Bone substitutes in orthopaedic surgery: from basic science to clinical practice

V Campana, G Milano, E Pagano, M Barba, C Cicione, G Salonna, W Lattanzi, G Logroscino, V Campana, G Milano, E Pagano, M Barba, C Cicione, G Salonna, W Lattanzi, G Logroscino

Abstract

Bone substitutes are being increasingly used in surgery as over two millions bone grafting procedures are performed worldwide per year. Autografts still represent the gold standard for bone substitution, though the morbidity and the inherent limited availability are the main limitations. Allografts, i.e. banked bone, are osteoconductive and weakly osteoinductive, though there are still concerns about the residual infective risks, costs and donor availability issues. As an alternative, xenograft substitutes are cheap, but their use provided contrasting results, so far. Ceramic-based synthetic bone substitutes are alternatively based on hydroxyapatite (HA) and tricalcium phosphates, and are widely used in the clinical practice. Indeed, despite being completely resorbable and weaker than cortical bone, they have exhaustively proved to be effective. Biomimetic HAs are the evolution of traditional HA and contains ions (carbonates, Si, Sr, Fl, Mg) that mimic natural HA (biomimetic HA). Injectable cements represent another evolution, enabling mininvasive techniques. Bone morphogenetic proteins (namely BMP2 and 7) are the only bone inducing growth factors approved for human use in spine surgery and for the treatment of tibial nonunion. Demineralized bone matrix and platelet rich plasma did not prove to be effective and their use as bone substitutes remains controversial. Experimental cell-based approaches are considered the best suitable emerging strategies in several regenerative medicine application, including bone regeneration. In some cases, cells have been used as bioactive vehicles delivering osteoinductive genes locally to achieve bone regeneration. In particular, mesenchymal stem cells have been widely exploited for this purpose, being multipotent cells capable of efficient osteogenic potential. Here we intend to review and update the alternative available techniques used for bone fusion, along with some hints on the advancements achieved through the experimental research in this field.

Figures

Fig. 1
Fig. 1
a Cortical strut autograft from fibula in a proximal humeral non union treated by ORIF. b One year X-ray control show bone healing and the persistence of the autograft
Fig. 2
Fig. 2
a, b Morcelized homologous bone graft obtained from a banked femoral head. c Severe acetabular bone loss in a mobilized hip revision cup. d X-ray control at 2 years with evidence of bony stable osseointegration of the new cup in the remodeled bone graft
Fig. 3
Fig. 3
a, b Bovine bone substitute (Xenograft) in chips and blocks shape. c The xenograft is clearly visible and not resorbed in a well bone healed proximal humeral fracture at 1 year of follow up. d Acetabular bone defect filled with the same material
Fig. 4
Fig. 4
HA-TCP bone substitutes in proximal humeral and tibial traumatic bone loss. a Intraoperatory implant of the material in the proximal humerus. b X-ray control at 1 year show the substitute inside the humeral head. cf X ray and CT scan at 3 year of follow up in the proximal tibia. The HA-TCP material resulted well osseointegrated, but without any sign of resorption or bone substitution
Fig. 5
Fig. 5
Injectable TCP cement bone substitutes: ab injectable cements have the advantage to be mouldable and contourable to the bone loss in mininvasive or open surgery; c bone loss in a distal tibial open fracture delayed union (CT scan); d 1 year X-ray control, showed bone consolidation and osseointegration of the TCP cement
Fig. 6
Fig. 6
Calcium sulphate (CS): a Pellets fill the residual gap after DHS explant in a healed intertrochanteric fracture. b Two months after the CS was totally resorbed. c Antibiotic loaded CS pellets in a tibial osteomyelitis. d Three years CT scan control do not show any evidence of bone regeneration. No signs of CS were founded while the infection was healed
Fig. 7
Fig. 7
Demineralized Bone Matrix (DBM): ac Complex proximal humeral fracture treated by ORIF, DBM and calcium sulphate (Allomatrix-Wright); d One year follow up demonstrate good consolidation of the fracture
Fig. 8
Fig. 8
Platelet Rich Plasma (PRP): ad autologous blood is obtained in the operating room. After centrifugation the different components are differentiate. e, f A platelet concentrate is obtained for injection or deposition into the bone gap or wound

References

    1. Bhatt RA, Rozental TD. Bone graft substitutes. Hand Clin. 2012;28(4):457–468.
    1. Greenwald AS, Boden SD, Goldberg VM, Khan Y, Laurencin CT, Rosier RN. Bone-graft substitutes: facts, fictions and applications. J Bone Joint Surg Am. 2001;83:98–103.
    1. Finkemeier CG. Bone-grafting and bone-graft substitutes. J Bone Joint Surg Am. 2002;84(3):454–464.
    1. Van Heest A, Swiontkowsi M. Bone-graft substitutes. Lancet. 1999;353(Suppl 1):S28–S29.
    1. Faour O, Dimitriou R, Cousins CA, Giannoudis PV. The use of bone graft substitutes in large cancellous voids: any specific needs? Injury. 2011;42(Suppl 2):S87–S90.
    1. Morone MA, Boden SD, Hair G, Martin GJJ, Racine M, Titus L, Button WC. Gene expression during autograft lumbar spine fusion and the effect of bone morphogenetic protein 2. Clin Orthop Relat Res. 1998;351:252–265.
