Single Fiber Reflectance Research Articles

Tissue-probe contact assessment during robotic surgery using Single-Fiber Reflectance Spectroscopy

Tissue-probe contact assessment during robotic surgery using Single-Fiber Reflectance Spectroscopy

Fluorescence detection of pituitary neuroendocrine tumour during endoscopic transsphenoidal surgery using bevacizumab-800CW: a non-randomised, non-blinded, single centre feasibility and dose finding trial [DEPARTURE trial

Achieving endocrine remission by gross total resection is challenging in pituitary neuroendocrine tumours (PitNETs) with cavernous sinus invasion. This study aims to assess the safety, feasibility, and optimal dose for intraoperative fluorescence imaging as an added instrument to discriminate PitNET from surrounding tissue using bevacizumab-800CW, targeting vascular endothelial growth factor A (VEGF-A). In part I, dose-escalation (0-4∙5-10-25mg) was performed in 4 groups of 3 patients with PitNETs Knosp grade 3-4. In part II, after interim analysis, the 10mg and 25mg groups were expanded to a total of 6 patients. Quantitative fluoroscence molecular endoscopy consisted of wide field fluorescence molecular endoscopy and multi-diameter single fiber reflectance / single fiber fluorescence spectroscopy. Mean fluorescence intensity (MFI) of the fresh surgical specimen was calculated and VEGF-staining was performed. Eighteen patients were included. All doses were well tolerated. Three serious adverse events were registered, but none were tracer-related. Part I showed an adequate in-vivo tumour-to-background ratio for both 10mg (TBR 2∙00 [1∙86, 2∙19]) and 25mg (TBR 2∙10, [1∙86, 2∙58]). Part II revealed a substantially higher MFI in the 25mg group. With both 10mg and 25mg a statistically significant difference between tumour and surrounding tissue was detected (p < 0∙0001). All surgical specimens had VEGF-A expression. This study demonstrates the safety and feasibility of quantitative fluorescence molecular endoscopy during PitNET surgery. Both 10mg and 25mg bevacizumab-800CW result in clear differentiation in-vivo, with improved contrast ex-vivo (MFI) in the 25mg group. NCT04212793 / Study Details| Detection of PitNET Tissue During TSS Using Bevacizumab800CW| ClinicalTrials.gov.

Diffuse photon remission associated with the center-illuminated-area-detection geometry. II. Approach to the time-domain model.

This part proposes a model of time-dependent diffuse photon remission for the center-illuminated-area-detection (CIAD) geometry, by virtue of area integration of the radially resolved time-dependent diffuse photon remission formulated with the master-slave dual-source scheme demonstrated in Part I for steady-state measurements. The time-domain model is assessed against Monte Carlo (MC) simulations limiting to only the Heyney-Greenstein scattering phase function for CIAD of physical scales and medium properties relevant to single-fiber reflectance (SfR) and over a 2ns duration, in compliance with the timespan of the only experimental report of SfR demonstrated with a 50µm gradient index fiber. The time-domain model-MC assessments are carried out for an absorption coefficient ranging three orders of magnitude over [0.001,0.01,0.1,1]m m -1 at a fixed scattering, and a reduced scattering coefficient ranging three orders of magnitude over [0.01,0.1,1,10]m m -1 at a fixed absorption, among others. Photons of shorter and longer propagation times, relative to the diameter of the area of collection, respond differently to the scattering and absorption changes. Limited comparisons of MC between CIAD and a top-hat geometry as the idealization of SfR reveal that the time-domain photon remissions of the two geometries differ appreciably in only the early arriving photons.

Detection of Early Esophageal Neoplastic Barrett Lesions with Quantified Fluorescence Molecular Endoscopy Using Cetuximab-800CW.

