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The Use of Biological Approaches in the Treatment of Shoulder Pathology A Critical Analysis Review

Jonas Pogorzelski, MD, MHBA Abstract » The major pathological conditions affecting the shoulder that are Jonathan A. Godin, MD, MBA treated with use of biological applications include focal cartilage Erik M. Fritz, MD lesions and rotator cuff tears. Biological modalities that previously have been used or investigated include platelet-rich plasma (PRP), growth Mark E. Cinque, MS factors, progenitor cells, bone-marrow stimulation, autologous chon- Jorge Chahla, MD drocyte implantation (ACI), matrix-induced ACI (MACI), and biological scaffolds. Johnny Huard, PhD Peter J. Millett, MD, MSc » Marrow-stimulating procedures have been reported to yield positive results when used for the treatment of focal cartilage lesions of the glenoid or humeral head. Limited data are available on the use of PRP, Investigation performed at the ACI, and MACI for the treatment of chondral lesions involving the Steadman Philippon Research shoulder, and therefore no conclusions can be drawn regarding the Institute, Vail, Colorado efficacy of these modalities. » Preclinical and in vitro studies have demonstrated that modulation of growth factors may be helpful for rotator cuff tear healing; however, the optimal modulation and delivery vehicle remain to be elucidated. PRP has received much research attention; however, most studies have been hindered by study setup and conflicting results. Therefore, the use of PRP to enhance rotator cuff healing remains controversial. Progenitor cells have shown positive results in a small number of preclinical and clinical studies, but further research is needed before conclusions can be drawn.

» In summary, basic-science studies investigating biological factors to enhance healing in the shoulder have shown potential. However, clinical data are still limited, contradictory, and controversial. Addi- tional research is needed. Most importantly, robust, consistent, well- powered clinical trials are necessary to definitively determine which methods improve clinical outcomes.

houlder pain is the second most However, because of increasing patient age common musculoskeletal com- and the rising number of active patients, plaint encountered in primary there is a demand for improved treatment care offices, occurring in about of all shoulder abnormalities. Therefore, 51%S of patients1. Over the last few years, the use of orthobiologics in shoulder sur- major advances have been made in both the gery has expanded rapidly over the past operative and nonoperative treatment of decade. Some of the commonly used shoulder pain and pathological conditions. biologics in shoulder surgery include

Disclosure: No funding was received during the preparation or execution of this manuscript. On the Disclosure of Potential Conflicts of Interest which are provided with the online version of the COPYRIGHT © 2017 BY THE forms, JOURNAL OF BONE AND JOINT article, one or more of the authors checked “yes” to indicate that the author had a relevant financial SURGERY, INCORPORATED relationship in the biomedical arena outside the submitted work (http://links.lww.com/JBJSREV/A265).

JBJS REVIEWS 2017;5(9):e5 · http://dx.doi.org/10.2106/JBJS.RVW.17.00035 1 | The Use of Biological Approaches in the Treatment of Shoulder Pathology

