Insertable Glucose Sensor Using a Compact and Cost-Effective Phosphorescence Lifetime Imager and Machine Learning.

Optical continuous glucose monitoring (CGM) systems are emerging for personalized glucose management owing to their lower cost and prolonged durability compared to conventional electrochemical CGMs. Here, we report a computational CGM system, which integrates a biocompatible phosphorescence-based insertable biosensor and a custom-designed phosphorescence lifetime imager (PLI). This compact and cost-effective PLI is designed to capture phosphorescence lifetime images of an insertable sensor through the skin, where the lifetime of the emitted phosphorescence signal is modulated by the local concentration of glucose. Because this phosphorescence signal has a very long lifetime compared to tissue autofluorescence or excitation leakage processes, it completely bypasses these noise sources by measuring the sensor emission over several tens of microseconds after the excitation light is turned off. The lifetime images acquired through the skin are processed by neural network-based models for misalignment-tolerant inference of glucose levels, accurately revealing normal, low (hypoglycemia) and high (hyperglycemia) concentration ranges. Using a 1 mm thick skin phantom mimicking the optical properties of human skin, we performed in vitro testing of the PLI using glucose-spiked samples, yielding 88.8% inference accuracy, also showing resilience to random and unknown misalignments within a lateral distance of ∼4.7 mm with respect to the position of the insertable sensor underneath the skin phantom. Furthermore, the PLI accurately identified larger lateral misalignments beyond 5 mm, prompting user intervention for realignment. The misalignment-resilient glucose concentration inference capability of this compact and cost-effective PLI makes it an appealing wearable diagnostics tool for real-time tracking of glucose and other biomarkers.

Rapid single-tier serodiagnosis of Lyme disease.

Point-of-care serological and direct antigen testing offers actionable insights for diagnosing challenging illnesses, empowering distributed health systems. Here, we report a POC-compatible serologic test for Lyme disease (LD), leveraging synthetic peptides specific to LD antibodies and a paper-based platform for rapid, and cost-effective diagnosis. Antigenic epitopes conserved across Borrelia burgdorferi genospecies, targeted by IgG and IgM antibodies, are selected to develop a multiplexed panel for detection of LD antibodies from patient sera. Multiple peptide epitopes, when combined synergistically with a machine learning-based diagnostic model achieve high sensitivity without sacrificing specificity. Blinded validation with 15 LD-positive and 15 negative samples shows 95.5% sensitivity and 100% specificity. Blind testing with the CDC's LD repository samples confirms the test accuracy, matching lab-based two-tier results, correctly differentiating between LD and look-alike diseases. This LD diagnostic test could potentially replace the cumbersome two-tier testing, improving diagnosis and enabling earlier treatment while facilitating immune monitoring and surveillance.

Repurposing Sewage and Toilet Systems: Environmental, Public Health, and Person-Centered Healthcare Applications.

Global terrestrial water supplies are rapidly depleting due to the consequences of climate change. Water scarcity results in an inevitable compromise of safe hygiene and sanitation practices, leading to the transmission of water-borne infectious diseases, and the preventable deaths of over 800.000 people each year. Moreover, almost 500 million people lack access to toilets and sanitation systems. Ecosystems are estimated to be contaminated by 6.2 million tons of nitrogenous products from human wastewater management practices. It is therefore imperative to transform toilet and sewage systems to promote equitable access to water and sanitation, improve public health, conserve water, and protect ecosystems. Here, the integration of emerging technologies in toilet and sewage networks to repurpose toilet and wastewater systems is reviewed. Potential applications of these systems to develop sustainable solutions to environmental challenges, promote public health, and advance person-centered healthcare are discussed.

Pyramid diffractive optical networks for unidirectional image magnification and demagnification.

