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Significance: Esophageal cancer is becoming increasingly prevalent in Western countries. Early detection is crucial for effective treatment. Multimodal imaging combining optical coherence tomography (OCT) with complementary optical imaging techniques may provide enhanced diagnostic capabilities by simultaneously assessing tissue morphology and biochemical content. Aim: We aim to develop a tethered capsule endoscope (TCE) that can accommodate a variety of point-scanning techniques in addition to OCT without requiring design iterations on the optical or mechanical design. Approach: We propose a TCE utilizing exclusively reflective optics to focus and steer light from and to a double-clad fiber. Specifically, we use an ellipsoidal mirror to achieve finite conjugation between the fiber tip and the imaging plane. Results: We demonstrate a functional all-reflective TCE. We first detail the design, fabrication, and assembly steps required to obtain such a device. We then characterize its performance and demonstrate combined OCT at 1300 nm and visible spectroscopic imaging in the 500- to 700-nm range. Finally, we discuss the advantages and limitations of the proposed design. Conclusions: An all-reflective TCE is feasible and allows for achromatic highquality imaging. Such a device could be utilized as a platform for testing various combinations of modalities to identify the optimal candidates without requiring design iterations. [ABSTRACT FROM AUTHOR]

The attenuation coefficient (μOCT) measured by optical coherence tomography (OCT) has been used to determine tissue hydration. Previous dual‐wavelength OCT systems could not attain the needed precision, which we attribute to the absence of wavelength‐dependent scattering of tissue in the underlying model. Assuming that scattering can be described using two parameters, we propose a triple/quadrupole‐OCT system to achieve clinically relevant precision in water volume fraction. In this study, we conduct a quantitative analysis to determine the necessary precision of μOCT measurements and compare it with numerical simulation. Our findings emphasize that achieving a clinically relevant assessment of a 2% water fraction requires determining the attenuation coefficient with a remarkable precision of 0.01 mm−1. This precision threshold is influenced by the chosen wavelength for attenuation measurement and can be enhanced through the inclusion of a fourth wavelength range. [ABSTRACT FROM AUTHOR]

Introduction: Microfluidic resistive pulse sensing (MRPS) can determine the concentration and size distribution of extracellular vesicles (EVs) by measuring the electrical resistance of single EVs passing through a pore. To ensure that the sample flows through the pore, the sample needs to contain a wetting agent, such as bovine serum albumin (BSA). BSA leaves EVs intact but occasionally results in unstable MRPS measurements. Here, we aim to find a new wetting agent by evaluating Poloxamer-188 and Tween-20. Methods: An EV test sample was prepared using an outdated erythrocyte blood bank concentrate. The EV test sample was diluted in Dulbecco's phosphate-buffered saline (DPBS) or DPBS containing 0.10% BSA (w/v), 0.050% Poloxamer-188 (v/v) or 1.00% Tween-20 (v/v). The effect of the wetting agents on the concentration and size distribution of EVs was determined by flow cytometry. To evaluate the precision of sample volume determination with MRPS, the interquartile range (IQR) of the particles transit time through the pore was examined. To validate that DPBS containing Poloxamer-188 yields reliable MRPS measurements, the repeatability of MRPS in measuring blood plasma samples was examined. Results: Flow cytometry results show that the size distribution of EVs in Tween 20, in contrast to Poloxamer-188, differs from the control measurements (DPBS and DPBS containing BSA). MRPS results show that Poloxamer-188 improves the precision of sample volume determination compared to BSA and Tween-20, because the IQR of the transit time of EVs in the test sample is 11 μs, which is lower than 56 μs for BSA and 16 μs for Tween-20. Furthermore, the IQR of the transit time of particles in blood samples with Poloxamer-188 are 14, 16, and 14 μs, which confirms the reliability of MRPS measurements. Conclusion: The solution of 0.050% Poloxamer-188 in DPBS does not lyse EVs and results in repeatable and unimpeded MRPS measurements. [ABSTRACT FROM AUTHOR]

