Thermo-Responsive Injectable Hydrogels for Wound Repair: Mechanistic Insights, Material Engineering, and Multimodal Therapeutic Applications.

Abstract

Chronic non-healing wounds remain a major clinical challenge, affecting millions of patients worldwide and imposing substantial socioeconomic burdens. Thermo-responsive hydrogels have emerged as a highly promising class of smart biomaterials for wound healing due to their unique sol-gel phase-transition behavior triggered by physiological temperatures. This review comprehensively reviews recent advances in the fundamental mechanisms, material design principles, and biomedical applications of thermo-responsive hydrogels in wound management. First, the thermo-induced gelation mechanisms of representative systems, including lower critical solution temperature (LCST)-type and upper critical solution temperature (UCST)-type polymers as well as poly(N-isopropylacrylamide) (PNIPAm)- and Pluronic F127-based platforms, are discussed from the perspectives of polymer-water interactions and self-assembly behavior. Second, key material engineering strategies are highlighted, including the integration of synthetic and natural polymers, copolymerization, block design, and crosslinking regulation, which collectively enable tunable mechanical properties, degradation kinetics, and biofunctionality. Third, the functional design of injectable thermo-gels is emphasized, particularly their capabilities in on-demand drug delivery, microenvironment regulation, and immunomodulation through multi-responsive systems (eg, pH-, ROS-, enzyme-, and photothermal responsiveness). Furthermore, their application to specific wound types-including diabetic chronic wounds, infected wounds, burns, and surgical injuries-is systematically discussed, demonstrating their advantages in antibacterial activity, promotion of angiogenesis, immune remodeling, and tissue regeneration. Finally, current translational challenges such as temperature variability in pathological wounds, manufacturing reproducibility, sterilization constraints, and long-term biosafety are analyzed, along with future directions integrating AI-driven design, organ-on-a-chip platforms, and 3D/4D bioprinting technologies. Collectively, thermo-responsive hydrogels represent a versatile preclinical platform with promising translational potential for precision wound therapy, pending rigorous clinical validation.

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