Innovative gel prevents post-surgery adhesions in animal models

Surgical adhesions - common, sometimes life-threatening complications that arise after open or laparoscopic abdominal surgery - can be prevented in mice and pigs by a gel impregnated with a molecule that blocks a key signaling pathway in the formation of scar tissue.

The gel can be applied as a spray or a wash to the inside of the abdominal cavity immediately after surgery. Over a period of two weeks, the gel releases a small molecule, T-5224, that blocks the activation of adhesion-forming cells called fibroblasts without affecting normal wound healing.

A practical, simple way to prevent or reduce the formation of post-surgical abdominal adhesions in humans, which are currently unpreventable and largely untreatable, could save billions of dollars in health care costs each year and significantly reduce the incidences of chronic pain, infertility and bowel obstructions that arise when adhesions are severe, the researchers believe. Showing success in large animals such as pigs is a key step toward human clinical trials.

Adhesions happen primarily when you injure or interact with the bowel during surgery, whether the surgery is open or laparoscopic. This gel reduces the likelihood of adhesions without compromising the ability of the animal to heal after surgery. And, as a surgeon, I'm already used to washing out the surgical site at the end of the procedure, so this would be easy to incorporate into our normal workflow."

Michael Longaker, MD, professor of surgery 

Longaker, the Deane P. and Louise Mitchell Professor in the School of Medicine, and assistant professor of surgery Daniel Delitto, MD, PhD, are the senior authors of the study, which was published March 12 in Science Translational Medicine. Former postdoctoral scholar and surgical resident Deshka Foster, MD, PhD, and postdoctoral scholar Jason Guo, PhD, are the lead authors of the research.

The problem with scar tissue

Abdominal adhesions form in the weeks after surgery as the body heals. Between 50% and 90% (depending upon the type and location of the surgery) of abdominal surgeries result in adhesions, characterized by excessive scar tissue that tethers organs and tissues to one another or to the abdominal wall.

Although many adhesions cause no symptoms, between 5% and 20% are severe, causing chronic pain, infertility and life-threatening bowel obstructions. There is no reliable method to prevent or treat them, and complications from abdominal adhesions are estimated to cost billions of health care dollars each year. 

Longaker, Foster and their colleagues have been studying scar formation and adhesions for many years. In 2020 they identified the biological pathway responsible for adhesion formation in mice and humans and showed that inhibiting the activity of a protein called c-Jun - produced by fibroblasts in response to injury - substantially reduced the formation of adhesions in laboratory mice.

The inhibitory molecule, called T-5224, had been identified for its ability to modulate the excessive scarring and inflammation, and has been tested in clinical trials as a treatment for rheumatoid arthritis and in animal models of cancer metastasis and inflammation.

"We wanted to learn whether we could deliver this small molecule inhibitor directly to the abdominal cavity over a period of several days and, if so, whether it would impact adhesion formation," Longaker said.

The researchers collaborated with study co-author and associate professor of materials science and engineering Eric Appel, PhD, to design a biomaterial called a shear-thinning hydrogel that flows like a liquid under pressure - such as being forced through a syringe - but stabilizes when the force is removed. When the gel is impregnated with T-5224, it slowly releases the small molecule over 14 days.

When tested in mice and minipigs, the T-5224-impregnated gel significantly reduced the formation of adhesions - scored from 0 to 5 by the degree of contact between neighboring tissues - by nearly 300% in response to abdominal surgery compared with animals that received a saline wash of the surgical site or application of the gel without T-5224.

"The sustained release formulation of T-5224-hydrogel and the ability to easily apply it to the abdominal cavity are ideal qualities for a potential clinical therapy for adhesions," Foster said. "We are eager to take the next steps to bring this approach into the clinic."

"It's great to find a treatment to block adhesions," Longaker said. "But more importantly, we saw no effect on wound healing. If we prevent adhesions, but the bowel falls apart or the abdominal opening doesn't close properly because of the treatment, it wouldn't be usable. Now we have enough data in a large animal model showing that this is a safe and effective treatment to talk about launching trials in people."

The study was supported by the National Institutes of Health (grants 1F32CA239312-01, 1F32HL167318, 1R01GM116892, 1R01GM136659 and T32GM008412), the National Science Foundation, Stanford SPARK Program, the Damon Runyon Cancer Research Foundation, the John and Marva Warnock Faculty Scholar Award, the Emerson Collective/Goldman Sachs Foundation, Stanford's Child Health Research Institute, Stanford's Transplant and Tissue Engineering Center of Excellence, the Gunn/Olivier Fund, the California Institute for Regenerative Medicine, and the Wu Tsai Human Performance Alliance.

Longaker, Foster and other study co-authors are inventors on patents held by Stanford University covering the use of the inhibitor molecule in hydrogels to prevent adhesions. Appel is a cofounder, equity holder and advisor for Appel Sauce Studios LLC, which holds an exclusive license from Stanford University to a patent application describing the hydrogel materials reported in this work.