Significance: Multi-laboratory initiatives are essential in performance assessment and standardization—crucial for bringing biophotonics to mature clinical use—to establish protocols and develop reference tissue phantoms that all will allow universal instrument comparison.
Aim: The largest multi-laboratory comparison of performance assessment in near-infrared diffuse optics is presented, involving 28 instruments and 12 institutions on a total of eight experiments based on three consolidated protocols (BIP, MEDPHOT, and NEUROPT) as implemented on three kits of tissue phantoms. A total of 20 synthetic indicators were extracted from the dataset, some of them defined here anew.
Approach: The exercise stems from the Innovative Training Network BitMap funded by the European Commission and expanded to include other European laboratories. A large variety of diffuse optics instruments were considered, based on different approaches (time domain/frequency domain/continuous wave), at various stages of maturity and designed for different applications (e.g., oximetry, spectroscopy, and imaging).
Results: This study highlights a substantial difference in hardware performances (e.g., nine decades in responsivity, four decades in dark count rate, and one decade in temporal resolution). Agreement in the estimates of homogeneous optical properties was within 12% of the median value for half of the systems, with a temporal stability of <5 % over 1 h, and day-to-day reproducibility of <3 % . Other tests encompassed linearity, crosstalk, uncertainty, and detection of optical inhomogeneities.
Conclusions: This extensive multi-laboratory exercise provides a detailed assessment of near-infrared Diffuse optical instruments and can be used for reference grading. The dataset—available soon in an open data repository—can be evaluated in multiple ways, for instance, to compare different analysis tools or study the impact of hardware implementations.
Standard techniques for detection of thyroid cancer (ultrasound screening and fine-needle aspiration biopsy) have limited sensitivity and specificity, leading to a very large number of unnecessary thyroid extraction surgeries. With the aim of improving diagnosis, hybrid diffuse optics and ultrasound were used on nodules patients to obtain tissue hemodynamic information. Nodules rated 4A or 4B in the thyroid imaging reporting and data system (TI-RADS) are of clinical relevance and were classified using a logistic regression model built on our results. Fourteen benign and four malignant nodules were classified with a sensitivity of 100% and specificity of 77%.
KEYWORDS: Near infrared spectroscopy, Continuous wave operation, Measurement devices, Medical devices, In vivo imaging, Tissues, Tissue optics, Spectroscopes, Reliability, Oxygen
During the first peak of the COVID-19 pandemic, we have set up a clinical campaign in ten hospitals worldwide to assess the endothelial health of COVID-19 patients using commercial continuous-wave near-infrared spectroscopy (CW-NIRS) devices (PortaMon, Artinis, NL). In spite of the wide range of clinical applications, the reliability of common CW-NIRS systems for absolute oxygenation measurements was often questioned, opening issues of standardization. In addition, a multi-center trial itself opens issues about how to compare measurements performed by different operators, in different conditions and longitudinally over more than a year. Here, we present how we address these challenges by characterizing and comparing the performance of the devices, with phantom and in vivo experiments.
The HEMOCOVID-19 clinical trial, carried out in 10 hospitals from 5 countries, aims to non-invasively assess, through continuous-wave near-infrared spectroscopy (CW-NIRS), the microvascular and endothelial health in COVID-19 patients admitted to intensive care. We achieve this by performing a vascular occlusion test on the forearm muscle while continuously measuring local tissue oxygen saturation and hemoglobin concentration. We found significant alterations in systemic microcirculation of COVID-19 patients with respect to healthy subjects (i.e. slower deoxygenation during the ischemia and reoxygenation after releasing the cuff, and lower hyperemic response). In addition, we found that, within the group of COVID-19 patients, the systemic microcirculation alterations correlate with severity of pulmonary disease.
Endothelial dysfunction represents a key factor in the worsening of the COVID-19 disease in up to 20% of the cases of infection from acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2). The combination of diffuse optics and vascular occlusion tests makes the assessment of endothelial and microvasculature health possible by accessing information about microvascular metabolism, reactivity and tissue perfusion just by performing a localized ischemia at the forearm of the patient. In this framework, we will present a smart platform integrating time-domain near-infrared spectroscopy and diffuse correlation spectroscopy alongside an automatized tourniquet and a pulse-oximeter for personalizing therapies targeting endothelial function and avoid ventilator-induced lung injuries.
