU. Transitory acantholytic dermatosis (Grover’s disease): an analysis of the clinical spectrum based on 21 histologically assessed cases [in German]. Hautarzt. 2000;51:244-249.
7. Joshi R, Taneja A. Grover’s disease with acrosyringeal acantholysis: a rare histological presentation of an uncommon disease. Indian J Dermatol. 2014;59(6):621-623.
8. Riemann H, High WA. Grover’s disease (transient and persistent acantholytic dermatosis). UpToDate. 2015. www.uptodate.com/contents/grovers-disease-transient-and-persistent-acantholytic-dermatosis. Accessed June 4, 2016.
9. Breuckmann F, Appelhans C, Altmeyer P, Kreuter A. Medium-dose ultraviolet A1 phototherapy in transient acantholytic dermatosis (Grover’s disease). J Am Acad Dermatol. 2005;52(1):169-170.
10. Norman R, Chau V. Use of etanercept in treating pruritus and preventing new lesions in Grover disease. J Am Acad Dermatol. 2011;64(4):796-798.

IN THIS ARTICLE

• Conditions associated with increased risk for case disease
• Outcome for the case patient
• Differential diagnosis

A 78-year-old white man with chronic lymphocytic leukemia is admitted to the hospital with worsening cough, shortness of breath, and fever. His medical history is significant for pneumonia caused by Pneumocystis jirovecii in the past year. In the weeks preceding hospital admission, the patient developed an erythematous rash over his trunk (see photographs).

During the man’s hospital stay, this eruption becomes increasingly pruritic and spreads to his proximal extremities. His pulmonary symptoms improve slightly following the initiation of broad-spectrum antibiotic therapy (piperacillin/tazobactam and vancomycin), but CT performed one week after admission reveals worsening pulmonary disease (see image). The radiologist’s differential diagnosis includes neoplasm, fungal infection, Kaposi sarcoma, and autoimmune disease.

A. The patient's back shows a distribution of lesions, with areas of excoriation caused by scratching.	B. A close-up reveals erythematous papules and keratotic papules.

Suspecting that the progressive rash is related to the systemic process, the provider orders a punch biopsy in an effort to reach a diagnosis with minimally invasive studies. When the patient’s clinical status further declines, he undergoes video-assisted thoracoscopic surgery to obtain an excisional biopsy of one of the pulmonary nodules. Subsequent analysis reveals fungal organisms consistent with histoplasmosis. Interestingly, in the histologic review of the skin biopsy, focal acantholytic dyskeratosis—suggestive of Grover disease—is identified.

Continue for discussion >>

DISCUSSION
Grover disease (GD), also known as transient acantholytic dermatosis, is a skin condition of uncertain pathophysiology. Its clinical presentation can be difficult to distinguish from other dermopathies.^1,2

Incidence
GD most commonly appears in fair-skinned persons of late middle age, with men affected at two to three times the rate seen in women.^1,2 Although GD has been documented in patients ranging in age from 4 to 100, this dermopathy is rare in younger patients.^1-3 Persons with a prior history of atopic dermatitis, contact dermatitis, or xerosis cutis are at increased risk for GD—likely due to an increased dermatologic sensitivity to irritants resulting from the aforementioned disorders.^1,4 Risk for GD is also elevated in patients with chronic medical conditions, immunodeficiency, febrile illnesses, or malignancies (see Table 1).^2-5

The true incidence of GD is not known; biopsy-proven GD is uncommon, and specific data on the incidence and prevalence of the condition are lacking. Swiss researchers who reviewed more than 30,000 skin biopsies in the late 1990s noted only 24 diagnosed cases of GD, and similar findings have been reported in the United States.^1,6 However, the variable presentation and often mild nature of GD may result in cases of misdiagnosis, lack of diagnosis, or empiric treatment in the absence of a formal diagnosis.⁷

Causative factors
Although the pathophysiology of GD is uncertain, the most likely cause is an occlusion of the eccrine glands.³ This is followed by acantholysis, or separation of keratinocytes within the epidermis, which in turn leads to the development of vesicular lesions.