    1. Goldberg VM, Stevenson S. The biology of bone grafts. Semin Arthroplast. 1993;4(2):58–63.
    1. Zipfel GJ, Guiot BH, Fessler RG. Bone grafting. Neurosurg Focus. 2003;14(2):e8.
    1. Schlickewie W, Schlickewie C. The use of bone substitutes in the treatment of bone defects—the clinical view and history. Macromol Symp. 2007;253(1):10–23.
    1. Arner JW, Santrock RD. A historical review of common bone graft materials in foot and ankle surgery. Foot Ankle Spec. 2014;7(2):143–51.
    1. Miron RJ, Zhang YF. Osteoinduction: a review of old concepts with new standards. J Dent Res. 2012;91(8):736–744.
    1. Pryor LS, Gage E, Langevin CJ, Herrera F, et al. Review of bone substitutes. Craniomaxillofac Trauma Reconstr. 2009;2(3):151–160.
    1. Rawlinson JN. Morbidity after anterior cervical decompression and fusion. The influence of the donor site on recovery, and the results of a trial of surgibone compared to autologous bone. Acta Neurochir. 1994;131(1–2):106–118.
    1. Blokhuis TJ, Calori GM, Schmidmaier G. Autograft versus BMPs for the treatment of non-unions: what is the evidence? Injury. 2013;44(Suppl 1):S40–S42.
    1. Pape HC, Evans A, Kobbe P. Autologous bone graft: properties and techniques. J Orthop Trauma. 2010;24(Suppl 1):S36–S40.
    1. Wang JC, Walsh MC. (2009) . .
    1. Baumhauer J, Pinzur MS, Donahue R, Beasley W, Digiovanni C. Site selection and pain outcome after autologous bone graft harvest. Foot Ankle Int. 2014;35(2):104–107.
    1. Boden SD. Overview of the biology of lumbar spine fusion and principles for selecting a bone graft substitute. Spine. 2002;27(16 Suppl 1):S26–S31.
    1. Calvo R, Figueroa D, Díaz-Ledezma C, Vaisman A, Figueroa F. Bone allografts and the functions of bone banks. Rev Med Chil. 2011;139(5):660–666.
    1. Khan SN, Cammisa FPJ, Sandhu HS, Diwan AD, Girardi FP, Lane JM. The biology of bone grafting. J Am Acad Orthop Surg. 2005;13(1):77–86.
    1. Manyalich M, Navarro A, Koller J, Loty B, de Guerra A, Cornu O, Vabels G, Fornasari P, Costa A, Siska I, et al. European quality system for tissue banking. Transplant Proc. 2009;41(6):2035–2043.
    1. Tomford WW. Transmission of disease through transplantation of musculoskeletal allografts. J Bone Joint Surg Am. 1995;77(11):1742–1754.
    1. Mroz TE, Joyce MJ, Steinmetz MP, Lieberman IH, Wang JC. Musculoskeletal allograft risks and recalls in the United States. J Am Acad Orthop Surg. 2008;16(10):559–565.
    1. Lomas R, Chandrasekar A, Board TN. Bone allograft in the UK: perceptions and realities. Hip Int. 2013;23(5):427–433.
    1. Bauermeister A, Maatz R. A method of bone maceration results of animal experiments. J Bone Joint Surg Am. 1957;39(1):153–166.
    1. Jensen SS, Terheyden H. Bone augmentation procedures in localized defects in the alveolar ridge: clinical results with different bone grafts and bone-substitute materials. Int J Oral Maxillofac Implants. 2009;24(Suppl):218–236.
    1. Dumitrescu AL. Bone grafts and bone graft substitutes in periodontal therapy. In: Chemicals in surgical periodontal therapy. Berlin: Springer; 2011. p. 92.
    1. Tampieri A, Sprio S, Ruffini A, Celotti G, Lesci IG, Roveri N. From wood to bone: multi-step process to convert wood hierarchical structures into biomimetic hydroxyapatite scaffolds for bone tissue engineering. J Mater Chem. 2009;19:4973–4980.
    1. Laurencin CT, El-Amin SF. Xenotransplantation in orthopaedic surgery. J Am Acad Orthop Surg. 2008;16(1):4–8.
    1. Lofgren H, Johannsson V, Olsson T, Ryd L, Levander B. Rigid fusion after cloward operation for cervical disc disease using autograft, allograft, or xenograft: a randomized study with radiostereometric and clinical follow-up assessment. Spine. 2000;25(15):1908–1916.
    1. Malca SA, Roche PH, Rosset E, Pellet W. Cervical interbody xenograft with plate fixation: evaluation of fusion after 7 years of use in post-traumatic discoligamentous instability. Spine. 1996;21(6):685–690.
    1. Ramani PS, Kalbag RM, Sengupta RP. Cervical spinal interbody fusion with Kiel bone. Br J Surg. 1975;62(2):147–150.
    1. Savolainen S, Usenius JP, Hernesniemi J. Iliac crest versus artificial bone grafts in 250 cervical fusions. Acta Neurochir. 1994;129(1–2):54–57.
    1. Siqueira EB, Kranzler LI. Cervical Interbody fusion using calf bone. Surg Neurol. 1982;18(1):37–39.
    1. Charalambides C, Beer M, Cobb AG. Poor results after augmenting autograft with xenograft (Surgibone) in hip revision surgery: a report of 27 cases. Acta Orthop. 2005;76(4):544–549.
