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Aydogan Ozcan

Aydogan Ozcan contributes to research discovery and scholarly infrastructure.

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Published work

31 published item(s)

preprint2026arXiv

Continuous quantification of viral plaque dynamics using ultra-large-area label-free imaging enables rapid antiviral susceptibility testing

The plaque reduction assay (PRA) remains the gold standard for antiviral susceptibility testing, evaluating drug potency by measuring reductions in plaque-forming units (PFUs). However, the traditional PRA is time-consuming, labor-intensive, prone to manual counting errors, and offers limited scalability. Moreover, its reliance on destructive fixation and chemical staining reduces the assay to a static, endpoint observation, obscuring the dynamic, time-resolved kinetics of dose-dependent viral inhibition. Here, we introduce a label-free, time-resolved PRA platform that transforms the conventional assay into a continuous, high-dimensional measurement of viral infection dynamics. Our system integrates a compact lens-free imaging setup with a custom-designed ultra-large-area (100 cm^2) thin-film transistor (TFT) image sensor and deep learning-based algorithms to autonomously quantify PFU dynamics within an incubator. Validated using herpes simplex virus type-1 (HSV-1) treated with acyclovir, the platform matched chemically-stained ground truth measurements with zero false positives while accelerating readout by ~26 hours. Crucially, our system revealed that increasing drug concentrations induce temporally distinct delays and suppress new PFU formation, enabling conclusive drug efficacy evaluations within ~60 hours post-infection. This scalable, label-free framework redefines antiviral susceptibility testing as a rapid, time-resolved and information-rich measurement framework, providing a generalizable platform for virology research, high-throughput drug screening, and clinical diagnostics.

preprint2026arXiv

Scalable, Energy-Efficient Optical-Neural Architecture for Multiplexed Deepfake Video Detection

The rapid proliferation of AI-generated visual media has created an urgent need for efficient, trustworthy deepfake detection systems. However, existing deep learning-based detection methods rely on computationally intensive and energy-demanding inference algorithms, limiting their scalability. Here, we present a hybrid digital-analog deepfake video detection framework that combines a lightweight digital front-end with a spatially multiplexed optical decoding back-end for massively parallel analog inference through a programmable spatial light modulator. By simultaneously processing 15 or more video streams within a single optical propagation pass, the system enables high-throughput and accurate video-level authenticity prediction at reduced computational cost compared with purely digital methods. We validated this hybrid deepfake video processor using different datasets spanning classical face-swapping, real-world deepfake recordings, and fully AI-generated videos. Using a spatially multiplexed experimental set-up operating in the visible spectrum, we achieved average deepfake detection accuracy, sensitivity and specificity of 97.79%, 99.86% and 95.72%, respectively, on the Celeb-DF video dataset with 15 videos tested in parallel in a single optical pass per inference. The multiplexed optical decoder also demonstrates resilience against various types of video degradation, noise, compression, experimental misalignments and black-box adversarial attacks. Our results show that integrating optical computation into AI inference enables simultaneous gains in throughput, energy efficiency, and adversarial robustness - three properties that are difficult to achieve together in purely digital systems.

preprint2025arXiv

Deep learning-enabled virtual multiplexed immunostaining of label-free tissue for vascular invasion assessment

Immunohistochemistry (IHC) has transformed clinical pathology by enabling the visualization of specific proteins within tissue sections. However, traditional IHC requires one tissue section per stain, exhibits section-to-section variability, and incurs high costs and laborious staining procedures. While multiplexed IHC (mIHC) techniques enable simultaneous staining with multiple antibodies on a single slide, they are more tedious to perform and are currently unavailable in routine pathology laboratories. Here, we present a deep learning-based virtual multiplexed immunostaining framework to simultaneously generate ERG and PanCK, in addition to H&E virtual staining, enabling accurate localization and interpretation of vascular invasion in thyroid cancers. This virtual mIHC technique is based on the autofluorescence microscopy images of label-free tissue sections, and its output images closely match the histochemical staining counterparts (ERG, PanCK and H&E) of the same tissue sections. Blind evaluation by board-certified pathologists demonstrated that virtual mIHC staining achieved high concordance with the histochemical staining results, accurately highlighting epithelial cells and endothelial cells. Virtual mIHC conducted on the same tissue section also allowed the identification and localization of small vessel invasion. This multiplexed virtual IHC approach can significantly improve diagnostic accuracy and efficiency in the histopathological evaluation of vascular invasion, potentially eliminating the need for traditional staining protocols and mitigating issues related to tissue loss and heterogeneity.

preprint2025arXiv

Model-free Optical Processors using In Situ Reinforcement Learning with Proximal Policy Optimization

