Hydrogen-delivering biomaterial carriers for diabetic foot ulcer healing: a systematic review and meta-analysis of preclinical animal studies

OBJECTIVE: This study aimed to systematically evaluate the preclinical evidence on the therapeutic efficacy and underlying mechanisms of hydrogen-delivering biomaterial carriers in the treatment of diabetic foot ulcer (DFU). METHOD: We conducted a comprehensive search across eight databases (PubMed, Web of Science, Embase, Cochrane Library, CBM, CNKI, Wanfang, and VIP) to identify randomized animal studies investigating biomaterial-based hydrogen delivery for DFUs from database inception through November 2025. After screening, eleven studies met inclusion criteria and were included in the final meta-analysis. Data synthesis and statistical analyses were performed using RevMan 5.4; risk of bias was assessed using the SYRCLE's tool for animal studies. RESULTS: The delivery of hydrogen via biomaterial carriers effectively promotes diabetic wound repair by enhancing wound closure rates, stimulating angiogenesis, and improving collagen deposition. Smart delivery systems, such as hydrogen-generating hydrogels, responsive microneedle patches, and photocatalytic dressings, enabled spatiotemporally controlled, sustained H₂ release. This modulation effectively attenuated oxidative stress and suppressed pro-inflammatory cytokine expression (e.g., TNF-α, IL-6). Collectively, biomaterial-mediated hydrogen delivery confers dual therapeutic actions: direct promotion of tissue regeneration and dynamic reprogramming of the impaired wound microenvironment, supporting its potential as a targeted, mechanism-informed intervention for DFUs. CONCLUSION: Biomaterial-based hydrogen delivery systems demonstrate multifaceted therapeutic benefits in preclinical DFU models, primarily through anti-inflammatory, pro-angiogenic, and collagen-enhancing mechanisms. The emergence of smart delivery systems enables localized, tunable, and prolonged hydrogen release, which improves bioavailability and therapeutic precision. Future research should prioritize optimization of release kinetics, pharmacokinetic-pharmacodynamic modeling in diabetic wound beds, and exploration of synergistic combinations (e.g., with growth factors or antimicrobial agents) to advance toward clinically translatable, precision wound therapeutics.