Engineering Commons^™

Using Natural Language Processing And Sentiment Analysis To Augment Traditional User-Centered Design: Development And Usability Study, Curtis L. Petersen, Ryan Halter, David Kotz, Lorie Loeb, Summer B. Cook, Dawna M. Pidgeon, Brock Christensen, John A. Batsis

Dartmouth Scholarship

Background: Sarcopenia, defined as the age-associated loss of muscle mass and strength, can be effectively mitigated through resistance-based physical activity. With compliance at approximately 40% for home-based exercise prescriptions, implementing a remote sensing system would help patients and clinicians to better understand treatment progress and increase compliance. The inclusion of end users in the development of mobile apps for remote-sensing systems can ensure that they are both user friendly and facilitate compliance. With advancements in natural language processing (NLP), there is potential for these methods to be used with data collected through the user-centered design process.

Objective: This study aims …

Biomedical Engineering Or Biomedical Optics: Will The Real Discipline Please Stand Up?, Brian W. Pogue

Dartmouth Scholarship

This editorial reflects on the shape of biomedical engineering as a discipline, and its relation to biomedical optics.

Characterizing Short-Wave Infrared Fluorescence Of Conventional Near-Infrared Fluorophores, Brook K. Byrd, Margaret R. Folaron, Joseph P. Leonor, Rendall R. Strawbridge, Xu Cao, Petr Bruza, Scott C. Davis

Dartmouth Scholarship

The observed behavior of short-wave infrared (SWIR) light in tissue, characterized by relatively low scatter and subdiffuse photon transport, has generated considerable interest for the potential of SWIR imaging to produce high-resolution, subsurface images of fluorescence activity in vivo. These properties have important implications for fluorescence-guided surgery and preclinical biomedical research. Until recently, translational efforts have been impeded by the conventional understanding that fluorescence molecular imaging in the SWIR regime requires custom molecular probes that do not yet have proven safety profiles in humans. However, recent studies have shown that two readily available near-infrared (NIR-I) fluorophores produce measurable SWIR fluorescence, …

Diagnostic Performance Of Receptor-Specific Surgical Specimen Staining Correlates With Receptor Expression Level, Jasmin M. Schaefer, Connor W. Barth, Scott C. Davis, Summer L. Gibbs

Dartmouth Scholarship

Intraoperative margin assessment is imperative to cancer cure but is a continued challenge to successful surgery. Breast conserving surgery is a relevant example, where a cosmetically improved outcome is gained over mastectomy, but re-excision is required in >25  %   of cases due to positive or closely involved margins. Clinical translation of margin assessment modalities that must directly contact the patient or required administered contrast agents are time consuming and costly to move from bench to bedside. Tumor resections provide a unique surgical opportunity to deploy margin assessment technologies including contrast agents on the resected tissues, substantially shortening the path to …

Ensuring Scientific Publishing Credibility In Translational Biomedical Optics., Brian W. Pogue

Dartmouth Scholarship

Optics has consistently been the largest singular technology sector used in medicine, and major advances in biomedical optics are documented daily in peer-reviewed publications. However, the academic stature of this field can be damaged by weaknesses in scientific publishing, where a “credibility crisis” has emerged as a popularized and increasingly studied dialogue. While there are still relatively few overt cases of fraud or erroneous research, more insidious aspects are seen in papers with results that have either low statistical power, selective reporting of observations, or data or computer codes that cannot be independently verified. Interestingly, the same solutions that improve …

Cherenkov Excited Short-Wavelength Infrared Fluorescence Imaging In Vivo With External Beam Radiation, Xu Cao, Shudong Jiang, Mengyu Jeremy Jia, Jason R. Gunn, Tianshun Miao, Scott C. Davis, Petr Bruza, Brian W. Pogue

