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  • Review Article
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Cell-free and cell-based approaches for bone regeneration

Nature Reviews Rheumatology volume 5, pages 685–697 (2009)Cite this article

Abstract

The clinical augmentation of bone currently involves the use of autogenous or allogeneic bone grafts and synthetic materials, all of which are associated with limitations. Research on the safe enhancement of bone formation concerns the potential value of scaffolds, stem cells, gene therapy, and chemical and mechanical signals. Optimal scaffolds are engineered to provide mechanical stability while supporting osteogenesis, osteoconduction and/or osteoinduction. Scaffold materials include natural or synthetic polymers, ceramics, and composites. The resorption, mechanical strength and efficacy of these materials can be manipulated through structural and chemical design parameters. Cell-seeded scaffolds contain stem cells or progenitor cells, such as culture-expanded marrow stromal cells and multipotent skeletal progenitor cells sourced from other tissues. Despite extensive evidence from proof-of-principle studies, bone tissue engineering has not translated to clinical practice. Much of the research involves in vitro and animal models that do not replicate potential clinical applications. Problem areas include cell sources and numbers, over-reliance on existing scaffold materials, optimum delivery of factors, control of transgene expression, vascularization, integration with host bone, and the capacity to form bone and marrow structures in vivo. Current thinking re-emphasizes the potential of biomimetic materials to stimulate, enhance, or control bone's innate regenerative capacity at the implantation site.

Key Points

  • Bone tissue engineering concerns the use of scaffolds, stem cells, gene therapy, and chemical or mechanical signals to repair bone lesions

  • Biocompatible scaffolds are engineered to provide mechanical stability and support osteogenesis, osteoconduction and/or osteoinduction

  • Cell-free approaches draw from engineering tools and biological knowledge of biomimetic (or 'smart') materials that enhance bone's innate regenerative capacity

  • Cell-based approaches to bone regeneration draw on recent advances to control osteoblast differentiation of stem cells or progenitor cells derived from a variety of tissues

  • Despite enthusiasm for cell-based bone tissue engineering, translation into clinical practice has not been achieved, and many challenges remain

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Figure 1: The mechanism of surface modification of bioactive glass upon exposure to body fluid.

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References

  1. Kaplan, F. S. et al. in Orthopaedic Basic Science (ed. Simon, S. R.) 127–184 (American Academy of Orthopaedic Surgeons, San Diego, 1994).

    Google Scholar 

  2. Glowacki, J. & Mulliken, J. B. Demineralized bone implants. Clin. Plast. Surg. 12, 233–241 (1985).

    CAS  PubMed  Google Scholar 

  3. Russell, J. L. & Block, J. E. Clinical utility of demineralized bone matrix for osseous defects, arthrodesis and reconstruction: impact of processing techniques and study methodology. Orthopedics 22, 524–531 (1999).

    CAS  PubMed  Google Scholar 

  4. Schwartz, Z. et al. Ability of commercial demineralized freeze-dried bone allograft to induce new bone formation. J. Periodontol. 67, 918–926 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Yaszemski, M. J., Oldham, J. B. & Currier, B. L. in Bone Engineering (ed. Davies, J. E.) 541–547 (EM Squared Incorporated, Toronto, 2000).

    Google Scholar 

  6. Temenoff, J. S., Lu, L. & Mikos, A. G. in Bone Engineering (ed. Davies, J. E.) 454–461 (EM Squared Incorporated, Toronto, 2000).

    Google Scholar 

  7. Buser, D. et al. Influence of surface characteristics on bone integration of titanium implants: a histomorphometric study in miniature pigs. J. Biomed. Mater. Res. 25, 889–902 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Webster, T. J., Siegel, R. W. & Bizios, R. Osteoblast adhesion on nanophase ceramics. Biomaterials 20, 1221–1227 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Sitharaman, B. et al. In vivo biocompatibility of ultra-short-single-walled carbon nanotube/biodegradable polymer nanocomposites for bone tissue engineering. Bone 43, 362–370 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Khan, Y., Yaszemski, M. J., Mikos, A. G. & Laurencin, C. T. Tissue engineering of bone: material and matrix considerations. J. Bone Joint Surg. Am. 90, 36–42 (2008).

