Current Oral Health Reports

, Volume 5, Issue 4, pp 286–294 | Cite as

Application of Stem Cells for Bone Regeneration in Critical-Sized Defects

  • Shuying YangEmail author
  • Brian P. Ford
  • Zahra Chinipardaz
  • Justin Kirkwood
Dental Stem Cells in Tissue Regeneration (F Setzer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Dental Stem Cells in Tissue Regeneration


Purpose of Review

To discuss tissue bioengineering for critical-sized bone defects. To review the current stem cells that are in use and to describe the importance of an animal model for studying critical-sized bone defects.

Recent Findings

Bone marrow mesenchymal stem cells (MSCs) are well investigated. Recently, other sources of MSCs have been identified and studied in critical-sized bone defects. As for animal models, several have been used to evaluate the use of stem cells in promoting regeneration in critical-sized bone defects. This review specifically focuses on one of the most widely used and accepted models, the rodent calvarium.


Stem cell therapy is promising for bone regeneration, especially for critical-sized bone defects. Additional studies are needed to better understand both the properties and mechanisms of the different types of stem cells, and to develop animal models that mimic human biology.


Critical-sized bone defects Bone regeneration Stem cells Mesenchymal stem cells Bone morphogenic protein BMP 


Compliance with Ethical Standards

Conflict of Interest

All authors declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. 1.
    Kanczler JM, Oreffo ROC. Osteogenesis and angiogenesis: the potential for engineering bone. Eur Cell Mater. 2008;15:100–14.PubMedGoogle Scholar
  2. 2.
    Laurencin C, Khan Y, El-Amin SF. Bone graft substitutes. Expert Rev Med Devices. 2006;3:49–57.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Laurell L, Gottlow J, Zybutz M, Persson R. Treatment of intrabony defects by different surgical procedures. A literature review. J Periodontol. 1998;69:303–13.PubMedGoogle Scholar
  4. 4.
    Block MS, Achong R. Bone morphogenetic protein for sinus augmentation. Atlas Oral Maxillofac Surg Clin North Am. 2006;14:99–105.PubMedGoogle Scholar
  5. 5.
    Holleville N, Quilhac A, Bontoux M, Monsoro-Burq AH. BMP signals regulate Dlx5 during early avian skull development. Dev Biol. 2003;257:177–89.PubMedGoogle Scholar
  6. 6.
    Urist MR. Bone: formation by autoinduction. Science. 1965;150:893–9.PubMedGoogle Scholar
  7. 7.
    Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84-A:2123–34.PubMedGoogle Scholar
  8. 8.
    Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002;27:2396–408.Google Scholar
  9. 9.
    Vaccaro AR, Anderson DG, Patel T, Fischgrund J, Truumees E, Herkowitz HN, et al. Comparison of OP-1 Putty (rhBMP-7) to iliac crest autograft for posterolateral lumbar arthrodesis: a minimum 2-year follow-up pilot study. Spine (Phila Pa 1976). 2005;30:2709–16.Google Scholar
  10. 10.
    Swiontkowski MF, Aro HT, Donell S, Esterhai JL, Goulet J, Jones A, et al. Recombinant human bone morphogenetic protein-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am. 2006;88:1258–65.PubMedGoogle Scholar
  11. 11.
    Jones AL, Bucholz RW, Bosse MJ, Mirza SK, Lyon TR, Webb LX, et al. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88:1431–41.PubMedGoogle Scholar
  12. 12.
    de Peppo GM, Svensson S, Lenneras M, Synnergren J, Stenberg J, Strehl R, et al. Human embryonic mesodermal progenitors highly resemble human mesenchymal stem cells and display high potential for tissue engineering applications. Tissue Eng A. 2010;16:2161–82.Google Scholar
  13. 13.
    Becker KA, Ghule PN, Therrien JA, Lian JB, Stein JL, Van Wijnen AJ, et al. Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. J Cell Physiol. 2006;209(3):883–93.PubMedGoogle Scholar
  14. 14.
    Hindley C, Philpott A. The cell cycle and pluripotency. Biochem J. 2013;451(2):135–43.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Moon SY, Park YB, Kim DS, Oh SK, Kim DW. Generation, culture, and differentiation of human embryonic stem cells for therapeutic applications. Mol Ther. 2006;13(1):5–14.PubMedGoogle Scholar
