Bioengineered Constructs of the Ramus/Condyle Unit

  • Sidney B. EisigEmail author
  • Michael Forman
  • Gordana Vunjak-Novakovic


One of the most challenging reconstructions in maxillofacial surgery is that involving the condyle and ramus. Common reconstructive techniques involve either autogenous bone grafting such as costochondral rib grafting, a sliding posterior ramus border osteotomy, microvascular free fibula graft, or alloplastic reconstruction involving either stock or custom total joint replacement. None of these techniques specifically address the articular disc and some address only bone and not soft tissue. Bioengineering, which uses cells, molecules, chemistry, and scaffolds with engineering principles, is now providing novel solutions to complex biological problems.


Temporomandibular Bioengineering Ramus Condyle Biomechanics 



The authors gratefully acknowledge funding of this work by NIH (grants DE016525 and EB002520).


  1. 1.
    Okeson J. Management of temporomandibular disorders and occlusion. St. Louis: Elsevier; 2008.Google Scholar
  2. 2.
    Dimitroulis G. A critical review of interpositional grafts following temporomandibular joint discectomy with an overview of the dermis-fat graft. Int J Oral Maxillofac Surg. 2011;40(6):561–8.PubMedGoogle Scholar
  3. 3.
    Wagner JD, Mosby EL. Assessment of Proplast-Teflon disc replacements. J Oral Maxillofac Surg. 1990;48(11):1140–4.PubMedGoogle Scholar
  4. 4.
    Chuong R, Piper MA. Cerebrospinal fluid leak associated with proplast implant removal from the temporomandibular joint. Oral Surg Oral Med Oral Pathol. 1992;74(4):422–5.PubMedGoogle Scholar
  5. 5.
    Mercuri LG, Urban RM, Hall DJ, Mathew MT. Adverse local tissue responses to failed temporomandibular joint implants. J Oral Maxillofac Surg. 2017;75(10):2076–84.PubMedGoogle Scholar
  6. 6.
    Kleinman HK, Philp D, Hoffman MP. Role of the extracellular matrix in morphogenesis. Curr Opin Biotechnol. 2003;14(5):526–32.PubMedGoogle Scholar
  7. 7.
    Atala A, Kasper FK, Mikos AG. Engineering complex tissues. Sci Transl Med. 2012;4(160):160rv12.PubMedGoogle Scholar
  8. 8.
    Spiller KL, Anfang RR, Spiller KJ, et al. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials. 2014;35(15):4477–88.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Ward BB, Brown SE, Krebsbach PH. Bioengineering strategies for regeneration of craniofacial bone: a review of emerging technologies. Oral Dis. 2010;16(8):709–16.PubMedGoogle Scholar
  10. 10.
    Meinel L, Karageorgiou V, Fajardo R, et al. Bone tissue engineering using human mesenchymal stem cells: effects of scaffold material and medium flow. Ann Biomed Eng. 2004;32(1):112–22.PubMedGoogle Scholar
  11. 11.
    Mano JF, Silva GA, Azevedo HS, et al. Natural origin biodegradable systems in tissue engineering and regenerative medicine: present status and some moving trends. J R Soc Interface. 2007;4(17):999–1030.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Hofmann S, Knecht S, Langer R, et al. Cartilage-like tissue engineering using silk scaffolds and mesenchymal stem cells. Tissue Eng. 2006;12(10):2729–38.PubMedGoogle Scholar
  13. 13.
    Lovett M, Eng G, Kluge JA, et al. Tubular silk scaffolds for small diameter vascular grafts. Organogenesis. 2010;6(4):217–24.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Altman GH, Horan RL, Lu HH, et al. Silk matrix for tissue engineered anterior cruciate ligaments. Biomaterials. 2002;23(20):4131–41.PubMedGoogle Scholar
  15. 15.
