Skip to main content

Advertisement

Log in

Orthopedic tissue regeneration: cells, scaffolds, and small molecules

  • Review Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Orthopedic tissue regeneration would benefit the aging population or patients with degenerative bone and cartilage diseases, especially osteoporosis and osteoarthritis. Despite progress in surgical and pharmacological interventions, new regenerative approaches are needed to meet the challenge of creating bone and articular cartilage tissues that are not only structurally sound but also functional, primarily to maintain mechanical integrity in their high load-bearing environments. In this review, we discuss new advances made in exploiting the three classes of materials in bone and cartilage regenerative medicine—cells, biomaterial-based scaffolds, and small molecules—and their successes and challenges reported in the clinic. In particular, the focus will be on the development of tissue-engineered bone and cartilage ex vivo by combining stem cells with biomaterials, providing appropriate structural, compositional, and mechanical cues to restore damaged tissue function. In addition, using small molecules to locally promote regeneration will be discussed, with potential approaches that combine bone and cartilage targeted therapeutics for the orthopedic-related disease, especially osteoporosis and osteoarthritis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hutton DL, Grayson WL. Stem cell-based approaches to engineering vascularized bone. Curr Opin Chem Eng. 2014;3:75–82.

    Article  Google Scholar 

  2. Srinivasan S, Gross TS, Bain SD. Bone mechanotransduction may require augmentation in order to strengthen the senescent skeleton. Ageing Res Rev. 2012;11:353–60.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ashhurst DE. The cartilaginous skeleton of an elasmobranch fish does not heal. Matrix Biol. 2004;23:15–22.

    Article  CAS  PubMed  Google Scholar 

  4. Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther. 2009;11:224.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Makris EA, Gomoll AH, Malizos KN, Hu JC, Athanasiou KA. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol. 2015;11:21–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kreuz PC, Steinwachs MR, Erggelet C, Krause SJ, Konrad G, Uhl M, et al. Results after microfracture of full-thickness chondral defects in different compartments in the knee. Osteoarthr Cartil. 2006;14:1119–25.

    Article  CAS  PubMed  Google Scholar 

  7. Amir G, Pirie CJ, Rashad S, Revell PA. Remodelling of subchondral bone in osteoarthritis: a histomorphometric study. J Clin Pathol. 1992;45:990–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yoon YM, Kim SJ, Oh CD, Ju JW, Song WK, Yoo YJ, et al. Maintenance of differentiated phenotype of articular chondrocytes by protein kinase C and extracellular signal-regulated protein kinase. J Biol Chem. 2002;277:8412–20.

    Article  CAS  PubMed  Google Scholar 

  9. Kassem M, Ankersen L, Eriksen EF, Clark BF, Rattan SI. Demonstration of cellular aging and senescence in serially passaged long-term cultures of human trabecular osteoblasts. Osteoporos Int. 1997;7:514–24.

    Article  CAS  PubMed  Google Scholar 

  10. Friedenstein AJ, Piatetzky II S, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morpholog. 1966;16:381–90.

    CAS  Google Scholar 

  11. Weir MD, Xu HH. Human bone marrow stem cell-encapsulating calcium phosphate scaffolds for bone repair. Acta Biomater. 2010;6:4118–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sumanasinghe RD, Bernacki SH, Loboa EG. Osteogenic differentiation of human mesenchymal stem cells in collagen matrices: effect of uniaxial cyclic tensile strain on bone morphogenetic protein (BMP-2) mRNA expression. Tissue Eng. 2006;12:3459–65.

    Article  CAS  PubMed  Google Scholar 

  13. Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthr Cartil. 2002;10:199–206.

    Article  CAS  PubMed  Google Scholar 

  14. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.

    Article  CAS  PubMed  Google Scholar 

  15. Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol. 2007;213:341–7.

    Article  CAS  PubMed  Google Scholar 

  16. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006;24:386–98.

    Article  CAS  PubMed  Google Scholar 

  17. Wang X, Wang Y, Gou W, Lu Q, Peng J, Lu S. Role of mesenchymal stem cells in bone regeneration and fracture repair: a review. Int Orthop. 2013;37:2491–8.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Grayson WL, Bunnell BA, Martin E, Frazier T, Hung BP, Gimble JM. Stromal cells and stem cells in clinical bone regeneration. Nat Rev Endocrinol. 2015;11:140–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lock J, Liu H. Nanomaterials enhance osteogenic differentiation of human mesenchymal stem cells similar to a short peptide of BMP-7. Int J Nanomedicine. 2011;6:2769–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Amini AR, Laurencin CT, Nukavarapu SP. Bone tissue engineering: recent advances and challenges. Crit Rev Biomed Eng. 2012;40:363–408.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Huebsch N, Lippens E, Lee K, Mehta M, Koshy ST, Darnell MC, et al. Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone formation. Nat Mater. 2015;14:1269–77.

  22. Kawate K, Yajima H, Ohgushi H, Kotobuki N, Sugimoto K, Ohmura T, et al. Tissue-engineered approach for the treatment of steroid-induced osteonecrosis of the femoral head: transplantation of autologous mesenchymal stem cells cultured with beta-tricalcium phosphate ceramics and free vascularized fibula. Artif Organs. 2006;30:960–2.

    Article  CAS  PubMed  Google Scholar 

  23. Qu Z, Yan J, Li B, Zhuang J, Huang Y. Improving bone marrow stromal cell attachment on chitosan/hydroxyapatite scaffolds by an immobilized RGD peptide. Biomed Mater. 2010;5:065001.

