REVIEW
Biologics and stem cell-based therapies for rotator cuff repair
Spencer T. Bianco,
Helen L. Moser,
Leesa M. Galatz,
Alice H. Huang,
Spencer T. Bianco
Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
Search for more papers by this authorHelen L. Moser
Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
Shoulder, Elbow and Orthopaedic Sports Medicine, Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Search for more papers by this authorLeesa M. Galatz
Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
Search for more papers by this authorCorresponding Author
Alice H. Huang
Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
Address for correspondence: Alice H. Huang, Ph.D., Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, Box 1188, New York, NY 10029. [email protected]Search for more papers by this authorSpencer T. Bianco,
Helen L. Moser,
Leesa M. Galatz,
Alice H. Huang,
Spencer T. Bianco
Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
Search for more papers by this authorHelen L. Moser
Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
Shoulder, Elbow and Orthopaedic Sports Medicine, Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Search for more papers by this authorLeesa M. Galatz
Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
Search for more papers by this authorCorresponding Author
Alice H. Huang
Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
Address for correspondence: Alice H. Huang, Ph.D., Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, Box 1188, New York, NY 10029. [email protected]Search for more papers by this authorAbstract
The rotator cuff is composed of several distinct muscles and tendons that function in concert to coordinate shoulder motion. Injuries to these tendons frequently result in permanent dysfunction and persistent pain. Despite considerable advances in operation techniques, surgical repair alone still does not fully restore rotator cuff function. This review focuses on recent research in the use of biologics and stem cell-based therapies to augment repair, highlighting promising avenues for future work and remaining challenges. While a number of animal models are used for rotator cuff studies, the anatomy of the rotator cuff varies dramatically between species. Since the rodent rotator cuff shares the most anatomical features with the human, this review will focus primarily on rodent models to enable consistent interpretation of outcome measures.
References
- 1Neer, C.S. 2nd. 1972. Anterior acromioplasty for the chronic impingement syndrome in the shoulder: a preliminary report. J. Bone Joint Surg. Am. 54: 41–50.
- 2Oliva, F., E. Piccirilli, M. Bossa, et al. 2015. I.S.Mu.L.T—rotator cuff tears guidelines. Muscles Ligaments Tendons J. 5: 227–263.
- 3Oh, L.S., B.R. Wolf, M.P. Hall, et al. 2007. Indications for rotator cuff repair: a systematic review. Clin. Orthop. Relat. Res. 455: 52–63.
- 4Roh, M.S., V.M. Wang, E.W. April, et al. 2000. Anterior and posterior musculotendinous anatomy of the supraspinatus. J. Shoulder Elbow Surg. 9: 436–440.
- 5Galatz, L.M., C.M. Ball, S.A. Teefey, et al. 2004. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears. J. Bone Joint Surg. Am. 86-A: 219–224.
- 6Benjamin, M., E.J. Evans & L. Copp. 1986. The histology of tendon attachments to bone in man. J. Anat. 149: 89–100.
- 7Benjamin, M., T. Kumai, S. Milz, et al. 2002. The skeletal attachment of tendons—tendon “entheses”. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 133: 931–945.
- 8Benjamin, M., H. Toumi, J.R. Ralphs, et al. 2006. Where tendons and ligaments meet bone: attachment sites (‘entheses’) in relation to exercise and/or mechanical load. J. Anat. 208: 471–490.
- 9Gerber, C., A.G. Schneeberger, S.M. Perren, et al. 1999. Experimental rotator cuff repair. A preliminary study. J. Bone Joint Surg. Am. 81: 1281–1290.
- 10Carpenter, J.E., S. Thomopoulos, C.L. Flanagan, et al. 1998. Rotator cuff defect healing: a biomechanical and histologic analysis in an animal model. J. Shoulder Elbow Surg. 7: 599–605.
- 11Burks, R.T., J. Crim, N. Brown, et al. 2009. A prospective randomized clinical trial comparing arthroscopic single- and double-row rotator cuff repair: magnetic resonance imaging and early clinical evaluation. Am. J. Sports Med. 37: 674–682.
- 12Franceschi, F., L. Ruzzini, U.G. Longo, et al. 2007. Equivalent clinical results of arthroscopic single-row and double-row suture anchor repair for rotator cuff tears: a randomized controlled trial. Am. J. Sports Med. 35: 1254–1260.
