Calibration Methods for Time-to-Digital Converters.

In this paper, two of the most common calibration methods of synchronous TDCs, which are the bin-by-bin calibration and the average-bin-width calibration, are first presented and compared. Then, an innovative new robust calibration method for asynchronous TDCs is proposed and evaluated. Simulation results showed that: (i) For a synchronous TDC, the bin-by-bin calibration, applied to a histogram, does not improve the TDC's differential non-linearity (DNL); nevertheless, it improves its Integral Non-Linearity (INL), whereas the average-bin-width calibration significantly improves both the DNL and the INL. (ii) For an asynchronous TDC, the DNL can be improved up to 10 times by applying the bin-by-bin calibration, whereas the proposed method is almost independent of the non-linearity of the TDC and can improve the DNL up to 100 times. The simulation results were confirmed by experiments carried out using real TDCs implemented on a Cyclone V SoC-FPGA. For an asynchronous TDC, the proposed calibration method is 10 times better than the bin-by-bin method in terms of the DNL improvement.

Carbon Dioxide Sensing-Biomedical Applications to Human Subjects.

Carbon dioxide (CO2) monitoring in human subjects is of crucial importance in medical practice. Transcutaneous monitors based on the Stow-Severinghaus electrode make a good alternative to the painful and risky arterial "blood gases" sampling. Yet, such monitors are not only expensive, but also bulky and continuously drifting, requiring frequent recalibrations by trained medical staff. Aiming at finding alternatives, the full panel of CO2 measurement techniques is thoroughly reviewed. The physicochemical working principle of each sensing technique is given, as well as some typical merit criteria, advantages, and drawbacks. An overview of the main CO2 monitoring methods and sites routinely used in clinical practice is also provided, revealing their constraints and specificities. The reviewed CO2 sensing techniques are then evaluated in view of the latter clinical constraints and transcutaneous sensing coupled to a dye-based fluorescence CO2 sensing seems to offer the best potential for the development of a future non-invasive clinical CO2 monitor.

Comparison of Time Resolved Optical Turbidity Measurements for Water Monitoring to Standard Real-Time Techniques.

Environmental water monitoring requires the estimation of the suspended solids load. In this paper, we compare the concentration range accessible through three different techniques: optical turbidity, acoustic backscattering and the newly in-lab developed time resolved optical turbidity. We focus on their comparison on measurements made in the laboratory on water suspensions of known particles and concentrations. We used laboratory grade kieselguhr, wheat starch and kaolin as suspended solid surrogates. The explored concentration domains are the ones, for the total suspended solid load, commonly encountered in wastewater and rivers in standard (less than 1 g/L to a few g/L) or extreme conditions such as floods or storm events (up to several dozen g/L). Regarding the operable concentration domain, the time resolved optical turbidity shows a clear advantage upon the other methods, whatever the kind of particle is.

An Ultrafast Active Quenching Active Reset Circuit with 50% SPAD Afterpulsing Reduction in a 28 nm FD-SOI CMOS Technology Using Body Biasing Technique.

An ultrafast Active Quenching-Active Reset (AQAR) circuit is presented for the afterpulsing reduction in a Single Photon Avalanche Diode (SPAD). The proposed circuit is designed in a 28 nm Fully Depleted Silicon On Insulator (FD-SOI) CMOS technology. By exploiting the body biasing technique, the avalanche is detected very quickly and, consequently, is quenched very fast. The fast quenching decreases the avalanche charges, therefore resulting in the afterpulsing reduction. Both post-layout and experimental results are presented and are highly in accordance with each other. It is shown that the proposed AQAR circuit is able to detect the avalanche in less than 40 ps and reduce the avalanche charge and the afterpulsing up to 50%.

Design and Characterization of an Asynchronous Fixed Priority Tree Arbiter for SPAD Array Readout.

The usage of single-photon avalanche diode arrays is becoming increasingly common in various domains such as medical imaging, automotive vision systems, and optical communications. Nowadays, thanks to the development of microelectronics technologies, the SPAD arrays designed for these applications has been drastically well-facilitated, allowing for the manufacturing of large matrices. However, there are growing challenges for the design of readout circuits with the needs of reducing their energy consumption (linked to the usage cost) and data rate. Indeed, the design of the readout circuit for the SPAD array is generally based on synchronous logic; the latter requires synchronization that may increase the dead time of the SPADs and clock trees management that are known to increase power consumption. With these limitations, the long-neglected asynchronous (clockless) logic proved to be a better alternative because of its ability to operate without a clock. In this paper, we presented the design of a 16-to-1 fixed-priority tree arbiter readout circuit for a SPAD array based on asynchronous logic principles. The design of this circuit was explained in detail and supported by simulation results. The manufactured chip was tested, and the experimental results showed that it is possible to record up to 333 million events per second; no reading errors were detected during the data extraction test.

High-dynamic-range microscope imaging based on exposure bracketing in full-field optical coherence tomography.

By applying the proposed high-dynamic-range (HDR) technique based on exposure bracketing, we demonstrate a meaningful reduction in the spatial noise in image frames acquired with a CCD camera so as to improve the fringe contrast in full-field optical coherence tomography (FF-OCT). This new signal processing method thus allows improved probing within transparent or semitransparent samples. The proposed method is demonstrated on 3 µm thick transparent polymer films of Mylar, which, due to their transparency, produce low contrast fringe patterns in white-light interference microscopy. High-resolution tomographic analysis is performed using the technique. After performing appropriate signal processing, resulting XZ sections are observed. Submicrometer-sized defects can be lost in the noise that is present in the CCD images. With the proposed method, we show that by increasing the signal-to-noise ratio of the images, submicrometer-sized defect structures can thus be detected.

Skin temperature influence on transcutaneous carbon dioxide (CO2) conductivity and skin blood flow in healthy human subjects at the arm and wrist.

Objective: present transcutaneous carbon dioxide (CO2)-tcpCO2-monitors suffer from limitations which hamper their widespread use, and call for a new tcpCO2 measurement technique. However, the progress in this area is hindered by the lack of knowledge in transcutaneous CO2 diffusion. To address this knowledge gap, this study focuses on investigating the influence of skin temperature on two key skin properties: CO2 permeability and skin blood flow. Methods: a monocentric prospective exploratory study including 40 healthy adults was undertaken. Each subject experienced a 90 min visit split into five 18 min sessions at different skin temperatures-Non-Heated (NH), 35, 38, 41, and 44°C. At each temperature, custom sensors measured transcutaneous CO2 conductivity and exhalation rate at the arm and wrist, while Laser Doppler Flowmetry (LDF) assessed skin blood flow at the arm. Results: the three studied metrics sharply increased with rising skin temperature. Mean values increased from the NH situation up to 44°C from 4.03 up to 8.88 and from 2.94 up to 8.11 m·s-1 for skin conductivity, and from 80.4 up to 177.5 and from 58.7 up to 162.3 cm3·m-2·h-1 for exhalation rate at the arm and wrist, respectively. Likewise, skin blood flow increased elevenfold for the same temperature increase. Of note, all metrics already augmented significantly in the 35-38°C skin temperature range, which may be reached without active heating-i.e. only using a warm clothing. Conclusion: these results are extremely encouraging for the development of next-generation tcpCO2 sensors. Indeed, the moderate increase (× 2) in skin conductivity from NH to 44°C tends to indicate that heating the skin is not critical from a response time point of view, i.e. little to no skin heating would only result in a doubled sensor response time in the worst case, compared to a maximal heating at 44°C. Crucially, a skin temperature within the 35-38°C range already sharply increases the skin blood flow, suggesting that tcpCO2 correlates well with the arterial paCO2 even at such low skin temperatures. These two conclusions further strengthen the viability of non-heated tcpCO2 sensors, thereby paving the way for the development of wearable transcutaneous capnometers.

Measuring hemoglobin spectra: searching for carbamino-hemoglobin.

SIGNIFICANCE: The arterial carbon dioxide (CO2) partial pressure PaCO2 is a clinically relevant variable. However, its measurement requires arterial blood sampling or bulky and expensive transcutaneous PtcCO2 meters. While the spectrophotometric determination of hemoglobin species-such as oxy-hemoglobin (O2Hb) and deoxy-hemoglobin (HHb)-allowed for the development of pulse oximetry, the measurement of CO2 blood content with minimal discomfort has not been addressed yet. AIM: Characterizing human carbamino-hemoglobin (CO2Hb) absorption spectrum, which is missing from the literature. Providing the theoretical background that will allow for transcutaneous, noninvasive PaCO2 measurements. APPROACH: A tonometry-based approach was used to obtain gas-equilibrated, lysed, diluted human blood. Equilibration was performed with both CO2, dinitrogen (N2), and ambient air. Spectrophotometric measurements were carried out on the 235- to 1000-nm range. A theoretical background was also derived from that of pulse oximetry. RESULTS: The absorption spectra of both CO2Hb and HHb were extremely close and comparable with that of state-of-the-art HHb. The above-mentioned theoretical background led to an estimated relative error above 30% on the measured amount of CO2Hb in a subject's blood. Auxiliary measurements revealed that the use of ethylene diamine tetraacetic acid did not interfere with spectrophotometric measurements, whereas sodium metabisulfite did. CONCLUSIONS: CO2Hb absorption spectrum was measured for the first time. Such spectrum being close to that of HHb, the use of a theoretical background based on pulse oximetry theory for noninvasive PaCO2 measurement seems extremely challenging.

Single snapshot of optical properties image quality improvement using anisotropic two-dimensional windows filtering.

