Skip to main content
SpringerLink
Log in

Toward Advanced Therapy Medicinal Products (ATMPs) Combining Bone Morphogenetic Proteins (BMP) and Cells for Bone Regeneration

  • Chapter
  • First Online:
Book cover Bone Morphogenetic Proteins: Systems Biology Regulators

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Cell-based implants with or without osteoinductive biomolecules on optimal carrier materials as an advanced therapeutic medicinal product (ATMP) are a promising strategy for poorly healing long-bone defects. This chapter will focus on ATMPs combining bone morphogenetic proteins (BMPs) and progenitor cells for the clinical treatment of large bone defects in compromised environments. We describe BMP signaling involved in the process of bone fracture healing with specific emphasis on clinically relevant BMP ligands, followed by characterization and BMP responsiveness of progenitor cells obtained from different sources. Then we explore different biomaterials and their contribution to achieve optimal BMP release and osteoinduction. Finally, we provide a perspective on the applicability of ATMPs in bone repair by reviewing the preclinical studies carried out so far in various animal models. We believe the era of regenerative medicine has just started. First-generation BMP and stem cell technologies have demonstrated that in the postnatal environment, one can successfully enhance the healing of damaged tissues by recapitulating the principles of developmental tissue formation. A second generation of products is needed that leads to successful bone healing in compromised environments.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Abarrategi A, Gutierrez MC, Moreno-Vicente C, Hortiguela MJ, Ramos V, Lopez-Lacomba JL, Ferrer ML, Del Monte F (2008) Multiwall carbon nanotube scaffolds for tissue engineering purposes. Biomaterials 29:94–102

    Article  CAS  PubMed  Google Scholar 

  2. Administration, U. F. A. D (2002) Infuse™ Bone Graft/Lt-Cage™ Lumbar Tapered Fusion device – P000058 [Online]. Available: http://www.Fda.Gov/Medicaldevices/Productsandmedicalprocedures/Deviceapprovalsandclearances/Recently-Approveddevices/Ucm083423.Htm. Accessed Aug 28 2015

  3. Administration, U. F. A. D (2004a) Infuse® Bone Graft – P000054 [Online]. Available: http://www.Fda.Gov/Medicaldevices/Productsandmedicalprocedures/Deviceapprovalsandclearances/Recently-Approveddevices/Ucm081154.Htm. Accessed 28 Aug 2015

  4. Administration, U. F. A. D (2004b) Op-1 Putty – H020008 [Online]. Available: http://www.Fda.Gov/Medicaldevices/Productsandmedicalprocedures/Deviceapprovalsandclearances/Recently-Approveddevices/Ucm081181.Htm. Accessed 28 Aug 2015

  5. Administration, U. F. A. D (2007) Infuse® Bone Graft – P050053 [Online]. Available: http://www.Fda.Gov/Medicaldevices/Productsandmedicalprocedures/Deviceapprovalsandclearances/Recently-Approveddevices/Ucm077024.Htm. Accessed 28 Aug 2015

  6. Hideki Agata (2013). Isolation of Bone Marrow Stromal Cells: Cellular Composition is Technique-Dependent, Regenerative Medicine and Tissue Engineering, Prof. Jose A. Andrades (Ed.), InTech, DOI: 10.5772/55543. Available from: http://www.intechopen.com/books/regenerative-medicine-and-tissueengineering/ isolation-of-bone-marrow-stromal-cells-cellular-composition-is-technique-dependent

    Google Scholar 

  7. Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA (2008) Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87:107–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Allen MR, Hock JM, Burr DB (2004) Periosteum: biology, regulation, and response to osteoporosis therapies. Bone 35:1003–1012

    Article  CAS  PubMed  Google Scholar 

  9. Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y (2008) The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat 29:992–1006

    Article  CAS  PubMed  Google Scholar 

  10. Arafat MT, Gibson I, Li X (2014) State of the art and future direction of additive manufactured scaffolds-based bone tissue engineering. Rapid Prototyping J 20:13–26

    Article  Google Scholar 

  11. Asprer JS, Lakshmipathy U (2015) Current methods and challenges in the comprehensive characterization of human pluripotent stem cells. Stem Cell Rev 11:357–372

    Article  CAS  PubMed  Google Scholar 

  12. Balmayor ER, Feichtinger GA, Azevedo HS, Van Griensven M, Reis RL (2009) Starch-poly-epsilon-caprolactone microparticles reduce the needed amount of BMP-2. Clin Orthop Relat Res 467:3138–3148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Barak MM, Lieberman DE, Hublin JJ (2013) Of mice, rats and men: trabecular bone architecture in mammals scales to body mass with negative allometry. J Struct Biol 183:123–131

    Article  PubMed  Google Scholar 

  14. Behravesh E, Jo S, Zygourakis K, Mikos AG (2002) Synthesis of in situ cross-linkable macroporous biodegradable poly(propylene fumarate-co-ethylene glycol) hydrogels. Biomacromolecules 3:374–381

    Article  CAS  PubMed  Google Scholar 

  15. Bengtsson L, Schwappacher R, Roth M, Boergermann JH, Hassel S, Knaus P (2009) PP2A regulates Bmp signalling by interacting with Bmp receptor complexes and by dephosphorylating both the C-terminus and the linker region of Smad1. J Cell Sci 122:1248–1257

    Article  CAS  PubMed  Google Scholar 

  16. Bernardo ME, Avanzini MA, Perotti C, Cometa AM, Moretta A, Lenta E, Del Fante C, Novara F, De Silvestri A, Amendola G, Zuffardi O, Maccario R, Locatelli F (2007) Optimization of in vitro expansion of human multipotent mesenchymal stromal cells for cell-therapy approaches: further insights in the search for a fetal calf serum substitute. J Cell Physiol 211:121–130

    Article  CAS  PubMed  Google Scholar 

  17. Bessa PC, Balmayor ER, Azevedo HS, Nurnberger S, Casal M, Van Griensven M, Reis RL, Redl H (2010) Silk fibroin microparticles as carriers for delivery of human recombinant Bmps. Physical characterization and drug release. J Tissue Eng Regen Med 4:349–355

    Article  CAS  PubMed  Google Scholar 

  18. Bidarra SJ, Barrias CC, Granja PL (2014) Injectable alginate hydrogels for cell delivery in tissue engineering. Acta Biomater 10:1646–1662

    Article  CAS  PubMed  Google Scholar 

  19. Bieback K, Hecker A, Kocaomer A, Lannert H, Schallmoser K, Strunk D, Kluter H (2009) Human alternatives to fetal bovine serum for the expansion of mesenchymal stromal cells from bone marrow. Stem Cells 27:2331–2341

    Article  CAS  PubMed  Google Scholar 

  20. Blackwood KA, Bock N, Dargaville TR, Woodruff MA (2012) Scaffolds for growth factor delivery as applied to bone tissue engineering. Int J Polymer Sci 2012:174942

    Article  CAS  Google Scholar 

  21. Bouvet-Gerbettaz S, Boukhechba F, Balaguer T, Schmid-Antomarchi H, Michiels JF, Scimeca JC, Rochet N (2014) Adaptive immune response inhibits ectopic mature bone formation induced by BMSCs/BCP/plasma composite in immune-competent mice. Tissue Eng Part A 20:2950–2962

    Article  CAS  PubMed  Google Scholar 

  22. Capelli C, Domenghini M, Borleri G, Bellavita P, Poma R, Carobbio A, Mico C, Rambaldi A, Golay J, Introna M (2007) Human platelet lysate allows expansion and clinical grade production of mesenchymal stromal cells from mall samples of bone marrow asopirates or marrow filter washouts. Bone Marrow Transplant 40:785–791

