Table 2.
Recent in vivo studies on synthetic/semi-synthetic hydrogels for diabetic wound healing.
| Ref. | Year | Polymer Source and Material |
Additional Functional Component(s) |
Synthesis Method | Diabetic Model | Therapeutic Effect |
|---|---|---|---|---|---|---|
| [69] | 2022 | Methacrylate gelatin (GelMA)/PEGDA microneedle patch | Tazarotene (1 mg/10 mL) and exosomes (100 µg/mL) from human umbilical vein endothelial cells (HUVECs) | Photopolymerization with lithium acylphosphinate salt (LAP 0.05%, g/mL) | STZ-induced male C57BL mice | Accelerated collagen deposition, epithelial regeneration, and angiogenesis. |
| [70] | 2022 | PLGA-PEG-PLGA thermosensitive hydrogel | Copper-based MOFs containing curcumin and metformin hydrochloride | Thermal gelation | STZ-induced male BALB/c mice | Significant reduction of oxidative stress; enhanced cell migration, neovascularization, and collagen formation. |
| [71] | 2022 | Injectable hydrogel prepared from 4,5-imidazoledicarboxylic acid, zinc nitrate hexahydrate, deferoxamine mesylate and glucose oxidase (GOX) | Deferoxamine mesylate (DFO, 8.3 µg/mL) | Phase- transfer-mediated programmed GOX loading | STZ-induced female BALB/c mice | Release of zinc ions and DFO resulted in enhanced antibacterial and angiogenic effect. Significant induction of re-epithelialization and collagen deposition. |
| [72] | 2022 | PDLLA-PEG-PDLLA (25% w/v) thermosensitive hydrogel | Prussian blue nanoparticles (PBNPs, 333.3 µg/mL and 666.6 µg/mL) | Thermal gelation | STZ-induced C57BL/6J mice | Decreased reactive oxygen species (ROS) production as well as IL-6 and TNF-α levels. PBNPs dose-dependent accelerated wound closure. |
| [73] | 2022 | pH/glucose dual responsive hydrogel prepared from dihydrocaffeic acid and L-Arginine co-grafting chitosan, phenylboronic acid and benzaldehyde difunctional polyethylene glycol-co-poly(glycerol sebacic acid) and polydopamine-coated graphene oxide (GO) | Metformin (2 mg/mL) | Double dynamic bond of a Schiff-base and phenylboronate ester | STZ-induced Sprague−Dawley rats | Antibacterial properties, tissue adhesion, hemostasis. Decreased inflammatory response. Increased wound closure ratio, re-epithelialization, and regeneration of blood vessels. |
| [74] | 2022 | Supramolecular guanosine-quadruplex hydrogel | Hemin (0.36–0.54 mg) and GOX (0.125–0.5 mg) | Self-assembled gelation | STZ-induced male BABL/c mice | Significantly faster antibacterial effect, relative to commercial antibiotic. Decreased glucose concentration in the wound. |
| [75] | 2022 | Chitosan/polyvinyl acetate heterogeneous hydrogel | Human epidermal growth factor (EGF)-loaded nanoparticles, polyhexamethylene biguanide, and perfluorocarbon emulsions | Freeze-thaw cycling | STZ-induced Sprague-Dawley rats | High antibacterial and anti-inflammatory effect. Enhanced collagen production and wound closure efficiency, relative to commercial dressings. |
| [76] | 2022 | Double-layered GelMA-PLL hydrogel | Vascular endothelial growth factor (VEGF)-mimetic peptide | Photopolymerization with lithium acylphosphinate salt (LAP) | STZ-induced Sprague-Dawley rats | Enhanced antibacterial and wound-healing effect. Improved collagen deposition, angiogenesis, and re-vascularization. |
| [77] | 2022 | Oxidized alginate / platelet-rich plasma (PRP) fibrin hydrogel | Ionic crosslinking with 1.22 M CaSO4·2H2O | Male db/db (BKS.Cg-m+/+Leprdb/J) mice | Accelerated wound maturation and closure. | |
| [78] | 2022 | PTFE/PU patch | Calcium-alginate hydrogel microparticles (MPs) containing Chlorella vulgaris and Bacillus licheniformis | MP encapsulation in porous PTFE membrane (inner lining) and a transparent PU film (back lining) | STZ-induced mice | Enhanced wound healing effect: 50% wound closure by day 3, and full wound closure on day 12. |
| [79] | 2021 | GelMA (10% w/v) hydrogel | Bioactive glass particles loaded with cerium (1% w/v) | Photopolymerization with LAP (0.1% w/v) | STZ-induced Sprague-Dawley rats | Wound closure of almost 95% on day 21. |
| [80] | 2021 | Cecropin-modified hyaluronic acid/ oxidized dextran / PRP composite hydrogel | Schiff base reaction | Male db/db mice | Accelerated healing of infected wounds. Shortened inflammatory stage. Increased mature collagen content. | |
