Quantitative Phase Imaging Meta-Sensors for Noninvasive Real-Time Capillaroscopy

Boston University (Charles River Campus), Boston MA

Investigators

Abstract

ABSTRACT Quantitative phase imaging is a powerful modality of widefield microscopy that allows visualizing transparent biological cells and extracting important biophysical parameters with subcellular resolution. A potential application of immediate and widespread impact is real-time imaging of blood cell flow in vivo by noninvasive label-free capillaroscopy (particularly on the oral mucosa, due to the presence of capillaries in close proximity to the surface and limited pigmentation). This capability could dramatically improve patient care management in situations where venipuncture is impractical, such as with immunocompromised patients or in resource-limited settings. Furthermore, it could significantly speed up decisions about life-saving treatments and provide dynamic information for disease diagnosis that is not directly available from static parameters such as blood count. However, existing techniques for in vivo capillaroscopy (by phase imaging or other methods) suffer from limited image contrast, high system complexity, high cost, and/or slow speed that hinder their clinical adoption. This project will demonstrate a new method for quantitative phase imaging that can be applied to noninvasive real-time capillaroscopy with a particularly simple measurement setup – an epi-mode miniaturized microscope with standard on-axis illumination and detection. The key innovation is the use of a new type of image sensors, where an integrated photonic metasurface is used to produce a sharp dependence of responsivity on direction of propagation of the incident light. These Phase Imaging Meta-Sensors (PIMSs) can simultaneously resolve phase and amplitude contrast in a single shot, with direct background subtraction and quantitative phase reconstruction capabilities. By virtue of their unique characteristics, these devices can provide an unmatched combination of image quality, system miniaturization, measurement simplicity, spatial resolution, speed, and low manufacturing cost that makes them ideally suited for capillaroscopy and other in vivo microscopy applications. The project goal will be achieved through three specific aims: (1) the development of dielectric metasurfaces enabling PIMS operation with uniform angular response across the bandwidth of green LEDs; (2) the fabrication of these metasurfaces on the individual pixels of commercial CMOS image sensor arrays; and (3) the development of a miniaturized PIMS microscope and its application to single-shot quantitative phase imaging with thick scattering samples, ranging from controlled scattering phantoms to blood vessels in the developing chick embryo. The latter samples will be used to demonstrate white blood cell counting with clinically relevant accuracy – a key milestone for widespread adoption in noninvasive real-time capillaroscopy. The image sensing technology developed through these aims can be expected to significantly expand the reach and functionality of life-saving blood testing, and more generally open up new applications in multiple areas of in vivo microscopy, such as microendoscopy for cancer surgical guidance.