Esophageal adenocarcinoma causes 6% of cancer-related deaths worldwide. Near-infrared fluorescence molecular endoscopy (NIR-FME) uses a tracer that targets overexpressed proteins. In this study, we aimed to investigate the feasibility of an epidermal growth factor receptor (EGFR)-targeted tracer, cetuximab-800CW, to improve detection of early-stage esophageal adenocarcinoma. Methods: We validated EGFR expression in 73 esophageal tissue sections. Subsequently, we topically administered cetuximab-800CW and performed high-definition white-light endoscopy (HD-WLE), narrow-band imaging, and NIR-FME in 15 patients with Barrett esophagus (BE). Intrinsic fluorescence values were quantified using multidiameter single-fiber reflectance and single-fiber fluorescence spectroscopy. Back-table imaging, histopathologic examination, and EGFR immunohistochemistry on biopsy samples collected during NIR-FME procedures were performed and compared with invivo imaging results. Results: Immunohistochemical preanalysis showed high EGFR expression in 67% of dysplastic tissue sections. NIR-FME visualized all 12 HD-WLE-visible lesions and 5 HD-WLE-invisible dysplastic lesions, with increased fluorescence signal in visible dysplastic BE lesions compared with nondysplastic BE as shown by multidiameter single-fiber reflectance/single-fiber fluorescence, reflecting a target-to-background ratio of 1.5. Invisible dysplastic lesions also showed increased fluorescence, with a target-to-background ratio of 1.67. Immunohistochemistry analysis showed EGFR overexpression in 16 of 17 (94%) dysplastic BE lesions, which all showed fluorescence signal. Conclusion: This study has shown that NIR-FME using cetuximab-800CW can improve detection of dysplastic lesions missed by HD-WLE and narrow-band imaging.

Optical fiber sensors for monitoring cement paste carbonation

The use of concrete has been widespread in our society in housing and infrastructure, despite the environmental cost associated with its production. Its decay poses a social, economic, and environmental problem. Currently, the carbonation of cement paste is monitored through the measurement of its pH, with several optical fiber sensors (OFS) have been produced for this purpose. In the current work the focus is, also, on the carbonation monitoring of cement paste through an OFS, but not through pH measurements. Single fiber reflectance spectroscopy, previously employed to measure cement paste durability, is used to monitor the discoloration of cement paste caused by carbonation. As the carbonation front reaches the fiber tip embedded in the cement paste, the signal reflected onto the fiber increases. The accelerated carbonation of two limestone cement paste samples in an atmosphere of 100% CO2 was successfully monitored. The applicability of the sensor for operational use with ambient CO2 was confirmed through the measurement of carbonation at 3% CO2. The cross interference from water ingress and egress was also evaluated, and it didn’t hinder the measurements of carbonation. Therefore, a novel OFS capable of measuring cement paste carbonation and durability, was achieved.

Diffuse photon remission associated with thecenter-illuminated-area-detection geometry: PartI, an approach to the steady-state model.

Diffuse photon remission associated with the center-illuminated-area-detection (CIAD) geometry has been useful for non-contact sensing and may inform single-fiber reflectance (SfR). This series of work advances model approaches that help enrich the understanding and applicability of the photon remission by CIAD. The general approach is to derive the diffuse photon remission by the area integration of the radially resolved diffuse reflectance while limiting the analysis to a medium exhibiting only the Heyney-Greenstein (HG) scattering phase function. Part I assesses the steady-state photon remission in CIAD over a reduced scattering scaled diameter of μ s ' d a r e a ∈[0.5×10-3,103] that covers the range extensively modeled for SfR. The corresponding radially resolved diffuse reflectance is obtained by concatenating an empirical expression for the semi-ballistic region near the point-of-illumination and a formula utilizing a master-slave dual-source scheme over the semi-diffusive to a diffusive regime while being constrained by an extrapolated zero-boundary condition. The terminal algebraic photon remission is examined against Monte Carlo simulations for an absorption coefficient over [0.001,1]m m -1, a reduced scattering coefficient over [0.01,1000]m m -1, a HG scattering anisotropy factor within [0.5,0.95], and a diameter of the area of collection ranging [50,1000]µm. The algebraic model is also applied to phantom data acquired over a ∼2c m non-contact CIAD configuration and with a 200µm SfR probe. The model approach will be extended in a subsequent work towards the time-of-flight characteristics of CIAD.

