With histopathology results typically taking several days, the ability to stage tumors during interventions could provide a step change in various cancer interventions. X-ray technology has advanced significantly in recent years with the introduction of phase-based imaging methods. These have been adapted for use in standard labs rather than specialized facilities such as synchrotrons, and approaches that enable fast 3D scans with conventional x-ray sources have been developed. This opens the possibility to produce 3D images with enhanced soft tissue contrast at a level of detail comparable to histopathology, in times sufficiently short to be compatible with use during surgical interventions. In this paper we discuss the application of one such approach to human esophagi obtained from esophagectomy interventions. We demonstrate that the image quality is sufficiently high to enable tumor staging based on the x-ray datasets alone. Alongside detection of involved margins with potentially life-saving implications, staging tumors intra-operatively has the potential to change patient pathways, facilitating optimization of therapeutic interventions during the procedure itself. Besides a prospective intra-operative use, the availability of high-quality 3D images of entire esophageal tumors can support histopathological characterization, from enabling "right slice first time" approaches to understanding the histopathology in the full 3D context of the surrounding tumor environment.

Interferometry offers a precise means of interrogating resonances in dielectric and plasmonic metasurfaces, surpassing spectrometer-imposed resolution limits. However, interferometry implementations often face complexity or instability issues due to heightened sensitivity. Here, we address the necessity for noise compensation and tolerance by harnessing the inherent capabilities of photonic resonances. Our proposed solution, termed "resonant phase noise matching," employs optical referencing to align the phases of equally sensitive, orthogonal components of the same mode. This effectively mitigates drift and noise, facilitating the detection of subtle phase changes induced by a target analyte through spatially selective surface functionalization. Validation of this strategy using Fano resonances in a 2D photonic crystal slab showcases noteworthy phase stability (). With demonstrated label-free detection of low-molecular-weight proteins at clinically relevant concentrations, resonant phase noise matching presents itself as a potentially valuable strategy for advancing scalable, high-performance sensing technology beyond traditional laboratory settings.

The peak power performance of ultrafast fiber lasers scales with fiber mode area, but large fibers host multiple modes that are difficult to control. We demonstrate a technique for single-mode operation of highly multimode fiber based on regenerative amplification. This results in a short-pulse fiber source with, to our knowledge, an unprecedented combination of features: high gain (>55 dB) with negligible amplified spontaneous emission, high pulse energy (>50 μJ), good beam quality ( ≤ 1.3), and transform-limited (300 fs) pulses from a single amplification stage. We discuss peak intensity scaling to much higher levels and other opportunities for short-pulse generation in regenerative fiber amplifiers.

Motile cilia are dynamic hair-like structures covering epithelial surfaces in multiple organs. The periodic coordinated beating of cilia creates waves propagating along the surface, known as the metachronal waves, which transport fluids and mucus along the epithelium. Motile ciliopathies result from disrupted coordinated cilia beating and are associated with serious clinical complications, including reproductive disorders. Despite the recognized clinical significance, research of cilia dynamics is extremely limited. Here, we present quantitative imaging of cilia metachronal waves volumetrically through tissue layers using dynamic optical coherence tomography (OCT). Our method relies on spatiotemporal mapping of the phase of intensity fluctuations in OCT images caused by the ciliary beating. We validated our new method and implemented it to visualize cilia metachronal wave propagation within the mouse fallopian tube. This method can be extended to the assessment of physiological cilia function and ciliary dyskinesias in various organ systems, contributing to better management of pathologies associated with motile ciliopathies.

X-ray microtomography is a nondestructive, three-dimensional inspection technique applied across a vast range of fields and disciplines, ranging from research to industrial, encompassing engineering, biology, and medical research. Phase-contrast imaging extends the domain of application of x-ray microtomography to classes of samples that exhibit weak attenuation, thus appearing with poor contrast in standard x-ray imaging. Notable examples are low-atomic-number materials, like carbon-fiber composites, soft matter, and biological soft tissues. We report on a compact and cost-effective system for x-ray phase-contrast microtomography. The system features high sensitivity to phase gradients and high resolution, requires a low-power sealed x-ray tube, a single optical element, and fits in a small footprint. It is compatible with standard x-ray detector technologies: in our experiments, we have observed that single-photon counting offered higher angular sensitivity, whereas flat panels provided a larger field of view. The system is benchmarked against known-material phantoms, and its potential for soft-tissue three-dimensional imaging is demonstrated on small-animal organs: a piglet esophagus and a rat heart. We believe that the simplicity of the setup we are proposing, combined with its robustness and sensitivity, will facilitate accessing quantitative x-ray phase-contrast microtomography as a research tool across disciplines, including tissue engineering, materials science, and nondestructive testing in general.