Optical computing holds promise for high-speed, energy-efficient information processing, with diffractive optical networks emerging as a flexible platform for implementing task-specific transformations. A challenge, however, is the effective optimization and alignment of the diffractive layers, which is hindered by the difficulty of accurately modeling physical systems with their inherent hardware imperfections, noise, and misalignments. While existing in situ optimization methods offer the advantage of direct training on the physical system without explicit system modeling, they are often limited by slow convergence and unstable performance due to inefficient use of limited measurement data. Here, we introduce a model-free reinforcement learning approach utilizing Proximal Policy Optimization (PPO) for the in situ training of diffractive optical processors. PPO efficiently reuses in situ measurement data and constrains policy updates to ensure more stable and faster convergence. We experimentally validated our method across a range of in situ learning tasks, including targeted energy focusing through a random diffuser, holographic image generation, aberration correction, and optical image classification, demonstrating in each task better convergence and performance. Our strategy operates directly on the physical system and naturally accounts for unknown real-world imperfections, eliminating the need for prior system knowledge or modeling. By enabling faster and more accurate training under realistic experimental constraints, this in situ reinforcement learning approach could offer a scalable framework for various optical and physical systems governed by complex, feedback-driven dynamics.

preprint2023arXiv

Plasmonic photoconductive terahertz focal-plane array with pixel super-resolution

Imaging systems operating in the terahertz part of the electromagnetic spectrum are in great demand because of the distinct characteristics of terahertz waves in penetrating many optically-opaque materials and providing unique spectral signatures of various chemicals. However, the use of terahertz imagers in real-world applications has been limited by the slow speed, large size, high cost, and complexity of the existing imaging systems. These limitations are mainly imposed due to the lack of terahertz focal-plane arrays (THz-FPAs) that can directly provide the frequency-resolved and/or time-resolved spatial information of the imaged objects. Here, we report the first THz-FPA that can directly provide the spatial amplitude and phase distributions, along with the ultrafast temporal and spectral information of an imaged object. It consists of a two-dimensional array of ~0.3 million plasmonic photoconductive nanoantennas optimized to rapidly detect broadband terahertz radiation with a high signal-to-noise ratio. As the first proof-of-concept, we utilized the multispectral nature of the amplitude and phase data captured by these plasmonic nanoantennas to realize pixel super-resolution imaging of objects. We successfully imaged and super-resolved etched patterns in a silicon substrate and reconstructed both the shape and depth of these structures with an effective number of pixels that exceeds 1-kilo pixels. By eliminating the need for raster scanning and spatial terahertz modulation, our THz-FPA offers more than a 1000-fold increase in the imaging speed compared to the state-of-the-art. Beyond this proof-of-concept super-resolution demonstration, the unique capabilities enabled by our plasmonic photoconductive THz-FPA offer transformative advances in a broad range of applications that use hyperspectral and three-dimensional terahertz images of objects for a wide range of applications.

preprint2022arXiv

Analysis of Diffractive Neural Networks for Seeing Through Random Diffusers

Imaging through diffusive media is a challenging problem, where the existing solutions heavily rely on digital computers to reconstruct distorted images. We provide a detailed analysis of a computer-free, all-optical imaging method for seeing through random, unknown phase diffusers using diffractive neural networks, covering different deep learning-based training strategies. By analyzing various diffractive networks designed to image through random diffusers with different correlation lengths, a trade-off between the image reconstruction fidelity and distortion reduction capability of the diffractive network was observed. During its training, random diffusers with a range of correlation lengths were used to improve the diffractive network's generalization performance. Increasing the number of random diffusers used in each epoch reduced the overfitting of the diffractive network's imaging performance to known diffusers. We also demonstrated that the use of additional diffractive layers improved the generalization capability to see through new, random diffusers. Finally, we introduced deliberate misalignments in training to 'vaccinate' the network against random layer-to-layer shifts that might arise due to the imperfect assembly of the diffractive networks. These analyses provide a comprehensive guide in designing diffractive networks to see through random diffusers, which might profoundly impact many fields, such as biomedical imaging, atmospheric physics, and autonomous driving.

preprint2022arXiv

Deep Learning-enabled Detection and Classification of Bacterial Colonies using a Thin Film Transistor (TFT) Image Sensor

Early detection and identification of pathogenic bacteria such as Escherichia coli (E. coli) is an essential task for public health. The conventional culture-based methods for bacterial colony detection usually take >24 hours to get the final read-out. Here, we demonstrate a bacterial colony-forming-unit (CFU) detection system exploiting a thin-film-transistor (TFT)-based image sensor array that saves ~12 hours compared to the Environmental Protection Agency (EPA)-approved methods. To demonstrate the efficacy of this CFU detection system, a lensfree imaging modality was built using the TFT image sensor with a sample field-of-view of ~10 cm^2. Time-lapse images of bacterial colonies cultured on chromogenic agar plates were automatically collected at 5-minute intervals. Two deep neural networks were used to detect and count the growing colonies and identify their species. When blindly tested with 265 colonies of E. coli and other coliform bacteria (i.e., Citrobacter and Klebsiella pneumoniae), our system reached an average CFU detection rate of 97.3% at 9 hours of incubation and an average recovery rate of 91.6% at ~12 hours. This TFT-based sensor can be applied to various microbiological detection methods. Due to the large scalability, ultra-large field-of-view, and low cost of the TFT-based image sensors, this platform can be integrated with each agar plate to be tested and disposed of after the automated CFU count. The imaging field-of-view of this platform can be cost-effectively increased to >100 cm^2 to provide a massive throughput for CFU detection using, e.g., roll-to-roll manufacturing of TFTs as used in the flexible display industry.