    Article  CAS  PubMed  Google Scholar 

  23. Capelli C, Pedrini O, Valgardsdottir R, Da Roit F, Golay J, Introna M (2015) Clinical grade expansion of MSCs. Immunol Lett 168(2):222–227

    Article  CAS  PubMed  Google Scholar 

  24. Caron MM, Emans PJ, Cremers A, Surtel DA, Coolsen MM, Van Rhijn LW, Welting TJ (2013) Hypertrophic differentiation during chondrogenic differentiation of progenitor cells is stimulated by BMP-2 but suppressed by BMP-7. Osteoarthritis Cartilage 21:604–613

    Article  CAS  PubMed  Google Scholar 

  25. Carragee EJ, Hurwitz EL, Weiner BK (2011) A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J 11:471–491

    Article  PubMed  Google Scholar 

  26. Chanavaz M (1995) Anatomy and histophysiology of the periosteum: quantification of the periosteal blood supply to the adjacent bone with 85Sr and gamma spectrometry. J Oral Implantol 21:214–219

    CAS  PubMed  Google Scholar 

  27. Chang H, Knothe Tate ML (2012) Concise review: the periosteum: tapping into a reservoir of clinically useful progenitor cells. Stem Cells Transl Med 1:480–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cho TJ, Gerstenfeld LC, Einhorn TA (2002) Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 17:513–520

    Article  CAS  PubMed  Google Scholar 

  29. Cipitria A, Wagermaier W, Zaslansky P, Schell H, Reichert JC, Fratzl P, Hutmacher DW, Duda GN (2015) BMP delivery complements the guiding effect of scaffold architecture without altering bone microstructure in critical-sized long bone defects: A multiscale analysis. Acta Biomater 23:282–294

    Article  CAS  PubMed  Google Scholar 

  30. Coleman CM, Scheremeta BH, Boyce AT, Mauck RL, Tuan RS (2011) Delayed fracture healing in growth differentiation factor 5-deficient mice: a pilot study. Clin Orthop Relat Res 469:2915–2924

    Article  PubMed  PubMed Central  Google Scholar 

  31. Colnot C (2009) Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J Bone Miner Res 24:274–282

    Article  PubMed  Google Scholar 

  32. Cooper GM, Mooney MP, Gosain AK, Campbell PG, Losee JE, Huard J (2010) Testing the critical size in calvarial bone defects: revisiting the concept of a critical-size defect. Plast Reconstr Surg 125:1685–1692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Das SP, Ganesh S, Pradhan S, Singh D, Mohanty RN (2014) Effectiveness of recombinant human bone morphogenetic protein-7 in the management of congenital pseudoarthrosis of the tibia: a randomised controlled trial. Int Orthop 38:1987–1992

    Article  PubMed  Google Scholar 

  34. De Bari C, Dell'accio F, Luyten FP (2001) Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age. Arthritis Rheum 44:85–95

    Article  CAS  PubMed  Google Scholar 

  35. Dickerson M, Winquist N, Bae Y (2014) Photo-inducible crosslinked nanoassemblies for pH-controlled drug release. Pharm Res 31:1254–1263

    Article  CAS  PubMed  Google Scholar 

  36. Diefenderfer DL, Osyczka AM, Garino JP, Leboy PS (2003a) Regulation of BMP-induced transcription in cultured human bone marrow stromal cells. J Bone Joint Surg Am 85-A(Suppl 3):19–28

    Article  Google Scholar 

  37. Diefenderfer DL, Osyczka AM, Reilly GC, Leboy PS (2003b) BMP responsiveness in human mesenchymal stem cells. Connect Tissue Res 44(Suppl 1):305–311

    Article  CAS  PubMed  Google Scholar 

  38. Dudley AT, Lyons KM, Robertson EJ (1995) A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev 9:2795–2807

    Article  CAS  PubMed  Google Scholar 

  39. Duhamel H (1742) Sur le devéloppement et la crue des os des animaux. Mem Acad R Sci Paris 55:354–370

    Google Scholar 

  40. Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K (2001) Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276:12477–12480

    Article  CAS  PubMed  Google Scholar 

  41. Ebisawa T, Tada K, Kitajima I, Tojo K, Sampath TK, Kawabata M, Miyazono K, Imamura T (1999) Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation. J Cell Sci 112(Pt 20):3519–3527

    CAS  PubMed  Google Scholar 

  42. Edwards RB 3rd, Seeherman HJ, Bogdanske JJ, Devitt J, Vanderby R Jr, Markel MD (2004) Percutaneous injection of recombinant human bone morphogenetic protein-2 in a calcium phosphate paste accelerates healing of a canine tibial osteotomy. J Bone Joint Surg Am 86-A:1425–1438

    Article  PubMed  Google Scholar 

  43. Estes BT, Wu AW, Guilak F (2006) Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6. Arthritis Rheum 54:1222–1232

    Article  CAS  PubMed  Google Scholar 

  44. FDA (2001) Op-1™ – H010002 [Online]. Available: http://www.Fda.Gov/Medicaldevices/Productsandmedicalprocedures/Deviceapprovalsandclearances/Recently-Approveddevices/Ucm085026.Htm

  45. Fernandez Vallone VB, Romaniuk MA, Choi H, Labovsky V, Otaegui J, Chasseing NA (2013) Mesenchymal stem cells and their use in therapy: what has been achieved? Differentiation 85:1–10

    Article  CAS  PubMed  Google Scholar 

  46. Flierl MA, Smith WR, Mauffrey C, Irgit K, Williams AE, Ross E, Peacher G, Hak DJ, Stahel PF (2013) Outcomes and complication rates of different bone grafting modalities in long bone fracture nonunions: a retrospective cohort study in 182 patients. J Orthop Surg Res 8:33

    Article  PubMed  PubMed Central  Google Scholar 

  47. Fong K, Truong V, Foote CJ, Petrisor B, Williams D, Ristevski B, Sprague S, Bhandari M (2013) Predictors of nonunion and reoperation in patients with fractures of the tibia: an observational study. BMC Musculoskelet Disord 14:103

    Article  PubMed  PubMed Central  Google Scholar 

  48. Franz S, Rammelt S, Scharnweber D, Simon JC (2011) Immune responses to implants - a review of the implications for the design of immunomodulatory biomaterials. Biomaterials 32:6692–6709

    Article  CAS  PubMed  Google Scholar 

  49. Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, Laforte AJ, Yin S (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83-A(Suppl 1):S151–S158

    Google Scholar 

  50. Fuentealba LC, Eivers E, Ikeda A, Hurtado C, Kuroda H, Pera EM, De Robertis EM (2007) Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131:980–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gan Q, Zhu JY, Yuan Y, Liu HL, Qian JC, Lib YS, Liu CS (2015) A dual-delivery system of pH-responsive chitosan-functionalized mesoporous silica nanoparticles bearing BMP-2 and dexamethasone for enhanced bone regeneration. J Mater Chem B 3:2056–2066

    Article  CAS  Google Scholar 

  52. Geiger M, Li RH, Friess W (2003) Collagen sponges for bone regeneration with rhBMP-2. Adv Drug Deliv Rev 55:1613–1629

