An End-to-End Platform for Digital Pathology Using Hyperspectral Autofluorescence Microscopy and Deep Learning-Based Virtual Histology.

Conventional histopathology involves expensive and labor-intensive processes that often consume tissue samples, rendering them unavailable for other analyses. We present a novel end-to-end workflow for pathology powered by hyperspectral microscopy and deep learning. First, we developed a custom hyperspectral microscope to nondestructively image the autofluorescence of unstained tissue sections. We then trained a deep learning model to use autofluorescence to generate virtual histologic stains, which avoids the cost and variability of chemical staining procedures and conserves tissue samples. We showed that the virtual images reproduce the histologic features present in the real-stained images using a randomized nonalcoholic steatohepatitis (NASH) scoring comparison study, where both real and virtual stains are scored by pathologists (D.T., A.D.B., R.K.P.). The test showed moderate-to-good concordance between pathologists' scoring on corresponding real and virtual stains. Finally, we developed deep learning-based models for automated NASH Clinical Research Network score prediction. We showed that the end-to-end automated pathology platform is comparable with an independent panel of pathologists for NASH Clinical Research Network scoring when evaluated against the expert pathologist consensus scores. This study provides proof of concept for this virtual staining strategy, which could improve cost, efficiency, and reliability in pathology and enable novel approaches to spatial biology research.

Clinical-Grade Validation of an Autofluorescence Virtual Staining System With Human Experts and a Deep Learning System for Prostate Cancer.

The tissue diagnosis of adenocarcinoma and intraductal carcinoma of the prostate includes Gleason grading of tumor morphology on the hematoxylin and eosin stain and immunohistochemistry markers on the prostatic intraepithelial neoplasia-4 stain (CK5/6, P63, and AMACR). In this work, we create an automated system for producing both virtual hematoxylin and eosin and prostatic intraepithelial neoplasia-4 immunohistochemistry stains from unstained prostate tissue using a high-throughput hyperspectral fluorescence microscope and artificial intelligence and machine learning. We demonstrate that the virtual stainer models can produce high-quality images suitable for diagnosis by genitourinary pathologists. Specifically, we validate our system through extensive human review and computational analysis, using a previously validated Gleason scoring model, and an expert panel, on a large data set of test slides. This study extends our previous work on virtual staining from autofluorescence, demonstrates the clinical utility of this technology for prostate cancer, and exemplifies a rigorous standard of qualitative and quantitative evaluation for digital pathology.

Large color gamut displays with diffraction gratings.

The ability to display a broad variety of colors has great benefits not only in the context of entertainment but also as a means to streamline design in prototyping and manufacturing processes. Displays that use RGB filters or backlights cannot span all colors that occur in nature. To improve the accuracy of color reproduction, there have been attempts to include additional color primaries in displays. Existing solutions, however, have an impact on cost, scalability, and spatial resolution and are predominantly applicable to projection systems. We propose an approach based on combining diffraction grating extractors and the HANS imaging pipeline initially developed for printing. This combination offers unprecedented potential to attain large color gamuts with the same backlights commercially used today.

Carrier dynamics in GaAs photonic crystal cavities near the material band edge.

We measure fast carrier decay rates (6 ps) in GaAs photonic crystal cavities with resonances near the GaAs bandgap energy at room temperature using a pump-probe measurement. Carriers generated via photoexcitation using an above-band femtosecond pulse cause a substantial blue-shift of three time the cavity linewidth for the cavity peak. The experimental results are compared to theoretical models based on free carrier effects near the GaAs band edge. The probe transmission is modified by nearly 30% for an estimated above-band pump energy of 4.2 fJ absorbed in the GaAs slab.

Picosecond all-optical switching in hydrogenated amorphous silicon microring resonators.

We utilize cross-phase modulation to observe all-optical switching in microring resonators fabricated with hydrogenated amorphous silicon (a-Si:H). Using 2.7-ps pulses from a mode-locked fiber laser in the telecom C-band, we observe optical switching of a cw telecom-band probe with full-width at half-maximum switching times of 14.8 ps, using approximately 720 fJ of energy deposited in the microring. In comparison with telecom-band optical switching in undoped crystalline silicon microrings, a-Si:H exhibits substantially higher switching speeds due to reduced impact of free-carrier processes.

High-sensitivity magnetometry based on quantum beats in diamond nitrogen-vacancy centers.