    Article  PubMed  Google Scholar 

  11. Issa, T. K., Bahgat, M. A. & Linthicum, F. H. Jr. Tissue reaction to prosthetic materials in human temporal bones. Am. J. Otol. 5, 40–43 (1983).

    CAS  PubMed  Google Scholar 

  12. James, K. et al. in Bone Engineering (ed. Davies, J. E.) 195–203 (EM Squared Incorporated, Toronto, 2000).

    Google Scholar 

  13. Moroni, L., De Wijn, J. R. & Van Blitterswijk, C. A. Integrating novel technologies to fabricate smart scaffolds. J. Biomater. Sci. Polymer Edn 19, 543–572 (2008).

    Article  CAS  Google Scholar 

  14. Hollister, S. J., Levy, R. A., Chu, T. M., Halloran, J. W. & Feinberg, S. E. An image-based approach for designing and manufacturing craniofacial scaffolds. Int. J. Oral Maxillofac. Surg. 29, 67–71 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Ciocca, L., De Crescenzio, F., Fantini, M. & Scotti, R. CAD/CAM and rapid prototyped scaffold construction for bone regenerative medicine and surgical transfer of virtual planning: a pilot study. Comput. Med. Imaging Graph. 33, 58–62 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Peter, S. J., Miller, S. T., Zhu, G., Yasko, A. W. & Mikos, A. G. In vivo degradation of a poly(propylene fumarate)/beta-tricalcium phosphate injectable composite scaffold. J. Biomed. Mater. Res. 41, 1–7 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Seeherman, H. J. et al. rh-BMP-2 delivered in a calcium phosphate cement accelerates bridging of critical-sized defects in rabbit radii. J. Bone Joint Surg. Am. 88, 1553–1565 (2006).

    Article  PubMed  Google Scholar 

  18. Link, D. P. et al. Bone response and mechanical strength of rabbit femoral defects filled with injectable CaP cements containing TGF-β1 loaded gelatin microparticles. Biomaterials 29, 675–682 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Hollinger, J. O. et al. Recombinant human bone morphogenetic protein-2 and collagen for bone regeneration. J. Biomed. Mater. Res. 43, 356–364 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Lisignoli, G. et al. Osteogenesis of large segmental radius defects enhanced by basic fibroblast growth factor activated bone marrow stromal cells grown on non-woven hyaluronic acid-based polymer scaffold. Biomaterials 23, 1043–1051 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Al-Munajjed, A. A. et al. Development of a biomimetic collagen-hydroxyapatite scaffold for bone tissue engineering using a SBF immersion technique. J. Biomed. Mater. Res. B Appl. Biomater. 90, 584–591 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Hong, Y., Gong, Y., Gao, C. & Shen, J. J. Collagen-coated polylactide microcarriers/chitosan hydrogel composite: injectable scaffold for cartilage regeneration. Biomed. Mater. Res. A 85, 628–637 (2008).

    Article  CAS  Google Scholar 

  23. Cancedda, R., Giannoni, P. & Mastrogiacomo, M. A tissue engineering approach to bone repair in large animal models and in clinical practice. Biomaterials 28, 4240–4250 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. White, A. P. et al. Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion. Int. Orthop. 31, 735–741 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Carter, J. D. et al. Clinical and radiographic assessment of transforaminal lumbar interbody fusion using HEALOS collagen-hydroxyapatite sponge with autologous bone marrow aspirate. Spine J. 9, 434–438 (2009).

    Article  PubMed  Google Scholar 

  26. Epstein, N. E. Beta tricalcium phosphate: observation of use in 100 posterolateral lumbar instrumented fusions. Spine J. 9, 630–638 (2009).

