Jul 2026· ACS Applied Bio Materials· Vol 9, pp. 7130-7142· 0 citations· 62 references
Medicine
TL;DR
Findings indicated that glucose-responsive antioxidant modulation using HA-based hydrogels can be a useful approach for managing oxidative stress in chronic diabetic wounds.
Abstract
Chronic diabetic wounds are associated with the excessive production of reactive oxygen species (ROS) under hyperglycemic conditions, which contribute to impaired tissue regeneration. In this study, we developed a dual-crosslinked hyaluronic acid (HA)-based hydrogel dressing with a glucose-responsive ROS-scavenging behavior. The hydrogel was composed of methacrylated HA-phenylboronic acid (HAMA-PBA) and HA-dopamine (HA-DA), forming a stable primary network through photocrosslinking and a dynamic secondary network via reversible boronate-catechol interactions. Under hyperglycemic conditions, the competitive binding of glucose to PBA modulates these dynamic interactions, enabling the glucose-responsive regulation of antioxidant activity. The resulting hydrogel exhibited mechanical properties suitable for wound dressing applications and showed good biocompatibility. Glucose-dependent ROS scavenging and enhanced keratinocyte migration were observed in vitro. In a mouse model of chronic diabetic wounds, hydrogel treatment was associated with accelerated wound closure accompanied by improved re-epithelialization and collagen organization compared with those in control groups. Overall, these findings indicated that glucose-responsive antioxidant modulation using HA-based hydrogels can be a useful approach for managing oxidative stress in chronic diabetic wounds.
Diabetic wounds are characterized by oxidative stress, chronic inflammation, and impaired tissue regeneration under persistent hyperglycemic conditions. Herein, we report an injectable dual-dynamic covalent hydrogel fabricated from phenylboronic-acid-functionalized oxidized sodium alginate and gallic-acid-conjugated chitosan. Crosslinked via reversible Schiff base and boronate ester bonds, the hydrogel exhibits excellent injectability, self-healing capability, and structural stability. Under hyperglycemic conditions, competitive glucose binding modulates the boronate ester equilibrium and induces glucose-responsive release of galloyl-containing species. These glucose-responsive release behaviors contribute to the antioxidant, antibacterial, and immunoregulatory activities of the hydrogel. In vitro and in vivo results demonstrate that the hydrogel promotes macrophage polarization toward the anti-inflammatory M2 phenotype, alleviates inflammatory responses, enhances angiogenesis, and accelerates skin regeneration. Collectively, the phenylboronic-acid-functionalized oxidized sodium alginate and gallic-acid-conjugated chitosan hydrogel represents a multifunctional glucose-responsive biomaterial with considerable potential for diabetic wound therapy.
Zhao-Yun Wang, Susu Lei, Feng Lai et al.· Biomaterials Research· 0 citations
Chronic diabetic wounds are difficult to treat because persistent oxidative stress, mitochondrial dysfunction, and impaired stromal-vascular communication jointly delay tissue repair. In this study, we developed a bioinspired hyaluronic acid-catechol-PEG-amine (HA-CPA) hydrogel through dynamic Schiff-base crosslinking for topical diabetic wound management. The HA-CPA hydrogel formed a porous, self-supporting network and showed favorable cytocompatibility and hemocompatibility. Owing to catechol-containing moieties, the hydrogel displayed strong antioxidant activity, with more than 80% radical-scavenging efficiency in DPPH and ABTS assays. Under diabetic-mimicking conditions, HA-CPA hydrogel extracts reduced intracellular reactive oxygen species, helped preserve mitochondrial membrane potential, and improved fibroblast migration and endothelial angiogenic behavior, including tube formation. In a streptozotocin-induced diabetic full-thickness wound model, HA-CPA treatment accelerated wound closure, enhanced collagen deposition, and promoted re-epithelialization without detectable systemic toxicity in major organs. These findings indicate that HA-CPA hydrogel provides a practical wound-dressing platform that combines redox regulation, inflammatory microenvironment modulation, cellular protection, and vascular-supportive activity.
