SiO2 nanoparticle-encapsulated metformin delivered by a poly(lactic-co-glycolic acid)/polycaprolactone electrospun nanofiber membrane promotes cell osteogenesis under high-glucose conditions: In vitro and in vivo studies

Restoring diabetic bone defects presents ongoing challenges due to the intrinsic healing mechanisms that are compromised by hyperglycemia. Metformin (Met) shows substantial potential for hyperglycemia-induced bone regeneration; however, the short half-life and poor bioavailability of Met have impeded its further clinical translation. To overcome these limitations, our study aims to develop an innovative drug delivery system that can effectively encapsulate and release Met in a controlled manner. We first fabricated Met-loaded SiO 2 nanoparticles (SiO 2 -Met NPs) via the sol-gel method and integrated these NPs onto a poly(lactic-co-glycolic acid)/polycaprolactone (PLGA/PCL) electrospun nanofiber membrane (PLGA/PCL/SiO 2 -Met). Subsequently, we conducted a series of in vitro and in vivo experiments to evaluate its therapeutic efficacy and bioavailability for diabetic bone regeneration. Incorporation of the SiO 2 -Met NPs significantly increased the hydrophilicity and mechanical strength of the electrospun nanofiber membrane and allowed the sustained release of Met for more than 28 days. PLGA/PCL/SiO 2 -Met reversed the high glucose-induced decrease in mesenchymal stem cell (MSC) osteogenic differentiation, as demonstrated by increases in osteogenic differentiation-related gene expression, alkaline phosphatase (ALP) activity, and calcium deposits. After being placed in critical-sized cranial bone defects in Sprague-Dawley (SD) rats with type 2 diabetes mellitus (T2DM), the composite nanofiber membranes exhibited an increased capacity to form new bone, as shown by microcomputed tomography (micro-CT) and immunohistochemical staining. The PLGA/PCL/SiO 2 -Met composite nanofiber membrane can serve as a local Met delivery system that achieves slow drug release and increases pro-osteogenic properties. This study holds great promise for future clinical translation, showcasing its considerable potential in advancing diabetic bone regeneration. • Diabetic bone healing challenged by hyperglycemia; Met shows potential but is limited by delivery. • Developed PLGA/PCL/SiO2-Met nanofiber membrane for controlled Met release. • PLGA/PCL/SiO2-Met nanofiber membrane reversed high glucose-induced MSC osteogenic differentiation. • PLGA/PCL/SiO2-Met nanofiber membrane increased new bone formation in diabetic rats.