Bioresorbable materials have gained interest for implantable optical components such as fibers for medical devices and have been demonstrated as suitable to perform diffuse optical measurements. In this work, we demonstrate interstitial, broadband, time-domain diffuse optical spectroscopy measurements using bioresorbable fibers, by employing a single-photon avalanche diode operated in an ultrafast time-gate mode for photon detection. Using tissue equivalent liquid phantoms, we test the system absorption linearity as per the MEDPHOT protocol and demonstrate the scattering independent absorption retrieval of the water spectrum in the 600-920 nm range. Consequently, we also attempt to distinguish the spectral changes due to the presence of optically denser speck inclusion in a tissue equivalent liquid phantom.
We present the application to time-domain diffuse optics of a device composed of 8x256 CMOS SPAD array with 256 7-bit time-to-digital converters. Thanks to its structure and despite the limitation on the maximum repetition rate of the laser (2 MHz), it has been demonstrated to be suitable for fast acquisitions (10 ms) provided that a high photon count-rate is used and pile-up distortion is corrected. We demonstrate that high penetration depth (>30 mm) and good linearity in absorption coefficient retrieval can be achieved. Finally, we were able to clearly record the heart beat in a resting state forehead measurement.
We present initial evidence of the SOLUS potential for the multimodal non-invasive diagnosis of breast cancer by describing the correlation between optical and standard radiological data and analyzing a case study.
By exploiting the recent components miniaturization trend, we realize a small and cheap multifunctional time-resolved (TR) single-photon detection chain. It is based on 16 channels, which can be configured either as 16 independently located channels for TR diffuse optical tomography or as a linear array for parallel TR fluorescence spectroscopy. Both applications require a detector with high time resolution and high light harvesting capability (i.e., large active area and detection efficiency). Thus, each detection channel contains a 1.3 x 1.3 mm2 active area silicon photomultiplier and its home-made electronics specifically designed for avalanche sensing and amplification, capable of optimizing the single-photon timing resolution despite the miniaturization. In this study we describe the timing performances of a first 8- channel prototype and its first application in fluorescence lifetime sensing. Then, we show the capability of the whole 16-channel array in detecting absorption changes within a homogeneous scattering medium. We have been able to obtain a single-photon timing resolution of almost 60 ps, that is close to the best ever achieved with this kind of detector. For the validation in fluorescence lifetime sensing, the fluorescence signal acquired by the proposed prototype is comparable to the one obtained using a state-of-the-art setup based on a PMT detector. In the validation in diffuse optics, we clearly detected the absorption perturbation. This confirms the suitability of this stackable solid-state detector array for both applications.
A machine learning classification algorithm is applied to the SOLUS database to discriminate benign and malignant breast lesions, based on absorption and composition properties retrieved through diffuse optical tomography. The Mann-Whitney test indicates oxy-hemoglobin (p-value = 0.0007) and lipids (0.0387) as the most significant constituents for lesion classification, but work is in progress for further analysis. Together with sensitivity (91%), specificity (75%) and the Area Under the ROC Curve (0.83), special metrics for imbalanced datasets (27% of malignant lesions) are applied to the machine learning outcome: balanced accuracy (83%) and Matthews Correlation Coefficient (0.65). The initial results underline the promising informative content of optical data.
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.
Time domain diffuse optics (TD-DO) relies on the injection of ps laser pulses and on the collection of the arrival times of scattered photons. To reach the ultimate limits of the technique (allowing to investigate even structures at depth <5 cm), a large area detector is needed. To this extent, we realized and present a new silicon photomultiplier featuring a 1 cm2 area. To the best of our knowledge, it represents the largest detector ever proposed for TD-DO and shows a light harvesting capability which is more than 1 decade larger than the state-of-the-art technology system. To assess its suitability for TDDO measurements, we tested the detector with several procedures from shared protocols (BIP, nEUROPt and MEDPHOT). However, the light harvesting capability of a detector with large area can be proficiently exploited only if coupled to timing electronics working in sustained count-rate CR (i.e., well above the single photon statistics). For this reason, we study the possibility to work in a regime where (even more than) one photon per laser pulse is detected (i.e., more than 100% laser repetition rate) exploiting in-silico technology. The results show that the possibility to use sustained count-rate represents a dramatic improvement in the number of photons detected with respect to current approaches (where count-rate of 1-5% of the laser repetition rate are used) without significant losses in the measurement accuracy. This represents a new horizon for TD-DO measurements, opening the way to new applications (e.g., optical investigation of the lung or monitoring of fast dynamics never studied before).
