Multimodal Bioactive Approaches in Smart Dressings for Diabetic Foot Ulcers

Diabetes mellitus, a metabolic disorder characterized by chronic inflammation and hyperglycemia, is projected to affect 589 million adults (aged 20-79) globally in 2024, soaring to 853 million by 2050. Diabetic wounds, particularly diabetic foot ulcers (DFUs), afflict over 15 million patients annually. These wounds are notoriously refractory to healing, prone to infection, and associated with high rates of amputation and mortality, posing a severe burden on healthcare systems worldwide. The impaired healing trajectory stems from a complex pathophysiology involving neuropathy, angiopathy, and immune dysfunction in the hyperglycemic milieu, which renders conventional passive dressings inadequate. Although extensive research has been devoted to developing advanced dressings loaded with various bioactive agents, the majority of these efforts remain confined to optimizing single-material platforms or isolated functional enhancements, lacking a comprehensive and globally integrated design theory that addresses the multi-stage, multi-target pathological features of diabetic wound healing. To address this gap, this review proposes and systematically articulates a tripartite design paradigm-namely, "pathology-timing matching, multimodal bioactivity synergy, and smart microenvironment responsiveness"-which serves as the overarching analytical framework throughout the manuscript. Within this framework, we comprehensively survey current diverse material platforms, such as hydrogels, polymer-based composites, and nanocomposites, alongside a broad spectrum of bioactive factors, including active compounds derived from traditional Chinese medicine (TCM) and placental-derived biologics. Importantly, we depart from conventional encyclopedic enumeration by shifting our focus to elucidate how distinct material-biofactor combinations exert spatiotemporal synergistic effects across specific healing phases, such as inflammation regulation, angiogenesis, and infection control. Furthermore, we delve into the dynamic responsiveness of smart dressings to wound microenvironmental cues (eg, pH, temperature, oxygen tension, and specific infectious biomarkers) Prospectively, we propose the integration of real-time data feedback from smart dressings with the construction of wound "digital twins", thereby charting a new avenue toward precision and personalized therapeutics Finally, we distill the core challenges associated with the deep convergence of multimodal synergistic strategies and intelligent responsive systems and outline future research directions for the development of next-generation personalized therapeutic solutions for diabetic wound management.