Mesenchymal stem cell therapy can help patients with non-healing diabetic foot ulcers

The new stem cell therapy will make diabetes-related amputations a thing of the past, according to the results of the phase 1 clinical trial. The trial involved administering a cell preparation containing adult mesenchymal stem cells (MSCs) derived from the patients’ own fat to patients with type 2 diabetes with diabetic foot ulcers (DFU). The results showed that the treatment stimulated the regeneration of the blood vessels surrounding the DFUs and accelerated healing. However, there were no serious side effects.

“Non-healing diabetic foot ulcers usually have no effective form of treatment”, – said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine in which this study was published, and Director of the Wake Forest Institute for Regenerative Medicine. “This work should be reviewed as it demonstrates the possibility of a novel cell injection therapy that can alleviate pain and infection, accelerate wound healing, and possibly avoid amputation.”

The American Diabetes Association estimates that a leg is amputated every 30 seconds worldwide. Moreover, in 85% of cases, this is due to complications caused by diabetic foot ulcers.

“Peripheral vascular disease (PVD) is an aggravating condition for DFU and either alone or in combination with diabetes often culminates in recurrent, non-healing ulcers and amputations. As surgery is not always feasible for these patients, an urgent need exists for alternative therapies capable of improving blood supply to the affected foot”, – said Michael Carstens, M.D., of Wake Forest University’s Institute of Regenerative Medicine.

He and Diego Correa, M.D., Ph.D., of the University of Miami, were leaders of the study that also included researchers at the Universidad Nacional de Nicaragua-León.

Cell therapy has attracted the attention of scientists as a promising method that helps restore damaged vessels by promoting the formation of new ones. Of particular interest is the stromal vascular fraction (SVF) of adipose tissue.

Heterogeneous SVF, among other cell types, contains endothelial cell progenitors (EPCs) and high concentrations of mesenchymal stem cells circulate in the bloodstream, are present in fat, and give rise to cells that form the inner lining of blood vessels.

MSCs are located in the perivascular space and can differentiate into different types of cells, depending on the culture conditions. When in close contact with blood vessels, they can create new vessels and have general angioprotective properties.

“Logistical advantages complement this key multi-phenotypic display, as SVF cells can be obtained from a same-day processing of readily accessed and harvested adipose tissue, without the need of a GMP processing facility to manufacture an MSC-based product”, – Dr. Carstens said.

The present study builds on two previous studies by Carstens and Correa’s team in Nicaragua to evaluate the value of stromal vascular fraction cells as an alternative and cost-effective treatment for peripheral vascular disease caused by atherosclerosis and/or diabetes.

“It’s difficult to treat vascular disease and chronic ulcers due to PVD and/or diabetes in resource-poor countries such as Nicaragua”, – Dr. Carstens said. “Patients frequently have to travel long distances under poor road conditions to obtain medical care. Revascularization procedures are not economically possible for most of the population, and advanced stem cell procedures that require cell processing facilities represent significant logistical and economic challenges. Under such conditions, non-healing ischemic wounds present patients and physicians with unpalatable choices: chronic pain and risk of infection or amputation.”

Given these factors, a pilot clinical trial led by Carstens and Correa’s team was approved by the Nicaraguan Ministry of Health in 2014. The results of the first 18-month follow-up period demonstrated the safety of therapy and complete wound healing within nine months.

At the end of the six-year follow-up, five of the first 10 patients still showed sustained positive treatment results. (Five died from cardiovascular disease unrelated to the trial.)

In a new study, the team wanted to determine the safety and efficacy of local injections of stromal-vascular fraction cells for non-healing DFUs with a diameter of more than 3 cm in patients from Nicaragua.

Sixty-three people aged 35 to 70 years with type 2 diabetes and chronic diabetic foot ulcers received injections of SVF cells injected into the ulcer bed, around the periphery, and along the course of pedal arteries (dorsalis pedis and tibialis posterior). All subjects were amputation candidates.

“SVF cells were locally administered along the vascular trajectories distally feeding the foot in an effort to concentrate the cell product around the diseased arteries, instead of the intra-muscular route used in our previous PVD study”, – Dr. Correa explained. “The dose of stem cells was also reduced to the lowest level tested in the earlier study in which the SVF dose ranged from 30×106 to 158×106 SVF cells. Based upon the observed clinical responses, even for the lowest dose, and taking into consideration the smaller injecting area, this time we used a fixed cell dose of 30×106 SVF cells.”

Patients were examined at intervals of 6 and 12 months to assess ulcer closure. Doppler ultrasound was also performed in a subgroup of 11 patients to determine the structural parameters of the vessels. In this group, 32 of 33 foot arteries showed increased blood flow due to distal foot neovascularization. 33 of 33 arteries showed significant changes in arterial wall elasticity and increases in peak systolic velocity and pulsation index.

After 12 months, 50 patients showed 100% healing of SDS, and four more than 85% healing.

trophic ulcers before and after the procedure

Images of trophic ulcers before and after the procedure. Graphical demonstration of diabetic foot ulcer closure, representing 3 out of 52 cases with 100% closure. Credit: AlphaMed Press

“The healing process was observed to take place in two different directions: from the periphery, as expected, but also by upward proliferation from the ulcer bed”, – Dr. Carstens said. “In several cases, newly developed tissue was capable of covering previously exposed tendons. Furthermore, even among ulcers greater than 10 cm2 virtually all patients achieved 85 percent closure or better by six months. No correlation between ulcer size and closure was observed.”

“By using SVF injection, surgeons can prevent limb loss, an outcome with devastating socioeconomic consequences for both the patient and society. The SVF protocol presented is easy to execute, can be carried out quickly and safely as an ambulatory procedure and can be done under the demanding conditions that are often experienced in the developing world”, – the researchers shared their findings.