    Article  CAS  PubMed  Google Scholar 

  53. Giannoudis PV, Panteli M, Calori GM (2014) Bone healing: the diamond concept. Eur Instructional Lect 14(14):3–16

    Article  Google Scholar 

  54. Gilboa L, Nohe A, Geissendorfer T, Sebald W, Henis YI, Knaus P (2000) Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell 11:1023–1035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, Van Der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, Mccoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T, Group, B. M. P. E. I. S. F. T. T. S (2002) 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 84-A:2123–2134

    Article  PubMed  Google Scholar 

  56. Greenblatt MB, Shim JH, Zou W, Sitara D, Schweitzer M, Hu D, Lotinun S, Sano Y, Baron R, Park JM, Arthur S, Xie M, Schneider MD, Zhai B, Gygi S, Davis R, Glimcher LH (2010) The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J Clin Invest 120:2457–2473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Greenwald J, Groppe J, Gray P, Wiater E, Kwiatkowski W, Vale W, Choe S (2003) The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol Cell 11:605–617

    Article  CAS  PubMed  Google Scholar 

  58. Grenier G, Leblanc E, Faucheux N, Lauzier D, Kloen P, Hamdy RC (2013) BMP-9 expression in human traumatic heterotopic ossification: a case report. Skelet Muscle 3:29

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Grimsrud CD, Romano PR, D'souza M, Puzas JE, Reynolds PR, Rosier RN, O'keefe RJ (1999) BMP-6 is an autocrine stimulator of chondrocyte differentiation. J Bone Miner Res 14:475–482

    Article  CAS  PubMed  Google Scholar 

  60. Guenther CA, Wang Z, Li E, Tran MC, Logan CY, Nusse R, Pantalena-Filho L, Yang GP, Kingsley DM (2015) A distinct regulatory region of the Bmp5 locus activates gene expression following adult bone fracture or soft tissue injury. Bone 77:31–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Guicheux J, Lemonnier J, Ghayor C, Suzuki A, Palmer G, Caverzasio J (2003) Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation. J Bone Miner Res 18:2060–2068

    Article  CAS  PubMed  Google Scholar 

  62. Guo YY, Zhang J, Zheng YF, Yang J, Zhu XQ (2011) Cytotoxic and genotoxic effects of multi-wall carbon nanotubes on human umbilical vein endothelial cells in vitro. Mutat Res 721:184–191

    Article  CAS  PubMed  Google Scholar 

  63. Guyot Y, Papantoniou I, Chai YC, Van Bael S, Schrooten J, Geris L (2014) A computational model for cell/ECM growth on 3D surfaces using the level set method: a bone tissue engineering case study. Biomech Model Mechanobiol 13:1361–1371

    Article  CAS  PubMed  Google Scholar 

  64. Gysel C (1983) Henri-Louis Duhamel du Monceau (1700-1782-1982), growth and osteogenic function of the periosteum. Orthod Fr 54:605–621

    CAS  PubMed  Google Scholar 

  65. Haidar ZS, Hamdy RC, Tabrizian M (2009) Delivery of recombinant bone morphogenetic proteins for bone regeneration and repair. Part A: current challenges in BMP delivery. Biotechnol Lett 31:1817–1824

    Article  CAS  PubMed  Google Scholar 

  66. Hamasaki M, Hashizume Y, Yamada Y, Katayama T, Hohjoh H, Fusaki N, Nakashima Y, Furuya H, Haga N, Takami Y, Era T (2012) Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance: mechanisms of reprogramming and strategy for drug identification. Stem Cells 30:2437–2449

    Article  CAS  PubMed  Google Scholar 

  67. Reggie C. Hamdy, Juan S. Rendon and Maryam Tabrizian (2012). Distraction Osteogenesis and Its Challenges in Bone Regeneration, Bone Regeneration, Prof. Haim Tal (Ed.), InTech, DOI: 10.5772/32229. Available from: http://www.intechopen.com/books/bone-regeneration/distraction-osteogenesis-and-itschallenges-in-bone-regeneration

  68. Harada S, Rodan GA (2003) Control of osteoblast function and regulation of bone mass. Nature 423:349–355

    Article  CAS  PubMed  Google Scholar 

  69. Hartung A, Bitton-Worms K, Rechtman MM, Wenzel V, Boergermann JH, Hassel S, Henis YI, Knaus P (2006) Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling. Mol Cell Biol 26:7791–7805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hata A, Lagna G, Massague J, Hemmati-Brivanlou A (1998) Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12:186–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Health, U. S. N. I. O. 2015. Clinicaltrials.Gov [Online]. Available: https://Clinicaltrials.Gov/Ct2/Results?Term=Bmp%2c+Fracture&Search=Search. Accessed 28 Aug 2015

  72. Hoffmann A, Preobrazhenska O, Wodarczyk C, Medler Y, Winkel A, Shahab S, Huylebroeck D, Gross G, Verschueren K (2005) Transforming growth factor-beta-activated kinase-1 (TAK1), a MAP3K, interacts with Smad proteins and interferes with osteogenesis in murine mesenchymal progenitors. J Biol Chem 280:27271–27283

    Article  CAS  PubMed  Google Scholar 

  73. Hollinger JO, Schmitt JM, Buck DC, Shannon R, Joh SP, Zegzula HD, Wozney J (1998) Recombinant human bone morphogenetic protein-2 and collagen for bone regeneration. J Biomed Mater Res 43:356–364

    Article  CAS  PubMed  Google Scholar 

  74. Horner EA, Kirkham J, Wood D, Curran S, Smith M, Thomson B, Yang XB (2010) Long bone defect models for tissue engineering applications: criteria for choice. Tissue Eng Part B Rev 16:263–271

    Article  PubMed  Google Scholar 

  75. Ilizarov S (2006). The ilizarov method: history and scope. In: Rozbruch R, Ilizarov S (eds) Limb lengthening and reconstruction surgery. CPC Press. Florida, USA

    Google Scholar 

  76. Jain D, Bar-Shalom D (2014) Alginate drug delivery systems: application in context of pharmaceutical and biomedical research. Drug Dev Ind Pharm 40:1576–1584

    Article  CAS  PubMed  Google Scholar 

  77. Janowska-Wieczorek A, Majka M, Ratajczak J, Ratajczak MZ (2001) Autocrine/paracrine mechanisms in human hematopoiesis. Stem Cells 19:99–107

    Article  CAS  PubMed  Google Scholar 

  78. Ji W, Wang H, Van Den Beucken JJ, Yang F, Walboomers XF, Leeuwenburgh S, Jansen JA (2012) Local delivery of small and large biomolecules in craniomaxillofacial bone. Adv Drug Deliv Rev 64:1152–1164

    Article  CAS  PubMed  Google Scholar 

  79. Jiang Y, Chen C, Li Z, Guo W, Gegner JA, Lin S, Han J (1996) Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem 271:17920–17926

    Article  CAS  PubMed  Google Scholar 

  80. Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298:1911–1912

    Article  CAS  PubMed  Google Scholar 

  81. Jones AL, Bucholz RW, Bosse MJ, Mirza SK, Lyon TR, Webb LX, Pollak AN, Golden JD, Valentin-Opran A, Group, B. M. P. E. I. S. F. T. T.-A. S (2006) 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 88:1431–1441

    PubMed  Google Scholar 

  82. Jun JH, Yoon WJ, Seo SB, Woo KM, Kim GS, Ryoo HM, Baek JH (2010) BMP2-activated Erk/MAP kinase stabilizes Runx2 by increasing p300 levels and histone acetyltransferase activity. J Biol Chem 285:36410–36419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Katagiri T, Tsukamoto S (2013) The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway. Biol Chem 394:703–714