    Article  PubMed  Google Scholar 

  27. Senn, N. On the healing of aseptic bone. Am. J. Med. Sci. 98, 219–243 (1889).

    Article  Google Scholar 

  28. Mulliken, J. B. & Glowacki, J. Induced osteogenesis for repair and construction in the craniofacial region. Plast. Reconstr. Surg. 65, 553–560 (1980).

    Article  CAS  PubMed  Google Scholar 

  29. Eid, K., Zelicof, S., Perona, B. P., Sledge, C. B. & Glowacki, J. Tissue reactions to particles of bone-substitute materials in intraosseous and heterotopic sites in rats: discrimination of osteoinduction, osteocompatibility, and inflammation. J. Orthop. Res. 19, 962–969 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Lewin-Epstein, J. Polyvinyl sponge as a scaffold for bone. Br. J. Oral Surg. 2, 115–119 (1964).

    Article  CAS  PubMed  Google Scholar 

  31. Braunecker, J., Baba, M., Milroy, G. E. & Cameron, R. E. The effects of molecular weight and porosity on the degradation and drug release from polyglycolide. Int. J. Pharm. 282, 19–34 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Thomson, R. C., Yaszemski, M. J., Powers, J. M. & Mikos, A. G. Fabrication of biodegradable polymer scaffolds to engineer trabecular bone. Biomater. Sci. Polym. Ed. 7, 23–38 (1995).

    Article  CAS  Google Scholar 

  33. Piskin, E. et al. In vivo performance of simvastatin-loaded electrospun spiral-wound polycaprolactone scaffolds in reconstruction of cranial bone defects in the rat model. J. Biomed. Mat. Res. A 90, 1137–1151 (2009).

    Article  CAS  Google Scholar 

  34. Mikos, A. G. & Temenoff, J. S. Formation of highly porous biodegradable scaffolds for tissue engineering. Electron. J. Biotechnol. 3, 1–6 (2000).

    Article  Google Scholar 

  35. Pitt, C. G. in Biodegradable Polymers As Drug Delivery System (ed. Chasin, M. & Langer, R.) 71–120 (Marcel Dekker, New York, 1990).

    Google Scholar 

  36. Fisher, J. P. et al. Soft and hard tissue response to photocrosslinked poly(propylene fumarate) scaffolds in a rabbit model. J. Biomed. Mater. Res. 59, 547–556 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Zhang, R. & Ma, P. X. Porous poly(L-lactic acid)/apatite composites created by biomimetic process. J. Biomed. Mater. Res. 45, 285–293 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Marcolongo, M., Ducheyne, P., Garino, J. & Schepers, E. Bioactive glass fiber/polymeric composites bond to bone tissue. J. Biomed. Mater. Res. 39, 161–170 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Laurencin, C. T. & Lu, H. H. in Bone Engineering (ed. Davies, J. E.) 463–472 (EM Squared Incorporated, Toronto, 2000).

    Google Scholar 

  40. Murphy, W. L., Simmons, C. A., Kaigler, D. & Mooney, D. J. Bone regeneration via a mineral substrate and induced angiogenesis. J. Dent. Res. 83, 204–210 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Datta, N., Holtorf, H. L., Sikavitsas, V. I. & Jansen, J. A. Effect of bone extracellular matrix synthesized in vitro on the osteoblastic differentiation of marrow stromal cells. Biomaterials 26, 971–977 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Hulbert, S. F. Potential of ceramic materials as permanently implantable skeletal prostheses. J. Biomed. Mat. Res. 4, 433–456 (1970).

