ABSTRACT
Oxidative stress caused by excessive reactive oxygen species (ROS) accumulation significantly hinders wound healing in patients with diabetes. Scavenging ROS and reducing inflammation are crucial for rapid healing. In this work, a multi-responsive sodium hyaluronate (HA)/tannic acid (TA) hydrogel was developed based on boronate ester bonds. Sodium hyaluronate with 3-aminophenyl boronic acid modification (HA-APBA) was mixed and crosslinked with TA to form HA-APBA/TA hydrogels. These hydrogels are injectable, self-healing, and biocompatible. The HA-APBA/TA hydrogels could release free TA through the collapse of the structure at low pH, high H2O2 concentration, and high glucose concentration, thus possessing good ROS scavenging ability. In full-thickness skin wounds of db/db mice, the HA-APBA/TA hydrogels promoted wound healing, collagen deposition, and significant angiogenesis. Furthermore, they have been shown to effectively reduce the levels of inflammatory factors in wounds and lower the expression of CD86, a pro-inflammatory macrophage surface marker. This resulted in a more effective transition of wound healing from the inflammatory phase to the proliferative phase. This study provides an optional strategy for alleviating oxidative stress and controlling excessive inflammation, thereby promoting diabetic wound healing.
Subject(s)
Hyaluronic Acid , Hydrogels , Reactive Oxygen Species , Wound Healing , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Hydrogels/chemistry , Hydrogels/pharmacology , Animals , Wound Healing/drug effects , Mice , Reactive Oxygen Species/metabolism , Free Radical Scavengers/pharmacology , Free Radical Scavengers/chemistry , Diabetes Mellitus, Experimental/drug therapy , Oxidative Stress/drug effects , PolyphenolsABSTRACT
Alginate (SA) comprises repeating unis of ß-1, 4 linked ß-D-mannuronic acid (M) and α-L-guloronic acid (G) in varying proportions. The M/G ratio greatly impacts its anti-inflammatory properties in tissue healing wound, as less knowledge reported. This study examined the performances of both SA and SA hydrogel crosslinked with copper ions (SA-Cu) with different M/G ratios are studied. SA with higher M/G ratios stimulated macrophage migration and shifted from M0 to the pro-inflammatory Ml phenotype, while lower M/G ratios shifted from M1 to the pro-repair M2 phenotype. Furthermore, SA-Cu hydrogels with lower M/G ratios exhibited enhanced cross-linking degree, mechanical and rheological properties, as well Cu releasing rate. The reason may be attributed to a relative easy binding between Cu ions and G unit among Cu ions, M unit and G unit. In vitro cell evaluation showed that SA-Cu hydrogel with M/G ratio of 1:1 activated M2 macrophages and up-regulated anti-inflammatory cytokines expression more effectively than those of SA-Cu ratios (2:1) and (1:2). In vivo, SA-Cu hydrogel with M/G ratio of 1:1 expedited diabetic wound healing, accelerating infiltration and phenotype shift of M2 macrophages, and enhancing anti-inflammatory factors, epithelialization and collagen deposition in healing phases. This research highlights the significant role of M/G ratios in SA materials in influencing macrophage behavior and inflammatory responses, which would benefit its application field.
Subject(s)
Alginates , Hydrogels , Macrophages , Wound Healing , Wound Healing/drug effects , Alginates/chemistry , Alginates/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Animals , Mice , Hydrogels/chemistry , Hydrogels/pharmacology , RAW 264.7 Cells , Diabetes Mellitus, Experimental , Cytokines/metabolism , Hexuronic Acids/chemistry , Hexuronic Acids/pharmacology , Copper/chemistry , Rats , Male , Cell Polarity/drug effects , Macrophage Activation/drug effectsABSTRACT
Chronic hypoxia and ischemia make diabetic wounds non-healing. Cellular functions of diabetic chronic wounds are inhibited under a pathological environment. Therefore, this work develops a composite hydrogel system to promote diabetic wound healing. The composite hydrogel system consists of ε-poly-lysine (EPL), calcium peroxide (CP), and borosilicate glass (BG). The hydrogel supplies continuous dissolved oxygen molecules to the wound that can penetrate the skin tissue to restore normal cellular function and promote vascular regeneration. Biofunctional ions released from BGs can recruit more macrophages through neovascularization and modulate macrophage phenotypic transformation. Combining oxygen-mediated vascular regeneration and ion-mediated inflammatory regulation significantly accelerated diabetic wound healing. These findings indicate that this composite hydrogel system holds promise as a novel tissue engineering material.