preprint2022arXiv

Diffractive all-optical computing for quantitative phase imaging

Quantitative phase imaging (QPI) is a label-free computational imaging technique that provides optical path length information of specimens. In modern implementations, the quantitative phase image of an object is reconstructed digitally through numerical methods running in a computer, often using iterative algorithms. Here, we demonstrate a diffractive QPI network that can synthesize the quantitative phase image of an object by converting the input phase information of a scene into intensity variations at the output plane. A diffractive QPI network is a specialized all-optical processor designed to perform a quantitative phase-to-intensity transformation through passive diffractive surfaces that are spatially engineered using deep learning and image data. Forming a compact, all-optical network that axially extends only ~200-300 times the illumination wavelength, this framework can replace traditional QPI systems and related digital computational burden with a set of passive transmissive layers. All-optical diffractive QPI networks can potentially enable power-efficient, high frame-rate and compact phase imaging systems that might be useful for various applications, including, e.g., on-chip microscopy and sensing.

preprint2022arXiv

Diffractive Interconnects: All-Optical Permutation Operation Using Diffractive Networks

Permutation matrices form an important computational building block frequently used in various fields including e.g., communications, information security and data processing. Optical implementation of permutation operators with relatively large number of input-output interconnections based on power-efficient, fast, and compact platforms is highly desirable. Here, we present diffractive optical networks engineered through deep learning to all-optically perform permutation operations that can scale to hundreds of thousands of interconnections between an input and an output field-of-view using passive transmissive layers that are individually structured at the wavelength scale. Our findings indicate that the capacity of the diffractive optical network in approximating a given permutation operation increases proportional to the number of diffractive layers and trainable transmission elements in the system. Such deeper diffractive network designs can pose practical challenges in terms of physical alignment and output diffraction efficiency of the system. We addressed these challenges by designing misalignment tolerant diffractive designs that can all-optically perform arbitrarily-selected permutation operations, and experimentally demonstrated, for the first time, a diffractive permutation network that operates at THz part of the spectrum. Diffractive permutation networks might find various applications in e.g., security, image encryption and data processing, along with telecommunications; especially with the carrier frequencies in wireless communications approaching THz-bands, the presented diffractive permutation networks can potentially serve as channel routing and interconnection panels in wireless networks.

preprint2022arXiv

Few-shot Transfer Learning for Holographic Image Reconstruction using a Recurrent Neural Network

Deep learning-based methods in computational microscopy have been shown to be powerful but in general face some challenges due to limited generalization to new types of samples and requirements for large and diverse training data. Here, we demonstrate a few-shot transfer learning method that helps a holographic image reconstruction deep neural network rapidly generalize to new types of samples using small datasets. We pre-trained a convolutional recurrent neural network on a large dataset with diverse types of samples, which serves as the backbone model. By fixing the recurrent blocks and transferring the rest of the convolutional blocks of the pre-trained model, we reduced the number of trainable parameters by ~90% compared with standard transfer learning, while achieving equivalent generalization. We validated the effectiveness of this approach by successfully generalizing to new types of samples using small holographic datasets for training, and achieved (i) ~2.5-fold convergence speed acceleration, (ii) ~20% computation time reduction per epoch, and (iii) improved reconstruction performance over baseline network models trained from scratch. This few-shot transfer learning approach can potentially be applied in other microscopic imaging methods, helping to generalize to new types of samples without the need for extensive training time and data.

preprint2022arXiv

Fourier Imager Network (FIN): A deep neural network for hologram reconstruction with superior external generalization

Deep learning-based image reconstruction methods have achieved remarkable success in phase recovery and holographic imaging. However, the generalization of their image reconstruction performance to new types of samples never seen by the network remains a challenge. Here we introduce a deep learning framework, termed Fourier Imager Network (FIN), that can perform end-to-end phase recovery and image reconstruction from raw holograms of new types of samples, exhibiting unprecedented success in external generalization. FIN architecture is based on spatial Fourier transform modules that process the spatial frequencies of its inputs using learnable filters and a global receptive field. Compared with existing convolutional deep neural networks used for hologram reconstruction, FIN exhibits superior generalization to new types of samples, while also being much faster in its image inference speed, completing the hologram reconstruction task in ~0.04 s per 1 mm^2 of the sample area. We experimentally validated the performance of FIN by training it using human lung tissue samples and blindly testing it on human prostate, salivary gland tissue and Pap smear samples, proving its superior external generalization and image reconstruction speed. Beyond holographic microscopy and quantitative phase imaging, FIN and the underlying neural network architecture might open up various new opportunities to design broadly generalizable deep learning models in computational imaging and machine vision fields.

preprint2022arXiv

Massively Parallel Universal Linear Transformations using a Wavelength-Multiplexed Diffractive Optical Network

