Development of an organotypic in-vitro model of the blood-brain barrier

DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) is a tight barrier formed by microvessels and capillaries controlling the passage of nutrients, fluids, metabolic products and drugs between the blood and the brain. Imbalance of the BBB is involved in a number of major pathologies afflicting the brain, such as Alzheimer's disease, stroke, and cancer. Although neurotherapeutics are among the largest and fastest growing markets in the pharmaceutical industry, progress is currently impaired by the lack of in-vitro assays that reliably predict in-vivo BBB permeability. None of the existing models adequately replicates the in-vivo organotypic microenvironment, which is seen as a key for achieving in-vivo-like functionality. We have previously developed a 3D model for the study of in-vitro angiogenesis, consisting of small fluidic devices with a collagen-filled chamber. We intend to advance our model into an organotypic in-vitro model of the blood-brain barrier with the following main attributes: (1) a tissue-engineered endothelial-cell microvessel, surrounded by pericytes and astrocytes arranged in physiological ratio and architecture; (2) direct contact between endothelial cells, pericytes, and astrocytes; (3) an extracellular matrix (ECM) that resembles the interstitial environment of the CNS; (4) luminal flow providing shear stress to the endothelium; (5) tightly-controlled physical and chemical conditions; (6) a mass- produced, disposable fluidic device that can be adapted for use in existing high-throughput analysis platforms. In Phase 1, we will establish the prototype of a model that comprises a central BBB-microvessel in a brain-specific extracellular matrix, surrounded by pericytes and astrocytes--cells that induce and maintain barrier tightness. In Phase 2 we will pursue the development of a commercial product, including the adaptation of the fluidic device to high- throughput analysis platforms. We predict that our model will facilitate a significant progress in the therapy of a number of devastating diseases. PUBLIC HEALTH RELEVANCE: A major obstacle to the successful development of drugs that treat diseases of the central nervous system (CNS) such as Alzheimer's, Parkinson's, stroke, brain cancers, and metastasis to the brain, is the inability of these drugs to cross the blood-brain barrier (BBB). This natural barrier, whose function is to protect CNS from potentially harmful molecules, unfortunately also prevents penetration of potentially beneficial drugs. The difficulty in assessing whether or not drugs will cross the BBB makes the development of new neurologic drugs a difficult and unusually unsuccessful task. For this reason, in- vitro models that successfully predict in vivo drug BBB-permeability are of paramount importance for the neuropharmaceutical industry. We propose the development of an in- vitro model that mimics the natural BBB architecture, including perfused microvessels This model promises to become a valuable system for drug developers as well as to CNS researchers in academia.