Artery-on-a-chip with perivascular adipose tissue for pressure myography

带有血管周围脂肪组织的动脉芯片，用于压力肌动描记

• 批准号: 9808634
• 负责人: Alisa S Morss Clyne
• 金额: $ 22.68万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808634
• 关键词: 3-Dimensional; Acetylcholine; Adipose tissue; Affect; Animals; Arteries; Biochemical; Biocompatible Materials; Biomanufacturing; Biomechanics; Blood Pressure; Blood Vessels; Blood flow; Caliber; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cell Culture Techniques; Cells; Collaborations; Consumption; Data; Devices; Disease; Drug toxicity; Endothelial Cells; Endothelium; Engineering; Equilibrium; Fiber; Giant Cells; Goals; Gold; Health; Heart; Heart Hypertrophy; Hemorrhage; Heterogeneity; Human; Hydrogels; Hypertension; In Vitro; Isometric Exercise; Laboratories; Lung; Measurement; Measures; Mechanics; Mediating; Mesenteric Arteries; Methods; Microfluidics; Modeling; Mus; Myography; Norepinephrine; Obesity; Pattern; Phenotype; Physiological; Process; Property; Relaxation; Research; Resistance; Smooth Muscle Myocytes; Source; Stimulus; Stress; Structure; System; Techniques; Testing; Time; Tissue Engineering; Tissues; Tube; Validation; Vascular Smooth Muscle; Vascular resistance; Vasodilation; Work; biofabrication; blood pressure regulation; brachial artery; constriction; drug testing; experience; fluid flow; human data; in vivo; innovation; iterative design; mechanical properties; mortality; novel; organ on a chip; pressure; response; standard measure; trend; vasoactive agent; vasoconstriction

Vasoconstriction and vasodilation are essential to blood pressure regulation and physiological responses in health and disease. Vascular contractility can be measured in humans in vivo and in animals ex vivo. Unfortunately human studies require a skilled technician and have limited ability to vary physiological stimuli, whereas animal studies are time consuming and may have limited applicability to human vascular function. While attempts have been made to develop in vitro systems to measure vasoconstriction and vasodilation, these systems do not include circumferentially aligned primary human vascular smooth muscle cells (vSMC) nor do they include perivascular adipose tissue (PVAT), which is critical to arterial response to vasoactive stimuli. Our long-term goal is to understand how PVAT affects arterial function in health and disease. The goal of this project is to create an artery-on-a-chip which includes PVAT and enables vasoconstriction and vasorelaxation measurements in response to both mechanical and biochemical stimuli. As an integral part of the iterative design process, we will thoroughly verify the in vitro artery-on-a-chip via ex vivo pressure myography of mouse resistance vessels and through comparisons to human studies. The artery-on-a-chip does not have to recapitulate all arterial structures (e.g., elastic lamina) or mechanical properties (e.g., burst strength); it only needs to demonstrate similar vasoconstriction and vasorelaxation trends to native arteries. To support the creation of the artery-on-a-chip with PVAT, we propose the following aims: Aim 1: Create an endothelialized tube of circumferentially aligned, contractile vSMCs We will use microribbons to circumferentially align vSMC in a cylindrical hydrogel channel and fluid flow to axially align endothelial cells (EC). We will determine how hydrogel composition and mechanical properties affects vSMC alignment as well as artery-on-a-chip vasoconstriction and vasodilation. Aim 2: Incorporate perivascular adipose tissue (PVAT) around the engineered vessel We will test which PVAT source and incorporation method best recapitulates PVAT effects on vasoconstriction and vasodilation in healthy and inflamed conditions in the artery-on-a-chip. Aim 3: Validate artery-on-a-chip with ex vivo pressure myography and in vivo human data We will thoroughly validate the artery-on-a-chip with PVAT by comparing it to ex vivo pressure myography of mouse vessels and in vivo human vasoreactivity data in healthy, inflamed, and obese conditions. This research will be the first to create a human artery-on-a-chip with PVAT to test vascular contractility. The device will have implications in drug testing as well as in elucidating mechanisms through which PVAT affects vascular function. In addition, the novel biofabrication methods will be applicable to other 3D aligned cell cultures.

血管收缩和血管舒张是血压调节和生理反应所必需的， 健康和疾病。血管收缩性可以在人体内和动物体内测量。 不幸的是，人类研究需要熟练的技术人员，并且改变生理刺激的能力有限， 而动物研究是耗时的，并且可能对人血管功能具有有限的适用性。而 已经尝试开发体外系统来测量血管收缩和血管舒张， 系统不包括周向排列的原代人血管平滑肌细胞（vSMC）， 它们包括血管周围脂肪组织（PVAT），其对于动脉对血管活性刺激的反应至关重要。 我们的长期目标是了解PVAT如何影响健康和疾病中的动脉功能。的目标 该项目是创建一个芯片上的动脉，其中包括PVAT，并使血管收缩， 对机械和生物化学刺激的血管舒张测量。作为其组成部分 迭代设计过程中，我们将彻底验证体外动脉芯片通过离体压力肌电图， 小鼠阻力血管，并通过与人类研究的比较。芯片上的动脉不必 概括所有动脉结构（例如，弹性层）或机械性能（例如，爆破强度）;它仅 需要证明与天然动脉相似的血管收缩和血管舒张趋势。支持 通过创建具有PVAT的芯片上动脉，我们提出以下目标： 目的1：创建周向排列、收缩性vSMC的内皮化管 我们将使用微带在圆柱形水凝胶通道中沿周向排列vSMC，并使流体流动， 轴向排列内皮细胞（EC）。我们将确定水凝胶的组成和机械性能 影响vSMC排列以及芯片上动脉血管收缩和血管舒张。 目的2：在工程血管周围掺入血管周围脂肪组织（PVAT） 我们将测试哪种PVAT来源和掺入方法最能概括PVAT对 血管收缩和血管舒张在健康和发炎的条件下，在动脉芯片。 目标3：具有离体压力肌造影术和体内人体数据的芯片上动脉 我们将通过与离体压力肌造影进行比较，彻底验证PVAT芯片上的动脉 的小鼠血管和在健康的，发炎的，和肥胖的条件下的体内人血管反应性数据。 这项研究将是第一个创建具有PVAT的人类动脉芯片来测试血管收缩性的研究。的 该装置将对药物测试以及阐明PVAT影响的机制产生影响， 血管功能此外，新的生物制造方法将适用于其他3D对齐的细胞培养。