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Title: Incorporating Real-Time Estimates of Physiological States in Artificial Pancreas Systems
Creator: Sevil, Mert
Date: 2020
Description: Type-1 diabetes is a chronic disease that has a negative impact on the life of a person with diabetes causing other chronic diseases, reducing...
Show moreType-1 diabetes is a chronic disease that has a negative impact on the life of a person with diabetes causing other chronic diseases, reducing the quality of life, and the possibility of causing dangerous reductions in blood glucose levels that may lead to coma or death. More than 100 million U.S. adults are now living with diabetes or pre-diabetes. Diabetes is one of the most expensive public health problems in the U.S. at $327 billion in 2017. Thus, alternative solutions or novel proposals are crucial to more effective treatments and cure. Artificial pancreas systems are one of the common treatment techniques of Type-1 Diabetes, which reduce the risk of diabetes-related complications and make diabetics' lives easier and make it convenient. Artificial pancreas systems aim to maintain blood glucose concentrations in a tighter target blood glucose range, which is a challenging problem. Several factors affect blood glucose concentrations including intensity of exercise, type of exercise, acute psychological stress and the physical state of a person with diabetes. These factors are unknown disturbances for artificial pancreas control systems. In this project, a single non-invasive wrist-worn device is used to obtain different biosignals in-real time. Biosignals are utilized with the development energy expenditure estimation model, psychological stress detection and physical state classification models. Several machine learning methods are tested and validated until the best classification and estimation accuracy is achieved for each estimate. Obtained models are incorporated with the current artificial pancreas design to improve its glycemic control performance. The controller is aware of such measurable disturbances with the proposed method, which allows for providing accurate and timely control action. Additional estimates are utilized to improve blood glucose concentration prediction model accuracy. Clinical trials are used to test and validate the proposed work. In summary, the presented work illustrates different machine learning techniques and algorithms that can enhance automated insulin delivery by a multivariable artificial pancreas system and enhance the quality of life of people with Type 1 diabetes.
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Title: Assistant to Dr. Daniel Graupe demonstrating a computerized arm prothesis, Illinois Institute of Technology, Chicago, Illinois, 1980s
Date: 1980-1989
Description: Photograph of an unknown assistant to Dr. Daniel Graupe demonstrating a computerized prosthetic arm. Photographer unknown. Date of photograph...
Show morePhotograph of an unknown assistant to Dr. Daniel Graupe demonstrating a computerized prosthetic arm. Photographer unknown. Date of photograph unknown. Date range listed is approximate.
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Collection: Office of Communications and Marketing photographs, 1905-1999

Title: Dr. Daniel Graupe and an assistant using a computerized arm prothesis, Illinois Institute of Technology, Chicago, Illinois, 1980s
Date: 1980-1989
Description: Photograph of Electrical Engineering professor Dr. Daniel Graupe and an assistant demonstrating a computerized prosthetic arm. Photographer...
Show morePhotograph of Electrical Engineering professor Dr. Daniel Graupe and an assistant demonstrating a computerized prosthetic arm. Photographer unknown. Date of photograph unknown. Date range listed is approximate.
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Collection: Office of Communications and Marketing photographs, 1905-1999

Title: Quantification of Vascular Permeability in the Retina Using Fluorescein Videoangiography Data as a Biomarker for Early Diabetic Retinopathy
Creator: Kayaalp Nalbant, Elif
Date: 2023
Description: Diabetic retinopathy, which is the most common reason for blindness in the working-age population, affects over one-third of those who have...