We report deep learning-based design of a massively parallel broadband diffractive neural network for all-optically performing a large group of arbitrarily-selected, complex-valued linear transformations between an input and output field-of-view, each with N_i and N_o pixels, respectively. This broadband diffractive processor is composed of N_w wavelength channels, each of which is uniquely assigned to a distinct target transformation. A large set of arbitrarily-selected linear transformations can be individually performed through the same diffractive network at different illumination wavelengths, either simultaneously or sequentially (wavelength scanning). We demonstrate that such a broadband diffractive network, regardless of its material dispersion, can successfully approximate N_w unique complex-valued linear transforms with a negligible error when the number of diffractive neurons (N) in its design matches or exceeds 2 x N_w x N_i x N_o. We further report that the spectral multiplexing capability (N_w) can be increased by increasing N; our numerical analyses confirm these conclusions for N_w > 180, which can be further increased to e.g., ~2000 depending on the upper bound of the approximation error. Massively parallel, wavelength-multiplexed diffractive networks will be useful for designing high-throughput intelligent machine vision systems and hyperspectral processors that can perform statistical inference and analyze objects/scenes with unique spectral properties.

preprint2022arXiv

Polarization Multiplexed Diffractive Computing: All-Optical Implementation of a Group of Linear Transformations Through a Polarization-Encoded Diffractive Network

Research on optical computing has recently attracted significant attention due to the transformative advances in machine learning. Among different approaches, diffractive optical networks composed of spatially-engineered transmissive surfaces have been demonstrated for all-optical statistical inference and performing arbitrary linear transformations using passive, free-space optical layers. Here, we introduce a polarization multiplexed diffractive processor to all-optically perform multiple, arbitrarily-selected linear transformations through a single diffractive network trained using deep learning. In this framework, an array of pre-selected linear polarizers is positioned between trainable transmissive diffractive materials that are isotropic, and different target linear transformations (complex-valued) are uniquely assigned to different combinations of input/output polarization states. The transmission layers of this polarization multiplexed diffractive network are trained and optimized via deep learning and error-backpropagation by using thousands of examples of the input/output fields corresponding to each one of the complex-valued linear transformations assigned to different input/output polarization combinations. Our results and analysis reveal that a single diffractive network can successfully approximate and all-optically implement a group of arbitrarily-selected target transformations with a negligible error when the number of trainable diffractive features/neurons (N) approaches N_p x N_i x N_o, where N_i and N_o represent the number of pixels at the input and output fields-of-view, respectively, and N_p refers to the number of unique linear transformations assigned to different input/output polarization combinations. This polarization-multiplexed all-optical diffractive processor can find various applications in optical computing and polarization-based machine vision tasks.

preprint2022arXiv

To image, or not to image: Class-specific diffractive cameras with all-optical erasure of undesired objects

Privacy protection is a growing concern in the digital era, with machine vision techniques widely used throughout public and private settings. Existing methods address this growing problem by, e.g., encrypting camera images or obscuring/blurring the imaged information through digital algorithms. Here, we demonstrate a camera design that performs class-specific imaging of target objects with instantaneous all-optical erasure of other classes of objects. This diffractive camera consists of transmissive surfaces structured using deep learning to perform selective imaging of target classes of objects positioned at its input field-of-view. After their fabrication, the thin diffractive layers collectively perform optical mode filtering to accurately form images of the objects that belong to a target data class or group of classes, while instantaneously erasing objects of the other data classes at the output field-of-view. Using the same framework, we also demonstrate the design of class-specific permutation cameras, where the objects of a target data class are pixel-wise permuted for all-optical class-specific encryption, while the other objects are irreversibly erased from the output image. The success of class-specific diffractive cameras was experimentally demonstrated using terahertz (THz) waves and 3D-printed diffractive layers that selectively imaged only one class of the MNIST handwritten digit dataset, all-optically erasing the other handwritten digits. This diffractive camera design can be scaled to different parts of the electromagnetic spectrum, including, e.g., the visible and infrared wavelengths, to provide transformative opportunities for privacy-preserving digital cameras and task-specific data-efficient imaging.

preprint2022arXiv

Virtual stain transfer in histology via cascaded deep neural networks

Pathological diagnosis relies on the visual inspection of histologically stained thin tissue specimens, where different types of stains are applied to bring contrast to and highlight various desired histological features. However, the destructive histochemical staining procedures are usually irreversible, making it very difficult to obtain multiple stains on the same tissue section. Here, we demonstrate a virtual stain transfer framework via a cascaded deep neural network (C-DNN) to digitally transform hematoxylin and eosin (H&E) stained tissue images into other types of histological stains. Unlike a single neural network structure which only takes one stain type as input to digitally output images of another stain type, C-DNN first uses virtual staining to transform autofluorescence microscopy images into H&E and then performs stain transfer from H&E to the domain of the other stain in a cascaded manner. This cascaded structure in the training phase allows the model to directly exploit histochemically stained image data on both H&E and the target special stain of interest. This advantage alleviates the challenge of paired data acquisition and improves the image quality and color accuracy of the virtual stain transfer from H&E to another stain. We validated the superior performance of this C-DNN approach using kidney needle core biopsy tissue sections and successfully transferred the H&E-stained tissue images into virtual PAS (periodic acid-Schiff) stain. This method provides high-quality virtual images of special stains using existing, histochemically stained slides and creates new opportunities in digital pathology by performing highly accurate stain-to-stain transformations.