    Correia C, Bhumiratana S, Yan LP, et al. Development of silk-based scaffolds for tissue engineering of bone from human adipose-derived stem cells. Acta Biomater. 2012;8(7):2483–92.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Petrie C, Tholpady S, Ogle R, Botchwey E. Proliferative capacity and osteogenic potential of novel dura mater stem cells on poly-lactic-co-glycolic acid. J Biomed Mater Res A. 2008;85(1):61–71.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Courtney T, Sacks MS, Stankus J, Guan J, Wagner WR. Design and analysis of tissue engineering scaffolds that mimic soft tissue mechanical anisotropy. Biomaterials. 2006;27(19):3631–8.PubMedGoogle Scholar
  18. 18.
    Ciocca L, Donati D, Fantini M, et al. CAD-CAM-generated hydroxyapatite scaffold to replace the mandibular condyle in sheep: preliminary results. J Biomater Appl. 2013;28(2):207–18.PubMedGoogle Scholar
  19. 19.
    Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials. 2000;21(24):2529–43.PubMedGoogle Scholar
  20. 20.
    Grayson WL, Chao PH, Marolt D, Kaplan DL, Vunjak-Novakovic G. Engineering custom-designed osteochondral tissue grafts. Trends Biotechnol. 2008;26(4):181–9.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Benya PD, Shaffer JD. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell. 1982;30(1):215–24.PubMedGoogle Scholar
  22. 22.
    Jang JH, Castano O, Kim HW. Electrospun materials as potential platforms for bone tissue engineering. Adv Drug Deliv Rev. 2009;61(12):1065–83.PubMedGoogle Scholar
  23. 23.
    Grayson WL, Frohlich M, Yeager K, et al. Engineering anatomically shaped human bone grafts. Proc Natl Acad Sci U S A. 2010;107(8):3299–304.PubMedGoogle Scholar
  24. 24.
    Bhumiratana S, Bernhard JC, Alfi DM, et al. Tissue-engineered autologous grafts for facial bone reconstruction. Sci Transl Med. 2016;8(343):343ra83.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Frohlich M, Grayson WL, Marolt D, et al. Bone grafts engineered from human adipose-derived stem cells in perfusion bioreactor culture. Tissue Eng Part A. 2010;16(1):179–89.PubMedGoogle Scholar
  26. 26.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.PubMedGoogle Scholar
  27. 27.
    Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418(6893):41–9.PubMedGoogle Scholar
  28. 28.
    Roelofs AJ, Zupan J, Riemen AHK, et al. Joint morphogenetic cells in the adult mammalian synovium. Nat Commun. 2017;8:15040.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.PubMedGoogle Scholar
  30. 30.
    Mao JJ, Giannobile WV, Helms JA, et al. Craniofacial tissue engineering by stem cells. J Dent Res. 2006;85(11):966–79.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Kang SK, Putnam LA, Ylostalo J, et al. Neurogenesis of Rhesus adipose stromal cells. J Cell Sci. 2004;117(Pt 18):4289–99.PubMedGoogle Scholar
  32. 32.
    Trottier V, Marceau-Fortier G, Germain L, Vincent C, Fradette J. IFATS collection: using human adipose-derived stem/stromal cells for the production of new skin substitutes. Stem Cells. 2008;26(10):2713–23.PubMedGoogle Scholar
  33. 33.
    Shanti RM, Li WJ, Nesti LJ, Wang X, Tuan RS. Adult mesenchymal stem cells: biological properties, characteristics, and applications in maxillofacial surgery. J Oral Maxillofac Surg. 2007;65(8):1640–7.PubMedGoogle Scholar
  34. 34.
    Weng Y, Cao Y, Silva CA, Vacanti MP, Vacanti CA. Tissue-engineered composites of bone and cartilage for mandible condylar reconstruction. J Oral Maxillofac Surg. 2001;59(2):185–90.PubMedGoogle Scholar
  35. 35.
    Tsuji W, Rubin JP, Marra KG. Adipose-derived stem cells: implications in tissue regeneration. World J Stem Cells. 2014;6(3):312–21.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–47.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279–95.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109(1):235–42.PubMedGoogle Scholar
  39. 39.
