Microfluidic Technology for Concurrent Assessment of Red Blood Cell Adhesion and Deformability

项目总结 变形性和非粘附性是红细胞(RBC)最固有的生物流变学特性，如 它们在通过微血管系统调节红细胞灌流方面起着关键作用。在后天或遗传的血液中 疾病，如镰状细胞病(SCD)，这两个相互关联的特性会在病理上发生变化。SCD是 一种常染色体隐性遗传病，在其受影响的人群中有相当大的发病率和死亡率。 在SCD中，红细胞经历了激进的形态和结构变化，导致变形性降低。 以及粘附性增加，进一步引发血管并发症和一些并存疾病 包括痛苦的危机、中风、急性胸部综合征和器官衰竭。闭塞芯片是一种新的标准化产品 体外微流控检测在广泛的临床条件下检测红细胞介导的微血管闭塞。 独特的设计体现了毛细管床的两个关键特征：微毛细管网络的梯度和侧边 模拟动静脉吻合的通道。闭合指数，通过闭塞芯片测试来测量， 可作为评价改善红细胞治疗临床疗效的新标准参数 粘附性和变形性，如血红蛋白修饰药物、抗镰刀剂和新兴基因 治疗。STTR第一阶段/第二阶段快速通道项目的目标是将小说翻译和商业化 结论芯片微流控技术是一种标准化、有效的SCD辅助诊断方法。 在第一阶段，我们建议与第三方制造商简化制造流程，并建立 质量控制策略。 在第二阶段，我们建议承包制造大量设备(1000台)，建立分析验证 以及与SCD的常规、靶向或根治疗法相关的临床验证。 我们的目标是建立闭塞芯片的可制造性、分析验证和临床实用 提供红细胞生物流变学特性的全面功能表征和评估 SCD患者对新出现的靶向和根治疗法的具体反应。

PROJECT SUMMARY Deformability and non-adherence are the most intrinsic biorheological properties of red blood cells (RBCs), as they play a critical role in modulating RBC perfusion through the microvasculature. In acquired or inherited blood disorders, such as sickle cell disease (SCD), these two interrelated properties are pathologically altered. SCD is an autosomal recessive disorder associated with considerable morbidity and mortality in its afflicted populations. In SCD, RBCs undergo radical morphological and structural transformations leading to decreased deformability and increased adhesiveness, which further trigger vascular complications and a number of co-morbidities including painful crises, stroke, acute chest syndrome, and organ failure. OcclusionChip is a novel standardized in vitro microfluidic assay to measure microvascular occlusion mediated by RBCs in a wide range of clinical conditions. The unique design embodies the two key features of the capillary bed: a gradient of microcapillary networks and side passageways mimicking the arteriovenous anastomoses. Occlusion Index, measured by the OcclusionChip assay, may serve as a new standard parameter to evaluate the clinical efficacy of treatments improving red blood cell adhesion and deformability, such as hemoglobin modifying drugs, anti-sickling agents, and emerging genetic therapies. The objective of this STTR Phase I/II Fast-Track project is to translate and commercialize novel OcclusionChip microfluidic technology as a standardized and validated companion diagnostic assay for SCD. In Phase I, we propose to streamline the manufacturing process with a third-party manufacturer and establish quality control strategy. In Phase II, we propose to contract manufacture a large number of devices (1000), establish analytical validation and clinical validation relative to conventional, targeted, or curative therapies in SCD. Our goal is to establish the manufacturability, analytical validation, and clinical utility of the OcclusionChip in providing comprehensive functional characterization of red cell biorheological properties and assessment of patient-specific response to emerging targeted and curative therapies in SCD.