    1. Boyan BD, McMillan J, Lohmann CH, Ranly DM, Schwartz Z. Basic information for successful clinical use with special focus on synthetic graft substitutes. In: Laurencin CT, editor. Bone graft substitutes. Philadelphia: ASTM Int; 2002. pp. 231–259.
    1. Lerner T, Bullmann V, Schulte TL, Schneider M, Liljenqvist U. A level-1 pilot study to evaluate of ultraporous beta-tricalcium phosphate as a graft extender in the posterior correction of adolescent idiopathic scoliosis. Eur Spine J. 2009;18(2):170–179.
    1. Chae T, Yang H, Leung V, Ko F, Troczynski T. Novel biomimetic hydroxyapatite/alginate nanocomposite fibrous scaffolds for bone tissue regeneration. J Mater Sci Mater Med. 2013;24(8):1885–1894.
    1. Landi E, Tampieri A, Celotti G, Belmonte MM, Logroscino G. Synthetic biomimetic nanostructured hydroxyapatite. Key Eng Mater. 2005;284:949–952.
    1. Landi E, Tampieri A, Celotti G, Sprio S, Sandri M, Logroscino G. Sr-substituted hydroxyapatites for osteoporotic bone replacement. Acta Biomater. 2007;3(6):961–969.
    1. Sprio S, Tampieri A, Landi E, Sandri M, Martorana S, Celotti G, Logroscino G. Physico-chemical properties and solubility behaviour of multi-substituted hydroxyapatite powders containing silicon. Mater Sci Eng. 2008;28(1):179–187.
    1. Bigi A, Foresti E, Gregoriani R, Ripamonti A, Roveri N, Shah JS. The role of magnesium on the structure of biological apatite. Calcif Tissue Int. 1992;50(5):439–444.
    1. Bigi A, Falini G, Foresti E, Gazzano M, Ripamonti A, Roveri N. Magnesium influence on hydroxyapatite crystallization. J Inorg Biochem. 1993;49(1):69–78.
    1. TenHuisen KS, Brown PW. Effects of magnesium on the formation of calcium deficient hydroxyapatite from CaHPO4·2H2O and Ca4(PO4)2O. J Biomed Mater Res. 1997;36(3):306–314.
    1. Rey C, Renugopalakrishnan V, Collins B, Glimcher M. Fourier transform infrared spectroscopic study of the carbonate ions in bone mineral during aging. Calcif Tissue Int. 1991;49(4):251–258.
    1. Landi E, Tampieri A, Mattioli-Belmonte M, Celotti G. Biomimetic Mg- and Mg, CO3-substituted hydroxyapatites: synthesis characterization and in vitro behaviour. J Eur Ceram Soc. 2006;26(13):2593–2601.
    1. Landi E, Logroscino G, Proietti L, Tampieri A, Sandri M, Sprio S. Biomimetic Mg-substituted hydroxyapatite: from synthesis to in vivo behaviour. J Mater Sci Mater Med. 2008;19(1):239–247.
    1. Friedman CD, Costantino PD, Takagi S, Chow LC. BoneSource™ hydroxyapatite cement: a novel biomaterial for craniofacial skeletal tissue engineering and reconstruction. J Biomed Mater Res. 1998;43(4):428–432.
    1. Constantz BR, Ison IC, Fulmer MT, Poser RD, Smith ST, VanWagoner M, Ross J, Goldstein SA, Jupiter JB, Rosenthal DI. Skeletal repair by in situ formation of the mineral phase of bone. Science. 1995;267(5205):1796–1799.
    1. Van der Stok J, Van Lieshout EM, El-Massoudi Y, Van Kralingen GH, Patka P. Bone substitutes in the Netherlands—a systematic literature review. Acta Biomater. 2011;7(2):739–750.
    1. Peltier LF, Bickel EY. The use of plaster of Paris to fill defects in bone. Ann Surg. 1957;146(1):61–69.
    1. Shue L, Yufeng Z, Mony U. Biomaterials for periodontal regeneration: a review of ceramics and polymers. Biomatter. 2012;2(4):271–277.
    1. Peltier LF. The use of plaster of Paris to fill defects in bone. Clin Orthop. 1961;21:1–31.
    1. Peltier LF, Jones RH. Treatment of unicameral bone cysts by curettage and packing with plaster-of-Paris pellets. J Bone Joint Surg Am. 1978;60(6):820–822.
    1. Kumar CY, K NB, Menon J, Patro DK, B BH. Calcium sulfate as bone graft substitute in the treatment of osseous bone defects, a prospective study. J Clin Diagn Res. 2013;7(12):2926–2928.
    1. Sidqui M, Collin P, Vitte C, Forest N. Osteoblast adherence and resorption activity of isolated osteoclasts on calcium sulphate hemihydrate. Biomaterials. 1995;16(17):1327–1332.
    1. Huff W, Grisoni B. Mechanical integrity of rat bone after autograft and calcium sulfate graft. In: Fifth world biomaterials congress, Toronto. 1996. p. 52–3.
    1. Blom AW, Cunningham JL, Hughes G, Lawes TJ, Smith N, Blunn G, Learmonth ID, Goodship AE. The compatibility of ceramic bone graft substitutes as allograft extenders for use in impaction grafting of the femur. J Bone Joint Surg Br. 2005;87(3):421–425.
