Biologics for tendon repair

Denitsa Docheva, Sebastian A Müller, Martin Majewski, Christopher H Evans, Denitsa Docheva, Sebastian A Müller, Martin Majewski, Christopher H Evans

Abstract

Tendon injuries are common and present a clinical challenge to orthopedic surgery mainly because these injuries often respond poorly to treatment and require prolonged rehabilitation. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. To date, none of these alternatives has provided a successful long-term solution, and often the restored tendons do not recover their complete strength and functionality. Unfortunately, our understanding of tendon biology lags far behind that of other musculoskeletal tissues, thus impeding the development of new treatment options for tendon conditions. Hence, in this review, after introducing the clinical significance of tendon diseases and the present understanding of tendon biology, we describe and critically assess the current strategies for enhancing tendon repair by biological means. These consist mainly of applying growth factors, stem cells, natural biomaterials and genes, alone or in combination, to the site of tendon damage. A deeper understanding of how tendon tissue and cells operate, combined with practical applications of modern molecular and cellular tools could provide the long awaited breakthrough in designing effective tendon-specific therapeutics and overall improvement of tendon disease management.

Keywords: Cell-based therapy; Embryonic stem cells; Gene therapy; Growth Factors; Mesenchymal stem cells; Natural biomaterials; Tendon; Tendon repair; Tendon-derived cells.

Copyright © 2014. Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
A schematic drawing of basic tendon structure. The collagen molecules are organized hierarchically in fibrils, fibers and fascicles. The cellular content is dominated by the tenocytes, which are terminally differentiated cells. Tendons contain stem and progenitor cell populations, whose exact location is still debated (therefore indicated with a?). Different sheets, endotenon and epitenon (loose connective tissues), and paratenon (fatty areolar tissue) are shown as well as blood vessels and nerves. Based on [227].
Fig. 2
Fig. 2
The tendon repair process in humans. The healing of ruptured tendons passes through three main phases containing distinctive cell and molecular cascades. These phases overlap and their duration depends upon the location and severity of the tendon injury. Currently, the tendon research field is actively exploring the use of growth factors, genes, stem cells and biomaterials, alone or in various combinations, for enhancing tendon healing. Mostly, the appropriate times of application are in the first two stages (indicated by white arrows), and depend on the type of growth factors, genes, stem cells or biomaterials implemented. Based on [47].
Fig. 3
Fig. 3
Key molecular, cellular and matrix changes occurring during the three main phases of tendon repair. Each healing stage is characterized by involvement of different growth factors, activation of certain cell types and production of essential matrix proteins, which collectively contribute to the replacement of the initial fibrous tissue with more a tendonous regenerate. Based on [45,46].
Fig. 4
Fig. 4
Studies on the use of biologics for tendon repair. Article counts were carried out after searching in PubMed using the following key words: tendon repair/healing in combination with growth factors, stem cells, biomaterials and gene therapy. The articles include in vivo and in vitro studies, and some articles scored in more then one category. The search results demonstrate that in the last decade the tendon research field has progressively expanded as represented by the continuous increase in the number of articles focusing on different strategies for enhancing tendon tissue healing. Such cumulative efforts may lead to the development of efficient biologics for tendon repair.

References

    1. Aslan H, Kimelman-Bleich N, Pelled G, Gazit D. Molecular targets for tendon neoformation. J. Clin. Invest. 2008;118:439–444.
    1. Benjamin M, Kaiser E, Milz S. Structure–function relationships in tendons: a review. J. Anat. 2008;212:211–228.
    1. Urwin M, Symmons D, Allison T, Brammah T, Busby H, Roxby M, Simmons A, Williams G. Estimating the burden of musculoskeletal disorders in the community: the comparative prevalence of symptoms at different anatomical sites, and the relation to social deprivation. Ann. Rheum. Dis. 1998;57:649–655.
    1. Chard MD, Hazleman R, Hazleman BL, King RH, Reiss BB. Shoulder disorders in the elderly: a community survey. Arthritis Rheum. 1991;34:766–769.
    1. Kannus P. Tendons — a source of major concern in competitive and recreational athletes. Scand. J. Med. Sci. Sports. 1997;7:53–54.
    1. Maffulli N, Khan KM, Puddu G. Overuse tendon conditions: time to change a confusing terminology. Arthroscopy. 1998;14:840–843.
    1. Gibson W. Are “spontaneous” Achilles tendon ruptures truly spontaneous? Br. J. Sports Med. 1998;32:266.
    1. Riley G. The pathogenesis of tendinopathy. A molecular perspective. Rheumatology (Oxford) 2004;43:131–142.
    1. Rees JD, Wilson AM, Wolman RL. Current concepts in the management of tendon disorders. Rheumatology (Oxford) 2006;45:508–521.
    1. Mokone GG, Schwellnus MP, Noakes TD, Collins M. The COL5A1 gene and Achilles tendon pathology. Scand. J. Med. Sci. Sports. 2006;16:19–26.
    1. Jozsa L, Balint JB, Kannus P, Reffy A, Barzo M. Distribution of blood groups in patients with tendon rupture. An analysis of 832 cases. J. Bone Joint Surg. (Br.) 1989;71:272–274.
    1. Benjamin M, Ralphs JR. Tendons and ligaments — an overview. Histol. Histopathol. 1997;12:1135–1144.
    1. Maffulli NR, Leadbetter WB. Tendon Injuries. Springer-Verlag New York Inc.; 2005. P.
    1. Wilkins R, Bisson LJ. Operative versus nonoperative management of acute Achilles tendon ruptures: a quantitative systematic review of randomized controlled trials. Am. J. Sports Med. 2012;40:2154–2160.
    1. Bishay V, Gallo RA. The evaluation and treatment of rotator cuff pathology. Prim. Care. 2013;40:889–910. (viii)
    1. Raschke D, Schuttrumpf JP, Tezval M, Sturmer KM, Balcarek P. Extensor-mechanism-reconstruction of the knee joint after traumatic loss of the entire extensor apparatus. Knee. 2014;21:793–796.
    1. Hintermann B, Knupp M. Injuries and dysfunction of the posterior tibial tendon. Orthopade. 2010;39:1148–1157.
    1. Drake DB, Tilt AC, DeGeorge BR. Acellular flexor tendon allografts: a new horizon for tendon reconstruction. J. Hand. Surg. [Am.] 2013;38:2491–2495.
    1. Shybut TB, Pahk B, Hall G, Meislin RJ, Rokito AS, Rosen J, Jazrawi LM, Sherman OH. Functional outcomes of anterior cruciate ligament reconstruction with tibialis anterior allograft. Bull. Hosp. Jt Dis. 2013;71:138–143.
    1. Liu CF, Aschbacher-Smith L, Barthelery NJ, Dyment N, Butler D, Wylie C. What we should know before using tissue engineering techniques to repair injured tendons: a developmental biology perspective. Tissue Eng. B Rev. 2011;17:165–176.
    1. Pennisi E. Tending tender tendons. Science. 2002;295:1011.
    1. Sun Y, Berger EJ, Zhao C, An KN, Amadio PC, Jay G. Mapping lubricin in canine musculoskeletal tissues. Connect. Tissue Res. 2006;47:215–221.
    1. Kannus P. Structure of the tendon connective tissue. Scand. J. Med. Sci. Sports. 2000;10:312–320.
    1. Kielty CM, Sherratt MJ, Shuttleworth CA. Elastic fibres. J. Cell Sci. 2002;115:2817–2828.
    1. Butler DL, Grood ES, Noyes FR, Zernicke RF. Biomechanics of ligaments and tendons. Exerc. Sport Sci. Rev. 1978;6:125–181.