| [81] | 2021 | Pluronic F-127 (20%) hydrogel | Ag nanocubes with virus-like mesoporous silica containing gentamicin | Thermal gelation | STZ-induced Kunming mice | Bacterial infected wounds were fully healed by day 20, with enhanced collagen production. |
| [82] | 2021 | Carboxymethyl chitosan/poly(dextran-g-4-formylbenzoic acid) hydrogel | Peptide-modified PAN nanofibers | Schiff base reaction | Diabetic ICR mice | Enhanced antibacterial and angiogenic effect. Reduced inflammatory response. Wound closure > 96% at day 14. |
| [83] | 2021 | Hydroxyl propyl methyl cellulose (2% w/w) hydrogel | Lipid nanoparticles loaded with Valsartan (1% w/w) | Thermal gelation | STZ-induced male Sprague-Dawley rats | Enhanced healing response mediated through COX-2, NF-κB, NO, TGF-β, MMPs and VEGF pathways. |
| [84] | 2021 | Polyacrylamide/gelatin/ε-polylysine composite hydrogel | Free-radical polymerization | STZ-induced male Sprague-Dawley rats | Increased granulation tissue formation, collagen deposition, and angiogenesis. Enhanced antibacterial effect. | |
| [85] | 2021 | Conductive hydrogel made from acrylamide-co-polymerized ionic liquid (VAPimBF4) and konjac glucomannan | Chemical crosslinking (EDC/NHS chemistry) | STZ-induced male Kunming mice | Highest wound healing rate when coupled with electrical stimulation. Increased antibacterial effect, Col-1 production, and new vessel growth. | |
| [86] | 2021 | N-carboxyethyl chitosan/adipic acid dihydrazide pH responsive hydrogel | Insulin (0.67 U/mL) | Crosslinking by hyaluronic acid-aldehyde (imine and acylhydrazone bonds) | STZ-induced male Sprague-Dawley rats | Significant reduction of glucose levels in the wound. Decreased inflammation phase. Increased granulation tissue formation, collagen deposition, and re-epithelialization. |
| [87] | 2021 | Quaternized chitosan/oxidized hyaluronic acid self-healing hydrogel | α-lipoic acid-loaded MOFs | Schiff base reaction | STZ-induced male Sprague-Dawley rats | Increased collagen deposition, cell proliferation and neovascularization. Accelerated wound healing. |
| [88] | 2021 | Chitosan/polyvinyl acetate hydrogel | Chitosan nanoparticles loaded with human epidermal growth factor (EGF, 60 µg/mL) and Ag+ ions | Freeze-thaw cycling | STZ-induced Sprague-Dawley rats | Remarkable antibacterial effect. Enhanced tissue maturation and wound closure: 40% on day 3, and 97% on day 14. |
| [89] | 2021 | Pluronic F-127 (20% w/v) hydrogel | Sodium ascorbyl phosphate (400 μM) and Wharton’s jelly mesenchymal stem cells (WJMSC) | Thermal gelation | STZ-induced male Sprague-Dawley rats | Shortened inflammatory response. Improved dermis regeneration, neovascularization, and collagen deposition. |
| [90] | 2020 | Supramolecular hydrogel based on ferrocene, hyaluronic acid, β-cyclodextrin, and rhein | Intermolecular π−π interactions and hydrogen bonds | STZ-induced C57 mice | Anti-inflammatory properties of rhein facilitated transition from the inflammatory phase into the proliferation phase, thus, favoring normal wound healing. | |
| [91] | 2020 | Pluronic F-127 hydrogel | Exosomes derived from human umbilical cord MSCs (300 μg/mL) | Thermal gelation | STZ-induced male Sprague-Dawley rats | Increased vascularization of wound granulation tissue, shortening wound healing time. Improved epithelial regeneration. |
| [92] | 2020 | 4-carboxybenzaldehyde-PEG/glycol chitosan/silk fibroin/PRP self-healing hydrogel | Schiff base reaction + crosslinking with 10% calcium gluconate | STZ-induced Sprague-Dawley rats | Enhanced angiogenesis, re-epithelialization, nerve repair, and wound healing rate. | |
| [93] | 2020 | Chitosan/polyurethane hydrogel membrane | Bone marrow mononuclear cells (1 × 106) injected into the edge of the wound prior to hydrogel application | Chemical crosslinking (urea/urethane bonds) | STZ-induced female Wistar rats | Hemostatic and anti-inflammatory effect. Wound closure > 90% after 14 days. |
| [94] | 2020 | Stimuli-responsive supramolecular hydrogel made from polyvinyl alcohol/N-carboxyethyl chitosan/agarose/Ag nanowires | Hydrogen bonding | STZ-induced male Sprague-Dawley rats | Bactericidal effect. Promoted angiogenesis and collagen deposition. Accelerated wound healing rate. | |