    Article  PubMed  CAS  Google Scholar 

  24. Bhumiratana S, Grayson WL, Castaneda A, Rockwood DN, Gil ES, Kaplan DL, et al. Nucleation and growth of mineralized bone matrix on silk-hydroxyapatite composite scaffolds. Biomaterials. 2011;32:2812–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang H, Bongio M, Farbod K, Nijhuis AW, van den Beucken J, Boerman OC, et al. Development of injectable organic/inorganic colloidal composite gels made of self-assembling gelatin nanospheres and calcium phosphate nanocrystals. Acta Biomater. 2014;10:508–19.

    Article  CAS  PubMed  Google Scholar 

  26. Maas M, Guo P, Keeney M, Yang F, Hsu TM, Fuller GG, et al. Preparation of mineralized nanofibers: collagen fibrils containing calcium phosphate. Nano Lett. 2011;11:1383–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ignjatovic N, Ajdukovic Z, Uskokovic D. New biocomposite [biphasic calcium phosphate/ poly-DL-lactide-co-glycolide/biostimulative agent] filler for reconstruction of bone tissue changed by osteoporosis. J Mater Sci Mater Med. 2005;16:621–6.

    Article  CAS  PubMed  Google Scholar 

  28. Yang F, Both SK, Yang X, Walboomers XF, Jansen JA. Development of an electrospun nano-apatite/PCL composite membrane for GTR/GBR application. Acta Biomater. 2009;5:3295–304.

    Article  CAS  PubMed  Google Scholar 

  29. Zaky SH, Cancedda R. Engineering craniofacial structures: facing the challenge. J Dent Res. 2009;88:1077–91.

    Article  CAS  PubMed  Google Scholar 

  30. Reichert JC, Cipitria A, Epari DR, Saifzadeh S, Krishnakanth P, Berner A, et al. A tissue engineering solution for segmental defect regeneration in load-bearing long bones. Sci Transl Med. 2012;4:141ra93.

    Article  PubMed  CAS  Google Scholar 

  31. Fu S, Ni P, Wang B, Chu B, Zheng L, Luo F, et al. Injectable and thermo-sensitive PEG-PCL-PEG copolymer/collagen/n-HA hydrogel composite for guided bone regeneration. Biomaterials. 2012;33:4801–9.

    Article  CAS  PubMed  Google Scholar 

  32. Huang CY, Reuben PM, D’Ippolito G, Schiller PC, Cheung HS. Chondrogenesis of human bone marrow-derived mesenchymal stem cells in agarose culture. Anat Rec A: Discov Mol Cell Evol Biol. 2004;278:428–36.

    Article  Google Scholar 

  33. Coleman RM, Case ND, Guldberg RE. Hydrogel effects on bone marrow stromal cell response to chondrogenic growth factors. Biomaterials. 2007;28:2077–86.

    Article  CAS  PubMed  Google Scholar 

  34. Xu J, Wang W, Ludeman M, Cheng K, Hayami T, Lotz JC, et al. Chondrogenic differentiation of human mesenchymal stem cells in three-dimensional alginate gels. Tissue Eng A. 2008;14:667–80.

    Article  CAS  Google Scholar 

  35. Pasquinelli G, Orrico C, Foroni L, Bonafe F, Carboni M, Guarnieri C, et al. Mesenchymal stem cell interaction with a non-woven hyaluronan-based scaffold suitable for tissue repair. J Anat. 2008;213:520–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fan H, Hu Y, Qin L, Li X, Wu H, Lv R. Porous gelatin-chondroitin-hyaluronate tri-copolymer scaffold containing microspheres loaded with TGF-beta1 induces differentiation of mesenchymal stem cells in vivo for enhancing cartilage repair. J Biomed Mater Res A. 2006;77:785–94.

    Article  PubMed  CAS  Google Scholar 

  37. Wilke MM, Nydam DV, Nixon AJ. Enhanced early chondrogenesis in articular defects following arthroscopic mesenchymal stem cell implantation in an equine model. J Orthop Res. 2007;25:913–25.

    Article  CAS  PubMed  Google Scholar 

  38. Kuroda R, Ishida K, Matsumoto T, Akisue T, Fujioka H, Mizuno K, et al. Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthr Cartil. 2007;15:226–31.

    Article  CAS  PubMed  Google Scholar 

  39. Favi PM, Benson RS, Neilsen NR, Hammonds RL, Bates CC, Stephens CP, et al. Cell proliferation, viability, and in vitro differentiation of equine mesenchymal stem cells seeded on bacterial cellulose hydrogel scaffolds. Mater Sci Eng C Mater Biol Appl. 2013;33:1935–44.

    Article  CAS  PubMed  Google Scholar 

  40. Hwang NS, Varghese S, Puleo C, Zhang Z, Elisseeff J. Morphogenetic signals from chondrocytes promote chondrogenic and osteogenic differentiation of mesenchymal stem cells. J Cell Physiol. 2007;212:281–4.

    Article  CAS  PubMed  Google Scholar 

  41. Sharma B, Williams CG, Khan M, Manson P, Elisseeff JH. In vivo chondrogenesis of mesenchymal stem cells in a photopolymerized hydrogel. Plast Reconstr Surg. 2007;119:112–20.

    Article  CAS  PubMed  Google Scholar 

  42. Pang Y, Cui P, Chen W, Gao P, Zhang H. Quantitative study of tissue-engineered cartilage with human bone marrow mesenchymal stem cells. Arch Facial Plast Surg. 2005;7:7–11.

