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Significance: Tissue-like solid phantoms with identical optical properties, known within tolerant uncertainty, are of crucial importance in diffuse optics for instrumentation assessment, interlaboratory comparison studies, industrial standards, and multicentric clinical trials. Aim: The reproducibility in fabrication of homogeneous solid phantoms is focused based on spectra measurements by instrument comparisons grounded on the time-resolved diffuse optics. Approach: Epoxy-resin and silicone phantoms are considered as matrices and both employ three different instruments for time-resolved diffuse spectroscopy within the spectral range of 540 to 1100 nm. In particular, we fabricated two batches of five phantoms each in epoxy resin and silicone. Then, we evaluated the intra- and interbatch variability with respect to the instrument precision, by considering the coefficient of variation (CV) of absorption and reduced scattering coefficients. Results: We observed a similar precision for the three instruments, within 2% for repeated measurements on the same phantom. For epoxy-resin phantoms, the intra- and the interbatch variability reached the instrument precision limit, demonstrating a very good phantom reproducibility. For the silicone phantoms, we observed larger values for intra- and interbatch variability. In particular, at worst, for reduced scattering coefficient interbatch CV was about 5%. Conclusions: Results suggest that the fabrication of solid phantoms, especially considering epoxy-resin matrix, is highly reproducible, even if they come from different batch fabrications and are measured using different instruments.

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

We present and validate a multi-wavelength time-domain near-infrared spectroscopy (TD-NIRS) system that avoids switching wavelengths and instead exploits the full capability of a supercontinuum light source by emitting and acquiring signals for the whole chosen range of wavelengths. The system was designed for muscle and brain oxygenation monitoring in a clinical environment. A pulsed supercontinuum laser emits broadband light and each of two detection modules acquires the distributions of times of flight of photons (DTOFs) for 16 spectral channels (used width 12.5 nm / channel), providing a total of 32 DTOFs at up to 3 Hz. Two emitting fibers and two detection fiber bundles allow simultaneous measurements at two positions on the tissue or at two source-detector separations. Three established protocols (BIP, MEDPHOT, and nEUROPt) were used to quantitatively assess the system’s performance, including linearity, coupling, accuracy, and depth sensitivity. Measurements were performed on 32 homogeneous phantoms and two inhomogeneous phantoms (solid and liquid). Furthermore, measurements on two blood-lipid phantoms with a varied amount of blood and Intralipid provide the strongest validation for accurate tissue oximetry. The retrieved hemoglobin concentrations and oxygen saturation match well with the reference values that were obtained using a commercially available NIRS system (OxiplexTS) and a blood gas analyzer (ABL90 FLEX), except a discrepancy occurs for the lowest amount of Intralipid. In-vivo measurements on the forearm of three healthy volunteers during arterial (250 mmHg) and venous (60 mmHg) cuff occlusions provide an example of tissue monitoring during the expected hemodynamic changes that follow previously well-described physiologies. All results, including quantitative parameters, can be compared to other systems that report similar tests. Overall, the presented TD-NIRS system has an exemplary performance evaluated with state-of-the-art performance assessment methods.

We have addressed the challenge of investigating the lung using diffuse optics along four different directions, namely: 1) broadband time-domain diffuse optics (TD-DO) in the 600-1100 nm range to derive the mean chest optical properties; 2) Monte Carlo simulations to investigate the depth-sensitivity of TD-DO measurements assuming a layered structure of the chest; 3) single-wavelength TD-DO using a high power pulsed laser on 5 healthy volunteers on a dynamic protocol; 4) single-wavelength TD-DO measurements using a novel large area Silicon Photomultiplier (SIPM) detector module permitting acquisitions at 12 cm source-detector distance.

A standardized approach to develop a reliable, reproducible, stable phantoms was proposed. A well-established instrument validation protocol (MEDPHOT) was adopted for this purpose. This approach was tested on two phantom recipes (silicone and polyurethane) over broadband (600-1100 nm) wavelength covering a wider range of optical properties (absorption 0.1-1 cm-1, reduced scattering 5-20 cm-1) relevant to human tissue. As an application of the recipe, a reliable tissue-mimicking 3D anthropomorphic head phantom was presented.

Time-domain diffuse optics exploits near infrared light pulses diffused in turbid samples to retrieve their optical properties e.g., absorption and reduced scattering coefficients. Typically, interference effect are discarded, but speckle effects are exploited in other techniques e.g., diffuse correlation spectroscopy (DCS) to retrieve information regarding the tissue dynamics. Here, using a highly coherent Ti:Sapphire mode-locked laser and a single-mode detection fiber, we report the direct observation of temporal fluctuations in the measured distribution of time-of-flights (DTOF) curve. We study the dependence of these fluctuations on the sample dynamical properties (moving from fluid to rigid tissue-mimicking phantoms) and on the area of the detection fiber, which is directly linked to the number of collected coherence areas. Our observation agree with a time-resolved speckle pattern, and may enable the simultaneous monitoring of the tissue optical and dynamical properties.

