Immunomodulatory Tissue-Engineering Strategies for Diabetic Foot Ulcer Management: A Systematic Review

The aim of this systematic review is to systematically compile evidence from the past 5 years on bioengineering and regenerative medicine approaches targeting the DFU immune microenvironment and to evaluate these findings from a translational perspective to inform clinical applications. This systematic review, conducted according to PRISMA 2020 guidelines, summarised evidence from 34 studies published between 2020 and 2025 on immunomodulatory tissue-engineering strategies for DFU management. Most studies used STZ-induced or db/db diabetic mouse models; only two included human data. Across natural polymer hydrogels, electrospun nanofibers, microneedles, and hybrid antimicrobial dressings, a consistent mechanistic theme emerged: promotion of macrophage polarisation from pro-inflammatory M1 to pro-regenerative M2. Cytokine delivery, exosome-based therapies, ROS-targeted nanozymes, metabolic reprogramming, and electrical or microcurrent stimulation resolved chronic inflammation, enhanced angiogenesis, and accelerated wound closure. Key signalling pathways (JAK/STAT, NF-κB, HMGB1-RAGE, HIF-1α) represent promising molecular targets. Despite encouraging preclinical outcomes, heterogeneity and limited human studies underscore the need for well-powered, long-term clinical trials and biomarker-driven personalised immunomodulatory strategies.