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Analysis and control of leukocyte motility on prosthetic vascular biomaterials.

机译：人工血管生物材料上白细胞运动的分析和控制。

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A recurrent problem with implantable vascular biomaterials is periprosthetic bacterial infection, which is hypothesized to arise due to impaired functions of leukocyte cells. Polymorphonuclear leukocytes (PMN) are integral to host defense against bacterial infections. Leukocyte contact with prosthetic biomaterial surfaces can activate these cells even in the absence of microbes. The biomaterial-induced PMN activation leads to an incomplete or “frustrated” phagocytosis, indicated by abnormal cell adherence on biomaterials. It is commonly believed that these processes may underlie the depletion of the bactericidal activity of PMN during contact with bacteria. Thus, this dissertation focuses on the analysis of behavior of adherent PMN on the biomaterial surfaces, primarily through the quantitation of PMN spreading, migration, and phagocytic potential.; On a phenomenological level, we quantified human PMN spreading and migration behavior on surfaces of expanded polytetrafluoroethlylene (ePTFE), a commonly used vascular prosthetic material. The morphology of chemoattractant-stimulated PMN was quantified following adhesion to the biomaterial using optical sectioning confocal fluorescence microscopy, yielding insights into changes in two-dimensional spreading and polarity as well as the three-dimensional spreading of human PMN adhered to ePTFE pretreated with different plasma proteins. A separate component of the thesis concerned the in situ analysis of chemoattractant stimulated, population level PMN migration on protein-treated ePTFE. This approach involved tracking the rate of random (chemokinetic) and directed migration of PMN sandwiched between an agar-gelatin composite and ePTFE. Overall, we have documented that both PMN spreading and migration responses on ePTFE are strongly determined by the nature of protein treatment, as well as chemoattractant dynamics. Based on our experimental data and a simple theory, we offer semi-quantitative comparisons of the individual roles of the PMN spreading, motility, and biomaterial-induced inactivation processes on the functional capacity of PMN.; On a mechanistic level, this thesis explored the molecular basis for PMN migration on ePTFE under two physiologic conditions: first, following the adsorption of blood plasma, and second, in the presence of active hemodynamic flow. Under static, chemoattractant activated conditions, we demonstrate that PMN migratory behavior on ePTFE is strongly mediated by the integrin β chain pool of PMN receptors, and only weakly regulated by the integrin α chain. In addition, we report the presence of fluid shear activated PMN migration on ePTFE even in the absence of any chemokinetic stimuli, and that this activation was differentially passivated by plasma proteins. Further, we identified a PMN membrane leukosialin molecule that may mediate flow-induced motility, highlighting a possible molecular approach to “engineer” leukocyte motility within a physiologic hemodynamic environment.
机译：植入性血管生物材料的复发性问题是假体周围细菌感染，据推测是由于白细胞功能受损而引起的。多形核白细胞（PMN）是抵抗细菌感染的宿主防御必不可少的。白细胞与人工生物材料表面的接触即使在没有微生物的情况下也可以激活这些细胞。生物材料诱导的PMN活化导致吞噬作用不完全或“受挫”，这是由于生物材料上异常的细胞粘附所致。通常认为，这些过程可能是与细菌接触期间PMN杀菌活性下降的基础。因此，本文主要通过定量分析PMN的扩散，迁移和吞噬潜力，着重分析粘附的PMN在生物材料表面的行为。在现象学层面上，我们量化了人类PMN在膨胀的聚四氟乙烯（ePTFE）（一种常用的人工血管材料）表面上的扩散和迁移行为。使用光学切片共聚焦荧光显微镜对化学吸附剂刺激的PMN的形态进行定量后，粘附到生物材料上，从而洞悉粘附在ePTFE上的人PMN的二维扩展和极性以及三维扩展的变化，并用不同血浆预处理蛋白质。论文的另一部分涉及在蛋白处理的ePTFE上原位分析化学引诱物刺激的，人群水平的PMN迁移。该方法涉及跟踪夹在琼脂-明胶复合材料和ePTFE之间的PMN的随机（化学代谢）速率和定向迁移。总的来说，我们已经证明，在ePTFE上PMN的扩散和迁移响应都由蛋白质处理的性质以及趋化动力学决定。基于我们的实验数据和简单的理论，我们提供了PMN扩散，运动和生物材料引起的失活过程对PMN功能能力的各个作用的半定量比较。在机理上，本文探讨了在两种生理条件下PMN在ePTFE上迁移的分子基础：首先是吸附血浆后，其次是在存在活跃的血液动力学流的情况下。在静态，化学引诱剂活化条件下，我们证明ePTFE上的PMN迁移行为受PMN受体的整联蛋白β链库强烈介导，而仅由整联蛋白α链弱调控。此外，我们报道了即使在没有任何化学动力学刺激的情况下，流体剪切活化的PMN在ePTFE上的迁移也存在，并且该活化被血浆蛋白差异钝化。此外，我们鉴定了可能介导血流诱导的运动性的PMN膜白细胞介素分子，强调了在生理性血液动力学环境中“工程化”白细胞运动性的可能分子方法。

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