Stephen C. Kanick

Sub-diffusive scattering parameter maps recovered using wide-field high-frequency structured light imaging

This study investigates the hypothesis that structured light reflectance imaging with high spatial frequency patterns [Formula: see text] can be used to quantitatively map the anisotropic scattering phase function distribution [Formula: see text] in turbid media. Monte Carlo simulations were used in part to establish a semi-empirical model of demodulated reflectance ([Formula: see text]) in terms of dimensionless scattering [Formula: see text] and [Formula: see text], a metric of the first two moments of the [Formula: see text] distribution. Experiments completed in tissue-simulating phantoms showed that simultaneous analysis of [Formula: see text] spectra sampled at multiple [Formula: see text] in the frequency range [0.05-0.5] [Formula: see text] allowed accurate estimation of both [Formula: see text] in the relevant tissue range [0.4-1.8] [Formula: see text], and [Formula: see text] in the range [1.4-1.75]. Pilot measurements of a healthy volunteer exhibited [Formula: see text]-based contrast between scar tissue and surrounding normal skin, which was not as apparent in wide field diffuse imaging. These results represent the first wide-field maps to quantify sub-diffuse scattering parameters, which are sensitive to sub-microscopic tissue structures and composition, and therefore, offer potential for fast diagnostic imaging of ultrastructure on a size scale that is relevant to surgical applications.

Monte Carlo analysis of single fiber reflectance spectroscopy: photon path length and sampling depth

Single fiber reflectance spectroscopy is a method to noninvasively quantitate tissue absorption and scattering properties. This study utilizes a Monte Carlo (MC) model to investigate the effect that optical properties have on the propagation of photons that are collected during the single fiber reflectance measurement. MC model estimates of the single fiber photon path length (L(SF)) show excellent agreement with experimental measurements and predictions of a mathematical model over a wide range of optical properties and fiber diameters. Simulation results show that L(SF) is unaffected by changes in anisotropy (g epsilon [0.8, 0.9, 0.95]), but is sensitive to changes in phase function (Henyey-Greenstein versus modified Henyey-Greenstein). A 20% decrease in L(SF) was observed for the modified Henyey-Greenstein compared with the Henyey-Greenstein phase function; an effect that is independent of optical properties and fiber diameter and is approximated with a simple linear offset. The MC model also returns depth-resolved absorption profiles that are used to estimate the mean sampling depth (Z(SF)) of the single fiber reflectance measurement. Simulated data are used to define a novel mathematical expression for Z(SF) that is expressed in terms of optical properties, fiber diameter and L(SF). The model of sampling depth indicates that the single fiber reflectance measurement is dominated by shallow scattering events, even for large fibers; a result that suggests that the utility of single fiber reflectance measurements of tissue in vivo will be in the quantification of the optical properties of superficial tissues.

Empirical model of the photon path length for a single fiber reflectance spectroscopy device.

A reflectance spectroscopic device that utilizes a single fiber for both light delivery and collection has advantages over classical multi-fiber probes. This study presents a novel empirical relationship between the single fiber path length and the combined effect of both the absorption coefficient, mua (range: 0.1-6 mm-1), and the reduced scattering coefficient, micros (range: 0.3 - 10 mm-1), for different anisotropy values (0.75 and 0.92), and is applicable to probes containing a wide range of fiber diameters (range: 200-2000 microm). The results indicate that the model is capable of accurately predicting the single fiber path length over a wide range (r = 0.995; range: 180-3940 microm) and predictions do not show bias as a function of either microa or micros .

Microscopic lymph node tumor burden quantified by macroscopic dual-tracer molecular imaging

Lymph node biopsy is employed in many cancer surgeries to identify metastatic disease and to determine cancer stage, yet morbidity and diagnostic delays associated with lymph node biopsy could be avoided if noninvasive imaging of nodal involvement were reliable. Molecular imaging has potential in this regard; however, variable delivery and nonspecific uptake of imaging tracers have made conventional approaches ineffective clinically. Here we present a method of correcting for nonspecific uptake with injection of a second untargeted tracer that allows for quantification of tumor burden in lymph nodes. We confirmed the approach in an athymic mouse model of metastatic human breast cancer by targeting epidermal growth factor receptor, a cell surface receptor overexpressed by many cancers. We observed a significant correlation between in vivo (dual-tracer) and ex vivo measures of tumor burden (r = 0.97, P < 0.01), with an ultimate sensitivity of approximately 200 cells (potentially more sensitive than conventional lymph node biopsy).

Integration of single-fiber reflectance spectroscopy into ultrasound-guided endoscopic lung cancer staging of mediastinal lymph nodes

We describe the incorporation of a single-fiber reflectance spectroscopy probe into the endoscopic ultrasound fine-needle aspiration (EUS-FNA) procedure utilized for lung cancer staging. A mathematical model is developed to extract information about the physiological and morphological properties of lymph tissue from single-fiber reflectance spectra, e.g., microvascular saturation, blood volume fraction, bilirubin concentration, average vessel diameter, and Mie slope. Model analysis of data from a clinical pilot study shows that the single-fiber reflectance measurement is capable of detecting differences in the physiology between normal and metastatic lymph nodes. Moreover, the clinical data show that probe manipulation within the lymph node can perturb the in vivo environment, a concern that must be carefully considered when developing a sampling strategy. The data show the feasibility of this novel technique; however, the potential clinical utility has yet to be determined.

