Abstract
Refractive index properties, especially at the nanoscale, have shown great potential in cancer diagnosis and screening. Due to the intrinsic complexity and weak refractive index fluctuation, the reconstruction of internal structures of a biological cell has been challenging. In this paper, we propose a simple and practical approach to derive the statistical properties of internal refractive index fluctuations within a biological cell with a new optical microscopy method – Low-coherence Statistical Amplitude Microscopy (SAM). We validated the capability of SAM to characterize the statistical properties of cell internal structures, which is described by numerical models of one-dimensional Gaussian random field. We demonstrated the potential of SAM in cancer detection with an animal model of intestinal carcinogenesis – multiple intestinal neoplasia mouse model. We showed that SAM-derived statistical properties of cell nuclear structures could detect the subtle changes that are otherwise undetectable by conventional cytopathology.
Highlights
A biological cell is a complex system in which the spatial variation of its refractive index arises from the presence of heterogeneous internal structures consisting of numerous macromolecules such as double-stranded DNAs, RNAs, aggregated chromatin and bound proteins
We do not focus on the accurate reconstruction of detailed three-dimensional refractive index distribution of the biological cell; instead, we aim to derive the simplified structural parameters to represent the statistical properties of cell internal subcellular structures
Statistical Amplitude Microscopy (SAM) does not give a detailed picture of complex refractive index distribution of cell internal structures, it provides quantitative parameters that are associated with the statistical properties of the spatial variation of refractive index within the biological cell
Summary
A biological cell is a complex system in which the spatial variation of its refractive index (i.e., refractive index variation) arises from the presence of heterogeneous internal structures consisting of numerous macromolecules such as double-stranded DNAs, RNAs, aggregated chromatin and bound proteins. Interferometric imaging techniques are among the most powerful modalities to detect subtle changes of refractive index structural properties, as sensitive as sub-nanometer scale [3,4]. Low-coherence interferometric imaging microscopes, digital holographic microscopy and quantitative phase microscopy have shown great promise in studying sub-nanometer dynamic structural properties of a biological cell [3,5,6]. The accurate reconstruction of refractive index map of a biological system has been challenging. Choi et al have developed tomographic phase microscopy to quantitatively map the three-dimensional (3D) refractive index in live cells and tissues using a phase-shifting laser interferometric microscope [8]. The significance of the complex three-dimensional refractive index distribution of cell internal structures in medicine and biological research has not been extensively addressed
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