progenitor cells, growth factors, platelet- contained cartilage lesions. The aim of of the patients stated that they would rich plasma (PRP), and biological this technique is to perforate the sub- have the surgery again. Last, Siebold and matrices. The potential advantages of chondral bone to promote the release colleagues11 reported significant im- biological augmentation of traditional of progenitor cells and multiple growth provements in pain and functional shoulder surgical techniques include factors to the chondral defect. Under scores (p 5 0.0053 and p 5 0.018, minimal invasiveness, improved healing favorable mechanical-stress character- respectively) in patients managed capacity, and more-rapid recovery. istics (stress-free joint movement with with microfracture combined with a Conversely, the use of biologics is cur- varying pressure, tensile, and shearing periosteal flap. Poor prognostic predic- rently expensive, and the evidence of forces), these progenitor cells will dif- tors included prior surgery and, poten- long-term effectiveness is limited. Fur- ferentiate into fibrochondrocytes, ul- tially, lesion size, although the results thermore, the body of literature on the timately creating a fibrocartilage layer. were not significant. use and efficacy of biologics in shoulder However, the higher content of type-I surgery is heterogeneous with regard to collagen makes this repair tissue one of Platelet-Rich Plasma (PRP) indications, therapies, processing lesser biomechanical quality than hy- PRP has been widely utilized for the methods, and inoculation. Although aline cartilage, as previously reported treatment of various musculoskeletal some studies have demonstrated en- in animal experiments3. Patient selec- conditions or as an augmentation tool couraging results following either iso- tion is most certainly key for successful on the basis of basic-science and lated treatment with biologics or outcomes. However, clear indications emerging clinical studies12,13.Thebi- biologic-augmented surgery, other are not available in the shoulder liter- ological reasoning behind the clinical studies have failed to demonstrate sub- ature; therefore, on the basis of an al- use of PRP includes local delivery of stantial benefit. Given the heterogeneity gorithm that has been extrapolated growth factors, modification of the in- and paucity of critical analyses within from the knee literature, microfracture flammatory response, increased hemo- the literature, the objective of the is considered to be suitable for the stasis, and positive effects on cell present review is to evaluate the value treatment of small, circumscribed car- proliferation and differentiation14-17. of orthobiologics in the treatment of tilage defects (maximum, 4 cm2)with Although symptomatic relief has been shoulder pathologies. More precisely, intact subchondral bone in young, ac- reported following the use of PRP for we aim to perform a balanced evaluation tive patients4-7. the treatment of early-stage knee oste- of biologic augmentation of existing In general, better results have oarthritis14, we are not aware of any modalities for the treatment of focal been reported for small unipolar de- studies that have evaluated the efficacy chondral defects, osteoarthritis, and ro- fects on either the glenoid or humeral of PRP in the shoulder. However, au- tator cuff tears. side, whereas the worst results have tologous platelet-poor plasma and been seen in association with bipolar platelet gel have been shown to reduce Focal Chondral Defects and glenohumeral lesions2,3,8.Millett pain scores and to yield significantly Glenohumeral Osteoarthritis et al., in a study of 31 shoulders, better functional outcomes (internal A trial of conservative therapy consisting reported significant (p , 0.05) reduc- rotation, p , 0.05) following total of physical therapy and nonsteroidal tion in pain and improvement in shoulder arthroplasty18.Inthestudyby anti-inflammatory medications is typi- function according to the American Lo et al.19, 55 patients with glenohu- cally seen as the primary treatment when Shoulder and Elbow Surgeons (ASES) meral arthritis were managed with a a symptomatic cartilage defect is iden- score9 at a mean of 4 years after the use biologically based resurfacing arthro- tified in the shoulder2. If symptoms of microfracture for the treatment of plasty with use of acellular human persist, biologic-based treatments such full-thickness articular cartilage in- dermal allograft in combination with as marrow-stimulation procedures, juries. Only 19% of the patients in that PRP. After an average duration of bone marrow aspirate concentrate cohort were considered to have had a follow-upof60months,theaverage (BMAC), PRP, and cell-based therapies failure requiring additional surgery2. ASES score was 76 6 22, the average such as autologous chondrocyte im- Likewise, Frank and colleagues, in a Western Ontario Osteoarthritis of the plantation (ACI) or matrix-induced ACI series of 16 patients (17 shoulders), Shoulder (WOOS) index was 76% 6 (MACI) can be used. reported significant improvement in 22%,andtheaverage visualanalogscale shoulder function as demonstrated by (VAS) score for pain was 2.4 6 2.6, Microfracture an increase in the Simple Shoulder Test with an 81% rate of patient satisfaction. The microfracture procedure has been (SST) and ASES scores (p , 0.01 for The average joint space increased from widely used in several joints because of both) and significant pain reduction 1 6 1 mm preoperatively to 2 6 1mm its ease of performance, low cost, and (p , 0.01) at .2 years postoperatively10. postoperatively. Fewer than 10% of the overall positive reported outcomes Outcomes did not significantly vary patients underwent revision to total when used for the treatment of small, with respect to sex or age. Of note, 93% shoulder arthroplasty.

