On-chip flow cytometer using integrated photonics for the detection of human leukocytes.

Differentiation between leukocyte subtypes like monocytes and lymphocytes is essential for cell therapy and research applications. To guarantee the cost-effective delivery of functional cells in cell therapies, billions of cells must be processed in a limited time. Yet, the sorting rates of commercial cell sorters are not high enough to reach the required yield. Process parallelization by using multiple instruments increases variability and production cost. A compact solution with higher throughput can be provided by multichannel flow cytometers combining fluidics and optics on-chip. In this work, we present a micro-flow cytometer with monolithically integrated photonics and fluidics and demonstrate that both the illumination of cells, as well as the collection of scattered light, can be realized using photonic integrated circuits. Our device is the first with sufficient resolution for the discrimination of lymphocytes and monocytes. Innovations in microfabrication have enabled complete integration of miniaturized photonic components and fluidics in a CMOS-compatible wafer stack. In combination with external optics, the device is ready for the collection of fluorescence using the on-chip excitation.

Toward point-of-care diagnostics: Running enzymatic assays on a photonic waveguide-based sensor chip with a portable, benchtop measurement system.

We demonstrate a portable, compact system to perform absorption-based enzymatic assays at a visible wavelength of 639 nm on a photonic waveguide-based sensor chip, suitable for lab-on-a-chip applications. The photonic design and fabrication of the sensor are described, and a detailed overview of the portable measurement system is presented. In this publication, we use an integrated photonic waveguide-based absorbance sensor to run a full enzymatic assay. An assay to detect creatinine in plasma is simultaneously performed on both the photonic sensor on the portable setup and on a commercial microplate reader for a clinically relevant creatinine concentration range. We observed a high correlation between the measured waveguide propagation loss and the optical density measurement from the plate reader and measured a limit-of-detection of 4.5 µM creatinine in the sensor well, covering the relevant clinical range for creatinine detection.

Molecular detection of SARS-COV-2 in exhaled breath at the point-of-need.

The SARS-CoV-2 pandemic has highlighted the need for improved technologies to help control the spread of contagious pathogens. While rapid point-of-need testing plays a key role in strategies to rapidly identify and isolate infectious patients, current test approaches have significant shortcomings related to assay limitations and sample type. Direct quantification of viral shedding in exhaled particles may offer a better rapid testing approach, since SARS-CoV-2 is believed to spread mainly by aerosols. It assesses contagiousness directly, the sample is easy and comfortable to obtain, sampling can be standardized, and the limited sample volume lends itself to a fast and sensitive analysis. In view of these benefits, we developed and tested an approach where exhaled particles are efficiently sampled using inertial impaction in a micromachined silicon chip, followed by an RT-qPCR molecular assay to detect SARS-CoV-2 shedding. Our portable, silicon impactor allowed for the efficient capture (>85%) of respiratory particles down to 300 nm without the need for additional equipment. We demonstrate using both conventional off-chip and in-situ PCR directly on the silicon chip that sampling subjects' breath in less than a minute yields sufficient viral RNA to detect infections as early as standard sampling methods. A longitudinal study revealed clear differences in the temporal dynamics of viral load for nasopharyngeal swab, saliva, breath, and antigen tests. Overall, after an infection, the breath-based test remains positive during the first week but is the first to consistently report a negative result, putatively signalling the end of contagiousness and further emphasizing the potential of this tool to help manage the spread of airborne respiratory infections.

Self-aligned micro-optic integrated photonic platform.

In this work, we present the fabrication technology of a monolithically integrated photonic platform combining key components for optical coherence tomography (OCT) imaging, thereby including a photonic interferometer, a collimating lens, and a 45° reflecting mirror that directs the light from the interferometer to the collimator. The proposed integration process simplifies the fabrication of an interferometric system and inherently overcomes the complexity of costly alignment procedures while complying with the necessarily stringent optical constraints. Fabricated waveguide characterization shows total optical losses as low as 3 dB, and less than 1 dB of additional loss due to the Si 45° mirror facet. The alignment standard deviation of all components is within 15 nm. The integrated lens profile achieves a divergence angle smaller than 0.7°, which is close to that of a collimator. The proposed photonic platform provides the premise for low-cost and small-footprint single-chip OCT systems.

Handheld multi-modal imaging for point-of-care skin diagnosis based on akinetic integrated optics optical coherence tomography.