Flow cytometry (FCM) offers a multiparametric technology capable of characterizing single extracellular vesicles (EVs). However, most flow cytometers are designed to detect cells, which are larger than EVs. Whereas cells exceed the background noise, signals originating from EVs partly overlap with the background noise, thereby making EVs more difficult to detect than cells. This technical mismatch together with complexity of EV‐containing fluids causes limitations and challenges with conducting, interpreting and reproducing EV FCM experiments. To address and overcome these challenges, researchers from the International Society for Extracellular Vesicles (ISEV), International Society for Advancement of Cytometry (ISAC), and the International Society on Thrombosis and Haemostasis (ISTH) joined forces and initiated the EV FCM working group. To improve the interpretation, reporting, and reproducibility of future EV FCM data, the EV FCM working group published an ISEV position manuscript outlining a framework of minimum information that should be reported about an FCM experiment on single EVs (MIFlowCyt‐EV). However, the framework contains limited background information. Therefore, the goal of this compendium is to provide the background information necessary to design and conduct reproducible EV FCM experiments. This compendium contains background information on EVs, the interaction between light and EVs, FCM hardware, experimental design and preanalytical procedures, sample preparation, assay controls, instrument data acquisition and calibration, EV characterization, and data reporting. Although this compendium focuses on EVs, many concepts and explanations could also be applied to FCM detection of other particles within the EV size range, such as bacteria, lipoprotein particles, milk fat globules, and viruses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Citrate is the recommended anticoagulant for studies on plasma extracellular vesicles (EVs). Because citrate incompletely blocks platelet activation and the release of platelet-derived EVs, we compared EDTA and citrate in that regard. Blood from healthy individuals (n = 7) was collected and incubated with thrombin receptor-activating peptide-6 (TRAP-6) to activate platelets, subjected to pneumatic tube transportation (n = 6), a freeze-thaw cycle (n = 10), and stored before plasma preparation (n = 6). Concentrations of EVs from platelets (CD61+), activated platelets (P-selectin+), erythrocytes (CD235a+), and leukocytes (CD45+) were measured by flow cytometry. Concentrations of EVs from platelets and activated platelets increased 1.4-fold and 1.9-fold in EDTA blood upon platelet activation, and 4.2-fold and 9.6-fold in citrate blood. Platelet EV concentrations were unaffected by pneumatic tube transport in EDTA blood but increased in citrate blood, and EV concentrations of erythrocytes and leukocytes were comparable. The stability of EVs during a freeze-thaw cycle was comparable for both anticoagulants. Finally, the concentration of platelet EVs was stable during storage of EDTA blood for six hours, whereas this concentration increased 1.5-fold for citrate blood. Thus, EDTA improves the robustness of studies on plasma EVs. [ABSTRACT FROM AUTHOR]

EVs were modelled as core-shell particles, having a 12 nm thick shell with an RI of 1.52 and a core RI of 1.353 (upper solid line), and having a 4 nm thick shell with an RI of 1.450 and a core RI of 1.380 (lower solid line). There are three explanations for the overestimation of the solid particle equivalent RI of CD61 + EVs by Brittain et al. For EVs with a diameter between 225 and 800 nm, which is the size range wherein Flow-SR is applicable for our flow-cytometer (A60-Micro, Apogee Flow Systems, UK), we found an RI of 1.383 ± 0.012 (median ± robust standard deviation), which is in agreement with other RI estimates of single EVs in plasma[14],[15] in this size range. Whereas we found a solid particle equivalent RI for EVs of 1.40-1.47 for 65 nm EVs and 1.39-1.40 for 150 nm EVs, Brittain et al. found 1.61 and 1.39, respectively. [Extracted from the article]

Optical coherence tomography (OCT) is an optical technique which allows for volumetric visualization of the internal structures of translucent materials. Additional information can be gained by measuring the rate of signal attenuation in depth. Techniques have been developed to estimate the rate of attenuation on a voxel by voxel basis. This depth resolved attenuation analysis gives insight into tissue structure and organization in a spatially resolved way. However, the presence of speckle in the OCT measurement causes the attenuation coefficient image to contain unrealistic fluctuations and makes the reliability of these images at the voxel level poor. While the distribution of speckle in OCT images has appeared in literature, the resulting voxelwise corruption of the attenuation analysis has not. In this work, the estimated depth resolved attenuation coefficient from OCT data with speckle is shown to be approximately exponentially distributed. After this, a prior distribution for the depth resolved attenuation coefficient is derived for a simple system using statistical mechanics. Finally, given a set of depth resolved estimates which were made from OCT data in the presence of speckle, a posterior probability distribution for the true voxelwise attenuation coefficient is derived and a Bayesian voxelwise estimator for the coefficient is given. These results are demonstrated in simulation and validated experimentally. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) present in blood originate from cells of different origins such as red blood cells (RBCs), platelets and leukocytes. In patients with cancer, a small portion of EVs originate from tumour cells and their load is associated with poor clinical outcome. Identification of these tumour-derived extracellular vesicles (tdEVs) is difficult as they are outnumbered by EVs of different tissue of origin as well a large number of lipoproteins (LPs) that are in the same size range. In order to detect tdEVs from the abundant presence of other particles, single-particle techniques are necessary. Here, synchronous Rayleigh and Raman scattering is used for that purpose. This combination of light scattering techniques identifies optically trapped single particles based on Rayleigh scattering and distinguishes differences in chemical composition of particle populations based on Raman scattering. Here, we show that tdEVs can be distinguished from RBC EVs and LPs in a label-free manner and directly in suspension. [ABSTRACT FROM AUTHOR]