- 13Grasso, A., G. Milano, M. Salvatore, et al. 2009. Single-row versus double-row arthroscopic rotator cuff repair: a prospective randomized clinical study. Arthroscopy 25: 4–12.
- 14Filardo, G., B. Di Matteo, E. Kon, et al. 2016. Platelet-rich plasma in tendon-related disorders: results and indications. Knee Surg. Sports Traumatol. Arthrosc. https://doi.org/10.1007/s00167-016-4261-4.
- 15Charles, M.D., D.R. Christian & B.J. Cole. 2018. The role of biologic therapy in rotator cuff tears and repairs. Curr. Rev. Musculoskelet. Med. 11: 150–161.
- 16Soslowsky, L.J., J.E. Carpenter, C.M. DeBano, et al. 1996. Development and use of an animal model for investigations on rotator cuff disease. J. Shoulder Elbow Surg. 5: 383–392.
- 17Derwin, K.A., A.R. Baker, J.P. Iannotti, et al. 2010. Preclinical models for translating regenerative medicine therapies for rotator cuff repair. Tissue Eng. Part B Rev. 16: 21–30.
- 18Liu, X., G. Manzano, H.T. Kim, et al. 2011. A rat model of massive rotator cuff tears. J. Orthop. Res. 29: 588–595.
- 19Zingman, A., H. Li, L. Sundem, et al. 2017. Shoulder arthritis secondary to rotator cuff tear: a reproducible murine model and histopathologic scoring system. J. Orthop. Res. 35: 506–514.
- 20Kuenzler, M.B., K. Nuss, A. Karol, et al. 2017. Neer Award 2016: reduced muscle degeneration and decreased fatty infiltration after rotator cuff tear in a poly(ADP-ribose) polymerase 1 (PARP-1) knock-out mouse model. J. Shoulder Elbow Surg. 26: 733–744.
- 21Bell, R., P. Taub, P. Cagle, et al. 2015. Development of a mouse model of supraspinatus tendon insertion site healing. J. Orthop. Res. 33: 25–32.
- 22Lebaschi, A.H., X.H. Deng, C.L. Camp, et al. 2018. Biomechanical, histologic, and molecular evaluation of tendon healing in a new murine model of rotator cuff repair. Arthroscopy 34: 1173–1183.
- 23Yoshida, R., F. Alaee, F. Dyrna, et al. 2016. Murine supraspinatus tendon injury model to identify the cellular origins of rotator cuff healing. Connect. Tissue Res. 57: 507–515.
- 24Schwartz, A.G., L.M. Galatz & S. Thomopoulos. 2017. Enthesis regeneration: a role for Gli1+ progenitor cells. Development 144: 1159–1164.
- 25Neer, C.S. 2nd, E.V. Craig & H. Fukuda. 1983. Cuff-tear arthropathy. J. Bone Joint Surg. Am. 65: 1232–1244.
- 26Carpenter, J.E., C.L. Flanagan, S. Thomopoulos, et al. 1998. The effects of overuse combined with intrinsic or extrinsic alterations in an animal model of rotator cuff tendinosis. Am. J. Sports Med. 26: 801–807.
- 27Schneeberger, A.G., R.W. Nyffeler & C. Gerber. 1998. Structural changes of the rotator cuff caused by experimental subacromial impingement in the rat. J. Shoulder Elbow Surg. 7: 375–380.
- 28Soslowsky, L.J., S. Thomopoulos, A. Esmail, et al. 2002. Rotator cuff tendinosis in an animal model: role of extrinsic and overuse factors. Ann. Biomed. Eng. 30: 1057–1063.
- 29Soslowsky, L.J., S. Thomopoulos, S. Tun, et al. 2000. Neer Award 1999. Overuse activity injures the supraspinatus tendon in an animal model: a histologic and biomechanical study. J. Shoulder Elbow Surg. 9: 79–84.
- 30Parks, A.N., J. McFaline-Figueroa, A. Coogan, et al. 2017. Supraspinatus tendon overuse results in degenerative changes to tendon insertion region and adjacent humeral cartilage in a rat model. J. Orthop. Res. 35: 1910–1918.
- 31Tucker, J.J., C.N. Riggin, B.K. Connizzo, et al. 2016. Effect of overuse-induced tendinopathy on tendon healing in a rat supraspinatus repair model. J. Orthop. Res. 34: 161–166.
