Bioimaging and Biomedical Optics Commons^™

Perspective Review Of What Is Needed For Molecular-Specific Fluorescence-Guided Surgery, Brian W. Pogue, Eben L. Rosenthal, Samuel Achilefu, Gooitzen M. Van Dam

Dartmouth Scholarship

Molecular image-guided surgery has the potential for translating the tools of molecular pathology to real-time guidance in surgery. As a whole, there are incredibly positive indicators of growth, including the first United States Food and Drug Administration clearance of an enzyme-biosynthetic-activated probe for surgery guidance, and a growing number of companies producing agents and imaging systems. The strengths and opportunities must be continued but are hampered by important weaknesses and threats within the field. A key issue to solve is the inability of macroscopic imaging tools to resolve microscopic biological disease heterogeneity and the limitations in microscopic systems matching surgery …

Light Scattering Measured With Spatial Frequency Domain Imaging Can Predict Stromal Versus Epithelial Proportions In Surgically Resected Breast Tissue, David M. Mcclatchy, Elizabeth J. Rizzo, Wendy A. Wells, Candice C. Black, Keith D. Paulsen, Stephen C. Kanick, Brian W. Pogue

Dartmouth Scholarship

This study aims to determine if light scatter parameters measured with spatial frequency domain imaging (SFDI) can accurately predict stromal, epithelial, and adipose fractions in freshly resected, unstained human breast specimens. An explicit model was developed to predict stromal, epithelial, and adipose fractions as a function of light scattering parameters, which was validated against a quantitative analysis of digitized histology slides for N  =  31 specimens using leave-one-out cross-fold validation. Specimen mean stromal, epithelial, and adipose volume fractions predicted from light scattering parameters strongly correlated with those calculated from digitized histology slides (r  =  0.90, 0.77, and 0.91, respectively, p-value× …

Quantifying Cancer Cell Receptors With Paired-Agent Fluorescent Imaging: A Novel Method To Account For Tissue Optical Property Effects., Negar Sadeghipour, Scott C. Davis, Kenneth M. Tichauer

Dartmouth Scholarship

Dynamic fluorescence imaging approaches can be used to estimate the concentration of cell surface receptorsin vivo. Kinetic models are used to generate the final estimation by taking the targeted imaging agent concentration as a function of time. However, tissue absorption and scattering properties cause the final readout signal to be on a different scale than the real fluorescent agent concentration. In paired-agent imaging approaches, simultaneous injection of a suitable control imaging agent with a targeted one can account for non-specific uptake and retention of the targeted agent. Additionally, the signal from the control agent can be a normalizing …

Grant Funding Needs Parallel The Start-Up Venture: An Analogy For Translational Research Success, Brian W. Pogue

Dartmouth Scholarship

This editorial offers some ways to think about how best to position a research group for funding, by examining the parallels between what is needed for translational grants versus industry start-ups.

Multi-Beam Scan Analysis With A Clinical Linac For High Resolution Cherenkov-Excited Molecular Luminescence Imaging In Tissue., Mengyu Jeremy Jia, Peter Bruza, Lesley A. Jarvis, David J. Gladstone, Brian W. Pogue

Dartmouth Scholarship

Cherenkov-excited luminescence scanned imaging (CELSI) is achieved with external beam radiotherapy to map out molecular luminescence intensity or lifetime in tissue. Just as in fluorescence microscopy, the choice of excitation geometry can affect the imaging time, spatial resolution and contrast recovered. In this study, the use of spatially patterned illumination was systematically studied comparing scan shapes, starting with line scan and block patterns and increasing from single beams to multiple parallel beams and then to clinically used treatment plans for radiation therapy. The image recovery was improved by a spatial-temporal modulation-demodulation method, which used the ability to capture simultaneous images …

Weighting Function Effects In A Direct Regularization Method For Image-Guided Near-Infrared Spectral Tomography Of Breast Cancer., Jinchao Feng, Shudong Jiang, Brian W. Pogue, Keith Paulsen

