Table 4 Animal experiments of application of ADSCs in diabetic wounds

STZ-induced rats [102]

Human ADSCs

1. Peri-wound Injection

2. 3 × 10⁶ADSCs

3. 24 h after surgery

1. Gross morphology

2. Histology

3. Tissue VEGF

1. After 25 days, the recovery rate of rats treated with ADSCs was higher than that of the non-diabetic group (the non-treatment group of diabetic rats did not all survive until the end of observation)

2. 25 days after ADSC transplantation, the stem cells were still recognizable and dispersed in the muscle tissue, without structural differentiation

3. Three days after ADSC transplantation, the serum VEGF level was significantly higher than that of the non-diabetic and diabetic non-treatment groups

Ketamine- and xylazine-induced rats [103]

Human ADSCs

1. Collagen gel directly covering the wound

2. N.M

3. Immediately after surgery

1. Wound size

2. Histology of wounds

1. After 10 days of treatment, the wound size of the ADSC group was significantly smaller than that of the untreated group

2. Histological morphology of the wound showed that the scar dermis of the ADSC-treated group was thicker than that of the untreated group

STZ-induced rats [104]

Rat ADSCs

1. Peri-wound Injection

2. 1 × 10⁶ Rat ADSCs

3. Immediately after surgery

1. Wound closure area

2. Histology of wounds

3. Vessel density

4. Immunofluorescent analysis

1. The time for complete wound closure was significantly shortened in the ADSC treatment group

2. Histological observations showed that the tissue regeneration ability of the ADSC group was significantly higher than that of the control group

3. Immunofluorescence showed that ADSCs were incorporated into the regenerating epidermal structure and enhanced wound epithelialization

4. ADSC treatment significantly increased the formation of new blood vessels in the wound, and the vascular density was significantly increased compared to the control group

STZ-induced rats [105]

Rat SVF

cells

1. Direct application of the reconstituted medium onto the wound

2. 5 × 10⁵ Rat SVF cells

3. Immediately after surgery

1. Cytokine levels

2. Cell amounts

3. Granulation tissue area

3. Vessel density

1. The granulation tissue of rats treated with SVF showed a relative increase in extension compared to untreated granulation tissue

2. The vascular density of rats treated with SVF showed a significant increase compared to untreated vascular density

Zucker diabetic obese rats [106]

Lewis rat and EGFP rat ADSCs

1. Cell sheet cover on the wound

2. N.M

3. N.M

1. Wound closure time

2. Vessel densities

1. The wound area and healing time of the transplantation group were superior to those of the non-transplantation group

2. The thickness of the connective tissue in the wounds of the transplantation group was significantly greater than that of the non-transplantation group

3. On experimental day 14, the vascular density of the transplantation group was approximately 2.5 times that of the non-transplantation group

STZ-induced rats [107]

Rat ADSCs

1. Peri-wound injection

2. 1 × 10⁷ Rat ADSCs

3. N.M

1. Wound size

2. Peri-wound inflammatory responses

1. The wound size in the ADSC transplantation group was significantly smaller than that in the non-transplantation group

2. Compared to the control group, the ADSC transplantation group inhibited the inflammatory response around the wound

3. ADSCs increased cell proliferation by enhancing the expression of Ki-67 and rPH

STZ-induced rats [108]

Human ADSCs

1. Peri-wound Injection

2. 5 × 10⁶ human ADSCs

3. Immediately after surgery

1. Ulceration contraction rate

2. Histology assessment

3. Vessel density

1. On experimental day 7, the size of foot ulcers in the diabetes transplant group was significantly smaller than that of the non-transplant group; the effect was even more pronounced on day 15

2. Compared with the non-transplant group, the tissue regeneration of the ADSC transplant group was significantly better, and the tissue staining on day 15 showed that the epithelial regeneration of the ADSC transplant group was also better, and the granulation tissue was thicker

3. The vascular density of the ADSC transplant group was also higher than that of the non-transplant group

Zucker diabetic obese rats [109]

