Fabrication and characterization of asiaticoside-incorporated silk fibroin/hyaluronic acid hydrogel with immunomodulatory properties for diabetic wound management.
Aug 2026· International Journal of Biological Macromolecules· pp.
154098
· 0 citations· 71 references
Medicine
TL;DR
Results suggest that ASHF supports diabetic wound repair through coordinated regulation of redox balance, macrophage polarization, and tissue reconstruction, highlighting its potential as a multifunctional dressing for chronic diabetic wounds.
Abstract
Diabetic foot ulcers (DFUs) arise within a dysregulated wound microenvironment in which sustained inflammation, bacterial susceptibility, and excessive oxidative stress collectively impede tissue repair. To address these interrelated barriers, we developed an asiaticoside-loaded silk fibroin/hyaluronic acid composite hydrogel (ASHF) as a bioactive dressing that couples structural support with localized drug delivery. By optimizing the mass ratio of its components, the resulting hydrogel achieved an excellent balance among mechanical compliance, swelling capacity, tissue adhesion, water vapor transmission rate, and enzymatic degradation. In vitro experiments demonstrated that ASHF released asiaticoside in a two-stage manner, was well tolerated by fibroblasts, promoted cell migration, and inhibited Escherichia coli and Staphylococcus aureus. In vivo evaluation in a diabetic mouse model revealed that ASHF-treated wounds closed more rapidly and showed stronger collagen deposition, CD31-positive neovascularization, and re-epithelialization. Dual immunofluorescence staining demonstrated a significant reduction in M1 macrophages (CD68+/CD86+) and a concurrent increase in M2 macrophages (CD68+/CD206+), alongside favorable shifts in local cytokines (decreased IL-6 and increased IL-10). These findings indicate an effective transition of the local immune microenvironment from persistent inflammation toward a pro-reparative state. Transcriptomic analysis of wound tissues further indicated that ASHF intervention was associated with enrichment of glutathione-related metabolic programs and epidermal differentiation signatures, together with upregulation of key genes including Gstm3, Aox4, Hal, and Krt1. These results suggest that ASHF supports diabetic wound repair through coordinated regulation of redox balance, macrophage polarization, and tissue reconstruction, highlighting its potential as a multifunctional dressing for chronic diabetic wounds.
Diabetic foot ulcers (DFUs) are common and serious problems in diabetes patients. They also represent one of the leading causes of non-traumatic lower limb amputation worldwide. Despite improvements in clinical care, numerous standard therapies fail to completely close chronic diabetic wounds. Cell-free fat extract (Ceffe) aids tissue repair and angiogenesis but its clinical worth is greatly reduced by rapid diffusion and enzymatic degradation in the wound. Silk fibroin methacryloyl (SilMA) can be formulated into a photocrosslinked hydrogel capable of sustained delivery of bioactive factors, whereas polydopamine (pDA) provides durable wet-tissue adhesion. In this work, we developed a multifunctional composite hydrogel pSilMA@Ceffe (polydopamine-coated SilMA hydrogel loaded with Ceffe) that integrates the prolonged release properties of SilMA with the tissue-binding strength of pDA to enhance healing of refractory diabetic wounds. We prepared and characterized pSilMA@Ceffe with respect to physicochemical properties, printability, and release kinetics. Cellular assays and diabetic mouse models employed used to assess biocompatibility. Cell proliferation, migration, and tube formation were evaluated using in vitro assays, while full-thickness skin wounds in db/db mice were used to determine in vivo efficacy. Wound closure was monitored at multiple time points, and tissue regeneration was assessed via H&E, Masson's trichrome, and immunofluorescent staining for CD31, keratin 1 (K1), Ki-67, and type I collagen (Col-1). The final hydrogel had satisfactory 3D printability, stable tissue adhesion, and constant long-term release of Ceffe. It supported cell survival and significantly enhanced proliferation, migration, and angiogenic activity in culture. In diabetic mice, pSilMA@Ceffe accelerated wound healing, neovascularization, and cell proliferation, and promoted more organized collagen deposition in the regenerating dermis. Combining photocrosslinkable handling with robust pro-regenerative activity, pSilMA@Ceffe represents an effective and translatable candidate for the clinical treatment of chronic diabetic wounds.
