Review| Volume 30, ISSUE 9, P1174-1185, September 2022

Stem cell-based therapies for temporomandibular joint osteoarthritis and regeneration of cartilage/osteochondral defects: a systematic review of preclinical experiments

  • H.R. Matheus
    Skeletal Biology Research Center, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard School of Dental Medicine, Boston, MA, USA

    Department of Diagnosis and Surgery – Periodontics Division, São Paulo State University (UNESP), School of Dentistry, Araçatuba, SP, Brazil
    Search for articles by this author
  • Ş.D. Özdemir
    Skeletal Biology Research Center, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard School of Dental Medicine, Boston, MA, USA

    Istanbul Medipol University, School of Dentistry, İstanbul, Turkey
    Search for articles by this author
  • F.P.S. Guastaldi
    Address correspondence and reprint requests to: F. P. Semeghini Guastaldi, Skeletal Biology Research Center, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard School of Dental Medicine, 50 Blossom Street, Thier 513A, Boston, MA 02114, USA. Tel.: 1-617-726-5205.
    Skeletal Biology Research Center, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard School of Dental Medicine, Boston, MA, USA
    Search for articles by this author



      The aim of this systematic review was to assess the effects of stem cell-based therapies on the treatment of Temporomandibular Joint Osteoarthritis (TMJ-OA) and the regeneration of cartilage/osteochondral defects.


      Data on preclinical studies evaluating the effectiveness of stem cell-based therapies for treating Temporomandibular Disorders (TMDs) were extracted from PubMed, Web of Science, and Cochrane Library and the grey literature by three independent reviewers. A manual search was performed in the databases, the reference list of review studies, and relevant journals in the field. Compliance with the ARRIVE guidelines was evaluated for quality assessment. SYRCLE's risk of bias tool for animal experimental studies was assessed to define internal validity.


      After applying the inclusion and exclusion criteria, 10 studies were included in the qualitative synthesis. Regardless of cell origin, stem cell-based therapeutic approaches induced protective, anti-inflammatory, and chondroregenerative potential in the treatment of TMJ-OA. Regeneration of the cartilage layer on the surface of the condyle was achieved when stem cells were directly flushed into the defect or when delivered within a carrier.


