Microelectromechanical handheld laser-scanning confocal microscope: application to breast cancer imaging
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Demographic data indicate that 60% of 6.7 million annual global cancer mortalities and 54% of 10.8 million new patients are in developing nations, unable or unwilling to avail of invasive screening tests that are the current norm. For most cancers, survival rate is strongly dependent on early detection, highlighting the need for improved screening methods. Studies have shown that cancers can be identified based on distinct sub-cellular morphological features and expression levels of specific molecular markers. Since 85% of cancers are known to originate in the epithelium, portable in vivo imaging techniques providing sub-cellular detail in tissue up to depths of 250 μm could help improve access to biopsy-free examination in low-infrastructure environments. The resultant early detection could dramatically improve patient prognosis, while reducing screening costs, treatment delay, and occurrences of unnecessary and potentially harmful medication. This dissertation investigates handheld instrumentation for laser-scanning confocal microscopy (LSCM) and its applicability to breast cancer detection and subsequent image-guided management. LSCM allows high-resolution mapping of spatial variations in refractive index or tumor marker expression within a single cell layer situated few hundred micrometers beneath the tissue surface. The main challenge facing miniaturization lies in the mechanism of beam deflection across the sample. The first part of the dissertation presents a fast, large-angle, high-reflectivity two-axis vertical comb driven silicon micromirror fabricated by a novel method compatible with complementary metal-oxide-semiconductor processing employed in the semiconductor industry. The process enables integration of rotation sensors on the chip to adaptively correct for aberrations in beam scanning while significantly reducing fabrication costs and barriers to market acceptance. The second part of the dissertation explores the integration of this micromirror with other optical and electronic components into a handheld laser-scanning confocal microscope. Applicability of the probe to epithelial breast cancer screening via reflectance and fluorescence imaging is investigated. Finally, enhanced imaging modalities based on the micromirror are presented. 3D cellular-level in vivo imaging via rapid swept-source optical coherence tomography is demonstrated. A method for “objective-less” microendoscopy, potentially resulting in substantially reduced probe dimensions, employing reflective binary-phase Fresnel zone plates monolithically integrated on the surface of the micromirror is presented.