Integrated optofluidic biosensors have demonstrated ultrasensitivity down to single particle detection and attomolar target concentrations. However, a wide dynamic range is highly desirable in practice and can usually only be achieved by using multiple detection modalities or sacrificing linearity. Here, we demonstrate an analysis technique that uses temporal excitation at two different time scales to simultaneously enable digital and analog detection of fluorescent targets. We demonstrated the seamless detection of nanobeads across eight orders of magnitude from attomolar to nanomolar concentration. Furthermore, a combination of spectrally varying modulation frequencies and a closed-loop feedback system that provides rapid adjustment of excitation laser powers enables multiplex analysis in the presence of vastly different concentrations. We demonstrated this ability to detect across scales via an analysis of a mixture of fluorescent nanobeads at femtomolar and picomolar concentrations. This technique advances the performance and versatility of integrated biosensors, especially toward point-of-use applications.

High-speed laser scanning microscopes are essential for monitoring fast biological phenomena. However, existing strategies that achieve millisecond time resolution with two-photon microscopes (2PMs) are generally technically challenging and suffer from compromises among imaging field of view, excitation efficiency, and depth penetration in thick tissue. Here, we present a versatile solution that enables a conventional video-rate 2PM to perform 2D scanning at kilohertz frame rates over large fields of view. Our system is based on implementation of a scan multiplier unit that provides inertia-free multiplication of the scanning speed while preserving all the benefits of standard 2PM. We demonstrate kilohertz subcellular-resolution 2PM imaging with an order of magnitude higher imaging throughput than previously achievable and penetration depths exceeding 500 μm, which we apply to the study of neurovascular coupling dynamics in the mouse brain.

X-ray free-electron lasers (XFELs) provide intense pulses that can generate stimulated X-ray emission, a phenomenon that has been observed and studied in materials ranging from neon to copper. Two schemes have been employed: amplified spontaneous emission (ASE) and seeded stimulated emission (SSE), where a second color XFEL pulse provides the seed. Both phenomena are currently explored for coherent X-ray laser sources and spectroscopy. Here, we report measurements of ASE and SSE of the 5.9 keV Mn K fluorescence line from a 3.9 molar NaMnO solution, pumped with 7 femtosecond FWHM XFEL pulses at 6.6 keV. We observed ASE at a pump pulse intensity of 1.7 × 10 W/cm, consistent with earlier findings. We observed SSE at dramatically reduced pump pulse intensities down to 1.1 × 10 W/cm. These intensities are well within the range of many existing XFEL instruments, which supports the experimental feasibility of SSE as a tool to generate coherent X-ray pulses, spectroscopic studies of transition metal complexes, and other applications.

Diffuse optics (DO) is a light-based technique used to study the human brain, but it suffers from low brain specificity. Interferometric diffuse optics (iDO) promises to improve the quantitative accuracy and depth specificity of DO, and particularly, coherent light fluctuations (CLFs) arising from blood flow. iDO techniques have alternatively achieved either time-of-flight (TOF) discrimination or highly parallel detection, but not both at once. Here, we break this barrier with a single iDO instrument. Specifically, we show that rapid tuning of a temporally coherent laser during the sensor integration time increases the effective linewidth seen by a highly parallel interferometer. Using this concept to create a continuously variable and user-specified TOF filter, we demonstrate a solution to the canonical problem of DO, measuring optical properties. Then, with a deep TOF filter, we reduce scalp sensitivity of CLFs by 2.7 times at 1 cm source-collector separation. With this unique combination of desirable features, i.e., TOF-discrimination, spatial localization, and highly parallel CLF detection, we perform multiparametric imaging of light intensities and CLFs via the human forehead.

Snapshot recording of transient dynamics in three dimensions (3-D) is highly demanded in both fundamental and applied sciences. Yet it remains challenging for conventional high-speed cameras to address this need due to limited electronic bandwidth and reliance on mechanical scanning. The emergence of light field tomography (LIFT) provides a new solution to these long-standing problems and enables 3-D imaging at an unprecedented frame rate. However, based on sparse-view computed tomography, LIFT can accommodate only a limited number of projections, degrading the resolution in the reconstructed image. To alleviate this problem, we herein present a spectral encoding scheme to significantly increase the number of allowable projections in LIFT while maintaining its snapshot advantage. The resultant system can record 3-D dynamics at a kilohertz volumetric frame rate. Moreover, by using a multichannel compressed sensing algorithm, we improve the image quality with an enhanced spatial resolution and suppressed aliasing artifacts.

