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Optical diffraction tomography measures the three-dimensional refractive index map of a specimen and visualizes biochemical phenomena at the nanoscale in a non-destructive manner. One major drawback of optical diffraction tomography is poor axial resolution due to limited access to the three-dimensional optical transfer function. This missing cone problem has been addressed through regularization algorithms that use a priori information, such as non-negativity and sample smoothness. However, the iterative nature of these algorithms and their parameter dependency make real-time visualization impossible. In this article, we propose and experimentally demonstrate a deep neural network, which we term DeepRegularizer, that rapidly improves the resolution of a three-dimensional refractive index map. Trained with pairs of datasets (a raw refractive index tomogram and a resolution-enhanced refractive index tomogram via the iterative total variation algorithm), the three-dimensional U-net-based convolutional neural network learns a transformation between the two tomogram domains. The feasibility and generalizability of our network are demonstrated using bacterial cells and a human leukaemic cell line, and by validating the model across different samples. DeepRegularizer offers more than an order of magnitude faster regularization performance compared to the conventional iterative method. We envision that the proposed data-driven approach can bypass the high time complexity of various image reconstructions in other imaging modalities.

We developed a machine learning algorithm (MLA) that can classify human thyroid cell clusters by exploiting both Papanicolaou staining and intrinsic refractive index (RI) as correlative imaging contrasts and evaluated the effects of this combination on diagnostic performance. Thyroid fine-needle aspiration biopsy (FNAB) specimens were analyzed using correlative optical diffraction tomography, which can simultaneously measure both, the color brightfield of Papanicolaou staining and three-dimensional RI distribution. The MLA was designed to classify benign and malignant cell clusters using color images, RI images, or both. We included 1535 thyroid cell clusters (benign: malignancy = 1128:407) from 124 patients. Accuracies of MLA classifiers using color images, RI images, and both were 98.0%, 98.0%, and 100%, respectively. As information for classification, the nucleus size was mainly used in the color image; however, detailed morphological information of the nucleus was also used in the RI image. We demonstrate that the present MLA and correlative FNAB imaging approach has the potential for diagnosing thyroid cancer, and complementary information from color and RI images can improve the performance of the MLA.

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