This Phase II Lab-to-Marketplace proposal aims to commercialize a new remote focusing technique that can change the focus of a microscope by as much as 500 ?m in less than 40 ?s, 3 orders of magnitude faster than other discrete focus change techniques. Our initial market is neuroscience imaging, where the ability of researchers to step between focal planes at the millisecond timescale of neuronal circuits is limited by the speed and/or complexity of current remote focusing techniques. Piezo translated objectives and liquid electrically tunable lenses have fairly long settling times, on the order of 10-20 ms, which lowers the effective duty cycle at high frame rate imaging. When these devices are operated in resonant mode, duty cycles are higher, but there are still long delays between accessing disparate axial regions. Our remote focusing device uses thin liquid crystal (LC) switches and liquid crystal polarization gratings (LCPGs) to create dynamic lenses. We originally introduced LCPGs as linear gratings for nonmechanical multiangle beamsteering, but realized they can also be leveraged for extremely high speed focusing. In Phase I, we demonstrated the first use of LC switches and circularly-patterned LCPG lenses for changing the focus of a multiphoton microscope system. We were able to shift the focus by ~300 micrometers in < 40 ?s; the settling time is independent of the device?s diameter or of the distance shifted. Axial focusing at these deeply submillisecond timescales is crucial in particular for imaging 3D neural circuits, but will also find applications in other areas where speed and/or hysteresis-free reproducibility is important. In Phase II we plan to bring the LCPG remote focusing lens stack to market with a target price of $1000 and an initial target application of optogenetics research. To reach this target price, we will undertake a systematic process development effort to increase yield, similar to techniques we have used in the LC microdisplay industry. We will also develop an in-house custom LC switch controller for greatly reduced cost and increased robustness and ease of use. With a new grating recording setup we will be able to record LCPGs with 50 mm diameter, and also address wavefront error. With our collaborators at Columbia University, we will characterize the PSF, magnification, dispersion, and wavelength-dependent signal-to-noise ratio in multiple commercial and homebuilt multiphoton microscopes, and with multiple microscope objectives. We will perform interlaminar, intralaminar, and multiplane imaging in live, behaving mice as demonstrations of the new capabilities enabled by this fast remote focusing device.

Public Health Relevance

We will commercialize a fast remote focusing lens to allow brain researchers to study 3D neural interconnections. This lens, based on a nonmechanical beamsteering method called liquid crystal polarization grating stacks, can change focus at timescales 3 orders of magnitude faster than other discrete focusing methods. This will enable new progress in brain imaging and optogenetics.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Grabb, Margaret C
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Boulder Nonlinear Systems, Inc.
United States
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