"Clinical Trials" on a Premature Vascular Aging-on-a-Chip Model

血管过早老化芯片模型的“临床试验”

• 批准号: 10687068
• 负责人: Yu Shrike Zhang
• 金额: $ 55.18万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687068
• 关键词: Acceleration; Adsorption; Aging; Aorta; Aortic Valve Stenosis; Arteries; Atherosclerosis; Autopsy; Behavior; Biochemical; Biological Markers; Biomimetics; Biophysics; Biosensor; Blood Vessels; CAV1 gene; Cardiovascular system; Carotid Arteries; Cells; Clinical Research; Clinical Trials; Clinical Trials Design; Collagen; Combined Modality Therapy; Congestive Heart Failure; Cultured Cells; Devices; Dose; Elasticity; Elastin; Encapsulated; Endothelial Cells; Extracellular Matrix; Fibroblasts; Genetic Diseases; Genetic Transcription; Goals; Human; Human body; Hydrogels; Hypertension; IL6 gene; Lead; Liquid substance; Lonafarnib; Maintenance; Measurement; Mechanical Stress; Mechanics; Medial; Membrane; Methodology; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Morphology; Muscle Cells; Myocardial Infarction; Optics; Outcome; Pathologic; Patients; Periodicity; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Polyurethanes; Progeria; Publishing; Rare Diseases; Reporting; Resistance; Scheme; Smooth Muscle Myocytes; Stretching; Structure; Symptoms; Syndrome; System; Technology; Thick; Thinness; Tissue Banks; Tissues; Translations; Tunica Adventitia; Vascular Smooth Muscle; absorption; cell bank; clinical trial on a chip; clinically relevant; cohort; dosage; drug candidate; experience; improved; in vitro Model; in vivo; induced pluripotent stem cell; inflammatory marker; jun Oncogene; monolayer; mortality; non-invasive imaging; polydimethylsiloxane; premature; prevent; response; response to injury; screening; shear stress; ultrasound

Abstract Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder that results in premature and accelerated aging, while accumulation of progerin also occurs during physiological aging. Notably, one of the major targets of HGPS is the cardiovascular system, which are mechanically active tissues. Typical symptoms include hypertension, myocardial infarction, congestive heart failure, calcific aortic stenosis, and peripheral atherosclerosis. For example, autopsy findings have illustrated profound loss of vascular smooth muscle cells (SMCs) in the medial layer of large arteries, such as the aorta and carotid arteries, with replacement by collagen and extracellular matrix. Vascular wall echodensity is also increased in HGPS patients associated with exaggerated fibrotic adventitia formation. The overarching goal of this proposal is to optimize a biomimetic HGPS-on-a-chip system generated with patient-derived fibroblasts (FBs), SMCs, and endothelial cells (ECs) that allow application of relevant cyclic stretch for performing ‘clinical trials’ or informing clinical trial designs for HGPS patients. In particular, we will generate a whole-thermoplastic microfluidic system with a dual-layer blood vessel-mimicking structure. Based on our preliminary device previously already reported, the proposed system will be whole-thermoplastic consisting of two channels separated by a thin thermoplastic polyurethane (TPU) membrane. On top, layers will include a collagen hydrogel encapsulating FBs (adventitia) and an elastin hydrogel embedded with SMCs (media), post-seeded again with a monolayer of ECs. This methodology recreates the in vivo microenvironment of blood vessels to faithfully model pathological changes in HGPS.

摘要 哈钦森-吉尔福德早衰症(HGPS)是一种导致早产和早衰的遗传性疾病。 在生理衰老过程中，孕激素的积累也会发生。值得注意的是，主要目标之一 HGPS的核心是心血管系统，它是机械活动的组织。典型症状包括 高血压、心肌梗死、充血性心力衰竭、钙化性主动脉狭窄和外周血管狭窄 动脉硬化。例如，尸检结果显示血管平滑肌细胞严重丧失。 (SMC)位于大动脉的内侧层，如主动脉和颈动脉，由 胶原蛋白和细胞外基质。与HGPS相关的患者血管壁回声密度也增加 伴有夸大的纤维性外膜形成。这项提案的首要目标是优化一种仿生生物 由患者来源的成纤维细胞(FBS)、SMC和内皮细胞(ECs)产生的HGPS芯片上系统 允许应用相关的循环拉伸来执行临床试验或通知临床试验设计 HGPS患者。特别是，我们将产生一个具有双层的全热塑性微流控系统 模拟血管的结构。根据我们之前已经报告的初步设备，建议的 整个系统将是热塑性的，由两个通道组成，通道之间由一层薄薄的热塑性聚氨酯隔开 (TPU)膜。在顶层，将包括包裹FBS(外膜)的胶原水凝胶和弹性蛋白 含SMC的水凝胶(介质)，再次接种单层内皮细胞。这种方法论 重建体内血管微环境，忠实地模拟HGPS的病理变化。