Biomedical Polymers With Heparin-Binding End Groups

具有肝素结合端基的生物医学聚合物

• 批准号: 6833758
• 负责人: ROBERT S WARD
• 金额: $ 10万
• 依托单位: POLYMER TECHNOLOGY GROUP, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833758
• 关键词: aminoalcohol; anticoagulants; antithrombin III; antithrombogenic surface; bioengineering /biomedical engineering; biomaterial evaluation; diamines; heparin; platelet aggregation inhibitors; polyurethanes

DESCRIPTION (provided by applicant): Endpoint immobilization of heparin on the surface of polymeric biomaterials is a well-established method for improving thrombo-resistance. The most effective currently-available heparinization methods are costly, multi-step procedures that may degrade the mechanical properties of the base polymer. This makes them impractical for both low-cost devices like IV catheters and for prosthetic implants in which retention of physical-mechanical properties is vital for assuring safety and efficacy, e.g., circulatory support devices and vascular grafts. The proposed study will determine the feasibility of synthesizing tough, thermoplastic polyurethane biomaterials with built-in covalently bonded end groups with binding sites for heparin. A novel diamine-diamide-alcohol (PIME-SME) synthesis procedure will be optimized for high yield and low cost. Several samples of Bionate (r), a biostable polycarbonate-urethane, will then be synthesized using the mono-functional PIME-SME in a range of bulk concentrations. The use of this new surface modifying end group will avoid the reduction of mechanical properties associated with modifications to the polymer backbone previously used for binding heparin. Heparinization will be performed by simply soaking the device or component made from the subject polymer in dilute heparin solution. Highly surface specific Sum Frequency Generation Vibrational Spectroscopy will be used to assure maximum concentration of heparin binding groups at the surface of the polymer before exposure to heparin, and to measure the resulting surface heparin concentration following heparin binding. The activity of the adsorbed heparin will first be determined by a chromogenic anti-Xa heparin assay. A biological assay that measures the amount of antithrombin III (ATIII) that binds to the heparinized surface will also be used to determine if the adsorbed heparin maintains a conformation that binds ATIII. From the analytical characterization and the biological assays, the optimal bulk concentration of PIME-SME will be determined to provide maximum heparin binding on the surface of the modified polymers. During Phase II, scale up to manufacturing on our existing continuous reactor will be performed following extensive in vivo and in vitro testing. In Phase III The Polymer Technology Group will offer polyurethanes and device components with heparin binding capacity for sales or license, as part of its existing catalog of biomaterials.

描述（由申请人提供）：将肝素端点固定在聚合生物材料的表面上是一种行之有效的改善抗血栓性的方法。目前最有效的肝素化方法是昂贵的、多步骤的过程，可能会降低基础聚合物的机械性能。这使得它们对于静脉导管等低成本装置和假体植入物来说都是不切实际的，在假体植入物中，保留物理机械特性对于确保安全性和有效性至关重要，例如循环支持装置和血管移植物。拟议的研究将确定合成坚韧的热塑性聚氨酯生物材料的可行性，该生物材料具有内置的共价键合端基和肝素结合位点。新型二胺-二酰胺-醇（PIME-SME）合成工艺将进行优化，以实现高产率和低成本。然后，将使用单功能 PIME-SME 在一系列批量浓度下合成 Bionate (r)（一种生物稳定的聚碳酸酯聚氨酯）的几个样品。这种新的表面修饰端基的使用将避免与先前用于结合肝素的聚合物主链的修饰相关的机械性能的降低。通过简单地将由主题聚合物制成的装置或组件浸泡在稀肝素溶液中来进行肝素化。高表面比和频率产生振动光谱将用于确保在暴露于肝素之前聚合物表面上肝素结合基团的最大浓度，并测量肝素结合后所得的表面肝素浓度。首先通过显色抗 Xa 肝素测定来测定吸附的肝素的活性。测量与肝素化表面结合的抗凝血酶 III (ATIII) 量的生物测定也将用于确定吸附的肝素是否保持结合 ATIII 的构象。根据分析表征和生物测定，将确定 PIME-SME 的最佳体积浓度，以在改性聚合物表面提供最大程度的肝素结合。在第二阶段，在进行广泛的体内和体外测试后，将在我们现有的连续反应器上进行扩大生产。在第三阶段，聚合物技术集团将提供具有肝素结合能力的聚氨酯和设备组件进行销售或许可，作为其现有生物材料目录的一部分。