Light-tissue Interaction Research Articles

Diffuse Optical Spectroscopy: Technology and Applications: introduction to the feature issue.

Welcome to the 2024 Feature Issue on Diffuse Optical Spectroscopy: Technology and Applications in Biomedical Optics Express! This feature issue provides an exemplary sample of established and emerging DOS technologies as well as their biomedical applications through 27 contributed research papers and 1 invited review article. DOS researchers are inherently multidisciplinary, advancing topics spanning the basic theory of light-tissue interactions, computational modeling, technique and system development and preclinical and clinical applications. You will find this full range of topics represented in this feature issue.

Tutorial on methods for estimation of optical absorption and scattering properties of tissue.

The estimation of tissue optical properties using diffuse optics has found a range of applications in disease detection, therapy monitoring, and general health care. Biomarkers derived from the estimated optical absorption and scattering coefficients can reflect the underlying progression of many biological processes in tissues. Complex light-tissue interactions make it challenging to disentangle the absorption and scattering coefficients, so dedicated measurement systems are required. We aim to help readers understand the measurement principles and practical considerations needed when choosing between different estimation methods based on diffuse optics. The estimation methods can be categorized as: steady state, time domain, time frequency domain (FD), spatial domain, and spatial FD. The experimental measurements are coupled with models of light-tissue interactions, which enable inverse solutions for the absorption and scattering coefficients from the measured tissue reflectance and/or transmittance. The estimation of tissue optical properties has been applied to characterize a variety of ex vivo and in vivo tissues, as well as tissue-mimicking phantoms. Choosing a specific estimation method for a certain application has to trade-off its advantages and limitations. Optical absorption and scattering property estimation is an increasingly important and accessible approach for medical diagnosis and health monitoring.

Monte Carlo simulation of the effect of melanin concentration on light-tissue interactions for transmittance pulse oximetry measurement.

Questions about the accuracy of pulse oximeters in measuring arterial oxygen saturation ( ) in individuals with darker skin pigmentation have resurfaced since the COVID-19 pandemic. This requires investigation to improve patient safety, clinical decision making, and research. We aim to use computational modeling to identify the potential causes of inaccuracy in measurement in individuals with dark skin and suggest practical solutions to minimize bias. An in silico model of the human finger was developed to explore how changing melanin concentration and arterial oxygen saturation ( ) affect pulse oximeter calibration algorithms using the Monte Carlo (MC) technique. The model generates calibration curves for Fitzpatrick skin types I, IV, and VI and an range between 70% and 100% in transmittance mode. was derived by inputting the computed ratio of ratios for light and dark skin into a widely used calibration algorithm equation to calculate bias ( ). These were validated against an experimental study to suggest the validity of the Monte Carlo model. Further work included applying different multiplication factors to adjust the moderate and dark skin calibration curves relative to light skin. Moderate and dark skin calibration curve equations were different from light skin, suggesting that a single algorithm may not be suitable for all skin types due to the varying behavior of light in different epidermal melanin concentrations, especially at 660nm. The ratio between the mean bias in White and Black subjects in the cohort study was 6.6 and 5.47 for light and dark skin, respectively, from the Monte Carlo model. A linear multiplication factor of 1.23 and exponential factor of 1.8 were applied to moderate and dark skin calibration curves, resulting in similar alignment. This study underpins the careful re-assessment of pulse oximeter designs to minimize bias in measurements across diverse populations.

Monte Carlo simulation of the effect of melanin concentration on light-tissue interactions in transmittance and reflectance finger photoplethysmography

Photoplethysmography (PPG) uses light to detect volumetric changes in blood, and is integrated into many healthcare devices to monitor various physiological measurements. However, an unresolved limitation of PPG is the effect of skin pigmentation on the signal and its impact on PPG based applications such as pulse oximetry. Hence, an in-silico model of the human finger was developed using the Monte Carlo (MC) technique to simulate light interactions with different melanin concentrations in a human finger, as it is the primary determinant of skin pigmentation. The AC/DC ratio in reflectance PPG mode was evaluated at source-detector separations of 1 mm and 3 mm as the convergence rate (Q), a parameter that quantifies the accuracy of the simulation, exceeded a threshold of 0.001. At a source-detector separation of 3 mm, the AC/DC ratio of light skin was 0.472 times more than moderate skin and 6.39 than dark skin at 660 nm, and 0.114 and 0.141 respectively at 940 nm. These findings are significant for the development of PPG-based sensors given the ongoing concerns regarding the impact of skin pigmentation on healthcare devices.

