About one-third of people with diabetes develop foot ulcers during their lifetime. In the U.S., more than 160,000 lower extremity amputations are performed annually due to complications from diabetic foot ulcers, costing the American health system about $30 billion a year. Those who have foot ulcers often die at younger ages than those without ulcers. CREDIT Courtesy UT Arlington

Researchers have developed a new shoe insole technology that helps reduce the risk of diabetic foot ulcers, a dangerous open sore that can lead to hospitalization and leg, foot or toe amputations.

“The goal of this innovative insole technology is to mitigate the risk of diabetic foot ulcers by addressing one of their most significant causes: skin and soft tissue breakdown due to repetitive stress on the foot during walking,” said Muthu B.J. Wijesundara, principal research scientist at The University of Texas at Arlington Research Institute (UTARI).

Affecting about 39 million people in the U.S., diabetes can damage the small blood vessels that supply blood to the nerves, leading to poor circulation and foot sores, also called ulcers. About one-third of people with diabetes develop foot ulcers during their lifetime. In the U.S., more than 160,000 lower extremity amputations are performed annually due to complications from diabetic foot ulcers, costing the American health system about $30 billion a year. Those who have foot ulcers often die at younger ages than those without ulcers.

“Although many shoe insoles have been created over the years to try to alleviate the problem of foot ulcers, studies have shown that their success in preventing them is marginal,” Wijesundara said. “We took the research a step further by creating a pressure-alternating shoe insole that works by cyclically relieving pressure from different areas of the foot, thereby providing rest periods to the soft tissues and improving blood flow. This approach aims to maintain the health of the skin and tissues, thereby reducing the risk of diabetic foot ulcers.”

In an article in the peer-reviewed International Journal of Lower Extremity Wounds, Wijesundara and UTA colleagues Veysel Erel, Aida Nasirian and Yixin Gu, along with Larry Lavery of UT Southwestern Medical Center, described their innovative insole technology. After this successful pilot project, the next step for the research team will be refining the technology to make it more accessible for users with varying weights and shoe sizes.

“Considering the impact of foot ulcers, it’s exciting that we may be able to make a real difference in the lives of so many people,” Wijesundara said.

The approach also holds potential for repairing internal organs such as the heart, intestine and liver, which can become damaged by age and disease

Watercolor depiction of the skin’s epidermal layer. In a new study, wounds healed quickly as skin cells bounced intro production mode after being treated with a newly discovered regenerative drug compound. CREDIT Kayla Nutsch of the Bollong Laboratory at Scripps Research

A discovery involving multiple teams from across Scripps Research has revealed a powerful new approach for treating diabetic foot ulcers, which affect millions of people in the US and often lead to serious complications.

By targeting a gene that controls tissue growth and regeneration, the scientists were able to boost cell division at the site of injury and repair chronic wounds quickly. The new research appears in Nature Chemical Biology.

Given the growing prevalence of diabetes and limited options for treating foot ulcers–which can lead to amputation, in severe cases–it’s clear that more effective treatments are needed, says chemist Michael Bollong, PhD, assistant professor at Scripps Research and senior author of the study.

“We developed a way to activate multiple aspects of wound healing using a small-molecule drug that can be applied topically, without affecting other tissues,” Bollong says. “Essentially, we were able to trick the cells into proliferating and closing the wound, restoring the outer layers of skin.”

Bollong’s group worked in concert with laboratory of Scripps Research President and CEO Peter Schultz, PhD, and drug discovery teams at Calibr, which screened more than 800,000 molecules to find one that stimulated key regenerative pathways. The drug, PY-60, acts on a previously unknown regulator of tissue growth.

The researchers tested their approach in animal models and on “human skin equivalents,” which are skin samples from people that are further cultivated in a petri dish. They hope to begin clinical trials within the next year.

Beyond treating chronic wounds, Bollong says the approach may lead to new regenerative therapies for heart disease, liver conditions and inflammatory bowel disease, or IBD. “We believe the future of this type of regenerative therapy is incredibly bright,” Bollong says.

In the near term, however, the focus is diabetic foot ulcers, which affect roughly 15 percent of people with diabetes. More than half of those diagnosed with a diabetic foot ulcer will not survive the next five years, Bollong says, and the only existing regenerative therapy was developed more than two decades ago and has limited efficacy.

At the core of the new approach is a gene known as YAP, which is known to control organ size and tissue regeneration. YAP is regulated via a pathway called Hippo–often a target of cancer drugs due to its ability to influence cell growth.

Through their research, the scientists found a previously unknown player in the Hippo pathway–a protein that works with YAP to communicate cell density; when an organ or other tissue reaches a certain concentration, the cells will stop growing. But by targeting this protein with the new drug molecule, tissue cells bounce back into production mode. The healing process happens quickly and without producing negative side effects; in experiments, the outer skin layer doubled in a week.

“We found the results of the study to be incredibly compelling,” Bollong says. “We hope this regenerative approach can eventually be added on to existing standards of care for diabetic foot ulcers.”