Fundamental understanding of large-scale dynamic connectivity within a living organism requires volumetric imaging over a large field of view (FOV) at biologically relevant speed and resolution. However, most microscopy methods make trade-offs between FOV and axial resolution, making it challenging to observe highly dynamic processes at cellular resolution in 3D across mesoscopic scales (e.g., whole zebrafish larva). To overcome this limitation, we have developed mesoscopic oblique plane microscopy (Meso-OPM) with a diffractive light sheet. By augmenting the illumination angle of the light sheet with a transmission grating, we improved the axial resolution approximately sixfold over existing methods and approximately twofold beyond the diffraction limitation of the primary objective lens. We demonstrated a FOV up to 5.4 mm × 3.3 mm with resolution of 2.5 μm × 3 μm × 6 μm, allowing volumetric imaging of 3D cellular structures with a single scan. Applying Meso-OPM for imaging of zebrafish larvae, we report here whole-body volumetric recordings of neuronal activity at 2 Hz volume rate and whole-body volumetric recordings of blood flow dynamics at 5 Hz with 3D cellular resolution.

Fluorescence microscopy is essential to study biological structures and dynamics. However, existing systems suffer from a trade-off between field of view (FOV), resolution, and system complexity, and thus cannot fulfill the emerging need for miniaturized platforms providing micron-scale resolution across centimeter-scale FOVs. To overcome this challenge, we developed a computational miniature mesoscope (CM) that exploits a computational imaging strategy to enable single-shot, 3D high-resolution imaging across a wide FOV in a miniaturized platform. Here, we present CM V2, which significantly advances both the hardware and computation. We complement the 3 × 3 microlens array with a hybrid emission filter that improves the imaging contrast by 5×, and design a 3D-printed free-form collimator for the LED illuminator that improves the excitation efficiency by 3×. To enable high-resolution reconstruction across a large volume, we develop an accurate and efficient 3D linear shift-variant (LSV) model to characterize spatially varying aberrations. We then train a multimodule deep learning model called CMNet, using only the 3D-LSV simulator. We quantify the detection performance and localization accuracy of CMNet to reconstruct fluorescent emitters under different conditions in simulation. We then show that CMNet generalizes well to experiments and achieves accurate 3D reconstruction across a ~7-mm FOV and 800-μm depth, and provides ~6-μm lateral and ~25-μm axial resolution. This provides an ~8× better axial resolution and ~1400× faster speed compared to the previous model-based algorithm. We anticipate this simple, low-cost computational miniature imaging system will be useful for many large-scale 3D fluorescence imaging applications.

Needle-shaped beams (NBs) featuring a long depth-of-focus (DOF) can drastically improve the resolution of microscopy systems. However, thus far, the implementation of a specific NB has been onerous due to the lack of a common, flexible generation method. Here we develop a spatially multiplexed phase pattern that creates many axially closely spaced foci as a universal platform for customizing various NBs, allowing flexible manipulations of beam length and diameter, uniform axial intensity, and sub-diffraction-limit beams. NBs designed via this method successfully extended the DOF of our optical coherence tomography (OCT) system. It revealed clear individual epidermal cells of the entire human epidermis, fine structures of human dermal-epidermal junction in a large depth range, and a high-resolution dynamic heartbeat of alive larvae.

Brillouin microscopy is an emerging label-free imaging technique used to assess local viscoelastic properties. Quantum-enhanced stimulated Brillouin scattering is demonstrated using low power continuous-wave lasers at 795 nm. A signal-to-noise ratio enhancement of 3.4 dB is reported by using two-mode intensity-difference squeezed light generated with the four-wave mixing process in atomic rubidium vapor. The low optical power and the excitation wavelengths in the water transparency window have the potential to provide a powerful bio-imaging technique for probing mechanical properties of biological samples prone to phototoxicity and thermal effects. The performance enhancement affordable through the use of quantum light may pave the way for significantly improved sensitivity that cannot be achieved classically. The proposed method for utilizing squeezed light for enhanced stimulated Brillouin scattering can be easily adapted for both spectroscopic and imaging applications in biology.