    1. Chuen FS, Chuk CY, Ping WY, Nar WW, Kim HL, Ming CK. Immunohistochemical characterization of cells in adult human patellar tendons. J. Histochem. Cytochem. 2004;52:1151–1157.
    1. Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat. Med. 2007;13:1219–1227.
    1. Tempfer H, Wagner A, Gehwolf R, Lehner C, Tauber M, Resch H, Bauer HC. Perivascular cells of the supraspinatus tendon express both tendon- and stem cell-related markers. Histochem. Cell Biol. 2009;131:733–741.
    1. Kohler J, Popov C, Klotz B, Alberton P, Prall WC, Haasters F, Muller-Deubert S, Ebert R, Klein-Hitpass L, Jakob F, Schieker M, Docheva D. Uncovering the cellular and molecular changes in tendon stem/progenitor cells attributed to tendon aging and degeneration. Aging Cell. 2013;12:988–999.
    1. Rui YF, Lui PP, Li G, Fu SC, Lee YW, Chan KM. Isolation and characterization of multipotent rat tendon-derived stem cells. Tissue Eng. A. 2010;16:1549–1558.
    1. Zhang J, Wang JH. Characterization of differential properties of rabbit tendon stem cells and tenocytes. BMC Musculoskelet. Disord. 2010;11:10.
    1. Haasters F, Polzer H, Prall WC, Saller MM, Kohler J, Grote S, Mutschler W, Docheva D, Schieker M. Bupivacaine, ropivacaine, and morphine: comparison of toxicity on human hamstring-derived stem/progenitor cells. Knee Surg. Sports Traumatol. Arthrosc. 2011;19:2138–2144.
    1. Steinert AF, Kunz M, Prager P, Barthel T, Jakob F, Noth U, Murray MM, Evans CH, Porter RM. Mesenchymal stem cell characteristics of human anterior cruciate ligament outgrowth cells. Tissue Eng. A. 2011;17:1375–1388.
    1. Lovati AB, Corradetti B, Lange Consiglio A, Recordati C, Bonacina E, Bizzaro D, Cremonesi F. Characterization and differentiation of equine tendon-derived progenitor cells. J. Biol. Regul. Homeost. Agents. 2011;25:S75–S84.
    1. Mienaltowski MJ, Adams SM, Birk DE. Regional differences in stem cell/progenitor cell populations from the mouse Achilles tendon. Tissue Eng. A. 2013;19:199–210.
    1. Carpenter JE, Hankenson KD. Animal models of tendon and ligament injuries for tissue engineering applications. Biomaterials. 2004;25:1715–1722.
    1. Warden SJ. Animal models for the study of tendinopathy. Br. J. Sports Med. 2007;41:232–240.
    1. Lin TW, Cardenas L, Soslowsky LJ. Biomechanics of tendon injury and repair. J. Biomech. 2004;37:865–877.
    1. Voleti PB, Buckley MR, Soslowsky LJ. Tendon healing: repair and regeneration. Annu. Rev. Biomed. Eng. 2012;14:47–71.
    1. Yang G, Rothrauff BB, Tuan RS. Tendon and ligament regeneration and repair: clinical relevance and developmental paradigm. Birth Defects Res. C Embryo Today. 2013;99:203–222.
    1. Fenwick SA, Hazleman BL, Riley GP. The vasculature and its role in the damaged and healing tendon. Arthritis Res. 2002;4:252–260.
    1. EVans CH. Cytokines and the role they play in the healing of ligaments and tendons. Sports Med. 1999;28:71–76.
    1. Sharma P, Maffulli N. Basic biology of tendon injury and healing. Surgeon. 2005;3:309–316.
    1. Sharma P, Maffulli N. Tendon injury and tendinopathy: healing and repair. J. Bone Joint Surg. Am. 2005;87:187–202.
    1. Kajikawa Y, Morihara T, Watanabe N, Sakamoto H, Matsuda K, Kobayashi M, Oshima Y, Yoshida A, Kawata M, Kubo T. GFP chimeric models exhibited a biphasic pattern of mesenchymal cell invasion in tendon healing. J. Cell. Physiol. 2007;210:684–691.
    1. James R, Kesturu G, Balian G, Chhabra AB. Tendon: biology, biomechanics, repair, growth factors, and evolving treatment options. J. Hand. Surg. [Am.] 2008;33:102–112.
    1. Sharma P, Maffulli N. Biology of tendon injury: healing, modeling and remodeling. J. Musculoskelet. Neuronal Interact. 2006;6:181–190.
    1. Heisterbach PE, Todorov A, Fluckiger R, Evans CH, Majewski M. Effect of BMP-12, TGF-beta1 and autologous conditioned serum on growth factor expression in Achilles tendon healing. Knee Surg. Sports Traumatol. Arthrosc. 2012;20:1907–1914.
    1. Wurgler-Hauri CC, Dourte LM, Baradet TC, Williams GR, Soslowsky LJ. Temporal expression of 8 growth factors in tendon-to-bone healing in a rat supraspinatus model. J. Shoulder Elbow Surg. 2007;16:S198–S203.
    1. Chen CH, Cao Y, Wu YF, Bais AJ, Gao JS, Tang JB. Tendon healing in vivo: gene expression and production of multiple growth factors in early tendon healing period. J. Hand. Surg. [Am.] 2008;33:1834–1842.
    1. Kobayashi M, Itoi E, Minagawa H, Miyakoshi N, Takahashi S, Tuoheti Y, Okada K, Shimada Y. Expression of growth factors in the early phase of supraspinatus tendon healing in rabbits. J. Shoulder Elbow Surg. 2006;15:371–377.
    1. Molloy T, Wang Y, Murrell G. The roles of growth factors in tendon and ligament healing. Sports Med. 2003;33:381–394.
    1. Chang J, Most D, Thunder R, Mehrara B, Longaker MT, Lineaweaver WC. Molecular studies in flexor tendon wound healing: the role of basic fibroblast growth factor gene expression. J. Hand. Surg. [Am.] 1998;23:1052–1058.
    1. Muller SA, Todorov A, Heisterbach PE, Martin I, Majewski M. Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. Knee Surg. Sports Traumatol. Arthrosc. 2013 .
    1. Park A, Hogan MV, Kesturu GS, James R, Balian G, Chhabra AB. Adipose-derived mesenchymal stem cells treated with growth differentiation factor-5 express tendon-specific markers. Tissue Eng. A. 2010;16:2941–2951.
    1. Wolfman NM, Hattersley G, Cox K, Celeste AJ, Nelson R, Yamaji N, Dube JL, DiBlasio-Smith E, Nove J, Song JJ, Wozney JM, Rosen V. 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. 1997;100:321–330.
    1. Rodeo SA, Suzuki K, Deng XH, Wozney J, Warren RF. Use of recombinant human bone morphogenetic protein-2 to enhance tendon healing in a bone tunnel. Am. J. Sports Med. 1999;27:476–488.
    1. Hashimoto Y, Yoshida G, Toyoda H, Takaoka K. Generation of tendon-to-bone interface “enthesis” with use of recombinant BMP-2 in a rabbit model. J. Orthop. Res. 2007;25:1415–1424.
