Systematic Review| Volume 28, ISSUE 7, P1018-1029, July 2012

Exploring the Application of Stem Cells in Tendon Repair and Regeneration


      To conduct a systematic review of the current evidence for the effects of stem cells on tendon healing in preclinical studies and human studies.


      A systematic search of the PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane, and Embase databases was performed for stem cells and tendons with their associated terminology. Data validity was assessed, and data were collected on the outcomes of trials.


      A total of 27 preclinical studies and 5 clinical studies met the inclusion criteria. Preclinical studies have shown that stem cells are able to survive and differentiate into tendon cells when placed into a new tendon environment, leading to regeneration and biomechanical benefit to the tendon. Studies have been reported showing that stem cell therapy can be enhanced by molecular signaling adjunct, mechanical stimulation of cells, and the use of augmentation delivery devices. Studies have also shown alternatives to the standard method of bone marrow–derived mesenchymal stem cell therapy. Of the 5 human studies, only 1 was a randomized controlled trial, which showed that skin-derived tendon cells had a greater clinical benefit than autologous plasma. One cohort study showed the benefit of stem cells in rotator cuff tears and another in lateral epicondylitis. Two of the human studies showed how stem cells were successfully extracted from the humerus and, when tagged with insulin, became tendon cells.


      The current evidence shows that stem cells can have a positive effect on tendon healing. This is most likely because stem cells have regeneration potential, producing tissue that is similar to the preinjury state, but the results can be variable. The use of adjuncts such as molecular signaling, mechanical stimulation, and augmentation devices can potentially enhance stem cell therapy. Initial clinical trials are promising, with adjuncts for stem cell therapy in development.

