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In near-infrared spectroscopy (NIRS) of human cerebral hemodynamics, detection of stimulus-related responses is confounded by the presence of unrelated trends in both the brain and the overlying scalp. A proposed strategy for reducing hemodynamic noise has been to record “scalp only” trends simultaneously via a second shorter-separation detector (~5 mm rather than ~30 mm) and perform a subtraction (C-NIRS, for “corrected near-infrared spectroscopy”). To compare the single- and dual-detector strategies, a 21-volunteer study of visual stimulation responses (6 stimulation blocks and 8 recording channels per measurement run) has been conducted. Activation-flagged channels were defined based upon (a) the significance (p-value) of the average rise in oxyhemoglobin concentration and (b) the average signal-to-noise over 6 stimulation epochs. At reasonable thresholds (p<0.025, SNR>1), the C-NIRS method increased the number of activation-flagged channels from 47 to 66, an increase of 40%, adding 24 channels and eliminating only 5. Of the 71 channels that were activation-flagged by at least one modality, the C-NIRS time series exhibited more significant oxyhemoglobin rise in 80% of such channels, and better signal-to-noise in 73%. In addition, single-subject C-NIRS stimulus responses were more consistent than NIRS over the six stimulation epochs, with significantly lower coefficients of variation in both amplitude and latency (i.e. time between stimulus onset and maximum hemoglobin rise). These results demonstrate that two-detector C-NIRS provides a straightforward way of (a) removing hemodynamic interference from NIRS data, (b) increasing the detection rate of cerebrally-unique responses, and (c) improving the quality of those recorded responses. Parallel insights regarding deoxyhemoglobin trends could not be drawn from this data set but should be attainable in future studies with higher signal to noise ratios. ► This study compared two fundamental geometries for functional near infrared spectroscopy. ► Dedicated detectors, 5mm from the sources, were added to provide sensitivity to the scalp hemodynamics. ► These “near” detector signals were subtracted from conventional measurements made using 3cm spacings. ► Visual stimulation responses were detected more frequently and with better quality when the “near” information was included. ► The advantage is readily implemented in both hardware and software.

Attempts to understand the changes in the structure and physiology of human skin abnormalities by non-invasive optical imaging are aided by spectroscopic methods that quantify, at the molecular level, variations in tissue oxygenation and melanin distribution. However, current commercial and research systems to map hemoglobin and melanin do not correlate well with pathology for pigmented lesions or darker skin. We developed a multimode dermoscope that combines polarization and hyperspectral imaging with an efficient analytical model to map the distribution of specific skin bio-molecules. This corrects for the melanin-hemoglobin misestimation common to other systems, without resorting to complex and computationally intensive tissue optical models. For this system's proof of concept, human skin measurements on melanocytic nevus, vitiligo and venous occlusion conditions were performed in volunteers. The resulting molecular distribution maps matched physiological and anatomical expectations, confirming a technologic approach that can be applied to next generation dermoscopes and having biological plausibility that is likely to appeal to dermatologists.

Burn wounds and wound healing invoke several biological processes that may complicate the interpretation of spectral imaging data. Through analysis of spatial frequency domain spectroscopy data (450 to 1000 nm) obtained from longitudinal investigations using a graded porcine burn wound healing model, we have identified features in the absorption spectrum that appear to suggest the presence of hemoglobin breakdown products, e.g., methemoglobin. Our results show that the calculated concentrations of methemoglobin directly correlate with burn severity, 24 h after the injury. In addition, tissue parameters such as oxygenation (StO2) and water fraction may be underestimated by 20% and 78%, respectively, if methemoglobin is not included in the spectral analysis.