Near-infrared (NIR) fluorescence lifetime imaging (FLI) provides a unique contrast mechanism to monitor biological parameters and molecular events . Single-photon avalanche diode (SPAD) cameras have been recently demonstrated in FLI microscopy (FLIM) applications, but their suitability for macroscopic FLI (MFLI) in deep tissues remains to be demonstrated. Herein, we report NIR MFLI measurement with SwissSPAD2, a large time-gated SPAD camera. We first benchmark its performance in well-controlled experiments, ranging from monitoring environmental effects on fluorescence lifetime, to quantifying Förster resonant energy transfer (FRET) between dyes. Next, we use it for studies of target-drug engagement in live and intact tumor xenografts using FRET. Information obtained with SwissSPAD2 was successfully compared to that obtained with a gated intensified charge-coupled device (ICCD) camera, using two different approaches. Our results demonstrate that SPAD cameras offer a powerful technology for preclinical applications in the NIR window.

Lensless imaging provides opportunities to design imaging systems free from the constraints imposed by traditional camera architectures. Thanks to advances in imaging hardware, fabrication techniques, and new algorithms, researchers have recently developed lensless imaging systems that are extremely compact, lightweight or able to image higher-dimensional quantities. Here we review these recent advances and describe the design principles and their effects that one should consider when developing and using lensless imaging systems.

We present snapshot hyperspectral light field tomography (Hyper-LIFT), a highly efficient method in recording a 5D (, , spatial coordinates; , , angular coordinates; λ, wavelength) plenoptic function. Using a Dove prism array and a cylindrical lens array, we simultaneously acquire multi-angled 1D projections of the object like those in standard sparse-view computed tomography. We further disperse those projections and measure the spectra in parallel using a 2D image sensor. Within a single snapshot, the resultant system can capture a 5D data cube with 270 × 270 × 4 × 4 × 360 voxels. We demonstrated the performance of Hyper-LIFT in imaging spectral volumetric scenes.

An imaging system capable of acquiring high-resolution data at a high speed is in demand. However, the amount of optical information captured by a modern camera is limited by the data transfer bandwidth of electronics, resulting in a reduced spatial and temporal resolution. To overcome this problem, we developed continuously streaming compressed high-speed photography, which can record a dynamic scene with an unprecedented space-bandwidth-time product. By performing compressed imaging in a time-delay-integration manner, we continuously recorded a 0.85 megapixel video at 200 kHz, corresponding to an information flux of 170 gigapixels per second.

In many physical systems, the interaction with an open environment leads to energy dissipation and reduced coherence, making it challenging to control these systems effectively. In the context of wave phenomena, such lossy interactions can be specifically controlled to isolate the system, a condition known as a bound-state-in-continuum (BIC). Despite the recent advances in engineered BICs for photonic waveguiding, practical implementations are still largely polarization- and geometry-specific, and the underlying principles remain to be systematically explored. Here, we theoretically and experimentally study low loss BIC photonic waveguiding within a two-layer heterogeneous electro-optically active integrated photonic platform. We show that coupling to the slab wave continuum can be selectively suppressed for guided modes with different polarizations and spatial structure. We demonstrate a low-loss same-polarization quasi-BIC guided mode enabling a high extinction Mach-Zehnder electro-optic amplitude modulator within a single SiN ridge waveguide integrated with an extended LiNbO slab layer. By elucidating the broad BIC waveguiding principles and demonstrating them in an industry-relevant photonic configuration, this work may inspire innovative approaches to photonic applications such as switching and filtering. The broader impact of this work extends beyond photonics, influencing research in other wave dynamics disciplines, including microwave and acoustics.

Optical parametric oscillators are widely used to generate coherent light at frequencies not accessible by conventional laser gain. However, chip-based parametric oscillators operating in the visible spectrum have suffered from pump-to-signal conversion efficiencies typically less than 0.1 %. Here, we demonstrate efficient optical parametric oscillators based on silicon nitride photonics that address frequencies between 260 THz (1150 nm) and 510 THz (590 nm). Pumping silicon nitride microrings near 385 THz (780 nm) yields monochromatic signal and idler waves with unprecedented output powers in this wavelength range. We estimate on-chip output powers (separately for the signal and idler) between 1 mW and 5 mW and conversion efficiencies reaching ≈15 %. Underlying this improved performance is our development of pulley waveguides for broadband near-critical coupling, which exploits a fundamental connection between the waveguide-resonator coupling rate and conversion efficiency. Finally, we find that mode competition reduces conversion efficiency at high pump powers, thereby constraining the maximum realizable output power. Our work proves that optical parametric oscillators built with integrated photonics can produce useful amounts of visible laser light with high efficiency.