Copyright
©The Author(s) 2023.
World J Diabetes. Apr 15, 2023; 14(4): 364-395
Published online Apr 15, 2023. doi: 10.4239/wjd.v14.i4.364
Published online Apr 15, 2023. doi: 10.4239/wjd.v14.i4.364
Type of GF | Source cells | Target cells | Receptor⁄signaling protein | Involved wound healing process | Acute wound | Chronic wound | Ref. |
VEGF | Keratinocytes, fibroblasts, macrophages, endothelial cells | Endothelial cells, macrophages | ICAM-1, VCAM-1, PLCγ/PKC/Ras/Raf/MEK/ERK | Inflammation, angiogenesis | Increased | Decreased | [151-158] |
TGF-β | Fibroblasts, keratinocytes, macrophages, platelets | Fibroblasts, keratinocytes, macrophages, leukocytes, endothelial cells | TGF-βRI-II, Smad 2-4, α-SMA, MAPK, integrins | Inflammation, angiogenesis, granulation tissue formation, collagen synthesis, matrix formation and remodeling, leukocyte chemotactic function | Increased | Decreased | [157,159-174] |
PDGF | Platelets | Leukocytes, macrophages, fibroblasts | PDGFR, Ras/Erk1/2/MAPK, PI3K | Inflammation, re-epithelialization, collagen deposition, tissue remodelling | Increased | Decreased | [108,157,175,176] |
HGF | Fibroblasts | Endothelial cells, keratinocytes | c-Met, ERK1/2, Akt, PAK-1/2, Gab1 | Suppression of inflammation, granulation tissue formation, angiogenesis, re-epithelialization | - | - | [155,176-180] |
bFGF | Keratinocytes, fibroblasts, endothelial cells | Keratinocytes, fibroblasts, endothelial cells | ERK2 | Angiogenesis, granulation tissue formation | Increased | Decreased | [108,175,181-184] |
FGF-7, FGF-10 | Fibroblasts, keratinocytes | Keratinocytes | Peroxiredoxin-6, Nrf2, Nrf3 | Re-epithelialization, detoxification of ROS | - | - | [185-188] |
EGF, HB-EGF, TGF-α | Platelets, macrophages, keratinocytes | Fibroblasts, endothelial cells, keratinocytes | EGFR, STAT3, AP1, PI3K, ERK | Tissue formation, re-epithelialization | Increased | Decreased | [189-197] |
Therapeutic agents | Delivery system and route | Animal type | Wound size | Response on wound closure | Ref. |
PDGF/TGF-α | Gel/topical spraying to wound bed | C57BL/KsJ-db/db mouse | Full-thickness wound measuring 1.5 cm × 1.5 cm | Accelerated wound closure at 15-21 d | [262] |
bFGF | Chitosan film/topical using | C57BL/KsJ-db/db mice | Full-thickness wound (1.6 cm diameter) | Reduced wound area and increased ECM formation | [318] |
bFGF | Chitosan/hydrogels implant | C57BL/KsJ-db/db mice | Full-thickness wounds (about 100 mm2) | 80% wound closure by 12 d | [319] |
pDNA TGF-β1 | PEG-PLGA-PEG/hydrogels implant | C57BKS.Cg-m +/+ Leprdb female mice | Full-thickness wounds (7 mm × 7 mm) | Accelerated wound closure at 5 d | [280] |
bFGF | Chitosan, hydrogel/topical using | C57BL/KsJ-db/db mice | Full-thickness circular wounds (about 100 mm2) | Accelerated tissue filling rate of wounds and increased number of CD-34-positive vessels | [320] |
PDGF-BB | Carboxymethyl cellulose hydrogel/topical using | C57/Bl6 wild-type mice and lep/r db/db homozygous diabetic mice | Either a 0.6 cm2, 1.0 cm2, or 1.5 cm2 full-thickness area of skin | Accelerated healing by enhanced granulation tissue formationand angiogenesis | [321] |
bFGF | Collagen, PGA/porous scaffolds implant | C57BLKS/J Iar- + Leprdb/ + Leprdb | Full-thickness wounds (6 mm diameter | NA | [322] |
rhPDGF | Gel/topical spraying to wound bed | Wistar diabetic rats | Full-thickness dermal wounds of 2.54 cm2 (1.8 cm diameter) | Outstanding re-epithelialization within the first 7 d | [323] |
