A Self-Healing Multifunctional Hydrogel System Accelerates Diabetic Wound Healing through Orchestrating Immunoinflammatory Microenvironment

Abstract

Developing an effective treatment strategy of drug delivery to improve diabetic wound healing remains a major challenge in clinical practice nowadays, due to multidrug-resistant bacterial infections, angiopathy, and oxidative damage in the wound microenvironment. Herein, an effective and convenient strategy was designed through a self-healing multiple-dynamic-bond cross-linked hydrogel with interpenetrating networks, which was formed by multiple-dynamicbond cross-linking of reversible catechol-Fe 3+ coordinate bonds, hydrogen bonding, and Schiff base bonds. The excellent autonomous healing of the hydrogel was initiated and accelerated by Schiff bonds with reversible breakage between 3,4-dihydroxybenzaldehyde containing catechol and aldehyde groups and chitosan chains, and further consolidated by the co-optation of other noncovalent interactions contributed of hydrogen bonding and Fe 3+ coordinate bonds. Intriguingly, cathelicidin LL-37 was introduced and uniformly dispersed in the dynamic interpenetrating networks of the hydrogel as a bioactive molecular to orchestrate the diabetic wound healing microenvironment. This multifunctional wound dressing can significantly promote diabetic wound healing by antibacterial activity, immunomodulation, anti-inflammation, neovascularization, and antioxidant activity. Therefore, this study provided an effective and safe strategy for guiding the diabetic wound treatment in clinical applications.

Antibacterial, antioxidant and injectable hydrogels constructed using CuS and curcumin co-loaded micelles for NIR-enhanced infected wound healing

“…Whereas for the control and CF hydrogel groups, rarely any new blood vessels were formed on day 7, which exhibited more CD31 expression on day 14, indicating that the wound repairing stage of these two groups lag behind that of the CF–CuS hydrogel + NIR, CF–cur hydrogel and CF–CuS–cur hydrogel + NIR groups. The different expressions of CD206, which was used to stain M2 macrophages with an anti-inflammatory and wound repairing capacity, 50 also existed among different experimental groups. On day 7, the CF–CuS hydrogel + NIR, CF–cur hydrogel and CF–CuS–cur hydrogel + NIR groups all exhibited significant CD206 expression, corresponding to the predominant M2 macrophage expression, which indicates the wounds were in the final healing and remodeling stage, as the local macrophage population was in the transition to anti-inflammatory M2 macrophage phenotypes.…”

Advancements and Challenges in Self-Healing Hydrogels for Wound Care

“…Innovative crosslinking techniques [9,16,70,71] are being investigated to enhance hydrogels' physical properties, such as durability, flexibility, and self-healing capabilities. The extensive research into chitosan derivatives [18,19,21,24,29,[31][32][33][34][72][73][74][75][76][77][78][79] showcases the ongoing efforts to improve its biomedical applications. Moreover, the exploration of hydrogels featuring novel materials and crosslinking methods [17,23,27,28,30,[39][40][41][80][81][82][83][84] reflects a commitment to innovation in developing more effective, responsive, and specialized systems.…”

“…Additionally, hydrogels crosslinked through multiple dynamic bonds have been developed to accelerate the healing of diabetic wounds by orchestrating the immunoinflammatory microenvironment. These include the integration of cathelicidin LL-37, which contributes antibacterial, immunomodulatory, and neovascularization properties [29]. Hydrogels made from oxidized Bletilla striata polysaccharide and cationic gelatin are designed specifically for skin trauma, offering hemostatic performance and improved wound healing [30].…”

“…Self-healing ability, mechanical strength and stretchability, cell affinity and tissue adhesiveness, in vivo and in vitro utility demonstration [26] Dual enzymatic co-crosslinking using glucose oxidase/horseradish peroxidase and electrostatic interaction Toughness, self-healing, moldability, injectability, 3D printability, swelling ratio, biodegradation, antioxidant properties, antibacterial activity, cytotoxicity, cell migration enhancement, blood vessel formation, in vivo wound healing in rat model [27] Salep/poly(vinyl alcohol) with ethylene diamine-modified salep and oxidized salep via hydrogen bonds and Schiff base crosslinking Mechanical strength, tissue adhesiveness, therapeutic properties (cell viability, wound healing), macroscopic evaluation of wound healing [28] Multiple-dynamic-bond crosslinked hydrogel with 3,4-dihydroxybenzaldehyde, chitosan, and Fe 3+ coordinate bonds Autonomous healing, antibacterial activity, immunomodulation, anti-inflammation, neovascularization, antioxidant activity, diabetic wound-healing promotion [29] Oxidized bletilla striata polysaccharide and cationic gelatin via Schiff base reaction Rheological properties, mechanical behavior, porous structure, degradation performance, hemostatic performance, wound-healing facilitation [30] Oxidized chondroitin sulfate and carboxymethyl chitosan with platelet-rich plasma Gelation, viscoelasticity, inhibition of PRP enzymolysis, sustained growth factor release, cell proliferation and migration, diabetic skin wound-healing acceleration [75]…”

“…Efforts to develop hydrogels with targeted functional crosslinking aim to create materials that not only adhere strongly to tissues but also can be easily removed without causing pain, maintaining their healing efficacy over time [24][25][26][27][28][29][30]. This is particularly important for immediate wound care, where hydrogels with hemostatic properties can significantly impact bleeding control and facilitate healing [30].…”