According to the results of a phase 1 clinical trial, just published in Stem cells Translational medicine, new stem cell therapy shows the promise that diabetes-related amputations will become a thing of the past. The experiment involved injecting diabetic patients suffering from diabetic foot ulcers (DFU) with a cell preparation containing adult stem cells harvested from their own fat. The results showed that the treatment induced the regeneration of the blood vessels surrounding the DFU, accelerating healing – all without serious side effects.
Incurable diabetic foot ulcers usually do not have an effective form of treatment. This work should be reviewed because it demonstrates the possibility of new cell injection therapy that can alleviate pain and infection, accelerate wound healing, and perhaps avoid amputation. “
Anthony Atala, Ph.D. Med., Editor-in-Chief Stem cells Translational medicine and director of the Wake Forest Institute for Regenerative Medicine
Worldwide, a leg is amputated every 30 seconds, and 85 percent is caused by complications from DFU, according to estimates by the American Diabetes Association. “Peripheral vascular disease (PVD) is an aggravating condition of DFU and often or in combination with diabetes often culminates in recurrent, non-healing ulcers and amputations. As surgery is not always feasible for these patients, there is an urgent need for alternative therapies capable of improving foot blood supply. “, said Michael Carstens, Ph.D. med., from the Institute of Regenerative Medicine, Wake Forest University. He and Diego Correa, dr. Med., From the University of Miami, were the leaders of a study that also included researchers from the National University of Nicaragua-Leon.
Cell therapies have attracted attention as viable options that help repair damaged blood vessels while encouraging the creation of new ones. Of particular interest is the stromal vascular fraction derived from adipose tissue, which forms a collection of different cell types, including adult stem cells harvested from adipose tissue. Heterogeneous SVF contains endothelial progenitor cells (EPC) and high concentrations of mesenchymal stem cells (MSCs), among other cell types. EPCs are rare cells that circulate in the blood and are present in fat and that produce cells that make up the inner lining of blood vessels, while MSCs sit in the perivascular space that surrounds blood vessels and can vary into different cell types, depending on the culture conditions in which they breed. Due to their inherent relationship with blood vessels, they can form stable blood vessels together.
“The logistical advantages complement this key multiphenotypic view, as SVF cells can be obtained by simultaneously processing readily available and harvested adipose tissue, without the need for a GMP processing plant to produce MSC-based products,” Dr. Carstens said.
The current study builds on two previous ones conducted by the Carstens-Correa team in Nicaragua to evaluate the value of SVF cells as an alternative and cost-effective treatment for PVD caused by arteriosclerosis and / or diabetes.
“It is difficult to treat vascular diseases and chronic ulcers due to PVD and / or diabetes in resource-poor countries, such as Nicaragua,” said Dr. Carstens. “Patients often have to travel long distances under poor road conditions to receive medical care. Revascularization procedures are not economically feasible for the majority of the population, and advanced stem cell procedures requiring cell processing plants pose significant logistical and economic challenges. Non-healing ischemic wounds pose a tasteless choice for patients and doctors: chronic pain and the risk of infection or amputation. “
Given these factors, the Nicaraguan Ministry of Health approved their pilot study in 2014. The results from the initial 18-month follow-up period showed the safety of the intervention and complete wound healing in nine months. By the final six-year follow-up, five of the initial 10 subjects continued to show consistent clinical benefits. (Five died of heart and non-study-related causes.) In the current study, the team wanted to determine the safety and efficacy of topical SVF cell injections for the treatment of non-healing DFUs larger than 3 cm in diameter, again working with patients in Nicaragua .
Sixty-three people aged 35 to 70 with type 2 diabetes and chronic DFU – all candidates for amputation – were treated with SVF cells injected into the trough, around the periphery and along the pedal arteries (dorsalis pedis and tibialis posterior).
“SVF cells were applied topically along the vascular pathways distally feeding the foot in an effort to concentrate the cell product around the diseased arteries, instead of the intramuscular pathway used in our previous PVD study,” explained Dr. Correa. “The stem cell dose was also reduced to the lowest level tested in an earlier study in which the SVF dose ranged from 30×106 to 158×106 SVF cells. Based on observed clinical responses, even for the lowest dose, and taking into account the smaller injection area, this time used we have a fixed dose of 30×106 SVF cells. “
Patients were seen at intervals of six and 12 months to assess ulcer closure. Doppler ultrasound was also performed in a subset of patients to determine vascular structural parameters. In this group, 32 of 33 pedal arteries showed an increase in flow in line with increased swelling due to distal foot neovascularization; 33/33 arteries showed significant changes in artery wall elasticity. After six months, 51 patients had 100 percent DFU closure and eight had more than 75 percent. Three were amputated early and one patient died.
After 12 months, 50 patients had 100 percent healing with DFU, while four had more than 85 percent healing. “It has been observed that the healing process took place in two different directions: from the periphery, as expected, but also by spreading upwards from the ulcer bed,” said Dr. Carstens. “In several cases, the newly developed tissue was able to cover previously exposed tendons. Furthermore, even among ulcers larger than 10 cm2, almost all patients achieved 85 percent closure or better in six months. No association was observed between ulcer size and closure.”
This led researchers to conclude: “By using SVF injection, surgeons can prevent limb loss, an outcome with devastating socioeconomic consequences for both the patient and society. The presented SVF protocol is easy to execute, can be implemented quickly and safely as an outpatient procedure and can be done under demanding conditions that are often experienced in the developing world. “
Carstens, MH, and others. (2021) Treatment of chronic diabetic foot ulcers with injections of adipose stromal vascular fractions: Safety and evidence of efficacy after 1 year Stem cell translational medicine. doi.org/10.1002/sctm.20-0497.