  16. 16.
    Liu X, Wang P, Chen W, Weir MD, Bao C, Xu HH. Human embryonic stem cells and macroporous calcium phosphate construct for bone regeneration in cranial defects in rats. Acta Biomater. 2014;10(10):4484–93.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Hentze H, Soong PL, Wang ST, Phillips BW, Putti TC, Dunn NR. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res. 2009;2(3):198–210.PubMedGoogle Scholar
  18. 18.
    Blum B, Bar-Nur O, Golan-Lev T, Benvenisty N. The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nat Biotechnol. 2009 Mar;27(3):281-7. Epub 2009 Mar 1. PubMed PMID: 19252483.PubMedGoogle Scholar
  19. 19.
    • Akutsu H, Nasu M, Morinaga S, Motoyama T, Homma N, Machida M, et al. In vivo maturation of human embryonic stem cell-derived teratoma over time. Regen Ther. 2016;5:31–9 This study performed in vivo tumorigenicity tests using teratoma formation and genome-wide sequencing analysis of undifferentiated hESCs.Google Scholar
  20. 20.
    •• Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N, et al. Ethical and safety issues of stem cell-based therapy. Int J Med Sci. 2018;15(1):36. In this review, the authors provided an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine45.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Ilic D, Polak JM. Stem cells in regenerative medicine: introduction. Br Med Bull. 2011;98(1):117–26.PubMedGoogle Scholar
  22. 22.
    Wang Y, You C, Wei R, Zu J, Song C, Li J, et al. Modification of human umbilical cord blood stem cells using polyethylenimine combined with modified TAT peptide to enhance BMP-2 production. Biomed Res Int. 2017;2017:2971413.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Zavatti M, Bertoni L, Maraldi T, Resca E, Beretti F, Guida M, et al. Critical-size bone defect repair using amniotic fluid stem cell/collagen constructs: effect of oral ferutinin treatment in rats. Life Sci. 2015;121:174–83.PubMedGoogle Scholar
  24. 24.
    •• Si JW, Wang XD, Shen SG. Perinatal stem cells: a promising cell resource for tissue engineering of craniofacial bone. World J Stem Cells. 2015;7(1):149. In this review, the authors summarized the current achievements and obstacles in stem cell-based craniofacial bone regeneration and addressed the characteristics of various types of perinatal stem cells and their novel application in tissue engineering of craniofacial bone–59.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Visweswaran M, Pohl S, Arfuso F, Newsholme P, Dilley R, Pervaiz S, et al. Multi-lineage differentiation of mesenchymal stem cells—to Wnt, or not Wnt. Int J Biochem Cell Biol. 2015;68:139–47.PubMedGoogle Scholar
  26. 26.
    •• Watanabe Y, Harada N, Sato K, Abe S, Yamanaka K, Matushita T. Stem cell therapy: is there a future for reconstruction of large bone defects? Injury. 2016;47:S47–51 Reviews the healing of large femur defects in rats by transplantation of “MSCs pre-differentiated in vitro into cartilage-forming chondrocytes”mesenchymal stem cell-derived chondrocytes (MSC-DCs). PubMedGoogle Scholar
  27. 27.
    Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, et al. Stromal cell–derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009;60(3):813–23.PubMedGoogle Scholar
  28. 28.
    Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol. 1974;2:83–92.PubMedGoogle Scholar
  29. 29.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca J, et al. Multilineage potential of mesenchymal cells. Science. 1999;284:143–7.PubMedGoogle Scholar
  30. 30.
    Sekiya I, Larson BL, Smith JR, Pochampally R, Cui JG, Prockop DJ. Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality. Stem Cells. 2002;20:530–41.PubMedGoogle Scholar
  31. 31.
