Implantable real-time troponin biosensor for early diagnosis of silent cardiac injuries

植入式实时肌钙蛋白生物传感器用于早期诊断无症状心脏损伤

• 批准号: 10932735
• 负责人: ZHENGUO LIU
• 金额: $ 42.3万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10932735
• 关键词: Implantable; real; time; troponin; biosensor

Project Summary Cardiovascular disease is the leading cause of death in the United States. Among them, silent heart attack, also known as silent myocardial infarction (SMI) that occurs without apparent symptoms, accounts for approximately half of the total number of heart attacks. When cardiac myocytes are damaged, cardiac troponin (cTn), a component of the heart muscle, is released into circulation. Currently, blood cTn is routinely measured in patients suspected of having Acute Myocardial Infarction (AMI). However, SMI is often undiagnosed until it is too late, although SMI causes similar level of damage to the heart as symptomatic typical AMI. We hypothesize that an implantable cTn sensor providing a real-time and continuous data on the blood levels of cTn will allow a timely diagnosis at the very time when a SMI occurs to a subject, enabling timely treatment. For an in vivo biosensor, the sensing reactions not only need to be sensitive and selective to the analyte but also need to be self-sustaining for a long time in complex physiological conditions. This requires that the sensing reactions can be self- regenerating while at the same time developing a signal related to the analytes. Currently there is no cTn sensors that can be operated in real-time and continuously. We propose to use a radically new biosensor approach to develop highly sensitive, specific, and self-sustaining biosensors based on our years of research and innovations in 1) uniquely designed peptide mimotope biosensing interface for label-free affinity based electrochemical biosensor; 2) the unique properties of bifunctional Pd/Au bimetallic substrate electrode for sensing interface self- regeneration; and 3) miniaturized, low cost and real-time electrochemical sensor platform. Peptide mimotopes, in lieu of antibodies, when immobilized on the surface via self-assemble monolayer (SAM) can significantly reduce the structural variability, retain biological activity, and minimize or eliminate non-specific adsorption from interfering proteins and provide real-time, highly sensitive and selective detection of protein antigens in human blood samples. In addition, our multifunctional bimetallic nanostructured Pd/Au electrode will allow the formation of stable and robust peptide SAM on gold (Au) as well as controlled rapid regeneration of the protein complex using palladium (Pd) chemistry to induce rapid local pH change. We have two research Aims to develop and validate this novel biosensing technology: 1. Develop self-regenerable electrochemical cTn biosensor for real-time detection of cTn; 2. Develop miniaturized implantable cTn biosensor and validate its in vivo sensing using rat cardiac ischemia model. Successful completing these Aims will validate the capability of our cTn biosensor for real-time, sensitive and selective sensing of cTn in vivo for early detection and monitoring of SMI. The sensor will have great potential in the diagnosis and monitoring of a variety of other forms of heart injuries including (but not limited to) viral myocarditis (such as myocardial injury related to COVID-19 infection), drug-induced cardiac toxicities, and radiation-induced cardiac injuries. The biosensor methods developed can also be applied to many other implantable real-time sensing applications.

项目概要 心血管疾病是美国的首要死因。其中，无声心脏病发作，也 称为无症状心肌梗死 (SMI)，发生时没有明显症状，约占 占心脏病发作总数的一半。当心肌细胞受损时，心肌肌钙蛋白 (cTn) 心肌的组成部分，被释放到循环中。目前，患者的血液 cTn 常规测量 怀疑患有急性心肌梗塞（AMI）。然而，SMI 常常未被诊断出来，直到为时已晚， 尽管 SMI 对心脏造成的损害程度与有症状的典型 AMI 相似。我们假设一个 植入式 cTn 传感器提供有关血液 cTn 水平的实时和连续数据，将有助于及时 当受试者发生SMI时立即诊断，以便及时治疗。对于体内生物传感器， 传感反应不仅需要对分析物具有敏感性和选择性，而且还需要能够自我维持 长时间处于复杂的生理条件下。这要求传感反应能够自我 再生的同时产生与分析物相关的信号。目前没有 cTn 传感器 可以实时、连续运行。我们建议使用一种全新的生物传感器方法 基于我们多年的研究和创新，开发高灵敏度、特异性和自我维持的生物传感器 1) 独特设计的肽模拟表位生物传感接口，用于基于无标记亲和力的电化学 生物传感器； 2）双功能Pd/Au双金属基底电极的独特性能，用于传感界面自 再生; 3）小型化、低成本、实时电化学传感器平台。肽模拟表位， 代替抗体，当通过自组装单层 (SAM) 固定在表面时，可以显着 减少结构变异性，保留生物活性，并最大限度地减少或消除非特异性吸附 干扰蛋白并提供对人体蛋白抗原的实时、高灵敏度和选择性检测 血液样本。此外，我们的多功能双金属纳米结构 Pd/Au 电极将允许形成 在金 (Au) 上构建稳定且稳健的肽 SAM 以及蛋白质复合物的受控快速再生 使用钯 (Pd) 化学物质诱导局部 pH 值快速变化。我们有两个研究目标要开发和 验证这种新颖的生物传感技术： 1. 开发自再生电化学 cTn 生物传感器 实时检测cTn； 2. 开发微型化植入式cTn生物传感器并进行体内验证 使用大鼠心脏缺血模型进行传感。成功完成这些目标将验证能力 我们的 cTn 生物传感器可实时、灵敏和选择性地感测体内 cTn，以便进行早期检测和监测 的SMI。该传感器在诊断和监测各种其他形式的心脏方面具有巨大潜力 损伤包括（但不限于）病毒性心肌炎（例如与 COVID-19 感染相关的心肌损伤）， 药物引起的心脏毒性和辐射引起的心脏损伤。开发的生物传感器方法可以 也可应用于许多其他植入式实时传感应用。