Upstream priming of platelets for adhesion to biomaterials

 描述：拟议研究的目标是调查上游血小板激动剂相互作用如何影响下游血小板与接触血液的生物材料的相互作用。过去在生物材料表面相容性方面的研究几乎都集中在生物材料的局部表面性质上。虽然这些观察对于预测物质在流通中的行为是必不可少的，但它们并不能反映整个故事。例如，血管移植物的上游缝合创造了一种吻合(生物材料和天然血管之间的外科连接)，有可能使不同的激动剂瞬时暴露于循环中的血小板。我们的初步实验和数学模型表明，血小板-激动剂相互作用的这种上游“历史”显著影响吻合口下游的平台行为。没有一种与血液接触的生物材料是完全兼容的，这一事实加剧了上游引爆效应。这里假设，下游生物材料-血小板相互作用的大小受到上游血小板激动剂瞬时暴露的强烈影响，上游血小板激动剂可以为血小板的黏附和激活做好准备。因此，与没有激动剂的情况相比，暴露于激动剂的血小板更有可能附着在下游生物材料上并被其激活。目前尚不清楚这些启动效应在下游持续了多长时间，需要多长时间才能使“启动”的血小板再次静止，以及这种现象是通过什么机制发生的。从生物材料的角度来看，这个问题转化为确定上游“引爆”程度的可接受容忍度。换句话说，即使是几乎没有激活血小板倾向的生物材料，也可能仅仅因为上游对血小板的“启动”而这样做。拟议的上游血小板激动剂效应研究有望在生物材料衍生的血小板聚集和血栓生长领域产生一种新的范式；一种不完全依赖于局部生物材料表面属性的范式，但包括上游吻合和扰动血流。在拟议的研究中，实验和建模的结合将为不同上游激动剂的作用提供新的见解，从而有可能建立预测参数，这些参数可用于改进血液接触设备的设计，如导管、移植物和其他血管植入物。

 DESCRIPTION: The goals of the proposed research are to investigate how upstream platelet-agonist interactions affect the downstream platelet interactions with blood-contacting biomaterials. Almost all past research efforts in the field of biomaterial hem compatibility have focused on the local biomaterial surface properties. While these observations are essential for predicting a material's behavior in circulation, they do not reflect the whole story. For example, upstream suturing of a vascular graft creates an anastomosis (a surgical connection between biomaterial and native blood vessel) that has the potential to transiently expose different agonists to circulating platelets. Our preliminary experiments and mathematical modeling suggest that this upstream "history" of platelet-agonist interaction significantly influences plateet behavior downstream of an anastomotic site. The upstream priming effects are compounded by the fact that no blood-contacting biomaterials are perfectly hem compatible. It is hypothesized here that the magnitude of the downstream biomaterial-platelet interactions is strongly influenced by the transient platelet exposure to upstream platelet agonists that can "prime" platelets for adhesion and activation. Platelets exposed to agonists are thus more likely to adhere to and become activated by a downstream biomaterial than in the absence of such agonists. It is not known how far downstream these priming effects persist, how much time is required for the "primed" platelets to become quiescent again, and by which mechanism this phenomenon takes place. From a biomaterials point of view, this problem translates into determining the acceptable tolerance for the extent of upstream "priming". In other words, even biomaterials that have very little tendency to activate platelets may do so simply because of the upstream "priming" of platelets. The proposed study of upstream platelet-agonist effects is expected to result in a new paradigm in the field of biomaterial-derived platelet aggregation and thrombus growth; one that is not exclusively dependent on the local biomaterial surface properties but includes upstream anastomoses and perturbed blood flow. The combination of experiments and modeling in the proposed study will provide new insight into the roles of different upstream agonists and thus has the potential for establishing predictive parameters that could be used to improve the design of blood contacting devices such as catheters, grafts, and other vascular implants.