preprint2021arXiv

Cascadable all-optical NAND gates using diffractive networks

Owing to its potential advantages such as scalability, low latency and power efficiency, optical computing has seen rapid advances over the last decades. A core unit of a potential all-optical processor would be the NAND gate, which can be cascaded to perform an arbitrary logical operation. Here, we present the design and analysis of cascadable all-optical NAND gates using diffractive neural networks. We encoded the logical values at the input and output planes of a diffractive NAND gate using the relative optical power of two spatially-separated apertures. Based on this architecture, we numerically optimized the design of a diffractive neural network composed of 4 passive layers to all-optically perform NAND operation using the diffraction of light, and cascaded these diffractive NAND gates to perform complex logical functions by successively feeding the output of one diffractive NAND gate into another. We demonstrated the cascadability of our diffractive NAND gates by using identical diffractive designs to all-optically perform AND and OR operations, as well as a half-adder. Cascadable all-optical NAND gates composed of spatially-engineered passive diffractive layers can serve as a core component of various optical computing platforms.

preprint2021arXiv

Characterization of exhaled e-cigarette aerosols in a vape shop using a field-portable holographic on-chip microscope

The past decade marked a drastic increase in the usage of electronic cigarettes (e-cigs). The adverse health impact of secondhand exposure due to exhaled e-cig particles has raised significant concerns, demanding further research on the characteristics of these particles. In this work, we report direct volatility measurements on exhaled e-cig aerosols using a field-portable device (termed c-Air) enabled by deep learning and lens-free holographic microscopy; for this analysis, we performed a series of field experiments in a vape shop where customers used/vaped their e-cig products. During four days of experiments, we periodically sampled the indoor air with intervals of ~15 minutes and collected the exhaled particles with c-Air. Time-lapse inline holograms of the collected particles were recorded by c-Air and reconstructed using a convolutional neural network yielding phase-recovered microscopic images of the particles. Volumetric decay of individual particles due to evaporation was used as an indicator of the volatility of each aerosol. Volatility dynamics quantified through c-Air experiments showed that indoor vaping increased the volatility of particles as well as the percentage of volatile and semi-volatile particles in air. The reported methodology and findings can guide further studies on volatility characterization of e-cig emission and regulations on indoor vaping.

preprint2021arXiv

Classification and reconstruction of spatially overlapping phase images using diffractive optical networks

Diffractive optical networks unify wave optics and deep learning to all-optically compute a given machine learning or computational imaging task as the light propagates from the input to the output plane. Here, we report the design of diffractive optical networks for the classification and reconstruction of spatially overlapping, phase-encoded objects. When two different phase-only objects spatially overlap, the individual object functions are perturbed since their phase patterns are summed up. The retrieval of the underlying phase images from solely the overlapping phase distribution presents a challenging problem, the solution of which is generally not unique. We show that through a task-specific training process, passive diffractive networks composed of successive transmissive layers can all-optically and simultaneously classify two different randomly-selected, spatially overlapping phase images at the input. After trained with ~550 million unique combinations of phase-encoded handwritten digits from the MNIST dataset, our blind testing results reveal that the diffractive network achieves an accuracy of >85.8% for all-optical classification of two overlapping phase images of new handwritten digits. In addition to all-optical classification of overlapping phase objects, we also demonstrate the reconstruction of these phase images based on a shallow electronic neural network that uses the highly compressed output of the diffractive network as its input (with e.g., ~20-65 times less number of pixels) to rapidly reconstruct both of the phase images, despite their spatial overlap and related phase ambiguity. The presented phase image classification and reconstruction framework might find applications in e.g., computational imaging, microscopy and quantitative phase imaging fields.

preprint2021arXiv

Computational Imaging Without a Computer: Seeing Through Random Diffusers at the Speed of Light

Imaging through diffusers presents a challenging problem with various digital image reconstruction solutions demonstrated to date using computers. We present a computer-free, all-optical image reconstruction method to see through random diffusers at the speed of light. Using deep learning, a set of diffractive surfaces are designed/trained to all-optically reconstruct images of objects that are covered by random phase diffusers. We experimentally demonstrated this concept using coherent THz illumination and all-optically reconstructed objects distorted by unknown, random diffusers, never used during training. Unlike digital methods, all-optical diffractive reconstructions do not require power except for the illumination light. This diffractive solution to see through diffusers can be extended to other wavelengths, and might fuel various applications in biomedical imaging, astronomy, atmospheric sciences, oceanography, security, robotics, among others.

preprint2021arXiv

Label-free virtual HER2 immunohistochemical staining of breast tissue using deep learning

