Biomaterial-mediated remodelling of the inflammatory microenvironment: a pH/ROS-responsive EGCG–metformin hydrogel for infected diabetic wound regeneration
Aug 2026· Frontiers in Cell and Developmental Biology· Vol 14· 0 citations· 44 references
Medicine
TL;DR
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.
Abstract
Introduction Diabetic chronic wounds resist healing because persistent bacterial infection, excessive reactive oxygen species (ROS), unresolved pro-inflammatory responses, impaired angiogenesis, and defective tissue remodelling act simultaneously and reinforce one another. We therefore developed an injectable, microenvironment-responsive nanocomposite hydrogel, AP@EM-gel, to target these interconnected pathological processes. Methods AP@EM-gel was constructed from dopamine-grafted alginate (Alg-DA), phenylboronic-acid-modified ε-poly-L-lysine (EPBA), and co-assembled epigallocatechin gallate–metformin nanoparticles (EGCG-MET NPs). Its physicochemical properties, pH/ROS-responsive drug release, antibacterial and antioxidant activities, cytocompatibility, pro-angiogenic effects, and macrophage-modulating capacity were evaluated in vitro. Therapeutic efficacy was further assessed in a streptozotocin-induced diabetic rat model of Staphylococcus aureus-infected full-thickness wounds. Results Dynamic boronate-ester crosslinking produced a self-healing and injectable network that released approximately 73% of EGCG and 68% of metformin under combined pH 6.4 and H2O2 conditions, compared with approximately 38% and 36%, respectively, at pH 7.4. AP@EM-gel achieved antibacterial rates of approximately 93% against S. aureus and 91% against Escherichia coli, exhibited broad-spectrum radical-scavenging activity, and showed favourable cyto- and haemocompatibility. It restored VEGF and bFGF expression in oxidatively stressed endothelial cells and promoted macrophage repolarisation toward the reparative M2 phenotype. 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. Discussion AP@EM-gel simultaneously interrupts infection, oxidative stress, dysregulated macrophage polarisation, and impaired angiogenesis. This pathology-responsive, multi-target hydrogel represents a promising smart dressing for infected diabetic wound regeneration.
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
A precision-engineered hydrogel that integrates structural integrity with environment-triggered delivery and seamlessly coupling nanocontrolled release with microenvironmental sensing is presented, presenting a precision-engineered platform for the synergistic treatment of recalcitrant diabetic wounds.
(1) Background: Impaired diabetic wound healing stems from systemic dysregulation of the wound-healing cascade under hyperglycemic conditions, producing a disordered microenvironment marked by sustained inflammation, defective angiogenesis, and aberrant extracellular matrix remodeling, multifactorial, multistage pathological interactions demanding multi-target intervention. (2) Methods: We constructed a multifunctional nanocomposite hydrogel dressing (PGAs@CDV) based on a “drug-carrier integration” strategy, targeting the dysregulated hemostasis, inflammation, and proliferation phases of diabetic wound healing. An amphiphilic micelle carrier (PNO-GA) was synthesized by covalently conjugating Panax notoginseng oligosaccharide with gallic acid, loaded with Anemoside B4 to yield drug-loaded nanomicelles (PGAs), embedded into a carboxymethyl chitosan-dopamine-vanillin hydrogel (CDV) matrix to form PGAs@CDV. We then examined how PGAs@CDV affected diabetic wound healing. (3) Results: In vitro, PGAs@CDV enhanced cell migration and angiogenic capacity, exhibited potent antioxidant activity, and promoted M1-to-M2 macrophage polarization. We tested PGAs@CDV in a streptozotocin-induced diabetic mouse wound model. Wounds treated with PGAs@CDV closed faster than those treated with the control, CDV, PNO@CDV, and AB4@CDV. Four readouts tracked this difference: hemostasis was quicker, inflammation was lower, more blood vessels formed, and collagen deposition was higher. At the pathway level, PGAs@CDV suppressed NF-κB signaling and activated PI3K/AKT/HIF-1α. These two arms map onto the anti-inflammatory and pro-angiogenic effects observed above. (4) Conclusions: This nanocomposite hydrogel integrates a bioactive carrier with a therapeutic payload to enable coordinated intervention across multiple phases of diabetic wound repair. By combining structural support with sustained pharmacological activity, it offers a promising strategy for the treatment of chronic diabetic wounds.
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
A multifunctional hydrogel dressing was constructed from carboxymethyl chitosan and oxidized dextran as the dynamic network, incorporating CeO2 nanozymes for early anti-inflammatory and antioxidant effects and PLGA microspheres loaded with astragaloside IV for sustained pro-regeneration.
Xihao Wang, Jingting Huang, Chuipin Kong et al.· ACS Applied Materials and In...· 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