Diffractive deep neural networks (D2NNs) are composed of successive transmissive layers optimized using supervised deep learning to all-optically implement various computational tasks between an input and output field-of-view. Here, we present a pyramid-structured diffractive optical network design (which we term P-D2NN), optimized specifically for unidirectional image magnification and demagnification. In this design, the diffractive layers are pyramidally scaled in alignment with the direction of the image magnification or demagnification. This P-D2NN design creates high-fidelity magnified or demagnified images in only one direction, while inhibiting the image formation in the opposite direction-achieving the desired unidirectional imaging operation using a much smaller number of diffractive degrees of freedom within the optical processor volume. Furthermore, the P-D2NN design maintains its unidirectional image magnification/demagnification functionality across a large band of illumination wavelengths despite being trained with a single wavelength. We also designed a wavelength-multiplexed P-D2NN, where a unidirectional magnifier and a unidirectional demagnifier operate simultaneously in opposite directions, at two distinct illumination wavelengths. Furthermore, we demonstrate that by cascading multiple unidirectional P-D2NN modules, we can achieve higher magnification factors. The efficacy of the P-D2NN architecture was also validated experimentally using terahertz illumination, successfully matching our numerical simulations. P-D2NN offers a physics-inspired strategy for designing task-specific visual processors.

Nonlinear encoding in diffractive information processing using linear optical materials.

Nonlinear encoding of optical information can be achieved using various forms of data representation. Here, we analyze the performances of different nonlinear information encoding strategies that can be employed in diffractive optical processors based on linear materials and shed light on their utility and performance gaps compared to the state-of-the-art digital deep neural networks. For a comprehensive evaluation, we used different datasets to compare the statistical inference performance of simpler-to-implement nonlinear encoding strategies that involve, e.g., phase encoding, against data repetition-based nonlinear encoding strategies. We show that data repetition within a diffractive volume (e.g., through an optical cavity or cascaded introduction of the input data) causes the loss of the universal linear transformation capability of a diffractive optical processor. Therefore, data repetition-based diffractive blocks cannot provide optical analogs to fully connected or convolutional layers commonly employed in digital neural networks. However, they can still be effectively trained for specific inference tasks and achieve enhanced accuracy, benefiting from the nonlinear encoding of the input information. Our results also reveal that phase encoding of input information without data repetition provides a simpler nonlinear encoding strategy with comparable statistical inference accuracy to data repetition-based diffractive processors. Our analyses and conclusions would be of broad interest to explore the push-pull relationship between linear material-based diffractive optical systems and nonlinear encoding strategies in visual information processors.

Automated HER2 Scoring in Breast Cancer Images Using Deep Learning and Pyramid Sampling.

Objective and Impact Statement: Human epidermal growth factor receptor 2 (HER2) is a critical protein in cancer cell growth that signifies the aggressiveness of breast cancer (BC) and helps predict its prognosis. Here, we introduce a deep learning-based approach utilizing pyramid sampling for the automated classification of HER2 status in immunohistochemically (IHC) stained BC tissue images. Introduction: Accurate assessment of IHC-stained tissue slides for HER2 expression levels is essential for both treatment guidance and understanding of cancer mechanisms. Nevertheless, the traditional workflow of manual examination by board-certified pathologists encounters challenges, including inter- and intra-observer inconsistency and extended turnaround times. Methods: Our deep learning-based method analyzes morphological features at various spatial scales, efficiently managing the computational load and facilitating a detailed examination of cellular and larger-scale tissue-level details. Results: This approach addresses the tissue heterogeneity of HER2 expression by providing a comprehensive view, leading to a blind testing classification accuracy of 84.70%, on a dataset of 523 core images from tissue microarrays. Conclusion: This automated system, proving reliable as an adjunct pathology tool, has the potential to enhance diagnostic precision and evaluation speed, and might substantially impact cancer treatment planning.

Information-hiding cameras: Optical concealment of object information into ordinary images.