LUCA platform combines clinical ultrasound with near-infrared time-domain and correlation spectroscopies to improve thyroid cancer screening. We characterized its precision and classified thyroid nodules in a clinical campaign on 45 subjects.
HEMOCOVID-19 project spans four countries and eight hospitals to evaluate the microvascular and endothelial health of severe COVID-19 patients using near-infrared spectroscopy (NIRS) of the forearm muscle. In order to implement the project, we have developed protocols and
tested ten commercial continuous-wave NIRS devices of the same model (PortaMon, Artinis, NL). They were characterized and compared for intra- and inter-device, inter- and intra-operator and temporal variability in solid phantoms and in vivo.
KEYWORDS: Hemodynamics, Near infrared spectroscopy, Tissues, In vivo imaging, Blood circulation, Tissue optics, Spectroscopes, Skin, Dubnium, Time metrology
A multi-distance Diffuse Correlation Spectroscopy system combined with a compact state-of-the-art Time Domain Near-Infrared Spectroscopy device is presented. The device was used to validate the protocol of VASCOVID project on healthy subject.
We propose a standardized approach for performance assessment and quality-control of the novel VASCOVID system based on optical phantoms. This approach is tailored to meet the requirements of the Medical Device Regulation, and is extendable to other biophotonics devices.
We present the HEMOCOVID-19 study spanning four countries and eight hospitals where near-infrared spectroscopy is utilized to evaluate microvascular and endothelial health of severe COVID-19 patients at the intensive care.
The VASCOVID project aims to develop an hybrid diffuse optical device with a vascular occlusion protocol for evaluating endothelial and microvascular health in severe COVID-19 patients admitted to the ICU.
The LUCA device combines clinical ultrasound, time-domain near infrared and diffuse correlation spectroscopies with the aim of improving thyroid cancer screening sensitivity and specificity. The preliminary clinical campaign on patients (n=31) with thyroid nodules and healthy controls (n=11) allowed the characterization of the precision of the instrument and demonstrated that using a couple of biomarkers the muscle-to-nodule contrast allows an area under the curve of 0.92 for single-nodule patients and 0.77 for all patients in differentiating benign and malignant nodules in a receiver operating characteristic curve. We will present the updated results from the ongoing study.
Diffuse correlation spectroscopy (DCS) is an emerging diffuse optical technique that quantifies microvascular blood flow. In spite of the wide range of clinical/research applications, DCS instrumentation is not yet standardized. In this study, we have analyzed the effect of experimental parameters as the measurement duration time and the number of detectors, at different photon count-rates, on the precision of a DCS experiment. This provides a recipe for finding device and experimental settings that optimize the precision while balancing cost and temporal resolution.
Performance assessment and standardization are indispensable for instruments of clinical relevance in general and clinical instrumentation based on photon migration/diffuse optics in particular. In this direction, a multi-laboratory exercise was initiated with the aim of assessing and comparing their performances. 29 diffuse optical instruments belonging to 11 partner institutions of a European level Marie Curie Consortium BitMap1 were considered for this exercise. The enrolled instruments covered different approaches (continuous wave, CW; frequency domain, FD; time domain, TD and spatial frequency domain imaging, SFDI) and applications (e.g. mammography, oximetry, functional imaging, tissue spectroscopy). 10 different tests from 3 well-accepted protocols, namely, the MEDPHOT2 , the BIP3 , and the nEUROPt4 protocols were chosen for the exercise and the necessary phantoms kits were circulated across labs and institutions enrolled in the study. A brief outline of the methodology of the exercise is presented here. Mainly, the design of some of the synthetic descriptors, (single numeric values used to summarize the result of a test and facilitate comparison between instruments) for some of the tests will be discussed.. Future actions of the exercise aim at deploying these measurements onto an open data repository and investigating common analysis tools for the whole dataset.
