Photocured, Styrenated Gelatin-Based Microspheres for de Novo Adipogenesis through Corelease of Basic Fibroblast Growth Factor, Insulin, and Insulin-Like Growth Factor I

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Abstract
De novo adipose tissue formation appears to proceed via two different biological events: neovascularization and spontaneous accumulation of preadipocytes and subsequent differentiation to mature adipocytes. In this article, we perform accelerated de novo adipose tissue engineering using photocured, styrenated, gelatin-based microspheres (SGMs) with different drug release rates of immobilized angiogenic and adipogenic factors. The concept of this system is to induce neovascularization and migration of endogenous preadipocytes by the rapid delivery of the angiogenic factor basic fibroblast growth factor (bFGF), followed by the proliferation and differentiation of preadipocytes into adipocytes by the prolonged delivery of the adipogenic factors, insulin and insulin-like growth factor I (IGF-I). Bioactive substance-immobilized SGMs with different drug release rates were prepared with different gelatin concentrations. An in vitro study showed the prolonged release of an immobilized model protein and the dependence of drug release rate on gelatin concentration. After the subcutaneous injections of SGMs immobilized with these bioactive substances in different combinations, the formation of masses or clusters of adipocytes was observed in rats. Triglyceride content in the injection site for the group that received bFGF-, insulin-, and IGF-I-immobilized SGMs was significantly higher than that for the group that received insulin- and IGF-I-immobilized SGMs 4 weeks after the injection of microspheres. These results suggest that the system developed here is effective for the de novo formation of adipose tissue as it enables the induction of the two-step biological reaction by single injection.