Hyaluronic acid-based tissue-engineered biomaterials for infected diabetic foot ulcers: mechanisms, evidence, and...

Diabetic foot ulcers (DFUs) have difficulty healing clinically when infection and mature biofilms coexist with hyperglycemic injury, immune dysregulation, oxidative stress, ischemia-hypoxia, repetitive mechanical loading, and extracellular matrix (ECM) degradation. Debridement, infection management, offloading, vascular assessment and revascularization, when indicated, constitute the foundation of care; biomaterials can be evaluated only as adjuncts to this pathway. Hyaluronic acid (HA) is an attractive hydrated ECM-associated and chemically adaptable matrix that can support local retention, controlled release and cell‒material interactions. It is not intrinsically superior to chitosan, alginate, collagen/gelatin or synthetic polymers in every respect: unmodified HA has limited antimicrobial activity and insufficient mechanical strength for many plantar applications. Moreover, antimicrobial, antioxidant, immunomodulatory and angiogenic effects in multicomponent systems are often provided primarily by incorporated antibiotics, metal ions, polyphenols, nitric oxide donors, growth factors or extracellular vesicles rather than by HA itself. This Review therefore distinguishes the contribution of the HA matrix from that of active cargo and separates direct evidence from explicit infected diabetic wound models, indirect evidence from noninfected diabetic wounds, in vitro mechanistic evidence and clinical DFU studies in which infection status was not reported or stratified. Only a minority of preclinical studies have used explicit infected diabetic wound models, and almost all published HA clinical studies have included general populations of DFU patients without biofilm or perfusion stratification. The proposed matching of HA platforms to biofilm-, inflammation/ROS-, ischemia- or ECM-dominant phenotypes is therefore a testable translational hypothesis, not a guideline-endorsed treatment algorithm. Progress requires claim-matched models, full reporting of the HA source, molecular weight distribution, and purification method, endotoxin burden, component deconvolution controls, stage-responsive rather than indiscriminate multifunctionality, long-term local and systemic safety monitoring, and clinical outcomes extending beyond short-term wound closure.