- 32Chen, H.S., Y.T. Su, T.M. Chan, et al. 2015. Human adipose-derived stem cells accelerate the restoration of tensile strength of tendon and alleviate the progression of rotator cuff injury in a rat model. Cell Transplant. 24: 509–520.
- 33Sevivas, N., S.C. Serra, R. Portugal, et al. 2015. Animal model for chronic massive rotator cuff tear: behavioural and histologic analysis. Knee Surg. Sports Traumatol. Arthrosc. 23: 608–618.
- 34Thangarajah, T., F. Henshaw, A. Sanghani-Kerai, et al. 2017. Supraspinatus detachment causes musculotendinous degeneration and a reduction in bone mineral density at the enthesis in a rat model of chronic rotator cuff degeneration. Shoulder Elbow 9: 178–187.
- 35Thomopoulos, S., G. Hattersley, V. Rosen, et al. 2002. The localized expression of extracellular matrix components in healing tendon insertion sites: an in situ hybridization study. J. Orthop. Res. 20: 454–463.
- 36Thomopoulos, S., G.R. Williams & L.J. Soslowsky. 2003. Tendon to bone healing: differences in biomechanical, structural, and compositional properties due to a range of activity levels. J. Biomech. Eng. 125: 106–113.
- 37Galatz, L.M., L.J. Sandell, S.Y. Rothermich, et al. 2006. Characteristics of the rat supraspinatus tendon during tendon-to-bone healing after acute injury. J. Orthop. Res. 24: 541–550.
- 38Bedi, A., D. Kovacevic, C. Hettrich, et al. 2010. The effect of matrix metalloproteinase inhibition on tendon-to-bone healing in a rotator cuff repair model. J. Shoulder Elbow Surg. 19: 384–391.
- 39Gulotta, L.V., D. Kovacevic, J.R. Ehteshami, et al. 2009. Application of bone marrow-derived mesenchymal stem cells in a rotator cuff repair model. Am. J. Sports Med. 37: 2126–2133.
- 40Gulotta, L.V., D. Kovacevic, F. Cordasco, et al. 2011. Evaluation of tumor necrosis factor α blockade on early tendon-to-bone healing in a rat rotator cuff repair model. Arthroscopy 27: 1351–1357.
- 41Beck, J., D. Evans, P.M. Tonino, et al. 2012. The biomechanical and histologic effects of platelet-rich plasma on rat rotator cuff repairs. Am. J. Sports Med. 40: 2037–2044.
- 42Killian, M.L., L. Cavinatto, S.A. Shah, et al. 2014. The effects of chronic unloading and gap formation on tendon-to-bone healing in a rat model of massive rotator cuff tears. J. Orthop. Res. 32: 439–447.
- 43Tornero-Esteban, P., J.A. Hoyas, E. Villafuertes, et al. 2015. Efficacy of supraspinatus tendon repair using mesenchymal stem cells along with a collagen I scaffold. J. Orthop. Surg. Res. 10: 124.
- 44Killian, M.L., L.M. Cavinatto, S.R. Ward, et al. 2015. Chronic degeneration leads to poor healing of repaired massive rotator cuff tears in rats. Am. J. Sports Med. 43: 2401–2410.
- 45Gumucio, J.P., M.D. Flood, S.M. Roche, et al. 2016. Stromal vascular stem cell treatment decreases muscle fibrosis following chronic rotator cuff tear. Int. Orthop. 40: 759–764.
- 46Smietana, M.J., P. Moncada-Larrotiz, E.M. Arruda, et al. 2017. Tissue-engineered tendon for enthesis regeneration in a rat rotator cuff model. Biores. Open Access 6: 47–57.
- 47Sevivas, N., F.G. Teixeira, R. Portugal, et al. 2018. Mesenchymal stem cell secretome improves tendon cell viability in vitro and tendon-bone healing in vivo when a tissue engineering strategy is used in a rat model of chronic massive rotator cuff tear. Am. J. Sports Med. 46: 449–459.
- 48Boswell, S.G., B.J. Cole, E.A. Sundman, et al. 2012. Platelet-rich plasma: a milieu of bioactive factors. Arthroscopy 28: 429–439.
- 49Hurley, E.T., D. Lim Fat, C.J. Moran, et al. 2018. The efficacy of platelet-rich plasma and platelet-rich fibrin in arthroscopic rotator cuff repair: a meta-analysis of randomized controlled trials. Am. J. Sports Med. https://doi.org/10.1177/0363546517751397.
