Thermoresponsive Injectable Microparticle–Gel Composites with Recombinant BMP-9 and VEGF Enhance Bone Formation in Rats

Abstract

Bone morphogenetic protein-9 (BMP-9) has been shown to be the most osteogenic BMP. Most of these experiments, however, involve an adenovirus-transfection strategy. Here, we used the scaffold-based strategy to study the bone forming ability of recombinant BMP-9 combined with vascular endothelial growth factor (VEGF). A robust, injectable, multicomponent-releasing scaffold in the form of a composite gel was developed by combining chitosan microparticles (MPs) with thermosensitive gel (MPs-gel). The MPs acted as the carriers for BMP-9 and the gel was loaded with VEGF. The developed gel consisted of hydrophobic chains of methyl cellulose (MC) and the cross-linked structures of alginate (Alg) and calcium. Gelation was achieved at physiological temperature and thus facilitated the injection and localization of MPs enabling an increased efficacy of incorporated growth factors at the target site. A release profile of incorporated growth factors over a two-week period showed higher release of VEGF at each time point compared to that of BMP-9. Human mesenchymal stem cells (hMSCs) encapsulated within the MPs-gel maintained their viability. BMP-9 enhanced the proliferation of hMSCs along the surface of MPs. Furthermore, BMP-9 potently induced the osteogenic differentiation of encapsulated hMSCs elucidated by the increased alkaline phosphatase (ALP) activity and the higher expression of ALP, collagen 1, and osteocalcin genes. In addition, in vivo experiments demonstrated that MPs-gel with the combination of BMP-9-VEGF could significantly enhance both subcutaneous and cranial bone formation (p < 0.05). Taken together, the results here strongly suggest that BMP-9-VEGF incorporated MPs-gel holds promise as an injectable bone tissue engineering platform.

Albumin grafted coaxial electrosparyed polycaprolactone-zinc oxide nanoparticle for sustained release and activity enhanced antibacterial drug delivery

“…All experiments were done in triplicate and mean cell viabilities were calculated against the negative control (cells only). 58 …”

“…All experiments were done in triplicate and mean cell viabilities were calculated against the negative control (cells only). 58 In vitro lung deposition test. Twin glass impinge set (Copley Scientic Limited, Nottingham, UK) was used to assess aerodynamic behavior of the nal particle (APCL-ZnO-CLOX) which showed the highest biocompatibility.…”

Injectable Composite Systems Based on Microparticles in Hydrogels for Bioactive Cargo Controlled Delivery

“…This growth factor is widely used in bone tissue engineering. The co-delivery of VEGF and BMP2 for synergetic effects has been the topic of some research works [ 71 , 72 ]. In a study [ 73 ], PLGA microcarriers, prepared using microfluidics and loaded with VEGF, had their surface modified with poly(3,4-dihy-droxyphenethylamine) (PDA) for BMP2 conjugation.…”

Hybrid Thermo-Responsive Polymer Systems and Their Biomedical Applications

“…Alternatively, a salt could be added to the gel to lower the gelation temperature, however, studies have shown a consequent decrease in the strength of such gels when in an aqueous solution or in a cell culture environment. To circumvent these issues and formulate a methylcellulose gel capable of thermogelation at physiological body temperature, Gaihre et al (2019) recently blended calcium chloride and alginate with methylcellulose, resulting in the formation of a crosslinked, strong gel within 10 min at 37 • C. The resulting formulation served as an injectable medium for the delivery of chitosan microparticles. Furthermore, faster gelation was observed upon the addition of the chitosan microparticles due to the absorption of water from the solution by the microparticles, thereby increasing the viscosity of the solution, as was evidenced by the swelling of the microparticles when added into the solution (Gaihre et al, 2019).…”