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<p>Diabetic wounds often result in non-healing chronic ulcers due to prolonged inflammation, oxidative stress and impaired tissue regeneration. Current hydrophilic wound dressings primarily function as absorption dressings and have limited tissue regeneration capabilities, leading to extended healing periods. Peptides have been identified as therapeutic macromolecules with several cellular modulatory functions. They possess cell adhesion, matrix formation, cell proliferation, angiogenesis and tissue regenerative properties that are essential for wound healing. Therefore, a novel fluorenylmethoxycarbonyl-substituted arginine–glycine–aspartic acid (FRGD) oligopeptide was co-incorporated with mesoporous silica into poloxamer 407/PEG 8000 hydrogel base in five formulations (F0–F4) intended to modulate the impaired regenerative microenvironment of diabetic wounds. Formulations were characterised for pH, texture, rheology, morphology, DSC and FT-IR, and the formulations were evaluated in streptozotocin–nicotinamide-induced diabetic Sprague Dawley rats with full-thickness dorsal excisional wounds using daily topical application for 15 days. Healing outcomes were assessed by wound closure measurements, histology, immunohistochemistry, immunofluorescence, qRT-PCR and ELISA. The hydrogels exhibited a near-physiological pH (7.26–7.33), suitable hardness (18.0–32.3&#xa0;g) and a thermoreversible sol–gel transition, with apparent viscosity at low shear rising from ≈ 33.2&#xa0;kPa·s at 25&#xa0;°C to ≈ 47.0&#xa0;kPa·s at 32&#xa0;°C, indicating in situ gelation at skin temperature. In vivo, F4 formulation with FRGD oligopeptide significantly accelerated wound closure from day 6 onwards (<i>p</i> &lt; 0.01), achieving near-complete re-epithelialisation by day 15 compared to the positive control. Histologically, F4 formulation-treated wounds showed continuous stratified epidermis, organised collagen alignment, hair-follicle regeneration and reduced inflammation. At the molecular level, F4 formulation significantly reduced Tgfb1 and Smad5, normalised Smad2 and reactivated the Wnt/β-catenin pathway (Wnt10a, Ctnnb1). Angiogenic (Vegfa, Pecam1, Hif1a) and ECM remodelling markers were restored, with enhanced COL1A1 deposition and CD31-positive neovascularisation. F4 formulation also suppressed pro-inflammatory mediators (Tnf, Il1b, Il6, Nfkb1) and elevated IL-10 at both gene and protein levels, indicating a reparative immune environment. Collectively, these findings indicate that the FRGD/mesoporous silica hydrogel can modulate the TGF-β/Smad and Wnt/β-catenin pathways and support tissue repair in a diabetic wound model. Long-term remodelling and scar-quantification studies are required to confirm accelerated healing.</p>

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Thermoresponsive hydrogel of a synthetic oligopeptide and mesoporous silica modulates TGF-β/Smad and Wnt/β-catenin pathways for enhanced diabetic wound healing

  • 期刊论文

  • 发表日期：

    2026年7月20日

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  • Rasika Krishnan,
  • Nelli Giribabu,
  • Najihah Mohd Hashim,
  • Rafl M. Kamil,
  • Srinivasa Rao Nelli,
  • Shaik Nyamathulla

摘要

Diabetic wounds often result in non-healing chronic ulcers due to prolonged inflammation, oxidative stress and impaired tissue regeneration. Current hydrophilic wound dressings primarily function as absorption dressings and have limited tissue regeneration capabilities, leading to extended healing periods. Peptides have been identified as therapeutic macromolecules with several cellular modulatory functions. They possess cell adhesion, matrix formation, cell proliferation, angiogenesis and tissue regenerative properties that are essential for wound healing. Therefore, a novel fluorenylmethoxycarbonyl-substituted arginine–glycine–aspartic acid (FRGD) oligopeptide was co-incorporated with mesoporous silica into poloxamer 407/PEG 8000 hydrogel base in five formulations (F0–F4) intended to modulate the impaired regenerative microenvironment of diabetic wounds. Formulations were characterised for pH, texture, rheology, morphology, DSC and FT-IR, and the formulations were evaluated in streptozotocin–nicotinamide-induced diabetic Sprague Dawley rats with full-thickness dorsal excisional wounds using daily topical application for 15 days. Healing outcomes were assessed by wound closure measurements, histology, immunohistochemistry, immunofluorescence, qRT-PCR and ELISA. The hydrogels exhibited a near-physiological pH (7.26–7.33), suitable hardness (18.0–32.3 g) and a thermoreversible sol–gel transition, with apparent viscosity at low shear rising from ≈ 33.2 kPa·s at 25 °C to ≈ 47.0 kPa·s at 32 °C, indicating in situ gelation at skin temperature. In vivo, F4 formulation with FRGD oligopeptide significantly accelerated wound closure from day 6 onwards (p < 0.01), achieving near-complete re-epithelialisation by day 15 compared to the positive control. Histologically, F4 formulation-treated wounds showed continuous stratified epidermis, organised collagen alignment, hair-follicle regeneration and reduced inflammation. At the molecular level, F4 formulation significantly reduced Tgfb1 and Smad5, normalised Smad2 and reactivated the Wnt/β-catenin pathway (Wnt10a, Ctnnb1). Angiogenic (Vegfa, Pecam1, Hif1a) and ECM remodelling markers were restored, with enhanced COL1A1 deposition and CD31-positive neovascularisation. F4 formulation also suppressed pro-inflammatory mediators (Tnf, Il1b, Il6, Nfkb1) and elevated IL-10 at both gene and protein levels, indicating a reparative immune environment. Collectively, these findings indicate that the FRGD/mesoporous silica hydrogel can modulate the TGF-β/Smad and Wnt/β-catenin pathways and support tissue repair in a diabetic wound model. Long-term remodelling and scar-quantification studies are required to confirm accelerated healing.