    Article  CAS  Google Scholar 

  43. US FDA. PMA—Premarket Approval [online] (2009).

  44. Delecrin, J., Takahashi, S., Gouin, F. & Passuti, N. A synthetic porous ceramic as a bone graft substitute in the surgical management of scoliosis: a prospective, randomized study. Spine 25, 563–569 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Ooms, E. M., Wolke, J. G., van der Waerden, J. P. & Jansen, J. A. Trabecular bone response to injectable calcium phosphate (Ca-P) cement. J. Biomed. Mater. Res. 61, 9–18 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Gauthier, O., Bouler, J. M., Aguado, E., Pilet, P. & Daculsi, G. Macroporous biphasic calcium phosphate ceramics: influence of macropore diameter and macroporosity percentage on bone ingrowth. Biomaterials 19, 133–139 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Ruhe, P. Q. et al. Porous poly(DL-lactic-co-glycolic acid)/calcium phosphate cement composite for reconstruction of bone defects. Tissue Eng. 12, 789–800 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Schepers, E. et al. Bioactive glass particulate material as a filler for bone lesions. J. Oral Rehabil. 18, 439–452 (1991).

    Article  CAS  PubMed  Google Scholar 

  49. Kokubo, T., Kim, H. M., Kawashita, M. & Nakamura, T. in Bone Engineering (ed. Davies, J. E.) 191–194 (EM Squared Incorporated, Toronto, 2000).

    Google Scholar 

  50. Oonishi, H. et al. Quantitative comparison of bone growth behavior in granules of Bioglass, A-W glass-ceramic, and hydroxyapatite. J. Biomed. Mater. Res. 51, 37–46 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Xu, S. et al. Reconstruction of calvarial defect of rabbits using porous calcium silicate bioactive ceramics. Biomaterials 29, 2588–2596 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Xue, W., Liu, X., Zheng, X. B. & Ding, C. In vivo evaluation of plasma-sprayed wollastonite coating. Biomaterials 26, 3455–3460 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Hedberg, E. L. et al. Effect of varied release kinetics of the osteogenic thrombin peptide TP508 from biodegradable, polymeric scaffolds on bone formation in vitro. J. Biomed. Mater. Res. A 72, 343–353 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Babensee, J. E., McIntire, L. V. & Mikos, A. G. Growth factor delivery for tissue engineering. Pharm. Res. 17, 497–504 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Reddi, A. H. Bone and cartilage differentiation. Curr. Op. Genet. Dev. 4, 737–744 (1994).

    Article  CAS  PubMed  Google Scholar 

  56. Cheng, H. et al. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J. Bone Joint Surg. Am. 85, 1544–1552 (2003).

    Article  PubMed  Google Scholar 

  57. Lakey, L. A., Akella, R. & Ranieri, J. P. in Bone Engineering (ed. Davies, J. E.) 137–142 (EM Squared Incorporated, Toronto, 2000).

    Google Scholar 

  58. McGuire, M. K., Scheyer, E. T. & Schupbach, P. Growth factor-mediated treatment of recession defects: a randomized controlled trial and histologic and microcomputed tomography examination. J. Periodontol. 80, 550–564 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Yukna, R. A. & Mellonig, J. T. Histologic evaluation of periodontal healing in humans following regenerative therapy with enamel matrix derivative. A 10-case series. J. Periodontol. 71, 752–759 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Kawana, F. et al. Porcine enamel matrix derivative enhances trabecular bone regeneration during wound healing of injured rat femur. Anat. Rec. 264, 438–446 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Hovey, L. R. et al. Application of periodontal tissue engineering using enamel matrix derivative and a human fibroblast-derived dermal substitute to stimulate periodontal wound healing in Class III furcation defects. J. Periodontol. 77, 790–799 (2006).

    Article  PubMed  Google Scholar 

  62. Savarino, L. et al. Evaluation of bone healing enhancement by lyophilized bone grafts supplemented with platelet gel: a standardized methodology in patients with tibial osteotomy for genu varus. J. Biomed. Mater. Res. B 76, 364–372 (2006).

    Article  CAS  Google Scholar 

  63. Boyan, B. D., Schwartz, Z., Patterson, T. E. & Muschler, G. Clinical use of platelet-rich plasma in orthopaedics. American Academy of Orthopaedic Surgeons [online] (2009).