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.

Multimodal imaging is an active branch of research as it has the potential to improve common medical imaging techniques. Diffuse optical tomography (DOT) is an example of a low resolution, functional imaging modality that typically has very low resolution due to the ill-posedness of its underlying inverse problem. Combining the functional information of DOT with a high resolution structural imaging modality has been studied widely. In particular, the combination of DOT with ultrasound (US) could serve as a useful tool for clinicians for the formulation of accurate diagnosis of breast lesions. In this paper, we propose a novel method for US-guided DOT reconstruction using a portable time-domain measurement system. B-mode US imaging is used to retrieve morphological information on the probed tissues by means of a semi-automatical segmentation procedure based on active contour fitting. A two-dimensional to three-dimensional extrapolation procedure, based on the concept of distance transform, is then applied to generate a three-dimensional edge-weighting prior for the regularization of DOT. The reconstruction procedure has been tested on experimental data obtained on specifically designed dual-modality silicon phantoms. Results show a substantial quantification improvement upon the application of the implemented technique. This article is part of the theme issue ‘Synergistic tomographic image reconstruction: part 2’.

Accurate monitoring of treatment is crucial in minimally-invasive radiofrequency ablation in oncology and cardiovascular disease. We investigated alterations in optical properties of ex-vivo bovine tissues of the liver, heart, muscle, and brain, undergoing the treatment. Time-domain diffuse optical spectroscopy was used, which enabled us to disentangle and quantify absorption and reduced scattering spectra. In addition to the well-known global (1) decrease in absorption, and (2) increase in reduced scattering, we uncovered new features based on sensitive detection of spectral changes. These absorption spectrum features are: (3) emergence of a peak around 840 nm, (4) redshift of the 760 nm deoxyhemoglobin peak, and (5) blueshift of the 970 nm water peak. Treatment temperatures above 100 °C led to (6) increased absorption at shorter wavelengths, and (7) further decrease in reduced scattering. This optical behavior provides new insights into tissue response to thermal treatment and sets the stage for optical monitoring of radiofrequency ablation.

The human abdominal region is very heterogeneous and stratified with subcutaneous adipose tissue (SAT) being one of the primary layers. Monitoring this tissue is crucial for diagnostic purposes and to estimate the effects of interventions like caloric restriction or bariatric surgery. However, the layered nature of the abdomen poses a major problem in monitoring the SAT in a non-invasive way by diffuse optics. In this work, we examine the possibility of using multi-distance broadband time domain diffuse optical spectroscopy to assess the human abdomen non-invasively. Broadband absorption and reduced scattering spectra from 600 to 1100 nm were acquired at 1, 2 and 3 cm source-detector distances on ten healthy adult male volunteers, and then analyzed using a homogeneous model as an initial step to understand the origin of the detected signal and how tissue should be modeled to derive quantitative information. The results exhibit a clear influence of the layered nature on the estimated optical properties. Clearly, the underlying muscle makes a relevant contribution in the spectra measured at the largest source-detector distance for thinner subjects related to blood and water absorption. More unexpectedly, also the thin superficial skin layer yields a direct contamination, leading to higher water content and steeper reduced scattering spectra at the shortest distance, as confirmed also by simulations. In conclusion, provided that data analysis properly accounts for the complex tissue structure, diffuse optics may offer great potential for the continuous non-invasive monitoring of abdominal fat.

We investigate the use of broadband time-domain diffuse optical spectroscopy (TD-DOS) to track in real time the changes in the optical properties of biological tissue undergoing radio frequency (RF) based thermal treatment.

A multi-laboratory exercise, involving 29 diffuse optical instruments, aimed at performance assessment of diffuse optics instruments on standardized protocols is presented. The overarching methodology and future actions will also be discussed.

We present a well-tested, broadband (600-1100 nm) characterized phantom recipe to manufacture tissue mimicking optical phantoms over a wider range of optical properties (absorption 0.1-1 cm-1, reduced scattering 5-25 cm-1) relevant to human organs. The results of various tests like linearity, reproducibility, homogeneity showed the phantom recipe is robust with less than 4 % coefficient of variation (CV). Finally, a non-scattering 3D phantom of the infant's torso was presented to project the futuristic aspect of our work that is to 3D print human organs of biomedical relevance.

A multivariate method integrating time-domain and space-domain techniques of near-infrared spectroscopy is proposed for simultaneously retrieving the absolute quantities of optical scattering and absorption properties in tissues. The concept is theoretically demonstrated by Monte-Carlo simulations in the homogenous case, and then applied on two-layer liquid phantoms. The deviations from nominal values are typically less than 6% for absorption coefficients in both layers

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 sub-component 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 tissue mimicking optical phantom recipe to create robust well tested solid phantoms. The recipe consists of black silicone pigment (absorber), silica microspheres (scatterer) and silicone rubber (SiliGlass, bulk material). The phantom recipe was characterized over a broadband spectrum (600-1100 nm) for a wide range of optical properties (absorption 0.1-1 cm(−1), reduced scattering 5-25 cm(−1)) that are relevant to human organs. The results of linearity show a proper scaling of optical properties as well as the absence of coupling between the absorber and scatterer at different concentrations. A reproducibility of 4% among different preparations was obtained, with a similar grade of spatial homogeneity. Finally, a 3D non-scattering mock-up phantom of an infant torso made with the same recipe bulk material (SiliGlass) was presented to project the futuristic aspect of our work that is 3D printing human organs of biomedical relevance.

Performance assessment of instruments is a growing demand in the diffuse optics community and there is a definite need to get together to address this issue. Within the EU Network BITMAP1, we initiated a campaign for the performance evaluation of 10 diffuse optical instrumentation from 7 partner institutions adopting a set of 3 well accepted, standardized protocols. A preliminary analysis of the outcome along with future perspectives will be presented.

We present a systematic characterization of the optical properties (µa and µs’) of nine representative ex vivo porcine tissues over a broadband spectrum (650-1100 nm). We applied time-resolved diffuse optical spectroscopy measurements for recovering the optical properties of porcine tissues depicting a realistic representation of the tissue heterogeneity and morphology likely to be found in different ex vivo tissues. The results demonstrate a large spectral and inter-tissue variation of optical properties. The data can be exploited for planning or simulating ex vivo experiments with various biophotonics techniques, or even to construct artificial structures mimicking specific pathologies exploiting the wide assortment in optical properties.

A periodic monitoring of the adipose tissue functions due to interventions, such as calorie restriction and bariatric surgery, or pathophysiological processes, has an increasing relevance in clinical diagnostics. Diffuse Optical Spectroscopy (DOS) is a valuable non-invasive tool that can be used in that direction. In this work, we present a pilot study based on Time Domain Broadband Diffuse Optical Spectroscopy (TD DOS) to characterize in vivo the subcutaneous fat tissue in the abdominal region. A first of its kind, portable TD DOS instrumentation, already enrolled in clinical studies, was used. Three healthy male volunteers were considered. Three source-detector separation distances (1, 2, and 3 cm) were used over the broad wavelength range of 600-1100 nm. The analysis was performed using a method based on a heterogeneous model to account for the multi-layered nature of the subcutaneous adipose tissue, and to obtain the optical properties specific to this fat localization. Inter-subject variation of tissue composition data was observed.

We investigate the effect of depth heterogeneity in the abdomen by multidistance time-domain diffuse optical spectroscopy on 4 volunteers finding a higher water content in shallower regions, possibly due to fat heterogeneity and/or dermis contributions.

This review presents recent developments and a wide overview of broadband time domain diffuse optical spectroscopy (TD-DOS). Various topics including physics of photon migration, advanced instrumentation, methods of analysis, applications covering multiple domains (tissue chromophore, in vivo studies, food, wood, pharmaceutical industry) are elaborated. The key role of standardization and recent studies in that direction are discussed. Towards the end, a brief outlook is presented on the current status and future trends in broadband TD-DOS.

In the last decade, multimodal imaging raised increasing interest to overcome the limits of single techniques and improve the diagnostic potential during the same examination. This gives rise to the need for phantoms and procedures for standardizing performance assessment of the multimodal instrument. The SOLUS1 project adopts this methodology with the aim to build a multimodal instrument (based on diffuse optics -DO-, shear wave elastography -SWE-, and ultrasound imaging -US-) to increase the specificity of breast cancer diagnosis. Here we propose a long-lasting phantom based on silicone material (easier to manipulate with respect to other material for bimodal phantom such as polyvinyl alcohol, PVA) and suitable for both diffuse optical imaging/tomography and ultrasound acquisitions, designed within the SOLUS project. To achieve this goal, we explored a new silicone material for diffuse optics and ultrasound (Ecoflex 00-30), creating a new fabrication recipe and demonstrating its suitability for multimodal imaging if coupled to another silicone elastomer (Sylgard 184), featuring similar optical and acoustical performances except for the echogenicity. The main advantage of the proposed phantom is the capability of tuning independently optical and acoustical performances, thus allowing one to mimic a wide range of clinical scenarios.

A well-characterized broadband (600-1100 nm) phantom recipe was presented to manufacture tissue-mimicking optical phantoms over a wider range of optical properties (absorption 0.1-1 cm−1, reduced scattering 5-25 cm−1) relevant to human organs. The recipe was well tested over broadband (600-1100 nm) range for linearity, reproducibility, homogeneity yielding a robust 4 % coefficient of variation (CV). Finally, we show various applications of the recipe to create standardized matrix phantoms and simply heterogeneous phantoms and anthropomorphic phantoms. The recipe could be exploited to characterize and calibrate the diffuse optical systems and explored for standardization and validation of technologies in Biophotonics.