Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions

用于预防特定部位手术粘连的可喷涂聚合物共混物

基本信息

批准号：
10674894
负责人：
PETER KOFINAS
金额：
$ 36.77万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674894
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 Blood Proteins Carboxymethylcellulose Cholesterol Homeostasis Chronic Cicatrix Clinical Clinical Treatment Clinical Trials Coagulation Process Complication Data Deposition Development Elasticity Elastomers Exhibits Extravasation Female infertility Fiber Fibrin Fibroblasts Film Foundations Gel Glycolates Goals Health Care Costs Hemostatic Agents Human Hyaluronic Acid Implant In Vitro Inflammatory Inflammatory Response Injury Intestinal Obstruction Intestines Ischemia Kinetics Ligation Lipoproteins Liquid substance Measures Mesothelium Modeling Molecular Weight Mus Oligopeptides Operative Surgical Procedures Organ Outcome Pathology Pathway interactions Peritoneal Pharmaceutical Preparations Polymers Postoperative Period Prevention Prevention strategy Proliferating Property Protein Isoforms Proteins Qualifying Research Safety Scheme Severities Site Small Intestines Solid Surface System Techniques Time Tissues Topical application Trauma Treatment Efficacy Work biodegradable polymer biomaterial compatibility chronic pelvic pain clinical translation combinatorial controlled release cytokine design efficacy evaluation elastomeric fabrication fibrogenesis holistic approach improved in vivo injured intraperitoneal lipid transport mechanical properties mouse model novel peptidomimetics porcine model preclinical efficacy preclinical evaluation pressure prevent prevention evaluation receptor binding seal sealant success targeted treatment therapeutic target tool translational barrier wound wound healing

项目摘要

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).}

项目概要粘连是由于以下缺血状况而邻接组织表面的刚性纤维桥研究表明腹部手术和术后间皮损伤的发生率为 93%。小肠梗阻、慢性盆腔疼痛和女性不孕的并发症，其中治疗占临床采用的预防策略包括透明质酸-超过 10 亿美元。羧甲基纤维素片状薄膜在实践中经常被描述为“脆”和“粘”，从而使其难以应用且治疗效果不一致其他策略包括设计基于凝胶的材料。维持体内器官永久移动所产生的剪切力，以及抗- 针对非物理途径的炎症和止血治疗。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，而传递抗炎药在局部给药时存在控释问题。将治疗剂转化为固体屏障宿主基质，具有改善的机械性能和可转化的适用性，将为预防粘连和肠道相关并发症提供整体方法吻合口处有肠液漏出等。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至关重要和能够有效抗炎释放的密封剂使用弹性、表面侵蚀聚合物作为药物。宿主为这两个问题提供了物理解决方案，因为我们勇敢地与异常分子有关纤维发生将在其功能时间尺度之前从屏障的外表面分离（具体目标 1）。然而，缺血性疾病和炎症反应中断凸显了其生物学基础。粘连和增强治疗方法的途径。粘附聚合物固体屏障可以抑制存在于纤维蛋白基质内的成纤维细胞的快速增殖通过增强受体结合亲和力的证据，我们捕获了粘连病理学的模拟肽。载脂蛋白 E (ApoE) 将抑制粘连发展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估预防效果。评估分离纤维疤痕组织所需的外观和相对难度的方案，而密封剂功效将通过离体和体内爆裂压力模型来测量{由于广泛性。腹腔表面积大，我们将验证粘连预防和密封剂的功效盲肠伤口腹膜内 (IP) 空间内的表面侵蚀和药物释放聚合物固体屏障小鼠和猪模型（具体目标 3）。}