Bio-Enhanced Silk Fibroin-Based Scaffolds for Chronic Diabetic Foot Ulcers: A Review

Abstract Diabetic foot ulcers (DFUs) represent a growing clinical challenge, driven by an aging global population and the increasing prevalence of diabetes. Affecting millions worldwide, DFUs remain one of the most serious complications of diabetes, frequently progressing to infection, amputation, and elevated mortality. Standard treatments typically include pressure offloading, circulation improvement, infection control, and topical wound care; however, many chronic DFUs fail to respond to these interventions due to persistent inflammation, impaired vascularization, and microbial burden. These challenges have accelerated interest in regenerative medicine approaches, including stem cells, growth factors, and skin substitutes. Among these, skin substitutes have shown particular promise; for example, the Food and Drug Administration (FDA)-approved collagen-Manuka honey-hydroxyapatite patch from SweetBio (Apis®) has demonstrated improved outcomes in patients with chronic ulcers. Silk fibroin (SF), a natural biopolymer with established clinical use, has emerged as a promising platform for chronic wound management due to its biocompatibility, tunable degradation, and capacity for controlled bio-additive delivery. SF scaffolds can be fabricated through various methods tailored to wound-healing applications: electrospun fibrous mats with high surface-area-to-volume ratio, freeze-dried porous constructs with interconnected architecture, and hydrogels designed for controlled drug delivery. In this review, we critically examine how SF scaffolds enhanced with bio-additives modulate cellular responses, redirect dysregulated healing pathways, accelerate wound closure, and promote tissue regeneration in diabetic wounds. We synthesize recent advances in preclinical and clinical studies, identify key translational barriers, and outline future directions for advancing SF-based dressings toward clinical adoption. Collectively, this review positions bio-enhanced SF scaffolds as next-generation, disease-informed candidates for improving outcomes in chronic DFU care.