- 50Saltzman, B.M., A. Jain, K.A. Campbell, et al. 2016. Does the use of platelet-rich plasma at the time of surgery improve clinical outcomes in arthroscopic rotator cuff repair when compared with control cohorts? A systematic review of meta-analyses. Arthroscopy 32: 906–918.
- 51Warth, R.J., G.J. Dornan, E.W. James, et al. 2015. Clinical and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears with and without platelet-rich product supplementation: a meta-analysis and meta-regression. Arthroscopy 31: 306–320.
- 52Jo, C.H., J.S. Shin, W.H. Shin, et al. 2016. Corrigendum. Platelet-rich plasma for arthroscopic repair of medium to large rotator cuff tears: a randomized controlled trial. Am. J. Sports Med. 44: NP3.
- 53Malavolta, E.A., M.E. Gracitelli, A.A. Ferreira Neto, et al. 2014. Platelet-rich plasma in rotator cuff repair: a prospective randomized study. Am. J. Sports Med. 42: 2446–2454.
- 54Kesikburun, S., A.K. Tan, B. Yilmaz, et al. 2013. Platelet-rich plasma injections in the treatment of chronic rotator cuff tendinopathy: a randomized controlled trial with 1-year follow-up. Am. J. Sports Med. 41: 2609–2616.
- 55Kovacevic, D., A.J. Fox, A. Bedi, et al. 2011. Calcium–phosphate matrix with or without TGF-β3 improves tendon-bone healing after rotator cuff repair. Am. J. Sports Med. 39: 811–819.
- 56Manning, C.N., H.M. Kim, S. Sakiyama-Elbert, et al. 2011. Sustained delivery of transforming growth factor beta three enhances tendon-to-bone healing in a rat model. J. Orthop. Res. 29: 1099–1105.
- 57Kim, H.M., L.M. Galatz, R. Das, et al. 2011. The role of transforming growth factor beta isoforms in tendon-to-bone healing. Connect. Tissue Res. 52: 87–98.
- 58Gulotta, L.V., D. Kovacevic, J.D. Packer, et al. 2011. Adenoviral-mediated gene transfer of human bone morphogenetic protein-13 does not improve rotator cuff healing in a rat model. Am. J. Sports Med. 39: 180–187.
- 59Lipner, J., H. Shen, L. Cavinatto, et al. 2015. In vivo evaluation of adipose-derived stromal cells delivered with a nanofiber scaffold for tendon-to-bone repair. Tissue Eng. Part A 21: 2766–2774.
- 60Buchmann, S., G.H. Sandmann, L. Walz, et al. 2013. Refixation of the supraspinatus tendon in a rat model—influence of continuous growth factor application on tendon structure. J. Orthop. Res. 31: 300–305.
- 61Wolfman, N.M., G. Hattersley, K. Cox, et al. 1997. Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6, and 7, members of the TGF-beta gene family. J. Clin. Invest. 100: 321–330.
- 62Blitz, E., S. Viukov, A. Sharir, et al. 2009. Bone ridge patterning during musculoskeletal assembly is mediated through SCX regulation of Bmp4 at the tendon–skeleton junction. Dev. Cell 17: 861–873.
- 63Pryce, B.A., S.S. Watson, N.D. Murchison, et al. 2009. Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation. Development 136: 1351–1361.
- 64Seo, H.S. & R. Serra. 2007. Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev. Biol. 310: 304–316.
- 65Thomas, M., B. Langley, C. Berry, et al. 2000. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J. Biol. Chem. 275: 40235–40243.
- 66Rosen, V., R.S. Thies & K. Lyons. 1996. Signaling pathways in skeletal formation: a role for BMP receptors. Ann. N.Y. Acad. Sci. 785: 59–69.
- 67Massague, J. 2012. TGFβ signalling in context. Nat. Rev. Mol. Cell Biol. 13: 616–630.
- 68Zhang, Y.E. 2009. Non-Smad pathways in TGF-beta signaling. Cell Res. 19: 128–139.
- 69Retting, K.N., B. Song, B.S. Yoon, et al. 2009. BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development 136: 1093–1104.
- 70You, X., Y. Shen, W. Yu, et al. 2018. Enhancement of tendon-bone healing following rotator cuff repair using hydroxyapatite with TGFβ1. Mol. Med. Rep. 17: 4981–4988.