    Article  PubMed  Google Scholar 

  43. Chen G, Liu D, Tadokoro M, Hirochika R, Ohgushi H, Tanaka J, et al. Chondrogenic differentiation of human mesenchymal stem cells cultured in a cobweb-like biodegradable scaffold. Biochem Biophys Res Commun. 2004;322:50–5.

    Article  CAS  PubMed  Google Scholar 

  44. Li WJ, Tuli R, Okafor C, Derfoul A, Danielson KG, Hall DJ, et al. A three-dimensional nanofibrous scaffold for cartilage tissue engineering using human mesenchymal stem cells. Biomaterials. 2005;26:599–609.

    Article  CAS  PubMed  Google Scholar 

  45. Johnstone B, Hering TM, Caplan AI, Goldberg VM, Yoo JU. In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res. 1998;238:265–72.

    Article  CAS  PubMed  Google Scholar 

  46. Barry F, Boynton RE, Liu B, Murphy JM. Chondrogenic differentiation of mesenchymal stem cells from bone marrow: differentiation-dependent gene expression of matrix components. Exp Cell Res. 2001;268:189–200.

    Article  CAS  PubMed  Google Scholar 

  47. Schmitt B, Ringe J, Haupl T, Notter M, Manz R, Burmester GR, et al. BMP2 initiates chondrogenic lineage development of adult human mesenchymal stem cells in high-density culture. Differentiation. 2003;71:567–77.

    Article  CAS  PubMed  Google Scholar 

  48. Indrawattana N, Chen G, Tadokoro M, Shann LH, Ohgushi H, Tateishi T, et al. Growth factor combination for chondrogenic induction from human mesenchymal stem cell. Biochem Biophys Res Commun. 2004;320:914–9.

    Article  CAS  PubMed  Google Scholar 

  49. Ishii I, Mizuta H, Sei A, Hirose J, Kudo S, Hiraki Y. Healing of full-thickness defects of the articular cartilage in rabbits using fibroblast growth factor-2 and a fibrin sealant. J Bone Joint Surg (Br). 2007;89:693–700.

    Article  CAS  Google Scholar 

  50. Uebersax L, Merkle HP, Meinel L. Insulin-like growth factor I releasing silk fibroin scaffolds induce chondrogenic differentiation of human mesenchymal stem cells. J Control Release. 2008;127:12–21.

    Article  CAS  PubMed  Google Scholar 

  51. Warzecha J, Gottig S, Bruning C, Lindhorst E, Arabmothlagh M, Kurth A. Sonic hedgehog protein promotes proliferation and chondrogenic differentiation of bone marrow-derived mesenchymal stem cells in vitro. J Orthop Sci. 2006;11:491–6.

    Article  CAS  PubMed  Google Scholar 

  52. Rudnicki JA, Brown AM. Inhibition of chondrogenesis by Wnt gene expression in vivo and in vitro. Dev Biol. 1997;185:104–18.

    Article  CAS  PubMed  Google Scholar 

  53. Giuliani N, Lisignoli G, Magnani M, Racano C, Bolzoni M, Dalla Palma B, et al. New insights into osteogenic and chondrogenic differentiation of human bone marrow mesenchymal stem cells and their potential clinical applications for bone regeneration in pediatric orthopaedics. Stem Cells Int. 2013;2013. doi:10.1155/2013/312501.

  54. Huey DJ, Hu JC, Athanasiou KA. Unlike bone, cartilage regeneration remains elusive. Science. 2012;338:917–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008;11:343–53.

    PubMed  Google Scholar 

  56. Nejadnik H, Hui JH, Feng Choong EP, Tai BC, Lee EH. Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med. 2010;38:1110–6.

    Article  PubMed  Google Scholar 

  57. Wakitani S, Mitsuoka T, Nakamura N, Toritsuka Y, Nakamura Y, Horibe S. Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transplant. 2004;13:595–600.

    Article  PubMed  Google Scholar 

  58. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28.

    Article  CAS  PubMed  Google Scholar 

  59. Parker AM, Katz AJ. Adipose-derived stem cells for the regeneration of damaged tissues. Expert Opin Biol Ther. 2006;6:567–78.

    Article  CAS  PubMed  Google Scholar 

  60. Zhang ZY, Teoh SH, Chong MS, Schantz JT, Fisk NM, Choolani MA, et al. Superior osteogenic capacity for bone tissue engineering of fetal compared with perinatal and adult mesenchymal stem cells. Stem Cells. 2009;27:126–37.

    Article  PubMed  CAS  Google Scholar 

  61. Liao HT, Lee MY, Tsai WW, Wang HC, Lu WC. Osteogenesis of adipose-derived stem cells on polycaprolactone-beta-tricalcium phosphate scaffold fabricated via selective laser sintering and surface coating with collagen type I. J Tissue Eng Regen Med. 2013. doi:10.1002/term.1811.

    PubMed Central  Google Scholar 

  62. Marino G, Rosso F, Cafiero G, Tortora C, Moraci M, Barbarisi M, et al. Beta-tricalcium phosphate 3D scaffold promote alone osteogenic differentiation of human adipose stem cells: in vitro study. J Mater Sci Mater Med. 2010;21:353–63.

    Article  CAS  PubMed  Google Scholar 

  63. Cowan CM, Shi YY, Aalami OO, Chou YF, Mari C, Thomas R, et al. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol. 2004;22:560–7.

    Article  CAS  PubMed  Google Scholar 

  64. Arrigoni E, de Girolamo L, Di Giancamillo A, Stanco D, Dellavia C, Carnelli D, et al. Adipose-derived stem cells and rabbit bone regeneration: histomorphometric, immunohistochemical and mechanical characterization. J Orthop Sci. 2013;18:331–9.

