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）：在高分子生物材料表面末端固定肝素是一种完善的改善血栓抵抗的方法。目前可用的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。这使得它们在低成本设备（如静脉导管）和假体植入物（如循环支持装置和血管移植）中都不实用，因为假体植入物的物理机械特性的保留对确保安全性和有效性至关重要。提出的研究将确定合成具有内置共价键末端基团与肝素结合位点的硬质热塑性聚氨酯生物材料的可行性。优化了一种新的二胺-二胺醇（PIME-SME）合成工艺，以提高收率和降低成本。Bionate (r)是一种生物稳定的聚碳酸酯-聚氨酯，随后将使用单功能PIME-SME在一定的体积浓度下合成几个样品。使用这种新的表面修饰端基将避免与先前用于结合肝素的聚合物主链修饰相关的机械性能降低。肝素化将通过简单地在稀肝素溶液中浸泡由主体聚合物制成的装置或组件来进行。高表面特异性和频率产生振动光谱将用于确保暴露于肝素之前聚合物表面肝素结合基团的最大浓度，并测量肝素结合后产生的表面肝素浓度。吸附的肝素的活性将首先由显色抗xa肝素测定测定。测定结合到肝素化表面的抗凝血酶III （ATIII）的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。通过分析表征和生物学试验，确定PIME-SME的最佳体积浓度，以使改性聚合物表面的肝素结合最大化。在第二阶段，将在广泛的体内和体外测试后，在我们现有的连续反应器上扩大生产规模。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，作为其现有生物材料目录的一部分进行销售或许可。