Abstract
Administration of bone morphogenetic protein-2 (BMP-2), which is commercially approved by the food and drug administration to damaged bone sites has been investigated for the purpose of bone tissue regeneration. BMP-2 can promote osteoblastic differentiation of mesenchymal stem cells as well as regeneration of bone formation in early phase. This review highlights various factors such as vitamin D, dexamethasone, platelet-derived growth factor, placental growth factor, BMP-7, and NEL-like protein-1 that enhance and stimulate angiogenesis, cell differentiation, and bone regeneration. These biochemical signals and growth factors (GFs) accelerate bone repair and remodeling either synergistically or individually. Delivery systems and scaffolds are used for sustained release of these cargo molecules and support at damaged bone sites. Compared with direct administration of BMP-2, current studies have demonstrated that a combination of multiple GFs and/or therapeutic chemical factors with delivery platforms synergistically facilitates bone regeneration. Therefore, in the future, multiple combinations of various GFs, chemicals, and materials could provide patients and surgeons with non-invasive treatment options without secondary surgery and pain. To the end, this review summarizes the biological functions and synergistic effects of dual administration modalities involving BMP-2 as well as recent developments in bone tissue engineering applications.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Brigaud I, Agniel R, Leroy-Dudal J, Kellouche S, Ponche A, Bouceba T, Mihailescu N, Sopronyi M, Viguier E, Ristoscu C, Sima F, Mihailescu IN, Carreira ACO, Sogayar MC, Gallet O, Anselme K (2017) Synergistic effects of BMP-2, BMP-6 or BMP-7 with human plasma fibronectin onto hydroxyapatite coatings: a comparative study. Acta Biomater 55:481–492
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307
Chang J, Sonoyama W, Wang Z, Jin Q, Zhang C, Krebsbach PH, Giannobile W, Shi S, Wang CY (2007) Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. J Biol Chem 282(42):30938–30948
Chen Y, Kawazoe N, Chen G (2017) Preparation of dexamethasone-loaded biphasic calcium phosphate nanoparticles/collagen porous composite scaffolds for bone tissue engineering. Acta Biomater 67:341–353
Chenard KE, Teven CM, He TC, Reid RR (2012) Bone morphogenetic proteins in craniofacial surgery: current techniques, clinical experiences, and the future of personalized stem cell therapy. J Biomed Biotechnol 2012:601549
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(3):513–520
Choi DH, Park CH, Kim IH, Chun HJ, Park K, Han DK (2010) Fabrication of core-shell microcapsules using PLGA and alginate for dual growth factor delivery system. J Control Release 147(2):193–201
Choi H, Jeong BC, Hur SW, Kim JW, Lee KB, Koh JT (2015) The angiopoietin-1 variant COMP-Ang1 enhances BMP2-induced bone regeneration with recruiting pericytes in critical sized calvarial defects. PLoS One 10(10):e0140502
Chubinskaya S, Hurtig M, Rueger DC (2007) OP-1/BMP-7 in cartilage repair. Int Orthop 31(6):773–781
Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480
Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS (2008) The cell biology of bone metabolism. J Clin Pathol 61(5):577–587
Demirtas TT, Goz E, Karakecili A, Gumusderelioglu M (2016) Combined delivery of PDGF-BB and BMP-6 for enhanced osteoblastic differentiation. J Mater Sci Mater Med 27(1):12