Autofluorescence Excitation Imaging of Nonmelanoma Skin Cancer for Margin Assessment Before Mohs Micrographic Surgery: A Pilot Study.

Autofluorescence photography can detect specific light-tissue interactions and record important pathophysiological changes associated with nonmelanoma skin cancer (NMSC), which has been ascribed to the fluorescence of an aromatic amino acid, tryptophan. To assess the impact of a novel, autofluorescence imaging (AFI) device on margin control for NMSCs before Mohs micrographic surgery (MMS) in an effort to decrease overall operating time. Before the initial stage of MMS, NMSCs were measured with a 2-mm margin as standard of care (normal margin). The tumor was then imaged with the AFI device. A 2-mm margin was drawn around the fluorescent area captured by the AFI device and was referred to as the camera margin. The tumor was excised based on the normal margin and evaluated on frozen histological section. Imaging based on the AFI device resulted in appropriate recommendations for margin control in 8 of 11 tumors. Four of these tumors did not fluoresce and demonstrated a lack of tumor residuum on stage I specimen, as anticipated. There were no side effects from the AFI device. This is an initial pilot study that supports the use of a novel, noninvasive imaging device to help with margin assessment before MMS. On optimization, this device has potential to extend applicability to surgical excisions for tumors that do not fulfill criteria for MMS.

Surface-Enhanced Spatially Offset Raman Spectroscopy in Tissue.

One aim of personalized medicine is to use continuous or on-demand monitoring of metabolites to adjust prescription dosages in real time. Surface-enhanced spatially offset Raman spectroscopy (SESORS) is an optical technique capable of detecting surface-enhanced Raman spectroscopy (SERS)-active targets under a barrier, which may enable frequent metabolite monitoring. Here we investigate how the intensity of the signal from SERS-active material varies spatially through tissue, both experimentally and in a computational model. Implant-sized, SERS-active hydrogel was placed under different thicknesses of contiguous tissue. Emission spectra were collected at the air-tissue boundary over a range of offsets from the excitation site. New features were added to the Monte Carlo light-tissue interaction model to modify the optical properties after inelastic scattering and to calculate the distribution of photons as they exit the model. The Raman signals were detectable through all barrier thicknesses, with strongest emission for the case of 0 mm offset between the excitation and detector. A steep decline in the signal intensities occurred for offsets greater than 2 mm. These results did not match published SORS work (where targets were much larger than an implant). However, the model and experimental results agree in showing the greatest intensities at 0 mm offset and a steep gradient in the intensities with increasing offset. Also, the model showed an increase in the number of photons when the new, longer wavelengths were used following the Stokes shift for scattering and the graphical display of the exiting photons was helpful in the determination and confirmation of the optimal offset.

Estimation of Photon Path Length and Penetration Depth in Articular Cartilage Zonal Architecture Over the Therapeutic Window.

The key characteristics of light propagation are the average penetration depth, average maximum penetration depth, average maximum lateral spread, and average path length of photons. These parameters depend on tissue optical properties and, thus, on the pathological state of the tissue. Hence, they could provide diagnostic information on tissue integrity. This study investigates these parameters for articular cartilage which has a complex structure. We utilize Monte Carlo simulation to simulate photon trajectories in articular cartilage and estimate the average values of the light propagation parameters (penetration depth, maximum penetration depth, maximum lateral spread, and path length) in the spectral band of 400-1400 nm based on the optical properties of articular cartilage zonal layers and bulk tissue. Our findings suggest that photons in the visible band probe a localized small volume of articular cartilage superficial and middle zones, while those in the NIR band penetrate deeper into the tissue and have larger lateral spread. In addition, we demonstrate that a simple model of articular cartilage tissue, based on the optical properties of the bulk tissue, is capable to provide an accurate description of the light-tissue interaction in articular cartilage. The results indicate that as the photons in the spectral band of 400-1400 nm can reach the full depth of articular cartilage matrix, they can provide viable information on its pathological state. Therefore, diffuse optical spectroscopy holds significant importance for objectively assessing articular cartilage health. In this study, for the first time, we estimate the light propagation parameters in articular cartilage.