We show both on phantoms and in-vivo the full potential of fast time-gated acquisitions exploiting an innovative custom-developed digital silicon photomultiplier, overcoming consolidated limitations showed by single-photon avalanche diodes linked to their small sensitive area.
KEYWORDS: Sensors, Optical properties, In vivo imaging, Diffuse optical imaging, Signal detection, Light harvesting, Absorption, Silicon, Radiography, Radio optics
We present the largest detectors for time-domain diffuse optics, showing superior performances in depth penetration and light-harvesting capability. In-vivo measurements demonstrate their potentialities for futuristic disruptive applications such as optical radiography.
Large-area detectors for time-domain diffuse optics are increasingly available, with enormous gain in collected light intensity. Pile-up distortion is nowadays the main limit, here studied to anticipate the possibility of a new working modality.
A multimodal instrument for breast imaging was developed, combining ultrasound (morphology), shear wave elastography (stiffness), and time domain multiwavelength diffuse optical tomography (blood, water, lipid, collagen) to improve the non-invasive diagnosis of breast cancer.
To improve non-invasively the specificity in the diagnosis of breast cancer after a positive screening mammography or doubt/suspicious ultrasound examination, the SOLUS project developed a multimodal imaging system that combines: Bmode ultrasound (US) scans (to assess morphology), Color Doppler (to visualize vascularization), shear-wave elastography (to measure stiffness), and time domain multi-wavelength diffuse optical tomography (to estimate tissue composition in terms of oxy- and deoxy-hemoglobin, lipid, water, and collagen concentrations). The multimodal probe arranges 8 innovative photonic modules (optodes) around the US transducer, providing capability for optical tomographic reconstruction. For more accurate estimate of lesion composition, US-assessed morphological priors can be used to guide the optical reconstructions. Each optode comprises: i) 8 picosecond pulsed laser diodes with different wavelengths, covering a wide spectral range (635-1064 nm) for good probing of the different tissue constituents; ii) a large-area (variable, up to 8.6 mm2 ) fast-gated digital Silicon Photomultiplier; iii) the acquisition electronics to record the distribution of time-of-flight of the re-emitted photons. The optode is the basic element of the optical part of the system, but is also a stand-alone, ultra-compact (about 4 cm3 ) device for time domain multi-wavelength diffuse optics, with potential application in various fields.
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.
Time-resolved multispectral imaging has recently found many applications ranging from biomedical to environmental field. Multidimensional approach measuring spectral and ultrafast temporal dynamics of fluorescence signal combined with spatial information (imaging) allows one to characterize biological processes at both microscopic and macroscopic level, representing a fundamental step towards development of diagnostic strategies. Long acquisition time is the main drawback of multidimensional approach because it is not compatible with biological system dynamics. In order to reduce the measurement times, it is necessary to parallelize the acquisition (hardware level) and to optimize the acquisition strategy to reduce the measurements number while preserving the information content. In this work we have developed a time-resolved multispectral fluorescence imaging system based on a spad array combined with compression techniques which allows to reduce the number of time-resolved acquisitions by a factor < 70%. The system is based on a double DMD configuration (excitation and detection) coupled to a 32x1 SPAD array, each one with its own TCSPC circuit, placed after an imaging spectrometer. This allows one to use the spatial modulation of the excitation/detection light to acquire images at different wavelengths following the single pixel camera (SPC) scheme. In order to compress the number of acquisitions, a CW fluorescence image is acquired through a CCD and Hadamard transform is applied to select most significative coefficients. The patterns related to these coefficients are subsequently used for SPC acquisition for time and spectral resolution. A Total-Variation based algorithm is used for the reconstruction of the 4D images.
A widefield system for multidimensional fluorescence imaging capable of resolving space, time and wavelength is developed and validated on a synthetic fluorescence sample. The system enables structured illumination and compressing detection. A compression strategy based on an a-priori information obtained by a camera is validated and proved to be effective at compression ratio of about 90%.
