"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: 10515795
• 负责人: Yu Shrike Zhang
• 金额: $ 53.93万
• 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/10515795
• 关键词: 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; 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; Myocardial Infarction; Optics; Outcome; Pathologic; Patients; Periodicity; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Polyurethanes; Progeria; Publishing; Rare Diseases; Reporting; Resistance; Scheme; Seeds; Smooth Muscle Myocytes; Stretching; Structure; Symptoms; Syndrome; System; Technology; Thick; Thinness; Tissue Banks; Tissues; Translations; Tunica Adventitia; Vascular Smooth Muscle; absorption; base; calcification; cell bank; 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 Hutchinson-Gilford早衰综合征（HGPS）是一种遗传性疾病， 老化，而早老蛋白的积累也发生在生理老化过程中。值得注意的是， HGPS的核心是心血管系统，它是机械活动组织。典型症状包括 高血压、心肌梗死、充血性心力衰竭、钙化性主动脉瓣狭窄和外周 动脉粥样硬化例如，尸检结果表明， 大动脉（如主动脉和颈动脉）的中层中的平滑肌细胞（SMC）， 胶原和细胞外基质。HGPS患者的血管壁回声密度也增加， 伴有过度的纤维化外膜形成。这项提案的首要目标是优化一种仿生 用患者来源的成纤维细胞（FB）、SMC和内皮细胞（EC）生成的HGPS-on-a-chip系统 其允许应用相关循环拉伸来进行“临床试验”或通知临床试验设计， HGPS患者特别是，我们将产生一个全热塑性微流体系统与双层 血管模拟结构。基于我们先前已经报道的初步装置， 系统将是全热塑性的，由两个通道组成，两个通道由薄的热塑性聚氨酯隔开 (TPU)膜的在顶部，层将包括包封FB（外膜）的胶原蛋白水凝胶和弹性蛋白。 包埋SMC的水凝胶（培养基），再次用单层EC后接种。这种方法 重建血管的体内微环境，以忠实地模拟HGPS中的病理变化。