Biomedical Polymers With Heparin-Binding End Groups

描述（由申请人提供）：肝素在聚合物生物材料表面的终点固定是一种完善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程序，可能会降低基础聚合物的机械性能。这使得它们对于低成本装置如IV导管和假体植入物都是不切实际的，其中物理机械性能的保持对于确保安全性和有效性是至关重要的，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，该材料具有内置的共价键合端基，该端基具有肝素结合位点。优化了一种新的二胺-二酰胺-醇（PIME-SME）合成工艺，以提高产率和降低成本。然后将使用单官能PIME-SME在一系列本体浓度下合成Bionate（r）（一种生物稳定的聚碳酸酯-氨基甲酸酯）的几个样品。这种新的表面改性端基的使用将避免与先前用于结合肝素的聚合物主链的改性相关的机械性能的降低。将通过简单地将由申报聚合物制成的器械或组件浸泡在稀释的肝素溶液中进行肝素化。将使用高表面特异性和频振动光谱法确保暴露于肝素前聚合物表面肝素结合基团的最大浓度，并测量肝素结合后所得的表面肝素浓度。吸附肝素的活性将首先通过显色抗Xa肝素试验测定。还将使用测量结合肝素化表面的抗凝血酶III（ATIII）量的生物测定法来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的最佳本体浓度，以在改性聚合物表面上提供最大肝素结合。在第II阶段，将在广泛的体内和体外试验后，在我们现有的连续反应器上进行规模扩大生产。在第三阶段，聚合物技术集团将提供聚氨酯和具有肝素结合能力的器械组件，作为其现有生物材料目录的一部分进行销售或许可。

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.