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

• 批准号: 8022517
• 负责人: WILLIAM R WAGNER
• 金额: $ 36.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8022517
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: It is estimated that 785,000 Americans will have a heart attack annually, and many of those who survive will ultimately face deteriorating function of their heart leading to later death. This research seeks to develop an approach where a gel-like material is injected into the heart after a heart attack to prevent the deterioration in heart function. This gel is being designed to protect the heart mechanically from further damage after the heart attack and to help stimulate the heart to heal itself.

描述（由申请人提供）：心力衰竭会在美国民众中造成重大的经济和社会负担，同时也提供了独特的技术挑战，因为治疗这种情况的选择仍然高度有限。在缺血性心肌病中，心室壁变薄与心室腔的扩张相结合。这种重塑过程与升高的心室壁应力相关，该壁应力将变薄和扩张过程驱动到终末期心力衰竭。在拟议的工作中，我们将为可注射的生物材料创建新颖的设计，以散装稀疏后心脏壁，减少壁应力升高，并有可能改善心脏重塑结果。设计目标包括合成材料，其拉伸特性适用于减少壁应力，降解性能，这些降解性能在重塑过程中的几个月内将水凝胶保持在梗塞壁中的几个月，以及允许受控释放的多种生长因子的药物递送特性，这些释放可能会刺激有益的心动重塑。我们将利用缺血性心肌病的大鼠和猪模型来评估3种不同的水凝胶设计，并使用旨在有效提供靶向水凝胶注射的最小侵入性机器人技术（Heartlander设备）。该项目的具体目的是：1）评估将热呼应水凝胶，聚凝胶（NIPAAM-CO-丙烯酸酸-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-2-羟基甲基乙酯）甲基丙烯酸甲酯（三甲基碳酸盐）使用莫切氏症的中心层型心脏层症状的中心区域，用于莫切氏症的中心区域，最小入侵的机器人系统。水凝胶设计优化将基于体内的体外和大鼠。 3）开发和表征热呼吸水凝胶聚（Nipaam-CO-N-羟基糖糖酰亚胺 - 甲基丙烯酸甲酯-CO-HEMA-CO-CO-MAPLA），以及该凝胶在体外递送BFGF的能力，并能够用含有IGF-1的微磷酶加载该凝胶以获得更广泛的对照释放。 4）评估从AIM＃3注射生长因子的水凝胶的功能和组织病理学效应，以减少大鼠和猪（带有Heartlander）模型的梗塞心肌，以减少缺血性心肌病。相关性：一旦心脏病发作后的早期，就有有限的选择可以治疗可能发育的心力衰竭。在拟议的资金期结束时，我们将开发出创新的注射材料，以治疗心脏病发作后的心力衰竭以及机器人输送系统，以允许材料交付，以最大程度地减少患者的不适，并发症和康复时间。 公共卫生相关性：据估计，每年有785,000名美国人心脏病发作，许多生存的人最终会面临其心脏不断恶化的功能，导致后来死亡。这项研究试图开发一种方法，在心脏病发作后将类似凝胶样材料注入心脏，以防止心脏功能恶化。这种凝胶的设计目的是在心脏病发作后机械保护心脏免受进一步的伤害，并帮助刺激心脏自我修复。