In this paper we present a Time Resolved Near Infrared device for bed-side neuromonitoring of ischemic stroke patients. This system features three wavelengths allowing a better and robust retrieval of the absolute values of oxy and deoxyhaemoglobin. The device has been fully characterized following the guidelines of the MEDPHOT and BIP protocols, developed under NEUROPt project. Time Resolved spectroscopy is a promising technology that can provide reproducible results in terms of absorption and scattering coefficients. This portable and non-invasive system has been proven suitable for operation in clinical settings.
Data were collected from a cohort of 47 ischemic stroke patients and, according to their cerebral impairment, compared with normal values obtained from a group of 35 healthy subjects. Significant differences in haemoglobin species concentration and saturation were found between healthy and ischemic stroke patients. In the ischemic area of both recanalized and non-recanalized ischemic stroke patients, deoxy-haemoglobin and total haemoglobin values are higher than in controls, while tissue oxygen saturation values are lower only in recanalized patients.
We present the current status of the LUCA project whose aim is to develop an innovative device combining ultrasound and diffuse optics for an improved screening of the thyroid cancer.
In this paper we present the ex-vivo characterization of a full-custom made multi-wavelength, two channel Time-Resolved Spectroscopy (TRS) module developed with the aim of being integrated in to a multi-modal spectroscopic device. This module overcomes all the main drawbacks of systems based on time-domain techniques such as high complexity and bulkiness while guaranteeing performances comparable to expensive state-of-the-art available devices. Each subcomponent of the module has been tailored and optimized to meet all the above-mentioned requirements. In order to assess and translate the performances of these tools for effective clinical use, we characterized the system following the guidelines of common standardization protocols. By following MEDPHOT guidelines, the linearity and accuracy in retrieving absolute values of absorption and scattering coefficients were determined by means of measurements on homogeneous phantoms. Finally, by means of a mechanically switchable solid inhomogeneous phantom (developed under the nEUROPT project) we simulated the clinical problem of detecting and localizing an absorption perturbation in a homogeneous background with broad applications such as detection of cancer lesions, thyroid, etc.
We present a new full-custom instrument for time-domain diffuse optical spectroscopy developed within Horizon 2020 LUCA (Laser and Ultrasound Co-Analyzer for thyroid nodules) project. It features eight different picosecond diode lasers (in the 635 - 1050 nm range), two 1.3 × 1.3 mm2 active-area SiPMs (Silicon PhotoMultipliers) working in single-photon mode and two 10 ps resolution time-to-digital converters. A custom FPGA-based control board manages the instrument and communicates with an external computer via USB connection. The instrument proved state-of-the-art performance: an instrument response function narrower than 160 ps (fullwidth at half-maximum), a long-term measurement stability better than 1%, and an output average optical power higher than 1 mW at 40 MHz. The instrument has been validated with phantom measurements.
Large vessel occlusion (LVO) stroke might cause different degrees of hemodynamic impairment that affects microcirculation and contributes to metabolic derangement. Time-domain near-infrared spectroscopy (TD-NIRS) estimates the oxygenation of microcirculation of cerebral outer layers. We measure hemoglobin species and tissue oxygen saturation (StO2) of anterior circulation stroke patients, classified as LVO or lacunar, and assess the differences compared with controls and according to LVO recanalization status. Fiducial markers categorize the brain region below each TD-NIRS probe as ischemic or nonstroke areas. The study includes 47 consecutive acute ischemic stroke patients and 35 controls. The ischemic area has significantly higher deoxy-hemoglobin (HbR) and total hemoglobin (HbT) compared with controls in both recanalized and nonrecanalized patients but lower StO2 only in recanalized patients. Recanalized patients have significantly lower mean StO2 in the ipsilateral hemisphere compared with nonrecanalized patients. This is the first study to report TD-NIRS measurements in acute ischemic stroke patients. TD-NIRS is able to detect significant differences in hemoglobin species in LVO stroke compared with controls and according to recanalization status. This preliminary data might suggest that StO2 can serve as a surrogate functional marker of the metabolic activity of rescued brain tissue.
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