An engineered platform for the study of metastasis (PQ #24)

用于研究转移的工程平台（PQ

• 批准号: 8513951
• 负责人: Peter C Searson
• 金额: $ 29.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513951
• 关键词: Address; Adhesions; Aluminum; Animal Model; Biologic Characteristic; Biological; Biology; Blood Vessels; Caliber; Cardiovascular system; Cells; Cessation of life; Chemicals; Clinical; Cytoskeleton; Data; Development; Disease; Distant; Endothelial Cells; Engineering; Event; Extracellular Matrix; Extravasation; Foundations; Goals; Growth Factor; Image; Laboratories; Malignant Neoplasms; Microfluidics; Modeling; Molds; Neoplasm Metastasis; One-Step dentin bonding system; Online Systems; Outcome; Perfusion; Physics; Primary Neoplasm; Process; Property; Protocols documentation; Research; Signaling Molecule; Site; Solutions; Structure; Time; Tissue Engineering; Tissue Grafts; Tissues; Translating; Translations; Tumor Biology; Vascular Endothelial Cell; Vascular System; Viscosity; angiogenesis; anticancer research; cancer cell; cancer imaging; cell type; chemical property; design; insight; meetings; metastatic process; migration; mortality; novel strategies; prevent; research study; stem; success; tumor

DESCRIPTION (provided by applicant): This application addresses PQ #24: Given the difficulty of studying metastasis, can we develop new approaches, such as engineered tissue grafts, to investigate the biology of tumor spread? Many of the steps in the metastatic process, specifically invasion, intravasation, and extravasation, take place at or near the interface between the local tissue microenvironment and the vascular system. Therefore the development of a platform that combines both extracellular matrix and a vessel is key to unraveling the events that guide the development of metastasis. The major challenge in developing such a platform is the complexity of this interface. To address this challenge we propose a microfluidic platform that incorporates both artificial extra cellular matrix and a vessel. Our objective is to produce a platform that: (1) recapitulates the relevant physical and biological characteristics of the interface between extracellular matrix and a vessel in a physiologically relevant geometry, (2) allows control over physicochemical and biological properties such that experiments can be performed systematically and reproducibly, and allowing variables to be adjusted independently, and (3) is sufficiently robust that fabrication can be readily translated to other laboratories. In preliminary data we have demonstrated fabrication of a functional platform and the feasibility of using the platform to study metastasis. In this research, we propose to lay the foundations for the refinement and further development of the platform to enable advances in the understanding of metastasis. The artificial extra cellular matrix/vessel platform allows study of invasion, intravasation and extravasation in a physiologically relevant geometry. To study invasion and intravasation a cavity is created in the extra cellular matrix near the artificial vessel. Prolifertion, detachment, and migration of cancer cells to the vessel, followed by intravasation into the vessel, can be imaged in real time. To study extravasation, cancer cells are added to the perfusion media flowing through the vessel. Depending on the vessel size, arrest can occur by adhesion or occlusion. In preliminary data, we have performed a proof-of-principle demonstration of the formation of a perfused artificial vessel using vascular endothelial cells and the incorporation of a tumor for the study of invasion and intravasation. The overall goal of this project is to develop an engineered ECM/vessel platform for the systematic study of key steps in the metastatic cascade. Building on these results we will optimize the engineered ECM/vessel platform (Aim 1), study the dynamics of invasion and intravasation (Aim 2a) and extravasation (Aim 2b), and develop modules for the translation of the engineered ECM/vessel platform for the study of metastasis (Aim 3).

描述（由申请人提供）：本申请解决了pq# 24：考虑到研究转移的困难，我们能否开发新的方法，如工程组织移植，来研究肿瘤扩散的生物学？转移过程中的许多步骤，特别是侵袭、内渗和外渗，发生在局部组织微环境和血管系统之间的界面或附近。因此，开发结合细胞外基质和血管的平台是揭示引导转移发展的事件的关键。开发这样一个平台的主要挑战是这个接口的复杂性。为了解决这一挑战，我们提出了一种结合人工细胞外基质和血管的微流控平台。我们的目标是打造一个平台：(1)以生理学上相关的几何形状概括细胞外基质和血管之间界面的相关物理和生物特性；(2)允许对物理化学和生物特性进行控制，以便实验可以系统地进行和可重复，并允许独立调整变量；(3)足够坚固，可以很容易地将制造转移到其他实验室。在