bFGF | Chondroitin-6-sulfate, heparin/hydrogels implant | C57BLKs/J-m1/db, db/db mice, heterozygous (m1/db) | Full-thickness wounds (1.6 cm diameter) | 89% wound closure by 2 wk | [324] |
rhEGF | PCL, PCL-PEG/non-woven mesh (electrospun) implant | Ful-thickness wounds (0.8 cm diameter) | Accelerated wound closure at 7 d | [325] | |
PDGF | 5% polyethylene glycol gel/intradermal injection | Wistar rats | Full-thickness wounds (1.8 cm diameter) | Significant wound improvement within 14 d | [237] |
aFGF | Collagen, chitosan/porous scaffolds implant | SD rats | Whole skin layer round wounds (1.8 cm diameter) | Complete healing at 14 d | [326] |
rhEGF | PLGA microspheres | SD rats | Full-thickness dermal wounds (2.54 cm2, 1.9 cm diameter) | 90% healing rate on the 14th day | [327] |
Collagen-binding domain (CBD)-VEGF | Collagen domain/praye onto the traumatic surface | SD rats | Full-thickness wounds (2 cm × 2.5 cm) | 95% healing rate basically reached after 21 d | [328] |
rhEGF | PLGA nanoparticles/topical spraying to wound bed | SD rats | Full-thickness dermal wounds (1.8 cm in diameter) | Complete wound closure by 21 d | [329] |
bFGF | PELA/non-woven mesh (electrospun) implant | SD rats | Full-thickness circular wounds (about 250 mm2 each) | Complete wound closure by 3 wk | [330] |
rhEGF | Dextrin conjugated/topical using | BKS.Cg-m a/a +/+ Leprdb/J db/db mice | Full-thickness wounds (10 mm × 10 mm) | Accelerated wound closure, neo-dermal tissue formation, increased granulation tissue deposition and angiogenesis | [331] |
EGF | Collagen, hyaluronic acid/porous scaffolds implant | BKS.Cg-+Leprdb/+Leprdb (db/db) mice | Full-thickness wounds (15 mm × 20 mm) | N/A | [332] |
pDNA bFGF | PELA/electrospun mesh implant | Male SD rats | Full-thickness wounds (about 250 mm2) | Complete wound closure by 3 wk | [333] |
bFGF | Collagen, gelatine/porous scaffolds implant | BKS.Cg- + Leprdb/+ Leprdb/Jcl | 8 mm diameter and 3 mm thickness | NA | [334] |
VEGF/bFGF | PLGA nps, fibrin/porous scaffolds implant | BKS.Cg-m+/+ Lepr, db/db | Full-thickness dermal wound (0.8 cm in diameter) | 85% wound closure at 15 d | [335] |
rhEGF | PLGA-alginate microspheres/intralesional injection | Wistar rats | Full-thickness dermal wound (1 cm in diameter) | 90% wound closure at 11 d | [336] |
rhEGF | Lipid nanocarriers/topical application to wound bed | BKS.Cg-m+/+Lepr 286 db/J | Full-thickness wounds 0.8 cm in diameter | 95% wound closure at 15 d | [337] |
VEGF, bFGF, EGF, PDGF | Collagen, hyaluronic acid, gelatine nps/non-woven mesh (electrospun) implant | SD rats | Full thickness wound (diameter of 15 mm) | Complete wound closure by 4 wk | [338] |
pDNA VEGF | Hyaluronic acid/hydrogels implant | db/db mice | Full-thickness wounds were then generated using a 6 mm biopsy punch (4 mm for wounds on smaller balb/c mice) | Induction of wound closure by day 8-10 | [339] |
VEGF | PLGA nanoparticles/intradermal injection | db/db mice | Full thickness excisional wounds, two (8 mm diameter) and four (6 mm diameter) | Complete wound closure by 19 d | [340] |
VEGF, PDGF | Poly (β-amino esters), poly (acrylic acid), heparan sulfate/woven nylon mesh implant | db/db mice | Full-thickness skin wound | Accelerated wound closure at 14 d | [341] |
rhEGF | NaCMCh-rhEGF/hydrogels implant | SD rats | Full-thickness wounds (2 cm diameter, 3.14 cm2 circular area) | Wound healed in day 15 | [342] |
