Development of an Advanced In-Vitro Model for Angiogenesis Research and Drug Test
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AbstractDESCRIPTION (provided by applicant): Disregulated angiogenesis-the growth of new blood-vessels from existing vasculature-plays a central role in more than 70 major health conditions including cancer, cardiovascular disease, and macular degeneration. More than one billion people worldwide are afflicted by angiogenesis-dependent diseases. Therapeutics that target blood-vessel growth promise new possibilities in the treatment of devastating diseases and have vast economic potential. However, progress in translation from basic research into the clinic is slowed by the lack of dependable models for angiogenesis research and drug testing. Presently, none of the existing in-vitro models for the study of angiogenesis integrates most of the critical elements that typify vascular growth in vivo, and none of the existing models includes the growth of capillary sprouts from existing blood vessels under flow- which is by definition the hallmark of angiogenesis. Previously, we have developed tissue-engineering techniques for the creation of microvessels within small fluidic devices. Within these devices, we generate luminally-perfused parent vessels from endothelial cells that subsequently sprout and form anatomizing capillary-like networks in collagen. We now propose to develop this method into an advanced in-vitro angiogenesis model with the following attributes: (1) tissue-engineered parent vessels mimicking architecture and cell composition in vivo, capable of angiogenic sprouting into a surrounding three-dimensional matrix; (2) human-derived cells; (3) direct luminal perfusion of parent vessels and sprouts; (4) tightly-controlled physical and chemical conditions; and (5) a mass produced, disposable fluidic device that can be adapted for the use in existing high-throughput analysis platforms. Aim 1 of the proposed project will be the completion of an optimized design of the fluidic device and the establishment of a system that allows for the tight control of perfusion, temperature, gas concentration and pH within the device. Aim 2 will be to achieve established techniques for the generation of microvasculature with the three structural key components of angiogenesis: endothelial cells, pericytes, and basement membrane. Once feasibility is established, we plan to advance ourmodel into a standardized, easy to use product that can be of significant value in the development of therapies for a range of devastating diseases. PUBLIC HEALTH RELEVANCE: Disregulated growth of blood vessels is a central element in cancer andother important diseases. More reliable assays and models for the study of vascular growth and the evaluation of therapeutic drugs are necessary to improve clinical results. We propose a new model for the study of vascular functions that closer mimics natural vessels.
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