- 71Schweitzer, R., J.H. Chyung, L.C. Murtaugh, et al. 2001. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development 128: 3855–3866.
- 72Yamamoto-Shiraishi, Y. & A. Kuroiwa. 2013. Wnt and BMP signaling cooperate with Hox in the control of Six2 expression in limb tendon precursor. Dev. Biol. 377: 363–374.
- 73Kabuto, Y., T. Morihara, T. Sukenari, et al. 2015. Stimulation of rotator cuff repair by sustained release of bone morphogenetic protein-7 using a gelatin hydrogel sheet. Tissue Eng. Part A 21: 2025–2033.
- 74Mikic, B., L. Bierwert & D. Tsou. 2006. Achilles tendon characterization in GDF-7 deficient mice. J. Orthop. Res. 24: 831–841.
- 75Mikic, B., K. Rossmeier & L. Bierwert. 2009. Sexual dimorphism in the effect of GDF-6 deficiency on murine tendon. J. Orthop. Res. 27: 1603–1611.
- 76Chhabra, A., D. Tsou, R.T. Clark, et al. 2003. GDF-5 deficiency in mice delays Achilles tendon healing. J. Orthop. Res. 21: 826–835.
- 77Lamplot, J.D., M. Angeline, J. Angeles, et al. 2014. Distinct effects of platelet-rich plasma and BMP13 on rotator cuff tendon injury healing in a rat model. Am. J. Sports Med. 42: 2877–2887.
- 78Murray, D.H., E.N. Kubiak, L.M. Jazrawi, et al. 2007. The effect of cartilage-derived morphogenetic protein 2 on initial healing of a rotator cuff defect in a rat model. J. Shoulder Elbow Surg. 16: 251–254.
- 79Ornitz, D.M. & N. Itoh. 2015. The fibroblast growth factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 4: 215–266.
- 80Brent, A.E., R. Schweitzer & C.J. Tabin. 2003. A somitic compartment of tendon progenitors. Cell 113: 235–248.
- 81Havis, E., M.A. Bonnin, I. Olivera-Martinez, et al. 2014. Transcriptomic analysis of mouse limb tendon cells during development. Development 141: 3683–3696.
- 82Tokunaga, T., C. Shukunami, N. Okamoto, et al. 2015. FGF-2 stimulates the growth of tenogenic progenitor cells to facilitate the generation of tenomodulin-positive tenocytes in a rat rotator cuff healing model. Am. J. Sports Med. 43: 2411–2422.
- 83Ide, J., K. Kikukawa, J. Hirose, et al. 2009. The effects of fibroblast growth factor-2 on rotator cuff reconstruction with acellular dermal matrix grafts. Arthroscopy 25: 608–616.
- 84Peterson, K., M. McDonagh, S. Thakurta, et al. 2010. Drug class review: nonsteroidal antiinflammatory drugs (NSAIDs): final update 4 report. Oregon Health & Science University, Portland, OR.
- 85Cabuk, H., A. Avci, H. Durmaz, et al. 2014. The effect of diclofenac on matrix metalloproteinase levels in the rotator cuff. Arch. Orthop. Trauma Surg. 134: 1739–1744.
- 86Chechik, O., O. Dolkart, G. Mozes, et al. 2014. Timing matters: NSAIDs interfere with the late proliferation stage of a repaired rotator cuff tendon healing in rats. Arch. Orthop. Trauma Surg. 134: 515–520.
- 87Connizzo, B.K., S.M. Yannascoli, J.J. Tucker, et al. 2014. The detrimental effects of systemic Ibuprofen delivery on tendon healing are time-dependent. Clin. Orthop. Relat. Res. 472: 2433–2439.
- 88Cohen, D.B., S. Kawamura, J.R. Ehteshami, et al. 2006. Indomethacin and celecoxib impair rotator cuff tendon-to-bone healing. Am. J. Sports Med. 34: 362–369.
- 89Oak, N.R., J.P. Gumucio, M.D. Flood, et al. 2014. Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair. Am. J. Sports Med. 42: 2860–2868.
- 90Dolkart, O., T. Liron, O. Chechik, et al. 2014. Statins enhance rotator cuff healing by stimulating the COX2/PGE2/EP4 pathway: an in vivo and in vitro study. Am. J. Sports Med. 42: 2869–2876.
