Abstract
Mandible defect is a difficult issue in dental surgery owing to limited therapeutic options. Recombinant human bone morphogenetic protein-2 (rhBMP2) is osteoinductive in bone regeneration. This article prepared chitosan/collagen hydrogels with rhBMP2-incorporated gelatin microsphere (GMs) for a sustained release of rhBMP2 to induce bone regeneration in rabbits. In experiments, mandibular defects of 8 mm in diameter and 3 mm in depth were surgically prepared on the right cheek of 27 rabbits. Either chitosan/collagen hydrogels alone, rhBMP2-incorporated hydrogels, or hydrogels with rhBMP2-incorporated GMs were implanted to the defect sites. The animals were euthanized at 2, 6, 12 weeks following surgery. In results, scanning electronic microscope images revealled spherical GMs. The complex delivery systems, hydrogels with rhBMP2-incorporated GMs, exhibited ideal release profiles in vitro. The complex delivery systems resulted in apparent new bone formation within 12 weeks, as evidenced by computed tomography and histological observations. All these results demonstrated that the chitosan/collagen hydrogels with rhBMP2-incorporated GMs had a better capacity to heal mandible defects than other two hydrogel scaffolds. Chitosan/collagen hydrogels with rhBMP2-incorporated GMs might be potential carriers of rhBMP2 for accelerating the repair of mandibular defects.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Cheng G, Li Z, Wan Q, Lv K, Li D, Xing X, et al. A novel animal model treated with tooth extraction to repair the full-thickness defects in the mandible of rabbits. J Surg Res 2015;194:706–716.
Li ZJ, Lu CT, Feng ZQ, Zhao QT, Zhou ZY, Lai RF. Antigen-extracted xenogeneic cancellous bone graft with recombinant human bone morphogenetic protein-2 enhances bone regeneration in repair of mandibular defect in rabbits. Kaohsiung J Med Sci 2015;31:18–25.
Yun YP, Lee SY, Kim HJ, Song JJ, Kim SE. Improvement of osteoblast functions by sustained release of bone morphogenetic protein-2 (BMP-2) from heparin-coated chitosan scaffold. Tissue Eng Regen Med 2013;10:183–191.
Sun B, Ma W, Su F, Wang Y, Liu J, Wang D, et al. The osteogenic differentiation of dog bone marrow mesenchymal stem cells in a thermo-sensitive injectable chitosan/collagen/β-glycerophosphate hydrogel: in vitro and in vivo. J Mater Sci Mater Med 2011;22:2111–2118.
Luca L, Rougemont AL, Walpoth BH, Boure L, Tami A, Anderson JM, et al. Injectable rhBMP-2-loaded chitosan hydrogel composite: osteoinduction at ectopic site and in segmental long bone defect. J Biomed Mater Res A 2011;96:66–74.
Jung UW, Lee IK, Park JY, Thoma DS, Hämmerle CH, Jung RE. The efficacy of BMP-2 preloaded on bone substitute or hydrogel for bone regeneration at peri-implant defects in dogs. Clin Oral Implants Res 2015;26:1456–1465.
Liu X, Zhao K, Gong T, Song J, Bao C, Luo E, et al. Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect. Biomacromolecules 2014;15:1019–1030.
Mirahmadi F, Tafazzoli-Shadpour M, Shokrgozar MA, Bonakdar S. Enhanced mechanical properties of thermosensitive chitosan hydrogel by silk fibers for cartilage tissue engineering. Mater Sci Eng C Mater Biol Appl 2013;33:4786–4794.
Ding K, Yang Z, Zhang YL, Xu JZ. Injectable thermosensitive chitosan/β-glycerophosphate/collagen hydrogel maintains the plasticity of skeletal muscle satellite cells and supports their in vivo viability. Cell Biol Int 2013;37:977–987.
Yun YP, Yang DH, Kim SW, Park K, Ohe JY, Lee BS, et al. Local delivery of recombinant human bone morphogenic protein-2 (rhBMP-2) from rhBMP-2/heparin complex fixed to a chitosan scaffold enhances osteoblast behavior. Tissue Eng Regen Med 2014;11:163–170.
Huang H, Zhang X, Hu X, Dai L, Zhu J, Man Z, et al. Directing chondrogenic differentiation of mesenchymal stem cells with a solid-supported chitosan thermogel for cartilage tissue engineering. Biomed Mater 2014;9:035008.
Yunoki S, Ohyabu Y, Hatayama H. Temperature-responsive gelation of type I collagen solutions involving fibril formation and genipin crosslinking as a potential injectable hydrogel. Int J Biomater 2013;2013:620765.
Yang IA, Fong KM, Sim EH, Black PN, Lasserson TJ. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007;(2):CD002991.
Kodali A, Lim TC, Leong DT, Tong YW. Cell-microsphere constructs formed with human adipose-derived stem cells and gelatin microspheres promotes stemness, differentiation, and controlled pro-angiogenic potential. Macromol Biosci 2014;14:1458–1468.
Kim S, Kang Y, Krueger CA, Sen M, Holcomb JB, Chen D, et al. Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with gelatin microspheres enhances early osteoblastic differentiation. Acta Biomater 2012;8:1768–1777.