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Autologous Chondrocyte improve the regeneration of the native mesenchymal stromal cells (MSCs), Implantation (ACI) and Matrix- cuff insertion site, and to inhibit the platelets, and growth factors. However, Induced ACI (MACI) formation of scar tissue23,24. These several studies have shown mixed results. The principle of these techniques is to approaches include tissue engineering, Osti et al., in a randomized controlled culture autologous cells and then to cell therapy, and growth factors. trial of 57 patients who underwent ar- implant these cells into the chondral throscopic rotator cuff repair, demon- defect20. These procedures can be per- Marrow-Venting Procedures strated that microfracture of the rotator formed with or without a 3-dimensional Bleeding bone surfaces, such as those cuff footprint resulted in reduced short- biocompatible scaffold. ACI and MACI brought about by venting of the greater term pain but did not result in signifi- are staged procedures in which an initial tuberosity or acromioplasty, can enable cantly different long-term clinical or arthroscopic harvest is performed to the release of growth factors, which radiographic outcomes30. Milano et al., obtain chondrocytes for culture. The can in turn lead to improved cuff in prospective randomized study of 80 chondrocytes are then expanded in cul- healing22,25. These factors, including patients who underwent arthroscopic ture to obtain 15 to 20 million cells. This platelet-derived growth factor (PDGF), rotator cuff repair with or without expansion takes approximately 1 month, basic fibroblast growth factor (bFGF), greater tuberosity microfracture, found and the cells are then implanted into the and vascular endothelial growth factor no significant difference between the chondral defect. There is a paucity of (VEGF), induce inflammation and an- groups on MRI evaluation; however, data in the orthopaedic literature on the giogenesis. Meanwhile, other growth patients receiving microfracture for large use of ACI for the treatment of chondral factors improve matrix synthesis, cellu- tears demonstrated significantly im- defects within the shoulder. We are lar proliferation, and cellular differenti- proved healing rates (p 5 0.040)31. aware of only a single case in which ACI ation (transforming growth factor-beta has been used for the treatment of a [TGF-b]), promote osseous incorpora- Platelet-Rich Plasma (PRP) shoulder defect; in that report, a 16- tion of tendon (bone morphogenetic The use of PRP as a biological adjuvant year-old male athlete with a full-thick- proteins [BMPs]), and remodel the to enhance the healing of rotator cuff ness lesion (3.3 3 1.5 cm) of the extracellular matrix (matrix metal- tendons has recently increased in pop- humeral head reported functional im- loproteinases [MMPs])26. Gotoh et al., ularity, which in turn has led to a num- provements at 12 months21. in a study of 24 patients with or without ber of published studies. PRP is a term For the MACI procedure, a few a retear following rotator cuff repair, that is used to describe preparations of days prior to implantation, a biodegrad- found increased levels of MMP-3 and whole blood enriched with platelets able scaffold is seeded with the expanded tissue inhibitor of MMP (TIMP)-1 in that, once activated, release a host of chondrocytes, which can then synthesize the retear group and concluded that growth factors that may contribute to extracellular matrix components21.We these findings may suggest a potential tissue repair. Several proteoglycans are aware of only 1 small report on the use approach for targeted drug therapy fol- (decorin, aggrecan, and biglycan) have of this procedure in the shoulder22.In lowing rotator cuff repair26. While there been shown to stimulate the production that study, 4 young adults were managed have been no studies investigating rota- of key extracellular matrix proteins and with ACI for the treatment of symptom- tor cuff healing following treatment to increase proliferation of rotator cuff- atic, isolated, large-diameter lesions of with recombinant growth factors in derived tenocytes32. Moreover, PRP the cartilage involving the humerus (3 humans, the results of preclinical studies inhibits the inflammatory effects of patients; defect size, 6 cm2) or glenoid (1 have indicated that the delivery or interleukin-1b (IL-1b), which contrib- patient; defect size, 2 cm2). After a mean modulation of these factors may aug- utes to rotator cuff tendon degeneration, duration of follow-up of .3 years, the ment rotator cuff healing27,28. Bedi and heightens levels of TGF-b, which mean pain and functional scores were et al., on the basis of their findings in a rat increases rotator cuff tendon repair considered satisfactory (VAS score for model, reported that MMP-13 activity strength33,34. However, these in vitro pain, 0.3 of 10; Constant score, 83.3 6 modulation with doxycycline following results have not translated into clinical 9.9; and ASES index, 95.3 6 8.1). rotator cuff repair may offer a novel bi- effects; controversial results have been Moreover, the coverage of the defect ological approach toimprove tendon-to- reported following clinicaltrialsinvolving on magnetic resonance imaging (MRI) bone healing29. However, the clinical the use of different PRP formulations to also was deemed satisfactory, with signs translation of these in vitro and animal enhance rotator cuff repairs32,35-43. of fibrocartilaginous repair tissue. studies remains a challenge. Multiple studies have documented significantly improved results in associa- Rotator Cuff Tears Microfracture tion with the use of PRP augmentation. A number of novel approaches have Microfracture of the greater tuberosity, Pandey et al. evaluated 102 patients who been described to enhance the biological immediately lateral to the rotator cuff underwent rotator cuff repair with or healing of the rotator cuff repair site, to repair site, results in extravasation of without moderately concentrated PRP