    Article  CAS  PubMed  Google Scholar 

  65. US National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT01218945. ClinicalTrials.gov;2013.

  66. US National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT01532076. ClinicalTrials.gov;2014.

  67. Xu Y, Balooch G, Chiou M, Bekerman E, Ritchie RO, Longaker MT. Analysis of the material properties of early chondrogenic differentiated adipose-derived stromal cells (ASC) using an in vitro three-dimensional micromass culture system. Biochem Biophys Res Commun. 2007;359:311–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yoon HH, Bhang SH, Shin JY, Shin J, Kim BS. Enhanced cartilage formation via three-dimensional cell engineering of human adipose-derived stem cells. Tissue Eng A. 2012;18:1949–56.

    Article  CAS  Google Scholar 

  69. Awad HA, Wickham MQ, Leddy HA, Gimble JM, Guilak F. Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate, and gelatin scaffolds. Biomaterials. 2004;25:3211–22.

    Article  CAS  PubMed  Google Scholar 

  70. Im GI, Shin YW, Lee KB. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthr Cartil. 2005;13:845–53.

    Article  PubMed  Google Scholar 

  71. Ogawa R, Orgill DP, Murphy GF, Mizuno S. Hydrostatic pressure-driven three-dimensional cartilage induction using human adipose-derived stem cells and collagen gels. Tissue Eng A. 2015;21:257–66.

    Article  CAS  Google Scholar 

  72. Debnath T, Ghosh S, Potlapuvu US, Kona L, Kamaraju SR, Sarkar S, et al. Proliferation and differentiation potential of human adipose-derived stem cells grown on chitosan hydrogel. PLoS One. 2015;10:e0120803.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Jin X, Sun Y, Zhang K, Wang J, Shi T, Ju X, et al. Ectopic neocartilage formation from predifferentiated human adipose derived stem cells induced by adenoviral-mediated transfer of hTGF beta2. Biomaterials. 2007;28:2994–3003.

    Article  CAS  PubMed  Google Scholar 

  74. Zhang K, Zhang Y, Yan S, Gong L, Wang J, Chen X, et al. Repair of an articular cartilage defect using adipose-derived stem cells loaded on a polyelectrolyte complex scaffold based on poly(l-glutamic acid) and chitosan. Acta Biomater. 2013;9:7276–88.

    Article  CAS  PubMed  Google Scholar 

  75. Kim HJ, Im GI. Chondrogenic differentiation of adipose tissue-derived mesenchymal stem cells: greater doses of growth factor are necessary. J Orthop Res. 2009;27:612–9.

    Article  PubMed  CAS  Google Scholar 

  76. Vicente Lopez MA, Vazquez Garcia MN, Entrena A, Olmedillas Lopez S, Garcia-Arranz M, Garcia-Olmo D, et al. Low doses of bone morphogenetic protein 4 increase the survival of human adipose-derived stem cells maintaining their stemness and multipotency. Stem Cells Dev. 2011;20:1011–9.

    Article  CAS  PubMed  Google Scholar 

  77. Estes BT, Wu AW, Guilak F. Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6. Arthritis Rheum. 2006;54:1222–32.

    Article  CAS  PubMed  Google Scholar 

  78. Knippenberg M, Helder MN, Zandieh Doulabi B, Wuisman PI, Klein-Nulend J. Osteogenesis versus chondrogenesis by BMP-2 and BMP-7 in adipose stem cells. Biochem Biophys Res Commun. 2006;342:902–8.

    Article  CAS  PubMed  Google Scholar 

  79. Van Pham P, Bui KH, Ngo DQ, Vu NB, Truong NH, Phan NL, et al. Activated platelet-rich plasma improves adipose-derived stem cell transplantation efficiency in injured articular cartilage. Stem Cell Res Ther. 2013;4:91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Koh YG, Choi YJ, Kwon SK, Kim YS, Yeo JE. Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2013;23:1308–16.

    Article  PubMed  Google Scholar 

  81. Dragoo JL, Carlson G, McCormick F, Khan-Farooqi H, Zhu M, Zuk PA, et al. Healing full-thickness cartilage defects using adipose-derived stem cells. Tissue Eng. 2007;13:1615–21.

    Article  CAS  PubMed  Google Scholar 

  82. Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. 2012;19:902–7.

    Article  PubMed  Google Scholar 

  83. Koh YG, Kwon OR, Kim YS, Choi YJ. Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study. Arthroscopy. 2014;30:1453–60.

    Article  PubMed  Google Scholar 

  84. Koh YG, Choi YJ, Kwon OR, Kim YS. Second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am J Sports Med. 2014;42:1628–37.

    Article  PubMed  Google Scholar 

  85. Kim YS, Choi YJ, Suh DS, Heo DB, Kim YI, Ryu JS, et al. Mesenchymal stem cell implantation in osteoarthritic knees is fibrin glue effective as a scaffold? Am J Sports Med. 2015;43:176–85.

    Article  PubMed  Google Scholar 

  86. Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014;32:1254–66.

    Article  CAS  PubMed  Google Scholar 

  87. Sun N, Longaker MT, Wu JC. Human iPS cell-based therapy: considerations before clinical applications. Cell Cycle. 2010;9:880–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kao CL, Tai LK, Chiou SH, Chen YJ, Lee KH, Chou SJ, et al. Resveratrol promotes osteogenic differentiation and protects against dexamethasone damage in murine induced pluripotent stem cells. Stem Cells Dev. 2010;19:247–58.