Show moreDiabetic retinopathy, which is the most common reason for blindness in the working-age population, affects over one-third of those who have had diabetes for over ten years. High blood sugar level (hyperglycemia) in the blood damages blood vessels and tight junction at the blood-retinal barrier (BRB). Chronic inflammation leads to changes in vascular health, and over time blood vessels tend to get damaged and exhibit higher “leakage” or permeability. In the late stage of DR, hemorrhages can occur, leading to irreversible damage of neuronal tissue in the retina and vision loss. In the clinic, there are some biomarkers and imaging modalities used to diagnose DR based on some of the more severe products of DR (e.g., hemorrhage), but there is no non-invasive, highly sensitive method to detect diabetic retinopathy before clinical signs occur, when mitigating therapies could be more effective. In this thesis, indicator dilution theory was explored to modeling the temporal dynamics of fluorescein in the retina after intravenous injection, with an aim to quantitatively map subtle changes in retinal blood flow and vascular permeability that could preempt subsequent irreversible damage. Specifically, a simplified version of indicator dilution theory—namely the “adiabatic approximation in tissue homogeneity” (AATH) model—was used to estimate physiological parameters such as the blood flow (F) and the extraction fraction (E: a parameter coupled with vascular permeability) from retinal fluorescein videoangiography data. The AATH fitting protocol was optimized through simulations using a more complex model (the AATH-vascular heterogeneity model, AATH-VH). It was determined that a two-step least square fitting method was more sensitive than a single-step least square fitting of AATH to simulated data to evaluate vascular permeability in early diabetic retinopathy. The optimized data analysis protocol was then evaluated in an initial clinical study comparing healthy control subjects to those with moderate non-proliferative DR. Volumetric blood flow and retinal vascular permeability maps were compared between patient groups with clear increases in extraction fraction observed in the mild NPDR patients compared to control. These promising early data have been the foundation to an ongoing 5 year study tracking 100 Diabetic patients with no DR so see if early changes in vascular permeability can predict which patients are more likely to progress to DR.
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Title: Development of MIITRA T1w, DTI and FOD templates of the older adult brain in a common space
Creator: Wu, Yingjuan
Date: 2022
Description: Human brain atlases play an important role in neuroimaging studies and are commonly used as references for spatial normalization, tissue...
Show moreHuman brain atlases play an important role in neuroimaging studies and are commonly used as references for spatial normalization, tissue segmentation, automated brain parcellation, seed selection for functional connectivity analyses and fiber-tracking, or standards for algorithm evaluation. A brain atlas typically consists of brain templates of different imaging modalities in a common space and semantic labels that delineate brain regions according to the characteristics of the underlying tissue.High-quality T1-weighted (T1w) and diffusion tensor imaging (DTI) brain templates that are representative of the individuals under study enhance the accuracy of template-based neuroimaging investigations, and when they are also located in a common space they facilitate optimal integration of information on brain morphometry and diffusion characteristics. However, such multimodal templates have not been constructed for the brain of older adults. This thesis introduced an iterative method for construction of multimodal T1w and DTI templates that aims at maximizing the quality of each template separately as well as the spatial matching between templates. The performance of the proposed method was evaluated across iterations and was compared to the performance of state-of-the-art multimodal template construction approaches based on multichannel registration. Using the proposed method, along with other recently developed techniques, high-quality T1w and DTI templates of the older adult brain were developed in a common space at 0.5mm resolution for the MIITRA atlas. In this thesis, the new templates were compared to other available templates in terms of the image quality, inter-subject and inter-modality spatial normalization accuracy achieved when used as a reference, and the representativeness of the older adult brain. Furthermore, as fiber orientation distribution (FOD) model is capable of resolving intravoxel heterogeneity, which overcomes the limitations of the DTI model especially in regions with complex neuronal microarchitecture, FOD template is in high demand to facilitate FOD-based, fixel-based analyses, white matter connectivity studies and white matter parcellations. In this thesis, several FOD template construction methods were compared and a FOD template was developed at 0.5mm resolution for the MIITRA atlas. Overall, the present work brought new insights into multimodal template construction, conducted a thorough, quantitative evaluation of available multimodal template construction methods, and generated much-needed high quality T1w, DTI and FOD templates of the older adult brain in a common space with 0.5mm resolution.
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Title: SIMULTANEOUS RELEASE OF BIOACTIVE AFLIBERCEPT AND DEXAMETHASONE FROM A MICROSPHERE- AND NANOPARTICLE-HYDROGEL OCULAR DRUG DELIVERY SYSTEM FOR THE ENHANCED TREATMENT OF NON-RESPONSIVE PATIENTS WITH CHOROIDAL NEOVASCULARIZATION
Creator: Rudeen, Kayla M
Date: 2022
Description: There is a growing subset of wet age-related macular degeneration (AMD) patients who do not fully respond to standard of care treatment, which...