Reconstructing in vivo spatially offset Raman spectroscopy of human skin tissue using a GPU-accelerated Monte Carlo platform

As one type of spatially offset Raman spectroscopy (SORS), inverse SORS is particularly suited to in vivo biomedical measurements due to its ring-shaped illumination scheme. To explain inhomogeneous Raman scattering during in vivo inverse SORS measurements, the light–tissue interactions when excitation and regenerated Raman photons propagate in skin tissue were studied using Monte Carlo simulation. An eight-layered skin model was first built based on the latest transmission parameters. Then, an open-source platform, Monte Carlo eXtreme (MCX), was adapted to study the distribution of 785 nm excitation photons inside the model with an inverse spatially shifted annular beam. The excitation photons were converted to emission photons by an inverse distribution method based on excitation flux with spatial offsets Δs of 1 mm, 2 mm, 3 mm and 5 mm. The intrinsic Raman spectra from separated skin layers were measured by continuous linear scanning to improve the simulation accuracy. The obtained results explain why the spectral detection depth gradually increases with increasing spatial offset, and address how the intrinsic Raman spectrum from deep skin layers is distorted by the reabsorption and scattering of the superficial tissue constituents. Meanwhile, it is demonstrated that the spectral contribution from subcutaneous fat will be improved when the offset increases to 5 mm, and the highest detection efficiency for dermal layer spectral detection could be achieved when Δs = 2 mm. Reasonably good matching between the calculated spectrum and the measured in vivo inverse SORS was achieved, thus demonstrating great utility of our modeling method and an approach to help understand the clinical measurements.

Numerical Modeling and Simulation of Non-Invasive Acupuncture Therapy Utilizing Near-Infrared Light-Emitting Diode.

Acupuncture is one of the most extensively used complementary and alternative medicine therapies worldwide. In this study, we explore the use of near-infrared light-emitting diodes (LEDs) to provide acupuncture-like physical stimulus to the skin tissue, but in a completely non-invasive way. A computational modeling framework has been developed to investigate the light-tissue interaction within a three-dimensional multi-layer model of skin tissue. Finite element-based analysis has been conducted, to obtain the spatiotemporal temperature distribution within the skin tissue, by solving Pennes' bioheat transfer equation, coupled with the Beer-Lambert law. The irradiation profile of the LED has been experimentally characterized and imposed in the numerical model. The experimental validation of the developed model has been conducted through comparing the numerical model predictions with those obtained experimentally on the agar phantom. The effects of the LED power, treatment duration, LED distance from the skin surface, and usage of multiple LEDs on the temperature distribution attained within the skin tissue have been systematically investigated, highlighting the safe operating power of the selected LEDs. The presented information about the spatiotemporal temperature distribution, and critical factors affecting it, would assist in better optimizing the desired thermal dosage, thereby enabling a safe and effective LED-based photothermal therapy.

Monte Carlo Simulation of Diffuse Optical Spectroscopy for 3D Modeling of Dental Tissues.

Three-dimensional precise models of teeth are critical for a variety of dental procedures, including orthodontics, prosthodontics, and implantology. While X-ray-based imaging devices are commonly used to obtain anatomical information about teeth, optical devices offer a promising alternative for acquiring 3D data of teeth without exposing patients to harmful radiation. Previous research has not examined the optical interactions with all dental tissue compartments nor provided a thorough analysis of detected signals at various boundary conditions for both transmittance and reflectance modes. To address this gap, a GPU-based Monte Carlo (MC) method has been utilized to assess the feasibility of diffuse optical spectroscopy (DOS) systems operating at 633 nm and 1310 nm wavelengths for simulating light-tissue interactions in a 3D tooth model. The results show that the system's sensitivity to detect pulp signals at both 633 nm and 1310 nm wavelengths is higher in the transmittance compared with that in the reflectance mode. Analyzing the recorded absorbance, reflectance, and transmittance data verified that surface reflection at boundaries can improve the detected signal, especially from the pulp region in both reflectance and transmittance DOS systems. These findings could ultimately lead to more accurate and effective dental diagnosis and treatment.