rhEGF | PU/porous scaffolds implant | SD rats | Full-thickness wounds (dimensions of 2 cm × 2 cm) | 97% wound closure at 21 d | [343] |
VEGF | PEG, heparin/hydrogels implant | Cg-m +/+ Leprdb/J (db/db) mice | Full-thickness punch biopsy wound | - | [344] |
rhPDGF | PLGA/Non-woven mesh (electrospun) implant | SD rats | Full-thickness excision (8.0 mm in diameter) | Complete wound closure by 14 d | [345] |
bFGF | Chitosan, hydrogel + heparin/topical using | C57BL/KsJ-db/db mice | - | Significant angiogenesis and collateral circulation construction | [346] |
bFGF | Gelatin hydrogel microspheres/topical injection | C57BL/KsJ-db/db mice | Full-thickness wounds (10 mm in diameter) | Accelerated diabetic skin wound healing and reduced scarring | [347] |
bFGF | Acidic gelatin sheet/topical coverage | C57BL/KsJ-db/db mice | Full-thickness wound (1.5 cm × 1.5 cm) | Promoted neoepithelialization, granulation, neovascularization, and wound healing | [348] |
Biomaterial | Forms | GFs | Effects | Ref. |
Chitosan | Film | rhEGF | Sustained release in vitro for 24 h and extended therapeutic effect | [350] |
Chitosan | Film | bFGF | The activity of bFGF remained stable for 21 d at 5 °C, and 86.2% of the activity was maintained at 25 °C | [318] |
Chitosan | Hydrogel | EGF | 97.3% release after 24 h in an in vitro study and sustained therapeutic effect | [351] |
Chitosan | Hydrogel | bFGF | Significant angiogenesis and collateral circulation construction after addition of heparin in chitosan-bFGF system | [346] |
CMC-Chitosan | Hydrogel (as the carrier of NaCMCh-rhEGF nanoparticle) | rhEGF | In vitro results indicated that the conjugated form exhibited greater stability to proteolysis and also retained EGF therapeutic activity | [342] |
CNC-HA-chitosan | Nanoparticle + scaffold | GM-CSF | Proper mechanical properties, high swelling capacity (swelling ratio: 2622.1% ± 35.2%) and controlled release of GM-CSF up to 48 h | [352] |
PVA-gelatin-chitosan | Hydrogel | bFGF | In vitro release-cumulative over 25 d, non-toxic to fibroblasts | [353] |
Chitosan-nanodiamond | Hydrogel | VEGF | 3-d sustained release, improved hydrogel mechanical properties and better biocompatibility | [354] |
N-carboxymethyl chitosan-alginate | Hydrogel | EGF | 12 h sustained release, non-toxic | [355] |
CMCS-poly (vinyl alcohol) (PVA)-alginate microspheres | Hydrogel | bFGF | 48 h sustained release, high activity for two weeks | [356] |
Hyaluronic acid-sulfated glycosaminoglycan-heparin | Hydrogel | bFGF | Remain highly active for 14 d | [357] |
Heparin + PEGDA | Hydrogel | bFGF | Remain active over 35 d | [358] |
Collagen-transglutaminase | Hydrogel | bFGF | Suitable mechanical properties and biocompatibility, sustained release up to 48 h | [359] |
CBD | Collagen membrane | PDGF | Maintain a higher concentration and stronger biological activity of PDGF | [360] |
Collagen | Scaffold | VEGF-A | Cross-linking slows the degradation rate of collagen scaffolds and improves the persistent activity of VEGF | [361] |
Extracellular matrix protein (INSUREGRAF®) | Scaffold | EGF | 8 h sustained release and active | [362] |
GTA-collagen sponge | Sponge | rhEGF | Sustained release and activity for about 10 d, no cytotoxicity | [363] |
TFA-denatured collagen | Sponge | bFGF | Sustained release for 18 d and remains largely active | [364] |
PCL nanofibers (surface coating with collagen type I) | Hydrogel | G-CSF | Accumulative in vitro release for 15 d, no cytotoxicity | [365] |
Gelatin | Microspheres | VEGF | Sustained release over 14 d | [347] |
Gelatin | Sheet | bFGF | Sustained release for about 14 d | [348] |
Gelatin | Sponge | EGF | Increased tensile strength | [366] |
Gelatin | TEECM + Gelatin hydrogel microspheres | EGF | Cumulative in vitro release over 14 d | [367] |
EUP polysaccharide, gelatin | Electrospun hydrogel sponge | PDGF-BB | In vitro release lasts 48 h | [368] |
Fibrin | Hydrogel | VEGF | In vitro release lasts 7 d | [369] |
Fibrin | Hydrogel | VEGF | Sustained release of VEGF for 15 d | [370] |
Therapeutic agents | Delivery system and route | Response on wound closure | Ref. |
EGF | Cream | Significantly improve wound healing rates and reduced the risk of amputation | [371] |
bFGF | CGS/suture to surrounding skin | Significant wound improvement within 14 d | [372] |
PDGF | Topical gel wound dressing | Reduce healing time by 30% | [373] |
PDGF | Topical becaplermin gel | Improve wound healing by 35% | [240] |
bFGF | 0.0005% benzalkonium chloride in saline/spray on the wound | Significantly reduce wound area | [374] |
rhVEGF | Methylcellulose gel/apply evenly to wounds and edges | Significantly increase incidence of complete wound healing | [375] |
PDGF | Becaplermin gel/topical apply | The incidence of complete closure was significantly increased by 43% | [241] |
EGF | Intralesional injection | Reduced wound area and increased re-epithelialization rate | [376] |
EGF | Topical spray | Faster healing velocity and higher complete healing rate | [377] |
EGF | Topical hydrogel | 78% of wounds healed after 30 d | [378] |
Therapeutic agents | Delivery system and route | Response on wound closure | Ref. |
Plasmid KGF-1 | Intradermal injection | Enhanced wound closure at day 9 | [382] |
Plasmid TGF-β1 | Intradermal injection | Complete wound closure by 7 d | [162] |
Plasmid TGF-β1 | Intradermal injection, Electroporation | Early induction of closure by day 5 | [383] |
Plasmid KGF-1 | Intradermal injection, Electroporation | Enhanced wound closure at day 12 | [384] |
Minicircle-VEGF | Subcutaneous injection, Sonoporation | Complete wound closure by 12 d | [385] |
Adenovirus encoding VEGF | Topical application to wound bed | Complete wound closure by 13 d | [386] |
Adenovirus encoding VEGF | Intradermal injection | Complete wound closure by 27 d | [387] |
Adenovirus encoding PDGF | Intralesional injection | Residual epithelial gap of 3 mm at day 7 | [388] |
Adenovirus encoding VEGF‐C | Intradermal injection | Complete wound closure by 21 d | [222] |
Lentivirus encoding PDGF | Injected into base and wound margin | No effect | [389] |
Adeno-associated virus encoding VEGF | Intradermal injection | Complete re-epithelialization at 28 d | [390] |
Bicistronic Adeno-associated virus encoding VEGF-A and FGF4 | Intradermal injection | Complete wound closure by 17 d | [391] |
RGDK‐lipopeptide:rhPDGF-B lipoplex | Subcutaneous injection | Complete wound closure by 12 d | [392] |
Minicircle VEGF | Subcutaneous injection | Complete wound closure by 12 d | [393] |
- Citation: Zheng SY, Wan XX, Kambey PA, Luo Y, Hu XM, Liu YF, Shan JQ, Chen YW, Xiong K. Therapeutic role of growth factors in treating diabetic wound. World J Diabetes 2023; 14(4): 364-395
- URL: https://www.wjgnet.com/1948-9358/full/v14/i4/364.htm
- DOI: https://dx.doi.org/10.4239/wjd.v14.i4.364