At this time, no commercially available biomedical instrument exists that provides optical sensitivity to a single molecule of interest. Single-molecule studies are only carried out in specialized research labs using costly and bulky setups based on various types of microscopy. In this context, the overall goals and long- term objectives of the research proposed here are two-fold: (I) Development of a new kind of sensor platform with single molecule sensitivity for biomedical characterization instruments, (ii) Use of these sensors to study individual biomolecules to gain better understanding of fundamental processes in molecular biology. Integrated optical waveguides based novel liquid-core optical waveguides were developed by two of the investigators under an NIBIB R21 grant. At present, these waveguides can be used to guide light through Pico liter volumes on a semiconductor chip, and to detect fluorescence from tens of molecules without the need for a bulky, external microscope. This novel silicon-based approach is compatible with further micro fluidic integration and represents a paradigm shift in the way optical signals from minute amounts of biological analytes can be detected. Building on this research, our specific aims for this application are: 1. Demonstration of single-molecule sensitivity: We will improve the optical waveguides and detection setup to improve the sensitivity from currently 40 to single molecules 2. Development of integrated electrical and optical nanopore waveguide sensor: Using synthetic nanopores as smart gates to the liquid-core optical waveguides, we will develop a novel sensor that enables simultaneous electrical and optical sensing of single biomolecules. 3. Study of individual ribosome's: As one representative biomolecule, we will demonstrate sensing of single fluorescently labeled ribosomes and use the integrated waveguides to study dynamic effects on a millisecond timescale with the ultimate goal of elucidating the dynamics of the RNA translation process. An instrument with single molecule level sensitivity based on integrated technology would be compact, inexpensive, and portable. It would have significant impact on biology, medicine, and public health. Widespread deployment of improved analytical instrumentation in clinical settings, doctor's offices, remote locations, and underdeveloped countries around the world would be possible. In addition, researchers at the forefront of molecular biology could focus on the experimental results instead of the measurement apparatus. As a result, new insight into fundamental life science with long-term effects on drug development, disease detection and treatment can be gained. ? ? ?
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