Abstract
Background
The capacity for bone healing reportedly is limited in osteoporosis with a less than ideal environment for healing of bone grafts. We therefore developed a composite bone substitute with rhBMP-2 loaded gelatin microsphere (GM) and calcium phosphate cement (CPC) to use in osteoporosis.
Questions/purposes
We asked whether (1) controlled release of rhBMP-2 could be improved in this composite bone substitute and (2) increasing factors released from the bone substitute could accelerate osteoporotic bone healing.
Methods
We soaked rhBMP-2/GM/CPC and rhBMP-2/CPC composites in simulated body fluid for 28 days and then determined the amount of rhBMP-2 released. Both composites were implanted in bone defects of osteoporotic goats and left in place for 45 and 140 days; the specimens then were evaluated mechanically (pushout test) and morphologically (CT scanning, histology).
Results
The in vitro study showed the new composite released more rhBMP-2 compared with rhBMP-2/CPC. CT showed the defects healed more quickly with new grafts. The bone mineralization rate was greater in rhBMP-2/GM/CPC than in rhBMP-2/CPC after 45 days of implantation and the pushout test was stronger after 45 and 140 days of implantation.
Conclusions
The new graft composite released more loaded factors and appeared to repair osteoporotic bone defects.
Clinical Relevance
These preliminary data suggest the new composite can be used as a bone substitute to accelerate healing of fractures and bone defects in osteoporosis.
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References
Bigi A, Bracci B, Panzavolta S. Effect of added gelatin on the properties of calcium phosphate cement. Biomaterials. 2004;25:2893–2899.
Bigi A, Panzavolta S, Sturba L, Torricelli P, Fini M, Giardino R. Normal and osteopenic bone-derived osteoblast response to a biomimetic gelatin-calcium phosphate bone cement. J Biomed Mater Res A. 2006;78:739–745.
Egermann M, Baltzer AW, Adamaszek S, Evans C, Robbins P, Schneider E, Lill CA. Direct adenoviral transfer of bone morphogenetic protein-2 cDNA enhances fracture healing in osteoporotic sheep. Hum Gene Ther. 2006;17:507–517.
Fei Z, Hu Y, Wu D, Wu H, Lu R, Bai J, Song H. Preparation and property of a novel bone graft composite consisting of rhBMP-2 loaded PLGA microspheres and calcium phosphate cement. J Mater Sci Mater Med. 2008;19:1109–1116.
Habraken WJ, Boerman OC, Wolke JG, Mikos AG, Jansen JA. In vitro growth factor release from injectable calcium phosphate cements containing gelatin microspheres. J Biomed Mater Res A. 2009;91:614–622.
Habraken WJ, de Jonge LT, Wolke JG, Yubao L, Mikos AG, Jansen JA. Introduction of gelatin microspheres into an injectable calcium phosphate cement. J Biomed Mater Res A. 2008;87:643–655.
Habraken WJ, Wolke JG, Mikos AG, Jansen JA. Injectable PLGA microsphere/calcium phosphate cements: physical properties and degradation characteristics. J Biomater Sci Polym Ed. 2006;17:1057–1074.
Kempen DH, Lu L, Hefferan TE, Creemers LB, Maran A, Classic KL, Dhert WJ, Yaszemski MJ. Retention of in vitro and in vivo BMP-2 bioactivities in sustained delivery vehicles for bone tissue engineering. Biomaterials. 2008;29:3245–3252.
Leung KS, Siu WS, Cheung NM, Lui PY, Chow DH, James A, Qin L. Goats as an osteopenic animal model. J Bone Miner Res. 2001;16:2348–2355.
Li M, Liu X, Liu X, Ge B, Chen K. Creation of macroporous calcium phosphate cements as bone substitutes by using genipin-crosslinked gelatin microspheres. J Mater Sci Mater Med. 2009;20:925–934.
Li RH, Bouxsein ML, Blake CA, D’Augusta D, Kim H, Li XJ, Wozney JM, Seeherman HJ. rhBMP-2 injected in a calcium phosphate paste (a-BSM) accelerates healing in the rabbit ulnar osteotomy model. J Orthop Res. 2003;21:997–1004.
Liang HC, Chang WH, Lin KJ, Sung HW. Genipin-crosslinked gelatin microspheres as a drug carrier for intramuscular administration: in vitro and in vivo studies. J Biomed Mater Res A. 2003;65:271–282.
Lill CA, Hesseln J, Schlegel U, Eckhardt C, Goldhahn J, Schneider E. Biomechanical evaluation of healing in a non-critical defect in a large animal model of osteoporosis. J Orthop Res. 2003;21:836–842.
Lindner T, Kanakaris NK, Marx B, Cockbain A, Kontakis G, Giannoudis PV. Fractures of the hip and osteoporosis: the role of bone substitutes. J Bone Joint Surg Br. 2009;91:294–303.
Link DP, van den Dolder J, Jurgens WJ, Wolke JG, Jasen JA. Mechanical evaluation of implanted calcium phosphate cement incorporated with PLGA microparticles. Biomaterials. 2006;27:4941–4947.
Link DP, van den Dolder J, van den Beucken JJ, Wolke JG, Mikos AG, Jansen JA. Bone response and mechanical strength of rabbit femoral defects filled with injectable CaP cements containing TGF-beta 1 loaded gelatin microparticles. Biomaterials. 2008;29:675–682.
