Review
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
Table 1 Main growth factors in wound healing
Type of GF
Source cells
Target cells
Receptor⁄signaling protein
Involved wound healing process
Acute wound
Chronic wound
Ref.
VEGFKeratinocytes, fibroblasts, macrophages, endothelial cellsEndothelial cells, macrophagesICAM-1, VCAM-1, PLCγ/PKC/Ras/Raf/MEK/ERKInflammation, angiogenesisIncreasedDecreased[151-158]
TGF-βFibroblasts, keratinocytes, macrophages, plateletsFibroblasts, keratinocytes, macrophages, leukocytes, endothelial cellsTGF-βRI-II, Smad 2-4, α-SMA, MAPK, integrinsInflammation, angiogenesis, granulation tissue formation, collagen synthesis, matrix formation and remodeling, leukocyte chemotactic functionIncreasedDecreased[157,159-174]
PDGFPlateletsLeukocytes, macrophages, fibroblastsPDGFR, Ras/Erk1/2/MAPK, PI3KInflammation, re-epithelialization, collagen deposition, tissue remodellingIncreasedDecreased[108,157,175,176]
HGFFibroblastsEndothelial cells, keratinocytesc-Met, ERK1/2, Akt, PAK-1/2, Gab1Suppression of inflammation, granulation tissue formation, angiogenesis, re-epithelialization--[155,176-180]
bFGFKeratinocytes, fibroblasts, endothelial cellsKeratinocytes, fibroblasts, endothelial cellsERK2Angiogenesis, granulation tissue formationIncreasedDecreased[108,175,181-184]
FGF-7, FGF-10Fibroblasts, keratinocytesKeratinocytesPeroxiredoxin-6, Nrf2, Nrf3Re-epithelialization, detoxification of ROS--[185-188]
EGF, HB-EGF, TGF-αPlatelets, macrophages, keratinocytesFibroblasts, endothelial cells, keratinocytesEGFR, STAT3, AP1, PI3K, ERKTissue formation, re-epithelializationIncreasedDecreased[189-197]
Table 2 Biomaterial systems applied for the delivery of growth factors in diabetic wounds
Therapeutic agents
Delivery system and route
Animal type
Wound size
Response on wound closure
Ref.
PDGF/TGF-αGel/topical spraying to wound bedC57BL/KsJ-db/db mouseFull-thickness wound measuring 1.5 cm × 1.5 cm Accelerated wound closure at 15-21 d[262]
bFGFChitosan film/topical usingC57BL/KsJ-db/db miceFull-thickness wound (1.6 cm diameter)Reduced wound area and increased ECM formation[318]
bFGFChitosan/hydrogels implantC57BL/KsJ-db/db miceFull-thickness wounds (about 100 mm2)80% wound closure by 12 d[319]
pDNA TGF-β1PEG-PLGA-PEG/hydrogels implantC57BKS.Cg-m +/+ Leprdb female miceFull-thickness wounds (7 mm × 7 mm) Accelerated wound closure at 5 d[280]
bFGFChitosan, hydrogel/topical usingC57BL/KsJ-db/db miceFull-thickness circular wounds (about 100 mm2)Accelerated tissue filling rate of wounds and increased number of CD-34-positive vessels[320]
PDGF-BBCarboxymethyl cellulose hydrogel/topical usingC57/Bl6 wild-type mice and lep/r db/db homozygous diabetic miceEither a 0.6 cm2, 1.0 cm2, or 1.5 cm2 full-thickness area of skinAccelerated healing by enhanced granulation tissue formationand angiogenesis[321]
bFGFCollagen, PGA/porous scaffolds implantC57BLKS/J Iar- + Leprdb/ + LeprdbFull-thickness wounds (6 mm diameterNA[322]
rhPDGFGel/topical spraying to wound bedWistar diabetic ratsFull-thickness dermal wounds of 2.54 cm2 (1.8 cm diameter) Outstanding re-epithelialization within the first 7 d[323]
bFGFChondroitin-6-sulfate, heparin/hydrogels implantC57BLKs/J-m1/db, db/db mice, heterozygous (m1/db) Full-thickness wounds (1.6 cm diameter)89% wound closure by 2 wk[324]
rhEGFPCL, PCL-PEG/non-woven mesh (electrospun) implantFul-thickness wounds (0.8 cm diameter)Accelerated wound closure at 7 d[325]
PDGF5% polyethylene glycol gel/intradermal injectionWistar ratsFull-thickness wounds (1.8 cm diameter)Significant wound improvement within 14 d[237]