Human ADSCs

1. Cell sheet applied to the wound, and artificial skin and adhesive dressings attached to the surface

2. 7 × 10⁵ human ADSCs

3. Immediately after surgery

1. Wound area

2. Histological analysis of wound

1. Compared with the control group, the ADSC transplantation group showed a significant acceleration in wound healing from day 3

2. The mean time for complete wound closure in the ADSC transplantation group was approximately half of that of the control group

3. Histological staining of the wound tissue showed that the dermal thickness in the ADSC transplantation group was significantly higher than that in the control group

STZ-induced rats [110]

Rat ADSCs

1. Cells and pluronic F17 topical gel applied to the wound site

2. 1 × 10⁶ rat ADSCs

3. Immediately after surgery

1. Percentage of wound closure

2. Histology assessment

3. Blood vessel density

4. Cytokine level

1. Starting from day 3, the wound healing speed of the fat-derived stem cell hydrogel group was significantly faster than that of the control group. By day 14, the wound of the fat-derived stem cell hydrogel group was almost completely healed

2. By day 14, the fat-derived stem cell hydrogel group had formed complete granulation tissue, with new hair follicles formed at the wound center. Fibroblast proliferation was observed, collagen deposits were sufficient, and orderly arrangement was found underneath the epidermis

3. By day 14, the blood vessel density of the wound in the fat-derived stem cell hydrogel group was significantly higher than that of the control group

4. The expression of VEGF and TGFβ1 in the fat-derived stem cell hydrogel group was significantly higher than that of the control group

Db/db mice [111]

Ex-4 + Human ADSCs

1. Peri-wound Injection

2. 2.5 × 10⁵ human ADSCs

3. 24 h after surgery

1. Wound healing rate

2. Histology of wound skin

3. Cytokines expression

1. Wound healing in the Ex-4 + ADSC treatment group was significantly faster than the other groups

2. Histological examination of the wound tissue in the Ex-4 + ADSC treatment group showed more prominent endothelial regeneration

4. The expression of VEGF was increased in the Ex-4 + ADSC group compared to the control group, but was lower than when expressed separately

STZ-induced Yorkshire swine [112]

Yorkshire swine ADSCs

1. Peri-wound injection

2. 5 × 10⁶, 10 × 10⁶ Yorkshire swine ADSCs

3. 72 h after surgery, with a 12-h interval

1. Wound closure

2. Histological analysis,

3. mRNA and protein analyses

1. Wound healing in the ADSC treatment group was faster than that in the control group

2. In the ADSC-treated skin samples, intact epidermis with dermal fibrosis and scattered lesions were observed, mainly chronic and occasional foreign body giant cell inflammation, consistent with scar formation

3. RNA analysis showed no significant differences in CD31, nitric oxide synthase, TNF-α and IL-1β, except for a decrease in PDGF in the treatment group; protein analysis showed no significant differences in TGF-β between the treatment and non-treatment groups

STZ-induced Sprague–Dawley rats [113]

Human ADSCs exosomes + EPCs

1. Peri-wound Injection

2. N.M

3. 7 days after surgery

1. Wound area

2. Histology of tissue healing

3. Changes in cytokine factors

1. The EPC + exosome treatment group showed a significant reduction in ulcer area compared to the control group

2. The wound vascular density in the EPC + exosome treatment group was significantly higher than that in the control group

3. Exosomes derived from adipose stem cells reduced glucose-induced EPC aging

STZ-induced Sprague–Dawley rats [114]

Diabetic rat autologous nano-lipid droplets (including ADSCs)

1. Peri-wound injection

2. 2 × 10⁵ ADSCs

3. Immediately after surgery

1. Wound area change

2. Vessel density

3. Angiogenic factor expression

1. Wound healing in the nano-lipid treatment group was significantly faster than that of the control group

2. The endothelial regeneration of the wounds in the nano-lipid treatment group was more complete

3. The capillary density of the granulation tissue in the nano-lipid treatment group was significantly higher than that of the control group

