**Background:** The global demand for tissue substitutes is rising, and autografts/allografts have limitations such as donor shortage and infection risk. Silk fibroin (SF), a natural fibrous protein from Bombyx mori silkworms, has been used for centuries as suture material and is now a key biopolymer for tissue engineering due to its biocompatibility, tunable mechanical properties, and low immunogenicity. This narrative review covers SF's composition, structure, processing methods, and biomedical applications.
**Methods:** The review synthesizes literature on SF's primary structure (heavy chain ~350 kDa, light chain ~25 kDa, P25 glycoprotein), amino acid composition (glycine 46%, alanine 30%, serine 12%, tyrosine 5%), and conformational states (amorphous, Silk I with α-helices, Silk II with β-sheets, and Silk III triple helix). Processing steps include degumming (removal of sericin using 0.02 M Na₂CO₃, boiling 30–60 min), dissolution (e.g., LiBr, Ajisawa's reagent), dialysis, and regeneration into films (thickness 10 nm–100 µm, transparency >90%), fibers (wet-spinning, electrospinning, dry-spinning, microfluidics), hydrogels (sol–gel transition via β-sheet network; compressive moduli: soft <29 kPa, tough 1.21–2.41 MPa), 3D porous scaffolds (freeze-drying, foaming, particulate leaching; aerogel porosity >90%, surface area 400–800 m² g⁻¹, density 0.11–0.2 g cm⁻³), particles (0.1–12 µm via powdering; spherical via electrospray, desolvation, salting out), and composites (e.g., with chitosan, PVA, PEDOT:PSS, polyurethane).
**Key Results:** SF-based materials demonstrate excellent biocompatibility in vitro and in vivo. For bone regeneration, SF/nano-HAp scaffolds loaded with SDF-1 and BMP-2 recruit BMSCs and promote osteogenic differentiation. SF/nano-HAp hydrogels support human BMSC proliferation and differentiation. Silver/gold nanoparticles in SF/nHAp hydrogels reduce bacterial proliferation against Staphylococcus aureus and Escherichia coli. For cartilage, SF/collagen scaffolds interact with TGF-β1 to enhance chondrogenesis; SF/curcumin scaffolds delay joint cell death. For cardiovascular applications, SF-PCL-PIBMD vascular grafts (2 mm) selectively promote HUVEC adhesion and endothelialization. SF-PVA-PCL/PLA three-layered nanofiber patches support cardiac cell adhesion and proliferation. For skin, electrospun SF/PCL scaffolds (cold plate-electrospinning) show wound healing comparable to commercial Matriderm®. Carded/hydroentangled 3D non-woven SF scaffolds with HaCaT keratinocytes and HDFs release exosomes containing angiogenic growth factors, promoting vascularization. For neural regeneration, SF/polypyrrole conductive nanofibers enhance Schwann cell proliferation, migration, and neurotrophic factor expression under electrical stimulation, promoting axonal regeneration and remyelination in vivo. SF/carbon nanofiber scaffolds improve electrical conductivity and fibroblast metabolic activity. For pancreatic tissue, SF sponge-like cryodevices allow islet vascularization and euglycemia in diabetic rats. SF hydrogels releasing heparin improve islet revascularization and survival. Hydrolysate SF decreases oxidative stress by elevating antioxidant enzyme activity. For breast implants, SF/PEO composites increase human fibroblast viability by 30% compared to conventional implants. For hernia treatment, SF/polypropylene composite meshes reduce adhesion area and degree without severe postoperative complications. SF/chitosan patches maintain adequate mechanical strength during remodeling. For sutures, SF-based sutures with antimicrobial peptides show lower inflammatory response than commercial drug-free sutures.
**Clinical Implications:** SF is FDA-approved as a biomaterial and is already used clinically as suture material. Its tunable degradation (complete degradation of electrospun fibers in rats after 8 weeks; SF scaffolds in middle ear tolerated for 26 weeks) and mechanical properties make it suitable for long-term implants. The ability to incorporate bioactive molecules (growth factors, drugs, antimicrobial agents) and conductive materials expands its utility in complex tissue regeneration. However, rare cases of delayed hypersensitivity are attributed to residual sericin, and some studies note amyloidogenic potential in mice. Future directions include 4D smart structures that adapt to the body microenvironment. Overall, SF-based materials offer a versatile, sustainable platform for regenerative medicine, with ongoing research needed to optimize long-term stability and immune modulation.