    1. Chen CH, Chang CH, Wang KC, Su CI, Liu HT, Yu CM, Wong CB, Wang IC, Whu SW, Liu HW. Enhancement of rotator cuff tendon-bone healing with injectable periosteum progenitor cells-BMP-2 hydrogel in vivo. Knee Surg. Sports Traumatol. Arthrosc. 2011;19:1597–1607.
    1. Trippel SB, Wroblewski J, Makower AM, Whelan MC, Schoenfeld D, Doctrow SR. Regulation of growth-plate chondrocytes by insulin-like growth-factor I and basic fibroblast growth factor. J. Bone Joint Surg. Am. 1993;75:177–189.
    1. Dahlgren LA, Mohammed HO, Nixon AJ. Temporal expression of growth factors and matrix molecules in healing tendon lesions. J. Orthop. Res. 2005;23:84–92.
    1. Sciore P, Boykiw R, Hart DA. Semiquantitative reverse transcription-polymerase chain reaction analysis of mRNA for growth factors and growth factor receptors from normal and healing rabbit medial collateral ligament tissue. J. Orthop. Res. 1998;16:429–437.
    1. Duffy FJ, Jr., Seiler JG, Gelberman RH, Hergrueter CA. Growth factors and canine flexor tendon healing: initial studies in uninjured and repair models. J. Hand. Surg. [Am.] 1995;20:645–649.
    1. Chan BP, Fu SC, Qin L, Rolf C, Chan KM. Supplementation-time dependence of growth factors in promoting tendon healing. Clin. Orthop. Relat. Res. 2006;448:240–247.
    1. Klein MB, Yalamanchi N, Pham H, Longaker MT, Chang J. Flexor tendon healing in vitro: effects of TGF-beta on tendon cell collagen production. J. Hand. Surg. [Am.] 2002;27:615–620.
    1. Chang J, Thunder R, Most D, Longaker MT, Lineaweaver WC. Studies in flexor tendon wound healing: neutralizing antibody to TGF-beta1 increases postoperative range of motion. Plast. Reconstr. Surg. 2000;105:148–155.
    1. Natsu-ume T, Nakamura N, Shino K, Toritsuka Y, Horibe S, Ochi T. Temporal and spatial expression of transforming growth factor-beta in the healing patellar ligament of the rat. J. Orthop. Res. 1997;15:837–843.
    1. Chang J, Most D, Stelnicki E, Siebert JW, Longaker MT, Hui K, Lineaweaver WC. Gene expression of transforming growth factor beta-1 in rabbit zone II flexor tendon wound healing: evidence for dual mechanisms of repair. Plast. Reconstr. Surg. 1997;100:937–944.
    1. Ngo M, Pham H, Longaker MT, Chang J. Differential expression of transforming growth factor-beta receptors in a rabbit zone II flexor tendon wound healing model. Plast. Reconstr. Surg. 2001;108:1260–1267.
    1. Juneja SC, Schwarz EM, O'Keefe RJ, Awad HA. Cellular and molecular factors in flexor tendon repair and adhesions: a histological and gene expression analysis. Connect. Tissue Res. 2013;54:218–226.
    1. Jorgensen HG, McLellan SD, Crossan JF, Curtis AS. Neutralisation of TGF beta or binding of VLA-4 to fibronectin prevents rat tendon adhesion following transection. Cytokine. 2005;30:195–202.
    1. Katzel EB, Wolenski M, Loiselle AE, Basile P, Flick LM, Langstein HN, Hilton MJ, Awad HA, Hammert WC, O'Keefe RJ. Impact of Smad3 loss of function on scarring and adhesion formation during tendon healing. J. Orthop. Res. 2011;29:684–693.
    1. Farhat YM, Al-Maliki AA, Chen T, Juneja SC, Schwarz EM, O'Keefe RJ, Awad HA. Gene expression analysis of the pleiotropic effects of TGF-beta1 in an in vitro model of flexor tendon healing. PLoS One. 2012;7:e51411.
    1. Farhat YM, Al-Maliki AA, Easa A, O'Keefe RJ, Schwarz EM, Awad HA. TGF-beta1 suppresses plasmin and MMP activity in flexor tendon cells via PAI-1: implications for scarless flexor tendon repair. J. Cell. Physiol. 2014 .
    1. Petersen W, Unterhauser F, Pufe T, Zantop T, Sudkamp NP, Weiler A. The angiogenic peptide vascular endothelial growth factor (VEGF) is expressed during the remodeling of free tendon grafts in sheep. Arch. Orthop. Trauma Surg. 2003;123:168–174.
    1. Zhang F, Liu H, Stile F, Lei MP, Pang Y, Oswald TM, Beck J, Dorsett-Martin W, Lineaweaver WC. Effect of vascular endothelial growth factor on rat Achilles tendon healing. Plast. Reconstr. Surg. 2003;112:1613–1619.
    1. Hamada Y, Katoh S, Hibino N, Kosaka H, Hamada D, Yasui N. Effects of monofilament nylon coated with basic fibroblast growth factor on endogenous intrasynovial flexor tendon healing. J. Hand. Surg. [Am.] 2006;31:530–540.
    1. Uggen C, Dines J, McGarry M, Grande D, Lee T, Limpisvasti O. The effect of recombinant human platelet-derived growth factor BB-coated sutures on rotator cuff healing in a sheep model. Arthroscopy. 2010;26:1456–1462.
    1. Rickert M, Jung M, Adiyaman M, Richter W, Simank HG. A growth and differentiation factor-5 (GDF-5)-coated suture stimulates tendon healing in an Achilles tendon model in rats. Growth Factors. 2001;19:115–126.
    1. Anaguchi Y, Yasuda K, Majima T, Tohyama H, Minami A, Hayashi K. The effect of transforming growth factor-beta on mechanical properties of the fibrous tissue regenerated in the patellar tendon after resecting the central portion. Clin. Biomech. (Bristol, Avon) 2005;20:959–965.
    1. Zhang AY, Pham H, Ho F, Teng K, Longaker MT, Chang J. Inhibition of TGF-beta-induced collagen production in rabbit flexor tendons. J. Hand. Surg. [Am.] 2004;29:230–235.
    1. Klass BR, Rolfe KJ, Grobbelaar AO. In vitro flexor tendon cell response to TGF-beta1: a gene expression study. J. Hand. Surg. [Am.] 2009;34:495–503.
    1. Bidder M, Towler DA, Gelberman RH, Boyer MI. Expression of mRNA for vascular endothelial growth factor at the repair site of healing canine flexor tendon. J. Orthop. Res. 2000;18:247–252.
    1. Boyer MI, Watson JT, Lou J, Manske PR, Gelberman RH, Cai SR. Quantitative variation in vascular endothelial growth factor mRNA expression during early flexor tendon healing: an investigation in a canine model. J. Orthop. Res. 2001;19:869–872.
    1. Thomopoulos S, Harwood FL, Silva MJ, Amiel D, Gelberman RH. Effect of several growth factors on canine flexor tendon fibroblast proliferation and collagen synthesis in vitro. J. Hand. Surg. [Am.] 2005;30:441–447.
    1. Thomopoulos S, Das R, Silva MJ, Sakiyama-Elbert S, Harwood FL, Zampiakis E, Kim HM, Amiel D, Gelberman RH. Enhanced flexor tendon healing through controlled delivery of PDGF-BB. J. Orthop. Res. 2009;27:1209–1215.
    1. Harwood FL, Goomer RS, Gelberman RH, Silva MJ, Amiel D. Regulation of alpha(v)beta3 and alpha5beta1 integrin receptors by basic fibroblast growth factor and platelet-derived growth factor-BB in intrasynovial flexor tendon cells. Wound Repair Regen. 1999;7:381–388.