| [95] | 2020 | Poly(N-isopropyl-acrylamide)/poly(γ-glutamic acid) hydrogel (20 mg/mL total concentration) | Superoxide dismutase (2 mg/mL) | Thermal gelation | STZ-induced male Sprague-Dawley rats | Reduced inflammation. Enhanced collagen production and epidermal formation. |
| [96] | 2020 | N-carboxyethyl chitosan (7.5% w/v)/adipic acid dihydrazide (7.5% w/v)/hyaluronic acid-aldehyde (5% w/v) composite hydrogel | Encapsulated bone marrow mesenchymal stem cells (2 × 105) | Crosslinking by hyaluronic acid-aldehyde (imine and acylhydrazone bonds) | STZ-induced male Sprague-Dawley rats | Inhibited chronic inflammation. Enhanced formation of granulation tissue, cell proliferation and neovascularization. |
| [97] | 2020 | γ-polyglutamic acid (0.5 g/mL) hydrogel | Human cell-free fat extract (5 mg/mL) | Chemical crosslinking (EDC/NHS chemistry) | Male BKS-Leprem2Cd479/Nju mice | Improved cell proliferation, collagen deposition and continuous epidermal formation. Significant angiogenesis. |
| [98] | 2020 | Silk fibroin-polyvinyl pyrrolidone hydrogel | L-carnosine and curcumin | Mixing/vortex shearing (physical crosslinking) | STZ-induced BALB/c mice | Significant antibacterial and anti-inflammatory effect. Enhanced wound healing. |
| [99] | 2020 | [2-(methacryloloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide (SBMA)/2-Hydroxyethyl methacrylate (HEMA) and 3-[[2-(Methacryloyloxy)ethyl] dimethylammonio] propionate (CBMA)/HEMA zwitterionic cryogels |
miRNA146a-conjugated cerium oxide nanoparticles | Free-radical polymerization with 13.6 mg/mL ammonium persulfate | Db/Db female mice | Full wound healing on day 14. Downregulation of inflammatory markers. Increased Col1a2 expression. |
| [100] | 2020 | Polyvinyl alcohol (8% w/v)/sodium alginate (1% w/v) hydrogel | Green tea polyphenol nanoparticles | Ionic crosslinking (CaCl2, 100 μg/mL) and hydrogen bonding | STZ-induced female Sprague-Dawley rats | Increased granulation tissue formation and collage deposition. Accelerated wound healing. |
| [101] | 2019 | Chitosan/PEG hydrogel | Ag nanoparticles | Chemical crosslinking with glutaraldehyde | Alloxan-induced rabbits | Increased bactericidal effect. Accelerated re-epithelialization and collagen deposition. Full wound closure on day 14. |
| [102] | 2018 | A5G81-modified poly(polyethylene glycol cocitric acid-co-N-isopropylacrylamide) hydrogel | Thermal gelation | B6.BKS(D)-Leprdb/J mice | Enhanced re-epithelialization and granulation tissue formation. Faster wound closure than that achieved with commercial dressings. | |
| [103] | 2018 | Hyperbranched PEG/thiolated hyaluronic acid injectable hydrogel | Encapsulated adipose-derived stem cells (2.5 × 106 cell/mL) | thiol-ene click reaction | STZ-induced male Sprague-Dawley rats | Reduced inflammatory response. Increased angiogenesis and re-epithelialization. |
| [104] | 2017 | Polymethyl methacrylate/Polyvinyl alcohol hydrogel particles | Collagen, Ag nanowires, and chitosan | UV photocrosslinking (Irgacure 184) | STZ-induced male Wistar ratsSTZ-induced Landrace pigs | Enhanced collagen production and epidermal cell migration. Reduced inflammatory response. |
| [105] | 2017 | Phenylboronic-modified chitosan (1.2 wt%)/poly(vinyl alcohol) (0.6 wt%)/benzaldehyde-capped PEG (0.6 wt%) hydrogel | Insulin (0.3 wt%) and L929 fibroblasts (1.2 × 106 cells/mL) | Schiff base reaction | STZ-induced Sprague-Dawley rats | Improved control of glucose levels in wound. Increased neovascularization and collagen deposition. Enhanced wound closure rate. |
| [106] | 2016 | Sodium carboxymethylcellulose/propylene glycol hydrogel | Blechnum orientale extract (2–4% wt) | Hydrogen bonding | STZ-induced male Sprague-Dawley rats | Significant bactericidal and antioxidative effect. Enhanced re-epithelialization, fibroblast proliferation, collagen synthesis, and angiogenesis. |
| [107] | 2016 | Gelatin methacrylate (15% w/v) hydrogel | Desferrioxamine (1% w/v) | UV photocrosslinking with Irgacure 2959 (0.5% w/v) | STZ-induced male Sprague-Dawley rats | Accelerated neovascularization, granulation tissue remodeling, and wound closure. |