Preparation and Biocompatibility of Core-Shell Microspheres for Sequential, Sustained Release of BMP-2 and VEGF

Abstract

Bone defect repair remains a challenge in orthopedics. This study describes the development and potential effectiveness of vascular endothelial growth factor (VEGF)/bone morphogenetic protein-2 (BMP-2) shell-core microspheres for promoting bone regeneration. Poly(L-lactic acid)/polylactic-co-glycolic acid (PLLA/PLGA) core-shell microspheres loaded with VEGF and BMP-2 were prepared by a coaxial electrospray technique, and their surface morphology, core-shell distribution, and particle size were examined. Different groups of microspheres were prepared with different placement of the growth factors, and the encapsulation efficiency and in vitro release curves were measured. Additionally, the effects of the different groups of microspheres on the proliferation and differentiation of osteoblasts and vascular endothelial cells were investigated. The prepared microspheres had a core-shell structure with good homogeneity and dispersion, a clear boundary, and a smooth surface. On scanning electron microscopy, the mean diameter of the microspheres was similar for all six preparations ( P > 0.05 ). During in vitro release, growth factor was initially released via a brief burst release from the outer shell of the microsphere followed by a slower sustained release. The release of growth factors from the inner core remained relatively slow and sustained. Sequential release of different growth factors was achieved through the inconsistent release rates from the microsphere shell and inner core. All groups of microspheres showed no cytotoxicity, good biocompatibility, and the ability to promote osteoblast proliferation. The microspheres loaded with BMP-2 also promoted osteoblast differentiation, and VEGF-loaded microspheres promoted the proliferation and differentiation of vascular endothelial cells. The BMP-2 (core)/VEGF (shell) microsphere group best promoted osteoblast differentiation. The microspheres prepared in this study exhibited slow sequential release of BMP-2 and VEGF and showed good biocompatibility along with the ability to promote osteoblast differentiation and vascular endothelial cell proliferation.

Cascaded controlled delivering growth factors to build vascularized and osteogenic microenvironment for bone regeneration

“…In addition, VEGF is expressed in the early stages of natural bone repair [ 19 , 34 ], regulates the formation of vascular networks, and brings critical elements for subsequent bone formation, including oxygen, osteoblast progenitor cells, and nutrients. BMP-2 is observed subsequent to the formation of the fully developed vascular network [ 35 , 36 ] subsequently enhancing the expression of Runx2, which in turn stimulates the synthesis of bone sialoprotein (BSP), OCN, and OPN, thereby initiating the process of bone mineralization. Consequently, in order to effectively replicate the natural bone healing process, it is imperative for bone biomaterials to possess the capability of releasing multiple cytokines in a sustained and organized manner [ 37 ].…”

The Sequential and Systemic Administration of BMP-2 and SDF-1α Nanocapsules for Promoting Osteoporotic Fracture Healing

“…Therefore, in the elderly, the above degenerative repair ability has caused terrible clinical problems such as delayed healing, nonunion, and even high disability and mortality [ 16 ]. BMP-2 has been shown to have a strong ability to promote bone repair in vivo [ 17 ]. In addition, SDF-1α was known to have the strongest ability to promote vascularization and also had the effect of promoting osteogenesis [ 18 ].…”

Advances and Trends of Photoresponsive Hydrogels for Bone Tissue Engineering

“…Angiogenesis and osteogenesis are highly coupled, and the formation of new blood vessels in implanted scaffolds is critical for the adequate supply of nutrients, the transport of oxygen, the recruitment of cells to the injured site, and the removal of waste products during bone repair . Various delivery systems have been utilized for delivering VEGF and BMP-2 sequentially . However, owing to the dose- and time-dependent activity of biomolecules, codelivery of VEGF and BMP-2 does not always result in synergistic bone regeneration.…”

“…209 Various delivery systems have been utilized for delivering VEGF and BMP-2 sequentially. 210 However, owing to the dose-and time-dependent activity of biomolecules, codelivery of VEGF and BMP-2 does not always result in synergistic bone regeneration. For example, Kempen et al found no significant effect of higher bone formation by the codelivery of VEGF and BMP-2, compared to BMP-2 alone.…”