Show moreThere is a growing subset of wet age-related macular degeneration (AMD) patients who do not fully respond to standard of care treatment, which consists of bimonthly/monthly bolus intravitreal injections of anti-vascular endothelial growth factors (anti-VEGFs). Some of these patients may respond to a combination therapy of anti-VEGF and corticosteroids. One treatment option uses a dexamethasone implant that releases for six months. This regimen, however, requires both the bimonthly/monthly intravitreal injections of anti-VEGF and semiannual intravitreal injections of the dexamethasone implant. Combining the two treatments into a single drug delivery system (DDS) would reduce the total number of injections, reducing the risk of potential complications (endophthalmitis, retinal detachment, intravitreal hemorrhage, increased intraocular pressure, and cataract) as well as the socioeconomic burden of treatment.The overarching goal of this study was to develop a single DDS that simultaneously releases anti-VEGF (aflibercept) and corticosteroid (dexamethasone) for the treatment of non-responsive wet AMD patients. Our laboratory previously developed a thermoresponsive, biodegradable microparticle-hydrogel DDS that releases anti-VEGF over a period of six months. The aims of the study were to (1) modify this system to include dexamethasone-loaded nanoparticles, optimize release kinetics for both drugs, and characterize the DDS; (2) evaluate the in vivo treatment efficacy in a laser-induced choroidal neovascularization (CNV) model; and (3) investigate the impacts of temperature and storage on the DDS integrity.
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Title: DEVELOPMENT AND EVALUATION OF MRI TEMPLATES OF THE MIITRA ATLAS
Creator: RIDWAN, ABDUR RAQUIB
Date: 2021
Description: Digital human brain atlases play a pivotal role in conducting wide range of neuroimaging studies and are commonly used as references for...
Show moreDigital human brain atlases play a pivotal role in conducting wide range of neuroimaging studies and are commonly used as references for spatial normalization in voxel-wise analysis, region-of interest analyses, automated tissue-segmentation, functional connectivity analyses, etc. A brain atlas typically consists of MRI-based multi-modal templates and semantic labels delineating brain regions according to the characteristics of the underlying tissue. In recent times there has been a plethora of magnetic resonance imaging (MRI) studies on older adults without dementia to explore the role of brain characteristics associated with cognitive functions in old age with the ultimate goal to develop strategies for prevention of cognitive decline. Increasing the accuracy in terms of sensitivity and specificity of such neuroimaging studies require an atlas with a comprehensive set of high-quality templates representative of the brain characteristics typical of older adults and detailed labels accurately mapping brain regions of interest. However, such an atlas has not been constructed for older adults without dementia. Hence this thesis aims to build high quality MRI templates which are the cornerstone resources needed for the development of a comprehensive, high quality, multi-channel, longitudinal, probabilistic digital human brain atlas for older adults termed as Multi-channel Illinois Institute of Technology and Rush University Aging (MIITRA) atlas. This dissertation focuses on a) to develop and evaluate a high performing 1mm isotropic structural T1-weighted brain template, b) to investigate the development and evaluation of a spatio-temporally consistent longitudinal structural T1-weighted template of the older adult brain, c) to develop and evaluate an unbiased 0.5 mm isotropic super-resolved high resolution and detail-preserving structural T1 weighted template of the older adult brain, d) to develop an unbiased 0.5 mm super-resolved high resolution and detail-preserving structural PD weighted and T2-weighted template of the older adult brain, e) to investigate and provide future directions in the development of a 0.5 mm super-resolved high resolution DTI template of the older adult brain, and f) to construct a novel approach in the development of MRI templates using both space and frequency information of spatially normalized older adult data. The thesis based on the aforementioned foundational points was constructed as follows: Firstly, this thesis presents the development of a 1mm isotropic T1-weighted structural template of the older adult brain utilizing state of the art registration algorithm ANTs with parameters carefully optimized for older adults, in an iterative groupwise spatial normalization framework. The preprocessing steps were also thoroughly investigated to ensure high quality data. It was demonstrated through systematic comparison of this new template to several other standardized and study-specific T1-weighted templates that a) it exhibited high image sharpness, b) allowed for high spatial normalization accuracy and detection of smaller