Patient: Male, 1-year-old. Final Diagnosis: Healthy. Symptoms: None. Clinical Procedure: Foster care. Specialty: Pediatrics and Neonatology. Objective: Rare disease. Background: The commercial software for hospitals, Weight Velocity for Age Standard Deviation Score (SDSWVA), claims to document the growth and development of children, although published details are unavailable. The statisticsderived parameter SDSWVA includes the weight velocity at age t, WV(t) (weight gained between t and (t-1.23) years, divided by 1.23), and 3 standard weight velocity curves at average age AA, defined as AA=t-1.23/2 years. SDSWVA denotes the number of standard deviations that WV(t) deviates from the 0 SD weight velocity at AA. WV(t) yielded erroneous outcomes when applied to weights of a seriously underweight boy with an allergy to cows' milk who showed strong weight growth after being fed on food free of cows' milk. The SDSWVA software tacitly suggests that it is more accurate than WV(t). Case Report: The case of this boy was previously described in this Journal. Using SDSWVA(t,AA) software, his weight growth was analyzed by his third pediatrician, beginning at age 1.5 years. The diagnosis of the mother with Pediatric Condition Falsification was confirmed, adding 6 months to foster care, which totalled 8.5 months. Testing of the SDSWVA software on the boy's weight curve yielded results that were complex, nontransparent, and as erroneous as WV(t), explaining the misdiagnosis by the third pediatrician. Conclusions: SDSWVA software should not be used for children under 3 years and during variable weight behavior. Erroneous performance, unpublished details, and an error identified in their new but untested software make the Dutch Growth Research Foundation unlikely to meet the 2020 European Union regulations for in vitro medical devices. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) present in blood originate from cells of different origins such as red blood cells (RBCs), platelets and leukocytes. In patients with cancer, a small portion of EVs originate from tumour cells and their load is associated with poor clinical outcome. Identification of these tumour‐derived extracellular vesicles (tdEVs) is difficult as they are outnumbered by EVs of different tissue of origin as well a large number of lipoproteins (LPs) that are in the same size range. In order to detect tdEVs from the abundant presence of other particles, single‐particle techniques are necessary. Here, synchronous Rayleigh and Raman scattering is used for that purpose. This combination of light scattering techniques identifies optically trapped single particles based on Rayleigh scattering and distinguishes differences in chemical composition of particle populations based on Raman scattering. Here, we show that tdEVs can be distinguished from RBC EVs and LPs in a label‐free manner and directly in suspension. [ABSTRACT FROM AUTHOR]

In this study, four optical techniques—Optical Coherence Tomography, Sidestream Darkfield Microscopy, Laser Speckle Contrast Imaging, and Fluorescence Angiography (FA)—were compared on performing an intraoperative quantitative perfusion assessment of the gastric conduit during oesophagectomy. We hypothesised that the quantitative parameters show decreased perfusion towards the fundus in the gastric conduit and in patients with anastomotic leakage. In a prospective study in patients undergoing oesophagectomy with gastric conduit reconstruction, measurements were taken with all four optical techniques at four locations from the base towards the fundus in the gastric conduit (Loc1, Loc2, Loc3, Loc4). The primary outcome included 14 quantitative parameters and the anastomotic leakage rate. Imaging was performed in 22 patients during oesophagectomy. Ten out of 14 quantitative parameters significantly indicated a reduced perfusion towards the fundus of the gastric conduit. Anastomotic leakage occurred in 4/22 patients (18.4%). At Loc4, the FA quantitative values for "T1/2" and "mean slope" differed between patients with and without anastomotic leakage (p = 0.025 and p = 0.041, respectively). A quantitative perfusion assessment during oesophagectomy is feasible using optical imaging techniques, of which FA is the most promising for future research. [ABSTRACT FROM AUTHOR]

Large (> 1 μm) tumor-derived extracellular vesicles (tdEVs) enriched from the cell fraction of centrifuged whole blood are prognostic in metastatic castration-resistant prostate cancer (mCRPC) patients. However, the highest concentration of tdEVs is expected in the cell-free plasma fraction. In this pilot study, we determine whether mCRPC patients can be discriminated from healthy controls based on detection of tdEVs (< 1μm, EpCAM+) and/or other EVs, in cell-free plasma and/or urine. The presence of marker+ EVs in plasma and urine samples from mCRPC patients (n = 5) and healthy controls (n = 5) was determined by flow cytometry (FCM) and surface plasmon resonance imaging (SPRi) using an antibody panel and lactadherin. For FCM, the concentrations of marker positive (+) particles and EVs (refractive index <1.42) were determined. Only the lactadherin+ particle and EV concentration in plasma measured by FCM differed significantly between patients and controls (p = 0.017). All other markers did not result in signals exceeding the background on both FCM and SPRi, or did not differ significantly between patients and controls. In conclusion, no difference was found between patients and controls based on the detection of tdEVs. For FCM, the measured sample volumes are too small to detect tdEVs. For SPRi, the concentration of tdEVs is probably too low to be detected. Thus, to detect tdEVs in cell-free plasma and/or urine, EV enrichment and/or concentration is required. Furthermore, we recommend testing other markers and/or a combination of markers to discriminate mCRPC patients from healthy controls. [ABSTRACT FROM AUTHOR]

