Abstract
This study was performed to determine if a combination of previously undifferentiated bone marrow-derived mesenchymal stem cells (BMMSCs) and exogenous bone morphogenetic protein-2 (BMP-2) delivered via heparin-conjugated PLGA nanoparticles (HCPNs) would extensively regenerate bone in vivo. In vitro testing found that the HCPNs were able to release BMP-2 over a 2-week period. Human BMMSCs cultured in medium containing BMP-2-loaded HCPNs for 2 weeks differentiated toward osteogenic cells expressing alkaline phosphatase (ALP), osteopontin (OPN) and osteocalcin (OCN) mRNA, while cells without BMP-2 expressed only ALP. In vivo testing found that undifferentiated BMMSCs with BMP-2-loaded HCPNs induce far more extensive bone formation than either implantation of BMP-2-loaded HCPNs or osteogenically differentiated BMMSCs. This study demonstrates the feasibility of extensive in vivo bone regeneration by transplantation of undifferentiated BMMSCs and BMP-2 delivery via HCPNs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Rauch F, Lauzier D, Croteau S, Travers R, Glorieux FH, Hamdy R (2006) Temporal and spatial expression of bone morphogenetic protein-2, -4, and -7 during distraction osteogenesis in rabbits. Bone 26(6):611–617
Cowan CM, Aalami OO, Shi YY, Chou YF, Mari C, Thomas R, Quarto N, Nacamuli RP, Contag CH, Wu B, Longaker MT (2005) Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover. Tissue Eng 11(3–4):645–658
Chu TM, Warden SJ, Turner CH, Stewart RL (2007) Segmental bone regeneration using a load-bearing biodegradable carrier of bone morphogenetic protein-2. Biomaterials 28(3):459–467
Jones AL, Bucholz RW, Bosse MJ, Mirza SK, Lyon TR, Webb LX, Pollak AN, Golden JD, Valentin-Opran A (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(7):1431–1441
Villavicencio AT, Burneikiene S, Nelson EL, Bulsara KR, Favors M, Thramann J (2005) Safety of transforaminal lumbar interbody fusion and intervertebral recombinant human bone morphogenetic protein-2. J Neurosurg Spine 3(6):436–443
Tamama K, Fan VH, Griffith LG, Blair HC, Wells A (2006) Epidermal growth factor as a candidate for ex vivo expansion of bone marrow-derived mesenchymal stem cells. Stem Cells 24(3):686–695
Petite H, Viateau V, Bensaid W, Meunier A, de Pollak C, Bourguignon M, Oudina K, Sedel L, Guillemin G (2000) Tissue-engineered bone regeneration. Nat Biotechnol 18(9):959–963
Quarto R, Mastrogiacomo M, Cancedda R, Kutepov SM, Mukhachev V, Lavroukov A, Kon E, Marcacci M (2001) Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med 344(5):385–386
Boland GM, Perkins G, Hall DJ, Tuan RS (2004) Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem 93(6):1210–1230
Niemeyer P, Krause U, Fellenberg J, Kasten P, Seckinger A, Ho AD, Simank HG (2004) Evaluation of mineralized collagen and alpha-tricalcium phosphate as scaffolds for tissue engineering of bone using human mesenchymal stem cells. Cells Tissues Organs 177(2):68–78
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147
Song S, Jeon O, Yang H, Kim B (2007) The effects of culture conditions on osteogenic differentiation in human mesenchymal stem cells. J Microbiol Biotechnol 17(7):1113–1119
Yoshikawa T, Ohgushi H, Akahane M, Tamai S, Ichijima K (1998) Analysis of gene expression in osteogenic cultured marrow/hydroxyapatite construct implanted at ectopic sites: a comparison with the osteogenic ability of cancellous bone. J Biomed Mater Res 41(4):568–573
Ito C, Evans WE, McNinch L, Coustan-Smith E, Mahmoud H, Pui CH, Campana D (1996) Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. J Clin Oncol 14(8):2370–2376
Chung YI, Ahn KM, Jeon SH, Lee SY, Lee JH, Tae G (2007) Enhanced bone regeneration with BMP-2 loaded functional nanoparticle-hydrogel complex. J Control Release 121(1–2):91–99
Jeon O, Kang SW, Lim HW, Hyung Chung J, Kim BS (2006) Long-term and zero-order release of basic fibroblast growth factor from heparin-conjugated poly(L-lactide-co-glycolide) nanospheres and fibrin gel. Biomaterials 27(8):1598–1607
Zhao B, Katagiri T, Toyoda H, Takada T, Yanai T, Fukuda T, Chung UI, Koike T, Takaoka K, Kamijo R (2006) Heparin potentiates the in vivo ectopic bone formation induced by bone morphogenetic protein-2. J Biol Chem 281(32):23246–23253
Jeon O, Song SJ, Kang SW, Putnam AJ, Kim BS (2007) Enhancement of ectopic bone formation by bone morphogenetic protein-2 released from a heparin-conjugated poly(L-lactic-co-glycolic acid) scaffold. Biomaterials 28(17):2763–2771
Acknowledgments
This work was supported, in part, by grant No. R01-2006-000-10933-0 from the Basic Research Program of the Korea Science & Engineering Foundation and by School of Dentistry, Kyung Hee University.
Author information
Authors and Affiliations
Corresponding author
Additional information
Sung Eun Kim and Oju Jeon equally contributed to this work
Rights and permissions
About this article
Cite this article
Kim, S.E., Jeon, O., Lee, J.B. et al. Enhancement of ectopic bone formation by bone morphogenetic protein-2 delivery using heparin-conjugated PLGA nanoparticles with transplantation of bone marrow-derived mesenchymal stem cells. J Biomed Sci 15, 771–777 (2008). https://doi.org/10.1007/s11373-008-9277-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11373-008-9277-4