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 98% of shunts fail after just ten years, a rate bumped up by the 80% of patients who suffer from tens if not hundreds of repetitive shunt failures. Shunts fail after becoming obstructed with attaching glia, creating a substrate for more glia or other cells and tissues (e.g. choroid plexus) to secondarily bind and block the flow of CSF through the shunt. Since glial attachment is a primary mechanism for shunt failure, we need to find out what it is about the pathophysiology of hydrocephalus that cause glia to attach and cause repetitive shunt failure. Until these cues are identified, we cannot address shunt failure in a principled way. In our first approach, we correlate patient revision history to change in cell attachment, hypothesizing that shunt failure exacerbates the likelihood for repeat shunt failure. In our second approach, we probe the mechanisms of shunt failure due to ever-present glia, specifically, how glial attachment changes as a function of factors influenced by repeat shunt failure. In our third approach, we probe mechanisms of shunt failure by blocking factors influenced by repeat shunt failure, and in doing so, propose methods to mitigate perpetual shunt failure. Methods include a first application of high-throughput, high-resolution, multi-spectral imaging and use of the FARSIGHT toolkit to provide a comprehensive quantitative analysis of the interaction between glia and the shunt. This project will set the stage for specific cause-effect engineering hypotheses to improve shunt design and ultimately lead to a fundamental leap of knowledge in hydrocephalus treatment. It will provide the foundation for my independent career managing a successful bioengineering research laboratory improving neuroprosthetics using biologically inspired design principles while providing professional development opportunities that allow me to train with the fields leading experts.