We introduce an information-hiding camera integrated with an electronic decoder that is jointly optimized through deep learning. This system uses a diffractive optical processor, which transforms and hides input images into ordinary-looking patterns that deceive/mislead observers. This information-hiding transformation is valid for infinitely many combinations of secret messages, transformed into ordinary-looking output images through passive light-matter interactions within the diffractive processor. By processing these output patterns, an electronic decoder network accurately reconstructs the original information hidden within the deceptive output. We demonstrated our approach by designing information-hiding diffractive cameras operating under various lighting conditions and noise levels, showing their robustness. We further extended this framework to multispectral operation, allowing the concealment and decoding of multiple images at different wavelengths, performed simultaneously. The feasibility of our framework was also validated experimentally using terahertz radiation. This optical encoder-electronic decoder-based codesign provides a high speed and energy efficient information-hiding camera, offering a powerful solution for visual information security.

A Paper-Based Multiplexed Serological Test to Monitor Immunity against SARS-COV-2 Using Machine Learning.

The rapid spread of SARS-CoV-2 caused the COVID-19 pandemic and accelerated vaccine development to prevent the spread of the virus and control the disease. Given the sustained high infectivity and evolution of SARS-CoV-2, there is an ongoing interest in developing COVID-19 serology tests to monitor population-level immunity. To address this critical need, we designed a paper-based multiplexed vertical flow assay (xVFA) using five structural proteins of SARS-CoV-2, detecting IgG and IgM antibodies to monitor changes in COVID-19 immunity levels. Our platform not only tracked longitudinal immunity levels but also categorized COVID-19 immunity into three groups: protected, unprotected, and infected, based on the levels of IgG and IgM antibodies. We operated two xVFAs in parallel to detect IgG and IgM antibodies using a total of 40 µL of human serum sample in <20 min per test. After the assay, images of the paper-based sensor panel were captured using a mobile phone-based custom-designed optical reader and then processed by a neural network-based serodiagnostic algorithm. The serodiagnostic algorithm was trained with 120 measurements/tests and 30 serum samples from 7 randomly selected individuals and was blindly tested with 31 serum samples from 8 different individuals, collected before vaccination as well as after vaccination or infection, achieving an accuracy of 89.5%. The competitive performance of the xVFA, along with its portability, cost-effectiveness, and rapid operation, makes it a promising computational point-of-care (POC) serology test for monitoring COVID-19 immunity, aiding in timely decisions on the administration of booster vaccines and general public health policies to protect vulnerable populations.

All-optical phase conjugation using diffractive wavefront processing.

Optical phase conjugation (OPC) is a nonlinear technique used for counteracting wavefront distortions, with applications ranging from imaging to beam focusing. Here, we present a diffractive wavefront processor to approximate all-optical phase conjugation. Leveraging deep learning, a set of diffractive layers was optimized to all-optically process an arbitrary phase-aberrated input field, producing an output field with a phase distribution that is the conjugate of the input wave. We experimentally validated this wavefront processor by 3D-fabricating diffractive layers and performing OPC on phase distortions never seen during training. Employing terahertz radiation, our diffractive processor successfully performed OPC through a shallow volume that axially spans tens of wavelengths. We also created a diffractive phase-conjugate mirror by combining deep learning-optimized diffractive layers with a standard mirror. Given its compact, passive and multi-wavelength nature, this diffractive wavefront processor can be used for various applications, e.g., turbidity suppression and aberration correction across different spectral bands.

All-optical complex field imaging using diffractive processors.

