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对于血压调节和生理反应至关重要 健康与疾病。可以在体内和动物的人体中测量血管收缩力。 不幸的是，人类的研究需要一名熟练的技术人员，并且具有有限的改变生理刺激的能力， 而动物研究很耗时，对人血管功能的适用性可能有限。尽管 已经尝试开发体外系统来测量血管收缩和血管舒张，这些 系统不包括周向原代人血管平滑肌细胞（VSMC），也不包括 它们包括血管周围脂肪组织（PVAT），这对于对血管活性刺激的动脉反应至关重要。 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。目标 该项目是为包括PVAT在内的芯片上创建一个动脉，并启用血管收缩和 响应机械和生化刺激的血管瘤测量。作为不可或缺的一部分 迭代设计过程，我们将通过体内压力密码图彻底验证体外动脉 小鼠抗性血管并通过与人类研究进行比较。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（例如爆发强度）；它只是 需要证明与天然动脉相似的血管收缩和血管延缓趋势。支持 使用PVAT创建动脉芯片，我们提出以下目的： 目标1：创建一个圆周对齐的内皮化管，收缩VSMC 我们将使用微纤维在圆柱形水凝胶通道中周围地对齐VSMC，并流动流到 轴向对齐内皮细胞（EC）。我们将确定水凝胶组成和机械性能 会影响VSMC对准以及片上的动脉血管收缩和血管舒张。 目标2：在工程容器周围纳入血管周围脂肪组织（PVAT） 我们将测试哪种PVAT源和合并方法最能概括PVAT对 在片上动脉的健康和发炎状态下的血管收缩和血管舒张。 AIM 3：用离体压力密码和体内数据验证片上的动脉 我们将通过将其比较与体内压力myography进行比较，从而用PVAT彻底验证动脉芯片 在健康，发炎和肥胖的情况下，小鼠血管和体内人体血管反应性数据。 这项研究将是第一个使用PVAT创建人类动脉来测试血管收缩力的研究。这 设备将对药物测试以及阐明PVAT影响的机制有影响 血管功能。此外，新型生物制造方法将适用于其他3D对齐细胞培养物。