Introduction: The role of Adipose-derived mesenchymal stem cells (AD-MSCs) in skin wound healing remains to be fully characterized. This study aims to evaluate the regenerative potential of autologous AD-MSCs in a non-healing porcine wound model, in addition to elucidate key miRNA-mediated epigenetic regulations that underlie the regenerative potential of AD-MSCs in wounds. Methods: The regenerative potential of autologous AD-MSCs was evaluated in porcine model using histopathology and spatial frequency domain imaging. Then, the correlations between miRNAs and proteins of AD-MSCs were evaluated using an integration analysis in primary human AD-MSCs in comparison to primary human keratinocytes. Transfection study of AD-MSCs was conducted to validate the bioinformatics data. Results: Autologous porcine AD-MSCs improved wound epithelialization and skin properties in comparison to control wounds. We identified 26 proteins upregulated in human AD-MSCs, including growth and angiogenic factors, chemokines and inflammatory cytokines. Pathway enrichment analysis highlighted cell signalling-associated pathways and immunomodulatory pathways. miRNA-target modelling revealed regulations related to genes encoding for 16 upregulated proteins. miR-155-5p was predicted to regulate Fibroblast growth factor 2 and 7, C-C motif chemokine ligand 2 and Vascular cell adhesion molecule 1. Transfecting human AD-MSCs cell line with anti-miR-155 showed transient gene silencing of the four proteins at 24 h post-transfection. Discussion: This study proposes a positive miR-155-mediated gene regulation of key factors involved in wound healing. The study represents a promising approach for miRNA-based and cell-free regenerative treatment for difficult-to-heal wounds. The therapeutic potential of miR-155 and its identified targets should be further explored in-vivo .

Spatial frequency domain imaging (SFDI) and spatial frequency domain spectroscopy (SFDS) are emerging tools to non-invasively assess tissues. However, the presence of aberrations can complicate processing and interpretation. This study develops a method to characterize optical aberrations when performing SFDI/S measurements. Additionally, we propose a post-processing method to compensate for these aberrations and recover arbitrary subsurface optical properties. Using a custom SFDS system, we extract absorption and scattering coefficients from a reference phantom at 0 to 15 mm distances from the ideal focus. In post-processing, we characterize aberrations in terms of errors in absorption and scattering relative to the expected in-focus values. We subsequently evaluate a compensation approach in multi-distance measurements of phantoms with different optical properties and in multi-layer phantom constructs to mimic subsurface targets. Characterizing depth-specific aberrations revealed a strong power law such as wavelength dependence from ∼40 to ∼10 % error in both scattering and absorption. When applying the compensation method, scattering remained within 1.3% (root-mean-square) of the ideal values, independent of depth or top layer thickness, and absorption remained within 3.8%. We have developed a protocol that allows for instrument-specific characterization and compensation for the effects of defocus and chromatic aberrations on spatial frequency domain measurements.

Significance: Tissue simulating phantoms are an important part of validating biomedical optical techniques. Tissue pathology in inflammation and oedema involves changes in both water and hemoglobin fractions. Aim: We present a method to create solid gelatin-based phantoms mimicking inflammation and oedema with adjustable water and hemoglobin fractions. Approach: One store-bought gelatin and one research grade gelatin were evaluated. Different water fractions were obtained by varying the water-to-gelatin ratio. Ferrous stabilized human hemoglobin or whole human blood was added as absorbers, and the stability and characteristics of each were compared. Intralipid® was used as the scatterer. All phantoms were characterized using spatial frequency domain spectroscopy. Results: The estimated water fraction varied linearly with expected values (R2  =  0.96 for the store-bought gelatin and R2  =  0.99 for the research grade gelatin). Phantoms including ferrous stabilized hemoglobin stayed stable up to one day but had methemoglobin present at day 0. The phantoms with whole blood remained stable up to 3 days using the store-bought gelatin. Conclusions: A range of physiological relevant water fractions was obtained for both gelatin types, with the stability of the phantoms including hemoglobin differing between the gelatin type and hemoglobin preparation. These low-cost phantoms can incorporate other water-based chromophores and be fabricated as thin sheets to form multilayered structures.

Significance: Spatial frequency domain imaging (SFDI) is a quantitative imaging method to measure absorption and scattering of tissue, from which several chromophore concentrations (e.g., oxy-/deoxy-/meth-hemoglobin, melanin, and carotenoids) can be calculated. Employing a method to extract additional spectral bands from RGB components (that we named cross-channels), we designed a handheld SFDI device to account for these pigments, using low-cost, consumer-grade components for its implementation and characterization. Aim: With only three broad spectral bands (red, green, blue, or RGB), consumer-grade devices are often too limited. We present a methodology to increase the number of spectral bands in SFDI devices that use RGB components without hardware modification. Approach: We developed a compact low-cost RGB spectral imager using a color CMOS camera and LED-based mini projector. The components’ spectral properties were characterized and additional cross-channel bands were calculated. An alternative characterization procedure was also developed that makes use of low-cost equipment, and its results were compared. The device performance was evaluated by measurements on tissue-simulating optical phantoms and in-vivo tissue. The measurements were compared with another quantitative spectroscopy method: spatial frequency domain spectroscopy (SFDS). Results: Out of six possible cross-channel bands, two were evaluated to be suitable for our application and were fully characterized (520  ±  20  nm; 556  ±  18  nm). The other four cross-channels presented a too low signal-to-noise ratio for this implementation. In estimating the optical properties of optical phantoms, the SFDI data have a strong linear correlation with the SFDS data (R2  =  0.987, RMSE  =  0.006 for μa, R2  =  0.994, RMSE  =  0.078 for μs′). Conclusions: We extracted two additional spectral bands from a commercial RGB system at no cost. There was good agreement between our device and the research-grade SFDS system. The alternative characterization procedure we have presented allowed us to measure the spectral features of the system with an accuracy comparable to standard laboratory equipment.

Significance: Spatial frequency domain imaging (SFDI) is a diffuse optical measurement technique that can quantify tissue optical absorption (μa) and reduced scattering (μs′) on a pixel-by-pixel basis. Measurements of μa at different wavelengths enable the extraction of molar concentrations of tissue chromophores over a wide field, providing a noncontact and label-free means to assess tissue viability, oxygenation, microarchitecture, and molecular content. We present here openSFDI: an open-source guide for building a low-cost, small-footprint, three-wavelength SFDI system capable of quantifying μa and μs′ as well as oxyhemoglobin and deoxyhemoglobin concentrations in biological tissue. The companion website provides a complete parts list along with detailed instructions for assembling the openSFDI system. Aim: We describe the design of openSFDI and report on the accuracy and precision of optical property extractions for three different systems fabricated according to the instructions on the openSFDI website. Approach: Accuracy was assessed by measuring nine tissue-simulating optical phantoms with a physiologically relevant range of μa and μs′ with the openSFDI systems and a commercial SFDI device. Precision was assessed by repeatedly measuring the same phantom over 1 h. Results: The openSFDI systems had an error of 0  ±  6  %   in μa and −2  ±  3  %   in μs′, compared to a commercial SFDI system. Bland–Altman analysis revealed the limits of agreement between the two systems to be   ±  0.004  mm  −  1 for μa and −0.06 to 0.1  mm  −  1 for μs′. The openSFDI system had low drift with an average standard deviation of 0.0007  mm  −  1 and 0.05  mm  −  1 in μa and μs′, respectively. Conclusion: The openSFDI provides a customizable hardware platform for research groups seeking to utilize SFDI for quantitative diffuse optical imaging.

Significance: For optical methods to accurately assess hemoglobin oxygen saturation in vivo, an independently verifiable tissue-like standard is required for validation. For this purpose, we propose three hemoglobin preparations and evaluate methods to characterize them. Aim: To spectrally characterize three different hemoglobin preparations using multiple spectroscopic methods and to compare their absorption spectra to commonly used reference spectra. Approach: Absorption spectra of three hemoglobin preparations in solution were characterized using spectroscopic collimated transmission: whole blood, lysed blood, and ferrous-stabilized hemoglobin. Tissue-mimicking phantoms composed of Intralipid, and the hemoglobin solutions were characterized using spatial frequency-domain spectroscopy (SFDS) and enhanced perfusion and oxygen saturation (EPOS) techniques while using yeast to deplete oxygen. Results: All hemoglobin preparations exhibited similar absorption spectra when accounting for methemoglobin and scattering in their oxyhemoglobin and deoxyhemoglobin forms, respectively. However, systematic differences were observed in the fitting depending on the reference spectra used. For the tissue-mimicking phantoms, SFDS measurements at the surface of the phantom were affected by oxygen diffusion at the interface with air, associated with higher values than for the EPOS system. Conclusions: We show the validity of different blood phantoms and what considerations need to be addressed in each case to utilize them equivalently.

Background Conventional photodynamic treatment (cPDT) of thin basal cell carcinomas (BCCs) has uncomfortably high rates of incomplete clearance. Incomplete clearance/recurrence rates for superficial BCCs are as high as 40% and even higher for tumours treated on the head and neck. Our experience has been that flushing is more pronounced on the head and neck during cPDT photoactivation. We postulated that haemoglobin, although delivering oxygen, may be acting as a competing chromophore. Objectives To determine whether a 2‐phased photoactivation protocol, in which blood is removed before the second phase intense pulsed light (IPL) activation, improves clearance rates. Methods Retrospective observational study of 206 treatment‐naïve BCCs ≤ 1 mm thickness treated over a 7‐year period with a 2‐phased photoactivation protocol (‘biphasic PDT’). The first phase consists of conventional red‐light activation (20−37 Jcm−2). Second phase photoactivation uses IPL (30−45 Jcm−2) delivered with sufficient mechanical pressure in the handpiece to blanch the skin. Optical coherence tomography (OCT) has been used to aid in lesion diagnosis, to establish suitability of tumour for treatment and to improve verification of treatment outcomes. Results In the final group of 175 tumours, of which most were located on the head and neck and over 40% were nodular, there were only four incomplete treatments over a 2‐year median follow‐up period (up to 7 years). The few incomplete clearances were easily managed. Conclusions One or two biphasic photodynamic treatments are highly effective (98% clearance) in thin, treatment‐naïve BCCs (≤ 1 mm in thickness) selected on clinical and OCT assessment. Photodynamic treatment using a 2‐phased activation protocol consisting of red light followed immediately by IPL delivered with mechanical pressure to squeeze out blood was highly successful in a group of 206 thin BCCs ( ≤ 1 mm maximum thickness). Optical coherence tomography (OCT) was used for triage and to monitor outcomes. Of the final group of 175 tumours followed up with OCT assessment, there was evidence of incomplete clearance in only four tumours. Most tumours were located on the head and neck. Summary What is already known about this topic? Conventional red‐light photodynamic treatment of BCCs has uncomfortably high rates of incomplete clearance. Incomplete clearance rates of superficial BCCs are approximately 40% and are highest in the face and neck and in younger patients. The study was designed around a central hypothesis that haemoglobin, although delivering oxygen, which is essential for successful PDT, may be acting as a competing chromophore.What does this study add? We present 7 years of data using PDT that incorporates a period of red‐light activation immediately followed by intense‐pulsed‐light (IPL) delivered after removing blood (‘biphasic‐PDT’). Adopting this protocol to thin, treatment‐naïve BCCs (≤ 1 mm thickness), the data presented show a 98% clearance rate with a median 2‐year follow‐up. Most tumours were on the face and neck and 43% were nodular. Optical coherence tomography (OCT) has been used to validate treatment outcomes.What are the clinical implications of this study? One or two biphasic photodynamic treatments are highly effective for treatment‐naïve BCCs (≤ 1 mm thickness) including thin nodular and superficially infiltrating tumours on faces and noses. The few incomplete clearances were easily managed. Diagnosis and triage for biphasic treatments is undertaken by clinicians, and treatment can be undertaken by well‐trained nurses. The results appear comparable with surgery in the treatment of such thin tumours.