The immunohistochemical (IHC) staining of the human epidermal growth factor receptor 2 (HER2) biomarker is widely practiced in breast tissue analysis, preclinical studies and diagnostic decisions, guiding cancer treatment and investigation of pathogenesis. HER2 staining demands laborious tissue treatment and chemical processing performed by a histotechnologist, which typically takes one day to prepare in a laboratory, increasing analysis time and associated costs. Here, we describe a deep learning-based virtual HER2 IHC staining method using a conditional generative adversarial network that is trained to rapidly transform autofluorescence microscopic images of unlabeled/label-free breast tissue sections into bright-field equivalent microscopic images, matching the standard HER2 IHC staining that is chemically performed on the same tissue sections. The efficacy of this virtual HER2 staining framework was demonstrated by quantitative analysis, in which three board-certified breast pathologists blindly graded the HER2 scores of virtually stained and immunohistochemically stained HER2 whole slide images (WSIs) to reveal that the HER2 scores determined by inspecting virtual IHC images are as accurate as their immunohistochemically stained counterparts. A second quantitative blinded study performed by the same diagnosticians further revealed that the virtually stained HER2 images exhibit a comparable staining quality in the level of nuclear detail, membrane clearness, and absence of staining artifacts with respect to their immunohistochemically stained counterparts. This virtual HER2 staining framework bypasses the costly, laborious, and time-consuming IHC staining procedures in laboratory, and can be extended to other types of biomarkers to accelerate the IHC tissue staining used in life sciences and biomedical workflow.

preprint2021arXiv

Single-shot autofocusing of microscopy images using deep learning

We demonstrate a deep learning-based offline autofocusing method, termed Deep-R, that is trained to rapidly and blindly autofocus a single-shot microscopy image of a specimen that is acquired at an arbitrary out-of-focus plane. We illustrate the efficacy of Deep-R using various tissue sections that were imaged using fluorescence and brightfield microscopy modalities and demonstrate snapshot autofocusing under different scenarios, such as a uniform axial defocus as well as a sample tilt within the field-of-view. Our results reveal that Deep-R is significantly faster when compared with standard online algorithmic autofocusing methods. This deep learning-based blind autofocusing framework opens up new opportunities for rapid microscopic imaging of large sample areas, also reducing the photon dose on the sample.

preprint2020arXiv

All-Optical Information Processing Capacity of Diffractive Surfaces

Precise engineering of materials and surfaces has been at the heart of some of the recent advances in optics and photonics. These advances around the engineering of materials with new functionalities have also opened up exciting avenues for designing trainable surfaces that can perform computation and machine learning tasks through light-matter interaction and diffraction. Here, we analyze the information processing capacity of coherent optical networks formed by diffractive surfaces that are trained to perform an all-optical computational task between a given input and output field-of-view. We show that the dimensionality of the all-optical solution space covering the complex-valued transformations between the input and output fields-of-view is linearly proportional to the number of diffractive surfaces within the optical network, up to a limit that is dictated by the extent of the input and output fields-of-view. Deeper diffractive networks that are composed of larger numbers of trainable surfaces can cover a higher dimensional subspace of the complex-valued linear transformations between a larger input field-of-view and a larger output field-of-view, and exhibit depth advantages in terms of their statistical inference, learning and generalization capabilities for different image classification tasks, when compared with a single trainable diffractive surface. These analyses and conclusions are broadly applicable to various forms of diffractive surfaces, including e.g., plasmonic and/or dielectric-based metasurfaces and flat optics that can be used to form all-optical processors.

preprint2020arXiv

An Automated, Cost-Effective Optical System for Accelerated Anti-microbial Susceptibility Testing (AST) using Deep Learning

Antimicrobial susceptibility testing (AST) is a standard clinical procedure used to quantify antimicrobial resistance (AMR). Currently, the gold standard method requires incubation for 18-24 h and subsequent inspection for growth by a trained medical technologist. We demonstrate an automated, cost-effective optical system that delivers early AST results, minimizing incubation time and eliminating human errors, while remaining compatible with standard phenotypic assay workflow. The system is composed of cost-effective components and eliminates the need for optomechanical scanning. A neural network processes the captured optical intensity information from an array of fiber optic cables to determine whether bacterial growth has occurred in each well of a 96-well microplate. When the system was blindly tested on isolates from 33 patients with Staphylococcus aureus infections, 95.03% of all the wells containing growth were correctly identified using our neural network, with an average of 5.72 h of incubation time required to identify growth. 90% of all wells (growth and no-growth) were correctly classified after 7 h, and 95% after 10.5 h. Our deep learning-based optical system met the FDA-defined criteria for essential and categorical agreements for all 14 antibiotics tested after an average of 6.13 h and 6.98 h, respectively. Furthermore, our system met the FDA criteria for major and very major error rates for 11 of 12 possible drugs after an average of 4.02 h, and 9 of 13 possible drugs after an average of 9.39 h, respectively. This system could enable faster, inexpensive, automated AST, especially in resource limited settings, helping to mitigate the rise of global AMR.

preprint2020arXiv

Digital synthesis of histological stains using micro-structured and multiplexed virtual staining of label-free tissue