    1. Yoshikawa Y, Abrahamsson SO. Dose-related cellular effects of platelet-derived growth factor-BB differ in various types of rabbit tendons in vitro. Acta Orthop. Scand. 2001;72:287–292.
    1. Chan BP, Chan KM, Maffulli N, Webb S, Lee KK. Effect of basic fibroblast growth factor. An in vitro study of tendon healing. Clin. Orthop. Relat. Res. 1997:239–247.
    1. Abrahamsson SO, Lundborg G, Lohmander LS. Recombinant human insulin-like growth factor-I stimulates in vitro matrix synthesis and cell proliferation in rabbit flexor tendon. J. Orthop. Res. 1991;9:495–502.
    1. Abrahamsson SO. Similar effects of recombinant human insulin-like growth factor-I and II on cellular activities in flexor tendons of young rabbits: experimental studies in vitro. J. Orthop. Res. 1997;15:256–262.
    1. Batten ML, Hansen JC, Dahners LE. Influence of dosage and timing of application of platelet-derived growth factor on early healing of the rat medial collateral ligament. J. Orthop. Res. 1996;14:736–741.
    1. Ide J, Kikukawa K, Hirose J, Iyama K, Sakamoto H, Mizuta H. The effects of fibroblast growth factor-2 on rotator cuff reconstruction with acellular dermal matrix grafts. Arthroscopy. 2009;25:608–616.
    1. Rodeo SA. Biologic augmentation of rotator cuff tendon repair. J. Shoulder Elbow Surg. 2007;16:S191–S197.
    1. Costa MA, Wu C, Pham BV, Chong AK, Pham HM, Chang J. Tissue engineering of flexor tendons: optimization of tenocyte proliferation using growth factor supplementation. Tissue Eng. 2006;12:1937–1943.
    1. Aspenberg P, Virchenko O. Platelet concentrate injection improves Achilles tendon repair in rats. Acta Orthop. Scand. 2004;75:93–99.
    1. Bosch G, van Schie HT, de Groot MW, Cadby JA, van de Lest CH, Barneveld A, van Weeren PR. Effects of platelet-rich plasma on the quality of repair of mechanically induced core lesions in equine superficial digital flexor tendons: a placebo-controlled experimental study. J. Orthop. Res. 2010;28:211–217.
    1. Majewski M, Ochsner PE, Liu F, Fluckiger R, Evans CH. Accelerated healing of the rat Achilles tendon in response to autologous conditioned serum. Am. J. Sports Med. 2009;37:2117–2125.
    1. Schnabel LV, Mohammed HO, Miller BJ, McDermott WG, Jacobson MS, Santangelo KS, Fortier LA. Platelet rich plasma (PRP) enhances anabolic gene expression patterns in flexor digitorum superficialis tendons. J. Orthop. Res. 2007;25:230–240.
    1. Gosens T, Den Oudsten BL, Fievez E, van 't Spijker P, Fievez A. Pain and activity levels before and after platelet-rich plasma injection treatment of patellar tendinopathy: a prospective cohort study and the influence of previous treatments. Int. Orthop. 2012;36:1941–1946.
    1. de Almeida AM, Demange MK, Sobrado MF, Rodrigues MB, Pedrinelli A, Hernandez AJ. Patellar tendon healing with platelet-rich plasma: a prospective randomized controlled trial. Am. J. Sports Med. 2012;40:1282–1288.
    1. Seijas R, Ares O, Catala J, Alvarez-Diaz P, Cusco X, Cugat R. Magnetic resonance imaging evaluation of patellar tendon graft remodelling after anterior cruciate ligament reconstruction with or without platelet-rich plasma. J. Orthop. Surg. (Hong Kong) 2013;21:10–14.
    1. Schepull T, Kvist J, Norrman H, Trinks M, Berlin G, Aspenberg P. Autologous platelets have no effect on the healing of human Achilles tendon ruptures: a randomized single-blind study. Am. J. Sports Med. 2011;39:38–47.
    1. de Vos RJ, Weir A, van Schie HT, Bierma-Zeinstra SM, Verhaar JA, Weinans H, Tol JL. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA. 2010;303:144–149.
    1. de Vos RJ, Windt J, Weir A. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br. J. Sports Med. 2014;48:952–956.
    1. Hall MP, Ward JP, Cardone DA. Platelet rich placebo? Evidence for platelet rich plasma in the treatment of tendinopathy and augmentation of tendon repair. Bull. Hosp. Jt Dis. 2013;71:54–59.
    1. Evans CH. Platelet-rich plasma a la carte: commentary on an article by Satoshi Terada, MD, et al.: “use of an antifibrotic agent improves the effect of platelet-rich plasma on muscle healing after injury”. J. Bone Joint Surg. Am. 2013;95:e801–e802.
    1. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 2005;6:1191–1197.
    1. Yuan T, Zhang CQ, Wang JH. Augmenting tendon and ligament repair with platelet-rich plasma (PRP) Muscles Ligaments Tendons J. 2013;3:139–149.
    1. Obaid H, Connell D. Cell therapy in tendon disorders: what is the current evidence? Am. J. Sports Med. 2010;38:2123–2132.
    1. Longo UG, Lamberti A, Maffulli N, Denaro V. Tissue engineered biological augmentation for tendon healing: a systematic review. Br. Med. Bull. 2011;98:31–59.
    1. Yin Z, Chen X, Chen JL, Ouyang HW. Stem cells for tendon tissue engineering and regeneration. Expert. Opin. Biol. Ther. 2010;10:689–700.
    1. Ahmad Z, Wardale J, Brooks R, Henson F, Noorani A, Rushton N. Exploring the application of stem cells in tendon repair and regeneration. Arthroscopy. 2012;28:1018–1029.
    1. Nixon AJ, Watts AE, Schnabel LV. Cell- and gene-based approaches to tendon regeneration. J. Shoulder Elbow Surg. 2012;21:278–294.
    1. Hogan MV, Bagayoko N, James R, Starnes T, Katz A, Chhabra AB. Tissue engineering solutions for tendon repair. J. Am. Acad. Orthop. Surg. 2011;19:134–142.
    1. Bocker W, Yin Z, Drosse I, Haasters F, Rossmann O, Wierer M, Popov C, Locher M, Mutschler W, Docheva D, Schieker M. Introducing a single-cell-derived human mesenchymal stem cell line expressing hTERT after lentiviral gene transfer. J. Cell. Mol. Med. 2008;12:1347–1359.
    1. Docheva D, Popov C, Mutschler W, Schieker M. Human mesenchymal stem cells in contact with their environment: surface characteristics and the integrin system. J. Cell. Mol. Med. 2007;11:21–38.
    1. Tan SL, Ahmad RE, Ahmad TS, Merican AM, Abbas AA, Ng WM, Kamarul T. Effect of growth differentiation factor 5 on the proliferation and tenogenic differentiation potential of human mesenchymal stem cells in vitro. Cells Tissues Organs. 2012;196:325–338.
    1. Violini S, Ramelli P, Pisani LF, Gorni C, Mariani P. Horse bone marrow mesenchymal stem cells express embryo stem cell markers and show the ability for tenogenic differentiation by in vitro exposure to BMP-12. BMC Cell Biol. 2009;10:29.
    1. Hoffmann A, Pelled G, Turgeman G, Eberle P, Zilberman Y, Shinar H, Keinan-Adamsky K, Winkel A, Shahab S, Navon G, Gross G, Gazit D. Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells. J. Clin. Invest. 2006;116:940–952.
