Cascade enzymatic preparation of carboxymethyl chitosan-based multifunctional hydrogels for promoting cutaneous wound healing.

Designing wound dressings with inherent multifunctional therapeutic effects is desirable for clinical applications. Herein, a series of multifunctional carboxymethyl chitosan (CMCS)-based hydrogels were fabricated by the facile urate oxidase (UOX)-horseradish peroxidase (HRP) cascade enzymatic crosslinking system. For the first time, the cascade enzymatic crosslinking system was not only used for preparing hydrogel wound dressings but also for accelerating wound healing due to the activity retention of the self-compartmental enzymes. A CMCS derivative (HCMCS-mF) synthesized by successively grafting 4-hydroxybenzaldehyde (H) and 5-methylfurfural (mF) on CMCS and a quaternary ammonium crosslinker (QMal) with terminal grafting maleimide (Mal) groups were combined with enzymatic system for the facile preparation of hydrogels. The mild Diels-Alder (DA) crosslinking reaction between mF and Mal groups constructed the first network of hydrogels. The cascade UOX-HRP system mediated the oxidative crosslinking of phenols thus forming the second gel network. Self-entrapped UOX maintained its enzymatic activity and could continuously catalyze the oxidation of uric acid, generating therapeutic allantoin. These porous, degradable, mechanically stable hydrogels with excellent antioxidant performance and enhanced antibacterial capacity could effectively accelerate skin wound repair by simultaneously reducing oxidative stress, relieving inflammation, promoting collagen deposition and upregulating the expression level of CD31.

Honokiol@PF127 crosslinked hyaluronate-based hydrogel for promoting wound healing by regulating macrophage polarization.

Bacterial infection, oxidative stress and inflammation are the main obstacles in wound healing. Hydrogels with moist and inherent properties are beneficial to wound healing. Here, we fabricated a honokiol-laden micelle-crosslinked hyaluronate-based hydrogel by simply mixing honokiol-laden PF127-CHO micelles, 3,3'-dithiobis(propionohydrazide) grafted hyaluronic acid and silver ions. PF127 could not only effectively load hydrophobic small molecules but also be macromolecular crosslinker for preparing hydrogels. Hyaluronic acid plays an essential role in wound healing processes including regulating macrophage polarization towards M2 phenotype. The chemical dynamic acylhydrazone crosslinking and physical crosslinking among PF127-CHO micelles constructed hydrogel's networks, which endowed hydrogel with excellent self-healing properties. PF-HA-3 hydrogel also exhibited outstanding antioxidant and antibacterial capabilities. In a full-thickness skin defect model, this degradable and biocompatible hydrogel could promote wound healing by remodeling wound tissues, regulating M2 polarization and angiogenesis. In summary, this inherent multifunctional hydrogel will provide a promising strategy for designing bioactive compounds-based wound dressings.

Facile preparation of polyphenol-crosslinked chitosan-based hydrogels for cutaneous wound repair.

The design and facile preparation of the smart hydrogel wound dressings with inherent excellent antioxidant and antibacterial capacity to effectively promote wound healing processes is highly desirable in clinical applications. Herein, a series of multifunctional hydrogels were prepared by the dynamic Schiff base and boronate ester crosslinking among phenylboronic acid (PBA) grafted carboxymethyl chitosan (CMCS), polyphenols and Cu2+-crosslinked polyphenol nanoparticles (CuNPs). The dynamic crosslinking bonds endowed hydrogels with excellent self-healing and degradable properties. Three polyphenols including tannic acid (TA), oligomeric proanthocyanidins (OPC) and (-)-epigallocatechin-3-O-gallate (EGCG) contributed to the outstanding antibacterial and antioxidant abilities of these hydrogels. The tissue adhesive capacity of hydrogels gave them good hemostatic effect. Through a full-thickness skin defect model of mice, these biocompatible hydrogels could accelerate wound healing processes by promoting granulation tissue formation, collagen deposition, M2 macrophage polarization and cytokine secretion, demonstrating that these natural-derived hydrogels with inherent physiological properties and low-cost preparation approaches could be promising dressing materials.