Complex field imaging, which captures both the amplitude and phase information of input optical fields or objects, can offer rich structural insights into samples, such as their absorption and refractive index distributions. However, conventional image sensors are intensity-based and inherently lack the capability to directly measure the phase distribution of a field. This limitation can be overcome using interferometric or holographic methods, often supplemented by iterative phase retrieval algorithms, leading to a considerable increase in hardware complexity and computational demand. Here, we present a complex field imager design that enables snapshot imaging of both the amplitude and quantitative phase information of input fields using an intensity-based sensor array without any digital processing. Our design utilizes successive deep learning-optimized diffractive surfaces that are structured to collectively modulate the input complex field, forming two independent imaging channels that perform amplitude-to-amplitude and phase-to-intensity transformations between the input and output planes within a compact optical design, axially spanning ~100 wavelengths. The intensity distributions of the output fields at these two channels on the sensor plane directly correspond to the amplitude and quantitative phase profiles of the input complex field, eliminating the need for any digital image reconstruction algorithms. We experimentally validated the efficacy of our complex field diffractive imager designs through 3D-printed prototypes operating at the terahertz spectrum, with the output amplitude and phase channel images closely aligning with our numerical simulations. We envision that this complex field imager will have various applications in security, biomedical imaging, sensing and material science, among others.

Broadband nonlinear modulation of incoherent light using a transparent optoelectronic neuron array.

Nonlinear optical processing of ambient natural light is highly desired for computational imaging and sensing. Strong optical nonlinear response under weak broadband incoherent light is essential for this purpose. By merging 2D transparent phototransistors (TPTs) with liquid crystal (LC) modulators, we create an optoelectronic neuron array that allows self-amplitude modulation of spatially incoherent light, achieving a large nonlinear contrast over a broad spectrum at orders-of-magnitude lower intensity than achievable in most optical nonlinear materials. We fabricated a 10,000-pixel array of optoelectronic neurons, and experimentally demonstrated an intelligent imaging system that instantly attenuates intense glares while retaining the weaker-intensity objects captured by a cellphone camera. This intelligent glare-reduction is important for various imaging applications, including autonomous driving, machine vision, and security cameras. The rapid nonlinear processing of incoherent broadband light might also find applications in optical computing, where nonlinear activation functions for ambient light conditions are highly sought.

Virtual Staining of Nonfixed Tissue Histology.

Surgical pathology workflow involves multiple labor-intensive steps, such as tissue removal, fixation, embedding, sectioning, staining, and microscopic examination. This process is time-consuming and costly and requires skilled technicians. In certain clinical scenarios, such as intraoperative consultations, there is a need for faster histologic evaluation to provide real-time surgical guidance. Currently, frozen section techniques involving hematoxylin and eosin (H&E) staining are used for intraoperative pathology consultations. However, these techniques have limitations, including a turnaround time of 20 to 30 minutes, staining artifacts, and potential tissue loss, negatively impacting accurate diagnosis. To address these challenges, researchers are exploring alternative optical imaging modalities for rapid microscopic tissue imaging. These modalities differ in optical characteristics, tissue preparation requirements, imaging equipment, and output image quality and format. Some of these imaging methods have been combined with computational algorithms to generate H&E-like images, which could greatly facilitate their adoption by pathologists. Here, we provide a comprehensive, organ-specific review of the latest advancements in emerging imaging modalities applied to nonfixed human tissue. We focused on studies that generated H&E-like images evaluated by pathologists. By presenting up-to-date research progress and clinical utility, this review serves as a valuable resource for scholars and clinicians, covering some of the major technical developments in this rapidly evolving field. It also offers insights into the potential benefits and drawbacks of alternative imaging modalities and their implications for improving patient care.

All-optical image denoising using a diffractive visual processor.

Image denoising, one of the essential inverse problems, targets to remove noise/artifacts from input images. In general, digital image denoising algorithms, executed on computers, present latency due to several iterations implemented in, e.g., graphics processing units (GPUs). While deep learning-enabled methods can operate non-iteratively, they also introduce latency and impose a significant computational burden, leading to increased power consumption. Here, we introduce an analog diffractive image denoiser to all-optically and non-iteratively clean various forms of noise and artifacts from input images - implemented at the speed of light propagation within a thin diffractive visual processor that axially spans <250 × λ, where λ is the wavelength of light. This all-optical image denoiser comprises passive transmissive layers optimized using deep learning to physically scatter the optical modes that represent various noise features, causing them to miss the output image Field-of-View (FoV) while retaining the object features of interest. Our results show that these diffractive denoisers can efficiently remove salt and pepper noise and image rendering-related spatial artifacts from input phase or intensity images while achieving an output power efficiency of ~30-40%. We experimentally demonstrated the effectiveness of this analog denoiser architecture using a 3D-printed diffractive visual processor operating at the terahertz spectrum. Owing to their speed, power-efficiency, and minimal computational overhead, all-optical diffractive denoisers can be transformative for various image display and projection systems, including, e.g., holographic displays.

