Time-resolved Diffuse Optical Spectroscopy Research Articles

Initial non-invasive in vivo sensing of the lung using time domain diffuse optics

The in vivo diagnosis and monitoring of pulmonary disorders (caused for example by emphysema, Covid-19, immature lung tissue in infants) could be effectively supported by the non-invasive sensing of the lung through light. With this purpose, we investigated the feasibility of probing the lung by means of time-resolved diffuse optics, leveraging the increased depth (a few centimeters) attained by photons collected after prolonged propagation time (a few nanoseconds). We present an initial study that includes measurements performed on 5 healthy volunteers during a breathing protocol, using a time-resolved broadband diffuse optical spectroscopy system. Those measurements were carried out across the spectral range of 600–1100 nm at a source-detector distance of 3 cm, and at 820 nm over a longer distance (7–9 cm). The preliminary analysis of the in vivo data with a simplified homogeneous model revealed a maximum probing depth of 2.6–3.9 cm, suitable for reaching the lung. Furthermore, we observed variations in signal associated with respiration, particularly evident at long photon propagation times. However, challenges stemming from both intra- and inter-subject variability, along with inconsistencies potentially arising from conflicting scattering and absorption effects on the collected signal, hindered a clear interpretation. Aspects that require further investigation for a more comprehensive understanding are outlined.

Eight-Wavelength, Dual Detection Channel Instrument for Near-Infrared Time-Resolved Diffuse Optical Spectroscopy

In this paper, we present an innovative instrument for near-infrared time-resolved spectroscopy. The system is based on eight custom-designed pulsed diode lasers emitting at different wavelengths in the near-infrared region (635–1050 nm), all exhibiting an average optical power higher than 1 mW at 40 MHz pulse repetition rate, two custom-made single-photon detectors based on wide-area silicon photomultipliers and two time-measurement units based on a custom time-to-digital converter with 10 ps timing resolution. The system instrument response function has a width narrower than 160 ps (fullwidth at half-maximum) and stability better than ±1% for several hours for all the wavelengths. All the components of the instrument were designed in order to be compact. The entire system will be hosted in a standard 19 inches, 5U rack case (size 48 × 38 × 20 cm3 ). The system communicates with the external computer through a USB 2.0 link and is designed to be employed in a clinical environment. The proposed instrument, thanks to the reduction of its cost and dimensions, paves the way to a wider diffusion of multiwavelengths near-infrared time-resolved spectroscopy systems.

Early Therapeutic Prediction Based on Tumor Hemodynamic Response Imaging: Clinical Studies in Breast Cancer with Time-Resolved Diffuse Optical Spectroscopy

This study reports data from three clinical studies using the time-resolved diffuse optical spectroscopy (TRS) system among breast cancer patients. The parameters of oxy-hemoglobin (O2Hb), deoxy-hemoglobin (HHb), total hemoglobin (tHb), and oxygen saturation (SO2) were evaluated using TRS, and its efficacy was tested in three trials. In trial 1, we recruited 118 patients with primary breast cancer to estimate the tumor detection rate. The cumulative detection rate was 62.7%, while that in T stage 0 was 31.3% and in T stage 1 was 44.7%. These were lower than those of T stage 2 (78.9%) and T stage 3 (100%). Next, we used TRS to monitor tumor hemodynamic response to neoadjuvant chemotherapy (n = 100) and found that pathological complete response (pCR) tumors had significantly lower tumor tHb than non-pCR tumors; a similar result was observed in estrogen receptor (ER)-negative tumors, but not in ER-positive tumors. The third trial monitored hemodynamic response to antiangiogenic therapy, bevacizumab (n = 28), and we demonstrated that sequential optical measurement of tumor SO2 might be useful for detecting acute hypoxia 1–3 days after bevacizumab initiation. Next, response monitoring of neoadjuvant endocrine therapy (n = 30) suggested that changes in tumor tHb during treatment can predict and distinguish between responsive and non-responsive tumors early in letrozole therapy. In conclusion, our results show that hemodynamic monitoring of tumors by TRS could pair the unique features of tumor physiology to drug therapy and contribute to patient-tailored medicine. We recently established a platform for performing TRS in patients with breast cancer.