    •• Oryan A, Kamali A, Moshiri A, Eslaminejad MB. Role of mesenchymal stem cells in bone regenerative medicine: what is the evidence? Cells Tissues Organs. 2017;204(2):59–83 In this review, recent advances in the mechanisms of MSC action and the delivery approaches in bone regenerative medicine were discussed. PubMedGoogle Scholar
  32. 32.
    Ganguly P, El-Jawhari JJ, Giannoudis PV, Burska AN, Ponchel F, Jones EA. Age-related changes in bone marrow mesenchymal stromal cells: a potential impact on osteoporosis and osteoarthritis development. Cell Transplant. 2017;26(9):1520–9.PubMedPubMedCentralGoogle Scholar
  33. 33.
    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.PubMedGoogle Scholar
  34. 34.
    Liao HT, Chen CT. Osteogenic potential: comparison between bone marrow and adipose-derived mesenchymal stem cells. World J Stem Cells. 2014;6(3):288–95.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Wang YH, Wu JY, Kong SC, Chiang MH, Ho ML, Yeh ML, et al. Low power laser irradiation and human adipose-derived stem cell treatments promote bone regeneration in critical sized calvarial defects in rats. PLoS One. 2018;13(4):e0195337.PubMedPubMedCentralGoogle Scholar
  36. 36.
    • Barba M, Di Taranto G, Lattanzi W. Adipose-derived stem cell therapies for bone regeneration. Expert Opin Biol Ther. 2017;17(6):677–89 This review defines the state-of-the-art on adipose-derived stem cells (ASCs), encompassing the biological features that make them suitable for bone regenerative strategies, and to provide an update on existing preclinical and clinical applications.PubMedGoogle Scholar
  37. 37.
    •• Ercal P, Pekozer GG, Kose GT. Dental stem cells in bone tissue engineering: current overview and challenges. Adv Exp Med Biol. 2018 Mar 2. Evaluates the regenerative potential of periodontal ligament-derived stem cells (PDLSCs) and osteoblast differentiated from PDLSCs in comparison with bone marrow-derived mesenchymal stem cells (BMSCs) and pre-osteoblasts in calvarial defects. Google Scholar
  38. 38.
    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. 2000;97(25):13625–30.PubMedGoogle Scholar
  39. 39.
    Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A. 2003;100:5807–12.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Annibali S, Cicconetti A, Cristalli MP, Giordano G, Trisi P, Pilloni A, et al. A comparative morphometric analysis of biodegradable scaffolds as carriers for dental pulp and periosteal stem cells in a model of bone regeneration. J Craniofac Surg. 2013;24(3):866–71.PubMedGoogle Scholar
  41. 41.
    Jang JY, Park SH, Park JH, Lee BK, Yun JH, Lee B, et al. In vivo osteogenic differentiation of human dental pulp stem cells embedded in an injectable in vivo-forming hydrogel. Macromol Biosci. 2016;16(8):1158–69.PubMedGoogle Scholar
  42. 42.
    Kwon DY, Kwon JS, Park SH, Park JH, Jang SH, Yin XY, et al. A computer-designed scaffold for bone regeneration within cranial defect using human dental pulp stem cells. Sci Rep. 2015;5:12721.PubMedGoogle Scholar
  43. 43.
    Behnia A, Haghighat A, Talebi A, Nourbakhsh N, Heidari F. Transplantation of stem cells from human exfoliated deciduous teeth for bone regeneration in the dog mandibular defect. World J Stem Cells. 2014;6(4):505–10.PubMedPubMedCentralGoogle Scholar
  44. 44.
    • Nakajima K, Kunimatsu R, Ando K, Ando T, Hayashi Y, Kihara T, et al. Comparison of the bone regeneration ability between stem cells from human exfoliated deciduous teeth, human dental pulp stem cells and human bone marrow mesenchymal stem cells. Biochem Biophys Res Commun. 2018;497(3):876–82 The study demonstrated that stem cells from human exfoliated deciduous teeth (SHED) are one of the best candidates as a cell source for the reconstruction of alveolar cleft due to the bone regeneration ability with less surgical invasion.PubMedGoogle Scholar
  45. 45.
    Alge DL, Zhou D, Adams LL, Wyss BK, Shadday MD, Woods EJ, et al. Donor-matched comparison of dental pulp stem cells and bone marrow-derived mesenchymal stem cells in a rat model. J Tissue Eng Regen Med. 2010;4(1):73–81.PubMedPubMedCentralGoogle Scholar
  46. 46.