    Article  CAS  PubMed  Google Scholar 

  84. Kato M, Namikawa T, Terai H, Hoshino M, Miyamoto S, Takaoka K (2006a) Ectopic bone formation in mice associated with a lactic acid/dioxanone/ethylene glycol copolymer-tricalcium phosphate composite with added recombinant human bone morphogenetic protein-2. Biomaterials 27:3927–3933

    Article  CAS  PubMed  Google Scholar 

  85. Kato M, Toyoda H, Namikawa T, Hoshino M, Terai H, Miyamoto S, Takaoka K (2006b) Optimized use of a biodegradable polymer as a carrier material for the local delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2). Biomaterials 27:2035–2041

    Article  CAS  PubMed  Google Scholar 

  86. Kim HD, Valentini RF (2002) Retention and activity of BMP-2 in hyaluronic acid-based scaffolds in vitro. J Biomed Mater Res 59:573–584

    Article  CAS  PubMed  Google Scholar 

  87. King JA, Marker PC, Seung KJ, Kingsley DM (1994) BMP5 and the molecular, skeletal, and soft-tissue alterations in short ear mice. Dev Biol 166:112–122

    Article  CAS  PubMed  Google Scholar 

  88. Kisiel M, Martino MM, Ventura M, Hubbell JA, Hilborn J, Ossipov DA (2013) Improving the osteogenic potential of BMP-2 with hyaluronic acid hydrogel modified with integrin-specific fibronectin fragment. Biomaterials 34:704–712

    Article  CAS  PubMed  Google Scholar 

  89. Kiskinis E, Eggan K (2010) Progress toward the clinical application of patient-specific pluripotent stem cells. J Clin Invest 120:51–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kloen P, Di Paola M, Borens O, Richmond J, Perino G, Helfet DL, Goumans MJ (2003) BMP signaling components are expressed in human fracture callus. Bone 33:362–371

    Article  CAS  PubMed  Google Scholar 

  91. Kloen P, Doty SB, Gordon E, Rubel IF, Goumans MJ, Helfet DL (2002) Expression and activation of the BMP-signaling components in human fracture nonunions. J Bone Joint Surg Am 84-A:1909–1918

    Article  PubMed  Google Scholar 

  92. Kloen P, Lauzier D, Hamdy RC (2012) Co-expression of BMPs and BMP-inhibitors in human fractures and non-unions. Bone 51:59–68

    Article  CAS  PubMed  Google Scholar 

  93. Kloxin AM, Kasko AM, Salinas CN, Anseth KS (2009) Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324:59–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Knaus P, Sebald W (2001) Cooperativity of binding epitopes and receptor chains in the BMP/TGFbeta superfamily. Biol Chem 382:1189–1195

    Article  CAS  PubMed  Google Scholar 

  95. Knychala J, Bouropoulos N, Catt CJ, Katsamenis OL, Please CP, Sengers BG (2013) Pore geometry regulates early stage human bone marrow cell tissue formation and organisation. Ann Biomed Eng 41:917–930

    Article  CAS  PubMed  Google Scholar 

  96. Koenig BB, Cook JS, Wolsing DH, Ting J, Tiesman JP, Correa PE, Olson CA, Pecquet AL, Ventura F, Grant RA et al (1994) Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3 T3 cells. Mol Cell Biol 14:5961–5974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Korchynskyi O, Ten Dijke P (2002) Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem 277:4883–4891

    Article  CAS  PubMed  Google Scholar 

  98. Kozawa O, Hatakeyama D, Uematsu T (2002) Divergent regulation by p44/p42 MAP kinase and p38 MAP kinase of bone morphogenetic protein-4-stimulated osteocalcin synthesis in osteoblasts. J Cell Biochem 84:583–589

    Article  PubMed  CAS  Google Scholar 

  99. Kuboki Y, Jin Q, Takita H (2001) Geometry of carriers controlling phenotypic expression in BMP-induced osteogenesis and chondrogenesis. J Bone Joint Surg Am 83-A(Suppl 1):S105–S115

    Google Scholar 

  100. Kugimiya F, Kawaguchi H, Kamekura S, Chikuda H, Ohba S, Yano F, Ogata N, Katagiri T, Harada Y, Azuma Y, Nakamura K, Chung UI (2005) Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation. J Biol Chem 280:35704–35712

    Article  CAS  PubMed  Google Scholar 

  101. Kuwahara K, Fang JY, Yang Z, Han B (2011) Enzymatic crosslinking and degradation of gelatin as a switch for bone morphogenetic protein-2 activity. Tissue Eng Part A 17:2955–2964

    Article  CAS  PubMed  Google Scholar 

  102. L O (1867) Traite Experimental Et Clinique De La Regeration Des Os Et De La Production Artificiele Du Tissu Osseux. In: Masson V (ed) Paris

    Google Scholar 

  103. Lai CF, Cheng SL (2002) Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-beta in normal human osteoblastic cells. J Biol Chem 277:15514–15522

    Article  CAS  PubMed  Google Scholar 

  104. Langer R, Vacanti JP (1993) Tissue engineering. Science 260:920–926

    Article  CAS  PubMed  Google Scholar 

  105. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586

    Article  CAS  PubMed  Google Scholar 

  106. Lechner C, Zahalka MA, Giot JF, Moller NP, Ullrich A (1996) ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A 93:4355–4359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lee J, Choi WI, Tae G, Kim YH, Kang SS, Kim SE, Kim SH, Jung Y, Kim SH (2011) Enhanced regeneration of the ligament-bone interface using a poly(L-lactide-co-epsilon-caprolactone) scaffold with local delivery of cells/BMP-2 using a heparin-based hydrogel. Acta Biomater 7:244–257

    Article  CAS  PubMed  Google Scholar 

  108. Lee WH, Loo CY, Rohanizadeh R (2014) A review of chemical surface modification of bioceramics: effects on protein adsorption and cellular response. Colloids Surf B Biointerfaces 122:823–834

    Article  CAS  PubMed  Google Scholar 

  109. Lenas P, Moos M, Luyten FP (2009a) Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part I: from three-dimensional cell growth to biomimetics of in vivo development. Tissue Eng Part B Rev 15:381–394

    Article  PubMed  Google Scholar 

  110. Lenas P, Moos M, Luyten FP (2009b) Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part II: from genes to networks: tissue engineering from the viewpoint of systems biology and network science. Tissue Eng Part B Rev 15:395–422

    Article  CAS  PubMed  Google Scholar 

  111. Levi B, James AW, Nelson ER, Peng M, Wan DC, Commons GW, Lee M, Wu B, Longaker MT (2011) Acute skeletal injury is necessary for human adipose-derived stromal cell-mediated calvarial regeneration. Plast Reconstr Surg 127:1118–1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Li X, Liu H, Niu X, Yu B, Fan Y, Feng Q, Cui FZ, Watari F (2012) The use of carbon nanotubes to induce osteogenic differentiation of human adipose-derived MSCs in vitro and ectopic bone formation in vivo. Biomaterials 33:4818–4827

    Article  CAS  PubMed  Google Scholar 

  113. Liu D, Yi C, Zhang D, Zhang J, Yang M (2010) Inhibition of proliferation and differentiation of mesenchymal stem cells by carboxylated carbon nanotubes. ACS Nano 4:2185–2195

    Article  CAS  PubMed  Google Scholar 

  114. Liu T, Wu G, Zheng Y, Wismeijer D, Everts V, Liu Y (2014a) Cell-mediated BMP-2 release from a novel dual-drug delivery system promotes bone formation. Clin Oral Implants Res 25:1412–1421

