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.