4. The expression of MCP-1 and VEGF was significantly increased in the nano-lipid treatment group

Pressure injury model mice [115]

Human ADSCs

1. PRP + ADSCs injection around the wound

2. 1 × 10⁶ human ADSCs

3. 2 days after surgery

1. Wound healing rate

2. Histology of wounds

3. Immunohistochemical assay

1. Wound healing in the PRP + ADSC treatment group was significantly faster than the other groups

2. The PRP + ADSC treatment group had a lighter wound inflammation reaction compared to the other groups, with a more complete skin structure, and regeneration of appendages was observed

3. More ADSCs gathered in the subcutaneous layer of the edge of the mouse wound

STZ-induced Wistar rats [116]

Rat ADSCs + PBM

1. Peri-wound injection

2. 1 × 10⁶ rat ADSCs

3. Immediately after surgery

1. Wound closure rate

2. Cell amount in the peri-wound area

1. Wound healing in the group treated with PBM and ADSCs was significantly faster than the other groups

2. The number of ulcers on wounds treated with PBM and ADSCs was significantly less than the other groups

3. The quantity of fibroblasts and length of blood vessels in wounds treated with PBM and ADSCs was significantly better than the other groups

STZ-induced mice [117]

Mice ADSCs (normal and diabetic mice)

1. Peri-wound injection

2. 5 × 10⁵ mice ADSCs

3. Immediately after surgery

1. Cell type after injection

2. Cytokine level

3. Wound closure rate

1. Wound healing in the ADSC treatment group was higher than that of the control group, and the healing rate of ADSCs from normal sources was higher than that from diabetic mice

2. ADSCs increased vascular regeneration and collagen expression in wounds of diabetic mice

3. ADSCs reduced the inflammatory response of wounds

4. After injection, ADSCs differentiated into endothelial cells and fibroblasts

Db/db mice [118]

Bcl-2-modified human ADSCs

1. Modified ADSCs and collagen scaffold directly applied to cover the wound

2. N.M

3. 7 days after surgery

1. Wound healing rate

2. Histology assessment

3. Vascularization

1. Wound healing in the ADSC and collagen scaffold treatment group was significantly faster than that of the other control groups

2. The vascular density of granulation tissue in the ADSC and collagen scaffold treatment group was significantly higher than that of the control group

3. Histological analysis performed 1 week after surgery showed that ADSCs maintained high vitality

STZ-induced rats [119]

Rat ADSCs + PBM

1. Peri-wound injection

2. 1 × 10⁶ rat ADSCs

3. N.M

1. Wound healing rate

2. Wound maximum force

3. Mast cell numbers

1. Wound healing of the PBM + ADSC treatment group was significantly faster than that of the other groups

2. The maximum tensile strength of wounds in the PBM + ADSC treatment group was higher than that of the control group

3. The number of mast cells and mast cell granules in the wounds of the PBM + ADSC treatment group decreased significantly

STZ-induced albino rats [120]

Rat ADSCs

1. PRP + ADSCs injection around the wound

2. 2 × 10⁶ rat ADSCs

3. Immediately after surgery

1. Wound area

2. Histological analysis

3. Epidermal thickness

4. Dermal collagen

5. Angiogenesis

1. The combination of ADSCs and PRP improved wound healing through the Notch signaling pathway, with the best wound healing effect observed in this group

2. Histological analysis showed that on the day 7, the wounds in the group treated with ADSCs and PRP had a complete skin structure, abundant collagen fiber status, and thick bundles of collagen in the reticular layer

3. The group treated with ADSCs and PRP showed significantly better epidermal thickness and vascular regeneration in the wound than the other groups

STZ-induced mice [121]

Mice ADSCs

1. Cell sheet cover on the wound

2. 4 × 10⁵ mice ADSCs

3. Immediately after surgery

1. Wound healing rate

2. Histology of wounds

1. Fat stem cell mice accelerated the rate of wound healing in diabetic ulcer mice

2. Adipose stem cells increased the proliferation, migration and regeneration of lymphoendothelial cells through METTL3