    Roufosse CA, Direkze NC, Otto WR, Wright NA. Circulating mesenchymal stem cells. Int J Biochem Cell Biol. 2004;36(4):585–97.PubMedGoogle Scholar
  40. 40.
    Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000;97(25):13625–30.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Miura M, Gronthos S, Zhao M, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A. 2003;100(10):5807–12.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Haniffa MA, Wang XN, Holtick U, et al. Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J Immunol. 2007;179(3):1595–604.PubMedGoogle Scholar
  43. 43.
    Sessarego N, Parodi A, Podesta M, et al. Multipotent mesenchymal stromal cells from amniotic fluid: solid perspectives for clinical application. Haematologica. 2008;93(3):339–46.PubMedGoogle Scholar
  44. 44.
    Yan XL, Fu CJ, Chen L, et al. Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. Breast Cancer Res Treat. 2012;132(1):153–64.PubMedGoogle Scholar
  45. 45.
    Noel D, Caton D, Roche S, et al. Cell specific differences between human adipose-derived and mesenchymal-stromal cells despite similar differentiation potentials. Exp Cell Res. 2008;314(7):1575–84.PubMedGoogle Scholar
  46. 46.
    Williams KJ, Picou AA, Kish SL, et al. Isolation and characterization of porcine adipose tissue-derived adult stem cells. Cells Tissues Organs. 2008;188(3):251–8.PubMedGoogle Scholar
  47. 47.
    Halvorsen YD, Franklin D, Bond AL, et al. Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue-derived stromal cells. Tissue Eng. 2001;7(6):729–41.PubMedGoogle Scholar
  48. 48.
    Reddi AH. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol. 1998;16(3):247–52.PubMedGoogle Scholar
  49. 49.
    Milat F, Ng KW. Is Wnt signalling the final common pathway leading to bone formation? Mol Cell Endocrinol. 2009;310(1–2):52–62.PubMedGoogle Scholar
  50. 50.
    Herford AS, Boyne PJ, Rawson R, Williams RP. Bone morphogenetic protein-induced repair of the premaxillary cleft. J Oral Maxillofac Surg. 2007;65(11):2136–41.PubMedGoogle Scholar
  51. 51.
    Liu Q, Cen L, Yin S, et al. A comparative study of proliferation and osteogenic differentiation of adipose-derived stem cells on akermanite and beta-TCP ceramics. Biomaterials. 2008;29(36):4792–9.PubMedGoogle Scholar
  52. 52.
    Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28.PubMedGoogle Scholar
  53. 53.
    Lendeckel S, Jodicke A, Christophis P, et al. Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report. J Craniomaxillofac Surg. 2004;32(6):370–3.PubMedGoogle Scholar
  54. 54.
    Warnke PH, Springer IN, Wiltfang J, et al. Growth and transplantation of a custom vascularised bone graft in a man. Lancet. 2004;364(9436):766–70.PubMedGoogle Scholar
  55. 55.
    Warnke PH, Wiltfang J, Springer I, et al. Man as living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible. Biomaterials. 2006;27(17):3163–7.PubMedGoogle Scholar
  56. 56.
    Abukawa H, Terai H, Hannouche D, et al. Formation of a mandibular condyle in vitro by tissue engineering. J Oral Maxillofac Surg. 2003;61(1):94–100.PubMedGoogle Scholar
  57. 57.
    Abukawa H, Shin M, Williams WB, et al. Reconstruction of mandibular defects with autologous tissue-engineered bone. J Oral Maxillofac Surg. 2004;62(5):601–6.PubMedGoogle Scholar
  58. 58.
    Alhadlaq A, Mao JJ. Tissue-engineered neogenesis of human-shaped mandibular condyle from rat mesenchymal stem cells. J Dent Res. 2003;82(12):951–6.PubMedGoogle Scholar
  59. 59.
    Alhadlaq A, Mao JJ. Tissue-engineered osteochondral constructs in the shape of an articular condyle. J Bone Joint Surg Am. 2005;87(5):936–44.PubMedGoogle Scholar
  60. 60.
