Pilot study tests cell therapy for difficult-to-heal diabetic foot ulcers

An experimental cell therapy was well tolerated in 10 people with chronic diabetic foot ulcers, according to first-in-human study led by researchers at Wake Forest Institute for Regenerative Medicine (WFIRM).

All 10 participants experienced complete wound closure within six months, and tests indicated improved sensation in the treated feet during the 12-month follow-up period. These encouraging findings support further investigation.

The findings were published last week in Stem Cells Translational Medicine.

Diabetic foot ulcers are open wounds that can develop when diabetes damages nerves, reduces a person's ability to feel injuries to the foot and are the leading cause of lower-limb amputation in the United States. Diabetic peripheral neuropathy, nerve damage associated with diabetes, is generally managed by controlling diabetes and treating symptoms. Options for restoring lost sensation remain limited. The recent findings and further study could provide additional insight into treatment for patients.

The investigational stem cells used to treat study participants were derived from healthy placental tissue donated following childbirth. This tissue is typically discarded after delivery but contains cells with properties that may help control inflammation and support tissue repair.

"This early study was designed foremost to answer a safety question," said Michael Carstens, M.D., an author of the study. "Within the doses we evaluated, the cells were well tolerated, and we did not observe treatment-related serious adverse events during the 12 months of follow-up."

Testing the treatment's safety

The study enrolled 10 adults, ages 40 to 74, whose diabetic foot ulcers had remained open for at least three months despite receiving the local standard of care. The ulcers ranged in size from 10 to 100 cm², representing substantial diabetic foot wounds. In Nicaragua, where the study was conducted, and in other parts of the world, there is a higher prevalence and severity of such ulcers and higher rates of amputation, compared to the U.S.

Participants received a single treatment containing 30 million, 40 million or 60 million investigational cells. The cells were injected into and around the wound and into nearby soft tissue in the foot and ankle. Four participants received the lowest dose, three received the middle dose and three received the highest dose.

They were then monitored in the hospital following treatment and contacted weekly for the first three weeks, then evaluated at one, three, six and 12 months to assess safety, wound healing, sensation and blood flow in the foot and ankle.

Encouraging signs of healing

In the study, all 10 participants' wounds closed by the six-month mark. Tests also showed improvements in the participants' ability to feel light touch and vibration in the treated foot. By 12 months, all but one participant had regained what researchers classified as normal protective sensation, the ability to feel enough discomfort or pressure to help recognize a potential injury.

"For people with diabetic nerve damage, losing sensation in the foot can make it difficult to notice an injury before it becomes a serious wound," said Anthony Atala, M.D., corresponding author of the study and director of WFIRM. "The improvements we observed in wound healing and two different measures of sensation are encouraging, but further studies are still needed.

The researchers did not find a clear overall improvement in blood flow. Although seven blood vessels changed from having no measurable flow at the beginning of the study to measurable flow after 12 months, results across participants included both increases and decreases.

What the early findings mean and what's next

The wound closure and improvements in sensation observed in this first-in-human study provide encouraging support for continued investigation of placental stem cell therapies.

A larger, controlled study could help researchers better understand the therapy's contribution to wound healing and sensation, as well as determine the most appropriate dose.

The researchers recommend evaluating the treatment in a larger, controlled study that includes a placebo or other appropriate comparison group. Future research may examine how doses might be adjusted based on wound size and further evaluate diabetic peripheral neuropathy as an outcome.

Researchers also recommend testing sensation in both legs, studying biological indicators of inflammation and healing, and following participants for a longer period to evaluate long-term safety and whether improvements last.

The clinical trial was registered at ClinicalTrials.gov as NCT06373809, and approved by the Ministry of Health of Nicaragua.

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About Wake Forest Institute for Regenerative Medicine (WFIRM)

Wake Forest Institute for Regenerative Medicine (WFIRM) is recognized as an international leader in scientific discovery and its translation into clinical therapies, with many world firsts, including the development of the first permanently implanted engineered organ in a human. Other firsts include discovering a novel source of highly multipotent stem cells from amniotic fluid and placenta now used clinically; advancing 3D printing methods to manufacture tissues and organs; and developing organoid and body-on-a-chip technologies through regenerative medicine for current patient-related applications. Over 500 people at the institute, the largest in the world, work on more than 40 different tissues and organs. A number of the basic principles of tissue engineering and regenerative medicine were first developed at the institute. WFIRM researchers have successfully engineered replacement tissues and organs in all four categories - flat structures, tubular tissues, hollow organs and solid organs - and 18 different applications of cell/tissue therapy technologies, such as skin, urethras, cartilage, bladders, muscle, kidney and vaginal organs, have been successfully used in human patients. The institute -which is part of Wake Forest University School of Medicine, the academic core of Advocate Health - is in the Innovation Quarter in downtown Winston-Salem, NC, and is driven by the urgent needs of patients. The institute is making a global difference in regenerative medicine through collaborations with over 600 entities and institutions worldwide, through its government, academic and industry partnerships, its start-up entities, and through major initiatives in breakthrough technologies, such as tissue engineering, cell therapies, diagnostics, drug discovery, biomanufacturing, nanotechnology, gene editing and 3D printing.