Effects of VEGF on Prefabricated Vascularized Bone Allografts in RatsFunding This study was supported by grant-in-aid for scientific research.
Background Massive bone defects after wide resection of malignant bone tumors or a serious injury require treatment using vascularized bone grafts. Although cadaveric bone allografts combined with vascularized bone autografts are currently thought to be ideal in terms of size and durability, this treatment requires the scarification of healthy bone tissue. In a previous study, we attempted to improve this situation by prefabricating a vascularized bone allograft in recipient rats. In this study, we added vascular endothelial growth factor (VEGF)-containing hydroxyapatite/collagen composite (HAp/Col) to a prefabricated vascularized bone allograft to stimulate angiogenesis, which is known to be important for bone formation.
Materials and Methods Sprague Dawley rats (n = 50) were used as donors and Wistar rats (n = 50) as recipients. All rats were 9 weeks old. The recipient rats were divided into five groups according to the use of vascular bundles, HAp/Col, and an additive substance (VEGF). The bone allografts collected from the donors were transplanted into the thigh region of the recipients, and a saphenous vein and 10 μg HAp/Col with VEGF were inserted into the bone allografts through the slit. After 4 weeks, the transplanted bone allografts were harvested, and histologic and genetic evaluations were performed in relation to bone formation and resorption.
Results The results showed that, compared with the control group, the implantation of the vascular bundles and VEGF-containing HAp/Col significantly stimulated angiogenesis and bone formation in the rats with the bone allografts. However, histological and genetic evaluations of bone resorption revealed that resorption was not observed in any group.
Conclusion These results suggest that VEGF-containing HAp/Col effectively stimulates angiogenesis and bone formation, but not bone resorption, in prefabricated vascularized bone allografts. This method could therefore become a useful tool for treating large bone defects.
Received: 14 January 2020
Accepted: 25 August 2020
14 October 2020 (online)
© 2020. Thieme. All rights reserved.
Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.
- 1 Weiland AJ. Current concepts review: vascularized free bone transplants. J Bone Joint Surg Am 1981; 63 (01) 166-169
- 2 Errani C, Ceruso M, Donati DM, Manfrini M. Microsurgical reconstruction with vascularized fibula and massive bone allograft for bone tumors. Eur J Orthop Surg Traumatol 2019; 29 (02) 307-311
- 3 Houdek MT, Rose PS, Milbrandt TA, Stans AA, Moran SL, Sim FH. Comparison of pediatric intercalary allograft reconstructions with and without a free vascularized fibula. Plast Reconstr Surg 2018; 142 (04) 1065-1071
- 4 Kotsougiani D, Hundepool CA, Bulstra LF, Friedrich PF, Shin AY, Bishop AT. Bone vascularized composite allotransplantation model in swine tibial defect: evaluation of surgical angiogenesis and transplant viability. Microsurgery 2019; 39 (02) 160-166
- 5 Nakamura O, Kaji Y, Imaizumi Y, Yamagami Y, Yamamoto T. Prefabrication of vascularized bone allograft in a recipient rat using a flow-through vascular pedicle, bone morphogenetic protein, and bisphosphonate. J Reconstr Microsurg 2013; 29 (04) 241-248
- 6 Kanatani M, Sugimoto T, Kaji H. et al. Stimulatory effect of bone morphogenetic protein-2 on osteoclast-like cell formation and bone-resorbing activity. J Bone Miner Res 1995; 10 (11) 1681-1690
- 7 Kaneko H, Arakawa T, Mano H. et al. Direct stimulation of osteoclastic bone resorption by bone morphogenetic protein (BMP)-2 and expression of BMP receptors in mature osteoclasts. Bone 2000; 27 (04) 479-486
- 8 Nicosia RF, Nicosia SV, Smith M. Vascular endothelial growth factor, platelet-derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro. Am J Pathol 1994; 145 (05) 1023-1029
- 9 Percival CJ, Richtsmeier JT. Angiogenesis and intramembranous osteogenesis. Dev Dyn 2013; 242 (08) 909-922
- 10 Ishii I, Mizuta H, Sei A, Hirose J, Kudo S, Hiraki Y. Healing of full-thickness defects of the articular cartilage in rabbits using fibroblast growth factor-2 and a fibrin sealant. J Bone Joint Surg Br 2007; 89 (05) 693-700
- 11 Yamaguchi K, Kaji Y, Nakamura O, Tobiume S, Yamamoto T. Prefabrication of vascularized allogenic bone graft in a rat by implanting a flow-through vascular pedicle and basic fibroblast growth factor containing hydroxyapatite/collagen composite. J Reconstr Microsurg 2017; 33 (05) 367-376
- 12 Mesri EA, Federoff HJ, Brownlee M. Expression of vascular endothelial growth factor from a defective herpes simplex virus type 1 amplicon vector induces angiogenesis in mice. Circ Res 1995; 76 (02) 161-167
- 13 Sivaraj KK, Adams RH. Blood vessel formation and function in bone. Development 2016; 143 (15) 2706-2715
- 14 Midy V, Plouët J. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem Biophys Res Commun 1994; 199 (01) 380-386
- 15 Street J, Bao M, deGuzman L. et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A 2002; 99 (15) 9656-9661
- 16 Duan X, Bradbury SR, Olsen BR, Berendsen AD. VEGF stimulates intramembranous bone formation during craniofacial skeletal development. Matrix Biol 2016; 52-54: 127-140
- 17 Lazarous DF, Shou M, Scheinowitz M. et al. Comparative effects of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. Circulation 1996; 94 (05) 1074-1082
- 18 Kikuchi M, Itoh S, Ichinose S, Shinomiya K, Tanaka J. Self-organization mechanism in a bone-like hydroxyapatite/collagen nanocomposite synthesized in vitro and its biological reaction in vivo. Biomaterials 2001; 22 (13) 1705-1711
- 19 Itoh S, Kikuchi M, Takakuda K. et al. 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 (03) 445-453
- 20 Campbell KT, Hadley DJ, Kukis DL, Silva EA. Alginate hydrogels allow for bioactive and sustained release of VEGF-C and VEGF-D for lymphangiogenic therapeutic applications. PLoS One 2017; 12 (07) e0181484
- 21 Li Z, Qu T, Ding C. et al. Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis. Acta Biomater 2015; 13: 88-100
- 22 Mohandas A, Anisha BS, Chennazhi KP, Jayakumar R. Chitosan-hyaluronic acid/VEGF loaded fibrin nanoparticles composite sponges for enhancing angiogenesis in wounds. Colloids Surf B Biointerfaces 2015; 127: 105-113
- 23 Pacelli S, Acosta F, Chakravarti AR. et al. Nanodiamond-based injectable hydrogel for sustained growth factor release: Preparation, characterization and in vitro analysis. Acta Biomater 2017; 58: 479-491
- 24 Hu K, Olsen BR. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest 2016; 126 (02) 509-526
- 25 Nakagawa M, Kaneda T, Arakawa T. et al. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett 2000; 473 (02) 161-164
- 26 Niida S, Kaku M, Amano H. et al. Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption. J Exp Med 1999; 190 (02) 293-298
- 27 Enoki Y, Sato T, Tanaka S. et al. Netrin-4 derived from murine vascular endothelial cells inhibits osteoclast differentiation in vitro and prevents bone loss in vivo. FEBS Lett 2014; 588 (14) 2262-2269