Thursday, November 21, 2024
11/21/2024
Abstract Molecular chirality is at the heart of many chemical processes that determine life and drives significant research in development and disease. All life has chiral asymmetry with naturally occurring molecules and long-range assemblies being of distinct handedness. Many exogenous molecules, for example those useful as drugs, also have a distinct enantiomeric dependence for their efficacy in benefiting human health. Thus, measurement of molecular chirality is of critical importance across the medical sciences. Vibrational Circular Dichroism (VCD) spectroscopy has emerged as a powerful platform for quantifying chirality and molecular structure. However, imaging has not been demonstrated due to technological challenges. VCD measurements are largely of homogeneous materials, neat or in solution and probed with sensitive Fourier transform infrared (FT-IR) spectrometers. Microscopy would require ~105 reduction of the typical sensing volume and increase in speed that would make imaging feasible. Instead of utilizing FT-IR spectroscopy, we built a custom quantum cascade laser (QCL) microscope to demonstrate feasibility of a point scanning VCD instrument capable of acquiring spectra rapidly across all fingerprint region wavelengths in both transflection and transmission configurations. Moreover, for the first time, we also demonstrate the VCD imaging performance of our instrument for site-specific chirality mapping of biological tissue samples. However, the feasibility data also point to several technological and conceptual challenges that this project seeks to address in developing a practical prototype. The prototype to be developed here, termed vibrational circular dichroism imaging microscope or VIM, aims to record chirality from microscopically heterogeneous biomedical samples. We propose a design for VIM using a laser scanning approach to minimize artifacts and maximize signal. Starting from a de novo design, we will use commercial and custom optics, custom electronics for control and data management, and in-house software to develop the prototype. Next, we model the VCD image formation process and develop the analytical methods for VIM. The theoretical model developed here builds on our models of IR microscopy and will guide prototype development while ultimately provide greater accuracy, precision and assurance to data recorded. Finally, we validate the performance and broad utility of VIM using well-characterized samples. Together, the work will develop new VCD imaging technology that opens capability to measure and research a wide variety of biological problems.
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