    1. Hadjipavlou AG, Simmons JW, Yang J, Nicodemus CL, Esch O, Simmons DJ. Plaster of Paris as an osteoconductive material for interbody vertebral fusion in mature sheep. Spine. 2000;25(1):10–15.
    1. Turner TM, Urban RM, Gitelis S, Haggard WO, Richelsoph K. Resorption evaluation of a large bolus of calcium sulfate in a canine medullary defect. Orthopedics. 2003;26(5 Suppl):s577–s579.
    1. Coetzee AS. Regeneration of bone in the presence of calcium sulfate. Arch Otolaryngol. 1980;106(7):405–409.
    1. Gitelis S, Piasecki P, Turner T, Haggard W, Charters J, Urban R. Use of a calcium sulfate-based bone graft substitute for benign bone lesions. Orthopedics. 2001;24(2):162–166.
    1. Kelly CM, Wilkins RM, Gitelis S, Hartjen C, Watson JT, Kim PT. The use of a surgical grade calcium sulfate as a bone graft substitute: results of a multicenter trial. Clin Orthop Relat Res. 2001;382:42–50.
    1. Robinson D, Alk D, Sandbank J, Farber R, Halperin N. Inflammatory reactions associated with a calcium sulfate bone substitute. Ann Transplant. 1999;4(3–4):91–97.
    1. Lee GH, Khoury JG, Bell JE, Buckwalter JA. Adverse reactions to OsteoSet bone graft substitute, the incidence in a consecutive series. Iowa Orthop J. 2002;22:35–38.
    1. Petruskevicius J, Nielsen S, Kaalund S, Knudsen PR, Overgaard S. No effect of Osteoset, a bone graft substitute, on bone healing in humans: a prospective randomized double-blind study. Acta Orthop Scand. 2002;73(5):575–578.
    1. Ladd A, Pliam N. The role of bone graft and alternatives in unstable distal radius fracture treatment. Orthop Clin North Am. 2001;32(2):337–351.
    1. Laurencin C, Khan Y, El-Amin SF. Bone graft substitutes. Expert Rev Med Devices. 2006;3(1):49–57.
    1. Palussière J, Berge J, Gangi A, et al. Clinical results of an open prospective study of a bis-GMA composite in percutaneous vertebral augmentation. Eur Spine J. 2005;14:982–991.
    1. Nandi SK, Roy S, Mukherjee P, Kundu B. Orthopaedic applications of bone graft & graft substitutes: a review. Indian J Med Res. 2010;132:15–30.
    1. Engelberg I, Kohn J. Physico-mechanical properties of degradable polymers used in medical applications: a comparative study. Biomaterials. 1991;12(3):292–304.
    1. Pitt CG, Gratzl MM, Kimmel GL, Surles J, Schindler A. Aliphatic polyesters II. The degradation of poly (DL-lactide), poly (epsilon-caprolactone), and their copolymers in vivo. Biomaterials. 1981;2(4):215–220.
    1. Porter JR, Henson A, Popat KC. Biodegradable poly(epsilon-caprolactone) nanowires for bone tissue engineering applications. Biomaterials. 2009;30(5):780–788.
    1. Mondrinos MJ, Dembzynski R, Lu L, Byrapogu VK, Wootton DM, Lelkes PI, Zhou J. Porogen-based solid freeform fabrication of polycaprolactone-calcium phosphate scaffolds for tissue engineering. Biomaterials. 2006;27(25):4399–4408.
    1. Tampieri A, Celotti G, Landi E, Sandri M, Roveri N, Falini G. Biologically inspired synthesis of bone-like composite: self-assembled collagen fibers/hydroxyapatite nanocrystals. J Biomed Mater Res A. 2003;67(2):618–625.
    1. Xie J, Baumann MJ, McCabe LR. Osteoblasts respond to hydroxyapatite surfaces with immediate changes in gene expression. J Biomed Mater Res A. 2004;71(1):108–117.
    1. Serre CM, Papillard M, Chavassieux P, Boivin G. In vitro induction of a calcifying matrix by biomaterials constituted of collagen and/or hydroxyapatite: an ultrastructural comparison of three types of biomaterials. Biomaterials. 1993;14(2):97–106.
    1. Wang RZ, Cui FZ, Lu HB, Wen HB, Ma CL, Li HD. Synthesis of nanophase hydroxyapatite/collagen composite. J Mater Sci Lett. 1995;14(7):490–492.
    1. Scabbia A, Trombelli L. A comparative study on the use of a HA/collagen/chondroitin sulphate biomaterial (Biostite) and a bovine-derived HA xenograft (Bio-Oss) in the treatment of deep intra-osseous defects. J Clin Periodontol. 2004;31(5):348–355.
    1. Yamauchi K, Goda T, Takeuchi N, Einaga H, Tanabe T. Preparation of collagen/calcium phosphate multilayer sheet using enzymatic mineralization. Biomaterials. 2004;25(24):5481–5489.
