Diabetic ulcer regeneration: stem cells, biomaterials, growth factors

Figures & data

Figure 1. Showing schematizes the phases and growth factors involved in diabetic wound healing processes in comparison with a regular wound. The cells involved include blood platelets, red blood cells, epithelial cells (blue coloured), fibroblast (green coloured), macrophages, fibrin, neutrophils and blood vessels (red) [78].

Table 1. Showing principal growth factors involved in wound healing [79].

Growth factors	Repair process	Source	Target cells/effects in wound repair	Clinical uses
Platelet-derived growth factor (PDGF)	Inflammation, tissue formation and tissue remodelling	Platelets, macrophages,endothelial cells	Chemo-attractant forneutrophils and fibroblasts, smooth muscle cells.	Neuropathic diabetic foot ulcers treatment
Fibroblast growth factor (FGF2)	Tissue formation and tissue remodelling	Fibroblasts, endothelial cells	Mitogenic for endothelial cells, fibroblasts and keratinocytes.	Have been demonstrated in pressure ulcers but no known effect on diabetic foot ulcers
Keratinocyte growth factor (KGF)	Tissue formation	Fibroblasts	Mitogenic and chemotactic for keratinocytes	No reported clinical trials
Epidermal growth factor (EGF)	Tissue formation	Platelets, macrophages and keratinocytes	Mitogenic for fibroblasts,endothelial cells and keratinocytes	There have been effects on venous ulcer but they are insignificant. No reported clinical trials on diabetic ulcer.
Transforming growth factor (TGF-β)	Inflammation, tissue formation and tissue remodelling	Platelets, macrophages,fibroblasts, keratinocytes, neutrophils	Stimulates fibroplasia and angiogenesis.	No reported clinical trials
Vascular endothelial growthfactor (VEGF)	Tissue formation	Neutrophils, platelets	Stimulates the process of angiogenesis	It promotes collateral blood vessel formation in peripheral arterial disease
Granulocyte colony-stimulating factor (G-CSF)	Inflammation	Monocytes, fibroblasts and lymphocytes	Formation of neutrophils	There has been report of clinical studies on diabetic foot ulcer.

Table 2. Showing randomized clinical trials of growth factors in diabetic foot ulcers [79].

Growth factor	Trial	Results	References
Platelet-derived growth factor (PDGF)	A double blinded and multicentre clinical trial on 118 patients	There was evidence of ulcer healing at 20 weeks: p = .01 There was reduction in ulcer volume at 20 weeks: p = .09	[15]
Platelet-derived growth factor (PDGF)	A double blinded and multicentre clinical trial on 379 patients	There was evidence of ulcer healing at 36 weeks: p = .007 The time to healing was 127 days; p = .013	[16]
Platelet-derived growth factor (PDGF)	A double blinded and multicentre clinical trial on 250 patients	There was evidence of ulcer healing at 36 weeks	[17]
Fibroblast growth factor (FGF)	A double blinded clinical trial on 17 patients	There was evidence ulcer healing at 33 weeks; p = .23	[18]
Granulocyte colony-stimulating factor(G-CSF)	A double blinded clinical trial on 40 patients	There was ulcer healing at 7 days: p = .09 The time to resolution of cellulitis was after 12 days; p = .03	[19]
Granulocyte colony-stimulating factor (G-CSF)	A double blinded clinical trial on 40 patients	There was amputation by 9 weeks: p = .038 The duration of antibiotic therapy was two months and 2 days	[20]
Platelet-derived wound healing factors (PDWHFs)	A double blinded clinical trial on 13 patients	There was evidence of ulcer healing: five of seven vs. one of six There was reduction in ulcer area; p < .02	[21]

Table 3. Showing clinical trials of stem cell therapy on the treatment of diabetic ulcer [80].

Clinical trials	Diabetic ulcer cases	Stem cell therapy	Efficacy
[41]	24	BM-MNCs/BM-MSCs	80% of the 24 cases significantly improved.
[42]	8	BM-MNCs	There was total wound healing in 3 cases and the other 5 cases improved significantly.
[43]	25	BM-MNCs	There was an increase in the rate of chronic lower extremity wound healing.
[30]	12	BM-MSCs	There was improvement evidence in pain-free walking distance and decrease in ulcer size.
[44]	3	BM-MNCs	There was evidence of wound healing.
[28]	20	MSCs	There was evidence of wound healing in 18 of the 20 cases.
[45]	1	BM-MNCs	There was evidence of total wound healing.
[46]	4	BM-MNCs	Total wound healing was achieved.
[44]	8	MSCs	It took an average of 7 weeks after surgery for all wounds to be healed totally.
[47]	1	BM-MNCs and bFGF	There was evidence of total wound healing.
[48]	2	BM-MNCs	Decrease in wound size was achieved and evidences of increased vascularization were noted.
[49]	1	Fibroblast and MSCs	There was evidence of both closing and healing of the non-healing diabetic ulcer.
[50]	3	BM-MNCs	There was dermal renewal and evidence of closure of non-healing chronic wounds.

