Controlling light propagation through a step-index multimode optical fiber (MMF) has several important applications, including biological imaging. However, little consideration has been given to the coupling of fiber and tissue optics. In this Letter, we characterized the effects of tissue-induced light distortions, in particular those arising from a mismatch in the refractive index of the pre-imaging calibration and biological media. By performing the calibration in a medium matching the refractive index of the brain, optimal focusing ability was achieved, as well as a gain in focus uniformity within the field-of-view. These changes in illumination resulted in a 30% improvement in spatial resolution and intensity in fluorescence images of beads and live brain tissue. Beyond refractive index matching, our results demonstrate that sample-induced aberrations can severely deteriorate images from MMF-based systems.
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