    •• Leyendecker Junior A, Gomes Pinheiro CC, Lazzaretti Fernandes T, Franco Bueno D. The use of human dental pulp stem cells for in vivo bone tissue engineering: a systematic review. J Tissue Eng. 2018;9:2041731417752766 Through a systematic review of the literature, the authors evaluated the efficacy of human dental pulp stem cells and stem cells from human exfoliated deciduous teeth (SHED) for bone regeneration.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhang Q, Shi S, Liu Y, Uyanne J, Shi Y, Shi S, et al. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J Immunol. 2009;183(12):7787–98.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Tomar GB, Srivastava RK, Gupta N, Barhanpurkar AP, Pote ST, Jhaveri HM, et al. Human gingiva-derived mesenchymal stem cells are superior to bone marrow-derived mesenchymal stem cells for cell therapy in regenerative medicine. Biochem Biophys Res Commun. 2010;393(3):377–83.PubMedGoogle Scholar
  49. 49.
    Wang F, Yu M, Yan X, Wen Y, Zeng Q, Yue W, et al. Gingiva-derived mesenchymal stem cell-mediated therapeutic approach for bone tissue regeneration. Stem Cells Dev. 2011;20(12):2093–102.PubMedGoogle Scholar
  50. 50.
    Xu QC, Wang ZG, Ji QX, Yu XB, Xu XY, Yuan CQ, et al. Systemically transplanted human gingiva-derived mesenchymal stem cells contributing to bone tissue regeneration. Int J Clin Exp Pathol. 2014;7(8):4922–9.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet. 2004;364:149–55.PubMedGoogle Scholar
  52. 52.
    Seo BM, Miura M, Sonoyama W, Coppe C, Stanyon R, Shi S. Recovery of stem cells from cryopreserved periodontal ligament. J Dent Res. 2005;84:907–12.PubMedGoogle Scholar
  53. 53.
    Yu X, Ge S, Chen S, Xu Q, Zhang J, Guo H, et al. Human gingiva-derived mesenchymal stromal cells contribute to periodontal regeneration in beagle dogs. Cells Tissues Organs. 2013;198(6):428–37.PubMedGoogle Scholar
  54. 54.
    Yu BH, Zhou Q, Wang ZL. Periodontal ligament versus bone marrow mesenchymal stem cells in combination with Bio-Oss scaffolds for ectopic and in situ bone formation: a comparative study in the rat. J Biomater Appl. 2014;29(2):243–53.PubMedGoogle Scholar
  55. 55.
    Yu M, Wang L, Ba P, Li L, Sun L, Duan X, et al. Osteoblast progenitors enhance osteogenic differentiation of periodontal ligament stem cells. J Periodontol. 2017;88(10):e159–68.PubMedGoogle Scholar
  56. 56.
    Diomede F, Zini N, Gatta V, Fulle S, Merciaro I, D’Aurora M, et al. Human periodontal ligament stem cells cultured onto cortico-cancellous scaffold drive bone regenerative process. Eur Cell Mater. 2016;32:181–201.PubMedGoogle Scholar
  57. 57.
    Kadkhoda Z, Safarpour A, Azmoodeh F, Adibi S, Khoshzaban A, Bahrami N. Histopathological comparison between bone marrow-and periodontium-derived stem cells for bone regeneration in rabbit calvaria. Int J Organ Transplant Med. 2016;7(1):9–18.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Moshaverinia A, Chen C, Xu X, Akiyama K, Ansari S, Zadeh HH, et al. Bone regeneration potential of stem cells derived from periodontal ligament or gingival tissue sources encapsulated in RGD-modified alginate scaffold. Tissue Eng A. 2014;20(3–4):611–21.Google Scholar
  59. 59.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.Google Scholar
  60. 60.
    Phillips MD, Kuznetsov SA, Cherman N, Park K, Chen KG, McClendon BN, et al. Directed differentation of human induced pluripotent stem cells toward bone and cartilage: in vitro versus in vivo assays. Stem Cells Transl Med. 2014;3:867–78.PubMedPubMedCentralGoogle Scholar
  61. 61.
    •• Bastami F, Nazeman P, Moslemi H, Rezai Rad M, Sharifi K, Khojasteh A. Induced pluripotent stem cells as a new getaway for bone tissue engineering: a systematic review. Cell Prolif. 2017;50(2) According to the review, osteoinduced pluripotent stem cells (iPSCs) revealed osteogenic capability equal to or superior than that of MSCs.Google Scholar
  62. 62.