Gold nanorods have interesting optical properties due to surface plasmon resonance effects. A variety of biomedical applications of these particles have been envisaged and feasibilities demonstrated in imaging, sensing, and therapy based on the interactions of light with these particles. In order to correctly interpret experimental data and tailor the nanorods and their environments for optimal use in these applications, simulations of the optical properties of the particles under various conditions are essential. Of various numerical methods available, the discrete dipole approximation (DDA) approach implemented in the publicly available DDSCAT code is a powerful method that had proved popular for studying gold nanorods. However, there is as yet no universal agreement on the shape used to represent the nanorods and on the dielectric function of gold required for the simulations. We systematically study the influence of these parameters on simulated results. We find large variations in the position of plasmon resonance peaks, their amplitudes, and shapes of the spectra depending on the choice of the parameters. We discuss these in the light of experimental optical extinction spectra of gold nanorods synthesized in our laboratory. We show that much care should be taken and prudence applied before DDA results be used to interpret experimental data and to help characterize nanoparticles synthesized. [ABSTRACT FROM AUTHOR]

Purpose: Urothelial carcinoma of the bladder (UCB) is the most common urinary cancer. White-light cystoscopy (WLC) forms the corner stone for the diagnosis of UCB. However, histopathological assessment is required for adjuvant treatment selection. Probe-based confocal laser endomicroscopy (pCLE) enables visualization of the microarchitecture of bladder lesions during WLC, which allows for real-time tissue differentiation and grading of UCB. To improve the diagnostic process of UCB, computer-aided classification of pCLE videos of in vivo bladder lesions were evaluated in this study. Materials and Methods: We implemented preprocessing methods to optimize contrast and to reduce striping artifacts in each individual pCLE frame. Subsequently, a semiautomatic frame selection was performed. The selected frames were used to train a feature extractor based on pretrained ImageNet networks. A recurrent neural network, in specific long short-term memory (LSTM), was used to predict the grade of bladder lesions. Differentiation of lesions was performed at two levels, namely (i) healthy and benign vs malignant tissue and (ii) low-grade vs high-grade papillary UCB. A total of 53 patients with 72 lesions were included in this study, resulting in ∼140,000 pCLE frames. Results: The semiautomated frame selection reduced the number of frames to ∼66,500 informative frames. The accuracy for differentiation of (i) healthy and benign vs malignant urothelium was 79% and (ii) high-grade and low-grade papillary UCB was 82%. Conclusions: A feature extractor in combination with LSTM results in proper stratification of pCLE videos of in vivo bladder lesions. [ABSTRACT FROM AUTHOR]

Most common complications of esophagectomy stem from a perfusion deficiency of the gastric conduit at the anastomosis. Fluorescent tracer imaging allows intraoperative visualization of tissue perfusion. Quantitative assessment of fluorescence dynamics has the potential to identify perfusion deficiency. We developed a perfusion model to analyze the relation between fluorescence dynamics and perfusion deficiency. The model divides the gastric conduit into two well-perfused and two anastomosed sites. Hemodynamics and tracer transport were modeled. We analyzed the value of relative time-to-threshold (RTT) as a predictor of the relative remaining flow (RRF). Intensity thresholds for RTT of 20% to 50% of the maximum fluorescence intensity of the well-perfused site were tested. The relation between RTT and RRF at the anastomosed sites was evaluated over large variations of vascular conductance and volume. The ability of RTT to distinguish between sufficient and impaired perfusion was analyzed using c-statistics. We found that RTT was a valuable estimate for low RRF. The threshold of 20% of the maximum fluorescence intensity provided the best prediction of impaired perfusion on the two anastomosed sites (AUC = 0.89 and 0.86). The presented model showed that for low flows, relative time-to-threshold may be used to estimate perfusion deficiency. [ABSTRACT FROM AUTHOR]

Histopathologic grading of prostate cancer using Gleason patterns (GPs) is subject to a large inter-observer variability, which may result in suboptimal treatment of patients. With the introduction of digitization and whole-slide images of prostate biopsies, computer-aided grading becomes feasible. Computer-aided grading has the potential to improve histopathological grading and treatment selection for prostate cancer. Automated detection of GPs and determination of the grade groups (GG) using a convolutional neural network. In total, 96 prostate biopsies from 38 patients are annotated on pixel-level. Automated detection of GP 3 and GP ≥ 4 in digitized prostate biopsies is performed by re-training the Inception-v3 convolutional neural network (CNN). The outcome of the CNN is subsequently converted into probability maps of GP ≥ 3 and GP ≥ 4, and the GG of the whole biopsy is obtained according to these probability maps. Differentiation between non-atypical and malignant (GP ≥ 3) areas resulted in an accuracy of 92% with a sensitivity and specificity of 90 and 93%, respectively. The differentiation between GP ≥ 4 and GP ≤ 3 was accurate for 90%, with a sensitivity and specificity of 77 and 94%, respectively. Concordance of our automated GG determination method with a genitourinary pathologist was obtained in 65% (κ = 0.70), indicating substantial agreement. A CNN allows for accurate differentiation between non-atypical and malignant areas as defined by GPs, leading to a substantial agreement with the pathologist in defining the GG. [ABSTRACT FROM AUTHOR]

