Development of bioactive surface for pediatric hemodialysis catheters to prevent thrombogenic, inflammatory and biofilm complications

开发用于儿科血液透析导管的生物活性表面，以预防血栓形成、炎症和生物膜并发症

• 批准号: 9134990
• 负责人: Ali Hussain
• 金额: $ 29.98万
• 依托单位: ENSION, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134990
• 关键词: Active Sites; Adherence; Adsorption; Animals; Binding; Biological; Blood; Blood Circulation; Blood Flow Cytometry; Blood Platelets; Blood flow; Blood specimen; Caliber; Caring; Catheters; Cells; Cephalic; Child; Childhood; Chronic; Citrates; Coagulation Process; Complement; Complement 3a; Complement 5a; 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; Funding Opportunities; Geometry; Glycocalyx; Goals; Hemodialysis; Heparin; Human; Hydrogels; Image Analysis; Immobilization; Immune response; Immune system; Implant; In Vitro; Individual; Inflammation; Inflammatory; Lead; Leukocytes; Lymphocyte; Measurement; Microbial Biofilms; Mitogens; Modeling; Modification; Molecular Conformation; Monitor; Neonatal; Newborn Infant; Patients; Perfusion; Phase; Plasma Enhancement; Platelet Activation; Polyurethanes; Positioning Attribute; Process; Proteins; Rattus; Reaction; 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; Vena caval structure; adjudicate; antithrombin III-protease complex; blood perfusion; complement system; functional group; in vivo; instrument; male; meetings; monocyte; mortality; neutrophil; novel; paraform; polycarbonate; polymerization; prevent; public health relevance; response; vapor

 DESCRIPTION (provided by applicant): 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.

 描述（通过施用）：最常见的血液透析导管并发症是Thombosis，生物膜和炎症是导致透析不足，并导致较高的并发症发生率和增加死亡率，并且可以采取不同的形式与导管尖端相邻，因为是arem和导管平板，当插入诸如导管之类的异物插入循环吸附时，启动了人体固有的非eign材料的基本机制。在表面上（组织因子和汇编C3A/C5A）具有导管表面 缓解异物的反应和生产和thombosis。表面M.多碳酸盐/聚氨酯导管表面清洁（特定的AIM1），可为随后的修饰提供符合的E。活化的表面。 进行评估，并符合血液灌注研究3）。 ：（1）导管（SEM）的组织化学分析（SEM）。