Histological staining is a vital step used to diagnose various diseases and has been used for more than a century to provide contrast to tissue sections, rendering the tissue constituents visible for microscopic analysis by medical experts. However, this process is time-consuming, labor-intensive, expensive and destructive to the specimen. Recently, the ability to virtually-stain unlabeled tissue sections, entirely avoiding the histochemical staining step, has been demonstrated using tissue-stain specific deep neural networks. Here, we present a new deep learning-based framework which generates virtually-stained images using label-free tissue, where different stains are merged following a micro-structure map defined by the user. This approach uses a single deep neural network that receives two different sources of information at its input: (1) autofluorescence images of the label-free tissue sample, and (2) a digital staining matrix which represents the desired microscopic map of different stains to be virtually generated at the same tissue section. This digital staining matrix is also used to virtually blend existing stains, digitally synthesizing new histological stains. We trained and blindly tested this virtual-staining network using unlabeled kidney tissue sections to generate micro-structured combinations of Hematoxylin and Eosin (H&E), Jones silver stain, and Masson's Trichrome stain. Using a single network, this approach multiplexes virtual staining of label-free tissue with multiple types of stains and paves the way for synthesizing new digital histological stains that can be created on the same tissue cross-section, which is currently not feasible with standard histochemical staining methods.

preprint2020arXiv

Early-detection and classification of live bacteria using time-lapse coherent imaging and deep learning

We present a computational live bacteria detection system that periodically captures coherent microscopy images of bacterial growth inside a 60 mm diameter agar-plate and analyzes these time-lapsed holograms using deep neural networks for rapid detection of bacterial growth and classification of the corresponding species. The performance of our system was demonstrated by rapid detection of Escherichia coli and total coliform bacteria (i.e., Klebsiella aerogenes and Klebsiella pneumoniae subsp. pneumoniae) in water samples. These results were confirmed against gold-standard culture-based results, shortening the detection time of bacterial growth by >12 h as compared to the Environmental Protection Agency (EPA)-approved analytical methods. Our experiments further confirmed that this method successfully detects 90% of bacterial colonies within 7-10 h (and >95% within 12 h) with a precision of 99.2-100%, and correctly identifies their species in 7.6-12 h with 80% accuracy. Using pre-incubation of samples in growth media, our system achieved a limit of detection (LOD) of ~1 colony forming unit (CFU)/L within 9 h of total test time. This computational bacteria detection and classification platform is highly cost-effective (~$0.6 per test) and high-throughput with a scanning speed of 24 cm2/min over the entire plate surface, making it highly suitable for integration with the existing analytical methods currently used for bacteria detection on agar plates. Powered by deep learning, this automated and cost-effective live bacteria detection platform can be transformative for a wide range of applications in microbiology by significantly reducing the detection time, also automating the identification of colonies, without labeling or the need for an expert.

preprint2020arXiv

Ensemble learning of diffractive optical networks

A plethora of research advances have emerged in the fields of optics and photonics that benefit from harnessing the power of machine learning. Specifically, there has been a revival of interest in optical computing hardware, due to its potential advantages for machine learning tasks in terms of parallelization, power efficiency and computation speed. Diffractive Deep Neural Networks (D2NNs) form such an optical computing framework, which benefits from deep learning-based design of successive diffractive layers to all-optically process information as the input light diffracts through these passive layers. D2NNs have demonstrated success in various tasks, including e.g., object classification, spectral-encoding of information, optical pulse shaping and imaging, among others. Here, we significantly improve the inference performance of diffractive optical networks using feature engineering and ensemble learning. After independently training a total of 1252 D2NNs that were diversely engineered with a variety of passive input filters, we applied a pruning algorithm to select an optimized ensemble of D2NNs that collectively improve their image classification accuracy. Through this pruning, we numerically demonstrated that ensembles of N=14 and N=30 D2NNs achieve blind testing accuracies of 61.14% and 62.13%, respectively, on the classification of CIFAR-10 test images, providing an inference improvement of >16% compared to the average performance of the individual D2NNs within each ensemble. These results constitute the highest inference accuracies achieved to date by any diffractive optical neural network design on the same dataset and might provide a significant leapfrog to extend the application space of diffractive optical image classification and machine vision systems.

preprint2020arXiv

Label-free detection of Giardia lamblia cysts using a deep learning-enabled portable imaging flow cytometer

We report a field-portable and cost-effective imaging flow cytometer that uses deep learning to accurately detect Giardia lamblia cysts in water samples at a volumetric throughput of 100 mL/h. This flow cytometer uses lensfree color holographic imaging to capture and reconstruct phase and intensity images of microscopic objects in a continuously flowing sample, and automatically identifies Giardia Lamblia cysts in real-time without the use of any labels or fluorophores. The imaging flow cytometer is housed in an environmentally-sealed enclosure with dimensions of 19 cm x 19 cm x 16 cm and weighs 1.6 kg. We demonstrate that this portable imaging flow cytometer coupled to a laptop computer can detect and quantify, in real-time, low levels of Giardia contamination (e.g., <10 cysts per 50 mL) in both freshwater and seawater samples. The field-portable and label-free nature of this method has the potential to allow rapid and automated screening of drinking water supplies in resource limited settings in order to detect waterborne parasites and monitor the integrity of the filters used for water treatment.