Imaging methods permitting real-time, wide-field, and quantitative optical mapping of biological tissue properties offer an unprecedented range of applications for clinical use. Following the development of spatial frequency domain imaging, we introduce a real-time demodulation method called single snapshot of optical properties (SSOPs). However, since this method uses only a single image to generate absorption and reduced scattering maps, it was limited by a degraded image quality resulting in artifacts that diminished its potential for clinical use. We present filtering strategies for improving the image quality of optical properties maps obtained using SSOPs. We investigate the effect of anisotropic two-dimensional filtering strategies for spatial frequencies ranging from 0.1 to 0.4 mm - 1 directly onto N = 10 hands. Both accuracy and image quality of the optical properties are quantified in comparison with standard, multiple image acquisitions in the spatial frequency domain. Overall, using optimized filters, mean errors in predicting optical properties using SSOP remain under 8.8% in absorption and 7.5% in reduced scattering, while significantly improving image quality. Overall this work contributes to advance real-time, wide-field, and quantitative diffuse optical imaging toward clinical evaluation.

Single snapshot imaging of optical properties using a single-pixel camera: a simulation study.

We present the effects of using a single-pixel camera approach to extract optical properties with the single-snapshot spatial frequency-domain imaging method. We acquired images of a human hand for spatial frequencies ranging from 0.1 to 0.4 mm - 1 with increasing compression ratios using adaptive basis scan wavelet prediction strategy. In summary, our findings indicate that the extracted optical properties remained usable up to 99% of compression rate at a spatial frequency of 0.2 mm - 1 with errors of 5% in reduced scattering and 10% in absorption.

Real-time optical properties and oxygenation imaging using custom parallel processing in the spatial frequency domain.

The development of real-time, wide-field and quantitative diffuse optical imaging methods is becoming increasingly popular for biological and medical applications. Recent developments introduced a novel approach for real-time multispectral acquisition in the spatial frequency domain using spatio-temporal modulation of light. Using this method, optical properties maps (absorption and reduced scattering) could be obtained for two wavelengths (665 nm and 860 nm). These maps, in turn, are used to deduce oxygen saturation levels in tissues. However, while the acquisition was performed in real-time, processing was performed post-acquisition and was not in real-time. In the present article, we present CPU and GPU processing implementations for this method with special emphasis on processing time. The obtained results show that the proposed custom direct method using a General Purpose Graphic Processing Unit (GPGPU) and C CUDA (Compute Unified Device Architecture) implementation enables 1.6 milliseconds processing time for a 1 Mega-pixel image with a maximum average error of 0.1% in extracting optical properties.

Real-time, wide-field, and quantitative oxygenation imaging using spatiotemporal modulation of light.

Quantitative diffuse optical imaging has the potential to provide valuable functional information about tissue status, such as oxygen saturation or blood content to healthcare practitioners in real time. However, significant technical challenges have so far prevented such tools from being deployed in the clinic. Toward achieving this goal, prior research introduced methods based on spatial frequency domain imaging (SFDI) that allow real-time (within milliseconds) wide-field imaging of optical properties but at a single wavelength. However, for this technology to be useful to clinicians, images must be displayed in terms of metrics related to the physiological state of the tissue, hence interpretable to guide decision-making. For this purpose, recent developments introduced multispectral SFDI methods for rapid imaging of oxygenation parameters up to 16 frames per seconds (fps). We introduce real-time, wide-field, and quantitative blood parameters imaging using spatiotemporal modulation of light. Using this method, we are able to quantitatively obtain optical properties at 100 fps at two wavelengths (665 and 860 nm), and therefore oxygenation, oxyhemoglobin, and deoxyhemoglobin, using a single camera with, at most, 4.2% error in comparison with standard SFDI acquisitions.

Towards sensitive, high-throughput, biomolecular assays based on fluorescence lifetime.

Time-resolved fluorescence detection for robust sensing of biomolecular interactions is developed by implementing time-correlated single photon counting in high-throughput conditions. Droplet microfluidics is used as a promising platform for the very fast handling of low-volume samples. We illustrate the potential of this very sensitive and cost-effective technology in the context of an enzymatic activity assay based on fluorescently-labeled biomolecules. Fluorescence lifetime detection by time-correlated single photon counting is shown to enable reliable discrimination between positive and negative control samples at a throughput as high as several hundred samples per second.

High-throughput time-correlated single photon counting.

We demonstrate time-correlated single photon counting (TCSPC) in microfluidic droplets under high-throughput conditions. We discuss the fundamental limitations in the photon acquisition rate imposed by the single photon detection technique and show that it does not preclude accurate fluorescence lifetime (FLT) measurements at a droplet throughput exceeding 1 kHz with remarkable sensitivity. This work paves the way for the implementation of innovative biomolecular interaction assays relying on the FLT detection of nanosecond-lived fluorophores for high-throughput biotechnological applications, including high-throughput screening or cell sorting potentially allowed by droplet microfluidics or other fast sample handling facilities.

Streak camera: a multidetector for diffuse optical tomography.

We describe an experimental setup for time-resolved diffuse optical tomography that uses a seven-channel light guide to transmit scattered light to a streak camera. This setup permits the simultaneous measurement of the time profiles of photons reemitted at different boundary sites of the objects studied. The instrument, its main specifications, and detector-specific data analysis before image reconstruction are described. The instrumentation was tested with phantoms simulating biological tissue, and the absorption and reduced scattering images that were obtained are discussed.