Multispectral Imaging for Skin Diseases Assessment-State of the Art and Perspectives.

Skin optical inspection is an imperative procedure for a suspicious dermal lesion since very early skin cancer detection can guarantee total recovery. Dermoscopy, confocal laser scanning microscopy, optical coherence tomography, multispectral imaging, multiphoton laser imaging, and 3D topography are the most outstanding optical techniques implemented for skin examination. The accuracy of dermatological diagnoses attained by each of those methods is still debatable, and only dermoscopy is frequently used by all dermatologists. Therefore, a comprehensive method for skin analysis has not yet been established. Multispectral imaging (MSI) is based on light-tissue interaction properties due to radiation wavelength variation. An MSI device collects the reflected radiation after illumination of the lesion with light of different wavelengths and provides a set of spectral images. The concentration maps of the main light-absorbing molecules in the skin, the chromophores, can be retrieved using the intensity values from those images, sometimes even for deeper-located tissues, due to interaction with near-infrared light. Recent studies have shown that portable and cost-efficient MSI systems can be used for extracting skin lesion characteristics useful for early melanoma diagnoses. This review aims to describe the efforts that have been made to develop MSI systems for skin lesions evaluation in the last decade. We examined the hardware characteristics of the produced devices and identified the typical structure of an MSI device for dermatology. The analyzed prototypes showed the possibility of improving the specificity of classification between the melanoma and benign nevi. Currently, however, they are rather adjuvants tools for skin lesion assessment, and efforts are needed towards a fully fledged diagnostic MSI device.

Deep learning-based optical approach for skin analysis of melanin and hemoglobin distribution.

Melanin and hemoglobin have been measured as important diagnostic indicators of facial skin conditions for aesthetic and diagnostic purposes. Commercial clinical equipment provides reliable analysis results, but it has several drawbacks: exclusive to the acquisition system, expensive, and computationally intensive. We propose an approach to alleviate those drawbacks using a deep learning model trained to solve the forward problem of light-tissue interactions. The model is structurally extensible for various light sources and cameras and maintains the input image resolution for medical applications. A facial image is divided into multiple patches and decomposed into melanin, hemoglobin, shading, and specular maps. The outputs are reconstructed into a facial image by solving the forward problem over skin areas. As learning progresses, the difference between the reconstructed image and input image is reduced, resulting in the melanin and hemoglobin maps becoming closer to their distribution of the input image. The proposed approach was evaluated on 30 subjects using the professional clinical system, VISIA VAESTRO. The correlation coefficients for melanin and hemoglobin were found to be 0.932 and 0.857, respectively. Additionally, this approach was applied to simulated images with varying amounts of melanin and hemoglobin. The proposed approach showed high correlation with the clinical system for analyzing melanin and hemoglobin distribution, indicating its potential for accurate diagnosis. Further calibration studies using clinical equipment can enhance its diagnostic ability. The structurally extensible model makes it a promising tool for various image acquisition conditions.

Photobiomodulation in the treatment of oral diseases

The modern conception of dentistry is based on the search for noninvasive clinical applicability methods that improve the prognoses of dental pathologies and, therefore, the interest in light-tissue interaction technology has increased in the last decade. The present study aims to explore the applicability of photobiomodulation (PBM) in dentistry with emphasis on wavelengths provided to target tissues and the underlying mechanisms of action of lasers observed in the treatment of various oral diseases, as well as the affected processes that include, but are not limited to wound healing, tissue biostimulation, tissue and nerve regeneration, inhibition of pain and inflammatory processes. The effects obtained through photobiomodulation are correlated with the parameters involved, such as the equipment used, wavelength, power dosages, irradiation duration, energy density, general patient conditions, target tissue, pathology and etiologies considered. Depending on the conditions reported, the photobiomodulator effect or also known as low intensity laser therapy (LLLT) influences the increase of cellular metabolism through the application of photonic energy that presents monochromaticity and propagates consistently in time and space. Thus, the protocols for the application of the photonic properties of this therapeutic modality should be analyzed in the treatment of oral conditions and pathologies associated with glandular, neural, autoimmune, traumatic, and idiopathic diseases.

