Treatment of chronic diabetic foot ulcers with adipose-derived stromal vascular fraction cell injections: Safety and evidence of efficacy at 1 year

Abstract

Diabetes affects multiple systems in complex manners. Diabetic foot ulcers (DFUs) are a result of diabetes-induced microarterial vessel disease and peripheral neuropathy. The presence of arteriosclerosis-induced macroarterial disease can further complicate DFU pathophysiology. Recent studies suggest that mesenchymal stromal cell therapies can enhance tissue regeneration. This phase I study was designed to determine the safety and explore the efficacy of local injections of autologous adipose-derived stromal vascular fraction (SVF) cells to treat nonhealing DFUs greater than 3 cm in diameter. Sixty-three patients with type 2 diabetes with chronic DFU-all amputation candidates-were treated with 30 × 106 SVF cells injected in the ulcer bed and periphery and along the pedal arteries. Patients were seen at 6 and 12 months to evaluate ulcer closure. Doppler ultrasounds were performed in a subset of subjects to determine vascular structural parameters. No intervention-related serious adverse events were reported. At 6 months, 51 subjects had 100% DFU closure, and 8 subjects had ≥75% closure. Three subjects had early amputations, and one subject died. At 12 months, 50 subjects had 100% DFU healing and 4 subjects had ≥85% healing. Five subjects died between the 6- and 12-month follow-up visits. No deaths were intervention related. Doppler studies in 11 subjects revealed increases in peak systolic velocity and pulsatility index in 33 of 33 arteries, consistent with enhanced distal arterial runoff. These results indicate that SVF can be safely used to treat chronic DFU, with evidence of efficacy (wound healing) and mechanisms of action that include vascular repair and/or angiogenesis.

Keywords: angiogenesis; diabetes complications; diabetic ulcers; microangiopathy; stromal vascular fraction.

Conflict of interest statement

M.H.C. is a paid consultant for the GID Bio Inc., in which he holds stock options. S.D.‐A. has been a paid consultant for GID Bio Inc., but not at the moment of manuscript submission. D.C. was a paid consultant of Lipogems USA, LLC, at the time of execution of the study. The other authors declared no potential conflicts of interest.

© 2021 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.

Figures

FIGURE 1

Summary of the study and graphical scheme showing sites of injection. A, Schematic representation of the sites of injection of the stromal vascular fraction cells, corresponding to the margins and bed of the ulcer and the vascular territories of the tibialis anterioris, dorsalis pedis, and tibialis posterioris. For these vascular structures, the injections run from proximal to distal. Created with BioRender.com. B, CONSORT diagram showing the flow of the study. *These three patients were amputated by nontreating surgeon based on previously scheduled surgery, leaving not time to evaluate the effect of the therapy. **The five patients who passed away between 6 and 12 months had 100% closure of their ulcers by the 6‐month follow‐up, so they were included in the final analysis. C, Demographics information of study participants and summary of findings

FIGURE 2

Ulcer characteristics and responses. Frequency distribution of diabetic foot ulcer based on size (cm2) (A) and time (weeks) to an observable response and final closure (B). C, Spearman rank correlation test evidencing lack of correlation between ulcer size and time to an observable response and final closure

FIGURE 3

Pre‐ and postprocedure images of the ulcers. Graphical demonstration of closure of diabetic foot ulcer, presenting 3 of the 52 cases with 100% closure and 3 of the 7 cases with incomplete (85%‐95%) closure. The remaining cases showed comparable results

FIGURE 4

Peak systolic velocity and pulsatility index. Peak systolic velocity (A) and pulsatility index (B) assessed in tibialis anterior, dorsalis pedis, and tibialis posterior by Doppler spectral color ultrasound, comparing pre‐ and postinjection results, and evidencing statistically significant differences in all arteries examined. PSV, peak systolic velocity