Vascular Drug Delivery - Supplement for Equipment

描述(由申请人提供)：血管内机械干预和局部血管药物输送(LVDD)影响血管愈合，但不同患者的情况不同。设备的设计，配方和部署影响，但不严格预测，临床反应。这其中隐含着两层含义。首先，修复生物学本身就是可变的，临床结果永远无法预测。第二，反应的可变性可以归类，但取决于更接近的生理因素，如果被识别，可以更好地定义程序成功和不良事件的预测。我们接受后一种观点，即维度和解剖参数可以在很大范围内和几乎不加区分地反映手术成功，而血管操作的生理后果是对性能的最强预测因素。在我们过去资助的工作的指导下，目前的提案检验了这样的假设，即诱导的流动模式和药物分布是血管干预生物反应的最近的驱动因素，并且可以更好地预测干预在动物身上和现在在人类身上的治疗结果。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来表征动物系统血管干预后的修复和血流中断，并建立了一个定量框架来预测LVDD的药代动力学和动力学。我们通过在更多受控动物模型、硅胶模型和人类临床数据中使用这些资源来扩展这项工作。三个具体目标将：(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，以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程序变量的预测作用，以及(3)调查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、工作的影响以及一个具有合作精神的跨学科调查小组的集合。OCT成像在原位量化生物效应，以相同的方式提供动物和人类支架-血管几何图形的高分辨率图像。内部计算机算法提取程序几何图形，创建生理血流中断和药物分布的3D计算模型。MALDI证实了药物在当地交付后的分配。动物实验使用定制的药物输送设备，以便在定义体内复杂的干预程序时进行精确控制。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试验台。在数据具有多层次、纵向和空间结构的情况下，统计学创新将准确地描述支架特性、血流和药物分布对生物学结果的影响。学到的经验教训可能会扩大我们对基础血管生物学、支架和其他组合装置、组织或病理条件下的局部药物输送的理解。

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.