    Article  CAS  PubMed  Google Scholar 

  89. Li F, Bronson S, Niyibizi C. Derivation of murine induced pluripotent stem cells (iPS) and assessment of their differentiation toward osteogenic lineage. J Cell Biochem. 2010;109:643–52.

    Article  CAS  PubMed  Google Scholar 

  90. Duan X, Tu Q, Zhang J, Ye J, Sommer C, Mostoslavsky G, et al. Application of induced pluripotent stem (iPS) cells in periodontal tissue regeneration. J Cell Physiol. 2011;226:150–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. de Peppo GM, Marcos-Campos I, Kahler DJ, Alsalman D, Shang L, Vunjak-Novakovic G, et al. Engineering bone tissue substitutes from human induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2013;110:8680–5.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Hwang NS, Kim MS, Sampattavanich S, Baek JH, Zhang Z, Elisseeff J. Effects of three-dimensional culture and growth factors on the chondrogenic differentiation of murine embryonic stem cells. Stem Cells. 2006;24:284–91.

    Article  CAS  PubMed  Google Scholar 

  93. Kramer J, Hegert C, Guan K, Wobus AM, Muller PK, Rohwedel J. Embryonic stem cell-derived chondrogenic differentiation in vitro: activation by BMP-2 and BMP-4. Mech Dev. 2000;92:193–205.

    Article  CAS  PubMed  Google Scholar 

  94. Diekman BO, Christoforou N, Willard VP, Sun H, Sanchez-Adams J, Leong KW, et al. Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2012;109:19172–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nakagawa T, Lee SY, Reddi AH. Induction of chondrogenesis from human embryonic stem cells without embryoid body formation by bone morphogenetic protein 7 and transforming growth factor beta1. Arthritis Rheum. 2009;60:3686–92.

    Article  CAS  PubMed  Google Scholar 

  96. Hwang NS, Varghese S, Zhang Z, Elisseeff J. Chondrogenic differentiation of human embryonic stem cell-derived cells in arginine-glycine-aspartate-modified hydrogels. Tissue Eng. 2006;12:2695–706.

    Article  CAS  PubMed  Google Scholar 

  97. Hwang NS, Varghese S, Lee HJ, Zhang Z, Ye Z, Bae J, et al. In vivo commitment and functional tissue regeneration using human embryonic stem cell-derived mesenchymal cells. Proc Natl Acad Sci U S A. 2008;105:20641–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Teramura T, Onodera Y, Mihara T, Hosoi Y, Hamanishi C, Fukuda K. Induction of mesenchymal progenitor cells with chondrogenic property from mouse-induced pluripotent stem cells. Cell Reprogram. 2010;12:249–61.

    Article  CAS  PubMed  Google Scholar 

  99. Saito T, Yano F, Mori D, Ohba S, Hojo H, Otsu M, et al. Generation of Col2a1-EGFP iPS cells for monitoring chondrogenic differentiation. PLoS One. 2013;8:e74137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Guzzo RM, Gibson J, Xu RH, Lee FY, Drissi H. Efficient differentiation of human iPSC-derived mesenchymal stem cells to chondroprogenitor cells. J Cell Biochem. 2013;114:480–90.

    Article  CAS  PubMed  Google Scholar 

  101. Ko JY, Kim KI, Park S, Im GI. In vitro chondrogenesis and in vivo repair of osteochondral defect with human induced pluripotent stem cells. Biomaterials. 2014;35:3571–81.

    Article  CAS  PubMed  Google Scholar 

  102. Wei Y, Zeng W, Wan R, Wang J, Zhou Q, Qiu S, et al. Chondrogenic differentiation of induced pluripotent stem cells from osteoarthritic chondrocytes in alginate matrix. Eur Cell Mater. 2012;23:1–12.

    CAS  PubMed  Google Scholar 

  103. Yamashita A, Morioka M, Kishi H, Kimura T, Yahara Y, Okada M, et al. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature. 2014;513:507–11.

    Article  CAS  PubMed  Google Scholar 

  104. Kim MJ, Son MJ, Son MY, Seol B, Kim J, Park J, et al. Generation of human induced pluripotent stem cells from osteoarthritis patient-derived synovial cells. Arthritis Rheum. 2011;63:3010–21.

    Article  CAS  PubMed  Google Scholar 

  105. Langle D, Halver J, Rathmer B, Willems E, Schade D. Small molecules targeting in vivo tissue regeneration. ACS Chem Biol. 2014;9:57–71.

    Article  PubMed  CAS  Google Scholar 

  106. Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell. 2012;10:244–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Johnson K, Zhu S, Tremblay MS, Payette JN, Wang J, Bouchez LC, et al. A stem cell-based approach to cartilage repair. Science. 2012;336:717–21.

    Article  CAS  PubMed  Google Scholar 

  108. Wu X, Ding S, Ding Q, Gray NS, Schultz PG. A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells. J Am Chem Soc. 2002;124:14520–1.

    Article  CAS  PubMed  Google Scholar 

  109. Sinha S, Chen JK. Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat Chem Biol. 2006;2:29–30.

    Article  CAS  PubMed  Google Scholar 

  110. Ito T, Takemasa M, Makino K, Otsuka M. Preparation of calcium phosphate nanocapsules including simvastatin/deoxycholic acid assembly, and their therapeutic effect in osteoporosis model mice. J Pharm Pharmacol. 2013;65:494–502.