Optical Properties of Perfused Rat Liver Tissues

In this work, we demonstrate the results of measuring the optical properties of rat liver tissue slices after the liver itself underwent the perfusion procedure with an isotonic solution. The approach is suggested as a means to attenuate the influence of blood absorption on recorded characteristics and demonstrates its effectiveness in changing the composition of recorded spectra in the visible range. The data obtained seem promising to be used to upgrade the proposed methodology and apply the results for the diagnosis and modeling of light-tissue interaction in liver under healthy and pathological conditions.

Flexible control of pulse intensity and repetition rate for multiphoton photostimulation

In deep tissue imaging, pulsed near-infrared lasers commonly provide high peak powers needed for nonlinear absorption, but average power and linear absorption can be limiting factors for tissue damage through heat. We implemented intra-cavity dumping within a mode-locked Ti:Sapphire laser used for two-photon computer generated holography stimulation. This system enables photostimulation in which pulse energy, average power, and repetition rate can each be varied and harnessed as degrees of freedom. We demonstrate how this system provides a new dimension of temporal control in photostimulation experiments to alter the ratio of nonlinear to linear light-tissue interactions, namely by tuning the laser repetition rate between single-shot and ≈ 3 MHz. Repetition rates below 1 MHz, yielding pulse energies over 60 nJ, facilitated holographic projections with more regions of interest than the highest repetition rate of 3 MHz. Even lower repetition rates ( ≈ 10 kHz) diminished thermal load on the sample, as characterized by quantification of heat shock protein expression in zebrafish tissue.

Opportunities and pitfalls in (sub)diffuse reflectance spectroscopy

For a long time, steady-state reflectance spectroscopy measurements have been performed so that diffusion theory could be used to extract tissue optical properties from the reflectance. The development of subdiffuse techniques, such as Single Fiber Reflectance Spectroscopy and subdiffuse SFDI, provides new opportunities for clinical applications since they have the key advantage that they are much more sensitive to the details of the tissue scattering phase function in comparison to diffuse techniques. Since the scattering phase function is related to the subcellular structure of tissue, subdiffuse measurements have the potential to provide a powerful contrast between healthy and diseased tissue. In the subdiffuse regime, the interrogated tissue volumes are much smaller than in the diffuse regime. Whether a measurement falls within the diffuse or subdiffuse regime depends on tissue optical properties and the distance between the source and detector fiber for fiber-optic techniques or the projected spatial frequency for hyperspectral imaging and SFDI. Thus, the distance between source and detector fibers or the projected spatial frequency has important implications for clinical applications of reflectance spectroscopy and should be carefully selected, since it influences which tissue optical properties the technique is sensitive to and the size of the tissue volume that is interrogated. In this paper, we will review the opportunities and pitfalls in steady-state reflectance spectroscopy in the subdiffuse and the diffuse regime. The discussed opportunities can guide the choice of either the diffuse or subdiffuse regime for a clinical application, and the discussed pitfalls can ensure these are avoided to enable the development of robust diagnostic algorithms. We will first discuss the relevant basics of light-tissue interaction. Next, we will review all the tissue scattering phase functions that have been measured and investigate which scattering phase function models are representative of tissue. Subsequently, we will discuss the sensitivity of diffuse and subdiffuse techniques to tissue optical properties and we will explore the difference in the interrogation depth probed by diffuse and subdiffuse techniques.

Conjugate heat transfer analysis of laser-irradiated cylindrical-shaped biological tissue embedded with the optical inhomogeneity

The current study is associated with the numerical investigation of the thermal behavior of cylindrical-shaped biological tissue during laser-based photo-thermal therapy. The light-tissue interaction has been modeled using the transient radiative transfer equation (TRTE). The TRTE in a cylindrical coordinate system is solved using the modified discrete ordinate method to obtain the intensity distribution inside the biological tissue. The solution of TRTE is coupled with Pennes bio-heat transfer equation (BHTE) to understand the thermic response of biological tissue. The Pennes BHTE is solved using the finite volume method (FVM). The two different types of optical inhomogeneity (absorption and scattering inhomogeneity) are considered in the current study. The inhomogeneity's optical and thermophysical properties may be the same/different from the homogeneous biological tissue. This conjugate heat transfer problem (CHTP) is solved using the harmonic mean technique. First, the present result is verified with the data available in the literature. Subsequently, the effect of inhomogeneity's optical properties on the temperature distribution is investigated. A comparative study between the same and different thermophysical properties of the biological tissue and inhomogeneity is performed. This study will help to accurately model the thermal characteristics of the laser-irradiated biological tissue having different thermophysical properties than the inhomogeneity.