The design, fabrication and characterization of phosphate based bioresorbable optical fibers is reported. Applications in diffuse optics, pH sensing and temperature sensing have been demonstrated paving the way to the use for a new generation of implantable and degradable devices for theranostics.
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.
We present here a novel time-domain diffuse optical detection chain consisting of a large area Silicon PhotoMultipliers (SiPM) coupled to a high count-rate timing electronics (TimeHarp 260 PICO) to achieve sustainable count-rates up to 10 Mcps without significant distortions to the distribution of time-of-flight (DTOF). Thanks to the large area of the detector (9 mm2) and the possibility to directly place it in contact with the sample (thus achieving a numerical aperture close to unity), the photon collection efficiency of the proposed detection chain is almost two orders of magnitude higher than traditional fiber-mounted PMT-based systems. This allows the detection also of the few late photons coming from deeper layers at short acquisition times, thus improving the robustness of the detection of localized inhomogeneities. We then demonstrate that, despite the high dark count rate of the detector, it is possible to reliably extract the optical properties of calibrated phantoms, with proper linearity and accuracy. We also explore the capability of the new detection chain for detecting brain activations. This work opens up the possibility of ultimate performance in terms of high signal and photon throughput, with compact, low cost, relatively simple front-end electronics detector coupled to innovative timing electronics, with exciting opportunities to expand it to tomographic applications.
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.
Diffuse optical imaging can be used to probe highly scattering media like biological tissue down to a depth of few centimeters, with spatial resolution limited by light scattering. Its combination with ultrasound imaging can potentially lead to medical imaging systems with, for instance, high specificity in the examination of tumors. However, the presence of the ultrasound coupling gel between probe and tissue can have detrimental effects on the accuracy of optical imaging techniques. Here we present an experimental study on the effect of ultrasound coupling fluids on diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS). We demonstrate on tissue-mimicking phantoms that the use of standard water-clear gels, providing a direct path for the light from the source to the detection point, can distort optical measurements generating strong underestimation of both the absorption and the reduced scattering coefficients in DOS measurements, as well as underestimation of the Brownian diffusion coefficient in DCS measurements. On the contrary, various turbid fluids demonstrate excellent performance in preventing this issue.
Time Domain Diffuse Optical Tomography (TD-DOT) performed at multiple wavelengths can be used to non-invasively probe tissue composition. Then, tissue composition can be related to breast tissue and lesion type. Thus, TD-DOT could be used for therapy monitoring for breast cancer. We developed a software tool for multi-wavelength TD-DOT and performed a validation on meat phantoms to mimic tissue heterogeneity. An inclusion of different meat was exploited to mimic the presence of a lesion in the breast. Results show good localization of the inclusion, but poor quantification of the reconstructed breast composition. The use of a morphological prior constraint, providing information on inclusion geometry and position, significantly improves both localization and composition estimate.
We propose a time domain speckle contrast optical spectroscopy (SCOS) system that makes use of a gated detector and pulsed light source to measure the blood flow variations at very short, quasi-null (<3mm) source-detector separation. We present the results of a human arm cuff occlusion and a comparison with standard SCOS, highlighting that we can probe deeper into tissue, reduce probe footprint, make efficient use of the signal and decrease cost.3
The use of bioresorbable fibers represents an innovative way to build optical implantable devices and to look inside the body. Recently, a new kind of bioresorbable fibers, based on calcium-phosphate glasses, has been introduced by some of us. They show a good biocompatibility and improved attenuation loss coefficient with respect to other bioresorbable fibers. In this work, we used those fibers to explore their suitability in diffuse optics. Indeed, the time-domain technique is a non-invasive methodology which allows to have an absolute estimate of the absorption and reduced scattering spectra of the diffusive medium. It allows to bring information about concentration of chemical components (water, oxyand deoxy-hemoglobin), thus conveying information about the functional status and/or the scattering properties (changes in tissue microstructure, edema). Such information can then be related to the tissue regeneration, healing process, or to a harmful evolution. This makes the time domain optical spectroscopy coupled to bioresorbable fibers a good candidate for future medical devices. Here we demonstrate the suitability of these fibers for diffuse optics by means of standardized tests and then we use them for a proof-of-principle measurement on ex-vivo chicken breast, obtaining results comparable with standard fibers. Thanks to the encouraging results, we are working on a system based on a single fiber (serving as both injection and collection fiber) to go closer to a single interstitial fiber which can lessen the effect of the implant.