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.

Monitoring of irrigated lesion formation with single fiber based multispectral system using machine learning.

In radiofrequency ablation (RFA) treatment of cardiac arrhythmias, intraprocedural assessment of treatment efficacy relies on indirect measures of adequate tissue destruction. Direct sensing of diffuse reflectance spectral changes at the ablation site using optically integrated RFA catheters has been shown to enable accurate prediction of lesion dimensions, ex vivo. Challenges of optical guidance can be due to obtaining reliable measurements under various catheter-tissue contact orientations. In this work, addressed this limitation by assessing the feasibility of monitoring lesion progression using single-fiber reflectance spectroscopy (SFRS). A total of 110 endocardial lesions of various sizes were generated in freshly excised swine right ventricular tissue using a custom-built, irrigated SFRS-RFA catheter. Models were developed for assessing catheter-tissue contact, the presence of nontransmural or transmural lesions and lesion depth percentage. These results support the use of SFRS-based catheters for irrigated lesion assessment and motivate further exploration of using multi-SFRS catheters for omnidirectionality.

Single fiber reflectance spectroscopy for pancreatic cancer detection during endoscopic ultrasound guided fine needle biopsy: a prospective cohort study.

This study aimed to determine the ability of single fiber reflectance (SFR) spectroscopy incorporated in endoscopic ultrasound fine needle biopsy (EUS-FNB) procedures in the pancreas to distinguish benign and malignant pancreatic tissue in patient with pancreatic masses suspected for malignancy.Methods: This study was designed as a prospective observational single center study and included consecutive adult patients, who were scheduled for EUS-FNB of a solid pancreatic mass suspected for pancreatic ductal adenocarcinoma (PDAC). In total, seven optical parameters, derived from the absorption acquired spectra, were analyzed: blood volume fraction (BVF), microvascular saturation, average vessel diameter, bilirubin concentration (BIL), Mie amplitude, Mie slope and Rayleigh amplitude.Results: Forty-five patients with a suspicious pancreatic lesion undergoing EUS-FNB were included, of which most of the patients (N=34) were ultimately diagnosed with PDAC. Finally, 27 out of 45 (60.0%) patients were used for the final analysis of the optical parameters. The median (IQR) BVF differed significantly in benign compared to malignant tissue (0.86 [0.30-2.03] and 4.49 [1.28-15.47]; p=0.046). Combining BVF and BIL to a new parameter (θ) improved the discrimination between PDAC and benign pancreatic tissue (p=0.026). The area under the curve of θ was 0.84, resulting in a 92.8%, 75.0%, 97.5%, 50.0% and 91.3% sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for detection of PDAC.Conclusion: Differentiation between PDAC and benign pancreatic tissue using SFR spectroscopy during EUS-FNB procedures is promising. Future work should focus on comparing the diagnostic performance combining SFR spectroscopy with EUS-FNB and EUS-FNB alone.

Detecting head and neck lymph node metastases with white light reflectance spectroscopy; a pilot study

IntroductionA challenge in the treatment of patients with head and neck cancer is the management of occult cervical lymph node (LN) metastases. Single-fiber reflectance (SFR) spectroscopy has the potential to detect physiological tissue changes that occur in a positive LN. This pilot study aimed to investigate whether SFR spectroscopy could serve as an alternative or additional technique to detect cervical lymph node metastases. Materials and MethodsWe performed intraoperative SFR spectroscopy measurements of LNs with and without malignancies. We analyzed if physiological and scattering parameters were significantly altered in positive LNs. ResultsNine patients with a total of nineteen LNs were included. Three parameters, blood volume fraction (BVF), microvascular saturation (StO2), and Rayleigh amplitude, were significantly lower in positive LNs. They were combined into one optical parameter ‘delta’, using discriminant analysis. Delta was significantly decreased in positive LNs, p = 0,0006. It had a high diagnostic accuracy where the sensitivity, specificity, PPV, and NPV were 90,0%, 88.9%, 90,0%, and 88.9%, respectively. The area under the ROC curve was 96.7% (95% confidence interval 89.7–100.0%). ConclusionThis proof of principle study is a first step in the development of an SFR spectroscopy technique to detect LN metastases in real time. A next step towards this goal is replicating these results in LNs with smaller metastases and in a larger cohort of patients. This future study will combine SFR spectroscopy with fine-needle aspiration, using the same needle, to perform preoperative in vivo measurements.

