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

项目摘要 变形性和非粘附性是红细胞（RBC）最固有的生物流变学特性， 它们在调节通过微脉管系统的RBC灌注中起关键作用。在获得或遗传的血液中 在疾病如镰状细胞病（SCD）中，这两种相互关联的性质在病理上改变。SCD是 一种常染色体隐性遗传疾病，在患病人群中与相当高的发病率和死亡率相关。 在SCD中，红细胞经历根本的形态和结构转变，导致变形能力降低 以及增加的血管收缩，这进一步引发血管并发症和一些合并症 包括疼痛危象、中风、急性胸部综合征和器官衰竭。OcclusionChip是一种新的标准化 体外微流控测定以测量在广泛临床条件下由RBC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 模拟动静脉动脉瘤的通道闭塞指数，通过闭塞芯片测定法测量， 可作为一个新的标准参数，以评估治疗改善红细胞的临床疗效， 粘附和变形能力，如血红蛋白修饰药物，抗镰状化剂，和新兴的遗传 治疗这个STTR第一/第二阶段快速通道项目的目标是翻译和商业化的小说 OcclusionChip微流控技术作为SCD的标准化和经验证的伴随诊断检测。 在第一阶段，我们建议与第三方制造商简化制造过程， 质量控制策略 在第二阶段，我们建议合同生产大量器械（1000件），建立分析验证 以及相对于SCD的常规、靶向或治愈性疗法的临床验证。 我们的目标是确定OcclusionChip的可制造性、分析验证和临床实用性， 提供红细胞生物流变特性的综合功能表征， SCD患者对新兴靶向治疗和治愈性治疗的特异性反应。

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.