Duarte RM, Varanda P, Reis RL, Duarte ARC, Correia-Pinto J (2017) Biomaterials and bioactive agents in spinal fusion. Tissue Eng Part B Rev 23(6):540–551
Dusso AS, Brown AJ, Slatopolsky E (2005) Vitamin D. Am J Physiol Renal Physiol 289(1):F8–F28
Fahmy-Garcia S, van Driel M, Witte-Buoma J, Walles H, van Leeuwen J, van Osch G, Farrell E (2017) NELL-1, HMGB1, and CCN2 enhance migration and vasculogenesis, but not osteogenic differentiation compared to BMP2. Tissue Eng Part A 24:207–218
Fernandes G, Wang C, Yuan X, Liu Z, Dziak R, Yang S (2016) Combination of controlled release platelet-rich plasma alginate beads and bone morphogenetic protein-2 genetically modified mesenchymal stem cells for bone regeneration. J Periodontol 87(4):470–480
Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131(3):463–475
Guney A, Akar M, Karaman I, Oner M, Guney B (2015) Clinical outcomes of platelet rich plasma (PRP) as an adjunct to microfracture surgery in osteochondral lesions of the talus. Knee Surg Sports Traumatol Arthrosc 23(8):2384–2389
Halvorsen YD, Franklin D, Bond AL, Hitt DC, Auchter C, Boskey AL, Paschalis EP, Wilkison WO, Gimble JM (2001) Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue-derived stromal cells. Tissue Eng 7(6):729–741
Hamidouche Z, Fromigue O, Nuber U, Vaudin P, Pages JC, Ebert R, Jakob F, Miraoui H, Marie PJ (2010) Autocrine fibroblast growth factor 18 mediates dexamethasone-induced osteogenic differentiation of murine mesenchymal stem cells. J Cell Physiol 224(2):509–515
Heldin CH, Miyazono K, ten Dijke P (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390(6659):465–471
Jain RK, Xu L (2007) alphaPlGF: a new kid on the antiangiogenesis block. Cell 131(3):443–445
James AW, Lachaud G, Shen J, Asatrian G, Nguyen V, Zhang X, Ting K, Soo C (2016) A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng Part B Rev 22(4):284–297
James AW, Shen J, Zhang X, Asatrian G, Goyal R, Kwak JH, Jiang L, Bengs B, Culiat CT, Turner AS, Seim Iii HB, Wu BM, Lyons K, Adams JS, Ting K, Soo C (2015) NELL-1 in the treatment of osteoporotic bone loss. Nat Commun 6:7362
Jo JY, Jeong SI, Shin YM, Kang SS, Kim SE, Jeong CM, Huh JB (2015) Sequential delivery of BMP-2 and BMP-7 for bone regeneration using a heparinized collagen membrane. Int J Oral Maxillofac Surg 44(7):921–928
Kim K, Dean D, Wallace J, Breithaupt R, Mikos AG, Fisher JP (2011) The influence of stereolithographic scaffold architecture and composition on osteogenic signal expression with rat bone marrow stromal cells. Biomaterials 32(15):3750–3763
Kim K, Yeatts A, Dean D, Fisher JP (2010) Stereolithographic bone scaffold design parameters: osteogenic differentiation and signal expression. Tissue Eng Part B Rev 16(5):523–539
Kneser U, Schaefer DJ, Polykandriotis E, Horch RE (2006) Tissue engineering of bone: the reconstructive surgeon's point of view. J Cell Mol Med 10(1):7–19
Kohara H, Tabata Y (2011) Enhancement of ectopic osteoid formation following the dual release of bone morphogenetic protein 2 and Wnt1 inducible signaling pathway protein 1 from gelatin sponges. Biomaterials 32(24):5726–5732
Kuroda S, Oyasu M, Kawakami M, Kanayama N, Tanizawa K, Saito N, Abe T, Matsuhashi S, Ting K (1999) Biochemical characterization and expression analysis of neural thrombospondin-1-like proteins NELL1 and NELL2. Biochem Biophys Res Commun 265(1):79–86
