Table 2.
Animal studies investigated effect of NO·-releasing hydrogels on DM wounds
| Study | Year | Species | DM model | BW (g) | Wound model | NO- donor | Concentration in hydrogel | Endpoints | Findings | |
|---|---|---|---|---|---|---|---|---|---|---|
| Liu et al.95 | 2024 | Male mice | STZ | NR | Excision (8 mm)- MRSA- infected | BNN6 | 0.2 mg/mL | Antibacterial, antioxidant, and angiogenic properties | ↑ Re-epithelialization ↑ Collagen deposition ↓ Expression of IL-6 ↑ Expression of IL-10 |
↑ VEGF and CD31 ↓ ROS generation ↑ Wound healing rate Eradication of S.A (97.3%) |
| Huang et al.95 | 2024 | Male mice | STZ | 20-22 | Excision (8 mm) M RSA- infected | GSNO | 50 μmol/mL | Antibacterial, angiogenic, anti-inflammatory, and wound-healing properties | ↑ Ml to M2 polarization ↓ Inflammatory cells ↓ Expression of TNF-α ↑ Fibroblasts ↑ Collagen concentration and deposition |
↑ Expression of VEGF ↑ Re-epithelialization and dermal regeneration ↓ Remaining scar Eradication of S.A and E.C (100%) |
| Yang et al.68 | 2024 | Male mice | STZ+ HFD | 20±5 | Excision (6 mm) | L-Arg | 200 μg/mL | Antioxidant, angiogenic, anti-inf lammatory, and wound-healing properties | ↑ NO· production ↓ ROS generation ↑ O2 in wound tissues ↓ Expression of IL-lβ and IL-6 |
↑ Polarization of M1 to M2 macrophages ↑ Expression of HIF-1α, VEGF, and PCNA |
| Sivaraj et al.59 | 2023 | Female mice | db/db | NR | Excision (6 mm) | NaNO2 | 2 g/100 mL, 10 nM NO•/h | Wound healing | ↑ Tissue density ↑ Collagen networks ↑ Expression of fibronectin, and TGF-β1 |
↑ Wound healing rate ↓ Wound closure time |
| He et al.97 | 2023 | Male mice | STZ | NR | Excision | BNN6 | 2 mg/mL | Antioxidant, angiogenic, anti-inf lammatory, and wound-healing properties | ↑ Wound contraction ↑ Collagen content ↑ Thickness of newly formed epidermis ↑ Angiogenesis |
↓ ROS generation ↑ Expression of VEGF ↓ Expression of TNF-α, Eradication of S.A and E.C (100%) |
| Zhang et al.98 | 2023 | Male mice | STZ | 20–25 | Excision (10 mm) | L-Arg | 1 g | Epithelization, angiogenic, anti-inflammatory, and wound-healing properties | ↑ Epithelial formation ↑ Collagen deposition ↓ Inflammation |
↑ Expression of HIF-1α ↑ Angiogenesis |
| He et al.99 | 2024 | Male rats | STZ | 200–250 | Excision (15 mm) S.A-infected | BNN6 | 2 mg/mL | Antibacterial, angiogenic, anti-inflammatory, and wound healing properties | ↓ ROS generation ↓ Expression of IL-6, TNF-α, CD86 ↑ Expression of IL-10 |
↑ Expression of CD31 and CD206 ↑ Wound healing rate |
| Zhao et al.100 | 2022 | Male rats | STZ | 180–220 | Ischemic-excision (15 mm) | NO· microbubble | 6.0 × 108 NO• microbubbles | Angiogenic, anti-inflammatory, and wound healing properties | ↓ Expression of IL-1β, IL-6, and TNF-α ↑ Expression of IL-10, IL-22, and IL-13 |
↑ Angiogenesis ↑ Blood perfusion at the wounds ↑ Wound healing rate |
| Liu et al.101 | 2022 | Male mice | db/db | NR | Excision (10 mm) | NONOate | 100 μmο1 | Angiogenic and wound healing properties | ↑ Granulation tissue ratio ↑ Vascularization |
↑Expression of CD31 and α-SMA |
| Yang et al.102 | 2021 | Mice† | STZ | NR | Excision S.A- infected | SNP | 200 μg/mL | Antibacterial, angiogenic, anti-inflammatory, and wound healing properties | ↑ HIF-1α protein stability ↑ VEGF secretion from endothelial cells ↑ Wound closure rate |
↓ S.A and E.C (86% and 94%) ↓ Inflammation score |
| Zheng et al.67 | 2024 | Male rats | STZ | 180–220 | Excision (10 mm) | L-Arg + GSNO | 0.5 mg + 3.66 mg/mL | Antibacterial, angiogenic, anti-inf lam matory, antioxidant, and wound healing properties | ↑ Expression of HIF-1α and VEGF ↑ Cell migration rate at the 36-h ↑ Bloodvessel regeneration |
↑ Collagen deposition ↓ S.A and E.C ↑ ROS clearance ↑ Wound healing rate |
| Xie et al.103 | 2024 | Male rats | STZ | NR | Excision (10 mm) S.A-infected | GSNO | 15 g, 25 μmol NO• over 6 h | Antibacterial, angiogenic, and wound healing properties | ↑ Angiogenesis ↑ Wound healing rate ↑ Epidermal thickness |
↓ Scar widths Eradication of S.A and E.C |
| Ahmed et al.70 | 2021 | Rabbits | ALX | 1000±200 | Excision (20 mm) | SNAP | 5% | Angiogenic and wound healing properties | ↑ Wound healing rate ↑Bloodvessels density ↑ Expression of VEGF, PCNA, SDF-1α, Bcl-2, and TGF-β1 |
↑ Hydroxyproline and collagen deposition ↑ Epithelial layer formation ↓ Healing time |
Phosphate-buffered saline-releasing hydrogel was used as control group. † Not reported sex. ALX: Alloxan; Bcl-2: B-cell lymphoma 2; BMSCs: bone marrow stem cells; BNN6: N,N'-di-sec-butyl-N,N'-dinitroso-1,4-phenylenediamine; BW: body weight; CMCS: carboxymethyl ch¡tosan; DM: diabetes mellitus; E.C: Escherichia coli; GSNO: S-nitrosoglutathione; HFD: high-fat diet; HIF-1: hypoxia-inducible factor-1; IL: interleukin; L-Arg: L-arginine; MRSA: methiciIIin-resistant Staphylococcus aureus; NaNO2: sodium nitrite; NO·: nitric oxide; NONOate: diazeniumdiolate; NR: not reported; PCNA: proliferating cell nuclear antigen; ROS: reactive oxygen species; S.A: Staphylococcus aureus; SDF-1α: stromal cell-derived factor-1α; SNAP: S-nitroso-N-acetyl-penicillamine; SNP: sodium nitroprusside; STZ: streptozotocin; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; VEGF: vascular endothelial growth factor; α-SMA: α-smooth muscle actin.