Thesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2013. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 165-191). / Cancer metastasis is the underlying mechanism of 90% of cancer-related deaths, yet few therapeutics exist that directly target it. Part of this scarcity is attributable to a general lack of knowledge with regards to the underlying mechanisms that mediate traversal of the sequential steps required for malignant dissemination. Recently, biologists and clinicians have gained appreciation for the role that the microenvironment plays in promoting or inhibiting metastasis. This thesis sought to expand our understanding of the involvement of extracellular matrix (ECM) interactions during metastasis through the development and use of a novel ECM microarray screening platform. This platform consists of 768 unique single and pairwise combinations spotted in quintuplicate as 150pm features onto polyacrylamide coated glass slides. Cells are seeded onto these arrays and queried for their adhesion, proliferation, and marker expression using automated fluorescence microscopy in conjunction with automated cell counting and image analysis. In the first part of this thesis, this platform is used in conjunction with a mouse model of lung adenocarcinoma metastasis (KraLSL-G12D/+; p53flox/flOx) where distinct stages of metastasis are defined by characteristic cell lines derived from these mice. Hierarchical clustering of the adhesion profiles revealed conserved alterations in ECM adhesion signatures that correlate with metastasis. Additionally, they identify a role for combinations of ECM composed of fibronectin with any of galectin-3, galectin-8, or laminin. In the next part of this thesis, these molecules are investigated for their involvement in mice bearing the autochthonous tumors or in humans with lung cancer. The integrin Q3p1 is found to mediate adhesion to the fibronectin-galectin combinations in vitro and promote metastasis in vivo. Subsequently, this thesis investigates the role of carbohydrate-mediated interactions in promoting galectin adhesion. The oncofetal T-Antigen glycan motif is found to be increasingly expressed on cells with elevated metastatic potential, and is found to be the result of aberrant glycosyltransferase activity. Finally the role of galectin-3 in the metastatic niche and its presentation on bone marrow derived cells recruited to tumors is investigated. The results of this thesis suggest a role for novel phenotypic screening platforms in investigating regulation of the cancer microenvironment. Additionally, we extend these studies to the role of ECM in the epithelial-mesenchymal transition (EMT) and lay the groundwork for the development of nanoparticle-based therapeutics targeting the conserved glycan-ECM interactions. Such technologies will likely prove useful to study other disease mechanisms as well as identify novel biomarkers. / by Nathan E. Reticker-Flynn. / Ph. D. in Biomedical Engineering

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 173-174). / Since the FDA Modernization Act of 1997, recent legislation has sought to establish performance goals and consistency in the regulatory review and clearance of new medical devices. Despite these goals, regulatory review times have varied dramatically for devices seeking clearance through the 510(k) pathway; devices that are by definition "substantially equivalent" to other devices previously cleared by the FDA and currently on the market. The goal of this thesis is to investigate the factors that impact the ability for a company to obtain a 510(k) clearance in a predictable timeframe and assess the most important factors that influence time to clearance. The Medical Device industry is a dynamic and rapidly evolving sector that presents complex challenges to regulatory oversight. The 510(k) program and larger device regulatory process has endured the test of time and is well structured to address these challenges. This research focuses on the 7,481 510(k) "substantially equivalent" clearances during the period from October 1, 2007 through June 30, 2010 (FY08 - Q3FY10) in order to analyze the variables that impact clearance times. By testing various hypotheses about the most important factors I aim to provide the device community with the data and suggestions for improving confidence around a particular 510(k) submission's likely approval time. I performed subset analyses on the dataset, segmenting clearances by the type of 510(k) (traditional, abbreviated, and special), clinical category, fiscal year of clearance, use of 3rd party review, submission volume, and product diversity according to clinical category. The results show a distinct increase in clearance time from FY08 to FY10 and suggest that recent scrutiny of the FDA premarket review process may be affecting the efficiency of the Agency FDA review process for medical devices. Further, the 3rd party review program is under-utilized with only 14%, on average, of eligible devices gaining clearance through this process. Through a discussion of two specific critiques of the 510(k) process, namely a recent Government Accountability Office study and an article by the Public Citizen (a public advocacy group), the potential implications of regulatory reform is explored from both a policy and industry perspective. / by Andrew J Koert. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003. / Includes bibliographical references. / Cardiovascular disease is the primary cause of mortality in developed nations. Current diagnostic techniques are not able to provide the information that is related to the majority of associated complications. Raman spectroscopy, which is capable of providing a detailed chemical analysis of biological tissue, has previously been shown to be a useful method for diagnosing atherosclerosis. However, widespread clinical implementation has been prohibited by the lack of optical fiber probes which can provide remote access to small diameter vessels. To this end, we have developed a new spectroscopic model and a novel Raman probe. The model interprets Raman spectra of intact tissue in terms of its morphology. The spectrally identifiable morphological structures include collagen and elastin fibers, cholesterol crystals, calcium mineralizations, adipocytes, crystals containing 3-carotene, foam cells, necrotic core, and smooth muscle cells. This model prospectively classifies atherosclerotic tissue into three categories: non-atherosclerotic, non-calcified plaque, and calcified plaque, with >94% accuracy. Furthermore, this model has the potential ability to identify the vulnerable atherosclerotic plaques whose rupture accounts for the majority of myocardial infarctions. By studying the distribution of Raman light in tissue, we have designed, constructed, and tested small diameter, high throughput optical fiber Raman probes which employ a modular micro-optical filter configuration to remove the intense background generated in the fibers. The probes have been extensively tested during peripheral vascular surgery, providing real-time disease diagnosis for the first time. These in vivo investigations demonstrate the clinical applicability of Raman spectroscopy and have also provided the first identification of vulnerable plaques with this technique. / (cont.) We have shown that plaque vulnerability is spectrally identified by determining the collagen, foam cell/necrotic core, calcification, cholesterol, and hemoglobin content of the lesion. This type of analysis may eventually lead to a diagnostic technique capable of staging atherosclerotic lesions, thereby providing a method to optimize therapeutic measures. In addition, the small diameter Raman probes have applicability for studying other diseases such as breast, oral, and gastrointestinal cancer. / by Jason Taylor Motz. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2004. / Includes bibliographical references. / This thesis integrates hardware development, data analysis, and mathematical modeling to facilitate our understanding of brain cognition. Exploration of these brain mechanisms requires both structural and functional knowledge to (i) reconstruct the spatial distribution of the activity, (ii) to estimate when these areas are activated and what is the temporal sequence of activations, and (iii)to determine how the information flows in the large-scale neural network during the execution of cognitive and/or behavioral tasks. Advanced noninvasive medical imaging modalities are able to locate brain activities at high spatial and temporal resolutions. Quantitative modeling of these data is needed to understand how large-scale distributed neuronal interactions underlying perceptual, cognitive, and behavioral functions emerge and change over time. This thesis explores hardware enhancement and novel analytical approaches to improve the spatiotemporal resolution of single (MRI) or combined (MRI/fMRI and MEG/EEG) imaging modalities. In addition, mathematical approaches for identifying large-scale neural networks and their correlation to behavioral measurements are investigated. Part I of the thesis investigates parallel MRI. New hardware and image reconstruction techniques are introduced to improve spatiotemporal resolution and to reduce image distortion in structural and functional MRI. Part II discusses the localization of MEG/EEG signals on the cortical surface using anatomical information from AMTRI, and takes advantage of the high temporal resolution of MEG/EEG measurements to study cortical oscillations in the human auditory system. Part III introduces a multivariate modeling technique to identify "nodes" and "connectivity" in a / (cont.) large-scale neural network and its correlation to behavior measurements in the human motor system. / by Fa-Hsuan Lin. / Ph.D.

Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2016. / "June 2016." Cataloged from PDF version of thesis. / Includes bibliographical references (pages 131-154). / Fluid volume status is a physiologic parameter that currently lacks a reliable diagnostic tool. Volume control becomes an issue during sickness and/or stress (physical and mental) in a wide range of populations. Unfortunately, current diagnostics suffer from being imprecise, invasive, and/or easily confounded and cannot unambiguously and practically inform volume status. There exists a need for a tool that can inform individuals and clinicians of fluid status in a noninvasive, rapid, and reliable manner. Drawing on the molecular sensitivity of IH nuclear magnetic resonance (NMR), we explored the ability of NMR methods to quantitate physiologic fluid volume changes. We first proved that NMR methods could detect volume changes in an animal model of dehydration. Correlation between NMR value changes in specific tissues and clinical tools used to assess dehydration validate NMR as a viable tool. We then proceeded to design and fabricate practical NMR sensors that could be easily integrated into the clinic. New methods of magnetic instrument design optimized for both field strength and spatial resolution were developed resulting in compact device prototypes with signal fidelity rivaling those of impractical commercial systems. Finally, we explored the ability of these devices to detect intravascular fluid changes during hemodialysis. Our methods and devices were able to detect intravascular blood property changes associated with blood dilution, in addition to overall fluid volume changes due to hemodialysis therapy. These results, methods, and devices provide the foundation and framework for the integration of NMR-based personalized fluid volume assessment into standard clinical practice. / by Matthew Li. / Ph. D. in Medical Engineering and Medical Physics

Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2017. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged from student-submitted PDF version of thesis. / Includes bibliographical references (pages 147-155). / Recent advances have allowed the hardware integration of positron emission tomography (PET) and magnetic resonance imaging (MRI). The spatiotemporally correlated data acquisition opened up opportunities for numerous applications. Furthermore, the MRI data can be utilized to improve the PET scanner performance. While PET has many advantages, including the fact that it could provide a quantitative means to assess in vivo biological processes, its accuracy is confounded by several factors. For example, attenuation correction is required to account for the interactions of the annihilation photons in the subject; motion correction is needed to minimize image degradation due to subject movements; partial volume effects correction is required due to the relatively limited spatial resolution. Although many applications could benefit from these methodological improvements, in this thesis we focused on dementia. MRI and PET are widely used and provide complementary information in the assessment of these patients. Equally important, dementia is a great test situation for these methodological developments because the confounding factors mentioned above are especially pronounced in this patient population. In this work, we developed a unified protocol to address these limitations, an approach we termed MR-assisted PET data optimization. Specifically, we first developed methods to derive head attenuation maps from the morphological MR images. Next, we used temporally-correlated MR data for PET motion compensation and spatially-correlated MR data for anatomy-aided reconstruction. Finally, we demonstrated that after applying these tools to data acquired in dementia patients the PET data quantification was positively impacted and the image quality improved substantially.. / by Kevin Tze-Hsiang Chen. / Ph. D. in Medical Engineering and Medical Physics

Thesis: Ph. D. in Medical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 99-108). / Non-invasive imaging plays an important role throughout the clinical diagnosis and management process of breast cancer. Unfortunately, existing imaging methods lack the combination of spatial resolution and soft-tissue contrast necessary to visualize pathological changes in the breast. X-ray phase-contrast imaging (XPCI) has emerged as a promising modality for providing enhanced soft tissue differentiation due to its inherent source of contrast being derived from diffraction effects rather than absorption. Studies using synchrotron sources have demonstrated the potential of XPCI in revealing structural details of the breast undetectable via existing modalities. However, the reliance on high-brilliance synchrotron sources significantly limits the use of XPCI in medical applications. In this thesis, we address this challenge by developing a compact XPCI system compatible with low-brilliance laboratory sources that retrieves phase from free-space propagation. We further combine quantitative phase imaging with computed tomography (CT) which enables us to investigate internal structures in 3D. Existing techniques for phase retrieval either require images to be acquired at multiple defocus planes, or assumptions to be made that do not hold true for many objects of interest. To address these limitations, we developed an iterative algorithm for phase retrieval using images acquired at two different energies. Our results show that this algorithm retrieves phase more accurately than existing methods. Finally, we illustrate the potential utility of our compact XPCI system in visualizing pathological features by imaging transgenic mouse models of breast cancer. These pre-clinical results show that phase CT is able to clearly distinguish tumor masses whereas the same features imaged using commercial microCT are obscured by noise. Overall, the methods developed in this thesis provide a proof of concept for conducting tomographic XPCI outside of synchrotron facilities, thus paving the way towards future clinical implementation. / by Ling Xu. / Ph. D. in Medical Engineering