    Article  PubMed  Google Scholar 

  115. Liu X, Zhao K, Gong T, Song J, Bao CY, Luo E, Weng J, Zhou SB (2014b) Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect. Biomacromolecules 15:1019–1030

    Article  CAS  PubMed  Google Scholar 

  116. Liu Y, Wang L, Kikuiri T, Akiyama K, Chen C, Xu X, Yang R, Chen W, Wang S, Shi S (2011) Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha. Nat Med 17:1594–1601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Liu Y, Yang R, Shi S (2015) Systemic infusion of mesenchymal stem cells improves cell-based bone regeneration via upregulation of regulatory T cells. Tissue Eng Part A 21:498–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Lopez-Rovira T, Chalaux E, Massague J, Rosa JL, Ventura F (2002) Direct binding of Smad1 and Smad4 to two distinct motifs mediates bone morphogenetic protein-specific transcriptional activation of Id1 gene. J Biol Chem 277:3176–3185

    Article  CAS  PubMed  Google Scholar 

  119. Luo G, Hofmann C, Bronckers AL, Sohocki M, Bradley A, Karsenty G (1995) BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev 9:2808–2820

    Article  CAS  PubMed  Google Scholar 

  120. Lutolf MP, Hubbell JA (2005) Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol 23:47–55

    Article  CAS  PubMed  Google Scholar 

  121. Lyon T, Scheele W, Bhandari M, Koval KJ, Sanchez EG, Christensen J, Valentin A, Huard F (2013) Efficacy and safety of recombinant human bone morphogenetic protein-2/calcium phosphate matrix for closed tibial diaphyseal fracture: a double-blind, randomized, controlled phase-II/III trial. J Bone Joint Surg Am 95:2088–2096

    Article  PubMed  Google Scholar 

  122. Ma J, Both SK, Yang F, Cui FZ, Pan J, Meijer GJ, Jansen JA, Van Den Beucken JJ (2014) Concise review: cell-based strategies in bone tissue engineering and regenerative medicine. Stem Cells Transl Med 3:98–107

    Article  CAS  PubMed  Google Scholar 

  123. Magyari K, Baia L, Vulpoi A, Simon S, Popescu O, Simon V (2015) Bioactivity evolution of the surface functionalized bioactive glasses. J Biomed Mater Res B Appl Biomater 103:261–272

    Article  PubMed  CAS  Google Scholar 

  124. Maherali N, Hochedlinger K (2008) Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 3:595–605

    Article  CAS  PubMed  Google Scholar 

  125. Mantripragada VP, Jayasuriya AC (2014) Injectable chitosan microparticles incorporating bone morphogenetic protein-7 for bone tissue regeneration. J Biomed Mater Res A 102:4276–4289

    PubMed  PubMed Central  Google Scholar 

  126. Marolt D, Knezevic M, Novakovic GV (2010) Bone tissue engineering with human stem cells. Stem Cell Res Ther 1:10

    Article  PubMed  CAS  Google Scholar 

  127. Marsell R, Einhorn TA (2011) The biology of fracture healing. Injury 42:551–555

    Article  PubMed  PubMed Central  Google Scholar 

  128. Marti M, Mulero L, Pardo C, Morera C, Carrio M, Laricchia-Robbio L, Esteban CR, Izpisua Belmonte JC (2013) Characterization of pluripotent stem cells. Nat Protoc 8:223–253

    Article  CAS  PubMed  Google Scholar 

  129. Martinez-Sanz E, Ossipov DA, Hilborn J, Larsson S, Jonsson KB, Varghese OP (2011) Bone reservoir: injectable hyaluronic acid hydrogel for minimal invasive bone augmentation. J Control Release 152:232–240

    Article  CAS  PubMed  Google Scholar 

  130. Matthews BG, Grcevic D, Wang L, Hagiwara Y, Roguljic H, Joshi P, Shin DG, Adams DJ, Kalajzic I (2014) Analysis of alphaSMA-labeled progenitor cell commitment identifies notch signaling as an important pathway in fracture healing. J Bone Miner Res 29:1283–1294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Megas P (2005) Classification of non-union. Injury 36(Suppl 4):S30–S37

    PubMed  Google Scholar 

  132. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma’ayan A, Enikolopov GN, Frenette PS (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466:829–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mikic B, Van Der Meulen MC, Kingsley DM, Carter DR (1996) Mechanical and geometric changes in the growing femora of BMP-5 deficient mice. Bone 18:601–607

    Article  CAS  PubMed  Google Scholar 

  134. Mont MA, Ragland PS, Biggins B, Friedlaender G, Patel T, Cook S, Etienne G, Shimmin A, Kildey R, Rueger DC, Einhorn TA (2004) Use of bone morphogenetic proteins for musculoskeletal applications – an overview. J Bone Joint Surg Am 86a:41–55

    Article  Google Scholar 

  135. Mountziaris PM, Mikos AG (2008) Modulation of the inflammatory response for enhanced bone tissue regeneration. Tissue Eng Part B Rev 14:179–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Mukai T, Otsuka F, Otani H, Yamashita M, Takasugi K, Inagaki K, Yamamura M, Makino H (2007) TNF-alpha inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling. Biochem Biophys Res Commun 356:1004–1010

    Article  CAS  PubMed  Google Scholar 

  137. Muraglia A, Cancedda R, Quarto R (2000) Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J Cell Sci 113(Pt 7):1161–1166

    CAS  PubMed  Google Scholar 

  138. Nilsson O, Parker EA, Hegde A, Chau M, Barnes KM, Baron J (2007) Gradients in bone morphogenetic protein-related gene expression across the growth plate. J Endocrinol 193:75–84

    Article  CAS  PubMed  Google Scholar 

  139. Nohe A, Hassel S, Ehrlich M, Neubauer F, Sebald W, Henis YI, Knaus P (2002) The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem 277:5330–5338

    Article  CAS  PubMed  Google Scholar 

  140. Ong KL, Villarraga ML, Lau E, Carreon LY, Kurtz SM, Glassman SD (2010) Off-label use of bone morphogenetic proteins in the United States using administrative data. Spine (Phila Pa 1976) 35:1794–1800

    Article  Google Scholar 

  141. Ortuno MJ, Ruiz-Gaspa S, Rodriguez-Carballo E, Susperregui AR, Bartrons R, Rosa JL, Ventura F (2010) p38 regulates expression of osteoblast-specific genes by phosphorylation of osterix. J Biol Chem 285:31985–31994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Osyczka AM, Damek-Poprawa M, Wojtowicz A, Akintoye SO (2009) Age and skeletal sites affect BMP-2 responsiveness of human bone marrow stromal cells. Connect Tissue Res 50:270–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Osyczka AM, Diefenderfer DL, Bhargave G, Leboy PS (2004) Different effects of BMP-2 on marrow stromal cells from human and rat bone. Cells Tissues Organs 176:109–119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pages G, Guerin S, Grall D, Bonino F, Smith A, Anjuere F, Auberger P, Pouyssegur J (1999) Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science 286:1374–1377

    Article  CAS  PubMed  Google Scholar 

  145. Pan W, Wei Y, Zhou L, Li D (2011) Comparative in vivo study of injectable biomaterials combined with BMP for enhancing tendon graft osteointegration for anterior cruciate ligament reconstruction. J Orthop Res 29:1015–1021

    Article  CAS  PubMed  Google Scholar 

  146. Papantoniou I, Mantalaris A, Sonnaert M, Lambrechts T, Aerts J-M, Geris L, Schrooten J (2014) Product and process design: toward industrial TE manufacturing. In: Van Blitterswijk CA, De Boer J (eds) Tissue engineering, 2nd ed. Ed.: Elsevier.