    Article  CAS  PubMed  Google Scholar 

  111. Yoshii T, Hafeman AE, Esparza JM, Okawa A, Gutierrez G, Guelcher SA. Local injection of lovastatin in biodegradable polyurethane scaffolds enhances bone regeneration in a critical-sized segmental defect in rat femora. J Tissue Eng Regen Med. 2014;8:589–95.

    Article  CAS  PubMed  Google Scholar 

  112. Petrie Aronin CE, Shin SJ, Naden KB, Rios Jr PD, Sefcik LS, Zawodny SR, et al. The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720. Biomaterials. 2010;31:6417–24.

    Article  CAS  PubMed  Google Scholar 

  113. Wu X, Walker J, Zhang J, Ding S, Schultz PG. Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway. Chem Biol. 2004;11:1229–38.

    Article  CAS  PubMed  Google Scholar 

  114. Lee SH, Shin H. Matrices and scaffolds for delivery of bioactive molecules in bone and cartilage tissue engineering. Adv Drug Deliv Rev. 2007;59:339–59.

    Article  CAS  PubMed  Google Scholar 

  115. Liechty WB, Kryscio DR, Slaughter BV, Peppas NA. Polymers for drug delivery systems. Annu Rev Chem Biomol Eng. 2010;1:149–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bellido M, Lugo L, Roman-Blas JA, Castaneda S, Caeiro JR, Dapia S, et al. Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis. Arthritis Res Ther. 2010;12:R152.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Neogi T, Felson D, Niu J, Lynch J, Nevitt M, Guermazi A, et al. Cartilage loss occurs in the same subregions as subchondral bone attrition: a within-knee subregion-matched approach from the Multicenter Osteoarthritis Study. Arthritis Rheum. 2009;61:1539–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Burr DB, Gallant MA. Bone remodelling in osteoarthritis. Nat Rev Rheumatol. 2012;8:665–73.

    Article  CAS  PubMed  Google Scholar 

  119. Sampson ER, Hilton MJ, Tian Y, Chen D, Schwarz EM, Mooney RA, et al. Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med. 2011;3:101ra93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Eswaramoorthy R, Chang CC, Wu SC, Wang GJ, Chang JK, Ho ML. Sustained release of PTH(1–34) from PLGA microspheres suppresses osteoarthritis progression in rats. Acta Biomater. 2012;8:2254–62.

    Article  CAS  PubMed  Google Scholar 

  121. Chang JK, Chang LH, Hung SH, Wu SC, Lee HY, Lin YS, et al. Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats. Arthritis Rheum. 2009;60:3049–60.

    Article  CAS  PubMed  Google Scholar 

  122. Bellido M, Lugo L, Roman-Blas JA, Castaneda S, Calvo E, Largo R, et al. Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis. Osteoarthr Cartil. 2011;19:1228–36.

    Article  CAS  PubMed  Google Scholar 

  123. Orth P, Cucchiarini M, Wagenpfeil S, Menger MD, Madry H. PTH [1–34]-induced alterations of the subchondral bone provoke early osteoarthritis. Osteoarthr Cartil. 2014;22:813–21.

    Article  CAS  PubMed  Google Scholar 

  124. Mwale F, Yao G, Ouellet JA, Petit A, Antoniou J. Effect of parathyroid hormone on type X and type II collagen expression in mesenchymal stem cells from osteoarthritic patients. Tissue Eng A. 2010;16:3449–55.

    Article  CAS  Google Scholar 

  125. Boyce BF, Xing LP. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 2007;9 (Suppl 1):S1.

  126. Kadri A, Ea HK, Bazille C, Hannouche D, Liote F, Cohen-Solal ME. Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis. Arthritis Rheum. 2008;58:2379–86.

    Article  CAS  PubMed  Google Scholar 

  127. Shimizu S, Asou Y, Itoh S, Chung UI, Kawaguchi H, Shinomiya K, et al. Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis. Arthritis Rheum. 2007;56:3358–65.

    Article  PubMed  Google Scholar 

  128. Henrotin Y, Labasse A, Zheng SX, Galais P, Tsouderos Y, Crielaard JM, et al. Strontium ranelate increases cartilage matrix formation. J Bone Miner Res. 2001;16:299–308.

    Article  CAS  PubMed  Google Scholar 

  129. Tat SK, Pelletier JP, Mineau F, Caron J, Martel-Pelletier J. Strontium ranelate inhibits key factors affecting bone remodeling in human osteoarthritic subchondral bone osteoblasts. Bone. 2011;49:559–67.

    Article  CAS  PubMed  Google Scholar 

  130. Pelletier JP, Kapoor M, Fahmi H, Lajeunesse D, Blesius A, Maillet J, et al. Strontium ranelate reduces the progression of experimental dog osteoarthritis by inhibiting the expression of key proteases in cartilage and of IL-1beta in the synovium. Ann Rheum Dis. 2013;72:250–7.

    Article  CAS  PubMed  Google Scholar 

  131. Reginster JY, Kaufman JM, Goemaere S, Devogelaer JP, Benhamou CL, Felsenberg D, et al. Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis. Osteoporos Int. 2012;23:1115–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Gentleman E, Fredholm YC, Jell G, Lotfibakhshaiesh N, O’Donnell MD, Hill RG, et al. The effects of strontium-substituted bioactive glasses on osteoblasts and osteoclasts in vitro. Biomaterials. 2010;31:3949–56.

    Article  CAS  PubMed  Google Scholar 

  133. Reginster JY. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind randomised, placebo-controlled trial. Ann Rheum Dis. 2014;73:e8.