Though diagnosed most often in the winter, GD has also been associated with exposure to sunlight, heat, xerosis, and diaphoresis.^1,3 Hospitalized or bedridden patients are at risk for occlusion of the eccrine glands and thus for GD. Use of certain therapies, including sulfadoxine/pyrimethamine (an antimalarial treatment), ionizing radiation, and interleukin-4, may also be precursors for the condition.²

Other exacerbating factors have been suggested, but reports are largely limited to case studies and other anecdotal publications.² Concrete data regarding the etiology and pathophysiology of GD are still relatively scarce.

Clinical presentation
Patients with GD present with pruritic dermatitis on the trunk and proximal extremities, most classically on the anterior chest and mid back.^2,3 The severity of the rash does not necessarily correlate to the degree of pruritus. Some patients report only mild pruritus, while others experience debilitating discomfort and pain. In most cases, erythematous and violaceous papules and vesicles appear first, followed by keratotic erosions.³

GD is a self-limited disorder that often resolves within a few weeks, although some cases will persist for several months.^3,5 Severity and duration of symptoms appear to be correlated with increasing age; elderly patients experience worse pruritus for longer periods than do younger patients.²

Although the condition is sometimes referred to as transient acantholytic dermatosis, there are three typical presentations of GD: transient eruptive, persistent pruritic, and chronic asymptomatic.⁴ Transient eruptive GD presents suddenly, with intense pruritus, and tends to subside over several weeks. Persistent pruritic disease generally causes a milder pruritus, with symptoms that last for several months and are not well controlled by medication. Chronic asymptomatic GD can be difficult to treat medically, yet this form of the disease typically causes little to no irritation and requires minimal therapeutic intervention.⁴

Systemic symptoms of GD have not been observed. Pruritus and rash are the main features in most affected patients. However, pruritic papulovesicular eruptions are commonly seen in other conditions with similar characteristics (see Table 2,^3,4), and GD is comparatively rare. While clinical appearance alone may suggest a diagnosis of GD, further testing may be needed to eliminate other conditions from the differential.

Treatment and prognosis
In the absence of randomized therapeutic trials for GD, there are no strict guidelines for treatment. When irritation, inflammation, and pruritus become bothersome, several interventions may be considered. The first step may consist of efforts to modify aggravating factors, such as dry skin, occlusion, excess heat, and rapid temperature changes. Indeed, for mild cases of GD, this may be all that is required.

The firstline pharmacotherapy for GD is medium- to high-potency topical corticosteroids, which reduce inflammation and pruritus in approximately half of affected patients.^3,6,8 Topical emollients and oral antihistamines can also provide symptom relief. Vitamin D analogues are considered secondline therapy, and retinoids (both topical and systemic) have also been shown to reduce GD severity.^3,4,8

Severe, refractory cases may require more aggressive systemic therapy with corticosteroids or retinoids. For pruritic relief, several weeks of oral corticosteroids may be necessary—and GD may rebound after treatment ceases.^3,4 Therefore, oral corticosteroids should only be considered for severe or persistent cases, since the systemic adverse effects (eg, immunosuppression, weight gain, dysglycemia) of these drugs may outweigh the benefits in patients with GD. Other interventions, including phototherapy and immunosuppressive drugs (eg, etanercept) have also demonstrated benefit in select patients.^4,9,10

The self-limited nature of GD, along with its lack of systemic symptoms, is associated with a generally benign course of disease and no long-term sequelae.^3,5

Continue to outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
This case involved an immunocompromised patient with systemic symptoms, vasculitic cutaneous lesions, and significant pulmonary disease. The differential diagnosis was extensive, and diagnosis based on clinical grounds alone was extremely challenging. In these circumstances, diagnostic testing was essential to reach a final diagnosis.

In this case, the skin biopsy yielded a diagnosis of GD, and the rash was found to be unrelated to the patient’s systemic and pulmonary symptoms. The providers were then able to focus on the diagnosis of histoplasmosis, with only minimal intervention for the patient’s GD (ie, oral diphenhydramine prn for pruritus).

CONCLUSION
In many cases of GD, skin biopsy can guide providers when the history and physical examination do not yield a clear diagnosis. The histopathology of affected tissue can provide invaluable information about an underlying disease process, particularly in complex cases such as this patient’s. Skin biopsy provides a minimally invasive opportunity to obtain a diagnosis in patients with a condition that affects multiple organ systems, and its use should be considered in disease processes with cutaneous manifestations.

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