The most common hemodialysis catheter complications are thrombosis, inflammation, and biofilms. Thrombotic deposition and inflammation have been shown to result in inadequate dialysis and lead to higher complication rates and increased mortality and can take many different forms including isolated clots, thrombosis in vessels adjacent to the catheter tip, or fibrin sheaths formed within the catheter lumen. The situation in pediatric dialysis is even more woeful because pediatric catheters are a smaller caliber with lower blood flow rates making them particularly prone to thrombosis and catheter complications. The fundamental mechanism initiating the catheter--?related complications is the body's inherent non--?specific immune response to contact with foreign materials. When a foreign object such as a catheter is inserted into the patient's circulation the immediate foreign body response is the adsorption of circulating proteins onto the catheter's surface (including thrombin, tissue factor and complement C3a/C5a). Adsorption directs conformational changes to the proteins that expose normally hidden epitopes activating inflammatory cells such as monocytes and platelets that leads to thrombosis. In addition, dialysis patients have compromised immune systems with additional stores of mitogens that induce a hyper reaction to foreign surfaces. Therefore, it is vital to have a catheter surface that mitigates the foreign body response and prevents chronic inflammation and thrombosis. This objective of this proposal is to develop and evaluate the efficacy of a novel surface inspired by the naturally occurring endothelial glycocalyx. The proposed bioactive surface will minimize the thrombogenic and inflammatory potential of the most commonly used pediatric hemodialysis catheter (Split CathTM, MedComp) thus preventing chronic inflammation and minimizing thrombosis. The surface modification (Specific Aim1) consists of four steps: 1) Cleaning of the polycarbonate/polyurethane catheter surface to provide a consistent, stable surface for subsequent modifications. 2) Activation by plasma enhanced vapor deposition to generate active sites to which the hydrogel can be grafted. 3) Grafting of a hydrogel via free radical polymerization to the activated surface. 4) Coupling of bioactive heparin. Each of the steps will be individually evaluated and subsequent steps will not be attempted until acceptance criteria are met. Blood perfusion studies (Specific Aim 2) will be used to evaluate surfaces that meet Specific Aim 1 acceptance criteria. Tested surfaces will be evaluated for protein/cell adherence and cellular activation in the circulating blood. Surfaces meeting in vitro acceptance criteria specified in Specific Aim 2 will be evaluated in a 30 day rat model (Specific Aim 3). Nine (9) control and nine (9) surface treated catheters will be evaluated using a ~1 cm segment catheter (surface treated or control) placed in the superior vena cava. The efficacy of the surface on the implanted catheters will be assessed by: (1) Immunohistochemical analysis of the tissue surrounding the catheter. (2) Scanning electron microscopy (SEM) on the cellular layer / biofilm on the catheter (3) Flow cytometry of blood samples to quantify white cell and platelet activation and thrombogenesis.
Public Health Relevance Statement: Public Health Relevance: The most common hemodialysis catheter complications are thrombosis, inflammation, and biofilms. Thrombotic deposition and inflammation have been shown to result in inadequate dialysis and lead to higher complication rates and increased mortality and can take many different forms including isolated clots, thrombosis in vessels adjacent to the catheter tip, or fibrin sheaths formed within the catheter lumen. The situation in pediatric dialysis is even more woeful because pediatric catheters are a smaller caliber with lower blood flow rates making them particularly prone to thrombosis and catheter complications. The goal of the proposed SBIR effort is to develop and evaluate a novel non-thrombogenic and non-fouling surface for pediatric hemodialysis catheters to reduce thrombosis and inflammation complications. The proposed surface will prevent protein and cellular adsorption on the surface which will minimize the activation of inflammatory and thrombogenic cascades.
Project Terms: Active Sites; Adherence; adjudicate; Adsorption; Animals; antithrombin III-protease complex; Binding; Biological; Blood; Blood Circulation; Blood flow; blood perfusion; Blood Platelets; Blood specimen; Caliber; Caring; Catheters; Cells; Cephalic; Child; Childhood; Chronic; Citrates; Coagulation Process; Complement; Complement 3a; Complement 5a; complement system; Complication; Computer software; Confocal Microscopy; Coupling; Deposition; Development; Devices; Dialysis patients; Dialysis procedure; Distal; Elements; Ensure; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; Excision; Family suidae; Fibrin; Fibrinogen; Flow Cytometry; Foreign Bodies; Free Radicals; functional group; Funding Opportunities; Geometry; Glycocalyx; Goals; Health; Hemodialysis; Heparin; Human; Hydrogels; Image Analysis; Immobilization; Immune response; Immune system; Implant; In Vitro; in vivo; Inflammation; Inflammatory; instrument; Lead; Leukocytes; Lymphocyte; male; manufacturing process; Measurement; meetings; Microbial Biofilms; Mitogens; Modeling; Modification; Monitor; monocyte; mortality; Neonatal; neutrophil; Newborn Infant; novel; paraform; Patients; Perfusion; Phase; Plasma; Platelet Activation; polycarbonate; polymerization; Polyurethanes; Positioning Attribute; prevent; Process; Proteins; Rattus; Reaction; response; Sampling; Scanning Electron Microscopy; Small Business Innovation Research Grant; Specific qualifier value; Staining method; Stains; Superior vena cava structure; Surface; Technology; Testing; Thrombin; Thromboplastin; Thrombosis; Tissues; vapor; Vena caval structure