    1. Lawson AC, Czernuszka JT. Collagen–calcium phosphate composites. Proc Inst Mech Eng H. 1998;212(6):413–425.
    1. Schierholz JM, Beuth J. Implant infections: a haven for opportunistic bacteria. J Hosp Infect. 2001;49(2):87–93.
    1. Wang X, Grogan SP, Rieser F, Winkelmann V, Maquet V, Berge ML, Mainil-Varlet P. Tissue engineering of biphasic cartilage constructs using various biodegradable scaffolds: an in vitro study. Biomaterials. 2004;25(17):3681–3688.
    1. Boughton P, Ferris D, Ruys AJ. A ceramic-polymer functionally graded material: a novel disk prosthesis. In: Singh M, Jessen T. 25th Annual conference on composites, advanced ceramics, materials, and structures: B: ceramic engineering and science proceedings. Vol 22. Westerville: American Ceramic Society; 2008. p. 593–600.
    1. Wahl DA, Czernuszka JT. Collagen-hydroxyapatite composites for hard tissue repair. Eur Cell Mater. 2006;11:43–56.
    1. Urist M, Mikulski A, Boyd S. A chemosterilized antigen-extracted autodigested alloimplant for bone banks. Arch Surg. 1975;110(4):416–428.
    1. Lane JM. Bone morphogenic protein science and studies. J Orthop Trauma. 2005;19(10 Suppl):S17–S22.
    1. Mahantesha, Shobha KS, Mani R, Deshpande A, Seshan H, Kranti K. Clinical and radiographic evaluation of demineralized bone matrix (grafton) as a bone graft material in the treatment of human periodontal intraosseous defects. J Indian Soc Periodontol. 2013;17(4):495–502.
    1. Kinney RC, Ziran BH, Hirshorn K, Schlatterer D, Ganey T. Demineralized bone matrix for fracture healing: fact or fiction? J Orthop Trauma. 2010;24(Suppl 1):S52–S55.
    1. Grabowski G, Cornett CA. Bone graft and bone graft substitutes in spine surgery: current concepts and controversies. J Am Acad Orthop Surg. 2013;21(1):51–60.
    1. Witte LD, Kaplan KL, Nossel HL, Lages BA, Weiss HJ, Goodman DS. Studies of the release from human platelets of the growth factor for cultured human arterial smooth muscle cells. Circ Res. 1978;42(3):402–409.
    1. Kaplan KL, Broekman MJ, Chernoff A, Lesznik GR, Drillings M. Platelet alpha-granule proteins: studies on release and subcellular localization. Blood. 1979;53(4):604–618.
    1. Ross R, Vogel A. The platelet-derived growth factor. Cell. 1978;14(2):203–210.
    1. Dabra S, Chhina K, Soni N, Bhatnagar R. Tissue engineering in periodontal regeneration: a brief review. Dent Res J. 2012;9(6):671–680.
    1. Ross R, Raines EW. Platelet-derived growth factor: its role in health and disease. In: Kudlow JE, MacLennan DH, Bernstein A, Gotlieb AI, editors. Biology of growth factors. Berlin: Springer; 1988. pp. 9–21.
    1. Kondo H, Matsuda R, Yonezawa Y. Platelet-derived growth factor in combination with collagen promotes the migration of human skin fibroblasts into a denuded area of a cell monolayer. Exp Cell Res. 1992;202(1):45–51.
    1. Oates TW, Rouse CA, Cochran DL. Mitogenic effects of growth factors on human periodontal ligament cells in vitro. J Periodontol. 1993;64(2):142–148.
    1. Yang D, Chen J, Jing Z, Jin D. Platelet-derived growth factor (PDGF)-AA: a self-imposed cytokine in the proliferation of human fetal osteoblasts. Cytokine. 2000;12(8):1271–1274.
    1. Kitoh H, Kawasumi M, Kaneko H, Ishiguro N. Differential effects of culture-expanded bone marrow cells on the regeneration of bone between the femoral and the tibial lengthenings. J Pediatr Orthop. 2009;29(6):643–649.
    1. Tsai CH, Hsu HC, Chen YJ, Lin MJ, Chen HT. Using the growth factors-enriched platelet glue in spinal fusion and its efficiency. J Spinal Disord Tech. 2009;22(4):246–250.
    1. Castro FPJ. Role of activated growth factors in lumbar spinal fusions. J Spinal Disord Tech. 2004;17(5):380–384.
    1. Weiner BK, Walker M. Efficacy of autologous growth factors in lumbar intertransverse fusions. Spine. 2003;28(17):1968–1970.
    1. Urist MR. Bone: formation by autoinduction. Science. 1965;150(698):893–899.
    1. Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev. 2005;16(3):251–263.
    1. Wu X, Shi W, Cao X. Multiplicity of BMP signaling in skeletal development. Ann N Y Acad Sci. 2007;1116:29–49.
    1. Boden SD. Clinical application of the BMPs. J Bone Joint Surg Am. 2001;83(Suppl 1):S161.
    1. Boden SD, Schimandle JH. Biologic enhancement of spinal fusion. Spine. 1995;20(24 Suppl):113S–123S.
    1. Cook SD, Barrack RL, Shimmin A, Morgan D, Carvajal JP. The use of osteogenic protein-1 in reconstructive surgery of the hip. J Arthroplasty. 2001;16(8 Suppl 1):88–94.
    1. Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review. Health Technol Assess. 2007;11(30):1–150.
    1. Mussano F, Ciccone G, Ceccarelli M, Baldi I, Bassi F. Bone morphogenetic proteins and bone defects: a systematic review. Spine. 2007;32(7):824–830.