Characterization of a Time-Resolved Diffuse Optical Spectroscopy Prototype Using Low-Cost, Compact Single Photon Avalanche Detectors for Tissue Optics Applications.

Time-resolved diffuse optical spectroscopy (TR-DOS) is an increasingly used method to determine the optical properties of diffusive media, particularly for medical applications including functional brain, breast and muscle measurements. For medical imaging applications, important features of new generation TR-DOS systems are low-cost, small size and efficient inverse modeling. To address the issues of low-cost, compact size and high integration capabilities, we have developed free-running (FR) single-photon avalanche diodes (SPADs) using 130 nm silicon complementary metal-oxide-semiconductor (CMOS) technology and used it in a TR-DOS prototype. This prototype was validated using assessments from two known protocols for evaluating TR-DOS systems for tissue optics applications. Following the basic instrumental performance protocol, our prototype had sub-nanosecond total instrument response function and low differential non-linearity of a few percent. Also, using light with optical power lower than the maximum permissible exposure for human skin, this prototype can acquire raw data in reflectance geometry for phantoms with optical properties similar to human tissues. Following the MEDPHOT protocol, the absolute values of the optical properties for several homogeneous phantoms were retrieved with good accuracy and linearity using a best-fitting model based on the Levenberg-Marquardt method. Overall, the results of this study show that our silicon CMOS-based SPAD detectors can be used to build a multichannel TR-DOS prototype. Also, real-time functional monitoring of human tissue such as muscles, breasts and newborn heads will be possible by integrating this detector with a time-to-digital converter (TDC).

Time-Resolved Diffuse Optical Spectroscopy and Imaging Using Solid-State Detectors: Characteristics, Present Status, and Research Challenges.

Diffuse optical spectroscopy (DOS) and diffuse optical imaging (DOI) are emerging non-invasive imaging modalities that have wide spread potential applications in many fields, particularly for structural and functional imaging in medicine. In this article, we review time-resolved diffuse optical imaging (TR-DOI) systems using solid-state detectors with a special focus on Single-Photon Avalanche Diodes (SPADs) and Silicon Photomultipliers (SiPMs). These TR-DOI systems can be categorized into two types based on the operation mode of the detector (free-running or time-gated). For the TR-DOI prototypes, the physical concepts, main components, figures-of-merit of detectors, and evaluation parameters are described. The performance of TR-DOI prototypes is evaluated according to the parameters used in common protocols to test DOI systems particularly basic instrumental performance (BIP). In addition, the potential features of SPADs and SiPMs to improve TR-DOI systems and expand their applications in the foreseeable future are discussed. Lastly, research challenges and future developments for TR-DOI are discussed for each component in the prototype separately and also for the entire system.

Time-resolved laser spectroscopy for the in situ characterization of methacrylate monomer flow within spruce

Time-resolved diffuse optical spectroscopy (TRS) was investigated as a nondestructive method to characterize the post-impregnation distribution of methacrylate monomers within spruce (Picea abies). TRS was also used to monitor the flow of methacrylate monomers in situ, within spruce, during impregnation with both spatial and temporal resolution. The data were compared to fluid flow models developed by Darcy and Bramhall demonstrating that neither of these models were able to accurately describe the experimental results, highlighting the need for development of new models. Nondestructive characterization by TRS did not require staining of the monomer treatment solution, multivariate analysis or complex sample pre-treatment, thus highlighting the facile applicability of this technique.

In Vivo, Non-Invasive Characterization of Human Bone by Hybrid Broadband (600-1200 nm) Diffuse Optical and Correlation Spectroscopies.

Non-invasive in vivo diffuse optical characterization of human bone opens a new possibility of diagnosing bone related pathologies. We present an in vivo characterization performed on seventeen healthy subjects at six different superficial bone locations: radius distal, radius proximal, ulna distal, ulna proximal, trochanter and calcaneus. A tailored diffuse optical protocol for high penetration depth combined with the rather superficial nature of considered tissues ensured the effective probing of the bone tissue. Measurements were performed using a broadband system for Time-Resolved Diffuse Optical Spectroscopy (TRS) to assess mean absorption and reduced scattering spectra in the 600–1200 nm range and Diffuse Correlation Spectroscopy (DCS) to monitor microvascular blood flow. Significant variations among tissue constituents were found between different locations; with radius distal rich of collagen, suggesting it as a prominent location for bone related measurements, and calcaneus bone having highest blood flow among the body locations being considered. By using TRS and DCS together, we are able to probe the perfusion and oxygen consumption of the tissue without any contrast agents. Therefore, we predict that these methods will be able to evaluate the impairment of the oxygen metabolism of the bone at the point-of-care.