    Article  PubMed  Google Scholar 

  134. Takahashi D, Iwasaki N, Kon S, Matsui Y, Majima T, Minami A, et al. Down-regulation of cathepsin K in synovium leads to progression of osteoarthritis in rabbits. Arthritis Rheum. 2009;60:2372–80.

    Article  CAS  PubMed  Google Scholar 

  135. Boonen S, Rosenberg E, Claessens F, Vanderschueren D, Papapoulos S. Inhibition of cathepsin K for treatment of osteoporosis. Curr Osteoporos Rep. 2012;10:73–9.

    Article  PubMed  Google Scholar 

  136. Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR, Nakamura T, et al. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the long-term odanacatib fracture trial. Osteoporos Int. 2015;26:699–712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Connor JR, LePage C, Swift BA, Yamashita D, Bendele AM, Maul D, et al. Protective effects of a Cathepsin K inhibitor, SB-553484, in the canine partial medial meniscectomy model of osteoarthritis. Osteoarthr Cartil. 2009;17:1236–43.

    Article  CAS  PubMed  Google Scholar 

  138. McDougall JJ, Schuelert N, Bowyer J. Cathepsin K inhibition reduces CTXII levels and joint pain in the guinea pig model of spontaneous osteoarthritis. Osteoarthr Cartil. 2010;18:1355–7.

    Article  CAS  PubMed  Google Scholar 

  139. Hayami T, Zhuo Y, Wesolowski GA, Pickarski M, le Duong T. Inhibition of Cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis. Bone. 2012;50:1250–9.

    Article  CAS  PubMed  Google Scholar 

  140. Schurigt U, Hummel KM, Petrow PK, Gajda M, Stockigt R, Middel P, et al. Cathepsin K deficiency partially inhibits, but does not prevent, bone destruction in human tumor necrosis factor-transgenic mice. Arthritis Rheum. 2008;58:422–34.

    Article  CAS  PubMed  Google Scholar 

  141. Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res. 1995;10:1478–87.

    Article  CAS  PubMed  Google Scholar 

  142. Bay-Jensen AC, Hoegh-Madsen S, Dam E, Henriksen K, Sondergaard BC, Pastoureau P, et al. Which elements are involved in reversible and irreversible cartilage degradation in osteoarthritis? Rheumatol Int. 2010;30:435–42.

    Article  PubMed  Google Scholar 

  143. Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 2004;50:1193–206.

    Article  CAS  PubMed  Google Scholar 

  144. Lv Y, Xia JY, Chen JY, Zhao H, Yan HC, Yang HS, et al. Effects of pamidronate disodium on the loss of osteoarthritic subchondral bone and the expression of cartilaginous and subchondral osteoprotegerin and RANKL in rabbits. BMC Musculoskelet Disord. 2014;15:370.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Lampropoulou-Adamidou K, Dontas I, Stathopoulos IP, Khaldi L, Lelovas P, Vlamis J, et al. Chondroprotective effect of high-dose zoledronic acid: an experimental study in a rabbit model of osteoarthritis. J Orthop Res. 2014;32:1646–51.

    Article  CAS  PubMed  Google Scholar 

  146. Strassle BW, Mark L, Leventhal L, Piesla MJ, Jian Li X, Kennedy JD, et al. Inhibition of osteoclasts prevents cartilage loss and pain in a rat model of degenerative joint disease. Osteoarthr Cartil. 2010;18:1319–28.

    Article  CAS  PubMed  Google Scholar 

  147. Carbone LD, Nevitt MC, Wildy K, Barrow KD, Harris F, Felson D, et al. The relationship of antiresorptive drug use to structural findings and symptoms of knee osteoarthritis. Arthritis Rheum. 2004;50:3516–25.

    Article  PubMed  Google Scholar 

  148. Nishii T, Tamura S, Shiomi T, Yoshikawa H, Sugano N. Alendronate treatment for hip osteoarthritis: prospective randomized 2-year trial. Clin Rheumatol. 2013;32:1759–66.

    Article  PubMed  Google Scholar 

  149. Spector TD, Conaghan PG, Buckland-Wright JC, Garnero P, Cline GA, Beary JF, et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Res Ther. 2005;7:R625–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Bingham 3rd CO, Buckland-Wright JC, Garnero P, Cohen SB, Dougados M, Adami S, et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum. 2006;54:3494–507.

    Article  CAS  PubMed  Google Scholar 

  151. Buckland-Wright JC, Messent EA, Bingham 3rd CO, Ward RJ, Tonkin C. A 2 yr longitudinal radiographic study examining the effect of a bisphosphonate (risedronate) upon subchondral bone loss in osteoarthritic knee patients. Rheumatology (Oxford). 2007;46:257–64.

    Article  CAS  Google Scholar 

  152. Garnero P, Aronstein WS, Cohen SB, Conaghan PG, Cline GA, Christiansen C, et al. Relationships between biochemical markers of bone and cartilage degradation with radiological progression in patients with knee osteoarthritis receiving Risedronate: the knee osteoarthritis structural arthritis randomized clinical trial. Osteoarthr Cartil. 2008;16:660–6.

    Article  CAS  PubMed  Google Scholar 

  153. Shamsul BS, Tan KK, Chen HC, Aminuddin BS, Ruszymah BH. Posterolateral spinal fusion with ostegenesis induced BMSC seeded TCP/HA in a sheep model. Tissue Cell. 2014;46:152–8.

    Article  CAS  PubMed  Google Scholar 

  154. TheinHan W, Liu J, Tang M, Chen W, Cheng L, Xu HH. Induced pluripotent stem cell-derived mesenchymal stem cell seeding on biofunctionalized calcium phosphate cements. Bone Res. 2013;4:371–84.