    1. Salkeld SL, Patron LP, Barrack RL, Cook SD. The effect of osteogenic protein-1 on the healing of segmental bone defects treated with autograft or allograft bone. J Bone Joint Surg Am. 2001;83-A(6):803–816.
    1. Pola E, Nasto L, Tampieri A, Lattanzi W, Di Giacomo G, Colangelo D, Ciriello V, Pagano E, Spinelli S, Robbins P, et al. Bioplasty for vertebral fractures: preliminary results of a pre-clinical study on goats using autologous modified skin fibroblasts. Int J Immunopathol Pharmacol. 2011;24(1 Suppl 2):139–142.
    1. Shields LB, Raque GH, Glassman SD, Campbell M, Vitaz T, Harpring J, Shields CB. Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion. Spine. 2006;31(5):542–547.
    1. Holland TA, Mikos AG. Biodegradable polymeric scaffolds. Improvements in bone tissue engineering through controlled drug delivery. Adv Biochem Eng Biotechnol. 2006;102:161–185.
    1. Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials. 2000;21:2529–2543.
    1. Lucas PA, Laurencin C, Syftestad GT, Domb A, Goldberg VM, Caplan AI, Langer R. Ectopic induction of cartilage and bone by water-soluble proteins from bovine bone using a polyanhydride delivery vehicle. J Biomed Mater Res. 1990;24:901–911.
    1. Mori M, Isobe M, Yamazaki Y, Ishihara K, Nakabayashi N. Restoration of segmental bone defects in rabbit radius by biodegradable capsules containing recombinant human bone morphogenetic protein-2. J Biomed Mater Res. 2000;50:191–198.
    1. Babensee JE, McIntire LV, Mikos AG. Growth factor delivery for tissue engineering. Pharm Res. 2000;17:497–504.
    1. Doll B, Sfeir C, Winn S, Huard J, Hollinger J. Critical aspects of tissue-engineered therapy for bone regeneration. Crit Rev Eukaryot Gene Expr. 2001;11:173–198.
    1. Raiche AT, Puleo DA. In vitro effects of combined and sequential delivery of two bone growth factors. Biomaterials. 2004;25:677–685.
    1. Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84A:2123–2134.
    1. Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001;83A(Suppl 1, Part 2):S151–S158.
    1. Jensen TB, Overgaard S, Lind M, Rahbek O, Bunger C, Soballe K. Osteogenic protein-1 increases the fixation of implants grafted with morcellised bone allograft and ProOsteon bone substitute: an experimental study in dogs. J Bone Joint Surg Br. 2007;89:121–126.
    1. Jensen TB, Overgaard S, Lind M, Rahbek O, Bunger C, Soballe K. Osteogenic protein 1 device increases bone formation and bone graft resorption around cementless implants. Acta Orthop Scand. 2002;73:31–39.
    1. Lind MC, Laursen M, Jensen TB, Overgaard S, Soballe K, Bunger CE. Stimulation of bone healing with growth factors in orthopedic surgery. Ugeskr Laeger. 2000;162:6399–6403.
    1. Klein C, Driessen AA, Degroot K, Vandenhooff A. Biodegradation behavior of various calcium-phosphate materials in bone tissue. J Biomed Mater Res. 1983;17:769–784.
    1. Kwon SH, Jun YH, Hong SH, Lee IS, Kim HE, Won YY. Calcium phosphate bioceramics with various porosities and dissolution rates. J Am Ceram Soc. 2002;85:3129–3131.
    1. Kwon SH, Jun YK, Hong SH, Kim HE. Synthesis and dissolution behavior of beta-TCP and HA/beta-TCP composite powders. J Eur Ceram Soc. 2003;23:1039–1045.
    1. Ji J, Ran J, Gou L, Wang F, Sun L. Microwave plasma sintering and in vitro study of porous HA/β-TCP biphasic bioceramics. Key Eng Mater. 2005;280–283:1519–1524.
    1. Lu J, Blary M, Vavasseur V, Descamps M, Anselme K, Hardouin P. Relationship between bioceramics sintering and micro-particles-induced cellular damages. J Mater Sci Mater Med. 2004;15:361–365.
    1. Burdick JA, Anseth KS. Photoencapsulation of osteoblasts in injectable RGD-modified PEG hydrogels for bone tissue engineering. Biomaterials. 2002;23:4315–4323.
    1. Burdick JA, Mason MN, Hinman AD, Thorne K, Anseth KS. Delivery of osteoinductive growth factors from degradable PEG hydrogels influences osteoblast differentiation and mineralization. J Control Release. 2002;83:53–63.
    1. Kretlow JD, Mikos AG. Review: mineralization of synthetic polymer scaffolds for bone tissue engineering. Tissue Eng. 2007;13:927–938.
    1. Rezwan K, Chen QZ, Blaker JJ, Boccaccini AR. Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials. 2006;27:3413–3431.
    1. Liu X, Ma PX. Polymeric scaffolds for bone tissue engineering. Ann Biomed Eng. 2004;32:477–486.
    1. Schliephake H, Weich HA, Schulz J, Gruber R. In vitro characterization of a slow release system of polylactic acid and rhBMP2. J Biomed Mater Res A. 2007;83:455–462.