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.
Time domain Diffuse Optical Tomography (TD-DOT) non-invasively probes the optical proprieties of biological tissue. These can be related to changes in tissue composition, thus making TD-DOT potentially valuable for cancer imaging. In particular, an application of interest is therapy monitoring for breast cancer. Thus, we developed a software tool for multiwavelength TD-DOT in reflectance geometry. While the use of multiple wavelengths probes the main components of the breast, the chosen geometry offers the advantage of linking the photon flight time to the investigated depth. We validated the tool on silicon phantoms embedding an absorbing inclusion to simulate a malignant lesion in breast tissue. Also, we exploited the a priori information on position and geometry of the inclusion by using a morphological prior constraint. The results show a good localization of the depth of inclusion but a reduced quantification. When the morphological constraint is used, though, the localization improves dramatically, also reducing surface artifacts and improving quantification as well. Still, there is room for improvement in the quantification of the “lesion” properties.
Light is a powerful non-invasive tool that can be exploited to probe highly scattering media like biological tissues for different purposes, from the detection of brain activity to the characterization of cancer lesions. In the last decade, timedomain diffuse optics (TDDO) systems demonstrated improved sensitivity when using time-gated acquisition chains and short source-detector separations (ρ), both theoretically and experimentally. However, the sensitivity to localized absorption changes buried inside a diffusive medium strongly depends on many parameters such as: SDS, laser power, delay and width of the gating window, absorption and scattering properties of the medium, instrument response function (IRF) shape, etc. In particular, relevant effects due to slow tails in the IRF were noticed, with detrimental effects on performances. We present simulated experimental results based on the diffusion approximation of the Radiative Transfer Equation and the perturbation theory subjected to the Born approximation. To quantify the system sensitivity to deep (few cm) and localized absorption perturbations, we exploited contrast and contrast-to-noise ratio (CNR), which are internationally agreed on standardized figures of merit. The purpose of this study is to determine which parameters have the greatest impact on these figures of merit, thus also providing a range of best operative conditions. The study is composed by two main stages: the former is a comparison between simulations and measurements on tissue-mimicking phantom, while the latter is a broad simulation study in which all relevant parameters are tuned to determine optimal measurement conditions. This study essentially demonstrates that under the influence of the slow tails in the IRF, the use of a small SDS no longer corresponds to optimal contrast and CNR. This work sets the ground for future studies with next-generation of TDDO components, presently under development, providing useful hints on relevant features to which one should take care when designing TDDO components.
We validate a miniaturized pulsed laser source for use in time-domain (TD) diffuse optics, following rigorous and shared protocols for performance assessment of this class of devices. This compact source (12×6 mm2) has been previously developed for range finding applications and is able to provide short, high energy (∼100 ps, ∼0.5 nJ) optical pulses at up to 1 MHz repetition rate. Here, we start with a basic level laser characterization with an analysis of suitability of this laser for the diffuse optics application. Then, we present a TD optical system using this source and its performances in both recovering optical properties of tissue-mimicking homogeneous phantoms and in detecting localized absorption perturbations. Finally, as a proof of concept of in vivo application, we demonstrate that the system is able to detect hemodynamic changes occurring in the arm of healthy volunteers during a venous occlusion. Squeezing the laser source in a small footprint removes a key technological bottleneck that has hampered so far the realization of a miniaturized TD diffuse optics system, able to compete with already assessed continuous-wave devices in terms of size and cost, but with wider performance potentialities, as demonstrated by research over the last two decades.
To evaluated capabilities of multispectral TD-DOT systems in reflection geometry, we
performed a measurement campaign on multimaterial composition phantoms. Results show correct
composition gradation of inclusions but still lack absolute accuracy.
