Jul 2026· International Journal of Biological Macromolecules· pp.
153831
· 0 citations· 186 references
Medicine
TL;DR
The physicochemical properties of chitosan are summarized and the molecular mechanisms underlying hydrogel-mediated diabetic wound repair are systematically examined, including cation-mediated disruption of microbial membranes, Keap1/Nrf2-dependent antioxidant signaling, NF-κB-regulated immunomodulation, and VEGF-driven angiogenic pathways.
Abstract
Diabetic ulcers pose significant therapeutic challenges driven by hyperglycemia-induced oxidative stress, chronic inflammation, and microbial infection. While conventional dressings often fail to address these complex microenvironments, hydrogels have emerged as a premier platform for advanced wound management. Among these, chitosan-based hydrogels stand out for their intrinsic antimicrobial activity, biocompatibility, and tunable properties, enabling active orchestration of wound healing. Their therapeutic effects involve neutralizing oxidative stress, polarizing macrophages to resolve inflammation, and promoting angiogenesis for extracellular matrix remodeling. Moreover, these hydrogels can serve as multifunctional, stimuli-responsive platforms for the controlled delivery of drugs, growth factors, extracellular vesicles, nucleic acids, and even living cells, allowing precise spatiotemporal control of cargo release. This review summarizes the physicochemical properties of chitosan and systematically examines the molecular mechanisms underlying hydrogel-mediated diabetic wound repair. These include cation-mediated disruption of microbial membranes, Keap1/Nrf2-dependent antioxidant signaling, NF-κB-regulated immunomodulation, and VEGF-driven angiogenic pathways. In parallel, recent advances are critically evaluated in three key areas: stimuli-responsive delivery systems (triggered by pH, reactive oxygen species, matrix metalloproteinases, or glucose), biologically functionalized scaffolds incorporating extracellular vesicles, microRNAs, and stem cells, and 3D-bioprinted constructs tailored to individual patients. Current translational challenges are also addressed, particularly the complexity of regulatory classification and the lack of standardized preclinical models. Finally, future strategies are discussed for the rational design and clinical translation of next-generation diabetic wound dressings, with an emphasis on bridging the gap between bench research and bedside application.
Refractory diabetic wounds are chronic healing disorders characterized by a complex pathological microenvironment involving excessive oxidative stress, persistent inflammation, bacterial infection, and impaired angiogenesis. Existing functional nanobiomaterials often exhibit rapid release and limited therapeutic functionality, resulting in insufficient retention at wound sites and inadequate regulation of the different stages of wound healing. To address these limitations, we developed a composite hydrogel incorporating organic-inorganic peptide-zinc nanoflowers for sustained local delivery. The nanoflowers were formed through the co-assembly of Zn²⁺ with azide-functionalized FP2 (N₃-ERGVVSIKGV) and subsequently covalently immobilized within a click-crosslinked hyaluronic acid network via strain-promoted azide-alkyne cycloaddition. The hierarchical nanoflower architecture, covalent immobilization, and hydrogel network confinement collectively prolonged local retention and enabled sustained release of the bioactive components. The resulting hydrogel regulated the diabetic wound microenvironment through antibacterial, antioxidant, anti-inflammatory, and pro-angiogenic activities, thereby promoting tissue regeneration and accelerating wound closure. These findings demonstrate a multifunctional sustained-delivery strategy for the treatment of complex diabetic wounds.
Xin Dan, Han Chen, Song-Jie Li et al.· Regenerative Biomaterials· 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.
Xi-Hao Wang, Jing-Ting Huang, Chuipin Kong et al.· ACS Applied Materials and In...· 0 citations
Chronic wounds are complex environments marked by persistent inflammation, oxidative stress, hypoxia, and conditions that favor antimicrobial resistance (AMR). Conventional antibiotics often fail due to bacterial persistence and the physicochemical barriers of the wound milieu. Biofilm-associated extracellular polymeric substances (EPS), efflux pump activity, quorum sensing (QS), and horizontal gene transfer (HGT) collectively drive antimicrobial tolerance and resistance dissemination, turning chronic wounds into reservoirs of multidrug-resistant pathogens. Consequently, emerging wound therapies demand multifunctional strategies that modulate the wound microenvironment while interfering with resistance-associated phenotypes. Hydrogel–metal–organic framework (MOF) composites have been explored as multifunctional interfaces that combine extracellular matrix-mimetic properties, tunable porosity, stimuli-responsiveness, and controlled therapeutic delivery with the bioactive functions of MOFs. Depending on their composition and architecture, these systems may exert antimicrobial and antibiofilm effects through ionic, electrostatic, osmotic, catalytic, and oxidative mechanisms, while also influencing ROS levels, inflammation, angiogenesis, and local drug transport. However, antimicrobial activity alone does not equate to resistance modulation. Evidence for direct effects on efflux systems, resistance phenotypes, or HGT remains inconsistent across reported platforms. This review critically examines representative hydrogel–MOF systems for chronic wound applications, comparing their composition, physicochemical properties, biological functions, proposed resistance-related mechanisms, advantages, limitations, and current level of evidence. We emphasize distinguishing experimentally demonstrated resistance-modulating effects from mechanistically proposed functions, and identifying design trade-offs and evidence gaps that must be addressed to develop wound interfaces capable of both supporting tissue regeneration and improving infection control.