Dartmouth Scholarship

Structural image-guided near-infrared spectral tomography (NIRST) has been developed as a way to use diffuse NIR spectroscopy within the context of image-guided quantification of tissue spectral features. A direct regularization imaging (DRI) method for NIRST has the value of not requiring any image segmentation. Here, we present a comprehensive investigational study to analyze the impact of the weighting function implied when weighting the recovery of optical coefficients in DRI based NIRST. This was done using simulations, phantom and clinical patient exam data. Simulations where the true object is known indicate that changes to this weighting function can vary the contrast …

Correcting For Targeted And Control Agent Signal Differences In Paired-Agent Molecular Imaging Of Cancer Cell-Surface Receptors, Negar Sadeghipour, Scott C. Davis, Kenneth M. Tichauer

Dartmouth Scholarship

Paired-agent kinetic modeling protocols provide one means of estimating cancer cell-surface receptors with in vivo molecular imaging. The protocols employ the coadministration of a control imaging agent with one or more targeted imaging agent to account for the nonspecific uptake and retention of the targeted agent. These methods require the targeted and control agent data be converted to equivalent units of concentration, typically requiring specialized equipment and calibration, and/or complex algorithms that raise the barrier to adoption. This work evaluates a kinetic model capable of correcting for targeted and control agent signal differences. This approach was compared with an existing …

Medical Perspective Articles To Stimulate The Field For Needs-Finding, Brian W. Pogue

Dartmouth Scholarship

This editorial by the journal's Editor in Chief, Brian Pogue, explains the need for a new type of paper.

Radiotherapy-Induced Cherenkov Luminescence Imaging In A Human Body Phantom, Syed Rakin Ahmed, Mengyu Jia, Petr Bruza, Sergei A. Vinogradov, Shudong Jiang, David J. Gladstone, Lesley A. Jarvis, Brian W. Pogue

Dartmouth Scholarship

Radiation therapy produces Cherenkov optical emission in tissue, and this light can be utilized to activate molecular probes. The feasibility of sensing luminescence from a tissue molecular oxygen sensor from within a human body phantom was examined using the geometry of the axillary lymph node region. Detection of regions down to 30-mm deep was feasible with submillimeter spatial resolution with the total quantity of the phosphorescent sensor PtG4 near 1 nanomole. Radiation sheet scanning in an epi-illumination geometry provided optimal coverage, and maximum intensity projection images provided illustration of the concept. This work provides the preliminary information needed to attempt …

Optimal Wavelength Selection For Optical Spectroscopy Of Hemoglobin And Water Within A Simulated Light-Scattering Tissue, Mikael Marois, Stephen L. Jacques, Keith D. Paulsen

Dartmouth Scholarship

An algorithm that selects optimal wavelengths for spectral fitting of diffuse light reflectance spectra using a nonnegative least squares method is presented. Oxyhemoglobin, deoxyhemoglobin, and water are considered representative absorbers, but the approach is not constrained or limited by absorber selection provided native basis spectra are available. The method removes wavelengths iteratively from a scattering-modulated absorption matrix by maximizing the product of its singular values and offers considerable improvements over previously published wavelength selection schemes. Resulting wavelength selections are valid for a broad range of optical properties and yield lower RMS errors than other wavelength combinations. The method is easily …

Biomedical Optics Scientific Community, Brian W. Pogue

Dartmouth Scholarship

The new Editor-in-Chief, Brian Pogue, gives an overview of the biomedical optics community.

Development And Evaluation Of A Connective Tissue Phantom Model For Subsurface Visualization Of Cancers Requiring Wide Local Excision, Kimberly S. Samkoe, Brent D. Bates, Niki N. Tselepidakis, Alisha V. Dsouza, Jason R. Gunn, Dipak B. Ramkumar, Keith D. Paulsen, Brian W. Pogue, Eric R. Henderson