      Stem cell-based therapies may be considered a promising approach for the treatment of TMJ-OA and for the regeneration of full-thickness cartilage and osteochondral defects in the TMJ. Human studies shall be performed to validate these results found in animals.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Osteoarthritis and Cartilage
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bordoni B.
        • Varacallo M.
        Anatomy, head and neck, temporomandibular joint.
        in: StatPearls. Treasure Island (FL). StatPearls Publishing, July 26, 2021
        • Gauer R.L.
        • Semidey M.J.
        Diagnosis and treatment of temporomandibular disorders.
        Am Fam Physician. 2015; 91: 378-386
        • Yadav S.
        • Yang Y.
        • Dutra E.H.
        • Robinson J.L.
        • Wadhwa S.
        Temporomandibular joint disorders in older adults.
        J Am Geriatr Soc. 2018; 66: 1213-1217
        • Stowell A.W.
        • Gatchel R.J.
        • Wildenstein L.
        Cost-effectiveness of treatments for temporomandibular disorders: biopsychosocial intervention versus treatment as usual.
        J Am Dent Assoc. 2007; 138: 202-208
        • Aryaei A.
        • Vapniarsky N.
        • Hu J.C.
        • Athanasiou K.A.
        Recent tissue engineering advances for the treatment of temporomandibular joint disorders.
        Curr Osteoporos Rep. 2016; 14: 269-279
        • Dym H.
        • Bowler D.
        • Zeidan J.
        Pharmacologic treatment for temporomandibular disorders.
        Dent Clin. 2016; 60: 367-379
        • Scrivani S.J.
        • Keith D.A.
        • Kaban L.B.
        Temporomandibular disorders.
        N Engl J Med. 2008; 359: 2693-2705
        • De Meurechy N.
        • Mommaerts M.Y.
        Alloplastic temporomandibular joint replacement systems: a systematic review of their history.
        Int J Oral Maxillofac Surg. 2018; 47: 743-754
        • Johnson N.R.
        • Roberts M.J.
        • Doi S.A.
        • Batstone M.D.
        Total temporomandibular joint replacement prostheses: a systematic review and bias-adjusted meta-analysis.
        Int J Oral Maxillofac Surg. 2017; 46: 86-92
        • Mittal N.
        • Goyal M.
        • Sardana D.
        • Dua J.S.
        Outcomes of surgical management of TMJ ankylosis: a systematic review and meta-analysis.
        J Cranio-Maxillo-Fac Surg. 2019; 47: 1120-1133
        • Ma J.
        • Jiang H.
        • Liang L.
        Interpositional arthroplasty versus reconstruction arthroplasty for temporomandibular joint ankylosis: a systematic review and meta-analysis.
        J Cranio-Maxillo-Fac Surg. 2015; 43: 1202-1207
        • Bavarian R.
        • Schatman M.E.
        • Keith D.A.
        Persistent pain following proplast-teflon implants of the temporomandibular joint: a case report and 35-year management perspective.
        J Pain Res. 2021; 14: 3033-3046
        • Berenbaum F.
        Osteoarthritis year 2010 in review: pharmacological therapies.
        Osteoarthritis Cartilage. 2011; 19: 361-365
        • Giannoni P.
        • Pagano A.
        • Maggi E.
        • Arbicò R.
        • Randazzo N.
        • Grandizio M.
        • et al.
        Autologous chondrocyte implantation (ACI) for aged patients: development of the proper cell expansion conditions for possible therapeutic applications.
        Osteoarthritis Cartilage. 2005; 13: 589-600
        • Minas T.
        • Bryant T.
        The role of autologous chondrocyte implantation in the patellofemoral joint.
        Clin Orthop Relat Res. 2005; 436: 30-39
        • Hettrich C.M.
        • Crawford D.
        • Rodeo S.A.
        Cartilage repair: third-generation cell-based technologies--basic science, surgical techniques, clinical outcomes.
        Sports Med Arthrosc Rev. 2008; 16: 230-235
        • Undt G.
        • Jahl M.
        • Pohl S.
        • Marlovits S.
        • Moser D.
        • Yoon H.H.
        • et al.
        Matrix-associated chondrocyte transplantation for reconstruction of articulating surfaces in the temporomandibular joint: a pilot study covering medium- and long-term outcomes of 6 patients.
        Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; 126: 117-128
        • Fu X.
        • Liu G.
        • Halim A.
        • Ju Y.
        • Luo Q.
        • Song A.G.
        Mesenchymal stem cell migration and tissue repair.
        Cells. 2019; 8 (Published 2019 Jul 28): 784
        • Trohatou O.
        • Roubelakis M.G.
        Mesenchymal stem/stromal cells in regenerative medicine: past, present, and future.
        Cell Reprogr. 2017; 19: 217-224
        • Yan H.
        • Yu C.
        Repair of full-thickness cartilage defects with cells of different origin in a rabbit model.
        Arthroscopy. 2007; 23: 178-187
        • Nejadnik H.
        • Hui J.H.
        • Feng Choong E.P.
        • Tai B.C.
        • Lee E.H.
        Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study.
        Am J Sports Med. 2010; 38: 1110-1116
        • Chamberlain G.
        • Fox J.
        • Ashton B.
        • Middleton J.
        Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing.
        Stem Cell. 2007; 25: 2739-2749
        • Kim H.
        • Yang G.
        • Park J.
        • Choi J.
        • Kang E.
        • Lee B.K.
