Biomarker methods and instrumentation to predict post-tPA hemorrhage in stroke

预测中风 tPA 后出血的生物标志物方法和仪器

• 批准号: 7407242
• 负责人: Daniel James Laser
• 金额: $ 36.76万
• 依托单位: WAVE 80 BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407242
• 关键词: AIDS/HIV problem; ATP8A2 gene; Acute; American Heart Association; Antigens; Area; Autoimmune Diseases; Beds; Bedside Testings; Binding; Biological Markers; Blood; Blood Clot; Blood Vessels; Blood capillaries; Blood coagulation; Blood specimen; Body Fluids; Caring; Cerebral hemisphere hemorrhage; Class; Clinic; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Coagulation Process; Complex; Condition; Data; Detection; Development; Device or Instrument Development; Devices; Diagnosis; Diagnostic; Disease Management; Disruption; Early identification; Engineering; Enrollment; Environment; Enzyme-Linked Immunosorbent Assay; Evaluation; Feasibility Studies; Fellowship; Fibronectins; Floor; Funding; Gelatinase B; Health; Hemorrhage; Hour; Human; Human Resources; Human body; Immunoassay; Intravenous; Ischemic Stroke; Label; Laboratories; Lasers; Malaria; Malignant Neoplasms; Measurable; Measurement; Mechanics; Methods; Modeling; Neurologist; Neurology; Nurses; Patients; Pennsylvania; Performance; Pharmaceutical Preparations; Phase; Plasma; Principal Investigator; Procedures; Process; Production; Range; Reagent; Reproducibility; Research; Research Infrastructure; Research Personnel; Research Project Grants; Research Subjects; Sampling; Schedule; Services; Standards of Weights and Measures; Stroke; System; Technology; Testing; Therapeutic; Time; Training; Treatment outcome; Universities; Validation; Variant; Week; acute stroke; analytical method; base; capillary; cohort; cost; day; experience; innovation; instrument; instrumentation; internal control; member; point of care; pre-clinical; progenitor; prospective; prototype; research and development; research clinical testing; research study; satisfaction; stroke therapy; success; tool

DESCRIPTION (provided by applicant): Acute ischemic stroke diagnosis is an area of high unmet need, with a complex and time-consuming evaluation process prior to administration of tPA and 5-10% of patients who receive intravenous tPA developing significant intracranial bleeding. Circulating biomarkers appear increasingly promising for guiding tPA administration. The well-established connection between time-to-treatment and outcome, however, dictates that any candidate biomarkers used to guide therapy must be measurable in a matter of minutes. This research project will make significant strides toward biomarker-informed prediction of post-tPA intracerebral hemorrhage in ischemic stroke. The research focuses on cellular fibronectin (cFN) and matrix metalloproteinase-9 (MMP-9). Indicators of disruption of vascular integrity, cFN and MMP-9 have been shown in small studies to have significant value for predicting post-tPA intracerebral hemorrhage. ELISA methods for cFN and MMP-9 are well established, but automated point-of-care instrumentation is not currently available. Phase I of this project entails developing a new point-of-care instrument for quantifying cFN and MMP-9 in fingerstick blood samples from acute ischemic stroke patients and validating this instrument both in bench- level experiments and in the clinic. The development process will leverage recent progress in point-of-care instrumentation, including flow- chamber microarrays for multiplexed analyte quantitation with internal controls and cartridge-integrated slit capillary array electroosmotic micropumps for fully active, bidirectional intracartridge sample/reagent transport with a static handheld-cartridge mechanical interface for high reliability. Through an innovative development process, fully functional prototype instruments are scheduled to be ready for clinical evaluation in only nine months. With ELISA-like quantitation performance and time-to-result of less than ten minutes, these instruments will be valuable tools for exhaustively studying cFN and MMP-9 as predictors of intracerebral hemorrhage. Accordingly, a multicenter clinical trial on cFN and MMP-9 making use of the newly developed devices is anticipated for Phase II of the project. This project is pioneering not only in the specific advancement of methods and instrumentation for cFN and MMP-9 quantitation with application to intracerebral hemorrhage, but also by advancing a broad new paradigm for clinical biomarker studies. The analytical methods and instruments developed here are intended to be progenitors of a class of point-of-care devices which can be produced quickly and at low cost to support clinicians' efforts to evaluate new biomarker candidates. The central hypothesis of this project is that integrated, modular point-of-care test devices can be rapidly developed and used to overcome research barriers to biomarker development in time-critical or infrastructure poor settings such as acute stroke. To be most effective, drugs to treat strokes caused by blood clots need to be administered quickly. But because some patients can be harmed, administering clot-busting drugs is not straightforward. This project explores new ways of predicting which patients might be harmed and which are most likely to benefit from stroke therapy, based on the levels of certain markers found in the blood.

描述（由申请人提供）：急性缺血性卒中诊断是一个高度未满足需求的领域，在给予tPA之前进行复杂且耗时的评估过程，5-10%接受静脉tPA治疗的患者发生严重颅内出血。循环生物标志物似乎越来越有希望指导tPA管理。然而，治疗时间和结果之间的良好联系决定了用于指导治疗的任何候选生物标志物必须在几分钟内可测量。 该研究项目将在预测缺血性卒中中tPA后脑出血的生物标志物方面取得重大进展。研究主要集中在细胞纤维连接蛋白（cFN）和基质金属蛋白酶-9（MMP-9）。小型研究显示，血管完整性破坏指标cFN和MMP-9对预测tPA后脑内出血具有重要价值。cFN和MMP-9的ELISA方法已经建立，但目前还没有自动化的即时检测仪器。该项目的第一阶段需要开发一种新的即时检测仪器，用于定量来自急性缺血性中风患者的手指针刺血液样品中的cFN和MMP-9，并在实验室水平实验和临床中验证该仪器。 该开发过程将利用即时检测仪器的最新进展，包括用于多重分析物定量的流动室微阵列和内部对照，以及用于完全主动、双向颅内样品/试剂运输的集成狭缝毛细管阵列电渗微泵，其具有静态手持式盒机械接口，具有高可靠性。通过创新的开发过程，功能齐全的原型仪器计划在短短九个月内准备好进行临床评估。ELISA样定量性能和不到10分钟的时间到结果，这些仪器将是有价值的工具，彻底研究cFN和MMP-9作为脑出血的预测因子。因此，预计该项目的II期将进行使用新开发器械的cFN和MMP-9多中心临床试验。 该项目不仅在应用于脑出血的cFN和MMP-9定量方法和仪器的具体进展方面具有开创性，而且还通过推进临床生物标志物研究的广泛新范式。本文开发的分析方法和仪器旨在成为一类即时设备的前身，这些设备可以快速且低成本地生产，以支持临床医生评估新生物标志物候选物的努力。该项目的中心假设是，集成的模块化即时检测设备可以快速开发，并用于克服时间紧迫或基础设施薄弱环境（如急性卒中）中生物标志物开发的研究障碍。为了最有效，治疗由血栓引起的中风的药物需要快速给药。但是由于一些患者可能会受到伤害，因此给予血栓破坏药物并不简单。该项目探索了新的方法来预测哪些患者可能受到伤害，哪些患者最有可能从中风治疗中受益，基于血液中发现的某些标志物的水平。