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）：心力衰竭给美国民众带来了重大的经济和社会负担，同时也带来了独特的技术挑战，因为治疗这种疾病的选择仍然非常有限。在缺血性心肌病中，心室壁变薄与心室腔扩张相结合。这种重塑过程与心室壁应力升高相关，从而积极推动心力衰竭终末期的变薄和扩张过程。在拟议的工作中，我们将为可注射生物材料创建新颖的设计，以增加梗死后心壁的厚度，减少心壁应力升高，并有可能改善心脏重塑结果。设计目标包括合成具有适合减少壁应力的拉伸特性、在重塑过程中将水凝胶保持在梗塞壁数月的降解特性以及允许多种生长因子受控释放的药物输送特性。刺激有益的心脏重塑。我们将利用大鼠和猪的缺血性心肌病模型以及旨在有效地进行目标水凝胶注射的微创机器人技术（HeartLander 设备）来评估 3 种复杂程度不断增加的不同水凝胶设计。该项目的具体目标是： 1) 评估将热响应水凝胶聚(NIPAAm-co-丙烯酸-co-2-羟乙基甲基丙烯酸酯-聚(三亚甲基碳酸酯))注射到心脏的中心和边缘区域的功能和组织病理学效果。使用改良的 HeartLander 微创机器人系统在猪缺血性心肌病模型中进行心肌梗塞 2) 评估注射的功能和组织病理学效果。将热响应水凝胶、聚（NIPAAm-co-HEMA-co-聚丙交酯-甲基丙烯酸酯）植入大鼠心肌梗塞的中心和边缘区域，然后植入猪（使用 HeartLander）缺血性心肌病模型。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，以及负载该凝胶的能力含有 IGF-1 的微球可延长控释时间。 4) 评估将来自目标 #3 的生长因子负载水凝胶注射到大鼠和猪（使用 HeartLander）缺血性心肌病模型的梗塞心肌中的功能和组织病理学效果。相关性：一旦心脏病发作后的早期阶段过去，治疗可能发生的心力衰竭的选择就有限。在拟议的资助期结束时，我们将开发创新的可注射材料来治疗心脏病发作后的心力衰竭，以及机器人输送系统，以最大限度地减少患者不适、并发症和恢复时间的方式输送材料。 公共卫生相关性：据估计，每年有 785,000 名美国人会心脏病发作，许多幸存者最终将面临心脏功能恶化，导致日后死亡。这项研究旨在开发一种方法，在心脏病发作后将凝胶状材料注入心脏，以防止心脏功能恶化。这种凝胶的设计目的是从机械角度保护心脏免受心脏病发作后的进一步损伤，并帮助刺激心脏自我愈合。