Head Phantom Optical Properties Validation for Near-Infrared Measurements: A Comparison with Animal Tissue.

The interest in optical healthcare technologies has increased significantly over the recent years. The innovation of new optical technologies such as Near Infrared Spectroscopy (NIRS), used for the monitoring of brain perfusion, demands a comprehensive understanding and knowledge of the light tissue interaction. Phantoms can provide a rigorous, reproducible and convenient approach for evaluating an optical sensor's performance. However, up to date literature does not provide a detailed description of a complete head model that involves the human anatomy, physiological changes, and the tissue optical properties. The latter is key for the design, development and testing of optical sensors, such as NIRS technologies. This paper compared the optical properties of the materials chosen to build a head phantom, against the optical properties of real brain and skull tissues extracted from animal models. The spectra of a silicone brain and resin skull samples were compared with the spectra of the respective tissues extracted from pigs and mice. The results of this study demonstrated that both phantom materials have similar optical properties to mice and pigs' tissues. The morphology of the phantom's spectra were very similar to the respective animal tissue comparator.

A Multilayer Monte Carlo Analysis of Optical Interactions in Reflectance Neck Photoplethysmography.

This paper presents a multilayer Monte Carlo model of a healthy human neck to investigate the light-tissue interaction during different perfusion states within its dermal layer. Whilst there is great interest in advancing wearable technologies for medical applications, and non-invasive techniques like photoplethysmography (PPG) have been studied in detail, research has focused on more conventional body regions like the finger, wrist, and ear. Alternatively, the neck could offer access to additional physiological parameters which other body regions are unsuitable for. The aim of this work was to investigate the effects of several factors that would influence the optimum design of a reflectance PPG sensor for the neck. These included the source-detector separation on the optical path, penetration depth, and light detection efficiency. The results were generated from a static multilayer model in a reflectance mode geometry at two wavelengths, 660 nm and 880 nm, containing different blood volume fractions with a fixed oxygen saturation. Simulations indicated that both wavelengths penetrated similar depths, where optimal source-detector separation should not exceed 3 mm or 2.4 mm, for red and infrared respectively. Within this range, light interrogates the dermal-fat boundary corresponding to the last neck tissue layer positively contributing to a neck PPG acquisition.

Nanoparticle-assisted, image-guided laser interstitial thermal therapy for cancer treatment.

Laser interstitial thermal therapy (LITT) guided by magnetic resonance imaging (MRI) is a new treatment option for patients with brain and non‐central nervous system (non‐CNS) tumors. MRI guidance allows for precise placement of optical fiber in the tumor, while MR thermometry provides real‐time monitoring and assessment of thermal doses during the procedure. Despite promising clinical results, LITT complications relating to brain tumor procedures, such as hemorrhage, edema, seizures, and thermal injury to nearby healthy tissues, remain a significant concern. To address these complications, nanoparticles offer unique prospects for precise interstitial hyperthermia applications that increase heat transport within the tumor while reducing thermal impacts on neighboring healthy tissues. Furthermore, nanoparticles permit the co‐delivery of therapeutic compounds that not only synergize with LITT, but can also improve overall effectiveness and safety. In addition, efficient heat‐generating nanoparticles with unique optical properties can enhance LITT treatments through improved real‐time imaging and thermal sensing. This review will focus on (1) types of inorganic and organic nanoparticles for LITT; (2) in vitro, in silico, and ex vivo studies that investigate nanoparticles' effect on light–tissue interactions; and (3) the role of nanoparticle formulations in advancing clinically relevant image‐guided technologies for LITT.This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological DiseaseImplantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery