Light sheet microscopy is a powerful method for three-dimensional imaging of large biological specimens. However, its imaging ability is greatly diminished by sample scattering and aberrations. Optical clearing, Bessel light modes, and background rejection have been employed in attempts to circumvent these deleterious effects. We present an in situ wavefront correction that offers a major advance by creating an “optimal” light sheet within a turbid sample. Crucially, we show that no tissue clearing or specialized sample preparation is required, and clear improvements in image quality and depth resolution are demonstrated both in Gaussian and Bessel beam-based light sheet modalities.

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