Diffuse optics using a dual window fast-gated counter

In this paper we demonstrate the advantages of a fast-gated counter in achieving high count-rate and reducing costs of timing equipment in a time-resolved diffuse optical spectroscopy setup. We experimentally prove the equivalence between the fast-gated counter we developed and a traditional time-correlated single-photon counting setup in terms of depth sensitivity and signal-to-noise ratio. Additionally, we show the suitability of this device for bilayer analysis and to estimate the absorption coefficient of homogeneous diffusing media. Finally, we present a proof-of-principle arterial occlusion measurement on a healthy volunteer to validate the proposed approach in a real application. Fast-gated counters can dramatically reduce both costs and complexity in time-resolved multichannel systems, while achieving high count-rate, thus offering a great advantage in applications like brain and muscle functional imaging.

Nondestructive optical detection of monomer uptake in wood polymer composites

A noninvasive method to assess the local monomer concentration within a wooden matrix, post monomer impregnation, by time-resolved diffuse optical spectroscopy is demonstrated. A data analysis technique for improving accuracy, which takes account of changes in the refractive index during the monomer uptake, has been employed. This technique can be potentially applied in the wood industry for the study of polymer composites as well as in cultural heritage science for noninvasively monitoring the penetration of chemical compounds used for consolidation or conservation purposes.

Recipes to make organic phantoms for diffusive optical spectroscopy

Three recipes are presented to make tissue constituent-equivalent phantoms of water and lipids. Different approaches to prepare the emulsion are proposed. Nature phantoms are made using no emulsifying agent, but just a professional disperser; instead Agar and Triton phantoms are made using agar or Triton X-100, respectively, as agents to emulsify water and lipids. Different water-to-lipid ratios ranging from 30% to 70% by mass were tested. A broadband time-resolved diffuse optical spectroscopy system was used to characterize the phantoms in terms of optical properties and composition. For some water/lipid ratios the emulsion fails or the phantom has limited lifetime, but in most cases the recipes provide phantoms with a high degree of homogeneity [coefficient of variation (CV) of 4.6% and 1.5% for the absorption and reduced scattering coefficient, respectively] and good reproducibility (CV of 8.3% and 12.4% for absorption and reduced scattering coefficient, respectively).

Diffuse Optical Techniques Applied to Wood Characterisation

We propose an optical method for non-invasive characterisation of wood samples based on two optical techniques: time-resolved diffuse optical spectroscopy and gas in scattering media absorption spectroscopy. While the latter is sensitive to gases present inside wood pores, the former extracts information on the bulk material regarding light scattering and absorption. Measurements on spruce samples, cut along different wood fibre directions, are presented to show an example of the advantages of this combined approach: by applying these two non-destructive techniques together, in fact, relevant information on wood such as porosity, permeability and moisture content can be assessed. Furthermore, the chemical composition, internal structure and the anisotropy due to the wood fibres can be investigated.

Absorption spectroscopy of powdered materials using time-resolved diffuse optical methods

In this paper a novel method, based on time-resolved diffuse optical spectroscopy, is proposed to measure the absorption of small amounts of nanostructured powder materials independent of scattering. Experimental validation, in the visible and near-infrared spectral range, has been carried out on India Ink<sup/>particles. The effectiveness of the technique to measure scattering-free absorption is demonstrated on carbon nanotubes. The comparison between the absorption spectra acquired by the proposed method and conventional measurements performed with a commercial spectrophotometer is discussed.

Time-Resolved Diffuse Optical Spectroscopy up to 1700 nm by Means of a Time-Gated InGaAs/InP Single-Photon Avalanche Diode

We present a new compact system for time-domain diffuse optical spectroscopy of highly scattering media operating in the wavelength range from 1100 nm to 1700 nm. So far, this technique has been exploited mostly up to 1100 nm: we extended the spectral range by means of a pulsed supercontinuum light source at a high repetition rate, a prism to spectrally disperse the radiation, and a time-gated InGaAs/InP single-photon avalanche diode working up to 1700 nm. A time-correlated single-photon counting board was used as processing electronics. The system is characterized by linear behavior up to absorption values of about 3.4 cm(-1) where the relative error is 17%. A first measurement performed on lipids is presented: the absorption spectrum shows three major peaks at 1200 nm, 1400 nm, and 1700 nm.

