Intelligent Natural Hydrogels for Wound Therapy: Spatiotemporal Microenvironment Sensing, Synergistic Regulation, and Translational Pathways

Wound healing represents a significant challenge within the realm of global healthcare. Traditional inert dressings often fail to effectively detect and respond to wound signals, thereby hindering precise therapeutic interventions. In contrast, natural hydrogels, characterized by their superior biocompatibility, biodegradability, and modifiability, facilitate the detection and in situ regulation of wound signals. This review provides a systematic analysis of the microenvironmental response mechanisms exhibited by natural hydrogels throughout various stages of wound healing. It delineates structural-functional-response synergistic design strategies, encompassing multi-modal response network integration, reversible self-healing structure hybridization, signal amplification and feedback regulation, and multi-scale structural synergy. Furthermore, the review proposes precise intervention pathways tailored for complex pathological scenarios, including diabetic chronic wounds, infected wounds, extensive burn injuries, and non-healing wounds resulting from radiotherapy or postoperative conditions. Additionally, it integrates organoid and 3D skin model validation, advanced imaging techniques, and AI-assisted optimization with state-of-the-art technologies. This paper anticipates the evolution of natural hydrogels from singular materials to comprehensive diagnostic and therapeutic platforms, highlighting their clinical potential and the forthcoming challenges in realizing personalized and precise wound treatment.