We demonstrate an absolute magnetometer based on quantum beats in the ground state of nitrogen-vacancy centers in diamond. We show that, by eliminating the dependence of spin evolution on the zero-field splitting D, the magnetometer is immune to temperature fluctuation and strain inhomogeneity. We apply this technique to measure low-frequency magnetic field noise by using a single nitrogen-vacancy center located within 500 nm of the surface of an isotopically pure (99.99% 12C) diamond. The photon-shot-noise limited sensitivity achieves 38 nT/sqrt[Hz] for 4.45 s acquisition time, a factor of sqrt[2] better than the implementation which uses only two spin levels. For long acquisition times (>10 s), we realize up to a factor of 15 improvement in magnetic sensitivity, which demonstrates the robustness of our technique against thermal drifts. Applying our technique to nitrogen-vacancy center ensembles, we eliminate dephasing from longitudinal strain inhomogeneity, resulting in a factor of 2.3 improvement in sensitivity.

Optical and spin coherence properties of nitrogen-vacancy centers placed in a 100 nm thick isotopically purified diamond layer.

We have studied optical and spin properties of near-surface nitrogen-vacancy (NV) centers incorporated during chemical vapor phase growth of isotopically purified (12)C single-crystal diamond layers. The spectral diffusion-limited line width of zero-phonon luminescence from the NV centers is 1.2 ± 0.5 GHz, a considerable improvement over that of NV centers formed by ion implantation and annealing. Enhanced spin dephasing times (T(2)* ≈ 90 µs, T(2) ≈ 1.7 ms) due to the reduction of (13)C nuclear spins persist even for NV centers placed within 100 nm of the surface.

Coupling of nitrogen-vacancy centers to photonic crystal cavities in monocrystalline diamond.

The zero-phonon transition rate of a nitrogen-vacancy center is enhanced by a factor of ∼70 by coupling to a photonic crystal resonator fabricated in monocrystalline diamond using standard semiconductor fabrication techniques. Photon correlation measurements on the spectrally filtered zero-phonon line show antibunching, a signature that the collected photoluminescence is emitted primarily by a single nitrogen-vacancy center. The linewidth of the coupled nitrogen-vacancy center and the spectral diffusion are characterized using high-resolution photoluminescence and photoluminescence excitation spectroscopy.

Coherent interference effects in a nano-assembled diamond NV center cavity-QED system.

Diamond nanocrystals containing NV color centers are positioned with 100-nanometer-scale accuracy in the near-field of a high-Q SiO(2) microdisk cavity using a fiber taper. The cavity modified nanocrystal photoluminescence is studied, with Fano-like quantum interference features observed in the far-field emission spectrum. A quantum optical model of the system is proposed and fit to the measured spectra, from which the NV(-) zero phonon line coherent coupling rate to the microdisk is estimated to be 28 MHz for a nearly optimally placed nanocrystal.

Hybrid photonic crystal cavity and waveguide for coupling to diamond NV-centers.

A design for an ultra-high Q photonic crystal nanocavity engineered to interact with nitrogen-vacancy (NV) centers located near the surface of a single crystal diamond sample is presented. The structure is based upon a nanowire photonic crystal geometry, and consists of a patterned high refractive index thin film, such as gallium phosphide (GaP), supported by a diamond substrate. The nanocavity supports a mode with quality factor Q > 1.5 x 10(6) and mode volume V < 0.52(lambda/nGaP)(3), and promises to allow Purcell enhanced collection of spontaneous emission from an NV located more than 50 nm below the diamond surface. The nanowire photonic crystal waveguide can be used to efficiently couple light into and out of the cavity, or as an efficient broadband collector of NV phonon sideband emission. The proposed structures can be fabricated using existing materials and processing techniques.

Observation of the dynamic Jahn-Teller effect in the excited states of nitrogen-vacancy centers in diamond.

The optical transition linewidth and emission polarization of single nitrogen-vacancy (NV) centers are measured from 5 K to room temperature. Interexcited state population relaxation is shown to broaden the zero-phonon line and both the relaxation and linewidth are found to follow a T(5) dependence for T < 100 K. This dependence indicates that the dynamic Jahn-Teller effect is the dominant dephasing mechanism for the NV optical transitions at low temperatures.

Coherent population trapping in diamond N-V centers at zero magnetic field.

Coherent population trapping at zero magnetic field was observed for nitrogen-vacancy centers in diamond under optical excitation. This was measured as a reduction in photoluminescence when the detuning between two excitation lasers matched the 2.88 GHz crystal-field splitting of the color center ground states. This behavior is highly sensitive to strain, which modifies the excited states, and was unexpected following recent experiments demonstrating optical readout of single nitrogen-vacancy electron spins based on cycling transitions. These results demonstrate for the first time that three-level Lambda configurations suitable for proposed quantum information applications can be realized simultaneously for all four orientations of nitrogen-vacancy centers at zero magnetic field.

Near-surface spectrally stable nitrogen vacancy centres engineered in single crystal diamond.