Kwak JH, Zhang Y, Park J, Chen E, Shen J, Chawan C, Tanjaya J, Lee S, Zhang X, Wu BM, Ting K, Soo C (2015) Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration. Biomaterials 57:73–83
Langenbach F, Handschel J (2013) Effects of dexamethasone, ascorbic acid and beta-glycerophosphate on the osteogenic differentiation of stem cells in vitro. Stem Cell Res Ther 4(5):117
Lee S, Zhang X, Shen J, James AW, Chung CG, Hardy R, Li C, Girgius C, Zhang Y, Stoker D, Wang H, Wu BM, Peault B, Ting K, Soo C (2015) Brief report: human perivascular stem cells and nel-like protein-1 synergistically enhance spinal fusion in osteoporotic rats. Stem Cells 33(10):3158–3163
Li CS, Zhang X, Peault B, Jiang J, Ting K, Soo C, Zhou YH (2016) Accelerated chondrogenic differentiation of human perivascular stem cells with NELL-1. Tissue Eng Part A 22(3–4):272–285
Li L, Zhou G, Wang Y, Yang G, Ding S, Zhou S (2015) Controlled dual delivery of BMP-2 and dexamethasone by nanoparticle-embedded electrospun nanofibers for the efficient repair of critical-sized rat calvarial defect. Biomaterials 37:218–229
Liu M, Wang Q, Tang R, Cao R, Wang X (2016a) Nel-like molecule 1 contributes to the odontoblastic differentiation of human dental pulp cells. J Endod 42(1):95–100
Liu Y, Deng LZ, Sun HP, Xu JY, Li YM, Xie X, Zhang LM, Deng FL (2016b) Sustained dual release of placental growth factor-2 and bone morphogenic protein-2 from heparin-based nanocomplexes for direct osteogenesis. Int J Nanomedicine 11:1147–1158
Marrony S, Bassilana F, Seuwen K, Keller H (2003) Bone morphogenetic protein 2 induces placental growth factor in mesenchymal stem cells. Bone 33(3):426–433
Marx RE, Carlson ER, Eichstaedt RM, Schimmele SR, Strauss JE, Georgeff KR (1998) Platelet-rich plasma: growth factor enhancement for bone grafts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85(6):638–646
McCoy RJ, Widaa A, Watters KM, Wuerstle M, Stallings RL, Duffy GP, O'Brien FJ (2013) Orchestrating osteogenic differentiation of mesenchymal stem cells--identification of placental growth factor as a mechanosensitive gene with a pro-osteogenic role. Stem Cells 31(11):2420–2431
Minear S, Leucht P, Jiang J, Liu B, Zeng A, Fuerer C, Nusse R, Helms JA (2010) Wnt proteins promote bone regeneration. Sci Transl Med 2(29):29ra30
Pakvasa M, Alverdy A, Mostafa S, Wang E, Fu L, Li A, Oliveira L, Athiviraham A, Lee MJ, Wolf JM, He TC, Ameer GA, Reid RR (2017) Neural EGF-like protein 1 (NELL-1): signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine. Genes Dis 4(3):127–137
Park J, Kim S, Kim K (2018) Bone morphogenetic protein-2 associated multiple growth factor delivery for bone tissue regeneration. J Pharm Investig
Perikamana SK, Lee J, Ahmad T, Jeong Y, Kim DG, Kim K, Shin H (2015) Effects of immobilized BMP-2 and nanofiber morphology on in vitro osteogenic differentiation of hMSCs and in vivo collagen assembly of regenerated bone. ACS Appl Mater Interfaces 7(16):8798–8808
Polakis P (2012) Wnt signaling in cancer. Cold Spring Harb Perspect Biol 4(5):a008052
Raina DB, Larsson D, Mrkonjic F, Isaksson H, Kumar A, Lidgren L, Tagil M (2018) Gelatin- hydroxyapatite- calcium sulphate based biomaterial for long term sustained delivery of bone morphogenic protein-2 and zoledronic acid for increased bone formation: in-vitro and in-vivo carrier properties. J Control Release 272:83–96
Roffi A, Di Matteo B, Krishnakumar GS, Kon E, Filardo G (2017) Platelet-rich plasma for the treatment of bone defects: from pre-clinical rational to evidence in the clinical practice. A systematic review. Int Orthop 41(2):221–237