Dartmouth Scholarship

Wide local excision (WLE) of tumors with negative margins remains a challenge because surgeons cannot directly visualize the mass. Fluorescence-guided surgery (FGS) may improve surgical accuracy; however, conventional methods with direct surface tumor visualization are not immediately applicable, and properties of tissues surrounding the cancer must be considered. We developed a phantom model for sarcoma resection with the near-infrared fluorophore IRDye 800CW and used it to iteratively define the properties of connective tissues that typically surround sarcoma tumors. We then tested the ability of a blinded surgeon to resect fluorescent tumor-simulating inclusions with ∼1-cm margins using predetermined target fluorescence intensities …

Performance Assessment Of Diffuse Optical Spectroscopic Imaging Instruments In A 2-Year Multicenter Breast Cancer Trial, Anais Leproux, Thomas D.O. Sullivan, Albert E. Cerussi, Amanda Durkin, Brian Hill, Nola M. Hylton, Arjun G. Yodh, Stefan A. Carp, David A. Boas, Shudong Jiang, Keith D. Paulsen, Brian W. Pogue, Darren M. Roblyr, Wei T. Yang, Bruce J. Tromberg

Dartmouth Scholarship

We present a framework for characterizing the performance of an experimental imaging technology, diffuse optical spectroscopic imaging (DOSI), in a 2-year multicenter American College of Radiology Imaging Network (ACRIN) breast cancer study (ACRIN-6691). DOSI instruments combine broadband frequency-domain photon migration with time-independent near-infrared (650 to 1000 nm) spectroscopy to measure tissue absorption and reduced scattering spectra and tissue hemoglobin, water, and lipid composition. The goal of ACRIN-6691 was to test the effectiveness of optically derived imaging endpoints in predicting the final pathologic response of neoadjuvant chemotherapy (NAC). Sixty patients were enrolled over a 2-year period at participating sites and received …

Optimization Of Fluorescent Imaging In The Operating Room Through Pulsed Acquisition And Gating To Ambient Background Cycling, Kristian J. Sexton, Yan Zhao, Scott C. Davis, Shudong Jiang, Brian Pogue

Dartmouth Scholarship

The design of fluorescence imaging instruments for surgical guidance is rapidly evolving, and a key issue is to efficiently capture signals with high ambient room lighting. Here, we introduce a novel time-gated approach to fluorescence imaging synchronizing acquisition to the 120 Hz light of the room, with pulsed LED excitation and gated ICCD detection. It is shown that under bright ambient room light this technique allows for the detection of physiologically relevant nanomolar fluorophore concentrations, and in particular reduces the light fluctuations present from the room lights, making low concentration measurements more reliable. This is particularly relevant for the light …

Raman Spectroscopy Detects Distant Invasive Brain Cancer Cells Centimeters Beyond Mri Capability In Humans, Michael Jermyn, Joannie Desroches, Jeanne Mercier, Karl St-Arnaud

Dartmouth Scholarship

Surgical treatment of brain cancer is limited by the inability of current imaging capabilities such as magnetic resonance imaging (MRI) to detect the entirety of this locally invasive cancer. This results in residual cancer cells remaining following surgery, leading to recurrence and death. We demonstrate that intraoperative Raman spectroscopy can detect invasive cancer cells centimeters beyond pathological T1-contrast-enhanced and T2-weighted MRI signals. This intraoperative optical guide can be used to detect invasive cancer cells and minimize post-surgical cancer burden. The detection of distant invasive cancer cells beyond MRI signal has the potential to increase the effectiveness of surgery and directly …

Microdose Fluorescence Imaging Of Aby-029 On An Operating Microscope Adapted By Custom Illumination And Imaging Modules, Jonathan T. Elliott, Alisha V. Dsouza, Kayla Marra, Brian W. Pogue, David Roberts, Keith Paulsen

Dartmouth Scholarship

Fluorescence guided surgery has the potential to positively impact surgical oncology; current operating microscopes and stand-alone imaging systems are too insensitive or too cumbersome to maximally take advantage of new tumor-specific agents developed through the microdose pathway. To this end, a custom-built illumination and imaging module enabling picomolar-sensitive near-infrared fluorescence imaging on a commercial operating microscope is described. The limits of detection and system specifications are characterized, and in vivo efficacy of the system in detecting ABY-029 is evaluated in a rat orthotopic glioma model following microdose injections, showing the suitability of the device for microdose phase 0 clinical trials.

