Topical and intravenous administration of human umbilical cord mesenchymal stem cells in patients with diabetic foot ulcer and peripheral arterial disease: a phase I pilot study with a 3-year follow-up

Abstract

Background: Diabetic foot ulcer (DFU) is a serious chronic complication of diabetes mellitus that contributes to 85% of nontraumatic lower extremity amputations in diabetic patients. Preliminary clinical benefits have been shown in treatments based on mesenchymal stem cells for patients with DFU or peripheral arterial disease (PAD). However, the long-term safety and benefits are unclear for patients with both DFU and PAD who are not amenable to surgical revascularization.

Methods: In this phase I pilot study, 14 patients with PAD and incurable DFU were enrolled to assess the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) administration based on conservative treatments. All patients received topical and intravenous administrations of hUC-MSCs at a dosage of 2 × 10⁵ cells/kg with an upper limit of 1 × 10⁷ cells for each dose. The adverse events during treatment and follow-up were documented for safety assessments. The therapeutic efficacy was assessed by ulcer healing status, recurrence rate, and 3-year amputation-free rate in the follow-up phase.

Results: The safety profiles were favorable. Only 2 cases of transient fever were observed within 3 days after transfusion and considered possibly related to hUC-MSC administration intravenously. Ulcer disclosure was achieved for more than 95% of the lesion area for all patients within 1.5 months after treatment. The symptoms of chronic limb ischaemia were alleviated along with a decrease in Wagner scores, Rutherford grades, and visual analogue scale scores. No direct evidence was observed to indicate the alleviation of the obstruction in the main vessels of target limbs based on computed tomography angiography. The duration of rehospitalization for DFU was 2.0 ± 0.6 years. All of the patients survived without amputation due to the recurrence of DFU within 3 years after treatments.

Conclusions: Based on the current pilot study, the preliminary clinical benefits of hUC-MSCs on DFU healing were shown, including good tolerance, a shortened healing time to 1.5 months and a favorable 3-year amputation-free survival rate. The clinical evidence in the current study suggested a further phase I/II study with a larger patient population and a more rigorous design to explore the efficacy and mechanism of hUC-MSCs on DFU healing.

Trial registration: The current study was registered retrospectively on 22 Jan 2022 with the Chinese Clinical Trial Registry (ChiCTR2200055885), http://www.chictr.org.cn/showproj.aspx?proj=135888.

Keywords: Diabetes complications; Diabetic foot ulcer; Human umbilical cord mesenchymal stem cells; Peripheral arterial disease.

Fig. 1

Flowchart of the study procedure. a The patients completed a long-term follow-up for 3 years after the last dose of hUC-MSCs and received laboratory tests, ulcer healing assessments, and vascular status monitoring for safety and efficacy evaluations. b Fourteen patients were included in the current study and completed the follow-up assessments

Fig. 2

The remission of clinical symptoms in patients with diabetic foot ulcers at 1.5 months posttreatment. a The closure status of the diabetic foot ulcers was assessed at baseline and 1.5 months after treatments. Complete closure was observed for 14 ulcers out of 15, while incomplete closure was identified for one ulcer with a closure area of over 95%. b The severity grades of ulcers were decreased significantly after treatments based on the Wagner scores (P = 0.001). c The symptoms of chronic limb ischaemia were alleviated based on the Rutherford grades (P = 0.003). d The pain of the lower limbs was relieved remarkably at the 1.5-month follow-up based on the VAS assessments (P < 0.001)

Fig. 3

Typical CTA images of the lower limbs of the patients. The severity of angiostenosis of the target lower limbs could not be alleviated after treatments based on the CTA images of the patients. Typical images are shown below for Pt 01 at baseline (a) and at the 1.5-month follow-up (b). Angiostenosis was detected in anterior and posterior tibial arteries as well as arteriae fibularis for Pt 01, especially for anterior tibial artery and arteriae fibularis of his left lower limb (white arrows). No significant improvement was observed in the angiostenosis status of these arteries, in which calcification was detected (white arrows in figures of cross section), at 1.5 months after treatments