Dartmouth Scholarship

Cherenkov emission induced by external beam radiation therapy from a clinical linear accelerator (LINAC) can be used to excite phosphors deep in biological tissues. As with all luminescence imaging, there is a desire to minimize the spectral overlap between the excitation light and emission wavelengths, here between the Cherenkov and the phosphor. Cherenkov excited short-wavelength infrared (SWIR, 1000 to 1700 nm) fluorescence imaging has been demonstrated for the first time, using long Stokes-shift fluorophore PdSe quantum dots (QD) with nanosecond lifetime and an optimized SWIR detection. The 1  /  λ2 intensity spectrum characteristic of Cherenkov emission leads to low overlap …

Review Of Methods For Intraoperative Margin Detection For Breast Conserving Surgery, Benjamin W. Maloney, David M. Mcclatchy, Brian W. Pogue, Keith D. Paulsen, Wendy A. Wells, Richard J. Barth

Dartmouth Scholarship

Breast conserving surgery (BCS) is an effective treatment for early-stage cancers as long as the margins of the resected tissue are free of disease according to consensus guidelines for patient management. However, 15% to 35% of patients undergo a second surgery since malignant cells are found close to or at the margins of the original resection specimen. This review highlights imaging approaches being investigated to reduce the rate of positive margins, and they are reviewed with the assumption that a new system would need high sensitivity near 95% and specificity near 85%. The problem appears to be twofold. The first …

Optical And X-Ray Technology Synergies Enabling Diagnostic And Therapeutic Applications In Medicine, Brian W. Pogue, Brian C. Wilson

Dartmouth Scholarship

X-ray and optical technologies are the two central pillars for human imaging and therapy. The strengths of x-rays are deep tissue penetration, effective cytotoxicity, and the ability to image with robust projection and computed-tomography methods. The major limitations of x-ray use are the lack of molecular specificity and the carcinogenic risk. In comparison, optical interactions with tissue are strongly scatter dominated, leading to limited tissue penetration, making imaging and therapy largely restricted to superficial or endoscopically directed tissues. However, optical photon energies are comparable with molecular energy levels, thereby providing the strength of intrinsic molecular specificity. Additionally, optical technologies are …

Tissue Oxygen Saturation Predicts Response To Breast Cancer Neoadjuvant Chemotherapy Within 10 Days Of Treatment, Jeffrey M. Cochran, David R. Busch, Anais Leproux, Zheng Zhang, Thomas D. O'Sullivan, Albert E. Cerussi, Philip M. Carpenter, Rita S. Mehta, Darren Roblyer, Wei Yang, Keith D. Paulsen, Brian Pogue, Shudong Jiang, Peter A. Kaufman

Dartmouth Scholarship

Ideally, neoadjuvant chemotherapy (NAC) assessment should predict pathologic complete response (pCR), a surrogate clinical endpoint for 5-year survival, as early as possible during typical 3- to 6-month breast cancer treatments. We introduce and demonstrate an approach for predicting pCR within 10 days of initiating NAC. The method uses a bedside diffuse optical spectroscopic imaging (DOSI) technology and logistic regression modeling. Tumor and normal tissue physiological properties were measured longitudinally throughout the course of NAC in 33 patients enrolled in the American College of Radiology Imaging Network multicenter breast cancer DOSI trial (ACRIN-6691). An image analysis scheme, employing z-score normalization to …

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 …

Preclinical Evaluation Of Spatial Frequency Domain-Enabled Wide-Field Quantitative Imaging For Enhanced Glioma Resection, Mira Sibai, Carl Fisher, Israel Veilleux, Jonathan T. Elliot, Frederic Leblond, David W. Roberts, Brian Wilson

Dartmouth Scholarship

5-Aminolevelunic acid-induced protoporphyrin IX (PpIX) fluorescence-guided resection (FGR) enables maximum safe resection of glioma by providing real-time tumor contrast. However, the subjective visual assessment and the variable intrinsic optical attenuation of tissue limit this technique to reliably delineating only high-grade tumors that display strong fluorescence. We have previously shown, using a fiber-optic probe, that quantitative assessment using noninvasive point spectroscopic measurements of the absolute PpIX concentration in tissue further improves the accuracy of FGR, extending it to surgically curable low-grade glioma. More recently, we have shown that implementing spatial frequency domain imaging with a fluorescent-light transport model enables recovery of …

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. …