New Bioreactor System to Test the Mechanisms that Underlay Catheter Malfunction Under Hydrocephalic Conditions.

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ABSTRACT For 70 years, the primary treatment for hydrocephalus has focused on cerebrospinal fluid shunt (CSF) derivation, which is performed to release the increased intracranial pressure (ICP). Unfortunately, CSF shunts malfunction at an unacceptable rate; 98% of patients suffer shunt failure in their lifetime, with obstruction of the ventricular catheter as the leading cause of failure in pediatric hydrocephalus. Therefore, understanding the mechanisms that underlie shunt blockage has become essential for pediatric neurosurgeons. Currently, there are only a few biological systems (bioreactors) that test ventricular catheters. However, these bioreactors fail to mimic the hydrocephalic pathology since they do not consider ICP, which is the main symptom that the shunts are meant to treat. The bioreactors developed to date are also cytologically limited since they do not consider ventricular zone (VZ) cells or choroid plexus (ChP). Thus, our central hypothesis is that inflammatory-dependent VZ glial activation and ChP proliferation play a fundamental role in the process of shunt obstruction. To test this hypothesis, our group is developing a unique in vitro bioreactor that mimics the cytopathology of hydrocephalus. The bioreactor is designed to test cellular obstruction in different ventricular catheters under normal and pathological conditions, with the capacity to modulate pressure and catheter flow. Three specific aims will test this hypothesis: (1) Validate our in vitro bioreactor to test catheters in normal-pressure conditions; (2) Test our in vitro bioreactor under high-pressure conditions; (3) Test available proximal catheters for susceptibility to obstruction and provide valuable clinical information to neurosurgeons. We will use our recently developed in vitro model as an ideal experimental platform to mimic the cytopathology of hydrocephalus, and we will leverage our experience with ChP organ cultures, in combination with this unique bioreactor, to provide a comprehensive understanding of ventricular catheter obstruction under hydrocephalic conditions.