preprint2020arXiv

Misalignment Resilient Diffractive Optical Networks

As an optical machine learning framework, Diffractive Deep Neural Networks (D2NN) take advantage of data-driven training methods used in deep learning to devise light-matter interaction in 3D for performing a desired statistical inference task. Multi-layer optical object recognition platforms designed with this diffractive framework have been shown to generalize to unseen image data achieving e.g., >98% blind inference accuracy for hand-written digit classification. The multi-layer structure of diffractive networks offers significant advantages in terms of their diffraction efficiency, inference capability and optical signal contrast. However, the use of multiple diffractive layers also brings practical challenges for the fabrication and alignment of these diffractive systems for accurate optical inference. Here, we introduce and experimentally demonstrate a new training scheme that significantly increases the robustness of diffractive networks against 3D misalignments and fabrication tolerances in the physical implementation of a trained diffractive network. By modeling the undesired layer-to-layer misalignments in 3D as continuous random variables in the optical forward model, diffractive networks are trained to maintain their inference accuracy over a large range of misalignments; we term this diffractive network design as vaccinated D2NN (v-D2NN). We further extend this vaccination strategy to the training of diffractive networks that use differential detectors at the output plane as well as to jointly-trained hybrid (optical-electronic) networks to reveal that all of these diffractive designs improve their resilience to misalignments by taking into account possible 3D fabrication variations and displacements during their training phase.

preprint2020arXiv

Neural network-based on-chip spectroscopy using a scalable plasmonic encoder

Conventional spectrometers are limited by trade-offs set by size, cost, signal-to-noise ratio (SNR), and spectral resolution. Here, we demonstrate a deep learning-based spectral reconstruction framework, using a compact and low-cost on-chip sensing scheme that is not constrained by the design trade-offs inherent to grating-based spectroscopy. The system employs a plasmonic spectral encoder chip containing 252 different tiles of nanohole arrays fabricated using a scalable and low-cost imprint lithography method, where each tile has a unique geometry and, thus, a unique optical transmission spectrum. The illumination spectrum of interest directly impinges upon the plasmonic encoder, and a CMOS image sensor captures the transmitted light, without any lenses, gratings, or other optical components in between, making the entire hardware highly compact, light-weight and field-portable. A trained neural network then reconstructs the unknown spectrum using the transmitted intensity information from the spectral encoder in a feed-forward and non-iterative manner. Benefiting from the parallelization of neural networks, the average inference time per spectrum is ~28 microseconds, which is orders of magnitude faster compared to other computational spectroscopy approaches. When blindly tested on unseen new spectra (N = 14,648) with varying complexity, our deep-learning based system identified 96.86% of the spectral peaks with an average peak localization error, bandwidth error, and height error of 0.19 nm, 0.18 nm, and 7.60%, respectively. This system is also highly tolerant to fabrication defects that may arise during the imprint lithography process, which further makes it ideal for applications that demand cost-effective, field-portable and sensitive high-resolution spectroscopy tools.

preprint2020arXiv

Terahertz Pulse Shaping Using Diffractive Surfaces

Recent advances in deep learning have been providing non-intuitive solutions to various inverse problems in optics. At the intersection of machine learning and optics, diffractive networks merge wave-optics with deep learning to design task-specific elements to all-optically perform various tasks such as object classification and machine vision. Here, we present a diffractive network, which is used to shape an arbitrary broadband pulse into a desired optical waveform, forming a compact pulse engineering system. We experimentally demonstrate the synthesis of square pulses with different temporal-widths by manufacturing passive diffractive layers that collectively control both the spectral amplitude and the phase of an input terahertz pulse. Our results constitute the first demonstration of direct pulse shaping in terahertz spectrum, where a complex-valued spectral modulation function directly acts on terahertz frequencies. Furthermore, a Lego-like physical transfer learning approach is presented to illustrate pulse-width tunability by replacing part of an existing network with newly trained diffractive layers, demonstrating its modularity. This learning-based diffractive pulse engineering framework can find broad applications in e.g., communications, ultra-fast imaging and spectroscopy.

preprint2019arXiv

Automated screening of sickle cells using a smartphone-based microscope and deep learning

Sickle cell disease (SCD) is a major public health priority throughout much of the world, affecting millions of people. In many regions, particularly those in resource-limited settings, SCD is not consistently diagnosed. In Africa, where the majority of SCD patients reside, more than 50% of the 0.2-0.3 million children born with SCD each year will die from it; many of these deaths are in fact preventable with correct diagnosis and treatment. Here we present a deep learning framework which can perform automatic screening of sickle cells in blood smears using a smartphone microscope. This framework uses two distinct, complementary deep neural networks. The first neural network enhances and standardizes the blood smear images captured by the smartphone microscope, spatially and spectrally matching the image quality of a laboratory-grade benchtop microscope. The second network acts on the output of the first image enhancement neural network and is used to perform the semantic segmentation between healthy and sickle cells within a blood smear. These segmented images are then used to rapidly determine the SCD diagnosis per patient. We blindly tested this mobile sickle cell detection method using blood smears from 96 unique patients (including 32 SCD patients) that were imaged by our smartphone microscope, and achieved ~98% accuracy, with an area-under-the-curve (AUC) of 0.998. With its high accuracy, this mobile and cost-effective method has the potential to be used as a screening tool for SCD and other blood cell disorders in resource-limited settings.