    1. Haddad-Weber M, Prager P, Kunz M, Seefried L, Jakob F, Murray MM, Evans CH, Noth U, Steinert AF. BMP12 and BMP13 gene transfer induce ligamentogenic differentiation in mesenchymal progenitor and anterior cruciate ligament cells. Cytotherapy. 2010;12:505–513.
    1. Alberton P, Popov C, Pragert M, Kohler J, Shukunami C, Schieker M, Docheva D. Conversion of human bone marrow-derived mesenchymal stem cells into tendon progenitor cells by ectopic expression of scleraxis. Stem Cells Dev. 2012;21:846–858.
    1. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–1822.
    1. Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009;20:419–427.
    1. Chaudhury S. Mesenchymal stem cell applications to tendon healing. Muscles Ligaments Tendons J. 2012;2:222–229.
    1. Mazzocca AD, McCarthy MB, Chowaniec D, Cote MP, Judson CH, Apostolakos J, Solovyova O, Beitzel K, Arciero RA. Bone marrow-derived mesenchymal stem cells obtained during arthroscopic rotator cuff repair surgery show potential for tendon cell differentiation after treatment with insulin. Arthroscopy. 2011;27:1459–1471.
    1. Ellera Gomes JL, da Silva RC, Silla LM, Abreu MR, Pellanda R. Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells. Knee Surg. Sports Traumatol. Arthrosc. 2012;20:373–377.
    1. Liu TM, Martina M, Hutmacher DW, Hui JH, Lee EH, Lim B. Identification of common pathways mediating differentiation of bone marrow- and adipose tissue-derived human mesenchymal stem cells into three mesenchymal lineages. Stem Cells. 2007;25:750–760.
    1. Yoshimura H, Muneta T, Nimura A, Yokoyama A, Koga H, Sekiya I. Comparison of rat mesenchymal stem cells derived from bone marrow, synovium, periosteum, adipose tissue, and muscle. Cell Tissue Res. 2007;327:449–462.
    1. Schneider PR, Buhrmann C, Mobasheri A, Matis U, Shakibaei M. Three-dimensional high-density co-culture with primary tenocytes induces tenogenic differentiation in mesenchymal stem cells. J. Orthop. Res. 2011;29:1351–1360.
    1. Kryger GS, Chong AK, Costa M, Pham H, Bates SJ, Chang J. A comparison of tenocytes and mesenchymal stem cells for use in flexor tendon tissue engineering. J. Hand. Surg. [Am.] 2007;32:597–605.
    1. Nixon AJ, Dahlgren LA, Haupt JL, Yeager AE, Ward DL. Effect of adipose-derived nucleated cell fractions on tendon repair in horses with collagenase-induced tendinitis. Am. J. Vet. Res. 2008;69:928–937.
    1. Behfar M, Sarrafzadeh-Rezaei F, Hobbenaghi R, Delirezh N, Dalir-Naghadeh B. Enhanced mechanical properties of rabbit flexor tendons in response to intratendinous injection of adipose derived stromal vascular fraction. Curr. Stem Cell Res. Ther. 2012;7:173–178.
    1. Uysal AC, Mizuno H. Tendon regeneration and repair with adipose derived stem cells. Curr. Stem Cell Res. Ther. 2010;5:161–167.
    1. Wobus AM, Boheler KR. Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol. Rev. 2005;85:635–678.
    1. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–872.
    1. Watts AE, Yeager AE, Kopyov OV, Nixon AJ. Fetal derived embryonic-like stem cells improve healing in a large animal flexor tendonitis model. Stem Cell Res. Ther. 2011;2:4.
    1. Guest DJ, Smith MR, Allen WR. Equine embryonic stem-like cells and mesenchymal stromal cells have different survival rates and migration patterns following their injection into damaged superficial digital flexor tendon. Equine Vet. J. 2010;42:636–642.
    1. Chen X, Zou XH, Yin GL, Ouyang HW. Tendon tissue engineering with mesenchymal stem cells and biografts: an option for large tendon defects? Front. Biosci. (Schol. Ed.) 2009;1:23–32.
    1. Xu W, Wang Y, Liu E, Sun Y, Luo Z, Xu Z, Liu W, Zhong L, Lv Y, Wang A, Tang Z, Li S, Yang L. Human iPSC-derived neural crest stem cells promote tendon repair in a rat patellar tendon window defect model. Tissue Eng. A. 2013;19:2439–2451.
    1. Lui PP, Chan KM. Tendon-derived stem cells (TDSCs): from basic science to potential roles in tendon pathology and tissue engineering applications. Stem Cell Rev. 2011;7:883–897.
    1. Lui PP. Identity of tendon stem cells — how much do we know? J. Cell. Mol. Med. 2013;17:55–64.
    1. Yao L, Bestwick CS, Bestwick LA, Maffulli N, Aspden RM. Phenotypic drift in human tenocyte culture. Tissue Eng. 2006;12:1843–1849.
    1. Schulze-Tanzil G, Mobasheri A, Clegg PD, Sendzik J, John T, Shakibaei M. Cultivation of human tenocytes in high-density culture. Histochem. Cell Biol. 2004;122:219–228.
    1. Cao Y, Liu Y, Liu W, Shan Q, Buonocore SD, Cui L. Bridging tendon defects using autologous tenocyte engineered tendon in a hen model. Plast. Reconstr. Surg. 2002;110:1280–1289.
    1. Chen JM, Willers C, Xu J, Wang A, Zheng MH. Autologous tenocyte therapy using porcine-derived bioscaffolds for massive rotator cuff defect in rabbits. Tissue Eng. 2007;13:1479–1491.
    1. Stoll C, John T, Conrad C, Lohan A, Hondke S, Ertel W, Kaps C, Endres M, Sittinger M, Ringe J, Schulze-Tanzil G. Healing parameters in a rabbit partial tendon defect following tenocyte/biomaterial implantation. Biomaterials. 2011;32:4806–4815.
    1. Pietschmann MF, Frankewycz B, Schmitz P, Docheva D, Sievers B, Jansson V, Schieker M, Muller PE. Comparison of tenocytes and mesenchymal stem cells seeded on biodegradable scaffolds in a full-size tendon defect model. J. Mater. Sci. Mater. Med. 2013;24:211–220.
    1. Ni M, Lui PP, Rui YF, Lee YW, Lee YW, Tan Q, Wong YM, Kong SK, Lau PM, Li G, Chan KM. Tendon-derived stem cells (TDSCs) promote tendon repair in a rat patellar tendon window defect model. J. Orthop. Res. 2012;30:613–619.
    1. Stolzing A, Scutt A. Age-related impairment of mesenchymal progenitor cell function. Aging Cell. 2006;5:213–224.
    1. Stolzing A, Jones E, McGonagle D, Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech. Ageing Dev. 2008;129:163–173.
    1. Baxter MA, Wynn RF, Jowitt SN, Wraith JE, Fairbairn LJ, Bellantuono I. Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells. 2004;22:675–682.
    1. Kasper G, Mao L, Geissler S, Draycheva A, Trippens J, Kuhnisch J, Tschirschmann M, Kaspar K, Perka C, Duda GN, Klose J. Insights into mesenchymal stem cell aging: involvement of antioxidant defense and actin cytoskeleton. Stem Cells. 2009;27:1288–1297.
    1. Jakob F, Ebert R, Rudert M, Noth U, Walles H, Docheva D, Schieker M, Meinel L, Groll J. In situ guided tissue regeneration in musculoskeletal diseases and aging: Implementing pathology into tailored tissue engineering strategies. Cell Tissue Res. 2012;347:725–735.
    1. Longo UG, Lamberti A, Maffulli N, Denaro V. Tendon augmentation grafts: a systematic review. Br. Med. Bull. 2010;94:165–188.
    1. Zhang X, Bogdanowicz D, Erisken C, Lee NM, Lu HH. Biomimetic scaffold design for functional and integrative tendon repair. J. Shoulder Elbow Surg. 2012;21:266–277.
    1. Longo UG, Lamberti A, Petrillo S, Maffulli N, Denaro V. Scaffolds in tendon tissue engineering. Stem Cells Int. 2012;2012:517165.
    1. Young RG, Butler DL, Weber W, Caplan AI, Gordon SL, Fink DJ. Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair. J. Orthop. Res. 1998;16:406–413.
    1. Awad HA, Boivin GP, Dressler MR, Smith FN, Young RG, Butler DL. Repair of patellar tendon injuries using a cell–collagen composite. J. Orthop. Res. 2003;21:420–431.
    1. Juncosa-Melvin N, Shearn JT, Boivin GP, Gooch C, Galloway MT, West JR, Nirmalanandhan VS, Bradica G, Butler DL. Effects of mechanical stimulation on the biomechanics and histology of stem cell–collagen sponge constructs for rabbit patellar tendon repair. Tissue Eng. 2006;12:2291–2300.
    1. Kishore V, Bullock W, Sun X, Van Dyke WS, Akkus O. Tenogenic differentiation of human MSCs induced by the topography of electrochemically aligned collagen threads. Biomaterials. 2012;33:2137–2144.
    1. Alfredo Uquillas J, Kishore V, Akkus O. Genipin crosslinking elevates the strength of electrochemically aligned collagen to the level of tendons. J. Mech. Behav. Biomed. Mater. 2012;15:176–189.
    1. Dejardin LM, Arnoczky SP, Ewers BJ, Haut RC, Clarke RB. Tissue-engineered rotator cuff tendon using porcine small intestine submucosa. Histologic and mechanical evaluation in dogs. Am. J. Sports Med. 2001;29:175–184.
    1. Badylak SF, Tullius R, Kokini K, Shelbourne KD, Klootwyk T, Voytik SL, Kraine MR, Simmons C. The use of xenogeneic small intestinal submucosa as a biomaterial for Achilles tendon repair in a dog model. J. Biomed. Mater. Res. 1995;29:977–985.
    1. Gilbert TW, Stewart-Akers AM, Simmons-Byrd A, Badylak SF. Degradation and remodeling of small intestinal submucosa in canine Achilles tendon repair. J. Bone Joint Surg. Am. 2007;89:621–630.
    1. Zheng MH, Chen J, Kirilak Y, Willers C, Xu J, Wood D. Porcine small intestine submucosa (SIS) is not an acellular collagenous matrix and contains porcine DNA: possible implications in human implantation. J. Biomed. Mater. Res. B Appl. Biomater. 2005;73:61–67.
    1. Zalavras CG, Gardocki R, Huang E, Stevanovic M, Hedman T, Tibone J. Reconstruction of large rotator cuff tendon defects with porcine small intestinal submucosa in an animal model. J. Shoulder Elbow Surg. 2006;15:224–231.
    1. Metcalf MH, Savoie FH, Kellum B. Surgical technique for xenograft (SIS) augmentation of rotator-cuff repairs. Oper. Tech. Orthop. 2002;12:4.
    1. Sclamberg SG, Tibone JE, Itamura JM, Kasraeian S. Six-month magnetic resonance imaging follow-up of large and massive rotator cuff repairs reinforced with porcine small intestinal submucosa. J. Shoulder Elbow Surg. 2004;13:538–541.
    1. Walton JR, Bowman NK, Khatib Y, Linklater J, Murrell GA. Restore orthobiologic implant: not recommended for augmentation of rotator cuff repairs. J. Bone Joint Surg. Am. 2007;89:786–791.
    1. Iannotti JP, Codsi MJ, Kwon YW, Derwin K, Ciccone J, Brems JJ. Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J. Bone Joint Surg. Am. 2006;88:1238–1244.
    1. Omae H, Zhao C, Sun YL, An KN, Amadio PC. Multilayer tendon slices seeded with bone marrow stromal cells: a novel composite for tendon engineering. J. Orthop. Res. 2009;27:937–942.
    1. Omae H, Sun YL, An KN, Amadio PC, Zhao C. Engineered tendon with decellularized xenotendon slices and bone marrow stromal cells: an in vivo animal study. J. Tissue Eng. Regen. Med. 2012;6:238–244.
    1. Omae H, Steinmann SP, Zhao C, Zobitz ME, Wongtriratanachai P, Sperling JW, An KN. Biomechanical effect of rotator cuff augmentation with an acellular dermal matrix graft: a cadaver study. Clin. Biomech. (Bristol, Avon) 2012;27:789–792.
    1. Adams JE, Zobitz ME, Reach JS, Jr., An KN, Steinmann SP. Rotator cuff repair using an acellular dermal matrix graft: an in vivo study in a canine model. Arthroscopy. 2006;22:700–709.
    1. Bond JL, Dopirak RM, Higgins J, Burns J, Snyder SJ. Arthroscopic replacement of massive, irreparable rotator cuff tears using a GraftJacket allograft: technique and preliminary results. Arthroscopy. 2008;24:403–409. (e401)
    1. Rotini R, Marinelli A, Guerra E, Bettelli G, Castagna A, Fini M, Bondioli E, Busacca M. Human dermal matrix scaffold augmentation for large and massive rotator cuff repairs: preliminary clinical and MRI results at 1-year follow-up. Musculoskelet. Surg. 2011;95(Suppl. 1):S13–S23.
    1. Snyder SJ, Arnoczky SP, Bond JL, Dopirak R. Histologic evaluation of a biopsy specimen obtained 3 months after rotator cuff augmentation with GraftJacket Matrix. Arthroscopy. 2009;25:329–333.
    1. Lee MS. GraftJacket augmentation of chronic Achilles tendon ruptures. Orthopedics. 2004;27:s151–s153.
    1. Lee DK. A preliminary study on the effects of acellular tissue graft augmentation in acute Achilles tendon ruptures. J. Foot Ankle Surg. 2008;47:8–12.
    1. Valentin JE, Badylak JS, McCabe GP, Badylak SF. Extracellular matrix bioscaffolds for orthopaedic applications. A comparative histologic study. J. Bone Joint Surg. Am. 2006;88:2673–2686.
    1. Evans CH, Robbins PD. Possible orthopaedic applications of gene therapy. J. Bone Joint Surg. Am. 1995;77:1103–1114.
    1. Evans CH, Robbins PD. Genetically augmented tissue engineering of the musculoskeletal system. Clin. Orthop. Relat. Res. 1999:S410–S418.
    1. Evans CH, Ghivizzani SC, Robbins PD. The 2003 Nicolas Andry Award. Orthopaedic gene therapy. Clin. Orthop. Relat. Res. 2004:316–329.
    1. Bandara G, Robbins PD, Georgescu HI, Mueller GM, Glorioso JC, Evans CH. Gene transfer to synoviocytes: prospects for gene treatment of arthritis. DNA Cell Biol. 1992;11:227–231.
