SBIR-STTR Award

This project will focus on the preparation and evaluation of nonthrombogenic, antibacterial nitric oxide (NO) releasing catheters. Phase 1 of this SBIR will: 1) develop unique NO secreting catheters (14-20 gauge); 2) test them in rabbit and sheep models to evaluate thrombogenicity and bacterial adherence; Phase 2 will scale up manufacturing and evaluate toxicity in preparation for human trials. The rationale for this research is to mimic the function of the endothelium. Low levels of NO released by the normal endothelium inhibit platelet adhesion and activation, thus preventing thrombus formation. Further, it has been shown that NO at low doses exhibits significant bactericidal activity. Hence, the preparation of catheters that secrete NO will solve two longstanding problems in the care of critically ill patients. The basic NO release polymer technology that employs novel diazeniumdiolate type NO donors has been developed in laboratories at the University of Michigan (U of M) over the past 10 years. Successful applications of this technology have already included the development of anti-platelet coatings for extracorporeal circulation devices and the preparation more biocompatible implantable chemical sensors with improved analytical performance. Via collaboration with the research team at the U of M that has been working on this technology, MC3 now intends to develop and test catheters that release NO at controlled rates in order to prevent thrombosis and infection, two major problems associated with the use of catheters.

Public Health Relevance:
Clotting and infection is a major problem in intravascular (IV) catheters. Normal blood vessels secrete a chemical called nitric oxide which prevents these problems. This research will develop 14-20 gauge catheters which secrete nitric oxide, decreasing the risk of clotting and infection.

Public Health Relevance Statement:
Clotting and infection is a major problem in intravascular (IV) catheters. Normal blood vessels secrete a chemical called nitric oxide which prevents these problems. This research will develop 14-20 gauge catheters which secrete nitric oxide, decreasing the risk of clotting and infection.

NIH Spending Category:
Bioengineering

Project Terms:
Adherence (attribute); Adhesions; Animal Model; Anti-Bacterial Agents; bacterial resistance; bactericide; bench to bedside; Biocompatible; biomaterial compatibility; Blood Platelets; Blood Vessels; Caring; Catheters; Chemicals; Chronic; Clinical assessments; Clinical Trials; Coagulation Process; Collaborations; commercialization; Consultations; Consumption; Critical Illness; crosslink; Development; Devices; diazeniumdiolate; Dimethylpolysiloxanes; Dose; Endothelium; Engineering; Ensure; Evaluation; Excision; Exhibits; Extracorporeal Circulation; Gamma Rays; Goals; Health; Hospitals; Human; Implant; implantation; improved; in vivo; Infection; Laboratories; Length; Licensing; Liquid substance; Local Anti-Infective Agents; Location; Manufacturer Name; manufacturing scale-up; Measures; Methods; Michigan; Microbial Biofilms; Modeling; new technology; Nitric Oxide; Nitric Oxide Donors; novel; Oryctolagus cuniculus; Patients; payment; Performance; Phase; Polymer Chemistry; Polymers; Polyurethanes; Preparation; prevent; Prevention; Procedures; Production; prototype; Research; research clinical testing; Risk; Safety; scale up; sensor; Sheep; Silicone Elastomers; Small Business Innovation Research Grant; Solutions; Surface; Technology; Testing; Thrombosis; Thrombus; Time; Toxic effect; Unithiol; Universities; Vinyl Chloride; Work

This proposal involves the incorporation of a proprietary nitric oxide (NO) releasing polymer material (NORL) into a venous catheter to reduce infection and clotting. Low levels of NO released by the normal endothelium inhibit platelet adhesion and activation, thus preventing thrombus formation. Further, it has been shown that NO at low doses exhibits significant bactericidal activity. Hence, the preparation of catheters that secrete NO will solve two longstanding problems in the care of critically ill patients. In Phase 1 of this SBIR, we: 1) developed a unique NO secreting polymer material that can release NO above physiological levels for up to 21 days, with minimal leaching of byproducts; 2) tested the materials for cytotoxicity and hemolysis, and conducted testing in a sheep model to evaluate thrombogenicity and bacterial adherence. We addressed handling and packaging requirements to maintain efficacy of the materials. Based on the cost of materials and the specialized handling requirements, we identified a product that would benefit from the prolonged protection offered by the material, and that has a high enough sale price to tolerate the increased handling expenses. This Phase II application is targeted at building out the manufacturing process found to be most effective for incorporating NORL in the catheter, performing extensive preclinical assessments, and evaluating the coating in vivo for anti-microbial and anti-platelet properties. The initial target product for NORL will be a dual lumen catheter (DLC) suitable for adult extracorporeal membrane oxygenation (ECMO). Specifically, we will construct a device for automated and controlled fabrication of the NORL catheter, and conduct design verification of the NORL loaded catheter. We will also work with our collaborators, at the University of Michigan, to perform extensive in vivo evaluations of the new NO release catheter. At the conclusion of Phase II, we will be prepared to transfer the developed process and equipment to a contract manufacturer. This approach is a significant advance in improving the biocompatibility and anti-microbial features of intravascular catheters since it utilizes chemistry that exactly mimics endogenous NO release function in our bodies, including from endothelial cells to inhibit platelet adhesion/activation, and by various immune cells (e.g., macrophages, neutrophils, etc.) to kill bacteria. By decreasing both clotting and infection, this technology will simultaneously increase catheter longevity and decrease patient morbidity and costs.

Thesaurus Terms:
Address;Adherence (Attribute);Adhesions;Adult;Aging;Antimicrobial;Bacteria;Bactericide;Base;Biochemistry;Biocompatible;Biocompatible Materials;Biomaterial Compatibility;Blood;Blood Platelets;Blood Vessels;Caring;Catheters;Cells;Chemicals;Chemistry;Clinical;Coagulation Process;Contracts;Cost;Critical Illness;Cytotoxicity;Design;Development;Devices;Dose;Drug Formulations;Endothelial Cells;Endothelium;Equipment;Evaluation;Exhibits;Extracorporeal Membrane Oxygenation;Falls;Generations;Goals;Growth;Hemolysis;Histologic;Immune;Implant;Improved;In Vivo;Infection;Investments;Killings;Laboratories;Lead;Letters;Local Anti-Infective Agents;Longevity;Macrophage;Manufacturer Name;Manufacturing Process;Marketing;Materials Testing;Mechanics;Methods;Michigan;Microbial;Modeling;Morbidity - Disease Rate;Neutrophil;Next Generation;Nitric Oxide;Novel;Patient Safety;Patients;Phase;Physiological;Platelet Activation;Polymers;Pre-Clinical;Preparation;Prevent;Price;Process;Production;Property;Public Health Relevance;Research;Resistance To Infection;Risk;S-Nitrosothiols;Sales;Sheep;Side;Small Business Innovation Research Grant;Sterilization;Technology;Testing;Thrombus;Universities;Venous;Work;