PROJECT SUMMARY Hydrocephalus, an imbalance between cerebrospinal fluid production and absorption, is diagnosed in more than 1 in 500 people in the United States. Approximately 80% of these patients will suffer long-term neurological deficits. Genetic diseases, meningitis, subarachnoid hemorrhage, stroke, traumatic brain injury, or tumors cause hydrocephalus. The common treatment for all hydrocephalus patients is CSF drainage by shunting. Despite all our efforts, shunts still have the highest failure rate of any neurological device. A shocking 85% of shunts fail after just ten years. Failed shunts are plagued with astrocytes and macrophages, but we still do not understand the process by which these cells are pulled in, migrate, and grow. In our first aim, we identify what patient conditions contribute to tissue contact and what variables trigger tissue pull in into shunt catheter holes. We clearly define physical variables that create instances of tissue pull in using computational fluid dynamics and a benchtop model (“Brain on a Bench”). We continue the use of this system in Aims 2 and 3. In this way, we investigate what single or repetitive events cause shunt catheter contact and tissue pull in with the ventricular wall, parenchyma, or choroid plexus. In our second aim, we determine if cell growth is a necessary component to shunt obstruction after contact with a tissue source occurs. We examine the growth, proliferation, and activation state of the cells following single or repetitive contact with ventricular wall, parenchyma, and choroid plexus just as we did in Aim 1. In our final aim, we use our heightened awareness of tissue pull in and tissue growth to understand how changes to shunt design can influence shunt obstruction. We prioritize the clinical conditions shown to exacerbate tissue contact and test under physical variables that show direct pull in and growth of ventricular wall, parenchyma, and choroid plexus. In summary: our patient data informs us of the patient conditions that correlate to contact of ventricular wall, parenchyma, and choroid plexus. Benchtop and computational fluid dynamics models prioritize these environmental conditions while systematically testing what variables cause tissue pull in and growth. Strategies to prevent obstruction by inhibition of pull in and growth are tailored for ideal performance under the conditions set by our patient and benchtop data. Altogether, these data improve our mechanistic understanding of shunt obstruction necessary to and narrow our area of focus for improved treatment of hydrocephalus.