    Google Scholar 

  147. Park DJ, Choi BH, Zhu SJ, Huh JY, Kim BY, Lee SH (2005) Injectable bone using chitosan-alginate gel/mesenchymal stem cells/BMP-2 composites. J Craniomaxillofac Surg 33:50–54

    Article  PubMed  Google Scholar 

  148. Pereira RF, O’hara MD, Laptev AV, Halford KW, Pollard MD, Class R, Simon D, Livezey K, Prockop DJ (1998) Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc Natl Acad Sci U S A 95:1142–1147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Perry MJ, Mcdougall KE, Hou SC, Tobias JH (2008) Impaired growth plate function in bmp-6 null mice. Bone 42:216–225

    Article  CAS  PubMed  Google Scholar 

  150. Pritchard EM, Kaplan DL (2011) Silk fibroin biomaterials for controlled release drug delivery. Expert Opin Drug Deliv 8:797–811

    Article  CAS  PubMed  Google Scholar 

  151. Pulskamp K, Diabate S, Krug HF (2007) Carbon nanotubes show no sign of acute toxicity but induce intracellular reactive oxygen species in dependence on contaminants. Toxicol Lett 168:58–74

    Article  CAS  PubMed  Google Scholar 

  152. Qutachi O, Vetsch JR, Gill D, Cox H, Scurr DJ, Hofmann S, Muller R, Quirk RA, Shakesheff KM, Rahman CV (2014) Injectable and porous PLGA microspheres that form highly porous scaffolds at body temperature. Acta Biomater 10:5090–5098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ratanavaraporn J, Furuya H, Tabata Y (2012) Local suppression of pro-inflammatory cytokines and the effects in BMP-2-induced bone regeneration. Biomaterials 33:304–316

    Article  CAS  PubMed  Google Scholar 

  154. Reichert JC, Saifzadeh S, Wullschleger ME, Epari DR, Schutz MA, Duda GN, Schell H, Van Griensven M, Redl H, Hutmacher DW (2009) The challenge of establishing preclinical models for segmental bone defect research. Biomaterials 30:2149–2163

    Article  CAS  PubMed  Google Scholar 

  155. Ricard N, Ciais D, Levet S, Subileau M, Mallet C, Zimmers TA, Lee SJ, Bidart M, Feige JJ, Bailly S (2012) BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood 119:6162–6171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Roberts SJ, Van Gastel N, Carmeliet G, Luyten FP (2015) Uncovering the periosteum for skeletal regeneration: the stem cell that lies beneath. Bone 70:10–18

    Article  PubMed  Google Scholar 

  157. Rockwood DN, Preda RC, Yucel T, Wang X, Lovett ML, Kaplan DL (2011) Materials fabrication from Bombyx mori silk fibroin. Nat Protoc 6:1612–1631

    Article  CAS  PubMed  Google Scholar 

  158. Rumpler M, Woesz A, Dunlop JW, Van Dongen JT, Fratzl P (2008) The effect of geometry on three-dimensional tissue growth. J R Soc Interface 5:1173–1180

    Article  PubMed  PubMed Central  Google Scholar 

  159. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, Tagliafico E, Ferrari S, Robey PG, Riminucci M, Bianco P (2007) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131:324–336

    Article  CAS  PubMed  Google Scholar 

  160. Saito N, Okada T, Horiuchi H, Ota H, Takahashi J, Murakami N, Nawata M, Kojima S, Nozaki K, Takaoka K (2003) Local bone formation by injection of recombinant human bone morphogenetic protein-2 contained in polymer carriers. Bone 32:381–386

    Article  CAS  PubMed  Google Scholar 

  161. Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, Woltjen K, Nagy A, Wrana JL (2010) Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7:64–77

    Article  CAS  PubMed  Google Scholar 

  162. Sapkota G, Alarcon C, Spagnoli FM, Brivanlou AH, Massague J (2007) Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol Cell 25:441–454

    Article  CAS  PubMed  Google Scholar 

  163. Sapkota G, Knockaert M, Alarcon C, Montalvo E, Brivanlou AH, Massague J (2006) Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways. J Biol Chem 281:40412–40419

    Article  CAS  PubMed  Google Scholar 

  164. Sawkins MJ, Mistry P, Brown BN, Shakesheff KM, Bonassar LJ, Yang J (2015) Cell and protein compatible 3D bioprinting of mechanically strong constructs for bone repair. Biofabrication 7:035004

    Article  CAS  PubMed  Google Scholar 

  165. Schmierer B, Hill CS (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8:970–982

    Article  CAS  PubMed  Google Scholar 

  166. Schmitz JP, Hollinger JO (1986) The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res (205):299–308

    Google Scholar 

  167. Schwappacher R, Weiske J, Heining E, Ezerski V, Marom B, Henis YI, Huber O, Knaus P (2009) Novel crosstalk to BMP signalling: cGMP-dependent kinase I modulates BMP receptor and Smad activity. EMBO J 28:1537–1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Schwartz AL, Ciechanover A (2009) Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu Rev Pharmacol Toxicol 49:73–96

    Article  CAS  PubMed  Google Scholar 

  169. Scott MA, Levi B, Askarinam A, Nguyen A, Rackohn T, Ting K, Soo C, James AW (2012) Brief review of models of ectopic bone formation. Stem Cells Dev 21:655–667

    Article  CAS  PubMed  Google Scholar 

  170. Seeherman H, Li R, Bouxsein M, Kim H, Li XJ, Smith-Adaline EA, Aiolova M, Wozney JM (2006) rhBMP-2/calcium phosphate matrix accelerates osteotomy-site healing in a nonhuman primate model at multiple treatment times and concentrations. J Bone Joint Surg Am 88:144–160

    PubMed  Google Scholar 

  171. Segklia A, Seuntjens E, Elkouris M, Tsalavos S, Stappers E, Mitsiadis TA, Huylebroeck D, Remboutsika E, Graf D (2012) Bmp7 regulates the survival, proliferation, and neurogenic properties of neural progenitor cells during corticogenesis in the mouse. PLoS One 7:E34088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Sekiya I, Colter DC, Prockop DJ (2001) BMP-6 enhances chondrogenesis in a subpopulation of human marrow stromal cells. Biochem Biophys Res Commun 284:411–418

    Article  CAS  PubMed  Google Scholar 

  173. Sekiya I, Vuoristo JT, Larson BL, Prockop DJ (2002) In vitro cartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis. Proc Natl Acad Sci U S A 99:4397–4402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Selever J, Liu W, Lu MF, Behringer RR, Martin JF (2004) Bmp4 in limb bud mesoderm regulates digit pattern by controlling AER development. Dev Biol 276:268–279

    Article  CAS  PubMed  Google Scholar 

  175. Serra T, Ortiz-Hernandez M, Engel E, Planell JA, Navarro M (2014) Relevance of PEG in PLA-based blends for tissue engineering 3D-printed scaffolds. Mater Sci Eng C Mater Biol Appl 38:55–62

    Article  CAS  PubMed  Google Scholar 

  176. Shen J, James AW, Zara JN, Asatrian G, Khadarian K, Zhang JB, Ho S, Kim HJ, Ting K, Soo C (2013) BMP2-induced inflammation can be suppressed by the osteoinductive growth factor NELL-1. Tissue Eng Part A 19:2390–2401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Shim JH, Greenblatt MB, Xie M, Schneider MD, Zou W, Zhai B, Gygi S, Glimcher LH (2009) TAK1 is an essential regulator of BMP signalling in cartilage. EMBO J 28:2028–2041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Shimasaki S, Moore RK, Otsuka F, Erickson GF (2004) The bone morphogenetic protein system in mammalian reproduction. Endocr Rev 25:72–101

    Article  CAS  PubMed  Google Scholar 

  179. Shin H, Quinten Ruhe P, Mikos AG, Jansen JA (2003) In vivo bone and soft tissue response to injectable, biodegradable oligo(poly(ethylene glycol) fumarate) hydrogels. Biomaterials 24:3201–3211

    Article  CAS  PubMed  Google Scholar 

  180. Shin M, Ohte S, Fukuda T, Sasanuma H, Yoneyama K, Kokabu S, Miyamoto A, Tsukamoto S, Hohjoh H, Jimi E, Katagiri T (2013) Identification of a novel bone morphogenetic protein (BMP)-inducible transcript, BMP-inducible transcript-1, by utilizing the conserved BMP-responsive elements in the Id genes. J Bone Miner Metab 31:34–43

    Article  CAS  PubMed  Google Scholar 

  181. Shu B, Zhang M, Xie R, Wang M, Jin H, Hou W, Tang D, Harris SE, Mishina Y, O’keefe RJ, Hilton MJ, Wang Y, Chen D (2011) BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development. J Cell Sci 124:3428–3440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Solloway MJ, Dudley AT, Bikoff EK, Lyons KM, Hogan BL, Robertson EJ (1998) Mice lacking Bmp6 function. Dev Genet 22:321–339

    Article  CAS  PubMed  Google Scholar 

  183. Squier CA, Ghoneim S, Kremenak CR (1990) Ultrastructure of the periosteum from membrane bone. J Anat 171:233–239

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Stephan SJ, Tholpady SS, Gross B, Petrie-Aronin CE, Botchway EA, Nair LS, Ogle RC, Park SS (2010) Injectable tissue-engineered bone repair of a rat calvarial defect. Laryngoscope 120:895–901

    PubMed  PubMed Central  Google Scholar 

  185. Storm EE, Huynh TV, Copeland NG, Jenkins NA, Kingsley DM, Lee SJ (1994) Limb alterations in brachypodism mice due to mutations in a new member of the TGF beta-superfamily. Nature 368:639–643

    Article  CAS  PubMed  Google Scholar 

  186. Strobel LA, Rath SN, Maier AK, Beier JP, Arkudas A, Greil P, Horch RE, Kneser U (2014) Induction of bone formation in biphasic calcium phosphate scaffolds by bone morphogenetic protein-2 and primary osteoblasts. J Tissue Eng Regen Med 8:176–185

    Article  CAS  PubMed  Google Scholar 

  187. Swiontkowski MF, Aro HT, Donell S, Esterhai JL, Goulet J, Jones A, Kregor PJ, Nordsletten L, Paiement G, Patel A (2006) 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 88:1258–1265

    PubMed  Google Scholar 

  188. Szpalski C, Barbaro M, Sagebin F, Warren SM (2012) Bone tissue engineering: current strategies and techniques--part II: Cell types. Tissue Eng Part B Rev 18:258–269

    Article  CAS  PubMed  Google Scholar 

  189. Szpalski C, Barr J, Wetterau M, Saadeh PB, Warren SM (2010) Cranial bone defects: current and future strategies. Neurosurg Focus 29:E8

    Article  PubMed  Google Scholar 

  190. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    Article  CAS  PubMed  Google Scholar 

  191. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    Article  CAS  PubMed  Google Scholar 

  192. Tam WL, O DF, Hiramatsu K, Tsumaki N, Luyten FP, Roberts SJ (2014) Sox9 reprogrammed dermal fibroblasts undergo hypertrophic differentiation in vitro and trigger endochondral ossification in vivo. Cell Reprogram 16:29–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Ten Dijke P, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DL, Ichijo H, Heldin CH, Miyazono K (1994) Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269:16985–16988

    CAS  PubMed  Google Scholar 

  194. Thomas JT, Lin K, Nandedkar M, Camargo M, Cervenka J, Luyten FP (1996) A human chondrodysplasia due to a mutation in a TGF-beta superfamily member. Nat Genet 12:315–317

    Article  CAS  PubMed  Google Scholar 

  195. Tibbles LA, Woodgett JR (1999) The stress-activated protein kinase pathways. Cell Mol Life Sci 55:1230–1254

    Article  CAS  PubMed  Google Scholar 

  196. Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V (2006) BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 38:1424–1429

    Article  CAS  PubMed  Google Scholar 

  197. Tsuji K, Cox K, Bandyopadhyay A, Harfe BD, Tabin CJ, Rosen V (2008) BMP4 is dispensable for skeletogenesis and fracture-healing in the limb. J Bone Joint Surg Am 90(Suppl 1): 14–18

    Article  PubMed  Google Scholar 

  198. Tsuji K, Cox K, Gamer L, Graf D, Economides A, Rosen V (2010) Conditional deletion of BMP7 from the limb skeleton does not affect bone formation or fracture repair. J Orthop Res 28:384–389

    PubMed  PubMed Central  Google Scholar 

  199. Tsuruga E, Takita H, Itoh H, Wakisaka Y, Kuboki Y (1997) Pore size of porous hydroxyapatite as the cell-substratum controls BMP-induced osteogenesis. J Biochem 121:317–324

    Article  CAS  PubMed  Google Scholar 

  200. Van Baardewijk LJ, Van Der Ende J, Lissenberg-Thunnissen S, Romijn LM, Hawinkels LJ, Sier CF, Schipper IB (2013) Circulating bone morphogenetic protein levels and delayed fracture healing. Int Orthop 37:523–527

    Article  PubMed  Google Scholar 

  201. Van Bael S, Chai YC, Truscello S, Moesen M, Kerckhofs G, Van Oosterwyck H, Kruth JP, Schrooten J (2012) The effect of pore geometry on the in vitro biological behavior of human periosteum-derived cells seeded on selective laser-melted Ti6AL4V bone scaffolds. Acta Biomater 8:2824–2834

    Article  CAS  PubMed  Google Scholar 

  202. Van Gastel N, Torrekens S, Roberts SJ, Moermans K, Schrooten J, Carmeliet P, Luttun A, Luyten FP, Carmeliet G (2012) Engineering vascularized bone: osteogenic and proangiogenic potential of murine periosteal cells. Stem Cells 30:2460–2471

    Article  CAS  PubMed  Google Scholar 

  203. Van Griensven M (2015) Preclinical testing of drug delivery systems to bone. Adv Drug Deliv Rev 94:151–164

    Article  CAS  PubMed  Google Scholar 

  204. Vashishth D (2008) Small animal bone biomechanics. Bone 43:794–797

    Article  PubMed  PubMed Central  Google Scholar 

  205. Verne E, Vitale-Brovarone C, Bui E, Bianchi CL, Boccaccini AR (2009) Surface functionalization of bioactive glasses. J Biomed Mater Res A 90:981–992

    Article  CAS  PubMed  Google Scholar 

  206. Wang K, Zhou C, Hong Y, Zhang X (2012) A review of protein adsorption on bioceramics. Interface Focus 2:259–277

    Article  PubMed  PubMed Central  Google Scholar 

  207. Wang L, Huang Y, Pan K, Jiang X, Liu C (2010) Osteogenic responses to different concentrations/ratios of BMP-2 and bFGF in bone formation. Ann Biomed Eng 38:77–87

    Article  PubMed  Google Scholar 

  208. Wang Z, Wang K, Lu X, Li M, Liu H, Xie C, Meng F, Jiang O, Li C, Zhi W (2015) Bmp-2 encapsulated polysaccharide nanoparticle modified biphasic calcium phosphate scaffolds for bone tissue regeneration. J Biomed Mater Res A 103:1520–1532

    Article  PubMed  CAS  Google Scholar 

  209. West FD, Roche-Rios MI, Abraham S, Rao RR, Natrajan MS, Bacanamwo M, Stice SL (2010) Kit ligand and bone morphogenetic protein signaling enhances human embryonic stem cell to germ-like cell differentiation. Hum Reprod 25:168–178

    Article  CAS  PubMed  Google Scholar 

  210. Winnier G, Blessing M, Labosky PA, Hogan BL (1995) Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev 9:2105–2116

    Article  CAS  PubMed  Google Scholar 

  211. Woo EJ (2013) Adverse events after recombinant human BMP2 in nonspinal orthopaedic procedures. Clin Orthop Relat Res 471:1707–1711

    Article  PubMed  Google Scholar 

  212. Xu RH, Chen X, Li DS, Li R, Addicks GC, Glennon C, Zwaka TP, Thomson JA (2002) BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol 20:1261–1264

    Article  CAS  PubMed  Google Scholar 

  213. Yamamoto M, Ikada Y, Tabata Y (2001) Controlled release of growth factors based on biodegradation of gelatin hydrogel. J Biomater Sci Polym Ed 12:77–88

    Article  CAS  PubMed  Google Scholar 

  214. Yang HS, La WG, Bhang SH, Jeon JY, Lee JH, Kim BS (2010) Heparin-conjugated fibrin as an injectable system for sustained delivery of bone morphogenetic protein-2. Tissue Eng Part A 16:1225–1233

    Article  CAS  PubMed  Google Scholar 

  215. Yang HS, La WG, Cho YM, Shin W, Yeo GD, Kim BS (2012) Comparison between heparin-conjugated fibrin and collagen sponge as bone morphogenetic protein-2 carriers for bone regeneration. Exp Mol Med 44:350–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Yao Y, Li W, Wu J, Germann UA, Su MS, Kuida K, Boucher DM (2003) Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation. Proc Natl Acad Sci U S A 100:12759–12764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Ying QL, Nichols J, Chambers I, Smith A (2003) Bmp induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115:281–292

    Article  CAS  PubMed  Google Scholar 

  218. Yoshimatsu Y, Lee YG, Akatsu Y, Taguchi L, Suzuki HI, Cunha SI, Maruyama K, Suzuki Y, Yamazaki T, Katsura A, Oh SP, Zimmers TA, Lee SJ, Pietras K, Koh GY, Miyazono K, Watabe T (2013) Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression. Proc Natl Acad Sci U S A 110:18940–18945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin I, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920

    Article  CAS  PubMed  Google Scholar 

  220. Yu L, Li Y, Zhao K, Tang Y, Cheng Z, Chen J, Zang Y, Wu J, Kong L, Liu S, Lei W, Wu Z (2013a) A novel injectable calcium phosphate cement-bioactive glass composite for bone regeneration. PLoS One 8:E62570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Yu N, Plachokova A, Yang F, Walboomers X, Jansen J (2013b) Engineering of dental tissues: scaffolds and preclinical models. In: Stem cells in craniofacial development, regeneration and repair. Wiley-Blackwell Press, Hoboken

    Google Scholar 

  222. Yu YY, Lieu S, Lu C, Miclau T, Marcucio RS, Colnot C (2010) Immunolocalization of BMPS, BMP antagonists, receptors, and effectors during fracture repair. Bone 46:841–851

    Article  CAS  PubMed  Google Scholar 

  223. Yusop AH, Bakir AA, Shaharom NA, Abdul Kadir MR, Hermawan H (2012) Porous biodegradable metals for hard tissue scaffolds: a review. Int J Biochem 2012:641430

    CAS  Google Scholar 

  224. Zhang H, Bradley A (1996) Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122:2977–2986

    CAS  PubMed  Google Scholar 

  225. Zhang H, Migneco F, Lin CY, Hollister SJ (2010) Chemically-conjugated bone morphogenetic protein-2 on three-dimensional polycaprolactone scaffolds stimulates osteogenic activity in bone marrow stromal cells. Tissue Eng Part A 16:3441–3448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Zhang WJ, Wang XL, Wang SY, Zhao J, Xu LY, Zhu C, Zeng DL, Chen J, Zhang ZY, Kaplan DL, Jiang XQ (2011) The use of injectable sonication-induced silk hydrogel for VEGF(165) and BMP-2 delivery for elevation of the maxillary sinus floor. Biomaterials 32:9415–9424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Zhang XS, Zheng GQ, Wang JQ, Zhang YG, Zhang GQ, Li ZL, Wang Y (2013) Porous Ti6al4v scaffold directly fabricated by sintering: preparation and in vivo experiment. J Nanomater 2013:205076

    Google Scholar 

  228. Zhong C, Wu J, Reinhart-King CA, Chu CC (2010) Synthesis, characterization and cytotoxicity of photo-crosslinked maleic chitosan-polyethylene glycol diacrylate hybrid hydrogels. Acta Biomater 6:3908–3918

    Article  CAS  PubMed  Google Scholar 

  229. Zhou T, Benda C, Dunzinger S, Huang Y, Ho JC, Yang J, Wang Y, Zhang Y, Zhuang Q, Li Y, Bao X, Tse HF, Grillari J, Grillari-Voglauer R, Pei D, Esteban MA (2012) Generation of human induced pluripotent stem cells from urine samples. Nat Protoc 7:2080–2089

    Article  CAS  PubMed  Google Scholar 

  230. Zhu J (2010) Bioactive modification of poly(Ethylene Glycol) hydrogels for tissue engineering. Biomaterials 31:4639–4656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium

    Wei Ji, Johanna Bolander, Yoke Chin Chai, Hiroki Katagiri, Marina Marechal & Frank P. Luyten

  2. Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium

    Wei Ji, Johanna Bolander, Yoke Chin Chai, Hiroki Katagiri, Marina Marechal & Frank P. Luyten

Authors
  1. Wei Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johanna Bolander
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoke Chin Chai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroki Katagiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marina Marechal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frank P. Luyten
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank P. Luyten .

Editor information

Editors and Affiliations

  1. School of Medicine, University of Zagreb, Zagreb, Croatia

    Slobodan Vukicevic

  2. perForm Biologics Inc, Holliston, Massachusetts, USA

    Kuber T. Sampath

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Ji, W., Bolander, J., Chai, Y.C., Katagiri, H., Marechal, M., Luyten, F.P. (2017). Toward Advanced Therapy Medicinal Products (ATMPs) Combining Bone Morphogenetic Proteins (BMP) and Cells for Bone Regeneration. In: Vukicevic, S., Sampath, K. (eds) Bone Morphogenetic Proteins: Systems Biology Regulators. Progress in Inflammation Research. Springer, Cham. https://doi.org/10.1007/978-3-319-47507-3_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-47507-3_6

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-47505-9

  • Online ISBN: 978-3-319-47507-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation