Reducing infections and blockage associated with long-term implantation of ventriculoperitoneal and related shunts

Wynnvision, Llc, Richmond VA

Investigators

Abstract

Ventriculoperitoneal shunting (VPS) is the most common US neurosurgical procedure performed to treat hydrocephalus, a neurological disorder caused by the dysregulation of cerebrospinal fluid (CSF) absorption in the brain. VPS provides an outlet for excess CSF in the cerebral ventricles to safely drain into extracranial locations, but it is often marred by high failure rates, associated with host cell obstruction of the shunt inlet ports and infections, which usually lead to irreversible neurological damage. Adverse Events (AE) of infection and cell adhesion are the leading causes of VPS failure and malfunction that occur at a rate of 40-50% for children within the first 2 years and 90% within 10 years, including 19% in adults within 6 months. VPS failure engenders substantial healthcare costs and seriously impacts the quality of life for patients and families over decades. Antibiotic impregnated shunts (AIS, e.g., Medtronic’s AresTM) reduce infections in the short-term but (1) become ineffective after 31-days, (2) do not kill Gm- bacteria, and (3) do not prevent host cell adhesion. To address these shortcomings, WynnVision (WV) will develop an Amine Gradient (AG) silicone ventricular catheter (VC), using a patented, economical dip-and-dry modification that functionalizes off-the-self silicone medical devices with a molecular amine. Phase I goals are to translate our successful in-vitro studies on AG silicone Foley catheters to develop AG silicone VCs. The Specific Aims are designed to validate comparable composition and performance to prior AG silicone technology. Studies include antimicrobial efficacy, resistance to host cell and biofilm adhesion, and mechanical testing of AG silicone VCs. Measurable outcomes are biocidal effectiveness against S. epidermidis (S.e.), in vitro resistance to host proteins (fibrinogen) and cell adhesion (astrocytes), and mechanical testing of AG silicone VCs compared to unmodified VCs. Phase II studies will build on Phase I studies by testing performance against other high-risk pathogens and host cells, stability in simulated CSF (sCSF) for up to 1 year, in vitro and in vivo studies recommended by FDA conducted by NAMSA® (GLP-certified) for biocompatibility, a 4-week in vitro study designed to evaluate safety and efficacy in a clinically relevant setting, and a clinically relevant in vivo hydrocephalus-pig model. Measurable outcomes include evaluation of broad- spectrum antimicrobial/biofilm resistance, statistical analyses of mean (±SD) glial viability, cell numbers, morphology for total glia over time and independent values for attachment at experiment end point, and stability of amine composition in simulated CSF over 1-year. Importantly, outcomes for in vivo hydrocephalus-pig model include shunt survival, changes in ventricular volume, biocompatibility, catheter obstruction using MRI, CSF inflammatory responses, neurological status, and histological and immunohistochemical analysis of surrounding tissues. These proposed studies systematically address the most urgent needs facing hydrocephalus treatments with the unique potential to improve patient outcomes by developing VCs with long-term resistance to obstruction and infection. All data obtained will be critical for FDA Approval and future commercialization plans.