Long-Term Outcomes of BMMSC Compared with BMMNC for Treatment of Critical Limb Ischemia and Foot Ulcer in Patients with Diabetes

Debin Lu, Youzhao Jiang, Wuquan Deng, Yan Zhang, Ziwen Liang, Qinan Wu, Xiaoyan Jiang, Ling Zhang, Fang Gao, Ying Cao, Bing Chen, Yaoming Xue, Debin Lu, Youzhao Jiang, Wuquan Deng, Yan Zhang, Ziwen Liang, Qinan Wu, Xiaoyan Jiang, Ling Zhang, Fang Gao, Ying Cao, Bing Chen, Yaoming Xue

Abstract

We first compared long-term clinical outcomes in treating critical limb ischemia (CLI) and foot ulcer in patients with diabetes between autologous bone marrow mesenchymal stem cell (BMMSC) and bone-marrow-derived mononuclear cell (BMMNC) transplants. Forty-one patients were enrolled and followed up for 3 years. They received an 18-day standard treatment before stem cell transplantation. Patients with bilateral CLI and foot ulcer were injected intramuscularly or basally with BMMSC, BMMNC, or normal saline (NS). Cox model analysis showed significant differences in the hazard ratio (HR) for amputation with treatment by BMMSC (HR 0.21 [95% CI (0.05, 0.95)], P = 0.043), infection of foot (HR 5.30 [95% CI (1.89, 14.92)], P = 0.002), and age ≥64 (HR 3.01 [95% CI (1.11, 8.15)], P = 0.030), but no significant differences by BMMNC at 9 months after transplantation. Regarding ulcer healing and recurrence rate, the BMMSC group demonstrated a significant difference from the NS group during the 3-6 months after transplantation or healing, but the BMMNC group did not. This trial suggests that, compared with BMMNC treatment, BMMSC treatment leads to a longer time of limb salvage and blood flow improvement, and, when compared with conventional therapy, it can promote limb blood flow and ulcerative healing, and reduce ulcer recurrence and amputation within 9 months.

Trial registration: ClinicalTrials.gov NCT00955669.

Keywords: autologous transplantation; cellular therapy; clinical trial; critical limb; diabetes; ischemia.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Fig. 1
Fig. 1
(A) Kaplan-Meier curves representing the estimated cumulative incidence rates of amputation-free survival in BMMSC, BMMNC, and NS groups over 36 months of follow up, with censored data for patients who died. (B) After age, smoking, and infection were taken into account in a Cox proportional hazard regression model, the curves represent the estimated cumulative rates of amputation-free survival in BMMSC, BMMNC, and NS groups at 9 months after transplantation.
Fig. 2
Fig. 2
(A) Ulcer recurrence rate and blood flow in limbs injected with BMMSCs, BMMNCs, or NS. Ulcer recurrence rate (i.e., the number of limbs with ulcers recurrence/the total number of limbs with ulcers healed in a group) (*P < 0.05, BMMSC group vs. NS group). (B–F) The results of rest pain, pain-free walking time, ABI, TcO2, and angiography are presented as mean ±SD (*P < 0.05, BMMSC group vs. NS group; #P < 0.05, BMMNC group vs. NS group).
Fig. 3
Fig. 3
MRA analysis of collateral vessel formation in limbs injected with BMMSCs, BMMNCs, and NS. (A) Abundant increased collateral circulation in a limb of the BMMSC group from +0 (A1) to +3 (A2) appeared 9 months after implantation. (B) A moderate increase in collateral circulation in a limb of BMMNC group from +0 (B1) to +2 (B2) appeared 9 months after implantation. (c) In contrast, there was no collateral circulation (+0) in a limb from the NS group before (C1) and 9 months after (C2) implantation.

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