Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier

{项目摘要} {粘连是刚性的纤维桥，由于缺血性疾病而与组织表面相邻， 术后间皮损伤。研究表明，腹部手术后的发生率为93%， 小肠梗阻、慢性盆腔疼痛和女性不孕症的并发症，其中治疗占 超过10亿美元的医疗费用。临床采用的预防策略包括透明质酸- 羧甲基纤维素片状膜在实践中通常被描述为“脆性”和“粘性”，从而使其 难以应用且治疗效果不一致。其他策略包括基于凝胶的材料， 以承受由体内器官的永久移动所赋予的剪切力，以及抗- 针对非物理途径的炎症和止血治疗剂。固体和固体的临床可翻译性 凝胶屏障在很大程度上受到其机械性能或施用方式的阻碍， 抗炎药在局部给药时存在控释问题。纳入有针对性的 将治疗剂转化为具有改善的机械性能和可转化的适用性的固体屏障主体基质， 将为粘连预防和与肠粘连相关的并发症提供一种整体方法。 肠吻合术，如肠液渗漏。 在固体屏障的组合设计中，粘附性和顺应受伤组织部位的能力是必要的。 以及能够有效抗炎释放的密封剂。弹性的、表面侵蚀的聚合物作为药物的用途 宿主为这两个问题提供了一个物理解决方案，因为我们假设与异常 纤维发生将在其功能时间尺度之前从屏障的外表面脱离（具体目标1）。 然而，缺血性疾病和破坏的炎症反应突出了 粘连和增强治疗方法的途径。局部抗炎释放从一个 粘附性聚合物固体屏障可以抑制纤维蛋白基质内的快速成纤维细胞增殖， 粘连病理学有了增强的受体结合亲和力的证据，我们假设 载脂蛋白E（ApoE）将抑制粘连形成中促炎细胞因子的分泌 （具体目标2）。通过并发症发生率和客观分级评价预防效果 评估分离纤维性瘢痕组织所需的外观和相对难度的方案， 而密封剂功效将通过离体和体内爆裂压力模型来测量。由于它的宽度和 大表面积的腹腔，我们将合格的粘连预防和密封剂的功效表面 盲肠创伤小鼠腹腔内（IP）空间内的侵蚀和药物释放聚合物固体屏障 和猪模型（具体目标3）。 已设计了一个补充这一建议的培训计划，以提高这两种材料的技术技能 科学和生物学，从而为生物材料研究提供了全面的职业道路。

{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).} A training plan complementary to this proposal has been designed to enhance technical skills in both materials science and biology, thus providing for a comprehensive career path in biomaterials research.