Abstract
In bone remodeling, osteogenesis is closely coupled to angiogenesis. Bone tissue engineering using multifunctional bioactive materials is a promising technique which has the ability to simultaneously stimulate osteogenesis and angiogenesis for repair of bone defects. We developed mesoporous bioactive glass (MBG)-doped poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) composite scaffolds as delivery vehicle. Two bioactive molecules, dimethyloxalylglycine (DMOG), a small-molecule angiogenic drug, and recombinant human bone morphogenetic protein-2 (rhBMP-2), an osteoinductive growth factor, were co-incorporated into the scaffold. The synergistic effects of DMOG and rhBMP-2 released in the composite scaffolds on osteogenic and angiogenic differentiation of hBMSCs were investigated using real-time quantitative polymerase chain reaction and western blotting. Moreover, in vivo studies were conducted to observe bone regeneration and vascular formation of critical-sized bone defects in rats using micro-computed tomography, histological analyses, Microfil® perfusion, fluorescence labeling, and immunohistochemical analysis. The results showed that DMOG and rhBMP-2 released in the MBG-PHBHHx scaffolds did exert synergistic effects on the osteogenic and angiogenic differentiation of hBMSCs. Moreover, DMOG and rhBMP-2 produced significant increases in newly-formed bone and neovascularization of calvarial bone defects in rats. It is concluded that the co-delivery strategy of both rhBMP-2 and DMOG can significantly improve the critical-sized bone regeneration.
Highlights
By factors such as the short half-life of the protein and its easy deactivation
Composite PHMG scaffolds with hierarchical pore structures were fabricated for their improved cellular affinity compared to a pure polymeric matrix, as well as their toughness compared to the fragile porous mesoporous bioactive glass (MBG)
BV/TV showed the same tendency as the bone mineral density (BMD) levels (Fig. 5F), i.e. there was a significant difference in the PHMBD group compared with the PHMD and PHMB groups (P < 0.05), and a significant difference between the PHMB and PHMD groups (P < 0.05). These results indicate that DMOG and rhBMP-2 released in the PHMBD group can synergistically improve bone regeneration compared with the other groups, which was consistent with the results of the real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting analysis
Summary
By factors such as the short half-life of the protein and its easy deactivation. design of a releasing system, as well as prolongation of the half-life, are needed before a biomaterial scaffold can be developed for the treatment of bone defects. Qu et al.[15] demonstrated that angiogenesis and osteogenesis enhanced by ex vivo gene therapy using basic fibroblast growth factor could serve as a form of bone tissue engineering for the reconstruction of calvarial defects These approaches still have many limitations, such as high cost and easy deactivation, and ways to promote the angiogenesis and vascularization of these bone constructs remains a big challenge. Min et al.[22] have reported that 3D-printed DMOG-loaded mesoporous bioactive glass (MBG)/poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) composite scaffolds can promote blood vessel growth and bone regeneration in vivo. Motivated by these previous investigations, we propose the concept of combination treatments of osteogenesis and angiogenesis via simultaneous co-delivery of rhBMP-2 and DMOG. This study has the following four groups: pure MBG-PHBHHx scaffolds were named PHMG, BMP-2 +MBG-PHBHHx scaffolds were named PHMB, DMOG +MBG-PHBHHx scaffolds were named PHMD and BMP-2 +DMOG +MBG-PHBHHx scaffolds were named PHMBD
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