Platelet Production in a Pulmonary-based Microfluidic Reactor

摘要 血小板输注用于治疗血小板数量和/或功能的缺陷，这在多种疾病中可见。 临床环境，如癌症和创伤后。鉴于人口结构的变化和对 血小板输注在现代医学中，其很可能是供者来源的血小板提供这种护理可能证明 在不久的将来，不足。在体外产生大量生理上有活力的血小板， 旨在为这类血小板缺陷患者提供一种新的治疗选择。从巨型开始- 在有核细胞（Megs）中，血小板释放（血小板生成）由通常在有核细胞（Megs）中发现的剪切力驱动。 血管以前的方法旨在模拟骨髓中血小板的产生， 从髓腔进入血液，但新的研究指出， 植入肺部的细胞该提案旨在利用这一发现， 提高我们对血小板生成的理解和体外产生血小板的能力， 模仿肺微血管的特殊性质。 本申请有四个目的：目的1：生产和测试重现肺动脉的器械 血管床将生产几种不同的产品来捕获Megs并允许发生血小板生成。目的 2：设计并测试在肺模拟机械应变下生产血小板的系统。我们将使用 柔性微流体层将B。目标3：设计和测试用于O2浓度的时间控制的系统 在反应堆内。将实现从低到高O2部分的切换，以复制生理变化 在肺部。目的4：优化肺模型参数的组合效应，检测血小板功能 性能使用所确定的所有最佳参数的最终微流体装置将通过以下测试： 输注Megs和测量产生血小板样颗粒的功效， 功能上与新鲜抽取的供体来源的血小板相匹配。 第一阶段研究的目的是验证与现有控制器兼容的耗材， 广泛研究血小板生产肺微环境，通过控制毛细血管，剪切力，变形， 毛细管床和气体浓度。如果成功的话，将扩大到临床上可行的血小板生产反应器 将在第二阶段进行验证。这项工作代表了一家生物工程公司之间的合作， 一直提供微流体研究系统的血小板功能的研究和实验室，是域 治疗血小板疾病的专家。

ABSTRACT Platelet transfusions are used to treat deficiencies in platelet number and/or function that is seen in multiple clinical settings such as cancer and post trauma. Given changing demographics and an increasing reliance on platelet transfusion in modern medicine, its is likely that donor-derived platelets to provide this care may prove inadequate in the near future. The generation of large numbers of physiologically viable platelets in-vitro is intended to provide a new treatment option for such patients with platelet deficies. Starting with mega- karyocytes (Megs), platelet release (thrombopoiesis) is driven by shear forces typically found in the vasculatures. Previous approaches were aimed at mimicking platelet production in the bone marrow as Megs emerge from the intramedullary space into the blood stream, but new research points to significant platelet production by Megs embedded in the lung. This proposal is aimed at taking advantage of this discovery to improve both our understanding of thrombopoiesis and our ability to produce platelets in vitro focused on mimicking the particular properties of the pulmonary microvasculature. There are four aims in this application: Aim 1: Produce and test devices recapitulating the pulmonary vascular bed. Several different will be manufactured to entrap Megs and allow thrombopoiesis to occur. Aim 2: Design and test a system for platelet production under lung-mimetic mechanical strain. We will use flexible microfluidic layers will b. Aim 3: Design and test a system for temporal control of O2 concentration within the reactor. Switching from a low to high O2 partial will be achieved to replicated physiological changes in the lung. Aim 4: Optimize the combined effects of lung model parameters and test platelet functional performance. The final microfluidic devices using all of the optimal parameter determined will be tested by infusions of Megs and measurement of the efficacy to produce platelet-like particles that physically and functionally match that of freshly-drawn donor-derived platelets. Phase I research is intended to validate a consumable compatible with existing controllers that can we used widely to study platelet production lung microenvironment by controlling cappillary, shear forces, defomation of capillary bed and gas concentration. If successful, a scale-up to a clinically feasible platelet production reactor will be attepted in Phase II. This work represents a collaboration between a bioengineering company that has been supplying microfluidic research systems for the study of platelet function and a laboratory that are domain experts in the treatment of platelet disorders.