    Sheehy EJ, Vinardell T, Buckley CT, Kelly DJ. Engineering osteochondral constructs through spatial regulation of endochondral ossification. Acta Biomater. 2013;9(3):5484–92.PubMedGoogle Scholar
  61. 61.
    Chen J, Chen H, Li P, et al. Simultaneous regeneration of articular cartilage and subchondral bone in vivo using MSCs induced by a spatially controlled gene delivery system in bilayered integrated scaffolds. Biomaterials. 2011;32(21):4793–805.PubMedGoogle Scholar
  62. 62.
    Re’em T, Witte F, Willbold E, Ruvinov E, Cohen S. Simultaneous regeneration of articular cartilage and subchondral bone induced by spatially presented TGF-beta and BMP-4 in a bilayer affinity binding system. Acta Biomater. 2012;8(9):3283–93.PubMedGoogle Scholar
  63. 63.
    Pelttari K, Winter A, Steck E, et al. Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice. Arthritis Rheum. 2006;54(10):3254–66.PubMedGoogle Scholar
  64. 64.
    Vinardell T, Sheehy EJ, Buckley CT, Kelly DJ. A comparison of the functionality and in vivo phenotypic stability of cartilaginous tissues engineered from different stem cell sources. Tissue Eng Part A. 2012;18(11–12):1161–70.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Farrell E, van der Jagt OP, Koevoet W, et al. Chondrogenic priming of human bone marrow stromal cells: a better route to bone repair? Tissue Eng Part C Methods. 2009;15(2):285–95.PubMedGoogle Scholar
  66. 66.
    Hollister SJ. Porous scaffold design for tissue engineering. Nat Mater. 2005;4(7):518–24.PubMedGoogle Scholar
  67. 67.
    Schek RM, Taboas JM, Segvich SJ, Hollister SJ, Krebsbach PH. Engineered osteochondral grafts using biphasic composite solid free-form fabricated scaffolds. Tissue Eng. 2004;10(9–10):1376–85.PubMedGoogle Scholar
  68. 68.
    Ng KW, Lima EG, Bian L, et al. Passaged adult chondrocytes can form engineered cartilage with functional mechanical properties: a canine model. Tissue Eng Part A. 2010;16(3):1041–51.PubMedGoogle Scholar
  69. 69.
    McCulloch PC, Kang RW, Sobhy MH, Hayden JK, Cole BJ. Prospective evaluation of prolonged fresh osteochondral allograft transplantation of the femoral condyle: minimum 2-year follow-up. Am J Sports Med. 2007;35(3):411–20.PubMedGoogle Scholar
  70. 70.
    Lowe J, Almarza AJ. A review of in-vitro fibrocartilage tissue engineered therapies with a focus on the temporomandibular joint. Arch Oral Biol. 2017;83:193–201.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Tan AR, Hung CT. Concise review: mesenchymal stem cells for functional cartilage tissue engineering: taking cues from chondrocyte-based constructs. Stem Cells Transl Med. 2017;6(4):1295–303.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Sampat SR, O'Connell GD, Fong JV, et al. Growth factor priming of synovium-derived stem cells for cartilage tissue engineering. Tissue Eng Part A. 2011;17(17–18):2259–65.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Sakaguchi Y, Sekiya I, Yagishita K, Muneta T. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005;52(8):2521–9.PubMedGoogle Scholar
  74. 74.
    Fan J, Varshney RR, Ren L, Cai D, Wang DA. Synovium-derived mesenchymal stem cells: a new cell source for musculoskeletal regeneration. Tissue Eng Part B Rev. 2009;15(1):75–86.PubMedGoogle Scholar
  75. 75.
    Kim JH, Lee MC, Seong SC, Park KH, Lee S. Enhanced proliferation and chondrogenic differentiation of human synovium-derived stem cells expanded with basic fibroblast growth factor. Tissue Eng Part A. 2011;17(7–8):991–1002.PubMedGoogle Scholar
  76. 76.