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and were followed for a minimum of Constant score. Additionally, a sub- differentiate into multiple musculo- 2 years44. At 24 months, the PRP group group analysis of patients who under- skeletal tissues, such as tendon, liga- demonstrated a significantly lower retear went double-row repair for the ment, cartilage, bone, and fat. rate than the control group (3.8% com- treatment of large (.3-cm) rotator cuff Interestingly, recent articles have dem- pared with 20%; p 5 0.01). The differ- tears showed significantly lower retear onstrated the presence of stem cells ob- ence in retear rates, however, was rates in association with PRP use (p 5 tained from bursal tissue. Of note, when significant only for large tears (p 5 0.03). 0.046). Vavken et al. performed a cost- treated with BMP-12, these cells Doppler ultrasound demonstrated that effectiveness analysis and meta-analysis expressed markers of tenocytes; there- the PRP group had significantly (p , of 13 published studies on the use of fore, BMP-12 potentially could be an 0.05) increased vascularity of the repair PRP for the repair of small and medium- important target in the treatment of site at 3 months postoperatively and in the sized rotator cuff tears. In contrast to rotator cuff degeneration50,51. peribursal tissue until 12 months44.In Warth et al.13, the authors found re- While preclinical studies have addition, the PRP group demonstrated duced retear rates following the arthro- demonstrated promising results52-54, significantly improved University of scopic repair of small and medium-sized there is still a paucity of clinical studies. California-Los Angeles (UCLA) scores at rotator cuff tears when patients who had Only 2 clinical studies have shown the 12 months postoperatively (p , 0.05) been managed with PRP were compared efficacy of BMSC injections in the and significantly improved Constant with controls47. However, for large and shoulder55,56. Ellera Gomes et al. scores at 24 months postoperatively massive tears, there was no decrease in reported on 14 patients in whom full- (p , 0.05). Jo et al., in a randomized the retear rate in association with PRP. thickness rotator cuff tears were repaired controlled trial, reported a significantly Cost analysis indicated that, with the cur- with transosseous sutures with use of a lower retear rate among patients who re- rent cost, the use of PRP was not cost- mini-open approach and subsequently ceived PRP than among those who did effective. Chahal et al., in a systematic augmented with 10 mL of BMSC con- not (3.0% compared with 20.0%; p 5 review, also noted a reduction in retear centrate, which was injected into the 0.043)45. Additionally, the supraspinatus rates for small and medium-sized rotator repaired tendon edges55. After 12 cross-sectional area was significantly larger cuff tears48. Most recently, Saltzman months of follow-up, MRI examina- in the PRP group (p 5 0.014); this find- et al., in a meta-analysis of available re- tions demonstrated intact tendons in all ing led the authors to conclude that the view studies, found that the use of PRP patients. Additionally, Hernigou et al. quality of postoperative tendon healing is for rotator cuff repair did not result in evaluated the 10-year results for 90 pa- increased by the use of PRP. Of note, the significantly lower overall retear rates or tients who underwent single-row rotator speed of healing and the functional out- improved clinical outcome scores49. cuff repair with (45 patients) or without comes were equivalent between the Subgroup analysis showed evidence of (45 patients) augmentation with con- 2 groups. Holtby et al., in a retrospective improved outcomes in association with centrated BMSCs56. Intact tendon was study of 82 patients who were followed for solid as compared with liquid PRP ma- found in 87% of the patients in the 6 months after the repair of small to trix, small or medium-sized tears as BMSC group, compared with only 44% medium-sized rotator cuff tears, reported compared with large or massive tears, of those in the control group. transient improvements in perioperative PRP application at the tendon-bone Adipose tissue represents an pain control when comparing the PRP interface as compared with over the abundant and reproducible progenitor group with the control group46.More- tendon, and in the setting of double-row cell source as ADSCs can be easily har- over, neither patient-oriented outcome as compared with single-row repair. vested from it. We are aware of only measures nor structural integrity of the re- Because of inconsistent clinical 1 study, involving a rabbit model, which pair significantly differed between groups. results, the use of PRP to improve has verified the positive rotator-cuff The varying protocols and con- postoperative rotator cuff healing con- healing effects of ADSCs54. The authors flicting results of studies investigating tinues to be an area of debate. Additional demonstrated that muscle function and PRP in the setting of rotator cuff repair randomized clinical trials and basic- tendon integrity were improved follow- have led to numerous meta-analyses to science studies are needed to determine ing local administration of ADSCs after further evaluate the data12. Warth et al., the optimal formulation of PRP to cuff repair. Additional preclinical and in an analysis of 11 Level-I and II studies, improve physiological healing. clinical studies are necessary to elucidate found that clinical outcomes did not the optimal utilization of progenitor differ between patients who received Progenitor Cells cells to enhance tendon healing. PRP and controls13. The authors The use of multipotent MSCs has be- reported that placing the PRP at the come an area of growing interest. Spe- Scaffolds tendon-bone interface rather than over cifically, adipose-derived stem cells An area of recent interest in research is the the surface of the repaired tendon was (ADSCs) and bone marrow-derived development of new ways to produce associated with an overall increase in the stem cells (BMSCs) can proliferate and synthetic, degradable scaffolds that