    Google Scholar 

  64. Yamada, Y. et al. Autogenous injectable bone for regeneration with mesenchymal stem cells and platelet-rich plasma: tissue-engineered bone regeneration. Tissue Eng. 10, 955–964 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Garcia, A. J. & Reyes, C. D. Bio-adhesive surfaces to promote osteoblast differentiation and bone formation. J. Dent. Res. 84, 407–413 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Dee, K. C., Anderson, T. T. & Bizios, R. Osteoblast population migration characteristics on substrates modified with immobilized adhesive peptides. Biomaterials 20, 221–227 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Eid, K., Chen, E., Griffith, L. & Glowacki, J. Effect of RGD coating on osteocompatibility of PLGA-polymer disks in a rat tibial wound. J. Biomed. Mater. Res. 57, 224–231 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Hennessy, K. M. et al. The effect of RGD peptides on osseointegration of hydroxyapatite biomaterials. Biomaterials 29, 3075–3083 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dee, K. C., Andersen, T. T. & Bizios, R. Design and function of novel osteoblast-adhesive peptides for chemical modification of biomaterials. J. Biomed. Mater. Res. 40, 371–377 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Rezania, A. & Healy, K. E. Biomimetic peptide surfaces that regulate adhesion, spreading, cytoskeletal organization, and mineralization of the matrix deposited by osteoblast-like cells. Biotechnol. Prog. 15, 19–32 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Jane, J. A. et al. Ectopic osteogenesis using adenoviral bone morphogenetic protein (BMP)-4 and BMP-6 gene transfer. Mol. Ther. 6, 464–470 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Betz, O. B. et al. Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects. Gene Ther. 14, 1039–1044 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Egerman, M. et al. Effect of BMP-2 gene transfer on bone healing in sheep. Gene Ther. 13, 1290–1299 (2006).

    Article  CAS  Google Scholar 

  74. Ito, H. et al. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat. Med. 11, 291–297 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bonadio, J., Smiley, E., Patil, P. & Goldstein, S. Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nat. Med. 5, 753–759 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Fang, J. et al. Stimulation of new bone formation by direct transfer or osteogenic plasmid genes. Proc. Natl Acad. Sci. USA 93, 5753–5758 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bright, C., Park, Y.-S., Sieber, A. N., Kostuik, J. P. & Leong, K. W. In vivo evaluation of plasmid DNA encoding OP-1 protein for spine fusion. Spine 31, 2163–2172 (2006).

    Article  PubMed  Google Scholar 

  78. Geiger, F. et al. Vascular endothelial growth factor gene-activated matrix (VEGF165-GAM) enhances osteogenesis and angiogenesis in large segmental bone defects. J. Bone Miner. Res. 20, 2028–2035 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Evans, C., Ghivizzani, S. C. & Robbins, P. D. Orthopedic gene therapy in 2008. Mol. Ther. 17, 231–244 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Burchardt, H. The biology of bone graft repair. Clin. Orthop. Rel. Res. 174, 28–42 (1983).

    Google Scholar 

  81. Glowacki, J. in Bone and Cartilage Allografts: Biology and Clinical Applications (eds Friedlaender, G. E. & Goldberg, V. M.) 55–73 (American Academy of Orthopaedic Surgeons, Park Ridge, IL, 1991).

    Google Scholar 

  82. Connolly, J. F. et al. Autologous marrow injection for delayed unions of the tibia. J. Orthop. Trauma 3, 276–282 (1989).

    Article  CAS  PubMed  Google Scholar 

  83. Hernigou, P. et al. The use of percutaneous autologous bone marrow transplantation in nonunion and avascular necrosis of bone. J. Bone Joint Surg. Br. 87, 896–902 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Friedenstein, A. J., Piatetzky-Shapiro, I. I. & Petrakova, K. V. Osteogenesis in transplants of bone marrow cells. J. Embryol. Exp. Morphol. 16, 381–390 (1966).