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Chronic diabetic wounds remain a major clinical challenge owing to persistent bacterial infection, prolonged inflammation, excessive exudation, and impaired tissue regeneration. Herein, an injectable thermosensitive hydrogel was developed by integrating N-[(2-hydroxy-3-trimethylammonium)propyl] chitosan chloride with aldehyde-functionalized Pluronic F127 for epidermal growth factor (EGF) delivery and diabetic wound repair. The hydrogel forms a dual-crosslinked network through temperature-induced micellization and dynamic Schiff base bonding, exhibiting rapid gelation under physiological conditions, shear-thinning behavior, and self-healing properties. In vitro, the hydrogel provides a sustained release profile of EGF exhibiting effective antibacterial activity against Gram-positive S. aureus. In vivo studies in streptozotocin-induced diabetic rats demonstrate significantly accelerated wound healing, achieving 83% wound closure within 14 days compared to 45% in the control group, along with enhanced tissue regeneration characteristics, including improved collagen deposition. This multifunctional hydrogel provides a promising strategy for diabetic wound management by integrating antibacterial potential and tissue regeneration.
Excessive fibrosis and implant-associated infections remain major challenges in wound healing and post-surgical tissue repair, often resulting in impaired regeneration and long-term complications. Although gelatin methacryloyl (GelMA) hydrogels are widely used in regenerative medicine due to their biocompatibility and tunable physicochemical properties, they intrinsically lack antifibrotic and antibacterial functionality. Herein, we report a dual-functional GelMA-based hydrogel (GelMA-AMP/AFP) achieved by the covalent co-conjugation of an antifibrotic peptide (DR8) and a broad-spectrum antimicrobial peptide (P9-4), enabling simultaneous regulation of fibrotic responses and bacterial colonization within a single biomaterial platform. The peptide-functionalized GelMA hydrogels preserved their porous microarchitecture, mechanical integrity, and swelling behavior while providing a sustained peptide release profile over 14 days. In a TGF-β1-induced in vitro fibrotic fibroblast model, the dual-functional hydrogel significantly suppressed fibroblast proliferation and migration, reduced collagen deposition, and downregulated key profibrotic markers, including COL1A1, ACTA2, FN1, and TGF-β1, at both gene and protein levels. In parallel, the same GelMA-AMP/AFP platform effectively inhibited bacterial adhesion and biofilm formation by multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA), without inducing cytotoxicity. This study reports a GelMA-based biomaterial to simultaneously integrate covalently conjugated antifibrotic and antimicrobial peptides, thereby achieving concurrent suppression of fibrosis and inhibition of biofilm formation within a single material system, in vitro. By combining complementary biological functionalities without compromising material properties, this study presents a chemically driven strategy for multifunctional biomaterial design. This strategy may provide a useful foundation for future studies targeting advanced wound dressings, post-surgical adhesion prevention, and infection-prone tissue repair, pending further in vivo validation.
Through rational core-shell design, this study integrates antioxidant and immunomodulatory functions within a single coaxially electrospun scaffold, offering a clinically translatable strategy for chronic diabetic wound repair and the comprehensive structural and functional reconstruction of skin tissue.
Kexin Feng, Xiaoyu Wang, Zichao Cai et al.· Journal of materials chemist...· 0 citations
Chronic diabetic wounds are characterized by persistent oxidative stress, impaired angiogenesis, and biofilm-associated infections, necessitating multifunctional biomaterials capable of modulating the wound microenvironment. Herein, we report an amyloid-reinforced hyaluronic acid (HA) composite hydrogel that integrates mechanical robustness, controlled drug delivery, and bioactive functionality within a single platform. The hydrogel is constructed through interpenetrating protein-polysaccharide networks, where thermally induced bovine serum albumin amyloid fibrils act as reinforcing scaffolds within the HA matrix via hydrogen bonding and chain entanglement. This architecture enhances viscoelastic properties, swelling behavior, and structural stability compared to nonreinforced systems. Curcumin is incorporated as a multifunctional therapeutic agent, exhibiting sustained and pH-responsive release governed by hydrophobic and π-π interactions within the composite network. The hydrogel demonstrates pronounced antibacterial and antibiofilm activity against both Gram-positive and Gram-negative bacteria, which is further amplified under near-infrared (NIR) irradiation via photothermal effects. In vitro studies confirm excellent cytocompatibility, hemocompatibility, and enhanced fibroblast migration, indicating favorable cellular interactions. Importantly, in a streptozotocin-induced diabetic wound model, the composite hydrogel significantly accelerates wound closure, promotes collagen deposition and neovascularization, and restores oxidative stress biomarkers toward physiological levels. Mechanistically, the combined integration of amyloid-mediated mechanical reinforcement, HA-driven bioactivity, and curcumin-enabled therapeutic functionality enables the simultaneous regulation of infection, inflammation, and tissue regeneration. This study establishes a protein-polysaccharide hybrid hydrogel platform that couples structural reinforcement with stimuli-responsive therapeutic delivery, offering a promising strategy for advanced diabetic wound management and translational biomaterial design.
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