Absorbable Thioether Grafted Hyaluronic Acid Nanofibrous Hydrogel for Synergistic Modulation of Inflammation Microenvironment to Accelerate Chronic Diabetic Wound Healing

Abstract

Current standard of care dressings are unsatisfactorily inefficacious for the treatment of chronic wounds. Chronic inflammation is the primary cause of the long‐term incurable nature of chronic wounds. Herein, an absorbable nanofibrous hydrogel is developed for synergistic modulation of the inflammation microenvironment to accelerate chronic diabetic wound healing. The electrospun thioether grafted hyaluronic acid nanofibers (FHHA‐S/Fe) are able to form a nanofibrous hydrogel in situ on the wound bed. This hydrogel degrades and is absorbed gradually within 3 days. The grafted thioethers on HHA can scavenge the reactive oxygen species quickly in the early inflammation phase to relieve the inflammation reactions. Additionally, the HHA itself is able to promote the transformation of the gathered M1 macrophages to the M2 phenotype, thus synergistically accelerating the wound healing phase transition from inflammation to proliferation and remodeling. On the chronic diabetic wound model, the average remaining wound area after FHHA‐S/Fe treatment is much smaller than both that of FHHA/Fe without grafted thioethers and the control group, especially in the early wound healing stage. Therefore, this facile dressing strategy with intrinsic dual modulation mechanisms of the wound inflammation microenvironment may act as an effective and safe treatment strategy for chronic wound management.

Designing responsive dressings for inflammatory skin disorders; encapsulating antioxidant nanoparticles into biocompatible electrospun fibres

“…27 More recently, thioether-functionalized hyaluronic acid was electrospun into nanofibres and formed fast-resorbing hydrogels that were highly antioxidant, anti-inflammatory, and significantly promoted wound closure/healing in a diabetic wound model. 28 These data lend support for the expanded use of polysulfides/ PPS as anti-inflammatory agents in topical wound-healing applications. However, slow-degrading crosslinked hydrogels and nanoparticle dispersions are not ideal for inflammatory skin disorders with a more diffuse skin coverage, such as chronic wounds (e.g.…”

The Dynamic Inflammatory Tissue Microenvironment: Signality and Disease Therapy by Biomaterials

“…The nCeO 2 -PHBV membranes can enhance cell proliferation and vascularization to promote the healing of diabetic wounds. Liu et al prepared a kind of electrospun thioether-grafted hyaluronic acid nanofibers (FHHA-S/Fe) that can form a nanofibrous hydrogel in situ on the wound, which combine the advantages of both hydrogel and nanofibers [ 237 ]. The in vivo test shows that this material can synergistically modulate the inflammation microenvironment to help diabetic wound healing by scavenging ROS effectively in the early inflammation phase and promoting transformation of the gathered M1 macrophages to the M2 phenotype.…”

Hydrogels for Engineering the Immune System

“…Liu et al reported a resorbable hydrogel composed of electrospun thioether grafted hyaluronic acid nanofibers crosslinked by Fe 3+ ions. [ 26 ] Using a chronic diabetic inflammation mouse model, they found that high‐molecular‐weight hyaluronic acid promoted macrophage polarization into M2 phenotype which secreted anti‐inflammatory and growth factors. [ 96 ] Thioether grafted on hyaluronic acid also scavenged ROS during early stage of inflammation.…”

“…StarPEG [62] Hydroexythylcellulose [63] Polyacrylamide [66] Peptide [79] HA [26] Alginate [97] Naturally occurring polymers like hyaluronic acids with inherent anti-inflammatory bioactivity Controlled porosity for inflammatory molecule absorption Optimal porosity and tunable biodegradability for controlled drug release ECM-like feature to improve wound healing Trigger responsive for on-demand drug release Improve cancer immunotherapy PCL-PEG-PCL [100] Piptide [110] Alginate [118] Fibrin [114] Poloxamer 407 [128] Polyvinyl alcohol [119] Betamethasone phosphate [134] Supramolecular prodrug [135] Phase-transition and in situ gel formation (induced by temperature, shear stress, light, ions, etc.) for good injectability Network structures make hydrogels as reservoir to physical encapsulate or chemically link some drug molecules.…”

“…[24,25] Moreover, through simple chemical modifications, hydrogels can be programmed to exhibit a range of biochemical and biophysical properties that are most conductive for immune tissue regeneration to support in vivo immune activities like T-cell activation and proliferation. [26] In this Review, we highlight recent innovations using hydrogels for engineering the immune system, the existing challenges in this field and how they can potentially be resolved.…”