      Level of Evidence

      Level IV, systematic review of Level II-IV studies.
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      1. Hospital Episodes Statistics.
        (Accessed August 10, 2011)
        • Nho S.J.
        • Delos D.
        • Yadav H.
        • et al.
        Biomechanical and biologic augmentation for the treatment of massive rotator cuff tears.
        Am J Sports Med. 2010; 38: 619-629
        • Gagey N.
        • Quillard J.
        • Gagey O.
        • Meduri G.
        • Bittoun J.
        • Lassau J.P.
        Tendon of the normal supraspinatus muscle: Correlations between MR imaging and histology.
        Surg Radiol Anat. 1995; 17: 329-334
        • Khan K.M.
        • Cook J.L.
        • Bonar F.
        • Harcourt P.
        • Astrom M.
        Histopathology of common tendinopathies.
        Sports Med. 1999; 27: 393-408
        • Riley G.
        Tendinopathy—From basic science to treatment.
        Nat Clin Pract Rheumatol. 2008; 4: 82-89
        • Crossett L.S.
        • Sinha R.K.
        • Sechriest V.F.
        • Rubash H.E.
        Reconstruction of a ruptured patellar tendon with Achilles tendon allograft following total knee arthroplasty.
        J Bone Joint Surg Am. 2002; 84: 1354-1361
        • Tadokoro K.
        • Matsui N.
        • Yagi M.
        • Kuroda R.
        • Kurosaka M.
        • Yoshiya S.
        Evaluation of hamstring strength and tendon regrowth after harvesting for anterior cruciate ligament reconstruction.
        Am J Sports Med. 2004; 32: 1644-1650
        • Chiou H.M.
        • Chang M.C.
        • Lo W.H.
        One-stage reconstruction of skin defect and patellar tendon rupture after total knee arthroplasty.
        J Arthroplasty. 1997; 12: 575-579
        • Butler D.L.
        • Juncosa-Melvin N.
        • Boivin G.P.
        • et al.
        Functional tissue engineering for tendon repair: A multidisciplinary strategy using mesenchymal stem cells, bioscaffolds, and mechanical stimulation.
        J Orthop Res. 2008; 26: 1-9
        • Sharma P.
        • Maffulli N.
        Tendon injury and tendinopathy: Healing and repair.
        J Bone Joint Surg Am. 2005; 87: 187-202
        • Omae H.
        • Mochizuki Y.
        • Yokoya S.
        • Adachi N.
        • Ochi M.
        Augmentation of tendon attachment to porous ceramics by bone marrow stromal cells in a rabbit model.
        Int Orthop. 2007; 31: 353-358
        • Lee J.Y.
        • Zhou Z.
        • Taub P.J.
        • et al.
        BMP-12 treatment of adult mesenchymal stem cells in vitro augments tendon-like tissue formation and defect repair in vivo.
        PLoS One. 2011; 6: e17531
        • Ellera Gomes J.L.
        • da Silva R.C.
        • Silla L.M.
        • Abreu M.R.
        • Pellanda R.
        Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells.
        Knee Surg Sports Traumatol Arthrosc. 2012; 20: 373-377
        • Clarke A.W.
        • Alyas F.
        • Morris T.
        • Robertson C.J.
        • Bell J.
        • Connell D.A.
        Skin-derived tenocyte-like cells for the treatment of patellar tendinopathy.
        Am J Sports Med. 2011; 39: 614-623
        • Connell D.
        • Datir A.
        • Alyas F.
        • Curtis M.
        Treatment of lateral epicondylitis using skin-derived tenocyte-like cells.
        Br J Sports Med. 2009; 43: 293-298
        • Zaidi N.
        • Nixon A.J.
        Stem cell therapy in bone repair and regeneration.
        Ann N Y Acad Sci. 2007; 1117: 62-72
        • Javazon E.H.
        • Beggs K.J.
        • Flake A.W.
        Mesenchymal stem cells: Paradoxes of passaging.
        Exp Hematol. 2004; 32: 414-425
        • Klyushnenkova E.
        • Mosca J.D.
        • Zernetkina V.
        • et al.
        T cell responses to allogeneic human mesenchymal stem cells: Immunogenicity, tolerance, and suppression.
        J Biomed Sci. 2005; 12: 47-57
        • Smith R.K.
        • Korda M.
        • Blunn G.W.
        • Goodship A.E.
        Isolation and implantation of autologous equine mesenchymal stem cells from bone marrow into the superficial digital flexor tendon as a potential novel treatment.
        Equine Vet J. 2003; 35: 99-102
        • Godwin E.E.
        • Young N.J.
        • Dudhia J.
        • Beamish I.C.
        • Smith R.K.
        Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon.
        Equine Vet J. 2012; 44: 25-32
        • Watts A.E.
        • Yeager A.E.
        • Kopyov O.V.
        • Nixon A.J.
        Fetal derived embryonic-like stem cells improve healing in a large animal flexor tendonitis model.
        Stem Cell Res Ther. 2011; 2: 4
        • Hankemeier S.
        • van Griensven M.
        • Ezechieli M.
        • et al.
        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
        • Nourissat G.
        • Diop A.
        • Maurel N.
        • et al.
        Mesenchymal stem cell therapy regenerates the native bone-tendon junction after surgical repair in a degenerative rat model.
        PLoS One. 2010; 5: e12248
        • Lim J.K.
        • Hui J.
        • Li L.
        • Thambyah A.
        • Goh J.
        • Lee E.H.
        Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction.
        Arthroscopy. 2004; 20: 899-910
        • Awad H.A.
        • Butler D.L.
        • Boivin G.P.
        • et al.
        Autologous mesenchymal stem cell-mediated repair of tendon.
        Tissue Eng. 1999; 5: 267-277
        • Chong A.K.
        • Ang A.D.
        • Goh J.C.
        • et al.
        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
        • Young R.G.
        • Butler D.L.
        • Weber W.
        • Caplan A.I.
        • Gordon S.L.
        • Fink D.J.
        Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair.
        J Orthop Res. 1998; 16: 406-413
        • Ouyang H.W.
        • Goh J.C.
        • Lee E.H.
        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
        • Ohtera K.
        • Yamada Y.
        • Aoki M.
        • Sasaki T.
        • Yamakoshi K.
        Effects of periosteum wrapped around tendon in a bone tunnel: A biomechanical and histological study in rabbits.
        Crit Rev Biomed Eng. 2000; 28: 115-118
        • Ouyang H.W.
        • Goh J.C.
        • Lee E.H.
        Viability of allogeneic bone marrow stromal cells following local delivery into patella tendon in rabbit model.
        Cell Transplant. 2004; 13: 649-657
        • Guest D.J.
        • Smith M.R.
        • Allen W.R.
