Silk-coated PLGA non-spherical microparticles for simvastatin delivery in rat maxillofacial bone regeneration

Abstract Maxillofacial bone defects present a major challenge in clinical practice. Bone graft and bone tissue engineering are limited by various side effects and potential risks, while local drug delivery is regarded as a convenient and efficient strategy for bone repair and regeneration. However, for bone tissue regeneration, drug delivery system should not only release osteogenic drugs, but also possess an appropriate morphology to provide structural support for cell proliferation and differentiation. Polymeric non-spherical counterparts may offer new osteogenic properties through altered cellular interactions, biodistribution, and immune responses, compared with spherical drug carriers. Poly(lactic-co-glycolic) acid (PLGA) has been widely used to prepare various drug carriers due to its excellent biocompatibility and controllable biodegradation. Shape regulation, surface modification, and drug incorporation are effective approaches to impart distinct functions to PLGA particles for various biomedical applications. However, PLGA has inherent limitations, including poor hydrophilicity, acidic degradation products, and a lack of functional ligands for cell attachment, which hinder its effectiveness in bone regeneration. To solve these problems, natural proteins were utilized to improve the bone/cartilage regeneration of polymeric particles/scaffolds through surface modification or physical complex due to their excellent biocompatibility and biodegradability. In this study, we successfully developed simvastatin (SIM)-loaded disc-shape PLGA microparticles with coarse surface (dPLGA) using W1/O/W2 followed by silk fibroin (SF) coating for hydrophilicity and biocompatibility improvement. In vitro and in vivo experiments revealed that SF-modified SIM-loaded dPLGA (SF-SIM@dPLGA) significantly promotes the osteogenic differentiation of stem cells and bone regeneration in cranial bone defects, indicating the superior osteoconductive and osteoinductive advantages arising from the physical morphology of particles and chemical effect. Additionally, SF-SIM@dPLGA demonstrated improved tissue adhesion and hemostatic ability. This novel PLGA non-spherical particle-based local delivery system provides a feasible strategy for practical maxillofacial bone repair due to the simple preparation procedures and enhanced bone regeneration performance.