Vascular Drug Delivery

描述（由申请方提供）：血管内机械介入和局部血管给药（LVDD）影响血管愈合，但不同患者的影响不同。器械设计、配方和展开影响但不能严格预测临床反应。由此产生了两个影响。首先，修复生物学本质上是可变的，临床结果永远无法预测。第二个是反应变异性可以分类，但取决于更接近的生理力，如果识别，可以更好地定义手术成功和预测不良事件。我们接受后一种观点，即尺寸和解剖参数可以说明手术成功，但仅在很大范围内，并且几乎没有区别，并且血管操作的生理后果是性能的最强预测因素。在我们过去资助的工作的指导下，目前的提案研究了这样一种假设，即诱导的流动和药物分布模式是血管干预的生物反应的直接驱动因素，并且可以更好地预测动物干预的治疗后果，现在也可以预测人类干预的治疗后果。 在过去的周期中，我们创建了分析，免疫组织化学和成像技术，以表征动物系统血管介入后的修复和血流中断，以及预测LVDD药效动力学和动力学的定量框架。我们通过在更受控的动物模型、计算机模型和人类临床数据中使用这些资源来扩展这项工作。三个具体目标是：（1）定义复杂干预的传统描述符的限制，无论多么精确，（2）开发和验证计算模型，其预测复杂动物模型中真实世界环境中的近壁流动模式和药物分布，并提供统计工具以确定这些力相对于单独的程序变量的预测作用，以及（3）研究所确定的变量是否预测人类的临床结果。 创新存在于我们使用的工具，我们分析的数据，我们采取的方法，工作的影响以及具有合作传统的跨学科研究小组的组装。OCT成像可量化原位生物效应，以相同的方式提供动物和人体支架-血管几何结构的高分辨率图像。内部计算机算法提取程序几何形状，创建生理流动中断和药物分布的3D计算模型。MALDI证实了局部给药后的药物分布。动物实验使用定制的药物输送装置，以允许精确控制体内复杂的介入手术。访问大学医院广泛的OCT临床图像数据库为临床验证提供了丰富的测试平台。统计学创新将在数据具有多层次、纵向和空间结构的环境中准确描述支架特征、流量和药物分布对生物学结局的影响。这些经验教训可能会扩展我们对基础血管生物学、支架和其他组合器械中的局部药物输送、组织或病理条件的理解。

DESCRIPTION (provided by applicant): Endovascular mechanical interventions and local vascular drug delivery (LVDD) affect vascular healing but differently across patients. Device design, formulation and deployment influence but do not strictly predict, clinical response. Two implications emerge. The first is that repair biology is inherently variable and clinical outcomes can never be predicted. The second is that response variability can be categorized but depends on more proximate physiological forces, which, if identified, can allow better definition of procedural success and prediction of adverse events. We embrace the latter view, that dimensional and anatomic parameters can speak to procedural success but only over a wide range and with little discrimination, and it is physiologic consequences of vascular manipulation that are the strongest predictors of performance. Guided by our past funded work, the current proposal examines the hypothesis that induced patterns of flow and drug distribution are the proximate drivers of biological response to vascular interventions, and can better predict the therapeutic consequences of interventions in animals and now in humans as well. In past cycles we created analytical, immunohistochemical and imaging technologies to characterize repair and flow disruptions after vascular intervention in animal systems, and a quantitative framework to predict pharmaco-kinetics and -dynamics of LVDD. We extend this work by using these resources in more controlled animal models, in silico models and with human clinical data. Three specific aims will: (1) define the limits of traditional descriptors of complex interventions no matter how precise, (2) develop and validate computational models that predict near-wall flow patterns and drug distributions in real-world settings in complex animal models and provide statistical tools to determine predictive roles of these forces relative to procedural variables alone, and (3) investigate whether the variables determined predict clinical outcomes in humans. Innovation exists in the tools we employ, data we analyze, approach we take, implications of the work and assembly of a pandisciplinary group of investigators with a legacy of collaboration. OCT imaging quantifies biologic effect in situ, providing high-resolution images of stent-vessel geometry in animals and humans in an identical manner. In-house computer algorithms extract procedural geometries, which create 3D computational models of physiological flow disruption and drug distribution. MALDI corroborates drug distribution after local delivery. Animal experiments use custom-made drug delivery devices to allow precise control in defining complex interventional procedures in vivo. Access to the University Hospital's extensive OCT databank of clinical images offers a rich test bed for clinical validation. Statisticl innovation will accurately describe the effects of stent characteristics, flow, and drug distributin on biological outcomes in a setting where the data have multilevel, longitudinal, and spatial structure. The lessons learned may extend our understanding of basic vascular biology, local drug delivery in stents and other combination devices, tissues, or pathologic conditions.