A time-resolved Diffuse Optical Tomography system based on multiple view
acquisition, pulsed structured light illumination and detection with spatial compression is
proposed. Reconstructions on heterogeneous tissue mimicking phantoms are presented.
Non-contact scanning at small source-detector separation enables imaging of cerebral and extracranial signals at high spatial resolution and their separation based on early and late photons accounting for the related spatio-temporal characteristics.
We show for the first time the aptness of Calcium Phosphate Glass-based bioresorbable fibers for time-domain diffuse optics using tests described by a standardized protocol and we also present a spectroscopic measurement on a chicken breast.
Diffuse Optical Tomography (DOT) can be described as a highly multidimensional problem generating a huge data set with long acquisition/computational times. Biological tissue behaves as a low pass filter in the spatial frequency domain, hence compressive sensing approaches, based on both patterned illumination and detection, are useful to reduce the data set while preserving the information content. In this work, a multiple-view time-domain compressed sensing DOT system is presented and experimentally validated on non-planar tissue-mimicking phantoms containing absorbing inclusions.
Laura Di Sieno, Antonio Pifferi, Edoardo Martinenghi, Judy Zouaoui, Lionel Hervé, Andrea Farina, Jacques Derouard, Jean-Marc Dinten, Alberto Dalla Mora
Silicon photomultipliers (SiPMs) have been very recently introduced as the most promising detectors in the field of diffuse optics, in particular due to the inherent low cost and large active area. We also demonstrate the suitability of SiPMs for time-domain diffuse optical tomography (DOT). The study is based on both simulations and experimental measurements. Results clearly show excellent performances in terms of spatial localization of an absorbing perturbation, thus opening the way to the use of SiPMs for DOT, with the possibility to conceive a new generation of low-cost and reliable multichannel tomographic systems.
The noninvasive assessment of flap viability in autologous reconstruction surgery is still an unmet clinical need. To cope with this problem, we developed a proof-of-principle fully automatized setup for fast time-gated diffuse optical tomography exploiting Mellin–Laplace transform to obtain three-dimensional tomographic reconstructions of oxy- and deoxy-hemoglobin concentrations. We applied this method to perform preclinical tests on rats inducing total venous occlusion in the cutaneous abdominal flaps. Notwithstanding the use of just four source-detector couples, we could detect a spatially localized increase of deoxyhemoglobin following the occlusion (up to 550 μM in 54 min). Such capability to image spatio-temporal evolution of blood perfusion is a key issue for the noninvasive monitoring of flap viability.
We developed a novel scanning system that relies on gated detection of late photons at short source-detector separation, enabling the recording of absorption changes in deep tissue compartments. The tissue was scanned by a galvanometer scanner from a distance of more than 10 cm, with a fixed separation of the illumination and the detection spot of a few mm. The light source was a supercontinuum laser with an acousto-optic tunable filter that was used to rapidly switch between two wavelength bands centered at 760 nm and 860 nm. A fast-gated single-photon avalanche diode was employed to eliminate the intense early part of the diffusely remitted signal and to detect photons with long times of flight with improved signal-to-noise ratio. A second detection channel contained a non-gated detector. The gated and non-gated time-of-flight distributions of photons were recorded by imaging time-correlated single photon counting synchronized with the movement of the scanner. A tissue area with dimensions of several cm was scanned with 32×32 pixels within a frame time of 1 s. Sensitivity and spatial resolution of the system were characterized by phantom measurements. In-vivo tests included functional brain activation by various tasks and demonstrated the feasibility of non-contact imaging of hemodynamic changes in the cerebral cortex.
We present a new setup for time-resolved diffuse optical tomography based on multiple source-detector acquisitions analysed by means of the Mellin-Laplace transform. The proposed setup has been used to perform pre-clinical measurements on rats in order to show its suitability for non-invasive assessment of flap viability.
