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Purpose <p>To critically review recent advances in hyaluronic acid–glutathione (HA–GSH) hybrid scaffolds, emphasizing their redox-responsive mechanisms, engineering strategies, and translational potential in wound healing applications.</p> Methods <p>A comprehensive literature analysis was conducted focusing on molecular mechanisms, fabrication chemistries, and preclinical outcomes of HA–GSH systems. Comparative evaluation of redox-responsive linkages (disulfide, thioketal, and boronate) and scaffold architectures (hydrogels, nanofibers, 4D-printed matrices) were performed to elucidate their role in modulating redox–immune balance and tissue regeneration.</p> Results <p>HA–GSH scaffolds demonstrated synchronized antioxidant release and immune modulation through CD44–Nrf2–NF-κB pathways. Preclinical models consistently showed accelerated wound closure, enhanced angiogenesis, and improved collagen organization compared with non-responsive scaffolds. However, limitations persist regarding GSH stability, scalable manufacturing, and quantitative mapping of redox–immune dynamics.</p> Conclusion <p>HA–GSH scaffolds represent an intelligent, bioadaptive platform for regenerative wound therapy. Future research should focus on AI-assisted scaffold optimization, organ-on-chip validation for preclinical translation, and sustainable fabrication to establish clinically viable, precision-guided wound healing solutions.</p> Lay Summary <p>Chronic and diabetic wounds often fail to heal because of persistent oxidative stress and inflammation. Hyaluronic acid–glutathione (HA–GSH) scaffolds are next-generation <i>redox-responsive biomaterials</i> that actively support tissue repair rather than serving as passive dressings. Hyaluronic acid (HA<b>)</b> maintains structure and hydration, while glutathione (GSH) restores antioxidant balance by neutralizing reactive oxygen species. When combined, they form smart scaffolds that release antioxidants only when oxidative stress is high, promoting immune balance, angiogenesis, and organized collagen formation. Advanced designssuch as multilayer hydrogels and 4D-printed matrices—allow these systems to adapt to the wound environment dynamically. Preclinical models show faster closure and improved tissue quality compared with conventional materials. Integrating biosensing, artificial intelligence, and green fabrication could further enable real-time feedback and personalized wound therapy. HA–GSH scaffolds thus mark a major step toward intelligent, self-regulating wound care platforms that heal by responding to the body’s own biochemical signals.</p> Graphical Abstract <p></p>

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Redox-Responsive HA–GSH Scaffolds for Immune Modulation and Advanced Wound Therapy

  • 期刊论文

  • 发表日期：

    2025年12月2日

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  • Renukadevi Jeyavelkumaran,
  • Premkumar Panneerpandian,
  • Sneha Panneerselvam,
  • Ranjani Muthu,
  • Safiq Husain Jahir

摘要

Purpose

To critically review recent advances in hyaluronic acid–glutathione (HA–GSH) hybrid scaffolds, emphasizing their redox-responsive mechanisms, engineering strategies, and translational potential in wound healing applications.

Methods

A comprehensive literature analysis was conducted focusing on molecular mechanisms, fabrication chemistries, and preclinical outcomes of HA–GSH systems. Comparative evaluation of redox-responsive linkages (disulfide, thioketal, and boronate) and scaffold architectures (hydrogels, nanofibers, 4D-printed matrices) were performed to elucidate their role in modulating redox–immune balance and tissue regeneration.

Results

HA–GSH scaffolds demonstrated synchronized antioxidant release and immune modulation through CD44–Nrf2–NF-κB pathways. Preclinical models consistently showed accelerated wound closure, enhanced angiogenesis, and improved collagen organization compared with non-responsive scaffolds. However, limitations persist regarding GSH stability, scalable manufacturing, and quantitative mapping of redox–immune dynamics.

Conclusion

HA–GSH scaffolds represent an intelligent, bioadaptive platform for regenerative wound therapy. Future research should focus on AI-assisted scaffold optimization, organ-on-chip validation for preclinical translation, and sustainable fabrication to establish clinically viable, precision-guided wound healing solutions.

Lay Summary

Chronic and diabetic wounds often fail to heal because of persistent oxidative stress and inflammation. Hyaluronic acid–glutathione (HA–GSH) scaffolds are next-generation redox-responsive biomaterials that actively support tissue repair rather than serving as passive dressings. Hyaluronic acid (HA) maintains structure and hydration, while glutathione (GSH) restores antioxidant balance by neutralizing reactive oxygen species. When combined, they form smart scaffolds that release antioxidants only when oxidative stress is high, promoting immune balance, angiogenesis, and organized collagen formation. Advanced designssuch as multilayer hydrogels and 4D-printed matrices—allow these systems to adapt to the wound environment dynamically. Preclinical models show faster closure and improved tissue quality compared with conventional materials. Integrating biosensing, artificial intelligence, and green fabrication could further enable real-time feedback and personalized wound therapy. HA–GSH scaffolds thus mark a major step toward intelligent, self-regulating wound care platforms that heal by responding to the body’s own biochemical signals.

Graphical Abstract