Rajan N, Habermehl J, Coté MF, Doillon CJ, Mantovani D. Preparation of ready-to-use, storable and reconstituted type I collagen from rat tail tendon for tissue engineering applications. Nat Protoc 2006;1:2753–2758.
Wang L, Stegemann JP. Thermogelling chitosan and collagen composite hydrogels initiated with beta-glycerophosphate for bone tissue engineering. Biomaterials 2010;31:3976–3985.
Patel ZS, Yamamoto M, Ueda H, Tabata Y, Mikos AG. Biodegradable gelatin microparticles as delivery systems for the controlled release of bone morphogenetic protein-2. Acta Biomater 2008;4:1126–1138.
Xu M, Zhang X, Meng S, Dai X, Han B, Deng X. Enhanced critical size defect repair in rabbit mandible by electrospun gelatin/β-TCP composite nanofibrous membranes. J Nanomater 2015;2015:1–9.
Kim J, Yang HJ, Cho TH, Lee SE, Park YD, Kim HM, et al. Enhanced regeneration of rabbit mandibular defects through a combined treatment of electrical stimulation and rhBMP-2 application. Med Biol Eng Comput 2013;51:1339–1348.
Srouji S, Rachmiel A, Blumenfeld I, Livne E. Mandibular defect repair by TGF-beta and IGF-1 released from a biodegradable osteoconductive hydrogel. J Craniomaxillofac Surg 2005;33:79–84.
Hou J, Wang J, Cao L, Qian X, Xing W, Lu J, et al. Segmental bone regeneration using rhBMP-2-loaded collagen/chitosan microspheres composite scaffold in a rabbit model. Biomed Mater 2012;7:035002.
Zamora DO, Natesan S, Christy RJ. Constructing a collagen hydrogel for the delivery of stem cell-loaded chitosan microspheres. J Vis Exp 2012; (64):e3624.
Dreifke MB, Ebraheim NA, Jayasuriya AC. Investigation of potential injectable polymeric biomaterials for bone regeneration. J Biomed Mater Res A 2013;101:2436–2447.
Yao L, Phan F, Li Y. Collagen microsphere serving as a cell carrier supports oligodendrocyte progenitor cell growth and differentiation for neurite myelination in vitro. Stem Cell Res Ther 2013;4:109.
Niu X, Feng Q, Wang M, Guo X, Zheng Q. Porous nano-HA/collagen/PLLA scaffold containing chitosan microspheres for controlled delivery of synthetic peptide derived from BMP-2. J Control Release 2009;134:111–117.
Li W, Lan Y, Guo R, Zhang Y, Xue W, Zhang Y. In vitro and in vivo evaluation of a novel collagen/cellulose nanocrystals scaffold for achieving the sustained release of basic fibroblast growth factor. J Biomater Appl 2015;29:882–893.
Yao AH, Li XD, Xiong L, Zeng JH, Xu J, Wang DP. Hollow hydroxyapatite microspheres/chitosan composite as a sustained delivery vehicle for rhBMP-2 in the treatment of bone defects. J Mater Sci Mater Med 2015;26:5336.
Wu Y, Hou J, Yin M, Wang J, Liu C. Enhanced healing of rabbit segmental radius defects with surface-coated calcium phosphate cement/bone morphogenetic protein-2 scaffolds. Mater Sci Eng C Mater Biol Appl 2014;44:326–335.
Gao L, Gan H, Meng Z, Gu R, Wu Z, Zhang L, et al. Effects of genipin cross-linking of chitosan hydrogels on cellular adhesion and viability. Colloids Surf B Biointerfaces 2014;117:398–405.
Moroi A, Ueki K, Okabe K, Marukawa K, Sotobori M, Mukozawa A, et al. Comparison between unsintered hydroxyapatite/poly-L-lactic acid mesh and titanium mesh in bone regeneration of rabbit mandible. Implant Dent 2013;22:255–262.
Huh JY, Choi BH, Kim BY, Lee SH, Zhu SJ, Jung JH. Critical size defect in the canine mandible. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:296–301.
Alfotawei R, Naudi KB, Lappin D, Barbenel J, Di Silvio L, Hunter K, et al. The use of TriCalcium Phosphate (TCP) and stem cells for the regeneration of osteoperiosteal critical-size mandibular bony defects, an in vitro and preclinical study. J Craniomaxillofac Surg 2014;42:863–869.
Wikesjö UM, Guglielmoni P, Promsudthi A, Cho KS, Trombelli L, Selvig KA, et al. Periodontal repair in dogs: effect of rhBMP-2 concentration on regeneration of alveolar bone and periodontal attachment. J Clin Periodontol 1999;26:392–400.
Wikesjö UM, Susin C, Qahash M, Polimeni G, Leknes KN, Shanaman RH, et al. The critical-size supraalveolar peri-implant defect model: characteristics and use. J Clin Periodontol 2006;33:846–854.
Author information
Authors and Affiliations
Corresponding authors
Additional information
These authors contributed equally to this work.
Rights and permissions
About this article
Cite this article
Song, WY., Liu, GM., Li, J. et al. Bone morphogenetic protein-2 sustained delivery by hydrogels with microspheres repairs rabbit mandibular defects. Tissue Eng Regen Med 13, 750–761 (2016). https://doi.org/10.1007/s13770-016-9123-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13770-016-9123-0