Microenvironment-based design of silk fibroin hydrogels for tissue repair

Abstract

Abstract Silk fibroin (SF) hydrogels have emerged as versatile matrices for tissue repair, supporting injectable delivery, biofabrication and implantation while offering tunable mechanics, mass transport and biodegradation. Repair outcomes, however, are often dictated by the local microenvironment, where prolonged inflammation, oxidative stress, infection, impaired vascularization, and mechanical mismatch can drive fibrosis and limit functional integration. In this review, we summarize microenvironment-based design strategies for SF hydrogels across skin wound healing, bone and cartilage regeneration (including osteochondral repair), neural repair, and additional applications such as periodontal, myocardial, and skeletal muscle repair. We first outline how SF molecular structure and processing routes govern hydrogel formation, and compare physical, chemical, and enzymatic crosslinking approaches with emerging injectable and 3D-printable formulations. We then highlight functional and composite designs that deliver coordinated biochemical and biophysical cues—through porous architectures, adhesives, inorganic phases, bioactive molecules, extracellular vesicles, and conductive components—to modulate immune responses, angiogenesis, antimicrobial activity, and redox balance in a spatiotemporally controlled manner. Finally, we discuss remaining challenges in reproducibility, long-term safety, and scalable manufacturing, and propose directions toward clinically relevant SF hydrogel platforms that actively steer repair microenvironments toward regeneration