Therapeutic role of growth factors in treating diabetic wound

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.
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]

ICAM-1: Intercellular adhesion molecule 1; VCAM-1: Vascular cell adhesion molecule 1; PLC: Phospholipase C; PKC: Protein kinase C; α-SMA: α smooth muscle actin; MAPK: Mitogen-activated protein kinase; PI3K: Phosphoinositide 3-kinase; VEGF: Vascular endothelial growth factor; PDGF: Platelet-derived growth factor; EGF: Epidermal growth factor; FGF: Fibroblast growth factor; HGF: Hepatocyte growth factor; HB-EGF: heparin-binding epidermal growth factor.

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-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]

VEGF: Vascular endothelial growth factor; PDGF: Platelet-derived growth factor; EGF: Epidermal growth factor; FGF: Fibroblast growth factor; rhEGF: Recombinant human epidermal growth factor.

Table 3 Summary of evaluation of the effectiveness of some biomaterial delivery systems

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]

CBD: Collagen-binding domain; CNC: Cellulose nanocrystal; CMC: Carboxymethyl cellulose; GTA: Glutaraldehyde; TFA: Trifluoroacetic acid; TEECM: Tissue-engineered extracellular matrix; CMCS: Carboxymethyl chitosan; PEGDA: Poly (ethylene glycol) diacrylate; PCL: Chitosan nanoparticles-Poly (ε-caprolactone); NaCMCh-rhEGF: Sodium carboxymethyl chitosan-recombinant human epidermal growth factor conjugate; VEGF: Vascular endothelial growth factor; PDGF: Platelet-derived growth factor; EGF: Epidermal growth factor; FGF: Fibroblast growth factor; rhEGF: Recombinant human epidermal growth factor.

Table 4 Clinical trials of growth factors in diabetic wounds

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]

CGS: Collagen/gelatin spong; rhVEGF: Recombinant human vascular endothelial growth factor; PDGF: Platelet-derived growth factor; EGF: Epidermal growth factor; FGF: Fibroblast growth factor.

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-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]

VEGF: Vascular endothelial growth factor; PDGF: Platelet-derived growth factor; FGF: Fibroblast growth factor.