Diffractive optical computing in free space.

Structured optical materials create new computing paradigms using photons, with transformative impact on various fields, including machine learning, computer vision, imaging, telecommunications, and sensing. This Perspective sheds light on the potential of free-space optical systems based on engineered surfaces for advancing optical computing. Manipulating light in unprecedented ways, emerging structured surfaces enable all-optical implementation of various mathematical functions and machine learning tasks. Diffractive networks, in particular, bring deep-learning principles into the design and operation of free-space optical systems to create new functionalities. Metasurfaces consisting of deeply subwavelength units are achieving exotic optical responses that provide independent control over different properties of light and can bring major advances in computational throughput and data-transfer bandwidth of free-space optical processors. Unlike integrated photonics-based optoelectronic systems that demand preprocessed inputs, free-space optical processors have direct access to all the optical degrees of freedom that carry information about an input scene/object without needing digital recovery or preprocessing of information. To realize the full potential of free-space optical computing architectures, diffractive surfaces and metasurfaces need to advance symbiotically and co-evolve in their designs, 3D fabrication/integration, cascadability, and computing accuracy to serve the needs of next-generation machine vision, computational imaging, mathematical computing, and telecommunication technologies.

Virtual histological staining of unlabeled autopsy tissue.

Traditional histochemical staining of post-mortem samples often confronts inferior staining quality due to autolysis caused by delayed fixation of cadaver tissue, and such chemical staining procedures covering large tissue areas demand substantial labor, cost and time. Here, we demonstrate virtual staining of autopsy tissue using a trained neural network to rapidly transform autofluorescence images of label-free autopsy tissue sections into brightfield equivalent images, matching hematoxylin and eosin (H&E) stained versions of the same samples. The trained model can effectively accentuate nuclear, cytoplasmic and extracellular features in new autopsy tissue samples that experienced severe autolysis, such as COVID-19 samples never seen before, where the traditional histochemical staining fails to provide consistent staining quality. This virtual autopsy staining technique provides a rapid and resource-efficient solution to generate artifact-free H&E stains despite severe autolysis and cell death, also reducing labor, cost and infrastructure requirements associated with the standard histochemical staining.

Rapid sensing of hidden objects and defects using a single-pixel diffractive terahertz sensor.

Terahertz waves offer advantages for nondestructive detection of hidden objects/defects in materials, as they can penetrate most optically-opaque materials. However, existing terahertz inspection systems face throughput and accuracy restrictions due to their limited imaging speed and resolution. Furthermore, machine-vision-based systems using large-pixel-count imaging encounter bottlenecks due to their data storage, transmission and processing requirements. Here, we report a diffractive sensor that rapidly detects hidden defects/objects within a 3D sample using a single-pixel terahertz detector, eliminating sample scanning or image formation/processing. Leveraging deep-learning-optimized diffractive layers, this diffractive sensor can all-optically probe the 3D structural information of samples by outputting a spectrum, directly indicating the presence/absence of hidden structures or defects. We experimentally validated this framework using a single-pixel terahertz time-domain spectroscopy set-up and 3D-printed diffractive layers, successfully detecting unknown hidden defects inside silicon samples. This technique is valuable for applications including security screening, biomedical sensing and industrial quality control.

Artificial intelligence-enabled quantitative phase imaging methods for life sciences.

