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（由申请人提供）：最常见的血液透析导管并发症是血栓形成、炎症和生物膜。血栓沉积和炎症已被证明会导致透析不充分，并导致并发症发生率较高和死亡率增加，并且可能采取许多不同的形式，包括孤立的凝块、导管头端附近血管中的血栓形成或导管腔内形成的纤维蛋白鞘。儿科透析的情况更加糟糕，因为儿科导管的口径更小，血液流速更低，特别容易发生血栓形成和导管并发症。引发导管相关并发症的基本机制是身体对接触异物的固有非特异性免疫反应。当异物（如导管）插入患者的循环时，立即的异物反应是循环蛋白质吸附到导管表面（包括凝血酶、组织因子和补体C3 a/C5 a）。吸附引导蛋白质的构象变化，暴露通常隐藏的表位，激活炎症细胞，如单核细胞和血小板，导致血栓形成。此外，透析患者的免疫系统受损，有丝分裂原的额外储存会诱导对外来表面的过度反应。因此，至关重要的是具有导管表面， 减轻异物反应并防止慢性炎症和血栓形成。本提案的目的是开发和评估受天然存在的内皮糖萼启发的新型表面的功效。申报的生物活性表面将最大限度地减少最常用的儿科血液透析导管（Split CathTM，MedComp）的血栓形成和炎症可能性，从而预防慢性炎症并最大限度地减少血栓形成。表面改性（特定目标1）包括四个步骤：1）清洁聚碳酸酯/聚氨酯导管表面，为后续改性提供一致、稳定的表面。2)通过等离子体增强气相沉积活化以产生水凝胶可以接枝的活性位点。 3)通过自由基聚合将水凝胶接枝到活化的表面。4)生物活性肝素的偶联。 每一步都将 进行单独评价，在满足验收标准之前，不会尝试后续步骤。血液灌注研究（特定目标2）将用于评价符合特定目标1验收标准的表面。将评价受试表面的蛋白质/细胞粘附和循环血液中的细胞活化。将在30天大鼠模型（特定目标3）中评价符合特定目标2中规定的体外验收标准的表面。将使用放置在上级腔静脉中的~1 cm节段导管（表面处理或对照）评价9件对照导管和9件表面处理导管。将通过以下方式评估植入导管表面的有效性：（1）导管周围组织的免疫组织化学分析。(2)导管上细胞层/生物膜的扫描电子显微镜（SEM）（3）血液样本的流式细胞术，以定量白色细胞和血小板活化和血栓形成。