Thursday, April 25, 2024
4/25/2024
Project Summary/Abstract Sepsis is one of the major healthcare problems in the United States with an annual patient care cost approaching $23 billion. Despite a substantial decrease in inpatient mortality over the past 15 years, the current epidemiology indicates a disturbing increase in the number of sepsis survivors who develop a chronic critical illness (CCI) phenotype featuring prolonged ICU stay and poor long-term outcomes. The most important clinical challenge in sepsis care today is identifying early and continuously monitor those patients with a high risk of either dying or developing CCI. Previous clinical studies show unstable sepsis patients have distinct immunologic subtypes (endotype) defined by the level and fluctuation of circulating immunomodulators over time. Unfortunately, current standard immunoassays (e.g. ELISA) provide only intermittent sampling of biomarker levels with a sample-to-result time of several hours to days, which is insufficient for timely clinical decision making using immune endotypes. The long-term goal of this research is to develop improved bioanalytical tools for predicting clinical trajectory and tailoring medical intervention based on sepsis patient’s individual pathophysiologic endotype. The overall objective in this application is to develop a biosensor platform that addresses the analytical needs of immunologic endotyping in sepsis patient care. A major technical challenge in the real-time monitoring of biomolecules is achieving fast response while maintaining low limit of detection (LOD). To resolve this conflict, the application proposes to adopt the thermal cycling process used in PCR and repurpose it for real-time protein detection. We will develop affinity reagents with temperature-selective binding properties (aim 1). This novel affinity reagent will be integrated with an ultrafast photothermal cycling sensor platform to enable sensitive and frequent biomolecular monitoring (aim 2). In aim 1 we will use in vitro selection to identify binders with temperature-sensitive affinity towards a 3- biomarker panel containing two immune-modulating proteins (i.e. IL-6 and sPD-L1) and a tissue injury indicator thrombomodulin. The optimum temperature range and binding curve for the selected reagents will be characterized. In aim 2 we will develop a sensor platform capable of frequent, multiplexed detection of IL-6, sPD-L1 and thrombomodulin in human whole blood. The research proposed is innovative because it combines novel affinity reagents and sensing mechanisms to reconcile the slow off-rate needed for sensitive detection and the fast off-rate needed for fast assay time. The proposed technology is significant because it is generally applicable to many diseases associated with uncontrolled, systematic inflammatory response, such as the management of severe COVID-19 patients and treatment for patients with cytokine release syndrome after immunotherapy. Furthermore, the successful completion of this project will form the basis for future studies, such as the clinical study on immunologic endotypes diagnostic values at different stages of sepsis, the pharmacokinetics of novel therapeutics, and the closed-loop intervention of chronic diseases.
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