Quantitative phase imaging, integrated with artificial intelligence, allows for the rapid and label-free investigation of the physiology and pathology of biological systems. This review presents the principles of various two-dimensional and three-dimensional label-free phase imaging techniques that exploit refractive index as an intrinsic optical imaging contrast. In particular, we discuss artificial intelligence-based analysis methodologies for biomedical studies including image enhancement, segmentation of cellular or subcellular structures, classification of types of biological samples and image translation to furnish subcellular and histochemical information from label-free phase images. We also discuss the advantages and challenges of artificial intelligence-enabled quantitative phase imaging analyses, summarize recent notable applications in the life sciences, and cover the potential of this field for basic and industrial research in the life sciences.

Learning diffractive optical communication around arbitrary opaque occlusions.

Free-space optical communication becomes challenging when an occlusion blocks the light path. Here, we demonstrate a direct communication scheme, passing optical information around a fully opaque, arbitrarily shaped occlusion that partially or entirely occludes the transmitter's field-of-view. In this scheme, an electronic neural network encoder and a passive, all-optical diffractive network-based decoder are jointly trained using deep learning to transfer the optical information of interest around the opaque occlusion of an arbitrary shape. Following its training, the encoder-decoder pair can communicate any arbitrary optical information around opaque occlusions, where the information decoding occurs at the speed of light propagation through passive light-matter interactions, with resilience against various unknown changes in the occlusion shape and size. We also validate this framework experimentally in the terahertz spectrum using a 3D-printed diffractive decoder. Scalable for operation in any wavelength regime, this scheme could be particularly useful in emerging high data-rate free-space communication systems.

Amphiphilic Particle-Stabilized Nanoliter Droplet Reactors with a Multimodal Portable Reader for Distributive Biomarker Quantification.

Compartmentalization, leveraging microfluidics, enables highly sensitive assays, but the requirement for significant infrastructure for their design, build, and operation limits access. Multimaterial particle-based technologies thermodynamically stabilize monodisperse droplets as individual reaction compartments with simple liquid handling steps, precluding the need for expensive microfluidic equipment. Here, we further improve the accessibility of this lab on a particle technology to resource-limited settings by combining this assay system with a portable multimodal reader, thus enabling nanoliter droplet assays in an accessible platform. We show the utility of this platform in measuring N-terminal propeptide B-type natriuretic peptide (NT-proBNP), a heart failure biomarker, in complex medium and patient samples. We report a limit of detection of ∼0.05 ng/mL and a linear response between 0.2 and 2 ng/mL in spiked plasma samples. We also show that, owing to the plurality of measurements per sample, "swarm" sensing acquires better statistical quantitation with a portable reader. Monte Carlo simulations show the increasing capability of this platform to differentiate between negative and positive samples, i.e., below or above the clinical cutoff for acute heart failure (∼0.1 ng/mL), as a function of the number of particles measured. Our platform measurements correlate with gold standard ELISA measurement in cardiac patient samples, and achieve lower variation in measurement across samples compared to the standard well plate-based ELISA. Thus, we show the capabilities of a cost-effective droplet-reader system in accurately measuring biomarkers in nanoliter droplets for diseases that disproportionately affect underserved communities in resource-limited settings.

High-throughput terahertz imaging: progress and challenges.

Many exciting terahertz imaging applications, such as non-destructive evaluation, biomedical diagnosis, and security screening, have been historically limited in practical usage due to the raster-scanning requirement of imaging systems, which impose very low imaging speeds. However, recent advancements in terahertz imaging systems have greatly increased the imaging throughput and brought the promising potential of terahertz radiation from research laboratories closer to real-world applications. Here, we review the development of terahertz imaging technologies from both hardware and computational imaging perspectives. We introduce and compare different types of hardware enabling frequency-domain and time-domain imaging using various thermal, photon, and field image sensor arrays. We discuss how different imaging hardware and computational imaging algorithms provide opportunities for capturing time-of-flight, spectroscopic, phase, and intensity image data at high throughputs. Furthermore, the new prospects and challenges for the development of future high-throughput terahertz imaging systems are briefly introduced.