Yang-Xi Chen, Ying Chen, Li Huang et al.· Journal of Biomaterials Appl...· 0 citations
Chronic diabetic wounds require continuous modulation of the hyperglycemia-induced pathological microenvironment. Although glucose-responsive biomaterials show promise for diabetic wound treatment, intelligent wound management with tissue specificity and multifactorial repair capacity remains urgently needed. Here, we develop a tissue-homologous, glucose-responsive hydrogel based on epidermis-derived keratin functionalized with phenylboronic acid (Keratin-PBA), which is crosslinked with oxidized sodium alginate (OSA) to form a double-network hydrogel (cOK) and integrated with bioactive nanomicelles for adaptive wound microenvironment regulation. Co-assembled nanomicelles (OA-PG NMs), composed of oleanolic acid (OA) and propyl gallate (PG), exhibit glucose-triggered release and complementary bioactivities targeting oxidative stress, inflammation, macrophage polarization, angiogenesis, fibroblast behavior, antibacterial activity, and MMP regulation. Notably, OA promotes angiogenesis via the TGR5-Akt-eNOS-NO signaling pathway. The resulting cOK@NM hydrogel enables spatiotemporally controlled nanomicelle release and significantly accelerates diabetic wound healing in vivo, as evidenced by rapid wound closure, enhanced M2 macrophage polarization, robust neovascularization, improved collagen remodeling, reduced AGEs, broad-spectrum antibacterial effects against E. coli and S. aureus, and increased granulation tissue formation. This work presents a tissue-homologous, intelligently adaptive platform integrating intrinsic regenerative bioactivity with glucose-responsive therapeutic adaptability.
Luyao Wang, Shengchao Wang, I. Ullah et al.· Small· 0 citations
In vivo, AP@EM-gel produced near-complete wound closure by day 14 and improved bacterial clearance, re-epithelialisation, collagen organisation, angiogenesis, and inflammatory resolution compared with the commercial dressing.
Rui Zhang, Suk Fei Tan, Ye Wang et al.· Frontiers in Cell and Develo...· 0 citations
Healing of diabetic wounds is severely hindered by a persistent vicious cycle of bacterial infection and metabolic disorders. Pathological microenvironments, characterized by high glucose levels and excessive reactive oxygen species (ROS), exacerbate chronic inflammation and impede the transition of macrophages toward a pro-healing phenotype. To address these challenges, we developed a multi-stimuli-responsive composite hydrogel platform (GHFA/Cu@TA) by integrating fulvic acid (FA) and copper-tannic acid nanozymes (Cu@TA NPs) into a dynamic covalent network composed of methacrylated gelatin (GelMA) and phenylboronic acid-modified hyaluronic acid (HA-PBA). This platform implements a self-feedback mechanism to restore metabolic homeostasis: glucose-triggered release of Cu@TA NPs effectively scavenges microenvironmental ROS to drive tissue microenvironment remodeling, thereby decelerating responsive hydrogel degradation upon homeostasis normalization to ensure synchronized on-demand drug delivery. Intelligently released FA promotes M2 macrophage polarization to reshape the immune microenvironment, while Cu@TA NPs achieve photothermal biofilm eradication under near-infrared (NIR) light. This "metabolic sensing-feedback regulation-homeostasis reconstruction" strategy offers a distinct therapeutic framework for addressing diabetic wound and contributes to the rational design of bioactive dressings with stimuli responsiveness.
Na Yang, Lingling Tang, Huanghe Zeng et al.· International Journal of Bio...· 0 citations
A multifunctional, mechanism-targeted strategy that provides a rational, disease-relevant approach for treating chronic diabetic wounds by dampening inflammatory signaling and protecting reparative cells is developed.
Yuefei Zhu, Na Yan, Yongqiang Xiao et al.· Small· 0 citations