Single Fiber Reflectance Spectroscopy for the Monitoring of Cement Paste

Reinforced concrete structures are an essential part of our modern society, and monitoring their structural health is of paramount importance. Early detection of decay allows for the reduction of repair costs and, more importantly, the prevention of catastrophic failure. For this purpose, a single fiber reflectance spectrometer was embedded in cement paste samples for the monitoring of water at the fiber tip through its sensitivity to changes in the refractive index. It monitored the curing of samples with different water-to-cement ratios (w/c), between 0.45 and 0.60, measuring the water exhaust during the hardening of the cement paste. It also measured the capillary coefficient from cement paste samples of 0.50, 0.55 and 0.60 w/c: 0.668 ± 0.002 mm/√h, 1.771 ± 0.052 mm/√h and 6.360 ± 0.269 mm/√h, respectively. The capillary coefficient values agree with gravimetric measurements of sorptivity and are further confirmed through porosity measurements made with a scanning electron microscope. Thus, single fiber reflectance spectroscopy can be a gateway to inexpensively measure the entire life cycle of cement, from its curing until its eventual decay, assessing, in situ, its durability through the capillary coefficient.

Diffuse photon-remission associated with single-fiber geometry may be a simple scaling of that collected over the same area when under centered-illumination.

Robust models for single-fiber reflectance (SFR) are relatively complex [Opt. Lett.45, 2078 (2020)OPLEDP0146-959210.1364/OL.385845] due to overlapping of the illumination and collection areas that entails probability weighting of the spatial integration of photon-remission. We demonstrate, via analytical means for limiting cases and Monte Carlo simulation of broader conditions, that diffuse photon-remission collected by single-fiber geometry may be scaled over the center-illuminated photon-remission. We specify for a medium revealing Henyey-Greenstein (HG) scattering anisotropy that the diffuse photon-remission from a sub-diffusive area of a top-hat illumination is ∼84.9% of that collected over the same area when under a centered-illumination. This ratio remains consistent over a reduced-scattering fiber-size product of μs'dfib=[10-5,100], for absorption varying 3 orders of magnitude. When applied to hemoglobin oxygenation changes induced in an aqueous phantom using a 200 µm single-fiber probe, the center-illumination-scaled model of SFR produced fitting results agreeing with reference measurements.

Experimental validation of a recently developed model for single-fiber reflectance spectroscopy.

.Significance: We recently developed a model for the reflectance measured with (multi-diameter) single-fiber reflectance (SFR) spectroscopy as a function of the reduced scattering coefficient , the absorption coefficient , and the phase function parameter . We validated this model with simulations.Aim: We validate our model experimentally. To prevent overfitting, we investigate the wavelength-dependence of and propose a parametrization with only three parameters. We also investigate whether this parametrization enables measurements with a single fiber, as opposed to multiple fibers used in multi-diameter SFR (MDSFR).Approach: We validate our model on 16 phantoms with two concentrations of Intralipid-20% ( and at 500 nm) and eight concentrations of Evans Blue ( to at 605 nm). We parametrize as .Results: Average errors were 7% for , 11% for , and 16% with the parametrization of ; and 7%, 17%, and 16%, respectively, without. The parametrization of improved the fit speed 25 times (94 s to ). Average errors for only one fiber were 50%, 33%, and 186%, respectively.Conclusions: Our recently developed model provides accurate results for MDSFR measurements but not for a single fiber. The parametrization prevents overfitting and speeds up the fit.

