Collagen-oxidized hyaluronic acid injectable self-healing hydrogel enabling sequential platelet-rich plasma release for microenvironment modulation in diabetic wound repair.

A fluorescent hydrogen sulfide donor featuring hydroxyl radical responsiveness promotes diabetic wound healing through the regulation of macrophage polarization.

Thermosensitive citrate-based mussel-inspired attack-defense integrated bioadhesives facilitate complicated wound healing.

Mitophagy-activating nanozyme hydrogel for enhanced diabetic wound healing.

MMP-9-responsive bFGF/FGF21 patch synergistically piloting the immune remodeling and regeneration of diabetic wounds.

Diabetic foot ulcer (DFU) is characterized by persistent inflammation, metabolic dysfunction, and impaired angiogenesis, leading to refractory chronic wounds. Here, we report an adhesive, metformin-loaded (1.0 mM) polyethylene glycol (PEG) based hydrogel (i.e., PEG/Met), constructed from equal volumes of PEG-SG (20 wt.%) and PEG-NH2 (20 wt.%), to regulate macrophage polarization and metabolism in DFU. Density functional theory (DFT) calculations and infrared spectra confirmed its crosslinking, yielding a homogeneous PEG network with strong tissue adhesion (31.4 ± 8.6 kPa) and sustained drug release till seven days (total release: 86.8 ± 0.6%). In a rat DFU model, the PEG/Met significantly accelerated wound closure (wound recovery: 91.9 ± 3.4%, which was 1.96-fold to the control), collagen deposition, M2-like macrophage infiltration, and neovascularization. Under lipopolysaccharides (LPS) or Staphylococcal protein A (SpA) induced pro-inflammatory stimulation, the PEG/Met suppressed glycolytic flux, reduced glucose uptake and consumption, yet increased adenosine triphosphate (ATP) production and restored oxygen consumption, indicating a shift from glycolysis toward oxidative phosphorylation (OXPHOS). Likewise, the PEG/Met restored mitochondrial membrane potential, reduced reactive oxygen species (ROS) accumulation, increased Egln3 expression, and decreased Hif-1α and IL-1β levels, thereby alleviating Hif-1α-driven inflammatory signaling. Pharmacologic inhibition of OXPHOS with rotenone reversed PEG/Met-induced M2 polarization and reactivated pro-inflammatory gene expression, confirming the intact mitochondrial respiration for its immunoregulatory effects. This PEG/Met hydrogel functioned as both an adhesive, drug-delivery platform and immune-metabolic modulator, effectively reprogramming macrophage phenotype and mitochondrial metabolism, which held substantial promise as a localized therapy for DFU and other chronic wounds. STATEMENT OF SIGNIFICANCE: Diabetic foot ulcer (DFU) is a leading cause of limb loss worldwide, as traditional dressings only passively cover wounds without resolving chronic inflammation caused by metabolic and immune disorders. Here, we fabricated a polyethylene glycol (PEG) based adhesive hydrogel for local metformin delivery (PEG/Met), which achieved strong tissue adhesion, biodegradability, and sustained drug release. The hydrogel reprogrammed macrophage metabolism from glycolysis to oxidative phosphorylation, thereby improving mitochondrial function, decreasing mitochondrial reactive oxygen species, enhancing Egln3-mediated Hif-1α ubiquitination, and alleviating IL-1β-mediated inflammation. This hydrogel created a pro-angiogenic microenvironment to accelerate DFU healing in vivo. By linking the clinically approved metformin, this adhesive hydrogel platform offered a translational strategy for treating DFU and other chronic wounds.

Procyanidin capsules attenuate PI3K/AKT-mediated mitochondrial dysfunction and accelerate skin wound healing in diabetic mice.

Biorthogonal click-immobilized probiotic membrane vesicles in a dynamic hydrogel for accelerated and scar-minimized wound healing

Aptamer-guided upconversion nanoconstructs enable proximity-dependent and precise photodynamic therapy for MRSA-infected wounds.

Aloe vera polysaccharides facilitate diabetic wound healing by promoting macrophage M2 polarization through inhibition of NLRP3 inflammasome activation.

Structural characterization of a fructan from Kalimeris indica and its efficacy in accelerating wound healing.

A self-healing, pH/glucose-responsive carboxymethyl chitosan and oxidized bacterial nanocellulose hydrogel for insulin and taurine delivery in diabetic wound healing.

Duo-nano exosome encapsulating hydrogel boosts wound healing across xenogenic and allogenic models.

A photocuring double-network hydrogel enhances mechanotransduction and scavenges ROS to accelerate pressure injury healing.

Glucose-responsive "sense-and-treat" microneedle patch for promoting diabetic chronic wound healing.

Endoscopic submucosal dissection (ESD), while a gold-standard minimally invasive technique for treating early-stage intestinal cancers, poses significant challenges for postoperative mucosal repair, owing to the risk of complications such as bleeding, perforation, and infection. Existing strategies often fail to provide a bioactive healing microenvironment. This study presents a Resolvin E1 (RvE1)-loaded, mucin-based injectable hydrogel (MHSR) designed to address these limitations. Employing a component-based biomimetic approach, this hydrogel combines thiol-modified mucin (MUC-S) with zwitterionic methacrylated hyaluronic acid (HA-SB-MA) via thiol-ene click chemistry. The MHSR hydrogel demonstrates good injectability, self-healing properties, and adhesion to positively charged inflamed tissues via electrostatic interactions and disulfide bonds. It establishes a strong physical barrier that effectively resists biofouling from proteins, cells, and bacteria. Notably, MHSR orchestrates comprehensive mucosal regeneration by scavenging reactive oxygen species (ROS), modulating inflammatory responses, enhancing angiogenesis, restoring tight junction integrity, normalizing goblet cell function, and regulating gut microbiota. In the rat model of rectal ESD, MHSR significantly accelerated wound closure, reduced inflammation, and promoted functional restoration of the mucosal barrier. This multifunctional hydrogel system constitutes a highly promising biomimetic strategy for promoting mucosal repair and remodeling of the intestinal microenvironment after ESD. STATEMENT OF SIGNIFICANCE: The study reports a mucin-based injectable hydrogel (MHSR) loaded with Resolvin E1 for rectal mucosal repair after endoscopic submucosal dissection. It combines thiol-modified mucin and zwitterionic hyaluronic acid to form an adhesive, self-healing barrier with anti-biofouling properties. The hydrogel scavenges reactive oxygen species, modulates inflammation, promotes angiogenesis, restores mucosal integrity, and regulates gut microbiota. It significantly accelerates wound healing and reduces complications in a rat ESD model, offering a promising strategy for post-operative regenerative therapy.

An adhesive chitosan microneedle patch incorporating a Sargassum-derived polysaccharide for skin repair.

Duo-nano exosome encapsulating hydrogel boosts wound healing across xenogenic and allogenic models.

Extracellular biogenic nanoscale mitochondria reprogram the wound microenvironment via ROS scavenging independent of cellular uptake

Thermally denatured dermal matrix enhances diabetic wound vascularization by reactivating mitophagy.