Biodegradable, Thermoresponsive Hydrogels to Treat Ischemic Cardiomyopathy

可生物降解的热响应水凝胶治疗缺血性心肌病

基本信息

批准号：
8402607
负责人：
WILLIAM R WAGNER
金额：
$ 34.19万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8402607
关键词：
2-hydroxyethyl methacrylate Address American Animal Model Animals Biocompatible Materials Body Temperature Carbonates Cardiac Cardiomyopathies Cessation of life Coupled Deterioration Device Designs Devices Drug Delivery Systems Economics Face Family suidae Fibroblast Growth Factor 2 Funding Gel Growth Factor Healed Heart Heart failure Hydrogels In Situ In Vitro Infarction Injectable Injection of therapeutic agent Insulin-Like Growth Factor I Liquid substance Mechanics Methacrylates Microspheres Modeling Molecular Myocardial Infarction Myocardium N-isopropylacrylamide Outcome Pathologic Processes Patients Pattern Positioning Attribute Process Property Proteins Rattus Recovery Reducing Agents Research Robotics Staging Stress System Technology Time United States Ventricular Work acrylic acid base controlled release copolymer cyclopropane design healing heart function improved in vivo innovation minimally invasive monomer novel poly(lactide)poly-N-isopropylacrylamide pre-clinical prevent research clinical testing social technology development

项目摘要

Summary: Cardiac failure incurs a major economic and social burden on the United States populace, while also providing a distinct technical challenge since options for treating this condition remain highly limited. In ischemic cardiomyopathy ventricular wall thinning is coupled with dilation of the ventricular cavity. This remodeling process is associated with elevated ventricular wall stress that positively drives the thinning and dilation process towards end-stage heart failure. In the proposed work we will create novel designs for injectable biomaterials to bulk the thinning, post-infarct cardiac wall, reducing elevated wall stress, and potentially improving cardiac remodeling outcomes. The design objectives include synthesizing materials with tensile properties suitable for reducing wall stresses, degradation properties that maintain the hydrogel in the infarcted wall for a period of months during the remodeling process, and drug delivery properties that allow the controlled release of multiple growth factors that may stimulate beneficial cardiac remodeling. We will evaluate 3 distinct hydrogel designs with increasing complexity, utilizing both rat and porcine models of ischemic cardiomyopathy and a minimally invasive robotic technology (the HeartLander device) designed to effectively deliver the targeted hydrogel injections. The project specific aims are to: 1) Evaluate the functional and histopathologic effect of injecting the thermoresponsive hydrogel, poly(NIPAAm-co-acrylic acid-co-2-hydroxyethyl methacrylate-poly(trimethylene carbonate) into the central and border regions of a myocardial infarct in a porcine model for ischemic cardiomyopathy using a modified HeartLander minimally invasive robotic system. 2) Evaluate the functional and histopathologic effect of injecting the thermoresponsive hydrogel, poly(NIPAAm-co-HEMA-co-polylactide-methacrylate) into the central and border regions of a myocardial infarct in rat and then porcine (with HeartLander) models for ischemic cardiomyopathy. Hydrogel design optimization will be based on in vitro and rat in vivo results. 3) Develop and characterize the thermoresponsive hydrogel poly(NIPAAm-co-N-hydroxysuccinimide- methacrylate-co-HEMA-co-MAPLA) and the ability of this gel to deliver bFGF in vitro, as well as the ability to load this gel with microspheres containing IGF-1 for more extended controlled release. 4) Evaluate the functional and histopathologic effect of injecting growth factor loaded hydrogel from Aim #3, into infarcted myocardium in rat and porcine (with HeartLander) models for ischemic cardiomyopathy. Relevance: Once the early period following a heart attack passes, there are limited options for treating the heart failure that can develop. At the end of the proposed funding period we will have developed innovative injectable materials to treat heart failure following a heart attack as well as a robotic delivery system to allow material delivery in a manner that would minimize patient discomfort, complications and recovery time.

摘要：心力衰竭给美国民众带来了重大的经济和社会负担，而由于治疗这种疾病的选择仍然非常有限，因此也带来了独特的技术挑战。在缺血性心肌病心室壁变薄伴有心室腔扩张。这重塑过程与心室壁应力升高相关，从而积极驱动心室壁变薄和终末期心力衰竭的扩张过程。在拟议的工作中，我们将为可注射的生物材料可以使梗塞后的心壁变薄，减少心壁应力升高，以及可能改善心脏重塑结果。设计目标包括合成材料具有适合减少壁应力的拉伸特性，以及维持水凝胶的降解特性在重塑过程中，在梗塞壁中存在数月的时间，以及药物输送特性允许多种生长因子的受控释放，从而刺激有益的心脏重塑。我们将利用大鼠和猪模型评估 3 种复杂程度不断增加的不同水凝胶设计缺血性心肌病和微创机器人技术（HeartLander 设备）旨在有效地提供目标水凝胶注射。该项目的具体目标是： 1) 评估注射热敏水凝胶的功能和组织病理学效果，聚(NIPAAm-共-丙烯酸-共-甲基丙烯酸2-羟乙酯-聚(碳酸三亚甲基酯))进入中心使用改良的方法研究缺血性心肌病猪模型中的心肌梗死和边界区域 HeartLander 微创机器人系统。 2) 评估注射热敏水凝胶的功能和组织病理学效果，将聚（NIPAAm-co-HEMA-co-聚丙交酯-甲基丙烯酸酯）注入心肌的中心和边缘区域大鼠梗塞和猪（使用 HeartLander）模型用于缺血性心肌病。水凝胶设计优化将基于体外和大鼠体内结果。 3) 开发并表征热响应水凝胶聚(NIPAAm-co-N-羟基琥珀酰亚胺- 甲基丙烯酸酯-co-HEMA-co-MAPLA）以及该凝胶在体外递送 bFGF 的能力，以及在该凝胶中装载含有 IGF-1 的微球，以实现更长时间的控释。 4) 评估目标 #3 注射负载生长因子的水凝胶的功能和组织病理学效果，进入缺血性心肌病大鼠和猪（使用 HeartLander）模型中的梗塞心肌。相关性：一旦心脏病发作后的早期阶段过去，治疗心脏病的选择就很有限。可能发展为心力衰竭。在拟议的资助期结束时，我们将开发出创新的用于治疗心脏病发作后心力衰竭的注射材料以及机器人输送系统以尽量减少患者不适、并发症和恢复时间的方式输送材料。