In Fourier-domain optical coherence tomography (FD-OCT), proper signal sampling and dispersion compensation are essential steps to achieve optimal axial resolution. These calibration steps can be performed through numerical signal processing, but require calibration information about the system that may require lengthy and complex measurement protocols. We report a highly robust calibration procedure that can simultaneously determine correction vectors for nonlinear wavenumber sampling and dispersion compensation. The proposed method requires only two simple mirror measurements and no prior knowledge about the system's illumination source or detection scheme. This method applies to both spectral domain and swept-source OCT systems. Furthermore, it may be implemented as a low-cost fail-safe to validate the proper function of calibration hardware such as k-clocks. We demonstrate the method's simple implementation, effectiveness, and robustness on both types of OCT systems. [ABSTRACT FROM AUTHOR]

Commercial software package "Growth Analyser Viewer Edition" ("GAVE") aims to document, monitor and analyze growth and development in children and adolescents. Although its clinical and scientific use is widespread, there are no published studies that describe the method and its validation. We were informed that GAVE calculates the weight velocity (kg/year) at age t from the weight difference between t and 448 days earlier or at birth, divided by the time difference. We recently discussed a case of false child abuse diagnosis (Pediatric Condition Falsification), resulting in the separation of the child from its parents, in which GAVE played a negative contributing role. To prevent such inappropriate diagnoses, we analyzed GAVE from a schematic representation of the measured clinical weight curve, with precisely defined weight velocities. In conclusion, the 448 days included for weight velocity predictions by GAVE caused the erroneous outcomes. Until the necessary changes to the software are implemented and validated, we advise against the use of GAVE in infants younger than 1.5 years, if multiple weight changes occur within 448 days, and following a long-lasting weight velocity change. Our analysis suggests to discard all medical software packages that lack public description and proof of validation. [ABSTRACT FROM AUTHOR]

This paper describes a proof-of-concept of a miniaturized spectral-domain optical coherence tomography system, based on photonic integrated circuit (PIC) technology. The integrated optics 512-channel spectrometer consists of cascaded arrayed waveguide gratings (AWG) with the output waveguides directly attached to a CCD detector. The spectrometer has a center wavelength of 850 nm and a spectral sampling interval of 0.22 nm. The PIC has a footprint of 2.0 × 2.7 cm2. The wavelength response of the cascaded AWG spectrometer is calibrated with a tunable laser. Free space OCT measurements are done with a mirror as sample. The signal-to-noise ratio is ∼77 dB. Due to the ∼three times larger optical bandwidth incident on each CCD pixel, the sensitivity rolls off faster in depth than based on the spectral sampling interval. The axial resolution of the OCT system is determined at 5.9 ± 0.4 μm. We demonstrate the imaging capabilities of this PIC based system by imaging a multilayered phantom. Our results show the basis for the development of a handheld OCT system based on PIC technology, thereby facilitating the development of more applications of OCT. [ABSTRACT FROM AUTHOR]

A fiber optic probe-based Raman spectroscopy system using a single laser module with two excitation wavelengths, at 680 and 785 nm, has been developed for measuring the fingerprint and high wavenumber regions using a single detector. This system is simpler and less expensive than previously reported configurations of combined fingerprint and high wavenumber Raman systems, and its probe-based implementation facilitates numerous in vivo applications. The high wavenumber region of the Raman spectrum ranges from 2800–3800 cm−1 and contains valuable information corresponding to the molecular vibrations of proteins, lipids, and water, which is complimentary to the biochemical signatures found in the fingerprint region (800–1800 cm−1), which probes DNA, lipids, and proteins. The efficacy of the system is demonstrated by tracking changes in water content in tissue-mimicking phantoms, where Voigtian decomposition of the high wavenumber water peak revealed a correlation between the water content and type of water-tissue interactions in the samples. This dual wavelength system was then used for in vivo assessment of cervical remodeling during mouse pregnancy, a physiologic process with known changes in tissue hydration. The system shows that Raman spectroscopy is sensitive to changes in collagen content in the fingerprint region and hydration state in the high wavenumber region, which was verified using an ex vivo comparison of wet and dry weight. Simultaneous fingerprint and high wavenumber Raman spectroscopy will allow precise in vivo quantification of tissue water content in the high wavenumber region, paired with the high biochemical specificity of the fingerprint region. [ABSTRACT FROM AUTHOR]

