PORTLAND, ORE. – Treating chronic venous leg ulcers with mesenchymal stem cells and fibrin spray significantly improved wound healing, compared with vehicle control or saline plus conventional therapy, according to the results of a small randomized, controlled, double-blind pilot trial.
“Topical application of autologous, bone-marrow–derived mesenchymal stem cells may be an effective way to promote healing in patients with difficult-to-heal wounds,” said Ayman Grada, MD, of the department of dermatology at Boston University. “However, larger studies are needed to confirm this finding.”
“Various treatment modalities have been used, but treatment outcomes are not always satisfactory,” said Dr. Grada. “In about 60% of cases, wounds fail to close, and there is also a high rate of recurrence.”
Preclinical work in several animal models indicated that applying mesenchymal stem cells to wounds accelerated healing through a variety of mechanisms, Dr. Grada noted. Based on that premise, he and his associates hypothesized that autologous cultured mesenchymal stem cells could accelerate wound healing in humans.
To test that idea, they randomly assigned the 11 trial participants to one of two control treatments or to the stem cell intervention. Four patients received normal saline with conventional standard care, three patients received fibrin spray plus conventional therapy, and four patients received conventional therapy plus autologous mesenchymal stem cells delivered in fibrin spray at a dose of 1 x 106 cells per square centimeter of wound surface. Patients were treated every 3 weeks, up to three times or until complete wound healing, and were followed for up to 24 weeks.
To acquire the stem cells, the researchers obtained 30- to 50-mL samples of bone marrow aspirate from the iliac crest, then separated and cultured the cells in-house. The controls underwent sham aspiration with needles that did not penetrate the bone, Dr. Grada said. At each 4-week follow-up visit, the investigators measured the perimeter and area of each wound and analyzed the results with public domain software called ImageJ. They calculated the linear advance of the wound margin by dividing change in area by average perimeter.
The healing rate of the intervention group outpaced that of either control group at each time point measured, Dr. Grada said. Average weekly healing rates by time point ranged between –0.002 cm and 0.006 cm for the saline group and between –0.05 cm and 0.01 cm for the fibrin spray group. Neither of these control groups achieved meaningful wound closure by week 24.
In contrast, stem cell recipients experienced consistent wound closure at rates of 0.11-0.13 cm per week. The study was too small for conventional statistical analysis, but a Bayesian time aggregated one-way analysis of variance yielded a statistically significant difference in healing rates among groups (P less than .0005).
Dr. Grada also discussed several case studies. An 82-year-old white woman with a decades-long history of venous ulcers experienced complete wound healing with mesenchymal stem cell therapy, which enabled her to become more independent within her long-term care facility. A 75-year-old African American woman achieved 80% wound healing with stem cell therapy after previously having failed to benefit from two applications of bioengineered skin.
Finally, a 39-year-old man with chronic, treatment-resistant venous ulcers achieved partial wound healing. “He has almost healed, with very thin epidermal coverage, but never to the point of no exudate and complete closure,” Dr. Grada said. “Therefore, we could not declare him healed, even though the ulcer was smaller at the end of the study.”
No patient in the study experienced adverse events from treatment. However, recruiting for the trial was difficult, because patients were reluctant to undergo bone marrow aspiration, Dr. Grada said.
Previous work indicates that the initial rate at which the wound heals dictates its final rate (), and that 4 weeks is enough to establish a healing trend, he noted. Dr. Grada concluded by quoting Hippocrates: “Natural forces within us are the true healers of disease.”
The National Institutes of Health supported the trial. Dr. Grada had no conflicts of interest.