Blinking Phase-Change Nanocapsules Enable Background-Free Ultrasound Imaging, Alexander S. Hannah, Geoffrey P. Luke, Stanislav Y. Emelianov

Dartmouth Scholarship

Microbubbles are widely used as contrast agents to improve the diagnostic capability of conventional, highly speckled, low-contrast ultrasound imaging. However, while microbubbles can be used for molecular imaging, these agents are limited to the vascular space due to their large size (> 1 μm). Smaller microbubbles are desired but their ultrasound visualization is limited due to lower echogenicity or higher resonant frequencies. Here we present nanometer scale, phase changing, blinking nanocapsules (BLInCs), which can be repeatedly optically triggered to provide transient contrast and enable background-free ultrasound imaging. In response to irradiation by near-infrared laser pulses, the BLInCs undergo cycles of …

Portable, Parallel 9-Wavelength Near-Infrared Spectral Tomography (Nirst) System For Efficient Characterization Of Breast Cancer Within The Clinical Oncology Infusion Suite, Yan Zhao, Brian W. Pogue, Steffen J. Haider, Jiang Gui, Roberta Diflorio-Alexander, Keith Paulsen, Shudong Jiang

Dartmouth Scholarship

A portable near-infrared spectral tomography (NIRST) system was developed with simultaneous frequency domain (FD) and continuous-wave (CW) optical measurements for efficient characterization of breast cancer in a clinical oncology setting. Simultaneous FD and CW recordings were implemented to speed up acquisition to 3 minutes for all 9 wavelengths, spanning a range from 661nm to 1064nm. An adjustable interface was designed to fit various breast sizes and shapes. Spatial images of oxy- and deoxy-hemoglobin, water, lipid, and scattering components were reconstructed using a 2D FEM approach. The system was tested on a group of 10 normal subjects, who were examined bilaterally …

Improved Sensitivity To Fluorescence For Cancer Detection In Wide-Field Image-Guided Neurosurgery, Michael Jermyn, Yoann Gosselin, Pablo A. Valdes, Mira Sibai, Kolbein Kolste

Dartmouth Scholarship

In glioma surgery, Protoporphyrin IX (PpIX) fluorescence may identify residual tumor that could be resected while minimizing damage to normal brain. We demonstrate that improved sensitivity for wide-field spectroscopic fluorescence imaging is achieved with minimal disruption to the neurosurgical workflow using an electron-multiplying charge-coupled device (EMCCD) relative to a state-of-the-art CMOS system. In phantom experiments the EMCCD system can detect at least two orders-of-magnitude lower PpIX. Ex vivo tissue imaging on a rat glioma model demonstrates improved fluorescence contrast compared with neurosurgical fluorescence microscope technology, and the fluorescence detection is confirmed with measurements from a clinically-validated spectroscopic probe. Greater PpIX …

Calibration And Optimization Of 3d Digital Breast Tomosynthesis Guided Near Infrared Spectral Tomography, Kelly E. Michaelsen, Venkataramanan Krishnaswamy, Linxi Shi, Srinivasan Vedantham, Steven Poplack, Andrew Karellas, Brian Pogue, Keith Paulsen

Dartmouth Scholarship

Calibration of a three-dimensional multimodal digital breast tomosynthesis (DBT) x-ray and non-fiber based near infrared spectral tomography (NIRST) system is challenging but essential for clinical studies. Phantom imaging results yielded linear contrast recovery of total hemoglobin (HbT) concentration for cylindrical inclusions of 15 mm, 10 mm and 7 mm with a 3.5% decrease in the HbT estimate for each 1 cm increase in inclusion depth. A clinical exam of a patient's breast containing both benign and malignant lesions was successfully imaged, with greater HbT was found in the malignancy relative to the benign abnormality and fibroglandular regions (11 μM vs. …

Review Of Fluorescence Guided Surgery Visualization And Overlay Techniques, Jonathan T. Elliott, Alisha V. Dsouza, Scott C. Davis, Jonathan D. Olson, Keith Paulsen, David Roberts, Brian Pogue