Nallely G. Hernández-Hernández, Irving A. González-Lara, L. K. Usme-Duque et al.· Gels· 0 citations
Abstract Diabetic chronic wounds (DCWs) are difficult to heal due to the synergistic effects of bacterial infection, immune dysregulation, persistent oxidative stress, and microcirculatory impairment, posing a major challenge in tissue regeneration. Self-assembled hydrogels (SAHs), owing to their molecular programmability, tunable network architectures, and ability to respond to the pathological wound microenvironment, have demonstrated unique advantages in the repair of complex chronic wounds. This review summarizes the roles of various interactions, including hydrogen bonding, π-π stacking, metal coordination, hydrophobic interactions, electrostatic interactions, and dynamic covalent bonds, in constructing three-dimensional hydrogel networks. It further discusses the main design strategies and biological functionalities of SAHs, encompassing short peptides, polysaccharides, metal ions, nucleic acids, cyclodextrins (CDs), and dynamic covalent crosslinking materials. This review focuses on the pathological characteristics of DCWs and highlights recent research progress on SAHs in antibacterial, anti-inflammatory, antioxidative, immunomodulatory, pro-angiogenic, and tissue regeneration applications. Although various SAHs have demonstrated promising therapeutic efficacy in preclinical animal models, clinical practice still largely relies on conventional hydrogel formulations. Future efforts should focus on strengthening the integration between material design and pathological mechanisms, as well as establishing standardized evaluation frameworks, to facilitate the clinical translation of SAHs for the treatment of DCWs.
Wan-Ru Wang, Bing-Tao Zhai, Jiang-Xue Cheng et al.· International Journal of Nan...· 0 citations
Chronic wounds affect over 20% of diabetic patients, imposing substantial socioeconomic and personal burdens. The diabetic wound microenvironment is characterized by hyperglycaemia, oxidative stress, persistent inflammation, and vascular damage, which disrupt tissue homeostasis and significantly hinder healing. The development of innovative multifunctional hydrogels is essential for treating diabetic wounds within such complex microenvironments. Based on metal-organic framework nanomaterials, this study introduces a dual-network crosslinked adhesive GelNB/HAMA hydrogel incorporating magnesium ions and Quercetin-based metal-organic frameworks (denoted as MgQu@GelNB/HAMA). In vitro experiments revealed that Mg-quercetin metal-organic framework (MgQu) promotes macrophage polarization from M1 to M2 type, scavenges reactive oxygen species, and stimulates neovascularization. Photopolymerization technology is employed to solidify the hydrogel into a dressing, ensuring strong adhesion to the wound site and minimizing secondary tissue damage while facilitating sustained, controlled release of Quercetin and magnesium ions. In a dorsal wound model of diabetic mice, this in situ formed multifunctional hydrogel dressing effectively reduces excessive inflammation, enhances neovascularization, accelerates collagen tissue regeneration, and advances wound healing. By improving the pathological microenvironment of diabetes, this study presents a promising new strategy for diabetic wound repair.
Yunshu Yang, Bin Tang, Meng Zhou et al.· Materials Today Bio· 0 citations
Diabetic refractory wounds are a prevalent and severe complication of diabetes, whose pathological progression is jointly mediated by multiple factors, including oxidative stress imbalance, chronic inflammation, impaired angiogenesis, bacterial infection, and biofilm formation. Current clinical hydrogel dressings generally suffer from drawbacks such as single-function performance, potential toxicity of nano-components, static networks incompatible with dynamic wound conditions, and the absence of bionic repair signals. Therefore, they cannot simultaneously satisfy the dual repair requirements of complex pathological microenvironments and dynamic mechanical properties for diabetic wounds. In this study, a multi-functional dynamically responsive composite hydrogel (MC group) with high-efficiency antioxidant, antibacterial, and pro-angiogenic capacities was fabricated. Using SDS-C18 micelles as hydrophobic units, a rigid–flexible dual-network framework was constructed with polyvinyl alcohol (PVA) and methacrylated hyaluronic acid (HAMA). Manganese dioxide nanozymes were introduced to scavenge reactive oxygen species (ROS) and mitigate oxidative stress. Calcium-ion-mediated dynamic micelle reconstruction was adopted to regulate the hydrophilic–hydrophobic balance, while achieving antibacterial effects and facilitating tissue regeneration. In vitro experiments verified that the MC hydrogel possesses mechanical properties well-matched to human soft tissues (fracture stress: 25 kPa) and excellent biocompatibility (cell viability > 100%, hemolysis rate: only 0.13%). It also exhibits prominent antioxidant activity (DPPH radical-scavenging rate: 36.95%), antibacterial performance (>99.86% bactericidal rate against Staphylococcus aureus, survival rate of Escherichia coli reduced to 15.95%), and cell-migration-promoting activity (endothelial cell migration rate of 83.72% and mouse fibroblast migration rate of 90.88% within 24 h). In the full-thickness skin defect model of diabetic mice, the wound-healing rate reached 99% on day 16. Moreover, it promoted ordered collagen deposition, skin appendage regeneration, and functional microvascular reconstruction, thereby accomplishing high-quality tissue repair. This design synergistically intervenes in multiple pathological links of diabetic wounds, overcomes several key limitations of existing dressings, and provides an innovative strategy for developing smart dressings.
Yan-Ling Li, Yu-Han Mao, Jie Zhang et al.· Gels· 0 citations
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