Biomarkers in the blood of cancer patients include circulating tumor cells (CTCs), tumor‐educated platelets (TEPs), tumor‐derived extracellular vesicles (tdEVs), EV‐associated miRNA (EV‐miRNA), and circulating cell‐free DNA (ccfDNA). Because the size and density of biomarkers differ, blood is centrifuged to isolate or concentrate the biomarker of interest. Here, we applied a model to estimate the effect of centrifugation on the purity of a biomarker according to published protocols. The model is based on the Stokes equation and was validated using polystyrene beads in buffer and plasma. Next, the model was applied to predict the biomarker behavior during centrifugation. The result was expressed as the recovery of CTCs, TEPs, tdEVs in three size ranges (1–8, 0.2–1, and 0.05–0.2 μm), EV‐miRNA, and ccfDNA. Bead recovery was predicted with errors <18%. Most notable cofounders are the 22% contamination of 1–8 μm tdEVs for TEPs and the 8–82% contamination of <1 μm tdEVs for ccfDNA. A Stokes model can predict biomarker behavior in blood. None of the evaluated protocols produces a pure biomarker. Thus, care should be taken in the interpretation of obtained results, as, for example, results from TEPs may originate from co‐isolated large tdEVs and ccfDNA may originate from DNA enclosed in <1 μm tdEVs. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry. [ABSTRACT FROM AUTHOR]

Discusses a study that focused on the use of the partial vaporization model for pulse mid-infrared laser ablation of water. Damage attributed to collapsing water vapor bubbles; Way that laser induced bubble formation was documented; Evidence for a novel ablation model; Information on the process of ablation with pulsed infrared laser radiation.

Diagnostic accuracy of needle-based optical coherence tomography (OCT) for prostate cancer detection by visual and quantitative analysis is defined. 106 three-dimensional (3-D)-OCT data sets were acquired in 20 prostates after radical prostatectomy and precisely matched with pathology. OCT images were grouped per histological category. Two reviewers performed blind assessments of the OCT images. Sensitivity and specificity for malignancy detection were calculated. Quantitative analyses by automated optical attenuation coefficient calculation were performed. OCT can reliably differentiate between fat, cystic, and regular atrophy and benign glands. The overall sensitivity and specificity for malignancy detection was 79% and 88% for reviewer 1 and 88% and 81% for reviewer 2. Quantitative analysis for differentiation between stroma and malignancy showed a significant difference (4.6 mm-1 versus 5.0 mm-1 Mann-Whitney U-test p < 0.0001). A Kruskal-Wallis test showed a significant difference in median attenuation coefficient between stroma, inflammation, Gleason 3, and Gleason 4 (4.6, 4.1, 5.9, and 5.0 mm-1, respectively). However, attenuation coefficient varied per patient and a related-samples Wilcoxon signed-rank test showed no significant difference per patient (p = 0.17). This study confirmed the one to one correlation of histopathology and OCT. Precise matching showed that most histological tissues categories in the prostate could be distinguished by their unique pattern in OCT images. In addition, the optical attenuation coefficient can play a role in the differentiation between stroma and malignancy; however, a per patient analysis of the optical attenuation coefficient did not show a significant difference. [ABSTRACT FROM AUTHOR]

Lung cancer survival is poor, and radiation therapy patients often suffer serious treatment side effects. The esophagus is particularly sensitive leading to acute radiation-induced esophageal damage (ARIED). We investigated the feasibility of optical coherence tomography (OCT) for minimally invasive imaging of the esophagus with high resolution (10 µm) to detect ARIED in mice. Thirty mice underwent cone-beam computed tomography imaging for initial setup assessment and dose planning followed by a single-dose delivery of 4.0, 10.0, 16.0, and 20.0 Gy on 5.0-mm spots, spaced 10.0 mm apart in the esophagus. They were repeatedly imaged using OCT up to three months postirradiation. We compared OCT findings with histopathology obtained three months postirradiation qualitatively and quantitatively using the contrast-to-background-noise ratio (CNR). Histopathology mostly showed inflammatory infiltration and edema at higher doses; OCT findings were in agreement with most of the histopathological reports. We were able to identify the ARIED on OCT as a change in tissue scattering and layer thickness. Our statistical analysis showed significant difference between the CNR values of healthy tissue, edema, and inflammatory infiltration. Overall, the average CNR for inflammatory infiltration and edema damages was 1.6-fold higher and 1.6-fold lower than for the healthy esophageal wall, respectively. Our results showed the potential role of OCT to detect and monitor the ARIED in mice, which may translate to humans. [ABSTRACT FROM AUTHOR]

By using integrated optics, it is possible to reduce the size and cost of a bulky optical coherence tomography (OCT) system. One of the OCT components that can be implemented on-chip is the interferometer. In this work, we present the design and characterization of a Mach-Zehnder interferometer consisting of the wavelength-independent splitters and an on-chip reference arm. The Si3N4 was chosen as the material platform as it can provide low losses while keeping the device size small. The device was characterized by using a home-built swept source OCT system. A sensitivity value of 83 dB, an axial resolution of 15.2 µm (in air) and a depth range of 2.5 mm (in air) were all obtained. [ABSTRACT FROM AUTHOR]