Dartmouth Scholarship

In fluorescence guided surgery, data visualization represents a critical step between signal capture and display needed for clinical decisions informed by that signal. The diversity of methods for displaying surgical images are reviewed, and a particular focus is placed on electronically detected and visualized signals, as required for near-infrared or low concentration tracers. Factors driving the choices such as human perception, the need for rapid decision making in a surgical environment, and biases induced by display choices are outlined. Five practical suggestions are outlined for optimal display orientation, color map, transparency/alpha function, dynamic range compression, and color perception check.

Direct Regularization From Co-Registered Anatomical Images For Mri-Guided Near-Infrared Spectral Tomographic Image Reconstruction, Limin Zhang, Yan Zhao, Shudong Jiang, Brian W. Pogue, Keith Paulsen

Dartmouth Scholarship

Combining anatomical information from high resolution imaging modalities to guide near-infrared spectral tomography (NIRST) is an efficient strategy for improving the quality of the reconstructed spectral images. A new approach for incorporating image information directly into the inversion matrix regularization was examined using Direct Regularization from Images (DRI), which encodes the gray-scale data into the NIRST image reconstruction problem. This process has the benefit of eliminating user intervention such as image segmentation of distinct regions. Specifically, the Dynamic Contrast Enhanced Magnetic Resonance (DCE-MR) image intensity value differences within the anatomical image were used to implement an exponentially-weighted regularization function between …

Review Of Biomedical Čerenkov Luminescence Imaging Applications, Kaveh Tanha, Ali Mahmoud Pashazadeh, Brian W. Pogue

Dartmouth Scholarship

Čerenkov radiation is a fascinating optical signal, which has been exploited for unique diagnostic biological sensing and imaging, with significantly expanded use just in the last half decade. Čerenkov Luminescence Imaging (CLI) has desirable capabilities for niche applications, using specially designed measurement systems that report on radiation distributions, radiotracer and nanoparticle concentrations, and are directly applied to procedures such as medicine assessment, endoscopy, surgery, quality assurance and dosimetry. When compared to the other imaging tools such as PET and SPECT, CLI can have the key advantage of lower cost, higher throughput and lower imaging time. CLI can also provide imaging …

Next-Generation Raman Tomography Instrument For Non-Invasive In Vivo Bone Imaging, Jennifer-Lynn H. Demers, Francis W. L. Esmonde-White, Karen A. Esmonde-White, Michael D. Morris, Brian Pogue

Dartmouth Scholarship

Combining diffuse optical tomography methods with Raman spectroscopy of tissue provides the ability for in vivo measurements of chemical and molecular characteristics, which have the potential for being useful in diagnostic imaging. In this study a system for Raman tomography was developed and tested. A third generation microCT coupled system was developed to combine 10 detection fibers and 5 excitation fibers with laser line filtering and a Cytop reference signal. Phantom measurements of hydroxyapatite concentrations from 50 to 300 mg/ml had a linear response. Fiber placement and experiment design was optimized using cadaver animals with live animal measurements acquired to …

Quantitative Spatial Frequency Fluorescence Imaging In The Sub-Diffusive Domain For Image-Guided Glioma Resection, Mira Sibai, Israel Veilleux, Jonathan T. Elliott, Frederic Leblond, Brian Wilson

Dartmouth Scholarship

Intraoperative 5- aminolevulinic acid induced-Protoporphyrin IX (PpIX) fluorescence guidance enables maximum safe resection of glioblastomas by providing surgeons with real-time tumor optical contrast. However, visual assessment of PpIX fluorescence is subjective and limited by the distorting effects of light attenuation and tissue autofluorescence. We have previously shown that non-invasive point measurements of absolute PpIX concentration identifies residual tumor that is otherwise non-detectable. Here, we extend this approach to wide-field quantitative fluorescence imaging by implementing spatial frequency domain imaging to recover tissue optical properties across the field-of-view in phantoms and ex vivo tissue.