    CAS  PubMed  Google Scholar 

  85. Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–148 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Sikavitsas, V. I., Bancroft, G. N., Holtorf, H. L., Jansen, J. A. & Mikos, A. G. Mineralized matrix deposition by marrow stromal osteoblasts in 3D perfusion culture increases with increasing fluid shear forces. Proc. Natl Acad. Sci. USA 100, 14683–14688 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lu, H. H., El-Amin, S. F., Scott, K. D. & Laurencin, C. T. Three-dimensional, bioactive, biodegradable, polymer-bioactive glass composite scaffolds with improved mechanical properties support collagen synthesis and mineralization of human osteoblast-like cells in vitro. J. Biomed. Mater. Res. A 64, 465–474 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Arthur, A., Zannettino, A. & Gronthos, S. The therapeutic applications of multipotential mesenchymal/stromal stem cells in skeletal tissue repair. J. Cell. Physiol. 218, 237–245 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Abdallah, B. M. & Kassem, M. The use of mesenchymal (skeletal) stem cells for treatment of degenerative diseases: current status and future perspectives. J. Cell. Physiol. 218, 9–12 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Lee, K., Chan, C. K., Patil, N. & Goodman, S. B. Cell therapy for bone regeneration—bench to bedside. J. Biomed. Mater. Res. B Appl. Biomat. 89, 252–263 (2009).

    Article  CAS  Google Scholar 

  91. Sterodimas, A., De Faria, J., Correa, W. E. & Pitanguy, I. Tissue engineering in plastic surgery: an up-to-date review of the current literature. Ann. Plast. Surg. 62, 97–103 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Robey, P. G. & Bianco, P. The use of adult stem cells in rebuilding the human face. J. Am. Dent. Assoc. 137, 961–972 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Vaccines, Blood & Biologics. US FDA [online] (2009).

  94. Quarto, R. et al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N. Engl. J. Med. 344, 385–386 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Marcacci, M. et al. Stem cells associated with macroporous bioceramics for long bone repair: 6 to 7-year outcome of a pilot clinical study. Tissue Eng. 13, 947–955 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Warnke, P. H. et al. Man as a living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible. Biomaterials 27, 3163–3167 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Vacanti, C. A., Bonassar, L. J., Vacanti, M. P. & Shufflebarger, J. Replacement of an avulsed phalanx with tissue-engineered bone. N. Engl. J. Med. 344, 1511–1514 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Ueda, M., Yamada, Y., Kagami, H. & Hibi, H. Injectable bone applied for ridge augmentation and dental implant placement: human progress study. Implant Dent. 17, 82–90 (2008).

    Article  PubMed  Google Scholar 

  99. Gimble, J. & Guilak, F. Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy 5, 362–369 (2003).

    Article  PubMed  Google Scholar 

  100. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Maherali, N. et al. A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell 3, 340–345 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Horwitz, E. M. et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat. Med. 5, 309–313 (1999).

    Article  CAS  PubMed  Google Scholar 

  103. Goshima, J., Goldberg, V. M. & Caplan, A. I. The origin of bone formed in composite grafts of porous calcium phosphate ceramic loaded with marrow cells. Clin. Orthop. Relat. Res. 269, 274–283 (1991).

    Google Scholar 

  104. 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. 31, 890–896 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Tasso, R. et al. Recruitment of a host's osteoprogenitor cells using exogenous mesenchymal stem cells seeded on porous ceramic. Tissue Eng. Part A 15, 1–10 (2009).

    Article  CAS  Google Scholar 

  106. Thoracic surgical solutions. NuVasive Inc. [online] (2009).

  107. Trinity®Evolution™. Orthofix Inc. [online] (2009).

  108. Kuznetsov, S. A. et al. Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo. J. Bone Miner. Res. 12, 1335–1347 (1997).