Toward improved endoscopic surveillance with multidiameter single fiber reflectance spectroscopy in patients with Barrett's esophagus.

Patients with Barrett's esophagus are at an increased risk to develop esophageal cancer and, therefore, undergo regular endoscopic surveillance. Early detection of neoplasia enables endoscopic treatment, which improves outcomes. However, early Barrett's neoplasia is easily missed during endoscopic surveillance. This study investigates multidiameter single fiber reflectance spectroscopy (MDSFR) to improve Barrett's surveillance. Based on the concept of field cancerization, it may be possible to identify the presence of a neoplastic lesion from measurements elsewhere in the esophagus or even the oral cavity. In this study, MDSFR measurements are performed on non-dysplastic Barrett's mucosa, squamous mucosa, oral mucosa, and the neoplastic lesion (if present). Based on logistic regression analysis on the scattering parameters measured by MDSFR, a classifier is developed that can predict the presence of neoplasia elsewhere in the Barrett's segment from measurements on the non-dysplastic Barrett's mucosa (sensitivity 91%, specificity 71%, AUC = 0.77). Classifiers obtained from logistic regression analysis for the squamous and oral mucosa do not result in an AUC significantly different from 0.5.

The refractive index of human blood measured at the visible spectral region by single-fiber reflectance spectroscopy

The refractive index is an essential biophysical parameter used in many diagnostic and therapeutic biomedical applications. In the present study, the refractive index of control and anemic blood was measured using the total internal reflection fiber optics technique. For control, the refractive index measured by the indicated method was significantly higher than anemic blood over the wavelengths in the visible spectral region used in this study. Strong linear correlations between refractive index and hemoglobin concentration were obtained for control and anemic blood. These findings could enhance the use of the refractive index in many applications of blood analysis and hematology.

Subdiffuse scattering and absorption model for single fiber reflectance spectroscopy.

Single fiber reflectance (SFR) spectroscopy is a technique that is sensitive to small-scale changes in tissue. An additional benefit is that SFR measurements can be performed through endoscopes or biopsy needles. In SFR spectroscopy, a single fiber emits and collects light. Tissue optical properties can be extracted from SFR spectra and related to the disease state of tissue. However, the model currently used to extract optical properties was derived for tissues with modified Henyey-Greenstein phase functions only and is inadequate for other tissue phase functions. Here, we will present a model for SFR spectroscopy that provides accurate results for a large range of tissue phase functions, reduced scattering coefficients, and absorption coefficients. Our model predicts the reflectance with a median error of 5.6% compared to 19.3% for the currently used model. For two simulated tissue spectra, our model fit provides accurate results.

Effect of probe pressure on skin tissue optical properties measurement using multi-diameter single fiber reflectance spectroscopy

Multi-Diameter Single Fiber Reflectance spectroscopy (MDSFR) allows rapid and noninvasive extraction of tissue optical properties that requires the fiberoptic to be placed in contact with the tissue. To ensure a good optical contact, the application of probe pressure is inevitable and usually not well controlled. In this study, we investigated the effect of probe pressure by performing in vivo MDSFR measurements (400–1600 nm) on human inner forearm skin with controlled probe indentation and continuous pressure monitoring. For the probe pressures up to 28.4 s mm−2 (213 mmHg), the reduced scattering coefficient pivoted around 800 nm (increasing scattering slope) while the phase function related parameter decreased (up to 20%, depending on the wavelength). A significant decrease of hemoglobin concentration (∼81%), oxygen saturation (∼86%), apparent vessel diameter (∼100%) as well as the displacement of extracellular water (∼24%) was observed with increasing probe pressure. A correlation was observed between the changes in water volume fraction and phase function related parameter gamma . We theorize that the latter changes in phase function may be due to the induced deformation of the tissue structure and the displacement of extracellular water. The extensive analysis of the pressure induced changes in the measured MDSFR spectra and the related changes in optical properties demonstrate that the effects of probe pressure must be minimized to avoid bias in the results.

