Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets

Table 1 Clinical trial of few therapeutic agents/approaches in the management of diabetic wound

Ref.	Type	Drug/ product /approach investigated	Type and number of participants	Type of wound	Observation
[132]	Homeopathic medicine	Silicea, Sulphur, Lycopodium, Arsenic album, Phosphorus	Observational study, 156 patients	DFU	Ulcer assessment score reduced significantly (P < 0.05) after treatment. Silicea, sulphur (n = 11), lycopodium, arsenic album, phosphorus were found more effective. Although, the effect of homeopathic therapy alone is difficult to establish
[133]		Silicea	Observational study, 22 patients	DFU	Positive and encouraging result of silicea in ulcer healing was reported. DFU assessment score was measured, and mean symptom scores at the end of the treatment were found to reduce significantly (P < 0.05)
[134]	Herbal Products	ON101 cream (contain extract of Plectranthus amboinicus and Centella asiatica)	Phase 3 RCT, 236 participants	DFU	Incidence of complete healing in ON101 and comparator group was 60.7% and 35.1% respectively. Although, the number of adverse events in the ON101 group was 7 vs 5 in the comparator group. ON101 produced a better healing effect compared to absorbent dressing alone
[135]		Intravenous Semelil (a naive herbal extract)	RCT, 25 participants	DFU	Mean foot ulcer surface area reduced significantly in semelil (i.v. route) group and the average wound closure in semelil group was significantly more than control group (64% vs 25%, P = 0.015). Semelil in combination with conventional therapy showed better effect than conventional therapy
[136]		Olive oil	Double blind RCT, 34 participants	DFU	Degree of ulcer, color, surrounding tissues, the status of ulcer and ulcer drainages were evaluated after topical application of olive oil. Complete ulcer healing in the treatment group was significantly better than the control group (73.3% vs 13.3%, P = 0.003). Olive oil treatment significantly reduced ulcer area and ulcer depth. Olive oil in combination with routine care was better than routine care alone
[137]		Polyherbal formulation (contain G. glabra, M. paradisiaca, C. longa, P. odaratissimus, A.e vera, C. nucifera oil)	Open label, phase III, comparative study, 40 participants	DFU	Polyherbal formulation was found effective similar to that of standard silver sulphadiazine cream
[138]		Semelil (ANGIPARS™, contain Melilotus officinalis)	Clinical study, 10 participants	DFU	ANGIPARS™ was found effective in reduction of wound size by at least 50% during 8 wk period
[139]	PRP	PRP gel	Single-arm clinical trial, 100 participants	DFU	PRP therapy (2 mL/cm2 of ulcers) was found highly effective in the treatment and healing of non-healing chronic DFUs
[140]		PRP	Prospective RCT, 20 participants	DFU	Wound healing time was estimated as 8 wk which is superior to the control group. People treated with PRP it found more effective in wound healing
[141]	Human EGF (hEGF)	Recombinant hEGF	Prospective, open-label trial, crossover study, 89 participants	DFU	Wound healing was noted within an average of 46 d in patients who were treated with 0.005% EGF twice a day. Topical application of hEGF combined with hydrocolloid dressing showed promoting healing effect in chronic DFU
[142]		Regen-D 150 (hEGF gel-based product)	RCT, 50 participants	DFU	Complete ulcer healing was detected in 78% population against 52% population in the placebo group. Collagen and fibroblasts were significantly developed in the treated group. The application of hEGF can be helpful to promote wound healing and in preventing leg amputations
[143]	PDGF	rhPDGF	RCT, 50 participants	DFU	Wounds contracted more in rhPDGF-treated group compared to the control group (38.55% vs 12.79%; P ≤ 0.001). Dressing with rhPDGF was found more effective and promoted safe wound healing
[144]		PDGF gel	RCT, 29 participants	Diabetic lower extremity ulcer	100% of ulcers were healed in subjects who received PDGF compared to 76.4% of wound healing in placebo group. The study confirms the effectiveness of PDGF gel
[145]	FGF	bFGF	Double-blind RCT, 150 participants	Non-ischaemic diabetic ulcer	Wound cure rate in 0.001% bFGF, 0.01% bFGF and control group was 57.4%, 66.7% and 46.8%. The area of the ulcer was also significantly decreased in bFGF treated groups. bFGF accelerates wound healing in diabetic people
[146]	Oxygen therapy	Topical oxygen therapy	RCT, 145 participants	DFU	A significant decrease in wound area was reported in the topical oxygen therapy + standard care group (70%) compare to the standard care group (40%) Addition of topical oxygen therapy with standard care facilitates wound closure in a better way