Measurement of the reduced scattering coefficient of turbid media using single fiber reflectance spectroscopy: Fiber diameter and phase function dependence

This paper presents a relationship between the intensity collected by a single fiber reflectance device (RSF) and the fiber diameter (dfib) and the reduced scattering coefficient ( μs′) and phase function (p(θ)) of a turbid medium. Monte Carlo simulations are used to identify and model a relationship between RSF and dimensionless scattering ( μs′dfib). For μs′dfib > 10 we find that RSF is insensitive to p(θ). A solid optical phantom is constructed with μs′ ≈ 220 mm−1 and is used to convert RSF of any turbid medium to an absolute scale. This calibrated technique provides accurate estimates of μs′ over a wide range ([0.05 – 8] mm−1) for a range of dfib ([0.2 – 1] mm).

A GAMOS plug-in for GEANT4 based Monte Carlo simulation of radiation-induced light transport in biological media

We describe a tissue optics plug-in that interfaces with the GEANT4/GAMOS Monte Carlo (MC) architecture, providing a means of simulating radiation-induced light transport in biological media for the first time. Specifically, we focus on the simulation of light transport due to the Čerenkov effect (light emission from charged particle’s traveling faster than the local speed of light in a given medium), a phenomenon which requires accurate modeling of both the high energy particle and subsequent optical photon transport, a dynamic coupled process that is not well-described by any current MC framework. The results of validation simulations show excellent agreement with currently employed biomedical optics MC codes, [i.e., Monte Carlo for Multi-Layered media (MCML), Mesh-based Monte Carlo (MMC), and diffusion theory], and examples relevant to recent studies into detection of Čerenkov light from an external radiation beam or radionuclide are presented. While the work presented within this paper focuses on radiation-induced light transport, the core features and robust flexibility of the plug-in modified package make it also extensible to more conventional biomedical optics simulations. The plug-in, user guide, example files, as well as the necessary files to reproduce the validation simulations described within this paper are available online at http://www.dartmouth.edu/optmed/research-projects/monte-carlo-software.

Pulsed-light imaging for fluorescence guided surgery under normal room lighting.

Fluorescence guided surgery (FGS) is an emerging technology that has demonstrated improved surgical outcomes. However, dim lighting conditions required by current FGS systems are disruptive to standard surgical workflow. We present a novel FGS system capable of imaging fluorescence under normal room light by using pulsed excitation and gated acquisition. Images from tissue-simulating phantoms confirm visual detection down to 0.25 μM of protoporphyrin IX under 125 μW/cm2 of ambient light, more than an order of magnitude lower than that measured with the Zeiss Pentero in the dark. Resection of orthotopic brain tumors in mice also suggests that the pulsed-light system provides superior sensitivity in vivo.

Characterization of Mediastinal Lymph Node Physiology In Vivo by Optical Spectroscopy during Endoscopic Ultrasound-Guided Fine Needle Aspiration

Introduction: Esophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a minimally invasive staging procedure for mediastinal lymph nodes in patients diagnosed with lung cancer. But, a substantial false negative rate necessitates that patients returning a negative EUS-FNA result must undergo a subsequent surgical staging procedure. This study incorporates a fiberoptic reflectance spectroscopy device into the EUS-FNA procedure to asses the vascular physiology within the sampled lymph node. The aims of this pilot study were to determine the feasibility of incorporating a reflectance spectroscopy device into the EUS-FNA clinical procedure and to gather preliminary information about the vascular physiology within the center of normal and metastatic lymph nodes. Methods: This study included 10 patients with proven or suspected lung cancer and an indication for EUS-FNA. The procedure was performed on seven normal (unenlarged, positron emission tomography negative) nodes and seven suspicious (enlarged, positron emission tomography positive), with the malignant status of all nodes cytologically confirmed. Reflectance spectra were acquired using a single optical fiber that fits through the end of the EUS-FNA biopsy needle, with an outer fiber diameter of 0.38 mm. Results: The procedure was successfully performed and did not introduce complications. Model-based analysis of single fiber reflectance spectra provided quantitative information about the vascular physiology within the sampled lymph node. We observed that metastatic lymph nodes were characterized by lower microvascular oxygen saturation (50% versus 84%, p < 0.01) and lower blood volume fraction (5.6% versus 13.5%, p < 0.01) than normal nodes. Conclusions: Single fiber reflectance spectroscopy has the potential to detect abnormal lymph node physiology.

Measurement of tissue scattering properties using multi-diameter single fiber reflectance spectroscopy: in silico sensitivity analysis

Multiple diameter single fiber reflectance (MDSFR) measurements of turbid media can be used to determine the reduced scattering coefficient (μ′s) and a parameter that characterizes the phase function (γ). The MDSFR method utilizes a semi-empirical model that expresses the collected single fiber reflectance intensity as a function of fiber diameter (dfiber), μ′s, and γ. This study investigated the sensitivity of the MDSFR estimates of μ′s and γ to the choice of fiber diameters and spectral information incorporated into the fitting procedure. The fit algorithm was tested using Monte Carlo simulations of single fiber reflectance intensities that investigated biologically relevant ranges of scattering properties (μ′s ∈ [0.4 – 4]mm−1) and phase functions (γ ∈ [1.4 – 1.9]) and for multiple fiber diameters (dfiber ∈ [0.2 – 1.5] mm). MDSFR analysis yielded accurate estimates of μ′s and γ over the wide range of scattering combinations; parameter accuracy was shown to be sensitive to the range of fiber diameters included in the analysis, but not to the number of intermediate fibers. Moreover, accurate parameter estimates were obtained without a priori knowledge about the spectral shape of γ. Observations were used to develop heuristic guidelines for the design of clinically applicable MDSFR probes.