- 91Takahashi, K. & S. Yamanaka. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663–676.
- 92Evans, M.J. & M.H. Kaufman. 1981. Establishment in culture of pluripotential cells from mouse embryos. Nature 292: 154–156.
- 93Martin, G.R. 1981. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl. Acad. Sci. USA 78: 7634–7638.
- 94Pittenger, M.F., A.M. Mackay, S.C. Beck, et al. 1999. Multilineage potential of adult human mesenchymal stem cells. Science 284: 143–147.
- 95Murphy, M.M., J.A. Lawson, S.J. Mathew, et al. 2011. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138: 3625–3637.
- 96Bunnell, B.A., M. Flaat, C. Gagliardi, et al. 2008. Adipose-derived stem cells: isolation, expansion and differentiation. Methods 45: 115–120.
- 97Brown, J.P., T.V. Galassi, M. Stoppato, et al. 2015. Comparative analysis of mesenchymal stem cell and embryonic tendon progenitor cell response to embryonic tendon biochemical and mechanical factors. Stem Cell Res. Ther. 6: 89.
- 98Nerurkar, N.L., S. Sen, A.H. Huang, et al. 2010. Engineered disc-like angle-ply structures for intervertebral disc replacement. Spine 35: 867–873.
- 99Estes, B.T., B.O. Diekman, J.M. Gimble, et al. 2010. Isolation of adipose-derived stem cells and their induction to a chondrogenic phenotype. Nat. Protoc. 5: 1294–1311.
- 100Huang, A.H., A. Stein & R.L. Mauck. 2010. Evaluation of the complex transcriptional topography of mesenchymal stem cell chondrogenesis for cartilage tissue engineering. Tissue Eng. Part A 16: 2699–2708.
- 101Luu, Y.K., E. Capilla, C.J. Rosen, et al. 2009. Mechanical stimulation of mesenchymal stem cell proliferation and differentiation promotes osteogenesis while preventing dietary-induced obesity. J. Bone Miner. Res. 24: 50–61.
- 102Bi, Y., D. Ehirchiou, T.M. Kilts, et al. 2007. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat. Med. 13: 1219–1227.
- 103Wang, J.H. & X. Nirmala. 2016. Application of tendon stem/progenitor cells and platelet-rich plasma to treat tendon injuries. Oper. Tech. Orthop. 26: 68–72.
- 104Zhang, J. & J.H. Wang. 2015. Moderate exercise mitigates the detrimental effects of aging on tendon stem cells. PLoS One 10: e0130454.
- 105Lee, J.Y., Z. Zhou, P.J. Taub, et al. 2011. BMP-12 treatment of adult mesenchymal stem cells in vitro augments tendon-like tissue formation and defect repair in vivo. PLoS One 6: e17531.
- 106Zhou, Z., T. Akinbiyi, L. Xu, et al. 2010. Tendon-derived stem/progenitor cell aging: defective self-renewal and altered fate. Aging Cell 9: 911–915.
- 107Mienaltowski, M.J., S.M. Adams & D.E. Birk. 2013. Regional differences in stem cell/progenitor cell populations from the mouse achilles tendon. Tissue Eng. Part A 19: 199–210.
- 108Mendias, C.L., J.P. Gumucio, K.I. Bakhurin, et al. 2012. Physiological loading of tendons induces scleraxis expression in epitenon fibroblasts. J. Orthop. Res. 30: 606–612.
- 109Sugg, K.B., J. Lubardic, J.P. Gumucio, et al. 2014. Changes in macrophage phenotype and induction of epithelial-to-mesenchymal transition genes following acute Achilles tenotomy and repair. J. Orthop. Res. 32: 944–951.
- 110Rux, D.R., J.Y. Song, I.T. Swinehart, et al. 2016. Regionally restricted Hox function in adult bone marrow multipotent mesenchymal stem/stromal cells. Dev. Cell 39: 653–666.
- 111Pinho, S., J. Lacombe, M. Hanoun, et al. 2013. PDGFRα and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J. Exp. Med. 210: 1351–1367.
- 112Yin, Z., J.J. Hu, L. Yang, et al. 2016. Single-cell analysis reveals a nestin(+) tendon stem/progenitor cell population with strong tenogenic potentiality. Sci. Adv. 2: e1600874.