[147]		Hyperbaric oxygen therapy	RCT, 75 participants	Chronic DFU	Complete healing of ulcer index was reported in 52% of participants who received hyperbaric oxygen therapy after 1 year, which was 29% in the placebo. Adjunctive treatment with hyperbaric oxygen therapy may facilitate the healing of foot ulcers
[148]	NPWT	NPWT	Prospective randomized study, 55 participants	DFU	Granulation tissue formation (91.14% vs 52.61%, P < 0.001) and a decrease in the size of ulcer size (40.78% vs 21.18%, P = 0.008) were reported in the NPWT group after 14 d. Duration of hospital and time for complete coverage of the wound with granulation tissue was significantly less in the NPWT group. NPWT led to an early decrease in the size of the ulcer, formation of more granulation tissue, and wound healing
[149]		NPWT	RCT, 55 participants	DFU	The rate of ulcer healing was found higher in the NPWT group (P-value 0.01). NPWT leads to a higher rate of healing, and causes a significant decrease in ulcer surface area, size, and depth of the wound, reducing the risk of amputations
[150]	Phototherapy	LLLT	RCT, 23 participants	DFU	Ulcers size reduced significantly in 4th week in LLLT group (P = 0.04). More patients healed completely in LLLT group compared to the placebo group. Meantime of complete healing in patients treated with LLLT was 11 wk vs 14 wk in placebo patients. LLLT promotes the healing process of chronic DFU, and reduces the time required for wound healing
[151]		LLLT	RCT, 56 participants	DFU	Increment in total hemoglobin was more using the highest intensity configuration compare to the lower intensity setup in patients with DFU. A decrease in the very-low frequency/low frequency ratio, slightly more than the highest intensity in DFU people was observed. LLLT was found to increase blood flow and regulation of the autonomic nervous system in patients with DFU
[152]	ESWT	ESWT	Single-blinded RCT, 38 participants	DFU	Patients received shock wave therapy 2/week for a total of 8 treatments. Average healing time was lower in ESWT-group when compared with the control group (64.5 vs 81.17 d, P < 0.05). AT 20 wk, 54% of ulcer healed completely in ESWT-groups compared to 28.5% in the control group
[153]		ESWT	Prospective RCT, 23 participants	DFU	At 7 wk, the mean reduction in ulcer area was 34.5% (CI, 0.7-68.3) in the ESWT group and 5.6% (CI, -42.1-53.3) in the control group. ESWT also enhances tissue oxygenation
[154]	Stem cell therapy	Topical application of MSC	Clinical case study of three patients	Neuropathic DFU	MSCs at low doses enhance the re-epithelialization of DFU. MSCs may start early to reduce overall wound closure time
[155]		HUCMSCs	RCT, 56 participants	DFU	Patients in HUCMSCs (endovascular infusion and injection around the foot ulcer) experienced greater and betterment in skin temperature, transcutaneous oxygen tension, ankle-brachial pressure index, and claudication distance. Three months after treatment significant enhancement in neovessels, and complete or gradual ulcer healing was observed in the experimental group
[156]	NO generating approach	EDX110 (nitric oxide generating medical device)	RCT, 135 participants	DFU	At 12 wk, EDX110 use resulted in 88.6% reduction in median wound area compared to 46.9% for the control group (P = 0.016). EDX110 was found to improve foot wound healing in diabetic people significantly by reducing the ulcer area
[157]	Other Approaches	Bemiparin (low MW heparin)	RCT, 70 participants	DFU	In bemiparin group, the ulcer improvement rate was 70.3% compared to 45.5% in the placebo group. Though, complete healing rates found similar in both groups at 3 mo were, as were the number of adverse events. Bemiparin is better than a placebo in the management of DFU and has few side effects
[158]		Honey dressing	RCT, 348 participants	DFU	In 75.97% of cases wound healed completely after honey dressing in comparision to 57.39% of case in the saline dressing group. The homey dressing also reduced the median wound healing time (18.00 d) compare to the control group (29.00 d). Honey is an effective dressing substance compared to conventional dressings
[159]		Omega-3–rich fish skin grafts	RCT, 49 participants	DFU	At 12 wk, 67% of foot wounds were completely closed compared with 32% in the standard care group. Study findings indicated that fish skin graft is useful in the treatment of chronic DFUs that do not heal with standard treatment

DFU: diabetic foot ulcers; RCT: randomized controlled trials; PRP: platelet-rich plasma; hEGF: Human endothelial growth factor; rhPDGF: Recombinant human platelet-derived growth factor; PDGF: platelet-derived growth factor; bFGF: Basic fibroblast growth factor; NPWT: Negative pressure wound therapy; LLLT: Low-level laser therapy; ESWT: Extracorporeal shock wave therapy; MSC: Mesenchymal stromal cell; HUCMSCs: Human umbilical cord mesenchymal stem cells; NO: nitric oxide.