VEGF‐loaded mineral‐coated microparticles improve bone repair and are associated with increased expression of epo and RUNX‐2 in murine non‐unions

Abstract

A poor vascular supply of the fracture gap is a key factor for the development of atrophic non‐unions. Mineral‐coated microparticles (MCM) represent a sophisticated carrier system for the delivery of vascular endothelial growth factor (VEGF). Hence, we investigated whether VEGF‐loaded MCM improve bone repair in non‐unions. For this purpose, we analyzed binding and release kinetics of MCM for VEGF in vitro. Moreover, we applied VEGF‐loaded or ‐unloaded MCM in a murine non‐union model in vivo and studied the process of bone healing by means of biomechanical, radiological, histomorphometric, and Western blot techniques. MCM‐free non‐unions served as controls. The binding efficiency of MCM for VEGF was 46 ± 3% and the release profile revealed an initial minor burst release followed by a sustained release over a 50‐day study period, thus, mimicking the physiological expression profile of VEGF during bone healing. In vivo, bone defects treated with VEGF‐loaded MCM exhibited a higher bending stiffness, a higher fraction of bone volume/tissue volume and a larger callus area on days 14 and 70 when compared to the other groups. Western blot analyses on day 14 revealed a higher expression of VEGF, erythropoietin (EPO), and runt‐related transcription factor 2, but not of EPO‐receptor in bone defects treated with VEGF‐loaded MCM. These findings demonstrate that the use of MCM for VEGF delivery shows great potential due to the ability to maintain protein stability and functionality in vivo. Moreover, the application of VEGF‐loaded MCM represent a promising strategy for the treatment of non‐unions. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Flunixin Meglumine Enhanced Bone Fracture Healing in Rabbits Associated with Activation of Early Collagen Deposition and Enhancement of Vascular Endothelial Growth Factor Expression

“…More importantly, vascular supply at the fracture site is an essential step in the healing process since a good blood supply means plenty of the oxygen and nutrients required for fast healing [54]. Furthermore, the key physiological regulator of angiogenesis during embryogenesis and skeletal growth is VEGF [54,55]. A previous study revealed that FM stimulates angiogenesis in the wound site, enhancing tendon healing [23].…”

Combination of an allogenic and a xenogenic bone substitute material with injectable platelet-rich fibrin – A comparative in vitro study

“…Another possible approach analyzed by others may represent the use of single growth factors such as VEGF or PDGF to enhance healing. 40,41 However, due to high costs and strict regulations, the use of single growth factors in addition to BSM is not implemented up-to-date in the clinical pathway. The main prerequisites for ideal BSM are both ease of its handling and application as well as biological characteristics close to autologous bone.…”

Vascularization Strategies in the Prevention of Nonunion Formation

“…Its local application in bone defects has already been shown to successfully increase vascularization and bone formation. 133,[137][138][139][140][141] BMP-2 on the other hand, despite its ability of inducing bone formation, 142 lacks the capacity to initiate angiogenesis. 143 However, another protein from the BMP family, BMP-7, induces early graft remodeling by stimulating blood vessel formation and osteoclastic activity, as well as the expression of angiogenic and inflammatory cytokines.…”

“…The technique of the local delivery of those substances ranges from the direct injection into the fracture area, 140 the coating of scaffolds and bone allografts with growth factors, 134,135 the application of hydrogel formulations, microspheres, and microparticles loaded with specific cytokines [137][138][139]157,165 to the transfection with proangiogenic gene vectors. [166][167][168][169] The geneactivated matrix concept, for instance, involves the preloading of matrices with gene vectors to guarantee a sustainable release of DNA to ingrowing cells at the fracture site.…”