aFGFCollagen, chitosan/porous scaffolds implantSD ratsWhole skin layer round wounds (1.8 cm diameter)Complete healing at 14 d[326]
rhEGFPLGA microspheresSD ratsFull-thickness dermal wounds (2.54 cm2, 1.9 cm diameter) 90% healing rate on the 14th day[327]
Collagen-binding domain (CBD)-VEGFCollagen domain/praye onto the traumatic surfaceSD ratsFull-thickness wounds (2 cm × 2.5 cm) 95% healing rate basically reached after 21 d[328]
rhEGFPLGA nanoparticles/topical spraying to wound bedSD ratsFull-thickness dermal wounds (1.8 cm in diameter)Complete wound closure by 21 d[329]
bFGFPELA/non-woven mesh (electrospun) implantSD ratsFull-thickness circular wounds (about 250 mm2 each) Complete wound closure by 3 wk[330]
rhEGFDextrin conjugated/topical usingBKS.Cg-m a/a +/+ Leprdb/J db/db miceFull-thickness wounds (10 mm × 10 mm) Accelerated wound closure, neo-dermal tissue formation, increased granulation tissue deposition and angiogenesis[331]
EGFCollagen, hyaluronic acid/porous scaffolds implantBKS.Cg-+Leprdb/+Leprdb (db/db) miceFull-thickness wounds (15 mm × 20 mm) N/A[332]
pDNA bFGFPELA/electrospun mesh implantMale SD ratsFull-thickness wounds (about 250 mm2)Complete wound closure by 3 wk[333]
bFGFCollagen, gelatine/porous scaffolds implantBKS.Cg- + Leprdb/+ Leprdb/Jcl8 mm diameter and 3 mm thicknessNA[334]
VEGF/bFGFPLGA nps, fibrin/porous scaffolds implantBKS.Cg-m+/+ Lepr, db/dbFull-thickness dermal wound (0.8 cm in diameter)85% wound closure at 15 d[335]
rhEGFPLGA-alginate microspheres/intralesional injectionWistar ratsFull-thickness dermal wound (1 cm in diameter)90% wound closure at 11 d[336]
rhEGFLipid nanocarriers/topical application to wound bedBKS.Cg-m+/+Lepr 286 db/JFull-thickness wounds 0.8 cm in diameter95% wound closure at 15 d[337]
VEGF, bFGF, EGF, PDGFCollagen, hyaluronic acid, gelatine nps/non-woven mesh (electrospun) implantSD ratsFull thickness wound (diameter of 15 mm)Complete wound closure by 4 wk[338]
pDNA VEGFHyaluronic acid/hydrogels implantdb/db miceFull-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]
VEGFPLGA nanoparticles/intradermal injectiondb/db miceFull thickness excisional wounds, two (8 mm diameter) and four (6 mm diameter) Complete wound closure by 19 d[340]
VEGF, PDGFPoly (β-amino esters), poly (acrylic acid), heparan sulfate/woven nylon mesh implantdb/db miceFull-thickness skin woundAccelerated wound closure at 14 d[341]
rhEGFNaCMCh-rhEGF/hydrogels implantSD ratsFull-thickness wounds (2 cm diameter, 3.14 cm2 circular area)Wound healed in day 15[342]
rhEGFPU/porous scaffolds implantSD ratsFull-thickness wounds (dimensions of 2 cm × 2 cm)97% wound closure at 21 d[343]
VEGFPEG, heparin/hydrogels implantCg-m +/+ Leprdb/J (db/db) miceFull-thickness punch biopsy wound-[344]
rhPDGFPLGA/Non-woven mesh (electrospun) implantSD ratsFull-thickness excision (8.0 mm in diameter)Complete wound closure by 14 d[345]
bFGFChitosan, hydrogel + heparin/topical usingC57BL/KsJ-db/db mice-Significant angiogenesis and collateral circulation construction[346]
bFGFGelatin hydrogel microspheres/topical injectionC57BL/KsJ-db/db miceFull-thickness wounds (10 mm in diameter)Accelerated diabetic skin wound healing and reduced scarring[347]
bFGFAcidic gelatin sheet/topical coverageC57BL/KsJ-db/db miceFull-thickness wound (1.5 cm × 1.5 cm)Promoted neoepithelialization, granulation, neovascularization, and wound healing[348]
Table 3 Summary of evaluation of the effectiveness of some biomaterial delivery systems
Biomaterial
Forms
GFs
Effects
Ref.