By using integrated optics, it is possible to reduce the size and cost of a bulky optical coherence tomography (OCT) system. One of the OCT components that can be implemented on-chip is the interferometer. In this work, we present the design and characterization of a Mach-Zehnder interferometer consisting of the wavelength-independent splitters and an on-chip reference arm. The Si3N4 was chosen as the material platform as it can provide low losses while keeping the device size small. The device was characterized by using a home-built swept source OCT system. A sensitivity value of 83 dB, an axial resolution of 15.2 μm (in air) and a depth range of 2.5 mm (in air) were all obtained. [ABSTRACT FROM AUTHOR]

Parametric imaging of the attenuation coefficient μOCT using optical coherence tomography (OCT) is a promising approach for evaluating abnormalities in tissue. To date, a standardized measure of accuracy and precision of μOCT by the depth-resolved estimation (DRE) method, as an alternative to least squares fitting, is missing. We present a robust theoretical framework to determine accuracy and precision of the DRE of μOCT. We derive and validate analytical expressions for the accuracy and precision of μOCT determination by the DRE using simulated OCT signals in absence and presence of noise. We compare the theoretically achievable precisions of the DRE method and the least-squares fitting approach. Our analytical expressions agree with the numerical simulations for high signal-to-noise ratios and qualitatively describe the dependence on noise otherwise. A commonly used simplification of the DRE method results in a systematic overestimation of the attenuation coefficient in the order of μOCT2×Δ , where Δ is the pixel stepsize. When μOCT · | AFR | ≲ 1.8, μOCT is reconstructed with higher precision by the depth-resolved method compared to fitting over the length of an axial fitting range | AFR |. We derived and validated expressions for the accuracy and precision of DRE of μOCT. A commonly used simplification of this method is not recommended as being used for OCT-attenuation reconstruction. We give a rule of thumb providing guidance in the choice of estimation method. [ABSTRACT FROM AUTHOR]

To accurately determine sample optical properties using single fiber reflectance spectroscopy (SFR), an absolute calibration of the reflectance is required. We investigated two SFR calibration methods, using a calibrated mirror and using the Fresnel reflection at the fiber tip as a reference. We compared these to commonly used calibration methods, using either Intralipid-20% in combination with Monte Carlo simulations or Spectralon as a reference. The Fresnel reflection method demonstrated the best reproducibility and yielded the most reliable result. We therefore recommend the Fresnel reflection method for the measured absolute reflectance calibration of SFR. [ABSTRACT FROM AUTHOR]

To detect small-scale changes in tissue with optical techniques, small sampling volumes and, therefore, short source--detector separations are required. In this case, reflectance measurements are not adequately described by the diffusion approximation. Previous studies related subdiffusive reflectance to γ or σ, which parameterize the phase function. Recently, it was demonstrated that σ predicts subdiffusive reflectance better than γ, and that σ becomes less predictive for lower numerical apertures (NAs). We derive and evaluate the parameter RpNA, which incorporates the NA of the detector and the integral of the phase function over the NA in the backward and forward directions. Monte Carlo simulations are performed for overlapping source/detector geometries for a range of phase functions, reduced scattering coefficients, NAs, and source/detector diameters. RpNA improves prediction of the measured reflectance compared to γ and σ. It is, therefore, expected that RpNA will improve derivation of optical properties from subdiffusive measurements. [ABSTRACT FROM AUTHOR]

A noninvasive method is introduced for quantification and visualization of fluence rate in light-irradiated biological tissues. The method is based on magnetic resonance thermometry (MRT) measurements of tissue temperature changes resulting from absorption of light. From the spatial-temporal temperature data, the generated heat is calculated. Finally, fluence rate maps are reconstructed by dividing the heat data by the tissue absorption coefficient. Simulations were performed using virtual MRT datasets based on analytically described fluence rate distributions, which could be accurately reconstructed by the method. Next, the approach was tested in gel phantoms. Resulting fluence rate maps matched well with theoretical predictions in a nonscattering phantom (R² = 0.93). Experimental validation was further obtained in a scattering phantom, by comparing fluence rates to invasive fluence rate probe measurements along and perpendicular to the optical axis (R² ≥ 0.71 for both cases). Finally, our technique was applied in vivo in a mouse tumor model. The resulting fluence rates matched invasive probe measurements (Pearson's p = 0.90, p = 0.0026). The method may be applied to investigate the relation between light dose and biological response in light-based treatments, such as photodynamic therapy. It may also be useful for experimental validation of light transport models. [ABSTRACT FROM AUTHOR]