        Therapeutic effect of mesenchymal stem cells derived from human umbilical cord in rabbit temporomandibular joint model of osteoarthritis.
        Sci Rep. 2019; 9: 13854
        • Putnová B.
        • Hurník P.
        • Jekl V.
        • Žiak D.
        • Machoň V.
        • Škorič M.
        • et al.
        Effect of human adipose-derived regenerative cells on temporomandibular joint healing in immunodeficient rabbits.
        Acta Vet. 2019 Apr 9; 88: 49-56
        • Gomez M.
        • Wittig O.
        • Diaz-Solano D.
        • Cardier J.E.
        Mesenchymal Stromal Cell Transplantation Induces Regeneration of Large and Full-Thickness Cartilage Defect of the Temporomandibular Joint.
        ([published online ahead of print, 2020 Jun 4]. Cartilage)2020 (1947603520926711)
        • Koh Y.G.
        • Jo S.B.
        • Kwon O.R.
        • Suh D.S.
        • Lee S.W.
        • Park S.H.
        • et al.
        Mesenchymal stem cell injections improve symptoms of knee osteoarthritis.
        Arthroscopy. 2013; 29: 748-755
        • Orozco L.
        • Munar A.
        • Soler R.
        • Alberca M.
        • Soler F.
        • Huguet M.
        • et al.
        Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study.
        Transplantation. 2013; 95: 1535-1541
        • Song Y.
        • Du H.
        • Dai C.
        • Zhang L.
        • Li S.
        • Hunter D.J.
        • et al.
        Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections.
        Regen Med. 2018; 13: 295-307
        • De Riu G.
        • Vaira L.A.
        • Carta E.
        • Meloni S.M.
        • Sembronio S.
        • Robiony M.
        Bone marrow nucleated cell concentrate autograft in temporomandibular joint degenerative disorders: 1-year results of a randomized clinical trial.
        J Cranio-Maxillo-Fac Surg. 2019; 47: 1728-1738
        • Helgeland E.
        • Shanbhag S.
        • Pedersen T.O.
        • Mustafa K.
        • Rosén A.
        Scaffold-based temporomandibular joint tissue regeneration in experimental animal models: a systematic review.
        Tissue Eng B Rev. 2018; 24: 300-316
        • Almarza A.J.
        • Brown B.N.
        • Arzi B.
        • Ângelo D.F.
        • Chung W.
        • Badylak S.F.
        • et al.
        Preclinical animal models for temporomandibular joint tissue engineering.
        Tissue Eng B Rev. 2018; 24: 171-178
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • Boutron I.
        • Hoffmann T.C.
        • Mulrow C.D.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372: n71
        • Miller S.A.
        • Forrest J.L.
        Enhancing your practice through evidence-based decision making: PICO, learning how to ask good questions.
        J Evid Base Dent Pract. 2001 Oct 1; 1: 136-141
        • Kilkenny C.
        • Browne W.J.
        • Cuthill I.C.
        • Emerson M.
        • Altman D.G.
        Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research.
        PLoS Biol. 2010; 8e1000412
        • Schwarz F.
        • Iglhaut G.
        • Becker J.
        Quality assessment of reporting of animal studies on pathogenesis and treatment of peri-implant mucositis and peri-implantitis. A systematic review using the ARRIVE guidelines.
        J Clin Periodontol. 2012; 39: 63-72
        • Monteiro J.L.G.C.
        • Guastaldi F.P.S.
        • Troulis M.J.
        • McCain J.P.
        • Vasconcelos B.C.D.E.
        Induction, treatment, and prevention of temporomandibular joint ankylosis-A systematic review of comparative animal studies.
        J Oral Maxillofac Surg. 2021; 79 (e6): 109-132
        • Hooijmans C.R.
        • Rovers M.M.
        • de Vries R.B.
        • Leenaars M.
        • Ritskes-Hoitinga M.
        • Langendam M.W.
        SYRCLE's risk of bias tool for animal studies.
        BMC Med Res Methodol. 2014; 14 (Published 2014 Mar 26): 43
        • Lu L.
        • Zhang X.
        • Zhang M.
        • Zhang H.
        • Liao L.
        • Yang T.
        • et al.
        RANTES and SDF-1 are keys in cell-based therapy of TMJ osteoarthritis.
        J Dent Res. 2015; 94: 1601-1609
        • Köhnke R.
        • Ahlers M.O.
        • Birkelbach M.A.
        • Ewald F.
        • Krueger M.
        • Fiedler I.
        • et al.
        Temporomandibular joint osteoarthritis: regenerative treatment by a stem cell containing advanced therapy medicinal product (ATMP)-An in vivo animal trial.
        Int J Mol Sci. 2021; 22 (Published 2021 Jan 5): 443
        • Zaki A.A.
        • Zaghloul M.
        • Helal M.E.
        • Mansour N.A.
        • Grawish M.E.
        Impact of autologous bone marrow-derived stem cells on degenerative changes of articulating surfaces associated with the arthritic temporomandibular joint: an experimental study in rabbits.
        J Oral Maxillofac Surg. 2017; 75: 2529-2539
        • Zhang S.
        • Teo K.Y.W.
        • Chuah S.J.
        • Lai R.C.
        • Lim S.K.
        • Toh W.S.
        MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis.
        Biomaterials. 2019; 200: 35-47
        • Zhang M.
        • Yang H.
        • Lu L.
        • Wan X.
        • Zhang J.
        • Zhang H.
        • et al.
        Matrix replenishing by BMSCs is beneficial for osteoarthritic temporomandibular joint cartilage.