    Hayashi K, Ochiai-Shino H, Shiga T, Onodera S, Saito A, Shibahara T, et al. Transplantation of human-induced pluripotent stem cells carried by self-assembling peptide nanofiber hydrogel improves bone regeneration in rat calvarial bone defects. BDJ Open. 2016;2:15007.PubMedPubMedCentralGoogle Scholar
  63. 63.
    •• Li Y, Chen S-K, Li L, Qin L, Wang X-L, Lai Y-X. Bone defect animal models for testing efficacy of bone substitute biomaterials. J Orthop Translat. 2015;3:95–104 This review discusses the most available and commonly used bone defect animal models for testing specific substitute biomaterials.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Spicer PP, Kretlow JD, Young S, Jansen JA, Kasper FK, Mikos AG. Evaluation of bone regeneration using the rat critical size calvarial defect. Nat Protoc. 2012;7:1918–29.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Einhorn TA. Clinically applied models of bone regeneration in tissue engineering research. Clin Orthop Relat Res. 1999;367:S59–67. Scholar
  66. 66.
    Schmitz JP, Hollinger JO. The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res. 1986.
  67. 67.
    Einhorn TA, Lane JM, Burstein AH, Kopman CR, Vigorita VJ. The healing of segmental bone defects induced by demineralized bone matrix. A radiographic and biomechanical study. J Bone Joint Surg. 1984;66:274–9.PubMedGoogle Scholar
  68. 68.
    Wang JC, Kanim LE, Yoo S, Campbell PA, Berk AJ, Lieberman JR. Effect of regional gene therapy with bone morphogenetic protein-2-producing bone marrow cells on spinal fusion in rats. J Bone Joint Surg Am. 2003;85:905–11.PubMedGoogle Scholar
  69. 69.
    Henslee A, Spicer P, Yoon D, Nair M, Meretoja V, Witherel K, et al. Biodegradable composite scaffolds incorporating an intramedullary rod and delivering bone morphogenetic protein-2 for stabilization and bone regeneration in segmental long bone defects. Acta Biomater. 2011;7:3627–37.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Kempen DH, Lu L, Hefferan TE, Creemers LB, Maran A, Classic KL, et al. Retention of in vitro and in vivo BMP-2 bioactivities in sustained delivery vehicles for bone tissue engineering. Biomaterials. 2008;29:3245–52.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Kempen DH, Lu L, Heijink A, Hefferan TE, Creemers LB, Maran A, et al. Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterials. 2009;30:2816–25.PubMedGoogle Scholar
  72. 72.
    Kempen DH, Yaszemski MJ, Heijink A, Hefferan TE, Creemers LB, Britson J, et al. Non-invasive monitoring of BMP-2 retention and bone formation in composites for bone tissue engineering using SPECT/CT and scintillation probes. J Control Release. 2009;134:169–76.PubMedGoogle Scholar
  73. 73.
    Meszaros LB, Usas A, Cooper GM, Huard J. Effect of host sex and sex hormones on muscle-derived stem cell-mediated bone formation and defect healing. Tissue Eng A. 2012;18:1751–9.Google Scholar
  74. 74.
    Behr B, Sorkin M, Lehnhardt M, Renda A, Longaker MT, Quarto N. A comparative analysis of the osteogenic effects of BMP-2, FGF-2, and VEGFA in a calvarial defect model. Tissue Eng A. 2012;18:1079–86.Google Scholar
  75. 75.
    Krebsbach PH, Mankani MH, Satomura K, Kuznetsov SA, Robey PG. Repair of craniotomy defects using bone marrow stromal cells. Transplantation. 1998;66:1272–8.PubMedGoogle Scholar
  76. 76.
    Lee JY, Musgrave D, Pelinkovic D, Fukushima K, Cummins J, Usas A, et al. Effect of bone morphogenetic protein-2-expressing muscle-derived cells on healing of critical sized bone defects in mice. J Bone Joint Surg Am. 2001;83:1032–9.PubMedGoogle Scholar
  77. 77.
    Barnes GL, Einhorn TA. Enhancement of fracture healing with parathyroid hormone. Clin Rev Bone Miner Metab. 2006;4:269–76.Google Scholar
  78. 78.
    Kellum E, Fulzele S, Wenger K, Hamrick M. Absence of myostatin (GDF-8) increases fracture callus size and expression of the chondrogenic factor Sox-5 during bone repair. Bone. 2008;43:S33. Scholar
  79. 79.