ChitosanFilmrhEGFSustained release in vitro for 24 h and extended therapeutic effect[350]
ChitosanFilmbFGFThe activity of bFGF remained stable for 21 d at 5 °C, and 86.2% of the activity was maintained at 25 °C[318]
ChitosanHydrogelEGF97.3% release after 24 h in an in vitro study and sustained therapeutic effect[351]
ChitosanHydrogelbFGFSignificant angiogenesis and collateral circulation construction after addition of heparin in chitosan-bFGF system[346]
CMC-ChitosanHydrogel (as the carrier of NaCMCh-rhEGF nanoparticle)rhEGFIn vitro results indicated that the conjugated form exhibited greater stability to proteolysis and also retained EGF therapeutic activity[342]
CNC-HA-chitosanNanoparticle + scaffoldGM-CSFProper mechanical properties, high swelling capacity (swelling ratio: 2622.1% ± 35.2%) and controlled release of GM-CSF up to 48 h[352]
PVA-gelatin-chitosanHydrogelbFGFIn vitro release-cumulative over 25 d, non-toxic to fibroblasts[353]
Chitosan-nanodiamondHydrogelVEGF3-d sustained release, improved hydrogel mechanical properties and better biocompatibility[354]
N-carboxymethyl chitosan-alginateHydrogelEGF12 h sustained release, non-toxic[355]
CMCS-poly (vinyl alcohol) (PVA)-alginate microspheresHydrogelbFGF48 h sustained release, high activity for two weeks[356]
Hyaluronic acid-sulfated glycosaminoglycan-heparinHydrogelbFGFRemain highly active for 14 d[357]
Heparin + PEGDAHydrogelbFGFRemain active over 35 d[358]
Collagen-transglutaminaseHydrogelbFGFSuitable mechanical properties and biocompatibility, sustained release up to 48 h[359]
CBDCollagen membranePDGFMaintain a higher concentration and stronger biological activity of PDGF[360]
CollagenScaffoldVEGF-ACross-linking slows the degradation rate of collagen scaffolds and improves the persistent activity of VEGF[361]
Extracellular matrix protein (INSUREGRAF®)ScaffoldEGF8 h sustained release and active[362]
GTA-collagen spongeSpongerhEGFSustained release and activity for about 10 d, no cytotoxicity[363]
TFA-denatured collagenSpongebFGFSustained release for 18 d and remains largely active[364]
PCL nanofibers (surface coating with collagen type I)HydrogelG-CSFAccumulative in vitro release for 15 d, no cytotoxicity[365]
GelatinMicrospheresVEGFSustained release over 14 d[347]
GelatinSheetbFGFSustained release for about 14 d[348]
GelatinSpongeEGFIncreased tensile strength[366]
GelatinTEECM + Gelatin hydrogel microspheresEGFCumulative in vitro release over 14 d[367]
EUP polysaccharide, gelatinElectrospun hydrogel spongePDGF-BBIn vitro release lasts 48 h[368]
FibrinHydrogelVEGFIn vitro release lasts 7 d[369]
FibrinHydrogelVEGFSustained release of VEGF for 15 d[370]
Table 4 Clinical trials of growth factors in diabetic wounds
Therapeutic agents
Delivery system and route
Response on wound closure
Ref.
EGFCreamSignificantly improve wound healing rates and reduced the risk of amputation[371]
bFGFCGS/suture to surrounding skinSignificant wound improvement within 14 d[372]
PDGFTopical gel wound dressingReduce healing time by 30%[373]
PDGFTopical becaplermin gelImprove wound healing by 35%[240]
bFGF0.0005% benzalkonium chloride in saline/spray on the woundSignificantly reduce wound area[374]
rhVEGFMethylcellulose gel/apply evenly to wounds and edgesSignificantly increase incidence of complete wound healing[375]
PDGFBecaplermin gel/topical applyThe incidence of complete closure was significantly increased by 43%[241]
EGFIntralesional injectionReduced wound area and increased re-epithelialization rate[376]
EGFTopical sprayFaster healing velocity and higher complete healing rate[377]
EGFTopical hydrogel78% of wounds healed after 30 d[378]
Table 5 Gene delivery vectors applied for the growth factor treatment of diabetic wounds
Therapeutic agents
Delivery system and route
Response on wound closure
Ref.
Plasmid KGF-1Intradermal injectionEnhanced wound closure at day 9[382]
Plasmid TGF-β1Intradermal injectionComplete wound closure by 7 d[162]
Plasmid TGF-β1Intradermal injection, ElectroporationEarly induction of closure by day 5[383]
Plasmid KGF-1Intradermal injection, ElectroporationEnhanced wound closure at day 12[384]
Minicircle-VEGFSubcutaneous injection, SonoporationComplete wound closure by 12 d[385]
Adenovirus encoding VEGFTopical application to wound bedComplete wound closure by 13 d[386]
Adenovirus encoding VEGFIntradermal injectionComplete wound closure by 27 d[387]
Adenovirus encoding PDGFIntralesional injectionResidual epithelial gap of 3 mm at day 7[388]
Adenovirus encoding VEGF‐CIntradermal injectionComplete wound closure by 21 d[222]
Lentivirus encoding PDGFInjected into base and wound marginNo effect[389]
Adeno-associated virus encoding VEGFIntradermal injectionComplete re-epithelialization at 28 d[390]
Bicistronic Adeno-associated virus encoding VEGF-A and FGF4Intradermal injectionComplete wound closure by 17 d[391]
RGDK‐lipopeptide:rhPDGF-B lipoplexSubcutaneous injectionComplete wound closure by 12 d[392]
Minicircle VEGFSubcutaneous injectionComplete wound closure by 12 d[393]