A stem cell trial for diabetic foot ulcers

UCHealth is part of a collaborative campus trial testing the safety of umbilical cord stem cells to treat diabetic foot ulcers, a devastating complication of the disease.
November 17th, 2020

The umbilical cord is the lifeline connecting a mother and her developing baby. A trial underway on the UCHealth at University of Colorado Anschutz Medical Campus is exploring whether cords cut after birth can continue to promote life and health – not in infants, but in adults battling a serious complication of diabetes.

The target is diabetic foot ulcers (DFUs): chronic open sores, usually on the soles, that stubbornly resist healing. They make patients vulnerable to infection and amputation and shorten the lives of many who suffer with them. A study of Veterans Administration patients, for example, put the five-year survival rate for patients with diabetic foot ulcers at just 29%.

Norma Armistead sits outside her home.
Norma Armistead has had trouble with her feet for years. Photos: Cyrus McCrimmon for UCHealth.

The cost of treating diabetic foot ulcers is also enormous – as much as a third of the well over $100 billion spent in the United States on direct care for diabetes. The number of visits to emergency rooms and hospitals for diabetic foot ulcers and the infections they cause exceeds those for congestive heart failure, kidney disease, most forms of cancer and other higher-profile health problems, noted Dr. Cecilia Low Wang, professor of Medicine in the Division of Endocrinology, Metabolism and Diabetes at the University of Colorado School of Medicine. Low Wang is also a clinician-scientist at CPC Clinical Research, which specializes in clinical trial design and management.

There are multiple causes of diabetic foot ulcers, Low Wang said. Diabetes can decrease sensation in the feet; make them drier and more vulnerable to cracking; and decrease blood flow, which impedes healing. Treatments are few. Patients most often rely on wound care specialists and podiatrists to manage their diabetic foot ulcers and prevent them from worsening.

Stem cell surprise for diabetic foot ulcers

But now Low Wang is the principal investigator for the campus trial of what she calls “an incredibly unexplored space in diabetic foot ulcer treatment.” The hope lies in mesenchymal stem cells (MSCs) – the kind that gives rise to connective tissue and solid organs – taken from the umbilical cord lining, which is the richest source of them. The phase 1 trial is looking at the safety of applying these stem cells to diabetic foot ulcers.

Dr. Cecilia Low Wang
Dr. Cecilia Low Wang, an endocrinologist at UCHealth, is the principal investigator for a phase one trial of the safety of mesenchymal stem cells to treat diabetic foot ulcers. Photo by UCHealth.

It’s a campus-wide effort (see box) that required years of effort and collaborations that stretch to researchers and providers in Southeast Asia. As far back as 2005, Singapore-based CellResearch Corporation began using mesenchymal stem cells on chronic wounds that had failed to heal with any other treatment, said Dr. Ivor Lim, a plastic surgeon and the company’s chief medical officer.

CellResearch initially used mesenchymal stem cells as a potential tool to promote connective tissue growth and assist in skin grafting, Lim said. Surprisingly, the wounds treated with the cells closed. That led to a series of cases using MSCs to promote healing in a variety of wounds.

“Success in these difficult wounds encouraged us to try application of cord lining MSCs to a variety of wounds, all of which responded extremely well,” Lim said.

Cells on trial for DFU treatment

The company, however, realized it needed formal clinical trials to “rigorously demonstrate” the wound-healing power of mesenchymal stem cells, he added. That led, several years ago, to a connection with Dr. Brian Freed, professor of Medicine-Allergy/Clinical Immunology at CU. Freed is also director of ClinImmune Labs on the Anschutz Medical Campus. Among other capabilities – including operating the University of Colorado’s public cord blood bank – Clinimmune processes and stores stem cells in sufficient quantities for clinical trials and in compliance with stiff Food and Drug Administration regulations. That requires proving the cells are safe, pure and potent.

Norma Armistead is seated under a tree
Norma Armistead

Freed designed a trial that included showing that human mesenchymal stem cells promoted diabetic foot ulcer healing in mouse models. He received help from Dr. Ken Liechty, professor of Pediatric Surgery at Children’s Hospital Colorado, whose research centers on wound healing and regeneration.

In the next phase, ClinImmune demonstrated how it could safely provide mesenchymal stem cells to clinicians who would ultimately use them on human patients. Some 100 mothers consented to donate their umbilical cord tissue, which would normally be discarded, Freed said. The MSC-rich tissue arrives in an antibiotic solution to ClinImmune, where it is processed and frozen. ClinImmune also reviews each mother’s medical history and the newborn’s health exam, sends out blood for infectious disease testing, and tests the umbilical cord tissue for sterility, Freed said.

ClinImmune selected 29 of the 100 cord tissue donations to grow mesenchymal stem cells in sufficient numbers to treat DFU trial patients. Freed said ClinImmune assessed the tissue for factors considered important in wound healing, such as preventing inflammation and promoting the growth of blood vessels and epithelial cells – the ones that form a protective barrier on the skin.

Dr. Brian Freed
Dr. Brian Freed, director of ClinImmune, designed the plan to process, manufacture and ensure the safety of mesenchymal stem cells to be used in the diabetic foot ulcer trial. Photo by UCHealth.

Marshalling the cell troops

Ultimately, ClinImmune grew three cell lines from tissue ideal for producing these crucial factors, Freed said. For each patient enrolled in the diabetic foot ulcer trial, ClinImmune grows 2 million mesenchymal stem cells in an on-site bioreactor. The cells go into rubber-stoppered vials delivered to the UCHealth Wound and Ostomy Care Clinic at UCHealth University of Colorado Hospital. There, clinicians who are also trial investigators, including Dr. Tae Chong, principal site investigator for the trial and co-director of the Wound Clinic, apply the cells directly to the patient’s diabetic foot ulcer, two times a week for up to eight weeks, Low Wang said.