In spatial frequency domain imaging (SDFI), tissue is illuminated with sinusoidal intensity patterns at different spatial frequencies. For low spatial frequencies, the reflectance is diffuse and a model derived by Cuccia et al. (doi 10.1117/1.3088140) is commonly used to extract optical properties. An improved model resulting in more accurate optical property extraction could lead to improved diagnostic algorithms. To develop a model that improves optical property extraction for the diffuse reflectance in SFDI compared to the model of Cuccia et al. We derive two analytical models for the diffuse reflectance, starting from the theoretical radial reflectance R (ρ) for a pencil-beam illumination under the partial current boundary condition (PCBC) and the extended boundary condition (EBC). We compare both models and the model of Cuccia et al. to Monte Carlo simulations. The model based on the PCBC resulted in the lowest errors, improving median relative errors compared to the model of Cuccia et al. by 45% for the reflectance, 10% for the reduced scattering coefficient and 64% for the absorption coefficient. For the diffuse reflectance in SFDI, the model based on the PCBC provides more accurate results than the currently used model by Cuccia et al. [ABSTRACT FROM AUTHOR]

To improve (pre)malignant lesion identification in Barrett's esophagus (BE), recent research focuses on new developments in fluorescence imaging and spectroscopy to enhance tissue contrast. Our aim was to validate the chorioallantoic membrane (CAM) model as a preclinical tool to study the fluorescence characteristics such as autofluorescence and exogenously induced fluorescence of human Barrett's tissue. Therefore, esophageal biopsy specimens from Barrett's patients were freshly grafted onto the CAM of fertilized hen's eggs to simulate the in vivo situation. The BE biopsy specimens stayed between 1 and 9 days on the CAM to study the persistence of vitality. Fluorescence spectroscopy was performed using six excitation wavelengths (369, 395, 400, 405, 410, 416 nm). Obtained autofluorescence spectra were compared with in vivo spectra of an earlier study. Exogenous administration of 5-aminolevulinic-acid to the biopsy specimens was followed by fluorescence spectroscopy at several time points. Afterwards, the biopsy specimens were harvested and histologically evaluated. In total, 128 biopsy specimens obtained from 34 patients were grafted on the CAM. Biopsy specimens which stayed on average 1.7 days on the CAM were still vital. Autofluorescence spectra of the specimens correlated well with in vivo spectra. Administered 5-aminolevulinic-acid to the biopsy specimens showed conversion into protoporphyrin-IX. In conclusion, we showed that grafting freshly collected human BE biopsy specimens on the CAM is feasible. Our results suggest that the CAM model might be used to study the fluorescence behavior of human tissue specimens. Therefore, the CAM model might be a preclinical research tool for new photosensitizers. [ABSTRACT FROM AUTHOR]

Optical coherence tomography (OCT) has the potential to quantitatively measure optical properties of tissue such as the attenuation coefficient and backscattering coefficient. However, to obtain reliable values for strong scattering tissues, accurate consideration of the effects of multiple scattering and the nonlinear relation between the scattering coefficient and scatterer concentration (concentration-dependent scattering) is required. We present a comprehensive model for the OCT signal in which we quantitatively account for both effects, as well as our system parameters (confocal point spread function and sensitivity roll-off). We verify our model with experimental data from controlled phantoms of monodisperse silica beads (scattering coefficients between 1 and 30 mm-1 and scattering anisotropy between 0.4 and 0.9). The optical properties of the phantoms are calculated using Mie theory combined with the Percus--Yevick structure factor to account for concentration-dependent scattering. We demonstrate excellent agreement between the OCT attenuation and backscattering coefficient predicted by our model and experimentally derived values. We conclude that this model enables us to accurately model OCT-derived parameters (i.e., attenuation and backscattering coefficients) in the concentration-dependent and multiple scattering regime for spherical monodisperse samples. [ABSTRACT FROM AUTHOR]

The learning curve and interobserver variance of attenuation coefficient (μOCT) determination from optical coherence tomography (OCT) images were quantified. The μOCT of normal and diseased vulvar tissues was determined at five time points by three novice students and three OCT experts who reached consensus for reference. Students received feedback between time points. Eventually, variance in μOCT was smaller in images of diseased tissue than in images of normal vulvar tissue. The difference between the consensus and student μOCT values was larger for smaller values of μOCT. We conclude that routine μOCT determination for tissue classification does not require extensive training. [ABSTRACT FROM AUTHOR]

Passive quadrature demultiplexing allows full-range optical coherence tomography (FR-OCT). However, imperfections in the wavelength- and frequency-response of the demodulation circuits can cause residual mirror artifacts, which hinder high-quality imaging on both sides of zero delay. We aim at achieving high mirror artifact extinction by calibrated postprocessing of the FR-OCT signal. We propose a mathematical framework for the origin of the residual mirror peaks as well as a protocol allowing the precise measurement and correction of the associated errors directly from mirror measurements. We demonstrate high extinction of the mirror artifact over the entire imaging range, as well as an assessment of the method's robustness to time and experimental conditions. We also provide a detailed description of the practical implementation of the method to ensure optimal reproducibility. The proposed method is simple to implement and produces high mirror artifact extinction. This may encourage the adoption of FR-OCT in clinical and industrial systems or loosen the performance requirements on the optical demodulation circuit, as the imperfections can be handled in postprocessing. [ABSTRACT FROM AUTHOR]