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TABLE I Grades of Recommendations for Clinical Care*†

Bone- ACI/ Progenitor Marrow Microfracture PRP MACI Cells Venting Scaffolds

Focal chondral defects Grade B Grade I Grade I Grade I Grade I NA Diffuse osteoarthritis NA Grade C NA Grade I NA NA Rotator cuff repair Grade C Grade C NA Grade I Grade I Grade I

*Grade A indicates good evidence (Level-I studies with consistent findings) for or against recommending intervention. Grade B indicates fair evidence (Level-II or III studies with consistent findings) for or against recommending intervention. Grade C indicates conflicting or poor-quality evidence (Level-IV or V studies) not allowing a recommendation for or against intervention. Grade I indicates that there is insufficient evidence to make a recommendation. †PRP 5 platelet-rich plasma, ACI 5 autologous chondrocyte implan- tation, MACI 5 matrix-induced autologous chondrocyte implantation, and NA 5 not applicable.

reproduce the function and structure of Conclusions 1Steadman Philippon Research Institute, the rotator cuff tendon. Notable advances In summary, basic-science studies in- Vail, Colorado include the recent development of vestigating biological factors to treat 2The Steadman Clinic, Vail, Colorado 3-dimensional electrospun scaffolds that chondral defects or enhance rotator cuff closely resemble extracellular matrix. In healing show promising results. How- 3Department of Orthopaedic Surgery, addition, coating and fabrication tech- ever, clinical data are still limited by in- McGovern School of Medicine, University niques that facilitate the integration of consistency and controversy, and of Texas Health Science Center at Houston, Houston, Texas bioactive molecules, including growth recommendations for clinical care are factors, within scaffolds have been not possible (Table I). For focal chondral E-mail address for P.J. Millett: 57,58 developed . Although these scaffolds lesions of the glenoid or humeral head, [email protected] are not ready for human implantation at microfracture has been reported to yield this time, collaboration between re- positive postoperative results in the in- References searchers focusing on cell biology, bio- termediate to long-term follow-up pe- 1. Pope DP, Croft PR, Pritchard CM, Silman AJ. material science, and tissue engineering riod. The use of PRP, ACI, and MACI Prevalence of shoulder pain in the community: the influence of case definition. Ann Rheum Dis. may lead to scaffolds with the requisite treatments for shoulder chondral lesions 1997 May;56(5):308-12. characteristics to initiate rotator cuff ten- also has been reported; however, no 2. Millett PJ, Huffard BH, Horan MP, Hawkins RJ, don regeneration. Other recently devel- Steadman JR. Outcomes of full-thickness conclusions can be drawn concerning articular cartilage injuries of the shoulder oped types of scaffold for the augmented the efficacy of these modalities. For ro- treated with microfracture. Arthroscopy. 