    1. Evans CH. Gene delivery to bone. Adv. Drug Deliv. Rev. 2012;64:1331–1340.
    1. Evans CH, Ghivizzani SC, Robbins PD. Getting arthritis gene therapy into the clinic. Nat. Rev. Rheumatol. 2011;7:244–249.
    1. Evans C. Using genes to facilitate the endogenous repair and regeneration of orthopaedic tissues. Int. Orthop. 2014;38:1761–1769.
    1. Dai Q, Manfield L, Wang Y, Murrell GA. Adenovirus-mediated gene transfer to healing tendon — enhanced efficiency using a gelatin sponge. J. Orthop. Res. 2003;21:604–609.
    1. Basile P, Dadali T, Jacobson J, Hasslund S, Ulrich-Vinther M, Soballe K, Nishio Y, Drissi MH, Langstein HN, Mitten DJ, O'Keefe RJ, Schwarz EM, Awad HA. Freeze-dried tendon allografts as tissue-engineering scaffolds for Gdf5 gene delivery. Mol. Ther. 2008;16:466–473.
    1. Evans CH. Advances in regenerative orthopedics. Mayo Clin. Proc. 2013;88:1323–1339.
    1. Evans CH, Palmer GD, Pascher A, Porter R, Kwong FN, Gouze E, Gouze JN, Liu F, Steinert A, Betz O, Betz V, Vrahas M, Ghivizzani SC. Facilitated endogenous repair: making tissue engineering simple, practical, and economical. Tissue Eng. 2007;13:1987–1993.
    1. Evans CH, Liu FJ, Glatt V, Hoyland JA, Kirker-Head C, Walsh A, Betz O, Wells JW, Betz V, Porter RM, Saad FA, Gerstenfeld LC, Einhorn TA, Harris MB, Vrahas MS. Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage. Eur. Cells Mater. 2009;18:96–111.
    1. Majewski M, Betz O, Ochsner PE, Liu F, Porter RM, Evans CH. Ex vivo adenoviral transfer of bone morphogenetic protein 12 (BMP-12) cDNA improves Achilles tendon healing in a rat model. Gene Ther. 2008;15:1139–1146.
    1. Majewski M, Porter RM, Betz OB, Betz VM, Clahsen H, Fluckiger R, Evans CH. Improvement of tendon repair using muscle grafts transduced with TGF-beta1 cDNA. Eur. Cells Mater. 2012;23:94–101. (discussion 101–102)
    1. Gerich TG, Kang R, Fu FH, Robbins PD, Evans CH. Gene transfer to the rabbit patellar tendon: potential for genetic enhancement of tendon and ligament healing. Gene Ther. 1996;3:1089–1093.
    1. Gerich TG, Kang R, Fu FH, Robbins PD, Evans CH. Gene transfer to the patellar tendon. Knee Surg. Sports Traumatol. Arthrosc. 1997;5:118–123.
    1. Hildebrand KA, Deie M, Allen CR, Smith DW, Georgescu HI, Evans CH, Robbins PD, Woo SL. Early expression of marker genes in the rabbit medial collateral and anterior cruciate ligaments: the use of different viral vectors and the effects of injury. J. Orthop. Res. 1999;17:37–42.
    1. Pelinkovic D, Lee JY, Engelhardt M, Rodosky M, Cummins J, Fu FH, Huard J. Muscle cell-mediated gene delivery to the rotator cuff. Tissue Eng. 2003;9:143–151.
    1. Ozkan I, Shino K, Nakamura N, Natsuume T, Matsumoto N, Horibe S, Tomita T, Kaneda Y, Ochi T. Direct in vivo gene transfer to healing rat patellar ligament by intra-arterial delivery of haemagglutinating virus of Japan liposomes. Eur. J. Clin. Invest. 1999;29:63–67.
    1. Nakamura N, Horibe S, Matsumoto N, Tomita T, Natsuume T, Kaneda Y, Shino K, Ochi T. Transient introduction of a foreign gene into healing rat patellar ligament. J. Clin. Invest. 1996;97:226–231.
    1. Goomer RS, Maris TM, Gelberman R, Boyer M, Silva M, Amiel D. Nonviral in vivo gene therapy for tissue engineering of articular cartilage and tendon repair. Clin. Orthop. Relat. Res. 2000:S189–S200.
    1. Jayankura M, Boggione C, Frisen C, Boyer O, Fouret P, Saillant G, Klatzmann D. In situ gene transfer into animal tendons by injection of naked DNA and electrotransfer. J. Gene Med. 2003;5:618–624.
    1. Hildebrand KA, Frank CB, Hart DA. Gene intervention in ligament and tendon: current status, challenges, future directions. Gene Ther. 2004;11:368–378.
    1. Lou J, Tu Y, Burns M, Silva MJ, Manske P. BMP-12 gene transfer augmentation of lacerated tendon repair. J. Orthop. Res. 2001;19:1199–1202.
    1. Bolt P, Clerk AN, Luu HH, Kang Q, Kummer JL, Deng ZL, Olson K, Primus F, Montag AG, He TC, Haydon RC, Toolan BC. BMP-14 gene therapy increases tendon tensile strength in a rat model of Achilles tendon injury. J. Bone Joint Surg. Am. 2007;89:1315–1320.
    1. Rickert M. BMP-14 gene therapy increases tendon tensile strength in a rat model of Achilles tendon injury. J. Bone Joint Surg. Am. 2008;90:445. (author reply 445–446)
    1. Gulotta LV, Kovacevic D, Packer JD, Ehteshami JR, Rodeo SA. Adenoviral-mediated gene transfer of human bone morphogenetic protein-13 does not improve rotator cuff healing in a rat model. Am. J. Sports Med. 2011;39:180–187.
    1. Forslund C, Rueger D, Aspenberg P. A comparative dose–response study of cartilage-derived morphogenetic protein (CDMP)-1, -2 and -3 for tendon healing in rats. J. Orthop. Res. 2003;21:617–621.
    1. Eliasson P, Fahlgren A, Aspenberg P. Mechanical load and BMP signaling during tendon repair: a role for follistatin? Clin. Orthop. Relat. Res. 2008;466:1592–1597.
    1. Gulotta LV, Kovacevic D, Packer JD, Deng XH, Rodeo SA. Bone marrow-derived mesenchymal stem cells transduced with scleraxis improve rotator cuff healing in a rat model. Am. J. Sports Med. 2011;39:1282–1289.
    1. Tang JB, Cao Y, Zhu B, Xin KQ, Wang XT, Liu PY. Adeno-associated virus-2-mediated bFGF gene transfer to digital flexor tendons significantly increases healing strength. an in vivo study. J. Bone Joint Surg. Am. 2008;90:1078–1089.
    1. Hou Y, Mao Z, Wei X, Lin L, Chen L, Wang H, Fu X, Zhang J, Yu C. Effects of transforming growth factor-beta1 and vascular endothelial growth factor 165 gene transfer on Achilles tendon healing. Matrix Biol. 2009;28:324–335.
    1. Uggen JC, Dines J, Uggen CW, Mason JS, Razzano P, Dines D, Grande DA. Tendon gene therapy modulates the local repair environment in the shoulder. J. Am. Osteopath. Assoc. 2005;105:20–21.
    1. Nakamura N, Shino K, Natsuume T, Horibe S, Matsumoto N, Kaneda Y, Ochi T. Early biological effect of in vivo gene transfer of platelet-derived growth factor (PDGF)-B into healing patellar ligament. Gene Ther. 1998;5:1165–1170.