    Article  PubMed  CAS  Google Scholar 

  155. Mesimaki K, Lindroos B, Tornwall J, Mauno J, Lindqvist C, Kontio R, et al. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int J Oral Maxillofac Surg. 2009;38:201–9.

    Article  CAS  PubMed  Google Scholar 

  156. Tang M, Chen W, Liu J, Weir MD, Cheng L, Xu HH. Human induced pluripotent stem cell-derived mesenchymal stem cell seeding on calcium phosphate scaffold for bone regeneration. Tissue Eng A. 2014;20:1295–305.

    Article  CAS  Google Scholar 

  157. Hicok KC, Du Laney TV, Zhou YS, Halvorsen YDC, Hitt DC, Cooper LF, et al. Human adipose-derived adult stem cells produce osteoid in vivo. Tissue Eng. 2004;10:371–80.

    Article  CAS  PubMed  Google Scholar 

  158. Grayson WL, Marolt D, Bhumiratana S, Frohlich M, Guo XE, Vunjak-Novakovic G. Optimizing the medium perfusion rate in bone tissue engineering bioreactors. Biotechnol Bioeng. 2011;108:1159–70.

    Article  CAS  PubMed  Google Scholar 

  159. Frohlich M, Grayson WL, Marolt D, Gimble JM, Kregar-Velikonja N, Vunjak-Novakovic G. Bone grafts engineered from human adipose-derived stem cells in perfusion bioreactor culture. Tissue Eng A. 2010;16:179–89.

    Article  CAS  Google Scholar 

  160. Hashemibeni B, Esfandiari E, Sadeghi F, Heidary F, Roshankhah S, Mardani M, et al. An animal model study for bone repair with encapsulated differentiated osteoblasts from adipose-derived stem cells in alginate. Iran J Basic Med Sci. 2014;17:854–9.

    PubMed  PubMed Central  Google Scholar 

  161. Kim HJ, Park SH, Durham J, Gimble JM, Kaplan DL, Dragoo JL. In vitro chondrogenic differentiation of human adipose-derived stem cells with silk scaffolds. J Tissue Eng. 2012;3:2041731412466405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Gabbay JS, Heller JB, Mitchell SA, Zuk PA, Spoon DB, Wasson KL, et al. Osteogenic potentiation of human adipose-derived stem cells in a 3-dimensional matrix. Ann Plast Surg. 2006;57:89–93.

    Article  CAS  PubMed  Google Scholar 

  163. Levi B, Hyun JS, Montoro DT, Lo DD, Chan CK, Hu S, et al. In vivo directed differentiation of pluripotent stem cells for skeletal regeneration. Proc Natl Acad Sci U S A. 2012;109:20379–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Yeon B, Park MH, Moon HJ, Kim SJ, Cheon YW, Jeong B. 3D culture of adipose-tissue-derived stem cells mainly leads to chondrogenesis in Poly(ethylene glycol)-Poly(L-alanine) Diblock Copolymer Thermogel. Biomacromolecules. 2013;14:3256–66.

    Article  CAS  PubMed  Google Scholar 

  165. Nejadnik H, Diecke S, Lenkov OD, Chapelin F, Donig J, Tong X, et al. Improved approach for chondrogenic differentiation of human induced pluripotent stem cells. Stem Cell Rev. 2015;11:242–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Mahmoudifar N, Doran PM. Chondrogenic differentiation of human adipose-derived stem cells in polyglycolic acid mesh scaffolds under dynamic culture conditions. Biomaterials. 2010;31:3858–67.

    Article  CAS  PubMed  Google Scholar 

  167. Yoon IS, Chung CW, Sung JH, Cho HJ, Kim JS, Shim WS, et al. Proliferation and chondrogenic differentiation of human adipose-derived mesenchymal stem cells in porous hyaluronic acid scaffold. J Biosci Bioeng. 2011;112:402–8.

    Article  CAS  PubMed  Google Scholar 

  168. Merceron C, Portron S, Masson M, Lesoeur J, Fellah BH, Gauthier O, et al. The effect of two- and three-dimensional cell culture on the chondrogenic potential of human adipose-derived mesenchymal stem cells after subcutaneous transplantation with an injectable hydrogel. Cell Transplant. 2011;20:1575–88.

    Article  PubMed  Google Scholar 

  169. Ragetly GR, Griffon DJ, Lee HB, Fredericks LP, Gordon-Evans W, Chung YS. Effect of chitosan scaffold microstructure on mesenchymal stem cell chondrogenesis. Acta Biomater. 2010;6:1430–6.

    Article  CAS  PubMed  Google Scholar 

  170. Gellynck K, Shah R, Parkar M, Young A, Buxton P, Brett P. Small molecule stimulation enhances bone regeneration but not titanium implant osseointegration. Bone. 2013;57:405–12.

    Article  CAS  PubMed  Google Scholar 

  171. Stadelmann VA, Gauthier O, Terrier A, Bouler JM, Pioletti DP. Implants delivering bisphosphonate locally increase periprosthetic bone density in an osteoporotic sheep model. A pilot study. Eur Cell Mater. 2008;16:10–6.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jennifer Elisseeff.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jeon, O.H., Elisseeff, J. Orthopedic tissue regeneration: cells, scaffolds, and small molecules. Drug Deliv. and Transl. Res. 6, 105–120 (2016). https://doi.org/10.1007/s13346-015-0266-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-015-0266-7

Keywords

Navigation