    1. Montjovent MO, Mathieu L, Schmoekel H, Mark S, Bourban PE, Zambelli PY, Laurent-Applegate LA, Pioletti DP. Repair of critical size defects in the rat cranium using ceramic-reinforced PLA scaffolds obtained by supercritical gas foaming. J Biomed Mater Res A. 2007;83:41–51.
    1. Schliephake H, Weich HA, Dullin C, Gruber R, Frahse S. Mandibular bone repair by implantation of rhBMP-2 in a slow release carrier of polylactic acid—an experimental study in rats. Biomaterials. 2008;29:103–110.
    1. Yoon SJ, Park KS, Kim MS, Rhee JM, Khang G, Lee HB. Repair of diaphyseal bone defects with calcitriol-loaded PLGA scaffolds and marrow stromal cells. Tissue Eng. 2007;13:1125–1133.
    1. Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric system for dual growth factor delivery. Nat Biotechnol. 2001;19:1029–1034.
    1. Virto MR, Elorza B, Torrado S, Elorza MDL, Frutos G. Improvement of gentamicin poly(d,l-lactic-co-glycolic acid) microspheres for treatment of osteomyelitis induced by orthopedic procedures. Biomaterials. 2007;28:877–885.
    1. Liu SJ, Chi PS, Lin SS, Ueng SW, Chan EC, Chen JK. Novel solvent-free fabrication of biodegradable poly-lactic-glycolic acid (PLGA) capsules for antibiotics and rhBMP-2 delivery. Int J Pharm. 2007;330:45–53.
    1. Nie H, Wang CH. Fabrication and characterization of PLGA/HAp composite scaffolds for delivery of BMP-2 plasmid DNA. J Control Release. 2007;120:111–121.
    1. Leach JK, Kaigler D, Wang Z, Krebsbach PH, Mooney DJ. Coating of VEGF-releasing scaffolds with bioactive glass for angiogenesis and bone regeneration. Biomaterials. 2006;27:3249–3255.
    1. Murphy WL, Peters MC, Kohn DH, Mooney DJ. Sustained release of vascular endothelial growth factor from mineralized poly(lactide-co-glycolide) scaffolds for tissue engineering. Biomaterials. 2000;21:2521–2527.
    1. Richardson TP, Murphy WL, Mooney DJ. Polymeric delivery of proteins and plasmid DNA for tissue engineering and gene therapy. Crit Rev Eukaryot Gene Expr. 2001;11:47–58.
    1. Peter SJ, Miller MJ, Yasko AW, Yaszemski MJ, Mikos AG. Polymer concepts in tissue engineering. J Biomed Mater Res. 1998;43:422–427.
    1. Chen RR, Silva EA, Yuen WW, Mooney DJ. Spatio-temporal VEGF and PDGF delivery patterns blood vessel formation and maturation. Pharm Res. 2007;24:258–264.
    1. Leach JK. Multifunctional cell-instructive materials for tissue regeneration. Regen Med. 2006;1:447–455.
    1. Salvay DM, Shea LD. Inductive tissue engineering with protein and DNA-releasing scaffolds. Mol BioSyst. 2006;2:36–48.
    1. Quirk R, Chan W, Davies M, Tendler S, Shakesheff K. Poly(l-lysine)-GRGDS as a biomimetic surface modifier for poly(lactic acid) Biomaterials. 2001;22:865–872.
    1. Yang X, Roach H, Clarke N, Howdle S, Quirk R, Shakesheff K, Oreffo R. Human osteoprogenitor growth and differentiation on synthetic biodegradable stru tures after surface modification. Bone. 2001;29:523–531.
    1. Whitaker M, Quirk R, Howdle S, Shakesheff K. Growth factor release from tissue engineering scaffolds. J Pharm Pharmacol. 2001;53:1427–1437.
    1. Seal B, Otero B, Panitch A. Polymeric biomaterials for tissue and organ regeneration. Mater Sci Eng. 2001;R34:147–230.
    1. Tabata Y. The importance of drug delivery systems in tissue engineering. Pharm Sci Tech Today. 2000;3:80–89.
    1. Lee K, Peters M, Anderson K, Mooney D. Controlled growth factor release from synthetic extracellular matrices. Nature. 2000;408:998–1000.
    1. Itoh S, Kikuchi M, Takakuda K, Koyama Y, Matsumoto H, Ichinose S, Tanaka J, Kawauchi T, Shinomiya K. The biocompatibility and osteoconductive activity of a novel hydroxyapatite/collagen composite biomaterial, and its function as a carrier of rhBMP-2. J Biomed Mater Res. 2001;54:445–453.
    1. Cooper A. Polymer synthesis and processing using supercritical carbon dioxide. J Mater Chem. 2001;10:207–234.
    1. Howdle S, Watson M, Whitaker M, Popov M, Davies M, Mandel F, Wang J, Shakesheff K. Supercritical fluid mixing: preparation of thermally sensitive polymer composites containing bioactive materials. Chem Commun. 2001;109–110.
    1. Cartmell S. Controlled release scaffolds for bone tissue engineering. J Pharm Sci. 2009;98:430–441.
    1. Sill TJ, von Recum HA. Electrospinning: applications in drug delivery and tissue engineering. Biomaterials. 2008;29:1989–2006.