Near-infrared diffuse optical tomography (DOT) is a medical imaging which gives the distribution of the optical properties of biological tissues. To obtain endogenous chromophore features in the depth of a scattering medium, a multiwavelength/time-resolved (MW/TR) DOT setup was used. Reconstructions of the three-dimensional maps of chromophore concentrations of probed media were obtained by using a data processing technique which manages Mellin-Laplace Transforms of their MW/TR optical signals and those of a known reference medium. The point was to
put a constraint on the medium absorption coefficient by using a material basis composed of a given set of chromophores of known absorption spectra. Experimental measurements were conducted by injecting the light of a picosecond near-
infrared laser in the medium of interest and by collecting, for several wavelengths and multiple positions, the backscattered light via two fibers (with a source-detector separation of 15 mm) connected to fast-gated single-photon
avalanche diodes (SPAD) and coupled to a time-correlated single-photon counting (TCSPC) system. Validations of the method were performed in simulation in the same configuration as the experiments for different combination of chromophores. Evaluation of the technique in real conditions was investigated on liquid phantoms composed of an
homogenous background and a 10 mm depth inclusion formed of combination of intralipid and inks scanned at 30
positions and at three wavelengths. Both numerical and preliminary phantom experiments confirm the potential of this method to determine chromophore concentrations in the depth of biological tissues.
Diffuse Optical Tomography (DOT) and Fluorescence Molecular Tomography (FMT) generally require a huge data set which poses severe limits to acquisition and computational time, especially with a multidimensional data set. The highly scattering behavior of biological tissue leads to a low bandwidth of the information spatial distribution and hence the sampling can be preferably carried out in the spatial frequency source/detector space. In this work, a time-resolved single pixel camera scheme combined with structured light illumination is presented and experimentally validated on phantoms measurements. This approach leads to a significant reduction of the data set while preserving the information content.
In order to increase sensitivity in the depth of diffusive media and to separate chromophores with distinct spectral signatures, we developed a method to process time-domain/multi-wavelength diffuse optical acquisitions: 3D Reconstructions of chromophore concentrations are performed with an algorithm based on the use of Mellin-Laplace Transform and material basis. A noise weighted data matching term is optimized by using the conjugated gradients method without expressing the Jacobian matrix of the system. As the algorithm uses reference measurements on a known medium, it does not require measurements or computations of the instrument response function of the system. Validations are performed in the reflectance geometry on a tissue-mimicking phantom composed of intralipid and black ink and a cylindrical blue dye inclusion with a radius of 4mm located at 15mm in depth. The optical tomography setup includes a laser whose picosecond pulses are injected via an optical fiber to the probed diffusive medium and the light collected by two fibers (located 15mm apart from the source), is sent to a Single-Photon Avalanche Diode (SPAD) connected to a Time-Correlated Single-Photon Counting (TCSPC) board. The source and two detectors scan the surface of the medium so as to provide 30 source-detector couples, 900 time-bins and 5 wavelength signals. 3D reconstructions performed on the black ink and blue dye materials on a mesh of around 10000 nodes show that we are able to detect, localize and determine the composition of the inclusion and the background.
Fiber optic probes with a width limited to a few centimeters can enable diffuse optical tomography (DOT) in intern
organs like the prostate or facilitate the measurements on extern organs like the breast or the brain. We have recently
shown on 2D tomographic images that time-resolved measurements with a large dynamic range obtained with fast-gated
single-photon avalanche diodes (SPADs) could push forward the imaged depth range in a diffusive medium at short
source-detector separation compared with conventional non-gated approaches. In this work, we confirm these
performances with the first 3D tomographic images reconstructed with such a setup and processed with the Mellin-
Laplace transform. More precisely, we investigate the performance of hand-held probes with short interfiber distances in
terms of spatial resolution and specifically demonstrate the interest of having a compact probe design featuring small
source-detector separations. We compare the spatial resolution obtained with two probes having the same design but
different scale factors, the first one featuring only interfiber distances of 15 mm and the second one, 10 mm. We evaluate
experimentally the spatial resolution obtained with each probe on the setup with fast-gated SPADs for optical phantoms
featuring two absorbing inclusions positioned at different depths and conclude on the potential of short source-detector
separations for DOT.
We present a compact time-resolved spectrometer suitable for optical spectroscopy from 400 nm to 1 μm wavelengths.
