Cellular Interactions and Biological Effects of Silk Fibroin: Implications for Tissue Engineering and Regenerative Medicine

Abstract Silk fibroin (SF), the core structural protein derived from Bombyx mori silk, is extensively employed in tissue engineering and regenerative medicine due to its exceptional mechanical properties, favorable biocompatibility, tunable biodegradability, and versatile processing capabilities. Despite these advantages, current research predominantly focuses on SF biomaterials as structural scaffolds or drug carriers, often overlooking their potential role in modulating cellular behavior and tissue regeneration. This review aims to present a comprehensive overview of the inherent biological effects of SF biomaterials, independent of any exogenous biomolecules, and their implications for various tissue regeneration. It will cover in vitro cellular interactions of SF with various cell types, including stem cells and functional tissue cells such as osteoblasts, chondrocytes, keratinocytes, endothelial cells, fibroblasts, and epithelial cells. Moreover, it will summarize in vivo immune responses, cellular responses, and tissue regeneration following SF implantation, specifically focusing on vascular, bone, skin, cartilage, ocular, and tendon/ligament regeneration. Furthermore, it will address current limitations and future perspectives in the design of bioactive SF biomaterials. A comprehensive understanding of these cellular interactions and the biological effects of SF is crucial for predicting regenerative outcomes with precision and for designing SF‐based biomaterials tailored to specific properties, enabling broader applications in regenerative medicine.