    1. Piskin E, Isoglu IA, Bolgen N, Vargel I, Griffiths S, Çavuşoğlu T, Korkusuz P, Guzel E, Cartmell S. In vivo performance of simvastatin-loaded electrospun spiral-wound polycaprolactone scaffolds in reconstruction of cranial bone defects in the rat model. J Biomed Mater Res A. 2009;90(4):1137–1151.
    1. Kato Y, Onishi H, Machida Y. Application of chitin and chitosan derivatives in the pharmaceutical field. Curr Pharm Biotechnol. 2003;4:303–309.
    1. Murphy WL, Mooney DJ. Controlled delivery of inductive proteins, plasmid DNA and cells from tissue engineering matrices. J Periodontal Res. 1999;34:413–419.
    1. Albuhairan B, Hind D, Hutchinson A. Antibiotic prophylaxis for wound infections in total joint arthroplasty: a systematic review. J Bone Joint Surg Br. 2008;90:915–919.
    1. Price JS, Tencer AF, Arm DM, Bohach AG. Controlled release of antibiotics from coated orthopedic implants. J Biomed Mater Res. 1996;30:281–286.
    1. Naraharisetti PK, Guan Lee HC, Fu YC, Lee DJ, Wang CH. In vitro and in vivo release of gentamicin from biodegradable discs. J Biomed Mater Res B Appl Biomater. 2006;77:329–337.
    1. Li H, Chang J. Preparation, characterization and in vitro release of gentamicin from PHBV/wollastonite composite microspheres. J Control Release. 2005;107:463–473.
    1. Ramchandani M, Robinson D. In vitro and in vivo release of ciprofloxacin from PLGA 50:50 implants. J Control Release. 1998;54:167–175.
    1. Porter JR, Ruckh TT, Popat KC. Bone tissue engineering: a review in bone biomimetics and drug delivery strategies. Biotechnol Prog. 2009;25(6):1539–1560.
    1. Raposo-Amaral CE, Bueno DF, Almeida AB, Jorgetti V, Costa CC, Gouveia CH, Vulcano LC, Fanganiello RD, Passos-Bueno MR, Alonso N. Is bone transplantation the gold standard for repair of alveolar bone defects? J Tissue Eng. 2014;5:2041731413519352.
    1. Lattanzi W, Pola E, Pecorini G, Logroscino CA, Robbins PD. Gene therapy for in vivo bone formation: recent advances. Eur Rev Med Pharmacol Sci. 2005;9(3):167–174.
    1. Lattanzi W, Parrilla C, Fetoni A, Logroscino G, Straface G, Pecorini G, et al. Ex vivo-transduced autologous skin fibroblasts expressing human Lim mineralization protein-3 efficiently form new bone in animal models. Gene Ther. 2008;15(19):1330–1343.
    1. Ludwig SC, Kowalski JM, Boden SD. Osteoinductive bone graft substitutes. Eur Spine J. 2000;9(Suppl 1):S119–S125.
    1. Logroscino G, Lattanzi W. Bone substitution in spine fusion: the past, the present and the future. In: Menchetti PPM, editor. Minimally invasive surgery of the lumbar spine. Berlin: Springer Verlag; 2014. pp. 311–331.
    1. Parrilla C, Saulnier N, Bernardini C, Patti R, Tartaglione T, Fetoni AR, Pola E, Paludetti G, Michetti F, Lattanzi W. Undifferentiated human adipose tissue-derived stromal cells induce mandibular bone healing in rats. Arch Otolaryngol Head Neck Surg. 2011;137(5):463–470.
    1. Gomez-Barrena E, Rosset P, Muller I, Giordano R, Bunu C, Layrolle P, et al. Bone regeneration: stem cell therapies and clinical studies in orthopaedics and traumatology. J Cell Mol Med. 2011;15(6):1266–1286.
    1. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineagepotential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–147.
    1. Saulnier N, Lattanzi W, Puglisi MA, Pani G, Barba M, Piscaglia AC, et al. Mesenchymal stromal cells multipotency and plasticity: induction toward the hepatic lineage. Eur Rev Med Pharmacol Sci. 2009;13(Suppl 1):71–78.
    1. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, et al. Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393–395.
    1. Prockop DJ, Oh JY. Medical therapies with adult stem/progenitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. J Cell Biochem. 2012;113(5):1460–1469.
    1. Muraglia A, Cancedda R, Quarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J Cell Sci. 2000;113(Pt 7):1161–1166.
    1. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med. 1999;5(3):309–313.
    1. Chamberlain JR, Schwarze U, Wang PR, Hirata RK, Hankenson KD, Pace JM, et al. Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science. 2004;303(5661):1198–1201.
    1. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8(9):726–736.
    1. Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, Wang CY. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19(1):35–42.
    1. Barba M, Cicione C, Bernardini C, Michetti F, Lattanzi W. Adipose-derived mesenchymal cells for bone regereneration: state of the art. Biomed Res Int. 2013;2013(416391):11.
    1. Barba M, Cicione C, Bernardini C, Campana V, Pagano E, Michetti F, Logroscino G, Lattanzi W. Spinal fusion in the next generation: gene and cell therapy approaches. Sci World J. 2014;2014(406159):9.
    1. Lattanzi W, Bernardini C. Genes and molecular pathways of the osteogenic process. In: Lin Y, editor. Osteogenesis. Rijeka: Intech; 2011. pp. 21–56.
    1. Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury. 2007;38(Suppl 4):S3–S6.

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