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 123-139). / Cells face a core tension between studiously preventing change in certain properties from extrinsic perturbations while allowing other properties to be tuned. One way cells have resolved this tension is to utilize systems that are both robust and tunable. Systems can achieve this through network design, which can contain submodules that are themselves either robust or tunable, or through network components that are robust over only a defined set of parameter ranges. This work examines these two categories with two specific examples described below. To explore how a simple network can be both robust and tunable, we make use of the osmosensing pathway in the budding yeast Saccharomyces cerevisiae. The pathway consists of two modules: a phosphorelay module that senses the osmotic shock signal that feeds into a mitogen-activated protein kinase (MAPK) module. Using a combination of systematic complementation experiments and computational sensitivity analysis, we show that the phosphorelay module is robust to changes in the kinetic parameters characterizing signal propagation through the module while signaling through the MAPK module can be tuned by changing the rate constants. Furthermore, we show that pathway robustness to rate constant changes has consequences for the evolvability of the osmosensing cascade. Populations of yeast cells challenged to alter the input/output relationship of the cascade saw their MAPK proteins preferentially targeted by natural selection over their phosphorelay counterparts. To explore how a simple regulatory element can be both robust and tunable, we turn our attention to gene regulation by microRNA (miRNA). MiRNAs are short regulatory RNA molecules that repress gene expression in a sequence-dependent manner. By observing the strength of miRNA-mediated repression in individual cells, we show that the strength of repression depends strongly on the relative abundance of the miRNA and its target. Below a threshold level of target message miRNA robustly silences the conversion of mRNA input into protein output, but above this threshold miRNAmediated repression generates an ultrasensitive response to mRNA input allowing the strength of repression to be tuned over a wide variety of values. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Includes bibliographical references (p. 111-118). / The Magnetic Guidance Keyboard System (MaGKeyS) embodies a new haptic guidance technology designed to facilitate sensorimotor training and rehabilitation. MaGKeyS works by employing active magnetic force to guide finger pressing movements during sensorimotor learning that involves sequential key presses, such as playing the piano. By combining this haptic guidance with an audiovisual learning paradigm, we have created a core technology with possible applications to such diverse fields as musical training, physical rehabilitation, and scientific investigation of sensorimotor learning. Two embodiments of this new technology were realized in this thesis. The first embodiment, the MaGKeyS Prototype, is a 5-key acrylic USB keyboard designed for a stationary right hand. A set of three behavioral experiments were executed to investigate the manner in which haptic guidance, via the MaGKeyS Prototype, facilitates rhythmic motor learning. In particular, the experiments examined the independent effects of haptic guidance on ordinal learning, which is the order of notes in a sequence, and temporal learning, which is the order of timing variations in a rhythmic sequence. A transfer test and 24-hour retention test were also administered. Our results provide conclusive evidence that haptic guidance can facilitate learning the ordinal pattern of a key press sequence. Furthermore, our results suggest that the advantage gained with haptic guidance can both transfer to learning a new rhythmic sequence, as well as extend to a demonstrable advantage a day later. The second embodiment, the MaGKeyS Trainer Piano, is an upright piano in which the keyboard has been modified and outfitted with electromagnets in a manner similar to the MaGKeyS Prototype. The Trainer Piano helps to teach by "feel" by providing an experience in which the user feels his or her fingers being pulled down into the correct piano keystrokes as the piano plays itself. / by Craig Edwin Lewiston. / Ph.D.

Thesis (Ph. D.)--Harvard University--Massachusetts Institute of Technology Division of Health Sciences and Technology, Program in Medical Engineering and Medical Physics, 1990. / Includes bibliographical references (p. 242-247). / by Scott David Greenwald. / Ph.D.