SBIR-STTR Award

Hydrocephalus patients suffer from long-term deficits in both neurologic function and overall quality of life. Current treatments in the field, most of which involve diversion of cerebrospinal fluid (CSF) with shunts, recurrently fail. Despite our efforts for 60 years, shunts still have the highest failure rate of any neurological device: 98% of all shunts fail after ten years. This failure rate is the dominant contributor to the $2 billion-per- year cost that hydrocephalus incurs on our health care system. 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 prevent it by inhibiting surface interactions with proteins, astrocytes, and microglia. Tethered liquid perfluorocarbon (TLP) coatings stably adheres a thin, inert liquid perfluorocarbon layer that prevents protein and cell attachment and subsequent activation. Previously developed solid surface coatings, even solid perfluorocarbon coatings, allow for some level of surface attachment and activation, which eventually leads to recruitment of thrombotic proteins and inflammatory cells. The omniphobic liquid surface repels hydrophilic and hydrophobic proteins, preventing recruitment and downstream cascades from initiating on the surface and leading to clogging. Based on our preliminary data which shows stability, low neurotoxicity, decreased protein adsorption, cell attachment, blood pooling, and tissue response, this is a top candidate to reduce shunt failure rate. In our first approach, we refine our coating technology to develop a durable and uniform coating. We measure initial surface characteristics, test durability under high flow rates and following purposeful scratching and bending, and assess the impact any free-floating TLP coating may have on shunt functionality. Our second aim begins to biologically analyze these relationships in a 3D culture system, designed and validated specifically to incorporate the shunt environment. By using quantitative immunofluorescence to identify attachment, activation, migration, proliferation, and binding strength, we will begin to understand the mechanisms of obstruction with and without the TLP coating. In this way, we can use these data to make specific hypotheses-driven design changes. Finally, in our third approach, we will test toxicity in the brain and systemically by inserting TLP coated shunts into the rodent brain. This Phase I project sets FreeFlow apart from others with its novel TLP coating that will reduce shunt failure. This project will set the stage for Phase II pre-clinical trials.

Project Terms:
Acute; Adsorption; Animal Model; Apoptosis; Astrocytes; Autophagocytosis; base; Binding; Biological; Biological Assay; biomaterial compatibility; Blood; Brain; Caring; Cell Death; Cell-Matrix Junction; Cells; Cerebrospinal Fluid; cerebrospinal fluid flow; Cerebrum; Characteristics; Chemistry; Chronic; Clinical Trials; clinically significant; Contracts; cost; Creation of ventriculo-peritoneal shunt; Cyclic GMP; Data; data mining; design; Development; Devices; Effectiveness; efficacy study; Engineering; Environment; Failure; Family suidae; Fluorocarbons; Future; Goals; Healthcare Systems; Hydrocephalus; hydrophilicity; Hydrophobicity; Image; Immunofluorescence Immunologic; Implant; improved; In Vitro; in vivo; in vivo Model; Infection; Inflammatory; innovation; interdisciplinary approach; Kidney; Knowledge; Liquid substance; Liver; manufacturing facility; Measurement; Measures; member; Methods; Microglia; migration; Modeling; Modification; Necrosis; Nervous System Physiology; Neuroglia; Neurologic; Neurologic Deficit; Neurosurgeon; neurotoxicity; novel; Obstruction; Pathway interactions; Patient Care; Patients; Phase; phase 2 study; preclinical trial; pressure; prevent; Procedures; Process; Proteins; Quality of life; Rattus; recruit; Recurrence; Reporting; response; Rodent; Safety; Secondary to; Shunt Device; Silicones; Solid; Stress; Structure of choroid plexus; Surface; surface coating; System; Technology; technology development; Testing; Thinness; three dimensional cell culture; Tissues; Toxicity Tests; Toxin; Whole Blood; Work;