Table 4. Showing application of stem cell and growth factors for diabetic foot ulcer (DFU) treatment [78].

Bioactive substances	Models used	Results	References
VEGF	db/db diabetic mice	There was an improved neovascularization, mobilization of bone marrow-derived cells into the wound site to fast-track the wound healing process.	[51]
PDGF	Streptozotocin (STZ) diabetic rats	The process of angiogenesis was enhanced as well as cell proliferation and epithelialization.	[52]
bFGF	Human patients with DFUs	There was about 75% decrease of the wound area in treated patients.	[53]
SDF-1α	STZ diabetic mice	There was an increase in EPC mobilization, homing process and as well as wound healing process.	[54]
BMSCS	STZ diabetic rats	The process of wound healing was accelerated and growth factors like TGF-β, KGF, EGF and VEGF were expressed.	[14]
CD133+ cells	STZ diabetic rats	Wound closure was fast tracked and promoted angiogenesis	[55]
Human adipose-derived stromal cells	db/db diabetic mice	Wound closure was fast tracked and that stimulated production of extracellular matrix proteins.	[56]
Embryonic stem cells	STZ diabetic rats	There was evidence of decreased in wound size significantly and as well as increased expression of EGF and VEGF	[57]
EPCs	db/db diabetic mice	Accelerated wound healing and induced expression of VEGF and bFGF	[58]

Table 5. Showing natural and synthetic poly based biomaterials used in DFUs treatment [78].

Polymers	Bioactive substance	Models used	Results	References
Chitosan-crosslinked collagen	Recombinant human aFGF	STZ diabetic rats	There were evidences of fast tracked wound healing process	[61]
Chitosan with different degrees of deacetylation	Acetylglucosamine oligomers	Human diabetic	There was reduction in the wound size and the process of angiogenesis was stimulated.	[62]
Thiolated chitosan-oxidized dextran hydrogel		STZ diabetic mice	There were non-cytotoxicity and resistant to degradation.	[63]
Chitosan, alginate, and poly(γ-glutamic acid) hydrogel		STZ diabetic rats	There was improvement in wound healing and increased deposition of collagen and hydroxyproline levels.	[64]
Microbial-derived cellulose hydrogel	Polyhexamethylasebiguanide (PHMB)	Human patients with non- healing ulcers	There was an inhibition of bacteria proliferation, provided an optimal moist healing micro-environment. There was also removal of necrotic tissue
Carboxymethyl cellulose hydrogel	Chestnut honey	db/db mice	There was reduction of wound area significantly and an increase of tissue granulation.	[65]
Alginate hydrogel	Phenytoin	Human patients with DFUs	Infections were removed and there was reduction in pain level.	[66]
Alginate gel	Honey	Human patients with DFUs	The rate of healing was fast tracked and increased tissue reepithelization
Gelatine microspheres	bFGF	db/db mice	There was decreased rate of infection, accelerated fibroblast proliferation.	[67]
Collagen matrix, Integra^® (Integra LifeSciences Corp., USA)		Human patients with DFUs at high risk of amputation	Saved 46% of the limbs and increased the rate of bacterial clearance.	[68]
Collagen–gelatine foam	bFGF	db/db mice	Fast tracked dermis tissue formation and stimulated increase in number of new capillaries.
Dextran-allyl isocyanate-ethylamine/polyethylene glycol diacrylate hydrogel		Human patients with chronic wounds	There was evidence of dermal regeneration and accelerated the early inflammatory cell infiltration	[69]
PVA aminated hydrogel	NO	db/db mice	There were evidences of increased collagen production	[70]
PCL-PEG block copolymer	rhEGF	STZ diabetic mice	Induced accelerated wound healing process.
PEG-PCL nanofibres	EGF and bFGF	STZ diabetic mice	There were evidences of increased accumulation of collagen and keratin.	[71]
PEGylated fibres	rhaFGF	STZ diabetic rats	Fast tracked rate of wound closure and tissue collagen formation as well as TGF expression.	[72]
Poly(ethylene imine) and PEG	Plasmid bFGF	STZ diabetic rats	There was increase in wound recovery rate significantly and improved collagen deposition.	[73]
Poly (vinyl methyl ether co-maleic anhydride) and PVP	NO	STZ diabetic rats	Accelerated wound closure was evident.	[74]
PHEMA and by PEG hydrogel	Matrix metalloproteinase(MMP) inhibitors	Human patients with DFUs	MMPs in the chronic wound fluid are inhibited.
PLGA microspheres	rhEGF	STZ diabetic rats	The growth rate of fibroblasts was significantly improved.	[75]
PCL nanofibres	Curcumin	STZ diabetic mice	These nanofibres improved the rate of wound closure.	[76]
PLA fibres	Curcumin	STZ diabetic mice	These nanofibres augmented the rate of wound closure.	[77]

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