Salazar VS, Gamer LW, Rosen V (2016) BMP signalling in skeletal development, disease and repair. Nat Rev Endocrinol 12(4):203–221
Samorezov JE, Alsberg E (2015) Spatial regulation of controlled bioactive factor delivery for bone tissue engineering. Adv Drug Deliv Rev 84:45–67
Samuel S, Sitrin MD (2008) Vitamin D's role in cell proliferation and differentiation. Nutr Rev 66(10 Suppl 2):S116–S124
Shah NJ, Hyder MN, Quadir MA, Dorval Courchesne NM, Seeherman HJ, Nevins M, Spector M, Hammond PT (2014) Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction. Proc Natl Acad Sci U S A 111(35):12847–12852
Song I, Kim BS, Kim CS, Im GI (2011) Effects of BMP-2 and vitamin D3 on the osteogenic differentiation of adipose stem cells. Biochem Biophys Res Commun 408(1):126–131
Stevens B, Yang Y, Mohandas A, Stucker B, Nguyen KT (2008) A review of materials, fabrication methods, and strategies used to enhance bone regeneration in engineered bone tissues. J Biomed Mater Res B Appl Biomater 85(2):573–582
Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87(7):1171–1180
Tan LL, Yu XM, Wan P, Yang K (2013) Biodegradable materials for bone repairs: a review. Journal of Materials Science & Technology 29(6):503–513
van Driel M, Koedam M, Buurman CJ, Roelse M, Weyts F, Chiba H, Uitterlinden AG, Pols HA, van Leeuwen JP (2006) Evidence that both 1alpha,25-dihydroxyvitamin D3 and 24-hydroxylated D3 enhance human osteoblast differentiation and mineralization. J Cell Biochem 99(3):922–935
Wozney JM (2002) Overview of bone morphogenetic proteins. Spine (Phila Pa 1976) 27(16 Suppl 1):S2–S8
Yilgor P, Tuzlakoglu K, Reis RL, Hasirci N, Hasirci V (2009) Incorporation of a sequential BMP-2/BMP-7 delivery system into chitosan-based scaffolds for bone tissue engineering. Biomaterials 30(21):3551–3559
Zhang W, Wang X, Wang S, Zhao J, Xu L, Zhu C, Zeng D, Chen J, Zhang Z, Kaplan DL, Jiang X (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(35):9415–9424
Zhang X, Kuroda S, Carpenter D, Nishimura I, Soo C, Moats R, Iida K, Wisner E, Hu FY, Miao S, Beanes S, Dang C, Vastardis H, Longaker M, Tanizawa K, Kanayama N, Saito N, Ting K (2002) Craniosynostosis in transgenic mice overexpressing Nell-1. J Clin Invest 110(6):861–870
Zhang Y, Dong R, Park Y, Bohner M, Zhang X, Ting K, Soo C, Wu BM (2016) Controlled release of NELL-1 protein from chitosan/hydroxyapatite-modified TCP particles. Int J Pharm 511(1):79–89
Zhu S, Song D, Jiang X, Zhou H, Hu J (2011) Combined effects of recombinant human BMP-2 and Nell-1 on bone regeneration in rapid distraction osteogenesis of rabbit tibia. Injury 42(12):1467–1473
Acknowledgment
This research was supported by Incheon National University Research Grant (2015).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Kim, S., Lee, S., Kim, K. (2018). Bone Tissue Engineering Strategies in Co-Delivery of Bone Morphogenetic Protein-2 and Biochemical Signaling Factors. In: Chun, H., Park, C., Kwon, I., Khang, G. (eds) Cutting-Edge Enabling Technologies for Regenerative Medicine. Advances in Experimental Medicine and Biology, vol 1078. Springer, Singapore. https://doi.org/10.1007/978-981-13-0950-2_12
Download citation
DOI: https://doi.org/10.1007/978-981-13-0950-2_12
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-13-0949-6
Online ISBN: 978-981-13-0950-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)