    Article  CAS  PubMed  Google Scholar 

  109. Mueller, S. M., Mizuno, S., Gerstenfeld, L. C. & Glowacki, J. Medium perfusion enhances osteogenesis by murine osteosarcoma cells in three-dimensional collagen sponges. J. Bone Miner. Res. 14, 2118–2126 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Glowacki, J. & Mizuno, S. Biomaterials in cartilage and bone tissue engineering. Curr. Opin. Orthop. 15, 347–354 (2004).

    Article  Google Scholar 

  111. Mikos, A. G., Sarakinos, G., Lyman, M. D., Ingber, D. E., Vacanti, J. P. & Langer, R. Prevascularization of porous biodegradable polymers. Biotechnol. Bioeng. 42, 716–723 (1993).

    Article  CAS  PubMed  Google Scholar 

  112. Arkudas, A. et al. Axial prevascularization of porous matrices using an arteriovenous loop promotes survival and differentiation of transplanted autologous osteoblasts. Tissue Eng. 13, 1549–1560 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Rouwkema, J., de Boer, J. & Van Blitterswijk, C. A. Endothelial cells assemble into a 3-dimensional prevascular network in a bone tissue engineering construct. Tissue Eng. 12, 2685–2693 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Unger, R. E. et al. Tissue-like self-assembly in cocultures of endothelial cells and osteoblasts and the formation of microcapillary-like structures on three-dimensional porous materials. Biomaterials 28, 3965–3976 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Functional Tissue Engineering Conference Group. Evaluation criteria for musculoskeletal and craniofacial tissue engineering constructs: a conference report. Tissue Eng. A 14, 2089–2104 (2008).

  116. Mountziaris, P. M. & Mikos, A. G. Modulation of the inflammatory response for enhanced bone tissue regeneration. Tissue Eng. B doi:10.1089/teb.2008.0038.

  117. Balga, R. et al. Tumor necrosis factor-alpha: alternative role as an inhibitor of osteoclast formation in vitro. Bone 39, 325–335 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Li, X. et al. TP508 accelerates fracture repair by promoting cell growth over cell death. Biochem. Biophys. Res. Commun. 364, 187–193 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Aspenberg, P. Drugs and fracture repair. Acta Orthop. 76, 741–748 (2005).

    Article  PubMed  Google Scholar 

  120. Paralkar, V. M. et al. An EP2 receptor-selective prostaglandin E2 agonist induces bone healing. Proc. Natl Acad. Sci. USA 100, 6736–6740 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ho, M. L., Chang, J. K. & Wang, G. J. Anti-inflammatory drug effects on bone repair and remodeling in rabbits. Clin. Orthop. Relat. Res. 313, 270–278 (1995).

    Google Scholar 

  122. Vuolteenaho, K., Moilanen, T. & Moilanen, E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic Clin. Pharmacol. Toxicol. 102, 10–14 (2007).

    PubMed  Google Scholar 

  123. Sheyn, D. et al. Nonvirally engineered porcine adipose tissue-derived stem cells: use in posterior spinal fusion. Stem Cells 26, 1056–1064 (2008).

    Article  PubMed  Google Scholar 

  124. Tolar, J. et al. Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 25, 371–379 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Tasso, R. et al. Development of sarcomas in mice implanted with mesenchymal stem cells seeded onto bioscaffolds. Carcinogenesis 30, 150–157 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Patel, Z. S. et al. Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model. Bone 43, 931–940 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Oest, M. E., Dupont, K. M. Kong, H.-J., Mooney, D. J. & Guldberg, R. E. Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects. J. Orthop. Res. 25, 941–950 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Cowan, C. M. et al. MicroCT evaluation of three-dimensional mineralization in response to BMP-2 doses in vitro and in critical sized rat calvarial defects. Tissue Eng. 13, 501–510 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Lee, S. C. et al. Healing of large segmental defects in rat femurs is aided by RhBMP-2 in PLGA matrix. J. Biomed. Mater. Res. 28, 1149–1156 (1994).

    Article  CAS  PubMed  Google Scholar 

  130. Leach, J. K., Kaigler, D., Wang, Z., Krebsbach, P. H. & Mooney, D. J. Coating of VEGF-releasing scaffolds with bioactive glass for angiogenesis and bone regeneration. Biomaterials 27, 3249–3255 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Zegzula, H. D., Buck, D. C., Brekke, J., Wozney, J. M. & Hollinger, J. O. Bone formation with use of rhBMP-2 (recombinant human bone morphogenetic protein 2). J. Bone Joint Surg. Am. 79, 1778–1790 (1997).

    Article  CAS  PubMed  Google Scholar 

  132. Chen, B. et al. Homogeneous osteogenesis and bone regeneration by demineralized bone matrix loading with collagen-targeting bone morphogenetic protein-2. Biomaterials 28, 1027–1035 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Cook, S. D., Wolfe, M. W., Salkeld, S. L. & Rueger, D. C. Effect of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates. J. Bone Joint Surg. Am. 77, 734–750 (1995).

    Article  CAS  PubMed  Google Scholar 

  134. Marden, L. J. et al. Recombinant human bone morphogenetic protein-2 is superior to demineralized bone matrix in repairing craniotomy defects in rats. J. Biomed. Mater. Res. 28, 1127–1138 (1994).

    Article  CAS  PubMed  Google Scholar 

  135. Kleinheinz, J., Stratmann, U., Joos, U. & Wiessman, H.-P. VEGF-activated angiogenesis during bone regeneration. J. Oral Maxillofac. Surg. 63, 1310–1316 (2005).

    Article  PubMed  Google Scholar 

  136. Bodde, E. W. H., Boerman, O. C., Russel, F. G. M. & Mikos, A. G. The kinetic and biological activity of different loaded rhBMP-2 calcium phosphate cement implants in rats. J. Biomed. Mater. Res. A 87, 780–791 (2008).

    Article  CAS  PubMed  Google Scholar 

  137. Stevenson, S., Cunningham, N., Toth, J., Davy, D. & Reddi, A. H. The effect of osteogenin (a bone morphogenetic protein) on the formation of bone in orthotopic segmental defects in rats. J. Bone Joint Surg. Am. 76, 1676–1687 (1994).

    Article  CAS  PubMed  Google Scholar 

  138. Mastrogiacomo, M. et al. Reconstruction of extensive long bone defects in sheep using resorbable bioceramics based on silicon stabilized tricalcium phosphate. Tissue Eng. 12, 1261–1273 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Black, J. & Hastings, G. Handbook of Biomaterial Properties, 590 (Chapman & Hall, London, 1998).

    Book  Google Scholar 

  140. Rezwan, K., Chen, Q. Z., Blaker, J. J. & Boccaccini, A. R. Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials 27, 3413–3431 (2006).

    Article  CAS  PubMed  Google Scholar 

  141. Lu, L. et al. In vitro and in vivo degradation of porous poly(DL-lactic-co-glycolic acid) foams. Biomaterials 21, 1837–1845 (2000).

    Article  CAS  PubMed  Google Scholar 

  142. Devin, J., Attawia, M. & Laurencin, C. Three-dimensional porous polymer-ceramic matrices for use in bone repair. J. Biomat. Sci. Polym. Edn 7, 661–669 (1996).

    Article  CAS  Google Scholar 

  143. Athanasiou, K. A., Zhu, C., Lanctot, D. R., Agrawal, C. M. & Wang, X. Fundamentals of biomechanics in tissue engineering of bone. Tissue Eng. 6, 361–381 (2000).

    Article  CAS  PubMed  Google Scholar 

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    Ericka M. Bueno & Julie Glowacki

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Bueno, E., Glowacki, J. Cell-free and cell-based approaches for bone regeneration. Nat Rev Rheumatol 5, 685–697 (2009). https://doi.org/10.1038/nrrheum.2009.228

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