    Wigner NA, Kulkarni N, Yakavonis M, Young M, Tinsley B, Meeks B, et al. Urine matrix metalloproteinases (MMPs) as biomarkers for the progression of fracture healing. Injury. 2012;43:274–8.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Gerstenfeld L, Cho T-J, Kon T, Aizawa T, Tsay A, Fitch J, et al. Impaired fracture healing in the absence of TNF-α signaling: the role of TNF-α in endochondral cartilage resorption. J Bone Miner Res. 2003;18:1584–92.PubMedGoogle Scholar
  81. 81.
    Haddock NT, Wapner K, Levin LS. Vascular bone transfer options in the foot and ankle. Plast Reconstr Surg. 2013;132:685–93.PubMedGoogle Scholar
  82. 82.
    Zhao Y-P, Tian Q-Y, Frenkel S, Liu C-J. The promotion of bone healing by progranulin, a downstream molecule of BMP-2, through interacting with TNF/TNFR signaling. Biomaterials. 2013;34:6412–21.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Ben-David D, Srouji S, Shapira-Schweitzer K, Kossover O, Ivanir E, Kuhn G, et al. Low dose BMP-2 treatment for bone repair using a PEGylated fibrinogen hydrogel matrix. Biomaterials. 2013;34:2902–10.PubMedGoogle Scholar
  84. 84.
    Yang F, Wang J, Hou J, Guo H, Liu C. Bone regeneration using cell-mediated responsive degradable PEG-based scaffolds incorporating with rhBMP-2. Biomaterials. 2013;34:1514–28.PubMedGoogle Scholar
  85. 85.
    Rosen V. BMP2 signaling in bone development and repair. Cytokine Growth Factor Rev. 2009;20:475–80.PubMedGoogle Scholar
  86. 86.
    Zhang H, Xing L. Ubiquitin E3 ligase itch negatively regulates osteoblast differentiation from mesenchymal progenitor cells. Stem Cells. 2013;31:1574–83.PubMedGoogle Scholar
  87. 87.
    Fricain JC, Schlaubitz S, Visage CL, et al. A nano-hydroxyapatite–pullulan/dextran polysaccharide composite macroporous material for bone tissue engineering. Biomaterials. 2013;34:2947–59.PubMedGoogle Scholar
  88. 88.
    Kumar S. Bone defect repair in mice by mesenchymal stem cells. Methods Mol Biol. 2014;1213:193–207.PubMedGoogle Scholar
  89. 89.
    Holstein JH, Karabin-Kehl B, Scheuer C, Garcia P, Histing T, Meier C, et al. Endostatin inhibits callus remodeling during fracture healing in mice. J Orthop Res. 2013;31:1579–84.PubMedGoogle Scholar
  90. 90.
    •• Ning B, Zhao Y, Buza JA, Li W, Wang W, Jia T. Surgically-induced mouse models in the study of bone regeneration: current models and future directions. Mol Med Rep. 2017;15:1017–23 The review introduces a classification of surgically induced mouse models in bone regeneration, evaluates the application and value of these models, and discusses the potential development of further innovations in this field in the future. PubMedPubMedCentralGoogle Scholar
  91. 91.
    Yoon E, Dhar S, Chun DE, Gharibjanian NA, Evans GR. In vivo osteogenic potential of human adipose-derived stem cells/poly lactide-co-glycolic acid constructs for bone regeneration in a rat critical sized calvarial defect model. Tissue Eng. 2007;13:619–27.PubMedGoogle Scholar
  92. 92.
    He X, Dziak R, Yuan X, Mao K, Genco R, Swihart M, et al. BMP2 genetically engineered MSCs and EPCs promote vascularized bone regeneration in rat critical sized calvarial bone defects. PLoS One. 2013;8:e60473. Scholar
  93. 93.
    • Liu Z, Yuan X, Fernandes G, Dziak R, Ionita CN, Li C, et al. The combination of nano-calcium sulfate/platelet rich plasma gel scaffold with BMP2 gene-modified mesenchymal stem cells promotes bone regeneration in rat critical sized calvarial defects. Stem Cell Res Ther. 2017. This study shows that nano-calcium sulfate/platelet-rich plasma (nCS/PRP) scaffolds containing BMP2-modified MSCs successfully promote bone regeneration in critical-sized bone defects.

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Shuying Yang
    • 1
    Email author
  • Brian P. Ford
    • 2
  • Zahra Chinipardaz
    • 3
  • Justin Kirkwood
    • 4
  1. 1.Department of Anatomy & Cell Biology, School of Dental MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of Periodontics, School of Dental MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  4. 4.School of Dental MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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