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

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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.