The detector consists of a monolithic array of 16 high-precision Time-to-Digital Converters (TDC) and Single-Photon
Avalanche Diodes (SPAD). The instrument has 10 ps resolution and reaches 70 ps (FWHM) timing precision over a 160
ns full-scale range with a Differential Non-Linearity (DNL) better than 1.5 % LSB. The core of the spectrometer is the
application-specific integrated chip composed of 16 pixels with 250 μm pitch, containing a 20 μm diameter SPAD and
an independent TDC each, fabricated in a 0.35 μm CMOS technology. In front of this array a monochromator is used to
focus different wavelengths into different pixels. The spectrometer has been used for fluorescence lifetime spectroscopy:
5 nm spectral resolution over an 80 nm bandwidth is achieved. Lifetime spectroscopy of Nile blue is demonstrated.
KEYWORDS: Photons, Optical fibers, Near infrared spectroscopy, Sensors, Signal to noise ratio, In vivo imaging, Picosecond phenomena, Tissue optics, Avalanche photodiodes, Biomedical optics
In this article, we show experimental results of time-resolved optical spectroscopy performed with small distance between launching and detecting fibers. It was already demonstrated that depth discrimination is independent of source-detector separation and that measurements at small source detector distance provide better contrast and spatial resolution. The main disadvantage is represent by the huge increase in early photons (scarcely diffused by tissue) peak that can saturate the dynamic range of most detectors, hiding information carried by late photons. Thanks to a fast-gated Single- Photon Avalanche Diode (SPAD) module, we are able to reject the peak of early photons and to obtain high-dynamic range acquisitions. We exploit fast-gated SPAD module to perform for the first time functional near-infrared spectroscopy (fNIRS) at small source-detector distance for in vivo measurements and we demonstrate the possibility to detect non-invasively the dynamics of oxygenated and deoxygenated haemoglobin occurring in the motor cortex during a motor task. We also show the improvement in terms of signal amplitude and Signal-to-Noise Ratio (SNR) obtained exploiting fast-gated SPAD performances with respect to “non-gated” measurements.
We present results of first in-vivo tests of an optical non-contact scanning imaging system, intended to study oxidative metabolism related processes in biological tissue by means of time-resolved near-infrared spectroscopy. Our method is a novel realization of the short source-detector separation approach and based on a fast-gated single-photon avalanche diode to detect late photons only. The scanning system is built in quasi-confocal configuration and utilizes polarizationsensitive detection. It scans an area of 4×4 cm2, recording images with 32×32 pixels, thus creating a high density of source-detector pairs. To test the system we performed a range of in vivo measurements of hemodynamic changes in several types of biological tissues, i.e. skin (Valsalva maneuver), muscle (venous and arterial occlusions) and brain (motor and cognitive tasks). Task-related changes in hemoglobin concentrations were clearly detected in skin and muscle. The brain activation shows weaker, but yet detectable changes. These changes were localized in pixels near the motor cortex area (C3). However, it was found that even very short hair substantially impairs the measurement. Thus the applicability of the scanner is limited to hairless parts of body. The results of our first in-vivo tests prove the feasibility of non-contact scanning imaging as a first step towards development of a prototype for biological tissue imaging for various medical applications.
We present experimental results of time-resolved reflectance diffuse optical tomography performed with fast-gated single-photon avalanche diodes (SPADs) and show an increased imaged depth range for a given acquisition time compared to the non gated mode.
In recent years, emerging applications, such as diffuse optical imaging and spectroscopy (e.g., functional brain imaging and optical mammography), in which a wide dynamic range is crucial, have turned the interest towards Single-Photon Avalanche Diode (SPAD). In these fields, the use of a fast-gated SPAD has proven to be a successful technique to increase the measurement sensitivity of different orders of magnitude. However, an unknown background noise has been observed at high illumination during the gate-OFF time, thus setting a limit to the maximum increase of the dynamic range. In this paper we describe this noise in thin-junction silicon single-photon avalanche diode when a large amount of photons reaches the gated detector during the OFF time preceding the enabling time. This memory effect increases the background noise with respect to primary dark count rate similarly to a classical afterpulsing process, but differently it is not related to a previous avalanche ignition in the detector. We discovered that memory effect increases linearly with the power of light impinging on the detector and it has an exponential trend with time constants far different from those of afterpulsing and independently of the bias voltage applied to the junction. For these reasons, the memory effect is not due to the same trapping states of afterpulsing and must be described as a different process.
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