Saturday, September 7, 2024
9/7/2024
Project Summary Adhesions are rigid, fibrous bridges that adjoin tissue surfaces as a result of ischemic conditions following postoperative mesothelial injury. Studies have shown a 93% occurrence rate following abdominal surgery and complications of small bowel obstruction, chronic pelvic pain, and female infertility, where treatment accounts for over $1 billion in healthcare costs. Clinically adopted prevention strategies include a hyaluronic acid- carboxymethylcellulose sheet-like film often described as “brittle” and “sticky” in practice, thereby rendering it difficult to apply and inconsistent in treatment efficacy. Additional strategies include gel-based materials designed to sustain shear forces imparted by the perpetual shifting of organs in vivo, as well as delivery of anti- inflammatory and hemostatic therapeutics targeting non-physical pathways. Clinical translatability of solid and gel barriers is largely impeded by either their mechanical properties or means of application, while delivery of anti-inflammatory drugs presents issues of controlled release when topically administered. Inclusion of a targeted therapeutic into a solid barrier host matrix with improved mechanical properties and translatable applicability, would provide for a holistic approach to both adhesions prevention {and complications associated with intestinal anastomosis such as intestinal fluid leakage. Adherence and ability to conform to an injured tissue site is imperative in combinatorial design of a solid barrier and sealant capable of effective anti-inflammatory release. Use of an elastic, surface eroding polymer as a drug host offers a physical solution to both concerns, as we hypothesize molecules implicated in abnormal fibrogenesis would detach from the barrier’s external surface prior to their functional time scale (Specific Aim 1). However, ischemic conditions and a disrupted inflammatory response highlight the biological foundation of adhesions and a pathway to an augmented treatment approach. Localized anti-inflammatory release from an adherent polymer solid barrier could inhibit the rapid fibroblast proliferation within a fibrin matrix presented in adhesions pathology. With evidence of enhanced receptor binding affinity, we hypothesize mimetic peptides of apolipoprotein E (ApoE) will inhibit the secretion of pro-inflammatory cytokines noted in adhesions development (Specific Aim 2). Evaluation of prevention efficacy is qualified through complication rate and an objective grading scheme assessing the appearance and relative degree of difficulty required to separate the fibrous scar tissue, while sealant efficacy will be measured via ex vivo and in vivo burst pressure models. {Due to the broadness and large surface area of the abdominal cavity, we will qualify adhesions prevention and sealant efficacy of surface eroding and drug releasing polymer solid barriers within the intraperitoneal (IP) space of cecal wound mouse and porcine models (Specific Aim 3).}
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