A handheld skin imaging system with joint optical coherence tomography (OCT) at 1300 nm and digital epiluminescence microscopy (EM) is presented. The 2 modalities are physically co-registered in a common-path configuration. The instrument is enabled by a dedicated planar lightwave circuit with a footprint of only 1.1 × 19.5 mm2 that provides akinetic axial OCT scanning at speeds up to 24 kHz. Lateral scanning is implemented through a low-voltage Micro Electro-Mechanical System (MEMS) mirror packaged with the axial scanner in a hermetic butterfly module. The OCT system, with a volume of only 80 × 27 × 14 mm3 , achieves an isotropic resolution of ~11 µm in tissue, -93 dB sensitivity, 12 mm lateral field of view, and an axial scanning range of 2.8 mm in air. The complete battery-powered device has a weight of 3 kg in a tablet format, enabling point-of-care use cases. This work shows that integration of complementary imaging modalities through miniaturization technology results in clinically valuable instruments supporting a patient-centered diagnostic imaging workflow.

Silicon chips detect intracellular pressure changes in living cells.

The ability to measure pressure changes inside different components of a living cell is important, because it offers an alternative way to study fundamental processes that involve cell deformation. Most current techniques such as pipette aspiration, optical interferometry or external pressure probes use either indirect measurement methods or approaches that can damage the cell membrane. Here we show that a silicon chip small enough to be internalized into a living cell can be used to detect pressure changes inside the cell. The chip, which consists of two membranes separated by a vacuum gap to form a Fabry-Pérot resonator, detects pressure changes that can be quantified from the intensity of the reflected light. Using this chip, we show that extracellular hydrostatic pressure is transmitted into HeLa cells and that these cells can endure hypo-osmotic stress without significantly increasing their intracellular hydrostatic pressure.

Nanophotonic lab-on-a-chip platforms including novel bimodal interferometers, microfluidics and grating couplers.

One of the main limitations for achieving truly lab-on-a-chip (LOC) devices for point-of-care diagnosis is the incorporation of the "on-chip" detection. Indeed, most of the state-of-the-art LOC devices usually require complex read-out instrumentation, losing the main advantages of portability and simplicity. In this context, we present our last advances towards the achievement of a portable and label-free LOC platform with highly sensitive "on-chip" detection by using nanophotonic biosensors. Bimodal waveguide interferometers fabricated by standard silicon processes have been integrated with sub-micronic grating couplers for efficient light in-coupling, showing a phase resolution of 6.6 × 10(-4)× 2π rad and a limit of detection of 3.3 × 10(-7) refractive index unit (RIU) in bulk. A 3D network of SU-8 polymer microfluidics monolithically assembled at the wafer-level was included, ensuring perfect sealing and compact packaging. To overcome some of the drawbacks inherent to interferometric read-outs, a novel all-optical wavelength modulation system has been implemented, providing a linear response and a direct read-out of the phase variation. Sensitivity, specificity and reproducibility of the wavelength modulated BiMW sensor has been demonstrated through the label-free immunodetection of the human hormone hTSH at picomolar level using a reliable biofunctionalization process.

Localised actuation in composites containing carbon nanotubes and liquid crystalline elastomers.

A liquid crystalline elastomer-carbon nanotube (LCE-CNT) composite displays a reversible shape change property in response to light. The development of some systems such as tactile devices requires localised actuation of this material. A method is reported that combines mechanical stretching and thermal crosslinking of an LCE-CNT for creating sufficiently well-aligned liquid crystal units to produce localised actuation. The method demonstrates that it is feasible to optically drive a LCE-CNT film within a localised area, since only the walls of the stretched parts of the film contain aligned LC domains.

Diffraction grating couplers milled in Si3N4 rib waveguides with a focused ion beam.

Focused ion beam milling is a processing technology which allows flexible direct writing of nanometer scale features efficiently substituting electron beam lithography. No mask need results in ability for patterns writing even on fragile micromechanical devices. In this work we studied the abilities of the tool for fabrication of diffraction grating couplers in silicon nitride waveguides. The gratings were fabricated on a chip with extra fragile cantilevers of sub micron thickness. Optical characterization of the couplers was done using excitation of the waveguides in visible range by focused Gaussian beams of different waist sizes. Influence of Ga+ implantation on the device performance was studied.

High-resolution photometric optical monitoring for thin-film deposition.

Real-time monitoring of thin-film deposition with high resolution is important for precise fabrication of thin-film devices in a technological environment with ever-increasing demands for smaller size and better performance. Using photometry, we were able to achieve a real-time optical monitoring resolution of film thickness that is comparable with a single atomic layer scale (i.e., subnanometer). Filtering noise efficiently and compensating for sources of error by use of an appropriate model produced this high resolution. The procedure proved reliable and can be useful in the thin-film-deposition industry.