- 113Kim, Y.S., C.H. Sung, S.H. Chung, et al. 2017. Does an injection of adipose-derived mesenchymal stem cells loaded in fibrin glue influence rotator cuff repair outcomes? A clinical and magnetic resonance imaging study. Am. J. Sports Med. 45: 2010–2018.
- 114Hernigou, P., C.H. Flouzat Lachaniette, J. Delambre, et al. 2014. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case–controlled study. Int. Orthop. 38: 1811–1818.
- 115 U.S. Food and Drug Administration. 2017. FDA warns about stem cell therapies. Accessed June 1, 2018. https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm286155.htm.
- 116Spalazzi, J.P., M.C. Vyner, M.T. Jacobs, et al. 2008. Mechanoactive scaffold induces tendon remodeling and expression of fibrocartilage markers. Clin. Orthop. Relat. Res. 466: 1938–1948.
- 117Zhang, X., D. Bogdanowicz, C. Erisken, et al. 2012. Biomimetic scaffold design for functional and integrative tendon repair. J. Shoulder Elbow Surg. 21: 266–277.
- 118Larkin, L.M., S. Calve, T.Y. Kostrominova, et al. 2006. Structure and functional evaluation of tendon-skeletal muscle constructs engineered in vitro. Tissue Eng. 12: 3149–3158.
- 119Yang, G., B.B. Rothrauff, H. Lin, et al. 2017. Tendon-derived extracellular matrix enhances transforming growth factor-β3-induced tenogenic differentiation of human adipose-derived stem cells. Tissue Eng. Part A 23: 166–176.
- 120Peach, M.S., D.M. Ramos, R. James, et al. 2017. Engineered stem cell niche matrices for rotator cuff tendon regenerative engineering. PLoS One 12: e0174789.
- 121Degen, R.M., A. Carbone, C. Carballo, et al. 2016. The effect of purified human bone marrow-derived mesenchymal stem cells on rotator cuff tendon healing in an athymic rat. Arthroscopy 32: 2435–2443.
- 122Zong, J.C., M.J. Mosca, R.M. Degen, et al. 2017. Involvement of Indian hedgehog signaling in mesenchymal stem cell-augmented rotator cuff tendon repair in an athymic rat model. J. Shoulder Elbow Surg. 26: 580–588.
- 123Omi, R., A. Gingery, S.P. Steinmann, et al. 2016. Rotator cuff repair augmentation in a rat model that combines a multilayer xenograft tendon scaffold with bone marrow stromal cells. J. Shoulder Elbow Surg. 25: 469–477.
- 124Liu, W., S.S. Watson, Y. Lan, et al. 2010. The atypical homeodomain transcription factor Mohawk controls tendon morphogenesis. Mol. Cell. Biol. 30: 4797–4807.
- 125Ito, Y., N. Toriuchi, T. Yoshitaka, et al. 2010. The Mohawk homeobox gene is a critical regulator of tendon differentiation. Proc. Natl. Acad. Sci. USA 107: 10538–10542.
- 126Gulotta, L.V., D. Kovacevic, J.D. Packer, et al. 2011. Bone marrow-derived mesenchymal stem cells transduced with scleraxis improve rotator cuff healing in a rat model. Am. J. Sports Med. 39: 1282–1289.
- 127Cheng, B., H. Ge, J. Zhou, et al. 2014. TSG-6 mediates the effect of tendon derived stem cells for rotator cuff healing. Eur. Rev. Med. Pharmacol. Sci. 18: 247–251.
- 128Gao, F., S.M. Chiu, D.A. Motan, et al. 2016. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 7: e2062.
- 129Valencia Mora, M., S. Antuna Antuna, M. Garcia Arranz, et al. 2014. Application of adipose tissue-derived stem cells in a rat rotator cuff repair model. Injury 45(Suppl. 4): S22–S27.
- 130Gao, Y., Y. Zhang, Y. Lu, et al. 2016. TOB1 deficiency enhances the effect of bone marrow-derived mesenchymal stem cells on tendon-bone healing in a rat rotator cuff repair model. Cell. Physiol. Biochem. 38: 319–329.
- 131Gulotta, L.V., D. Kovacevic, S. Montgomery, et al. 2010. Stem cells genetically modified with the developmental gene MT1-MMP improve regeneration of the supraspinatus tendon-to-bone insertion site. Am. J. Sports Med. 38: 1429–1437.
