Microfluidic Impedance Red Cell Assay (MIRCA) for Emerging Pharmacologic and Gene based Therapies for Sickle Cell Disease

微流控阻抗红细胞测定 (MIRCA) 用于镰状细胞病的新兴药理学和基因疗法

• 批准号: 10687427
• 负责人: Umut A. Gurkan
• 金额: $ 66.32万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687427
• 关键词: Abnormal Hemoglobins; Academia; Adhesives; Adoption; Affect; American; Basic Science; Biological Assay; Biological Markers; Biomedical Engineering; Biomimetics; Biophysics; Blood; Blood Banks; Blood Circulation; Blood Vessels; Blood specimen; Cell physiology; Cellular Assay; Clinic; Clinical; Clinical Trials; Collaborations; Development; Devices; Diabetes Mellitus; Disease; Endothelium; Engineering; Erythrocytes; Etiology; Event; Explosion; Feedback; Functional disorder; Gene therapy trial; Guidelines; Health; Hematological Disease; Hematologist; Hematology; Hereditary Disease; Hypoxia; Incentives; Individual; Inherited; Kidney Failure; Laboratories; Lesion; Malaria; Measurement; Measures; Methods; Microfluidic Microchips; Microfluidics; Modification; Monitor; Organ; Organ failure; Outcome; Pain; Pathologic; Pathology; Patient Care; Patient Monitoring; Patients; Pharmaceutical Preparations; Pharmacology; Physicians; Population; Property; Reporting; Reproducibility; Research Project Grants; Scientist; Selection for Treatments; Severity of illness; Sickle Cell Anemia; Surrogate Endpoint; Technology; Testing; Therapeutic; Training; Translating; Translations; Validation; Work; analytical tool; blood damage; design; diagnostic tool; electric impedance; experience; gene therapy; indexing; innovation; innovative technologies; instrumentation; microfluidic technology; mortality; novel; polymerization; portability; primary endpoint; prognostic value; tool; transfusion medicine; user-friendly; vaso-occlusive pain

PROJECT SUMMARY Acquired or inherited diseases can alter the red blood cell (RBC), causing severe clinical complications affecting the vasculature and organ health. Inherited red cell disorders, renal failure, diabetes, and blood bank storage lesions can all produce stiff, non-deformable RBCs. Red cell stiffness is particularly problematic in sickle cell disease (SCD), a debilitating inherited blood disorder. An estimated 100,000 individuals in the US, and millions more world-wide, have SCD. The field has experienced an explosion of novel SCD therapeutics, designed to target specific individual abnormalities in the RBC in the last five years. Numerous gene-based therapies intending to cure SCD are in clinical trials. This marked shift in SCD therapeutics produced a need for diagnostics and analytical tools that assess RBC health and quality. We need biomarkers of red cell function to serve as endpoints in clinical trials, assist in optimal drug selection and personalized monitoring for the individual, and to determine if gene-based therapy has normalized the red cell. Many aspects of the red cell must be assessed, but a key feature is deformability. There is a lack of robust, inexpensive devices sensitive enough to capture small populations of poorly deformable red cells able to continue to hemolyze, damage the blood vessels, and cause organ damage and early mortality. It is essential that we vet therapies for their ability to normalize the entire population of red cells. Here we propose to develop and translate the Microfluidic Impedance Red Cell Assay (MIRCA) to functionally measure red cell deformability, reported as Occlusion Index (OI) of a biomimetic microcapillary network array on a chip. We propose an innovative approach and a novel collaboration between engineers and a hematology-trained physician scientist. We will do so with the following steps: 1. We will achieve instrumentation and analytical validation of MIRCA measurement of red cell OI. Analytic validation will be performed both in PI’s laboratory (Dr. Umut Gurkan, CWRU) and in Co-I’s hematology laboratory (Dr. Vivien Sheehan, Emory) to prove generalizability and permit stakeholder feedback and design modification. 2. We will clinically validate MIRCA by assessing the association between OI and clinical complications and traditional laboratory measures of disease severity in SCD. 3. We will expand the use of the optimized MIRCA to the clinical space by demonstrating its prognostic value in longitudinal assessments of patients with SCD experiencing clinical complications and transitions in therapy. Using our unique collaboration between biomedical engineers and a hematology trained physician-scientist, we will optimize, validate, and achieve clinical adoption of MIRCA technology in clinical trials and patient care for individuals living with SCD in the US and world-wide.

项目摘要 获得或遗传的疾病会改变红细胞（RBC），导致严重的临床并发症 影响脉管系统和器官健康。遗传的红细胞疾病，肾衰竭，糖尿病和血库 存储病变都可以产生僵硬的，不可构造的RBC。红细胞僵硬在镰刀中尤其有问题 细胞疾病（SCD），一种使遗传性血液疾病衰弱的。估计在美国有100,000个人， 全球范围内的数百万，拥有SCD。该领域经历了新型SCD疗法的爆炸， 旨在针对过去五年中RBC中特定的个人异常。许多基于基因的 打算治愈SCD的疗法正在临床试验中。 SCD疗法的这种明显转变导致了需要 评估RBC健康和质量的诊断和分析工具。我们需要红细胞功能的生物标志物 作为临床试验的终点，协助对个人进行最佳药物选择和个性化监测， 并确定基于基因的治疗是否使红细胞归一化。红细胞的许多方面必须是 评估，但关键功能是可变形。缺乏足够敏感的健壮，廉价设备的敏感设备 捕获少量可变形不良的红细胞的种群可以继续溶解，损害血管， 并造成器官损害和早期死亡率。我们必须审查疗法以使其正常化的能力 整个红细胞种群。在这里，我们建议开发和翻译微流体阻抗红细胞 测定（MIRCA）以在功能上测量红细胞的可变形性，报道为仿生的闭塞指数（OI） 芯片上的微毛细管网络阵列。我们提出了一种创新的方法和一次新颖的合作 工程师和由血液学训练的身体科学家。我们将采用以下步骤进行： 1。我们将实现红细胞OI MIRCA测量的仪器和分析验证。分析 验证将在PI的实验室（Umut Gurkan博士，CWRU）和Co-I的血液学中进行。 实验室（Emory Vivien Sheehan博士），以证明并允许利益相关者的反馈和设计 修改。 2。我们将通过评估OI与临床并发症和临床并发症的关联以及 SCD中疾病严重程度的传统实验室措施。 3。我们将通过证明其预后价值将优化的MIRCA扩展到临床空间 在对患有SCD患者的纵向评估中，经历了临床并发症和过渡 治疗。 利用我们在生物医学工程师和血液学训练的物理科学家之间的独特合作， 我们将在临床试验和患者护理中优化，验证和实现MIRCA技术的临床采用 对于在美国和全球与SCD一起生活的个人。