Pixel-Based Absorption Correction For Dual-Tracer Fluorescence Imaging Of Receptor Binding Potential, Stephen C. Kanick, Kenneth M. Tichauer, Jason Gunn, Kimberley S. Samkoe, Brian W. Pogue

Dartmouth Scholarship

Ratiometric approaches to quantifying molecular concentrations have been used for decades in microscopy, but have rarely been exploited in vivo until recently. One dual-tracer approach can utilize an untargeted reference tracer to account for non-specific uptake of a receptor-targeted tracer, and ultimately estimate receptor binding potential quantitatively. However, interpretation of the relative dynamic distribution kinetics is confounded by differences in local tissue absorption at the wavelengths used for each tracer. This study simulated the influence of absorption on fluorescence emission intensity and depth sensitivity at typical near-infrared fluorophore wavelength bands near 700 and 800 nm in mouse skin in order …

Sub-Diffusive Scattering Parameter Maps Recovered Using Wide-Field High-Frequency Structured Light Imaging, Stephen C. Kanick, David M. Mcclatchy, Venkataramanan Krishnaswamy, Jonathan T. Elliott, Keith D. Paulsen, Brian W. Pogue

Dartmouth Scholarship

This study investigates the hypothesis that structured light reflectance imaging with high spatial frequency patterns (fx) can be used to quantitatively map the anisotropic scattering phase function distribution (P(θs)) in turbid media. Monte Carlo simulations were used in part to establish a semi-empirical model of demodulated reflectance (Rd) in terms of dimensionless scattering (μ′sf−1x) and γ, a metric of the first two moments of the P(θs) distribution. Experiments completed in tissue-simulating phantoms showed that simultaneous analysis of Rd spectra sampled at multiple f …

Sensitivity Of Mri-Guided Near-Infrared Spectroscopy Clinical Breast Exam Data And Its Impact On Diagnostic Performance, Michael A. Mastanduno, Junqing Xu, Fadi El-Ghussein, Shudong Jiang, Hong Yin, Yan Zhao, Kelly E. Michaelson, Ke Wang, Fang Ren, Brian W. Pogue, Keith D. Paulsen

Dartmouth Scholarship

In this study, data from breast MRI-guided near infrared spectroscopy (NIRS) exams delivered to 44 patients scheduled for surgical resection (ending in 16 benign and 28 malignant diagnoses) were analyzed using a spatial sensitivity metric to quantify the adequacy of the optical measurements for interrogating the tumor region of interest, as derived from the concurrent MRI scan. Along with positional sensitivity, the incorporation of spectral priors and the selection of an appropriate regularization parameter in the image reconstruction were considered, and found to influence the diagnostic accuracy of the recovered images. Once optimized, the MRI/NIRS data was able to differentiate …

Extraction Of Intrinsic Fluorescence From Single Fiber Fluorescence Measurements On A Turbid Medium: Experimental Validation, U. A. Gamm, C. L. Hoy, F. Van Leeuwen - Van Zaane, H. J. C. M. Sterenborg, S. C. Kanick, D J. Robinson, A. Amelink

Dartmouth Scholarship

Abstract

The detailed mechanisms associated with the influence of scattering and absorption properties on the fluorescence intensity sampled by a single optical fiber have recently been elucidated based on Monte Carlo simulated data. Here we develop an experimental single fiber fluorescence (SFF) spectroscopy setup and validate the Monte Carlo data and semi-empirical model equation that describes the SFF signal as a function of scattering. We present a calibration procedure that corrects the SFF signal for all system-related, wavelength dependent transmission efficiencies to yield an absolute value of intrinsic fluorescence. The validity of the Monte Carlo data and semi-empirical model is …

Advances In Optics For Biotechnology, Medicine And Surgery, Maryann Fitzmaurice, Brian W. Pogue, Guillermo J. Tearney, James W. Tunnell

Dartmouth Scholarship

The guest editors introduce a Biomedical Optics Express feature issue that includes contributions from participants at the 2013 conference on Advances in Optics for Biotechnology, Medicine and Surgery XIII.