Time-Resolved Diffuse Optical Spectroscopy: A Differential Absorption Approach

A method is presented for the estimate of spectral changes in the absorption properties of turbid media from time-resolved diffuse optical spectroscopy. The method relies on the hypothesis of constant scattering over the wavelength range of interest, but no limitations come from the sample size and shape as the method is derived directly from the Beer-Lambert law. The effects of a moderate spectral dependence of the scattering properties and of the non-ideal instrument response function were investigated theoretically, and the results were confirmed experimentally, showing that the method can be profitably applied in cases of practical interest.

Noninvasive assessment of breast cancer risk using time-resolved diffuse optical spectroscopy

Breast density is a recognized strong and independent risk factor for breast cancer. We propose the use of time-resolved transmittance spectroscopy to estimate breast tissue density and potentially provide even more direct information on breast cancer risk. Time-resolved optical mammography at seven wavelengths (635 to 1060 nm) is performed on 49 subjects. Average information on breast tissue of each subject is obtained on oxy- and deoxyhemoglobin, water, lipids, and collagen content, as well as scattering amplitude and power. All parameters, except for blood volume and oxygenation, correlate with mammographic breast density, even if not to the same extent. A synthetic optical index proves to be quite effective in separating different breast density categories. Finally, the estimate of collagen content as a more direct means for the assessment of breast cancer risk is discussed.

Quantitative characterization of optical and physiological parameters in normal breasts using time-resolved spectroscopy: in vivo results of 19 Singapore women

We report the quantitative measurements of optical and physiological parameters of normal breasts from 19 Singapore women by using time-resolved diffuse optical spectroscopy. Intrinsic absorption coefficient (mu(a)) and reduced scattering coefficients (mu(s) (')) of breasts were calculated from the time-resolved photon migration data. Physiology of breasts was characterized using the concentrations of oxyhemoglobin, deoxyhemoglobin, total hemoglobin (THC), and oxygenation saturation. On average, the experiment results showed that the mu(a) of young women (below 40 years old) was 36 to 38% greater than that of older women (above 40 years old) and that parameter THC was approximately 42% greater. Results also showed that the THC of premenopausal women was 24.3 microMol/L, which was approximately 69% larger than that of postmenopausal women at 14.1 microMol/L. Meanwhile, the mu(a) of premenopausal women was approximately 60% larger than that of postmenopausal women. Correlation analysis further showed that the optical and physiological parameters of breasts were strongly influenced by changes in the women's age, menopausal states, and body mass index. These in vivo experiment results will contribute to the breast tissue diagnosis between healthy and diseased breast tissues.

Assessment of variations in moisture content of wood using time-resolved diffuse optical spectroscopy

Time-resolved spectroscopy using a pulsed supercontinuum source was employed for the assessment of moisture content (MC) in dry wood. The MC of wood at different relative humidities between 94% and 12% has been monitored. Following curve fitting, absorption spectra between 700 and 1100 nm of samples suggest that differences in the MC of wood are appreciable at around 970 nm. Further, dynamic changes in MC were simulated following a change in relative humidity. Differences in absorption spectra with changes in MC of around 1% can be detected. Various applications of the technique are suggested.

Time-resolved diffuse optical spectroscopy of small tissue samples

Time-resolved transmittance spectroscopy was performed in the wavelength range of 610 or 700 to 1050 nm on phantom parallelepipeds and bone tissue cubes of different sizes. The data were best fitted with solutions of the diffusion equation for a laterally infinite slab and for a parallelepiped to investigate how size and optical properties of the samples affect the results obtained with the two models. Monte Carlo simulations were also performed to support and help with the interpretation of the experimental data. The parallelepiped model performs much better than the infinite slab model for the estimate of the reduced scattering coefficient and, even more, the absorption coefficient. It can profitably be used to quantify the optical properties of biological tissue samples and to derive information such as tissue composition, when small volumes are involved.