Hydrocephalus causes long term neurological problems and patient suffering. Current treatments, most of which involve surgical diversion of cerebrospinal fluid (CSF) with shunt catheters, fail at an alarming rate. Approximately 98% of all shunts fail within 10 years, and this failure rate is the dominant contributor to the $2 billion-per-year cost that hydrocephalus incurs on our health care system. The most common causes of shunt failure are clogging and infections; clogging is associated with glia cell attachment, which promotes the attachment of other cells and tissues, finally inhibiting the CSF flow. Therefore, directly inhibiting cell attachment on catheter surfaces should ameliorate shunt obstruction. During our phase I proposal, we conducted a proof of concept study to evaluate the merit of tethered liquid perfluorocarbon (TLP) coating to ameliorate shunt clogging. Importantly, previous work demonstrated that TLP-coated medical devices exhibit reduced protein adsorption, successfully resist adherent fibroblast and glial cell attachment in vitro and in vivo, repel blood and its protein constituents, reduce foreign body encapsulation, and can inhibit adsorption of a broad class of infectious pathogens onto surfaces. During our phase I research, we improved the coating process for hydrocephalus shunt catheters and demonstrated that the TLP coating could dramatically inhibit glia cell attachment and therefore mechanistically minimize shunt clogging during in vivo studies. We also established that the coating is biocompatible and could sustain long term physiological flow. The objectives of Phase II research is to commercialize the shunt catheter by good manufacturing practice (GMP), as required by FDA, and demonstrate the efficacy of TLP-coated shunt catheters by implanting the device in a hydrocephalus-induced animal model. This will be achieved by manufacturing the TLP so it is ready for FDA and clinical trials, testing efficacy in a hydrocephalic animal model, and testing biocompatibility in a GLP lab. We have already established communications with a major shunt manufacturer. Upon successful completion of these studies and after obtaining FDA approval, FFMD will license the coating technology for further clinical trials and marketing. The successful development and commercialization of this highly innovative technology will provide a paradigm shift in the treatment of hydrocephalus by focusing on mechanisms that reduce cell and tissue adhesion on ventricular catheters.

Public Health Relevance Statement:
PROJECT NARRATIVE Hydrocephalus causes long term neurological problem and patient suffering, but 98% of the catheters used to treat the condition fail within 10 years; this is the dominant contributor to the $2 billion-per-year cost that hydrocephalus incurs on our health care system. We have developed a novel coating that can be applied to catheters to prevent the attachment of glial cells, which lead to shunt failure by causing clogging and infections, respectively. In this phase II proposal, we will and demonstrate the efficacy of TLP-coated shunt catheter by implanting the device in a hydrocephalus-induced animal model and manufacture the shunt catheter using good manufacturing practice (GMP), as required by FDA, ready for commercialization.

Project Terms:
Address; Adhesions; Adsorption; Animal Model; Astrocytes; base; Binding; biobank; biomaterial compatibility; Blood; Brain; Businesses; Catheters; Cell Culture Techniques; Cell Death; cell type; Cell-Matrix Junction; Cells; Cerebrospinal Fluid; cerebrospinal fluid flow; Cerebrum; Chemicals; Chemistry; Chronic; Clinical; Clinical Trials; clinically relevant; commercialization; Communication; cost; Cyclic GMP; Data; Development; Devices; Effectiveness; efficacy testing; Exhibits; Failure; Family suidae; FDA approved; Fibroblasts; flexibility; Fluorocarbons; Foreign Bodies; Fracture; Friction; Functional disorder; Goals; Hardness; Healthcare Systems; Hydrocephalus; Implant; implantable device; improved; In Vitro; in vivo; Infection; innovation; innovative technologies; Institutes; Lead; Licensing; Liquid substance; Manufacturer Name; manufacturing process; Marketing; Medical; Medical Device; Microglia; Modeling; Modification; Neuroglia; Neurologic; Neurologic Deficit; novel; Obstruction; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; pathogen; Patient Care; Patient-Focused Outcomes; Patients; Phase; phase 3 study; physical property; Physiological; Polymers; prevent; Procedures; Process; Production; Proteins; prototype; Quality of life; Rattus; Reporting; Research; Research Contracts; Resistance; response; Safety; Secondary to; Shunt Device; Small Business Technology Transfer Research; Standardization; Structure of choroid plexus; subcutaneous; Surface; Surgical sutures; System; systemic toxicity; Technology; Testing; Time; Tissues; Universities; Ventricular; Washington; Work