Combined Transplantation of Mesenchymal Stem Cells and Endothelial Colony-Forming Cells Accelerates Refractory Diabetic Foot Ulcer Healing

Abstract

Background: This study is aimed at investigating the effect of combined transplantation of umbilical cord mesenchymal stem cells (UCMSCs) and umbilical cord blood-derived endothelial colony-forming cells (ECFCs) on diabetic foot ulcer healing and at providing a novel therapy for chronic diabetic foot ulcer.

Methods: We reported the treatment of refractory diabetic foot ulcers in twelve patients. Among them, five patients had two or more wounds; thus, one wound in the same patient was treated with cell injection, and other wounds were regarded as self-controls. The remaining seven patients had only one wound; therefore, the difference between the area of wound before and after treatment was estimated. The UCMSCs and ECFCs were injected into the wound along with topically applied hyaluronic acid (HA).

Results: In this report, we compared the healing rate of multiple separate wounds in the same foot of the same patient: one treated with cell injection combined with topically applied HA-based hydrogel and was later covered by the hydrocolloid dressings, while the self-control wounds were only treated with conventional therapy and covered by the hydrocolloid dressings. The wound underwent cell injection showed accelerated healing in comparison to control wound within the first week after treatment. In other diabetic patients with only one refractory wound, the healing rate after cell transplantation was significantly faster than that before injection. Two large wounds healed without needing skin grafts after combination therapy of cell injection and HA. After four weeks of combination treatment, wound closure was reached in six patients, and the wounds of the other six patients were significantly reduced in size.

Conclusions: Our study suggests that the combination of UCMSCs, ECFCs, and HA can safely synergize the accelerated healing of refractory diabetic foot ulcers.

Figure 1

Photographs of treated ulcer (right foot) and control ulcer (left foot) over time with depiction of wound surface area of patient #1 (a). Patient #1 had two wounds in both foots; the right foot was injected cells and the left foot as control. The healing rate of the wound injected cells was obviously faster than control wounds. Photographs of treated ulcer (the first and third toes) and control ulcer (the other two toes) over time with depiction of wound surface area of patient #2 (b). Patient #2 had four wounds in his left foot; the first and third toes were injected cells (red arrow) and the other two toes as control. The healing rate of the toes injected cells was obviously faster than control wounds. Photographs of treated ulcer (the fifth toe) and control ulcer (the other two toes) over time with depiction of wound surface area of patient #3 (c). Patient #3 had three wounds in his left foot; the fifth toe was injected cells (red arrow) and the other two toes as control. The wound was covered with white epithelium at the fourth day after cell treatment. The healing rate of the fifth toe was obviously faster than control wounds.

Figure 2

Photographs of ulcer before and after treatment (a) with depiction of wound surface area (b). Patient #7, a 64-year-old woman with a 5-year history of type 2 diabetes, presented with ulcer and infection on her left foot (Wagner 3) for 2 months.

Figure 3

Photographs of ulcer before and after treatment (a) with depiction of wound surface area (b). Patient #8, a 64-year-old man with an 11-year history of type 2 diabetes, had the wound on his left foot for one month (Wagner 3); moreover, the wound area was 7.33 cm² with bone exposure after debridement of the first toe.

Figure 4

Photographs of ulcer before and after treatment (a) with depiction of wound surface area (b). Patient #11, a 47-year-old man with a 10-year history of type 2 diabetes, presented with infection of his right foot (Wagner 4), which was present for two months; the wound area was 52.39 cm² after debridement.

Figure 5

Photographs of ulcer before and after treatment (a) with depiction of wound surface area (b). Patient #12, a 69-year-old man with a 30-year history of type 2 diabetes, presented with infection of his right foot and exposed bones and tendons (Wagner 3), which was present for one week; the wound area was 3.10 cm² after debridement of the foot.