A method for engineering thin (<100 nm) layers of homoepitaxial diamond containing high quality, spectrally stable, isolated nitrogen-vacancy (NV) centres is reported. The photoluminescence excitation linewidth of the engineered NVs are as low as 140 MHz, at temperatures below 12 K, while the spin properties are at a level suitable for quantum memory and spin register applications. This methodology of NV fabrication is an important step toward scalable and practical diamond based photonic devices suitable for quantum information processing.

A gallium nitride single-photon source operating at 200 K.

Fundamentally secure quantum cryptography has still not seen widespread application owing to the difficulty of generating single photons on demand. Semiconductor quantum-dot structures have recently shown great promise as practical single-photon sources, and devices with integrated optical cavities and electrical-carrier injection have already been demonstrated. However, a significant obstacle for the application of commonly used III-V quantum dots to quantum-information-processing schemes is the requirement of liquid-helium cryogenic temperatures. Epitaxially grown gallium nitride quantum dots embedded in aluminium nitride have the potential for operation at much higher temperatures. Here, we report triggered single-photon emission from gallium nitride quantum dots at temperatures up to 200 K, a temperature easily reachable with thermo-electric cooling. Gallium nitride quantum dots also open a new wavelength region in the blue and near-ultraviolet portions of the spectrum for single-photon sources.

Coherent population trapping of single spins in diamond under optical excitation.

Coherent population trapping is demonstrated in single nitrogen-vacancy centers in diamond under optical excitation. For sufficient excitation power, the fluorescence intensity drops almost to the background level when the laser modulation frequency matches the 2.88 GHz splitting of the ground states. The results are well described theoretically by a four-level model, allowing the relative transition strengths to be determined for individual centers. The results show that all-optical control of single spins is possible in diamond.

Coherent population trapping of electron spins in a high-purity n-type GaAs semiconductor.

In high-purity n-type GaAs under a strong magnetic field, we are able to isolate a lambda system composed of two Zeeman states of neutral-donor-bound electrons and the lowest Zeeman state of bound excitons. When the two-photon detuning of this system is zero, we observe a pronounced dip in the excited-state photoluminescence, indicating the creation of the coherent population-trapped state. Our data are consistent with a steady-state three-level density-matrix model. The observation of coherent population trapping in GaAs indicates that this and similar semiconductor systems could be used for various electromagnetically induced transparency type experiments.

Indistinguishable photons from a single-photon device.

Single-photon sources have recently been demonstrated using a variety of devices, including molecules, mesoscopic quantum wells, colour centres, trapped ions and semiconductor quantum dots. Compared with a Poisson-distributed source of the same intensity, these sources rarely emit two or more photons in the same pulse. Numerous applications for single-photon sources have been proposed in the field of quantum information, but most--including linear-optical quantum computation--also require consecutive photons to have identical wave packets. For a source based on a single quantum emitter, the emitter must therefore be excited in a rapid or deterministic way, and interact little with its surrounding environment. Here we test the indistinguishability of photons emitted by a semiconductor quantum dot in a microcavity through a Hong-Ou-Mandel-type two-photon interference experiment. We find that consecutive photons are largely indistinguishable, with a mean wave-packet overlap as large as 0.81, making this source useful in a variety of experiments in quantum optics and quantum information.

Condensation of semiconductor microcavity exciton polaritons.

A phase transition from a classical thermal mixed state to a quantum-mechanical pure state of exciton polaritons is observed in a GaAs multiple quantum-well microcavity from the decrease of the second-order coherence function. Supporting evidence is obtained from the observation of a nonlinear threshold behavior in the pump-intensity dependence of the emission, a polariton-like dispersion relation above threshold, and a decrease of the relaxation time into the lower polariton state. The condensation of microcavity exciton polaritons is confirmed.

Entanglement formation and violation of Bell's inequality with a semiconductor single photon source.

We report the generation of polarization-entangled photons, using a quantum dot single photon source, linear optics, and photodetectors. Two photons created independently are observed to violate Bell's inequality. The density matrix describing the polarization state of the postselected photon pairs is reconstructed and agrees well with a simple model predicting the quality of entanglement from the known parameters of the single photon source. Our scheme provides a method to create no more than one entangled photon pair per cycle after postselection, a feature useful to enhance quantum cryptography protocols based on shared entanglement.

Efficient source of single photons: a single quantum dot in a micropost microcavity.

We have demonstrated efficient production of triggered single photons by coupling a single semiconductor quantum dot to a three-dimensionally confined optical mode in a micropost microcavity. The efficiency of emitting single photons into a single-mode traveling wave is approximately 38%, which is nearly 2 orders of magnitude higher than for a quantum dot in bulk semiconductor material. At the same time, the probability of having more than one photon in a given pulse is reduced by a factor of 7 as compared to light with Poissonian photon statistics.