ABSTRACT 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.
Özsezer et al. (2026) studied this question.