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

## TL;DR

This review explores bioengineering strategies that target the immune environment in diabetic foot ulcers to improve healing and reduce inflammation.

## Contribution

The paper provides a systematic review of recent immunomodulatory tissue-engineering approaches for diabetic foot ulcers with a translational focus.

## Key findings

- Most studies used diabetic mouse models and showed a shift from pro-inflammatory M1 to pro-regenerative M2 macrophages.
- Strategies like cytokine delivery and nanozymes reduced inflammation and improved wound healing.
- Key pathways like JAK/STAT and NF-κB are highlighted as potential molecular targets.

## 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.