Biomedical Engineering and Bioengineering Commons^™

Modeling The Effect Of Igg Subclasses And Specificity In The Translocation Of Monoclonal Antibodies Across The Placental Barrier, Sayuri Tais Miyamoto Magnabosco

ENGS 88 Honors Thesis (AB Students)

Infections are responsible for over half a million neonatal deaths every year (Lawn et al., 2014). Thus, there is huge interest in leveraging maternal immunization against infectious diseases to grant fetal protection during its development through the vertical transferring of IgG antibodies, the only Ig subclass that can significantly cross the placental barrier. Studies about vertical immunization rely on in-vitro models to extrapolate physiological conditions of the human placenta. The BeWo Transwell model (Bode et al., 2006) presents itself as a reliable model to mimic the transplacental transport mechanism of antibodies (Ellinger et al., 1999; Poulsen et al., 2009) …

Flash Radiotherapy: Skin Pigmentation As A Non-Invasive Indicator For Radiation-Induced Damage, Brady Mccallister

ENGS 88 Honors Thesis (AB Students)

FLASH ultra-high dose rate radiotherapy (RT) is one of the most rapidly growing subfields of radiation oncology today due to its potential to increase the limits of the therapeutic ratio. The FLASH effect, which includes heightened normal tissue sparing paired with iso-effective tumor cell killing, has been literature documented, in a limited manner, in rodent models, a few large animals, and one clinical patients.

A porcine-based experiment was conducted to test the effects of FLASH RT on normal tissue compared to conventional (CONV) RT. A clinical linear accelerator (LINAC) was reversibly converted to be capable of FLASH RT. A female …

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 …

Bio Circuits For Evolutionary Biotech, Camilo Toruno

ENGS 86 Independent Projects (AB Students)

The field of bioengineering has much promise for renewable chemical production, bioremediation, and of course medical applications. Developing new useful microorganisms is extremely time and capital intensive, typically taking 50 million USD and eight years. This is due in large part to the low throughput techniques that are characteristic of the field of metabolic engineering. Here we describe the modification of an existing synthetic biosensor to measure the pharmaceutical dopamine, and the use of a circuit simulator Cadence to predict improvements to the biosensor. This biosensor paired with directed evolution techniques could reach throughputs of 5 million cells per day …

A Convolutional Neural Network For Fast Fluence Estimation In Complex Tissues, Nicholas Blasey, Geoffrey P. Luke

ENGS 88 Honors Thesis (AB Students)

Photoacoustic (PA) imaging is a non-invasive diagnostic imaging technique that gives images of photoabsorbers based on their absorption of optical energy. These optical absorption properties can then be linked to important tissue properties. For the method to be quantitative, however, it is necessary to have an accurate estimation of the light fluence in the tissue. The current gold standard in addressing the fluence estimation problem, a Monte Carlo Simulation, is costly in time and computation. In this work, we developed a deep neural network to quickly and accurately estimate light fluence in arbitrary tissue types and geometries. The network was …

Utilizing Neural Networks And Wearables To Quantify Hip Joint Angles And Moments During Walking And Stair Ascent, Megan V. Mccabe

ENGS 88 Honors Thesis (AB Students)

Wearable sensors were leveraged to develop two methods for computing hip joint angles and moments during walking and stair ascent that are more portable than the gold standard. The Insole-Standard (I-S) approach replaced force plates with force-measuring insoles and achieved results that match the curvature of results from similar studies. Peaks in I-S kinetic results are high due to error induced by applying the ground reaction force to the talus. The Wearable-ANN (W-A) approach combines wearables with artificial neural networks to compute the same results. Compared against the I-S, the W-A approach performs well (average rRMSE = 18%, R^{2 …}

Developing A Control System To Better Understand The Effects Of Pyruvate Decarboxylase Activity On Clostridium Thermocellum Metabolism, Nicholas Cervenka

ENGS 88 Honors Thesis (AB Students)

In order for cellulosic biofuels from Clostridium thermocellum to be commercially viable, the ethanol yield and titer of the microbe must be increased. To accomplish this, it has been suggested to introduce the Pyruvate Decarboxylase (PDC) enzyme into C. thermocellum. In order to demonstrate effects on ethanol production by PDC prior to genetic modification, a cell free system (CFS) has been developed. A purified enzyme system was developed with the CFS to function as a control. Using the purified enzyme system, PDC from Saccharomyces cerevisiae was demonstrated to be a good candidate for further testing in the CFS.

A Physical And Computational Reverse-Engineering Approach To Determine Dimensional Change And Its Relationship To Oxidation In Retrieved Orthopedic Implants, Josephine Kalshoven

ENGS 88 Honors Thesis (AB Students)

Oxidation of the Ultra-High Molecular Weight Polyethylene (UHMWPE) tibial inserts of total knee arthroplasty devices is a major factor underlying multiple modes of failure for these devices, including delamination, wear, and fracture. Previous research has demonstrated that oxidation of UHMWPE is driven by a high concentration of free radicals in the polyethylene. However, even new devices created with undetectable amounts of free radicals are oxidizing in vivo. One theory is that, in the absence of residual free radicals, oxidation is facilitated by absorbed species (e.g. lipids, ROS) delivered or exacerbated by contact stress. However, no method exists to comprehensively …

Spatial Frequency Domain Imaging Of Short-Wave Infrared Fluorescence For Biomedical Applications, Joseph P. Leonor

ENGS 88 Honors Thesis (AB Students)

Fluorescence imaging has become a standard in many clinical applications, such as tumor and vasculature imaging. One application that is becoming more prominent in cancer treatment is fluorescence-guided surgery (FGS). Currently, FGS allows surgeons the ability to visually navigate tumors and tissue structures intraoperatively. As a result, they can remove tumor more efficiently while maintaining critical structures within the patient, creating better outcomes and lower recovery times. However, background fluorescence and inability to localize depth create challenges when determining resection boundaries.

Different techniques, such as spatially modulating the illumination and imaging at longer light wavelengths, have been developed to accurately …

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 …

Impact In Practice, Maria Garman

ENGS 88 Honors Thesis (AB Students)

Medial Tibial Stress Syndrome (Shin splits) is an overuse injury caused by repetitive impact. If ignored it can lead to stress reactions and then stress fractures in the shins. This nagging injury is something that plagues many track athletes especially as they start to wear their competition shoes more frequently at practice to work on technical aspects of their events.

This paper investigates the relationship between ground reaction forces experienced by the athletes in each stride and what shoes they are wearing on their feet. Due to the fact that repetitive impact is a cause for shin splints, the conclusion …

Abso2luteu-Net: Tissue Oxygenation Calculation Using Photoacoustic Imaging And Convolutional Neural Networks, Kevin Hoffer-Hawlik, Geoffrey P. Luke

ENGS 88 Honors Thesis (AB Students)

Photoacoustic (PA) imaging uses incident light to generate ultrasound signals within tissues. Using PA imaging to accurately measure hemoglobin concentration and calculate oxygenation (sO₂) requires prior tissue knowledge and costly computational methods. However, this thesis shows that machine learning algorithms can accurately and quickly estimate sO₂. absO₂luteU-Net, a convolutional neural network, was trained on Monte Carlo simulated multispectral PA data and predicted sO₂ with higher accuracy compared to simple linear unmixing, suggesting machine learning can solve the fluence estimation problem. This project was funded by the Kaminsky Family Fund and the Neukom Institute.

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.