    Bhumiratana S, Eton RE, Oungoulian SR, et al. Large, stratified, and mechanically functional human cartilage grown in vitro by mesenchymal condensation. Proc Natl Acad Sci U S A. 2014;111(19):6940–5.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Thomas M, Grande D, Haug RH. Development of an in vitro temporomandibular joint cartilage analog. J Oral Maxillofac Surg. 1991;49(8):854–6; discussion 57.PubMedGoogle Scholar
  78. 78.
    Puelacher WC, Wisser J, Vacanti CA, et al. Temporomandibular joint disc replacement made by tissue-engineered growth of cartilage. J Oral Maxillofac Surg. 1994;52(11):1172–7; discussion 77–8.PubMedGoogle Scholar
  79. 79.
    Almarza AJ, Athanasiou KA. Seeding techniques and scaffolding choice for tissue engineering of the temporomandibular joint disk. Tissue Eng. 2004;10(11–12):1787–95.PubMedGoogle Scholar
  80. 80.
    Hagandora CK, Gao J, Wang Y, Almarza AJ. Poly (glycerol sebacate): a novel scaffold material for temporomandibular joint disc engineering. Tissue Eng Part A. 2013;19(5–6):729–37.PubMedGoogle Scholar
  81. 81.
    Brown BN, Chung WL, Pavlick M, et al. Extracellular matrix as an inductive template for temporomandibular joint meniscus reconstruction: a pilot study. J Oral Maxillofac Surg. 2011;69(12):e488–505.PubMedGoogle Scholar
  82. 82.
    Brown BN, Chung WL, Almarza AJ, et al. Inductive, scaffold-based, regenerative medicine approach to reconstruction of the temporomandibular joint disk. J Oral Maxillofac Surg. 2012;70(11):2656–68.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Anderson DE, Athanasiou KA. Passaged goat costal chondrocytes provide a feasible cell source for temporomandibular joint tissue engineering. Ann Biomed Eng. 2008;36(12):1992–2001.PubMedGoogle Scholar
  84. 84.
    Johns DE, Athanasiou KA. Growth factor effects on costal chondrocytes for tissue engineering fibrocartilage. Cell Tissue Res. 2008;333(3):439–47.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Kalpakci KN, Kim EJ, Athanasiou KA. Assessment of growth factor treatment on fibrochondrocyte and chondrocyte co-cultures for TMJ fibrocartilage engineering. Acta Biomater. 2011;7(4):1710–8.PubMedGoogle Scholar
  86. 86.
    MacBarb RF, Chen AL, Hu JC, Athanasiou KA. Engineering functional anisotropy in fibrocartilage neotissues. Biomaterials. 2013;34(38):9980–9.PubMedGoogle Scholar
  87. 87.
    Hagandora CK, Tudares MA, Almarza AJ. The effect of magnesium ion concentration on the fibrocartilage regeneration potential of goat costal chondrocytes. Ann Biomed Eng. 2012;40(3):688–96.PubMedGoogle Scholar
  88. 88.
    Xiao C, Zhou H, Liu G, et al. Bone marrow stromal cells with a combined expression of BMP-2 and VEGF-165 enhanced bone regeneration. Biomed Mater. 2011;6(1):015013.PubMedGoogle Scholar
  89. 89.
    Steinhardt Y, Aslan H, Regev E, et al. Maxillofacial-derived stem cells regenerate critical mandibular bone defect. Tissue Eng Part A. 2008;14(11):1763–73.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sidney B. Eisig
    • 1
    • 2
    Email author
  • Michael Forman
    • 3
  • Gordana Vunjak-Novakovic
    • 4
  1. 1.Section of Hospital Dentistry, Division of Oral and Maxillofacial Surgery, Columbia University College of Dental MedicineNew YorkUSA
  2. 2.New York Presbyterian/Columbia University Medical Center, Morgan Stanley Children’s Hospital of New York-PresbyterianNew YorkUSA
  3. 3.Division of Oral and Maxillofacial SurgeryNew York Presbyterian/Columbia University Medical CenterNew YorkUSA
  4. 4.Department of Biomedical Engineering, Fu Foundation School of Engineering and Applied ScienceColumbia UniversityNew YorkUSA

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