Analytical model for diffuse reflectance in single fiber reflectance spectroscopy.

Cancer progression leads to changing scattering properties of affected tissues. Single fiber reflectance (SFR) spectroscopy detects these changes at small spatial scales, making it a promising tool for early in situ detection. Despite its simplicity and versatility, SFR signal modeling is hugely complicated so that, presently, only approximate models exist. We use a classic approach from geometrical probability to derive accurate analytical expressions for diffuse reflectance in SFR that shows a strong improvement over existing models. We consider the case of limited collection efficiency and the presence of absorption. A Monte Carlo light transport study demonstrates that we adequately describe the contribution of diffuse reflectance to the SFR signal. Additional steps are required to include semi-ballistic, non-diffuse reflectance also present in the SFR measurement.

Subdiffuse scattering model for single fiber reflectance spectroscopy.

.To detect small-scale changes in tissue with optical techniques, small sampling volumes are required. Single fiber reflectance (SFR) spectroscopy has a sampling depth of a few hundred micrometers. SFR spectroscopy uses a single fiber to emit and collect light. The only available model to determine optical properties with SFR spectroscopy was derived for tissues with modified Henyey–Greenstein phase functions. Previously, we demonstrated that this model is inadequate for other tissue phase functions. We develop a model to relate SFR measurements to scattering properties for a range of phase functions, in the absence of absorption. Since the source and detector overlap, the reflectance cannot be accurately described by diffusion theory alone: SFR measurements are subdiffuse. Therefore, we describe the reflectance as a combination of a diffuse and a semiballistic component. We use the model of Farrell et al. for the diffuse component, solved for an overlapping source and detector fiber. For the semiballistic component, we derive a new parameter, , which incorporates the integrals of the phase function over 1 deg in the backward direction and 23 deg in the forward direction. Our model predicts the reflectance with a median error of 2.1%, compared to 9.0% for the currently available model.

C-Met targeted fluorescence molecular endoscopy in Barrett's esophagus patients and identification of outcome parameters for phase-I studies.

Fluorescence molecular endoscopy (FME) is an emerging technique in the field of gastroenterology that holds potential to improve diagnosis and guide therapy, by serving as a 'red-flag' endoscopic imaging technique. Here, we investigated the safety, feasibility and optimal method of administration of EMI-137, targeting c-Met, during FME in Barrett's Esophagus (BE) and report several outcome parameters for early phase FME studies.Methods: FME was performed in 15 Barrett's neoplasia patients. EMI-137 was administered to three cohorts of five patients: 0.13 mg/kg intravenously (IV); 0.09 mg/kg IV or topically at a dose of 200 μg/cm BE (n=1) or 100 μg/cm BE (n=4). Fluorescence was visualized in vivo, quantified in vivo using multi-diameter single-fiber reflectance, single-fiber fluorescence (MDSFR/SFF) spectroscopy and correlated to histopathology and immunohistochemistry. EMI-137 localization was assessed using fluorescence microscopy.Results: FME using different IV and topical doses of EMI-137 appeared to be safe and correctly identified 16/18 lesions, although modest target-to-background ratios were observed (median range of 1.12-1.50). C-Met overexpression varied between lesions, while physiological expression in the stomach-type epithelium was observed. Microscopically, EMI-137 accumulated around the neoplastic cell membranes. We identified several outcome parameters important for the validation of EMI-137 for FME: 1) the optimal administration route; 2) optimal dose and safety; 3) in vivo FME contrast; 4) quantification of intrinsic fluorescence; 5) ex vivo correlation of fluorescence, histopathology and target expression; and 6) microscopic tracer distribution.Conclusions: C-Met targeted FME using EMI-137 may not be the ideal combination to improve BE surveillance endoscopies, however the identified outcome parameters may serve as a valuable guidance for designing and performing future early phase clinical FME studies, independent of which fluorescent tracer is investigated.