Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models

Abstract

Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224-hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224-hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that JUN and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224-hydrogel. The JUN-inhibiting T-5224-hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.