Executive Committee for the trial of mesenchymal stem cells to treat diabetic foot ulcers:

Low Wang and Hiatt are on the faculty of the University of Colorado School of Medicine and CPC Clinical Research. which is noted in the story. Freed is also a School of Medicine faculty member and, as noted, director of ClinImmune Labs. Lakin is associate vice chancellor for Regulatory Compliance at University of Colorado Denver – Anschutz Medical Campus.

Key collaborators in the trial include:

Nicola Haakonsen, Mercedes Zirbes, and colleagues on the Clinical Research Support Team (CReST), which provides study coordination and regulatory staff for clinical trials through the Colorado Clinical and Translational Science Institute (CCTSI).

Both Freed and Low Wang said the healing promise of mesenchymal stem cells seems not to lie in the cells themselves. Rather, they produce beneficial cytokines – proteins essential to wound healing – and may act as a spur for the production of the key restorative factors needed to blunt diabetic foot ulcer damage.

“The cells may trigger the host tissue to repair itself,” Freed said.

Diabetic foot ulcer trial in early stages

The trial is in its early stages; as of early October, five patients had completed the initial treatment regimen, which includes a month of follow-up, Low Wang said. All have diabetic foot ulcers classified as Grade 1, or superficial, that they have had for at least four weeks. The trial team aims to enroll another 10 to 15 patients, Low Wang added.

As a phase one trial, the study is looking at safety only, but Low Wang said the team is photographing the patients’ diabetic foot ulcers and tracking wound healing – a possible prelude to a phase two trial of the treatment’s effectiveness, possibly against deeper ulcers. But the evidence will drive that decision, she emphasized.

“We’re not promoting the treatment,” she said. “We have to have some level of optimism but we also have to be as objective as possible.”

A study case for DFUs

Norma Armistead, 51, of Aurora illustrates the devastation of diabetic foot ulcers and the potential that mesenchymal stem cell treatment may offer. Diagnosed with Type 2 diabetes in her early 30s, Armistead said she controls her blood sugar levels with insulin, but is disabled because of sarcoidosis, an inflammatory disease that requires her to use up to 4 liters of oxygen around the clock.

A little more than a decade ago, Armistead broke the pinky toe on her right foot. That led to a cascade of problems that continue to this day, she said. The broken toe was slow to heal and eventually became infected. Her podiatrist, who she said recognized her diabetes as the root of the problem, eventually recommended that she have the toe amputated. She agreed.

A year or so later, however, she developed a blister under the big toe of the same foot. It became a constant source of torment.

“No matter what I tried, it wouldn’t heal,” Armistead said. Like the broken toe, the blister led to an infection. The situation worsened to the point that her podiatrist told her she faced a grim choice: lose the rest of her toes or lose her life.

She chose to have them amputated. “I told him, ‘Do what you gotta do,’” she recalled. “I want to live.”

Armistead’s now toeless right foot remained under assault. She developed another blister that refused to heal. That cost her half of the foot.

Another blow leads to trial enrollment

The problem foot continued to dog her. In the most recent mishap, she hit it on the corner of a bathroom door that wasn’t completely closed. The impact opened up the fragile skin.

“It was pretty nasty,” Armistead said. “I hit it good.” Once again, the wound would not heal.

She sought care at UCHealth, where Dr. Garrett Moore, co-director of the Wound and Ostomy Care Clinic, examined the damage and invited her to join the diabetic foot ulcer stem cell trial. She went home, discussed the option with her fiancé and decided to do it.

“I thought that if it works it would be worth it to help people with diabetes who have foot ulcers that won’t heal,” Armistead said.

The treatment phase of diabetic foot ulcers

During the regular visits, Moore removed any calluses Armistead developed on her foot, then applied a layer of mesenchymal stem cells over the wound and a clear bandage for protection. She completed the treatment phase of the trial and goes on with her life.

Today, she wants to continue to take care of her six-year-old grandson. She wears custom-made diabetic shoes with cushions that reduce the pressure on her feet and regularly applies moisturizing lotion to prevent problem-producing cracks. Armistead said she wants people to understand the devastation that a seemingly harmless diabetic foot ulcer can cause if it continues to fester.

“Take care of your feet and they will take care of you,” she said. “I had to learn that the hard way. I still have my life and that’s the important thing.”

Armistead is also grateful to UCHealth for the treatment she received and the opportunity to join the trial. “Everybody there was fantastic,” she said. “They listened to what I had to say, and I listened to them.”

Exercise caution with stem cell treatments

For her part, Low Wang is hopeful but she emphasized that people should exercise caution before seeking stem cell treatments. Unsubstantiated claims about their effectiveness abound. In fact, the FDA has issued a detailed warning about the dangers of illegal and unproven stem cell therapies.

In contrast, the collaborations between researchers, clinicians and regulatory specialists that led to the rigorous clinical trial she helps to lead offer many avenues for further investigations of the safety and effectiveness of stem cells and other therapies, Low Wang said.

“The University of Colorado Anschutz Medical Campus, with ClinImmune, CPC Clinical Research and UCHealth has a synergy you don’t see elsewhere,” she said. “We hope to set the stage for future trials of biological treatments to help people. We couldn’t do this without the involvement of patients who volunteer for clinical research.”

For more information about the trial, contact Nicola Haakonsen at 720-848-2425 or nicola.haakonsen@cuanschutz.edu.

About the author

Tyler Smith has been a health care writer, with a focus on hospitals, since 1996. He served as a writer and editor for the Marketing and Communications team at University of Colorado Hospital and UCHealth from 2007 to 2017. More recently, he has reported for and contributed stories to the University of Colorado School of Medicine, the Colorado School of Public Health and the Colorado Bioscience Association.