    1. Ricchetti ET, Reddy SC, Ansorge HL, Zgonis MH, Van Kleunen JP, Liechty KW, Soslowsky LJ, Beredjiklian PK. Effect of interleukin-10 overexpression on the properties of healing tendon in a murine patellar tendon model. J. Hand. Surg. [Am.] 2008;33:1843–1852.
    1. Schnabel LV, Lynch ME, van der Meulen MC, Yeager AE, Kornatowski MA, Nixon AJ. Mesenchymal stem cells and insulin-like growth factor-I gene-enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons. J. Orthop. Res. 2009;27:1392–1398.
    1. Coen MJ, Chen ST, Rundle CH, Wergedal JE, Lau KH. Lentiviral-based BMP4 in vivo gene transfer strategy increases pull-out tensile strength without an improvement in the osteointegration of the tendon graft in a rat model of biceps tenodesis. J. Gene Med. 2011;13:511–521.
    1. Martinek V, Latterman C, Usas A, Abramowitch S, Woo SL, Fu FH, Huard J. Enhancement of tendon-bone integration of anterior cruciate ligament grafts with bone morphogenetic protein-2 gene transfer: a histological and biomechanical study. J. Bone Joint Surg. Am. 2002;84-A:1123–1131.
    1. Lattermann C, Zelle BA, Whalen JD, Baltzer AW, Robbins PD, Niyibizi C, Evans CH, Fu FH. Gene transfer to the tendon–bone insertion site. Knee Surg. Sports Traumatol. Arthrosc. 2004;12:510–515.
    1. Gulotta LV, Kovacevic D, Montgomery S, Ehteshami JR, Packer JD, Rodeo SA. Stem cells genetically modified with the developmental gene MT1-MMP improve regeneration of the supraspinatus tendon-to-bone insertion site. Am. J. Sports Med. 2010;38:1429–1437.
    1. Zhu Z, Yu A, Hou M, Xie X, Li P. Effects of Sox9 gene therapy on the healing of bone–tendon junction: an experimental study. Indian J. Orthop. 2014;48:88–95.
    1. Lin L, Chen L, Wang H, Wei X, Fu X, Zhang J, Ma K, Zhou C, Yu C. Adenovirus-mediated transfer of siRNA against Runx2/Cbfa1 inhibits the formation of heterotopic ossification in animal model. Biochem. Biophys. Res. Commun. 2006;349:564–572.
    1. Xue T, Mao Z, Lin L, Hou Y, Wei X, Fu X, Zhang J, Yu C. Non-virus-mediated transfer of siRNAs against Runx2 and Smad4 inhibit heterotopic ossification in rats. Gene Ther. 2010;17:370–379.
    1. Lu P, Zhang GR, Cai YZ, Heng BC, Ren H, Wang LL, Ji J, Zou XH, Ouyang HW. Lentiviral-encoded shRNA silencing of proteoglycan decorin enhances tendon repair and regeneration within a rat model. Cell Transplant. 2013;22:1507–1517.
    1. Evans CH, Ghivizzani SC, Robbins PD. Orthopedic gene therapy — lost in translation? J. Cell. Physiol. 2012;227:416–420.
    1. Wang JH. Mechanobiology of tendon. J. Biomech. 2006;39:1563–1582.
    1. Huang TF, Yew TL, Chiang ER, Ma HL, Hsu CY, Hsu SH, Hsu YT, Hung SC. Mesenchymal stem cells from a hypoxic culture improve and engraft Achilles tendon repair. Am. J. Sports Med. 2013;41:1117–1125.
    1. Nourissat G, Diop A, Maurel N, Salvat C, Dumont S, Pigenet A, Gosset M, Houard X, Berenbaum F. Mesenchymal stem cell therapy regenerates the native bone–tendon junction after surgical repair in a degenerative rat model. PLoS One. 2010;5:e12248.
    1. Okamoto N, Kushida T, Oe K, Umeda M, Ikehara S, Iida H. Treating Achilles tendon rupture in rats with bone-marrow-cell transplantation therapy. J. Bone Joint Surg. Am. 2010;92:2776–2784.
    1. Chong AK, Ang AD, Goh JC, Hui JH, Lim AY, Lee EH, Lim BH. Bone marrow-derived mesenchymal stem cells influence early tendon-healing in a rabbit Achilles tendon model. J. Bone Joint Surg. Am. 2007;89:74–81.
    1. Ouyang HW, Goh JC, Thambyah A, Teoh SH, Lee EH. Knitted poly-lactide-coglycolide scaffold loaded with bone marrow stromal cells in repair and regeneration of rabbit Achilles tendon. Tissue Eng. 2003;9:431–439.
    1. Ouyang HW, Goh JC, Lee EH. Use of bone marrow stromal cells for tendon graft-to-bone healing: histological and immunohistochemical studies in a rabbit model. Am. J. Sports Med. 2004;32:321–327.
    1. Juncosa-Melvin N, Boivin GP, Galloway MT, Gooch C, West JR, Butler DL. Effects of cell-to-collagen ratio in stem cell-seeded constructs for Achilles tendon repair. Tissue Eng. 2006;12:681–689.
    1. Hankemeier S, Hurschler C, Zeichen J, van Griensven M, Miller B, Meller R, Ezechieli M, Krettek C, Jagodzinski M. Bone marrow stromal cells in a liquid fibrin matrix improve the healing process of patellar tendon window defects. Tissue Eng. A. 2009;15:1019–1030.
    1. Hankemeier S, van Griensven M, Ezechieli M, Barkhausen T, Austin M, Jagodzinski M, Meller R, Bosch U, Krettek C, Zeichen J. Tissue engineering of tendons and ligaments by human bone marrow stromal cells in a liquid fibrin matrix in immunodeficient rats: results of a histologic study. Arch. Orthop. Trauma Surg. 2007;127:815–821.
    1. Juncosa-Melvin N, Boivin GP, Gooch C, Galloway MT, West JR, Dunn MG, Butler DL. The effect of autologous mesenchymal stem cells on the biomechanics and histology of gel–collagen sponge constructs used for rabbit patellar tendon repair. Tissue Eng. 2006;12:369–379.
    1. Dressler MR, Butler DL, Boivin GP. Effects of age on the repair ability of mesenchymal stem cells in rabbit tendon. J. Orthop. Res. 2005;23:287–293.
    1. Ouyang HW, Goh JC, Lee EH. Viability of allogeneic bone marrow stromal cells following local delivery into patella tendon in rabbit model. Cell Transplant. 2004;13:649–657.
    1. Awad HA, Butler DL, Boivin GP, Smith FN, Malaviya P, Huibregtse B, Caplan AI. Autologous mesenchymal stem cell-mediated repair of tendon. Tissue Eng. 1999;5:267–277.
    1. Smith RK, Werling NJ, Dakin SG, Alam R, Goodship AE, Dudhia J. Beneficial effects of autologous bone marrow-derived mesenchymal stem cells in naturally occurring tendinopathy. PLoS One. 2013;8:e75697.
    1. Crovace A, Lacitignola L, De Siena R, Rossi G, Francioso E. Cell therapy for tendon repair in horses: an experimental study. Vet. Res. Commun. 2007;31(Suppl. 1):281–283.
    1. Suwalski A, Dabboue H, Delalande A, Bensamoun SF, Canon F, Midoux P, Saillant G, Klatzmann D, Salvetat JP, Pichon C. Accelerated Achilles tendon healing by PDGF gene delivery with mesoporous silica nanoparticles. Biomaterials. 2010;31:5237–5245.

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