        Monitoring the fate of autologous and allogeneic mesenchymal progenitor cells injected into the superficial digital flexor tendon of horses: Preliminary study.
        Equine Vet J. 2008; 40: 178-181
        • Guest D.J.
        • Smith M.R.
        • Allen W.R.
        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
        • Dressler M.R.
        • Butler D.L.
        • Boivin G.P.
        Effects of age on the repair ability of mesenchymal stem cells in rabbit tendon.
        J Orthop Res. 2005; 23: 287-293
        • Gulotta L.V.
        • Kovacevic D.
        • Ehteshami J.R.
        • Dagher E.
        • Packer J.D.
        • Rodeo S.A.
        Application of bone marrow-derived mesenchymal stem cells in a rotator cuff repair model.
        Am J Sports Med. 2009; 37: 2126-2133
        • Gulotta L.V.
        • Kovacevic D.
        • Montgomery S.
        • Ehteshami J.R.
        • Packer J.D.
        • Rodeo S.A.
        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
        • Gulotta L.V.
        • Kovacevic D.
        • Packer J.D.
        • Deng X.H.
        • Rodeo S.A.
        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
        • Schnabel L.V.
        • Lynch M.E.
        • van der Meulen M.C.
        • Yeager A.E.
        • Kornatowski M.A.
        • Nixon A.J.
        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
        • Juncosa-Melvin N.
        • Boivin G.P.
        • Galloway M.T.
        • et al.
        Effects of cell-to-collagen ratio in mesenchymal stem cell-seeded implants on tendon repair biomechanics and histology.
        Tissue Eng. 2005; 11: 448-457
        • Juncosa-Melvin N.
        • Boivin G.P.
        • Gooch C.
        • et al.
        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
        • Juncosa-Melvin N.
        • Matlin K.S.
        • Holdcraft R.W.
        • Nirmalanandhan V.S.
        • Butler D.L.
        Mechanical stimulation increases collagen type I and collagen type III gene expression of stem cell-collagen sponge constructs for patellar tendon repair.
        Tissue Eng. 2007; 13: 1219-1226
        • Chen J.L.
        • Yin Z.
        • Shen W.L.
        • et al.
        Efficacy of hESC-MSCs in knitted silk-collagen scaffold for tendon tissue engineering and their roles.
        Biomaterials. 2010; 31: 9438-9451
        • Little D.
        • Guilak F.
        • Ruch D.S.
        Ligament-derived matrix stimulates a ligamentous phenotype in human adipose-derived stem cells.
        Tissue Eng Part A. 2010; 16: 2307-2319
        • Yao J.
        • Korotkova T.
        • Smith R.L.
        Viability and proliferation of pluripotential cells delivered to tendon repair sites using bioactive sutures—An in vitro study.
        J Hand Surg Am. 2011; 36: 252-258
        • Angelidis I.K.
        • Thorfinn J.
        • Connolly I.D.
        • Lindsey D.
        • Pham H.M.
        • Chang J.
        Tissue engineering of flexor tendons: The effect of a tissue bioreactor on adipoderived stem cell-seeded and fibroblast-seeded tendon constructs.
        J Hand Surg Am. 2010; 35: 1466-1472
        • Vaquette C.
        • Slimani S.
        • Kahn C.J.
        • Tran N.
        • Rahouadj R.
        • Wang X.
        A poly(lactic-co-glycolic acid) knitted scaffold for tendon tissue engineering: An in vitro and in vivo study.
        J Biomater Sci Polym Ed. 2010; 21: 1737-1760
        • Nixon A.J.
        • Dahlgren L.A.
        • Haupt J.L.
        • Yeager A.E.
        • Ward D.L.
        Effect of adipose-derived nucleated cell fractions on tendon repair in horses with collagenase-induced tendinitis.
        Am J Vet Res. 2008; 69: 928-937
        • Nagy K.
        • Sung H.K.
        • Zhang P.
        • et al.
        Induced pluripotent stem cell lines derived from equine fibroblasts.
        Stem Cell Rev. 2011; 7: 693-702
        • Bi Y.
        • Ehirchiou D.
        • Kilts T.M.
        • et al.
        Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche.
        Nat Med. 2007; 13: 1219-1227
        • Lui P.P.
        • Chan K.M.
        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
        • Karousou E.
        • Ronga M.
        • Vigetti D.
        • Passi A.
        • Maffulli N.
        Collagens, proteoglycans, MMP-2, MMP-9 and TIMPs in human Achilles tendon rupture.
        Clin Orthop Relat Res. 2008; 466: 1577-1582
        • Rui Y.F.
        • Lui P.P.
        • Chan L.S.
        • Chan K.M.
        • Fu S.C.
        • Li G.
        Does erroneous differentiation of tendon-derived stem cells contribute to the pathogenesis of calcifying tendinopathy?.
        Chin Med J (Engl). 2011; 124: 606-610
        • Blatt A.
        • Cotter G.
        • Leitman M.
        • et al.
        Intracoronary administration of autologous bone marrow mononuclear cells after induction of short ischemia is safe and may improve hibernation and ischemia in patients with ischemic cardiomyopathy.
        Am Heart J. 2005; 150: 986
        • Cho S.W.
        • Park H.J.
        • Ryu J.H.
        • et al.
        Vascular patches tissue-engineered with autologous bone marrow-derived cells and decellularized tissue matrices.
        Biomaterials. 2005; 26: 1915-1924
        • 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: 281-283
        • Bidula J.
        • Boehm C.
        • Powell K.
        • et al.
        Osteogenic progenitors in bone marrow aspirates from smokers and nonsmokers.
        Clin Orthop Relat Res. 2006; 442: 252-259
        • Hernigou P.
        • Poignard A.
        • Beaujean F.
        • Rouard H.
        Percutaneous autologous bone-marrow grafting for nonunions.
        J Bone Joint Surg Am. 2005; 87: 1430-1437
        • Mazzocca A.D.
        • McCarthy M.B.
        • Chowaniec D.M.
        • Cote M.P.
        • Arciero R.A.
        • Drissi H.
        Rapid isolation of human stem cells (connective tissue progenitor cells) from the proximal humerus during arthroscopic rotator cuff surgery.
        Am J Sports Med. 2010; 38: 1438-1447
        • Mazzocca A.D.
        • McCarthy M.B.
        • Chowaniec D.
        • et al.
        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
        • Charousset C.
        • Grimberg J.
        • Duranthon L.D.
        • Bellaïche L.
        • Petrover D.
        • Kalra K.
        The time for functional recovery after arthroscopic rotator cuff repair: Correlation with tendon healing controlled by computed tomography arthrography.
        Arthroscopy. 2008; 24: 25-33