2009 repair of massive rotator cuff tears or the tator cuff tear healing, animal and basic- Aug;25(8):856-63. 3. replacement of irreparable cuff tissue are Wang VM, Karas V, Lee AS, Yin Z, Van Thiel GS, science studies have demonstrated that Hussey K, Sumner DR, Chubinskaya S, Magin RL, 59,60 human acellular dermal allograft and modulation of growth factors and pro- Verma NN, Romeo AA, Cole BJ. Assessment of xenograft61. In addition to biomechanical glenoid chondral healing: comparison of genitor cells may be helpful, but the microfracture to autologous matrix-induced strengthening of the tendon tissue, the optimal modulation and delivery vehicle chondrogenesis in a novel rabbit shoulder rationale behind these techniques is to model. J Shoulder Elbow Surg. 2015 Nov;24(11): remain to be elucidated. Conflicting 1789-800. Epub 2015 Aug 1. render the graft acellular, decreasing its results have been reported about the role 4. Steadman JR, Briggs KK, Matheny LM, Guillet immunogenicity, while leaving an intact of PRP as biological augmentation for A, Hanson CM, Willimon SC. Outcomes collagen extracellular matrix; the intact following microfracture of full-thickness rotator cuff repairs, making this subject articular cartilage lesions of the knee in matrix thereby promotes growth of new an area of continuing debate. In general, adolescent patients. J Knee Surg. 2015 Apr;28 62 host tissue into the graft . Short-term additional clinical trials are necessary to (2):145-50. Epub 2014 Apr 24. 5. results after 24 months of follow-up have Steadman JR, Hanson CM, Briggs KK, elucidate the ideal biological approaches Matheny LM, James EW, Guillet A. Outcomes 59,61-63 been promising ;Barberetal.,for to improve the healing of a variety of after knee microfracture of chondral defects in example, in a randomized prospective alpine ski racers. J Knee Surg. 2014 Oct;27(5): musculoskeletal tissues. 407-10. Epub 2014 May 22. trial, demonstrated superior outcome 6. Steadman JR, Matheny LM, Briggs KK, Rodkey scores and a lower failure rate with aug- Jonas Pogorzelski, MD, MHBA1, WG, Carreira DS. Outcomes following healing Jonathan A. Godin, MD, MBA1,2, response in older, active patients: a primary mented compared with non-augmented anterior cruciate ligament repair technique. 62 Erik M. Fritz, MD1, rotator cuff repairs . However, further J Knee Surg. 2012 Jul;25(3):255-60. 1 Mark E. Cinque, MS , 7. studies are necessary to evaluate the long- 1 Steadman JR, Rodkey WG, Rodrigo JJ. Jorge Chahla, MD , Microfracture: surgical technique and term benefits of human acellular dermal Johnny Huard, PhD1,3, rehabilitation to treat chondral defects. Clin scaffolds. Peter J. Millett, MD, MSc1,2 Orthop Relat Res. 2001 Oct;(391)(Suppl):S362-9.

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