        Osteoarthritis Cartilage. 2017; 25: 1551-1562
        • Guastaldi F.P.S.
        • Hakim M.A.
        • Liapaki A.
        • Lowe B.
        • Faquin W.C.
        • Thamm J.R.
        • et al.
        Are stem cells useful in the regeneration and repair of cartilage defects in the TMJ condyle? An in vivo study.
        J Dent & Oral Disord. 2021; 7: 1159
        • Sumarta N.P.M.
        • Kamadjaja D.B.
        • Hendrijantini N.
        • Danudiningrat C.P.
        • Rantam F.A.
        Human umbilical cord mesenchymal stem cells over platelet rich fibrin scaffold for mandibular cartilage defects regenerative medicine.
        Pesqui Bras Odontopediatria Clin Integr. 2021; 21: e0034
        • Guo Y.W.
        • Yang S.M.
        Shang Hai Kou Qiang Yi Xue. 2018; 27: 567-573
        • Zhang W.B.
        • Zheng L.W.
        • Chua D.T.
        • Cheung L.K.
        Treatment of irradiated mandibles with mesenchymal stem cells transfected with bone morphogenetic protein 2/7.
        J Oral Maxillofac Surg. 2012; 70: 1711-1716
        • Gong Z.
        • Xiong H.
        • Long X.
        • Wei L.
        • Li J.
        • Wu Y.
        • et al.
        Use of synovium-derived stromal cells and chitosan/collagen type I scaffolds for cartilage tissue engineering.
        Biomed Mater. 2010; 5055005
        • Bailey M.M.
        • Wang L.
        • Bode C.J.
        • Mitchell K.E.
        • Detamore M.S.
        A comparison of human umbilical cord matrix stem cells and temporomandibular joint condylar chondrocytes for tissue engineering temporomandibular joint condylar cartilage.
        Tissue Eng. 2007; 13: 2003-2010
        • Sun J.
        • Liao W.
        • Su K.
        • Jia J.
        • Qin L.
        • Liu W.
        • et al.
        Suberoylanilide hydroxamic acid attenuates interleukin-1β-induced interleukin-6 upregulation by inhibiting the microtubule affinity-regulating kinase 4/nuclear factor-κb pathway in synovium-derived mesenchymal stem cells from the temporomandibular joint.
        Inflammation. 2020; 43: 1246-1258
        • LeResche L.
        Epidemiology of temporomandibular disorders: implications for the investigation of etiologic factors.
        Crit Rev Oral Biol Med. 1997; 8: 291-305
        • Wang X.D.
        • Zhang J.N.
        • Gan Y.H.
        • Zhou Y.H.
        Current understanding of pathogenesis and treatment of TMJ osteoarthritis.
        J Dent Res. 2015; 94: 666-673
        • Tanaka E.
        • Detamore M.S.
        • Mercuri L.G.
        Degenerative disorders of the temporomandibular joint: etiology, diagnosis, and treatment.
        J Dent Res. 2008; 87: 296-307
        • Schminke B.
        • Miosge N.
        Cartilage repair in vivo: the role of migratory progenitor cells.
        Curr Rheumatol Rep. 2014; 16: 461
        • Zhou Y.
        • Liu S.Q.
        • Yu L.
        • He B.
        • Wu S.H.
        • Zhao Q.
        • et al.
        Berberine prevents nitric oxide-induced rat chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model via AMPK and p38 MAPK signaling.
        Apoptosis. 2015; 20: 1187-1199
        • Harth M.
        • Nielson W.R.
        Pain and affective distress in arthritis: relationship to immunity and inflammation.
        Expet Rev Clin Immunol. 2019; 15: 541-552
        • Meirelles Lda S.
        • Fontes A.M.
        • Covas D.T.
        • Caplan A.I.
        Mechanisms involved in the therapeutic properties of mesenchymal stem cells.
        Cytokine Growth Factor Rev. 2009; 20: 419-427
        • Mianehsaz E.
        • Mirzaei H.R.
        • Mahjoubin-Tehran M.
        • Rezaee A.
        • Sahebnasagh R.
        • Pourhanifeh M.H.
        • et al.
        Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis?.
        Stem Cell Res Ther. 2019; 10: 340
        • Ryan J.M.
        • Barry F.P.
        • Murphy J.M.
        • Mahon B.P.
        Mesenchymal stem cells avoid allogeneic rejection.
        J Inflamm (Lond). 2005; 2: 8
        • Le Blanc K.
        • Tammik C.
        • Rosendahl K.
        • Zetterberg E.
        • Ringdén O.
        HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells.
        Exp Hematol. 2003; 31: 890-896
        • Naujoks C.
        • Meyer U.
        • Wiesmann H.P.
        • Jäsche-Meyer J.
        • Hohoff A.
        • Depprich R.
        • et al.
        Principles of cartilage tissue engineering in TMJ reconstruction.
        Head Face Med. 2008; 4: 3
        • Langer R.
        • Vacanti J.P.
        Tissue engineering.
        Science. 1993; 260: 920-926
        • Wei D.
        • Tang K.
        • Wang Q.
        • Estill J.
        • Yao L.
        • Wang X.
        • et al.
        The use of GRADE approach in systematic reviews of animal studies.
        J Evid Base Med. 2016; 9: 98-104
        • Sakalys D.
        • Dvylys D.
        • Simuntis R.
        • Leketas M.
        Comparison of different intraarticular injection substances followed by temporomandibular joint arthroscopy.
        J Craniofac Surg. 2020; 31: 637-641
      1. Liu Y, Wu JS, Tang YL, Tang YJ, Fei W, Liang XH. Multiple treatment meta-analysis of intra-articular injection for temporomandibular osteoarthritis. J Oral Maxillofac Surg, 78 (3), 2020, 373.e1-373.e18, doi: 10.1016/j.joms.2019.10.016. Epub 2019 Oct 31.