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} {粘附是刚性的纤维桥 术后间皮损伤。研究表明，腹部手术后发生93％的发生率 小肠异常，慢性骨盆疼痛和女性不育症的并发症，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 - 羧甲基纤维素片状薄膜通常被描述为“脆性”和“粘性”，从而呈现 难以应用和不一致的治疗效率。其他策略包括设计的基于凝胶的材料 维持由体内器官的永久转移所赋予的剪切力 针对非物理途径的炎症和止血治疗剂。固体和 凝胶屏障在很大程度上受到其机械性能或应用方式的阻碍，同时交付 抗炎药局部给药时会出现受控释放的问题。包括目标 将具有改善的机械性能和可翻译适用性的实心屏障矩阵进行治疗， 将为预防广告和与肠道相关的并发症提供整体方法 吻合术，例如肠液泄漏。} {在固体屏障的组合设计中，必须遵守和符合受伤的组织部位的能力 以及能够有效抗炎释放的密封剂。将弹性，表面侵蚀的聚合物用作药物 主机为这两个问题提供了物理解决方案，因为我们假设异常实施的分子 纤维发生在其功能时间尺度之前将从障碍物的外表面脱离（特定目标1）。 但是，缺血性疾病和炎症反应中断突出了生物学基础 粘连和增强治疗方法的途径。来自 粘附的聚合物固体屏障可以抑制在纤维蛋白基质中的快速成纤维细胞增殖 粘连病理学。有了增强受体结合亲和力的证据，我们假设 载脂蛋白E（APOE）将抑制粘附发育中指出的促炎细胞因子的分泌 （特定目标2）。预防效率的评估是通过并发症率和客观评分的资格 评估分离纤维疤痕组织所需的外观和相对困难的方案， 虽然密封剂效率将通过离体和体内爆发压力模型来测量。由于广泛和 腹腔的大表面积，我们将符合表面预防和密封效率的依从性 在盲肠伤口小鼠的腹膜内（IP）空间内侵蚀和药物释放聚合物实心屏障 和猪模型（特定目标3）。} 该提案的培训计划完善旨在提高两种材料的技术技能 科学与生物学，因此为生物材料研究提供了全面的职业道路。