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

通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连

• 批准号: 10532480
• 负责人: Metecan Erdi
• 金额: $ 2.25万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532480
• 关键词: Abdomen; Abdominal Cavity; Acute; Adherence; Adhesions; Adopted; Adsorption; Affinity; Agonist; Anastomosis - action; Animal Model; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Apolipoprotein E; Apolipoproteins; Appearance; Area; Biocompatible Materials; Biological; Biology; Biomaterials Research; Blood Proteins; Carboxymethylcellulose; Career Choice; Cecum; Cholesterol Homeostasis; Chronic; Cicatrix; Clinical; Clinical Treatment; Clinical Trials; Coagulation Process; Complication; Data; Deposition; Development; Exhibits; Extravasation; Female infertility; Fiber; Fibrin; Fibroblasts; Film; Foundations; Gel; Glycolates; Goals; Health Care Costs; Hemostatic Agents; Human; Hyaluronic Acid; Immunology; In Vitro; Inflammatory; Inflammatory Response; Injury; Intestinal Obstruction; Intestines; Intra-abdominal; Kinetics; Ligation; Lipoproteins; Liquid substance; Measures; Modeling; Molecular Weight; Mus; Oligopeptides; Operative Surgical Procedures; Organ; Outcome; Pathology; Pathway interactions; Pharmaceutical Preparations; Polymers; Postoperative Period; Prevention; Prevention strategy; Property; Protein Isoforms; Proteins; Research; Safety; Scheme; Science; Severities; Site; Small Intestines; Solid; Surface; Surgical complication; System; Technical Expertise; Techniques; Time; Tissues; Topical application; Training; Treatment Efficacy; Work; base; biodegradable polymer; caprolactone; chronic pelvic pain; clinical translation; clinically translatable; combinatorial; controlled release; cytokine; design; efficacy evaluation; elastomeric; fibrogenesis; holistic approach; improved; improved functioning; in vitro testing; in vivo; infertility treatment; injured; intraperitoneal; lipid transport; materials science; mechanical properties; mouse model; novel; peptidomimetics; porcine model; preclinical efficacy; preclinical evaluation; preclinical trial; pressure; prevent; prevention evaluation; receptor binding; seal; sealant; success; targeted treatment; therapeutic target; tool; translational barrier; wound; wound care; wound healing

{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.

{项目摘要} {粘连是一种刚性的纤维桥，由于以下缺血情况而与组织表面相邻 术后间皮损伤。研究表明，腹部手术后93%的发生率 小肠梗阻、慢性盆腔疼痛和女性不孕的并发症，在这些情况下，治疗占主导地位 超过10亿美元的医疗成本。临床上采用的预防策略包括一种透明质酸- 羧甲基纤维素片状薄膜在实践中常被描述为“脆”和“粘”，从而使其 应用困难，治疗效果不一致。其他策略包括设计基于凝胶的材料 以维持体内器官的永久移位所产生的剪切力，以及传递抗 针对非物理途径的炎症和止血疗法。Solid and的临床可译性 凝胶屏障在很大程度上受到其机械性能或应用手段的阻碍，而提供 消炎药在局部使用时会出现控制释放的问题。包括有针对性的 治疗转化为具有改进的机械性能和可平移适用性的固体屏障基质， 将为粘连预防和与肠道相关的并发症提供全面的方法 吻合口如肠液渗漏。 {在固体屏障的组合设计中，粘附性和与受损组织部位的顺应性是必不可少的 以及能够有效抗炎释放的密封胶。使用有弹性的、表面有腐蚀性的聚合物作为药物 宿主为这两个问题提供了物理解决方案，因为我们假设分子与异常情况有关 纤维化形成将在其功能时间尺度之前从屏障的外表面分离(特定目标1)。 然而，缺血条件和紊乱的炎症反应突出了 粘连和扩大治疗方法的途径。安慰剂的局部抗炎释放 粘附性聚合物固体屏障可以抑制纤维蛋白基质内成纤维细胞的快速增殖。 粘连病理学。根据受体结合亲和力增强的证据，我们假设 载脂蛋白E(ApoE)将抑制粘连发生过程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来评价预防效果 评估分离纤维疤痕组织所需的外观和相对难度的方案， 而密封剂的效果将通过体外和体内破裂压力模型进行测量。由于它的广度和 腹部表面积大，我们将合格的粘连预防和密封表面的效果 盲肠创伤小鼠腹膜腔内聚合物固体屏障的侵蚀和释药 和猪模型(特定目标3)。 为补充这一提议，设计了一项培训计划，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一条全面的职业道路。