Liu Xingyan, Li Meng, Liu Xudong, Hao Xiaodong, Ge Baofeng. Enhancement of bone defects healing by a local treatment with rhBMP-2/CPC in an osteoporotic goat. Chin J Osteoporos. 2009;15:16–19.
Mankin HJ Doppelt S, Tomford W. Clinical experience with allograft transplantation: the first ten years. Clin Orthop Relat Res. 1983;174:69–86.
McCann RM, Colleary G, Geddis C, Clarke SA, Jordan GR, Dickson GR, Marsh D. Effect of osteoporosis on bone mineral density and fracture repair in a rat femoral fracture model. J Orthop Res. 2008;26:384–393.
Nakano M, Hirano N, Ishihara H, Kawaguchi Y, Watanabe H, Matsuura K. Calcium phosphate cement-based vertebroplasty compared with conservative treatment for osteoporotic compression fractures: a matched case-control study. J Neurosurg Spine. 2006;4:110–117.
Namkung-Matthai H, Appleyard R, Jansen J, Hao Lin J, Maastricht S, Swain M, Mason RS, Murrell GAC, Diwan AD, Diomand T. Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone. 2001;28:80–86.
Nemzek JA, Arnoczky SP, Swenson CL. Retroviral transmission in bone allotransplantation: the effects of tissue processing. Clin Orthop Relat Res. 1996;324:275–282.
Phillips FM, Turner AS, Seim HB 3rd, MacLeay J, Toth CA, Pierce AR, Wheeler DL. In vivo BMP-7 (OP-1) enhancement of osteoporotic vertebral bodies in an ovine model. Spine J. 2006;6:500–506.
Ruhé PQ, Boerman OC, Russel FG, Spauwen PH, Mikos AG, Jansen JA. Controlled release of rhBMP-2 loaded poly(dl-lactic-co-glycolic acid)/calcium phosphate cement composites in vivo. J Control Release. 2005;106:162–171.
Ruhe PQ, Hedberg EL, Padron NT, Spauwen PH, Jansen JA, Mikos AG. rhBMP-2 release from injectable poly(DL-lactic-co-glycolic acid)/calcium-phosphate cement composites. J Bone Joint Surg Am. 2003;85(suppl 3):75–81.
Ruhe PQ, Hedberg EL, Padron NT, Spauwen PH, Jansen JA, Mikos AG. Biocompatibility and degradation of poly(DL-lactic-co-glycolic acid)/calcium phosphate cement composites. J Biomed Mater Res A. 2005;74:533–544.
Ruhé PQ, Hedberg EL, Padron NT, Spauwen PH, Jansen JA, Mikos AG. Porous poly(DL-lactic-co-glycolic acid)/calcium phosphate cement composite for reconstruction of bone defects. Tissue Eng. 2006;12:789–800.
Seeherman HJ, Azari K, Bidic S, Rogers L, Li XJ, Hollinger JO, Wozney JM. rhBMP-2 delivered in a calcium phosphate cement accelerates bridging of critical-sized defects in rabbit radii. J Bone Joint Surg Am. 2006;88:1553–1565.
Seeherman H, Li R, Wozney J. A review of preclinical program development for evaluating injectable carriers for osteogenic factors. J Bone Joint Surg Am. 2003;85(suppl 3):96–108.
Siu WS, Qin L, Cheung WH, Leung KS. A study of trabecular bones in ovariectomized goats with micro-computed tomography and peripheral quantitative computed tomography. Bone. 2004;35:21–26.
Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K. Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol. 2003;1:E69.
Turgeman G, Zilberman Y, Zhou S, Kelly P, Moutsatsos IK, Kharode YP, Borella LE, Bex FJ, Komm BS, Bodine PV, Gazit D. Systemically administered rhBMP-2 promotes MSC activity and reverses bone and cartilage loss in osteopenic mice. J Cell Biochem. 2002;86:461–474.
Young S, Wong M, Tabata Y, Mikos AG. Gelatin as a delivery vehicle for the controlled release of bioactive molecules. J Control Release. 2005;109:256–274.
Younger EM, Chapman MW. Morbidity at bone graft donor sites. J Orthop Trauma. 1989;3:192–195.
Zimmermann R, Gabl M, Lutz M, Angermann P, Gschwentner M, Pechlaner S. Injectable calcium phosphate bone cement Norian SRS for the treatment of intra-articular compression fractures of the distal radius in osteoporotic women. Arch Orthop Trauma Surg. 2003;123:22–27.
Acknowledgments
We thank Xiaodong Hao for help with the CT examination.
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One or more of the authors (ML, XL) have received funding from a research grant at the Chinese People’s Liberation Army (Grant Number of 06MA090) and a grant of Gansu Natural Science Foundation (Grant Number of 0710RJZA068).
Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
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Li, M., Liu, X., Liu, X. et al. Calcium Phosphate Cement with BMP-2-loaded Gelatin Microspheres Enhances Bone Healing in Osteoporosis: A Pilot Study. Clin Orthop Relat Res 468, 1978–1985 (2010). https://doi.org/10.1007/s11999-010-1321-9
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DOI: https://doi.org/10.1007/s11999-010-1321-9