inter-group morphometric differences compared to other standardized templates, c) had similar performance to that of study-specific templates and d) was highly representative of the older adult brain. Secondly, with the acquired technical know-how from the aforementioned research findings a new method was introduced for the construction of a spatio-temporally consistent longitudinal template based on high quality cross-sectional older adult data from a large cohort. The new template was compared to templates generated with previously published methods in terms of spatio-temporal consistency and image quality and was shown to have superior performance. In addition, a novel approach was introduced for image quality enhancement of the longitudinal templates utilizing both space and frequency information. Thirdly, the thesis presents a method that involves a) thoroughly refining registration parameters, b) patch-based tissue-guided sparse-representation approach in a super-resolved unbiased minimum deformation space to construct and evaluate an unbiased 0.5 mm isotropic super-resolved high resolution and detail-preserving structural T1 weighted template of the older adult brain. This method accounts for misregistration specially in the cortical regions, ensuring sharp delineation of structures representative of the older adult brain. The new template developed using this approach maintained high anatomical consistency with sharp and detailed cortical features in the brain and exhibited higher image sharpness compared to other high-resolution standardized templates and allowed for high spatial normalization accuracy when used as a reference for normalization of older adult data. Additionally, this approach of template building was investigated on DTI tensors of older adult participants, and the constructed DTI template was shown to perform better than templates developed using the best approach currently present in the literature. Finally, the thesis presents the development of an unbiased 0.5 mm super-resolved high resolution and detail-preserving structural PD weighted and T2-weighted template of the older adult brain, from nonlocal super-resolution based upsampled PD and T2w older adult participant data, using this new template building approach.
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Title: FUNCTIONAL CONNECTIVITY LABELS FOR THE MULTICHANNEL IIT AND RUSH UNIVERSITY AGING (MIITRA) ATLAS
Creator: Badhon, Rashadul Hasan
Date: 2022
Description: In the field of medical imaging, a brain atlas refers to a specific model of the brain of a population where different parts of the atlas...
Show moreIn the field of medical imaging, a brain atlas refers to a specific model of the brain of a population where different parts of the atlas correspond to different anatomical parts of the average brain of the population. A brain atlas is composed of MRI templates and semantic labels and is a crucial component of neuroscience for its critical role in facilitating spatial normalization, temporal characterization and automated segmentation for the purposes of voxel-wise, region of interest and network analyses. Building a brain atlas requires registering multi-dimensional brain datasets from a population into a reference space and, during the last decade, the advent of new technologies and computational modeling approaches has made it possible to build high-quality, detailed brain atlases. At the same time developments in data acquisition now allow the construction of comprehensive brain atlases containing a variety of information about the brain. The Multichannel Illinois Institute of Technology and Rush university Aging (MIITRA) atlas project is developing a high-quality comprehensive atlas of the older adult brain containing a multitude of templates and labels. These templates are constructed with state-of-the-art spatial normalization of high-quality data and as a result, they are characterized by higher image quality, are more representative of the brain of non-demented older adults and provide higher inter-subject spatial normalization accuracy of older adult data compared to other available templates. The methodology used in the development of the MIITRA templates facilitates the construction of accurate structural and connectivity labels. Functional connectivity MRI reveals sets of functionally connected brain regions, forming networks, by investigating synchronous fluctuations in MRI signal over time across these brain regions during rest. The purpose of this work was to generate functional connectivity labels for several brain networks in MIITRA space.
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Title: RADIAL MAP ASSESSMENT APPROACH FOR DEEP LEARNING DENOISED CARDIAC MAGNETIC RESONANCE RECONSTRUCTION SHARPNESS
Creator: Mo, Fei
Date: 2021
Description: Deep Learning (DL) and Artificial Intelligence (AI) play important roles in the computer-aided medical diagnostics and precision medicine...
Show moreDeep Learning (DL) and Artificial Intelligence (AI) play important roles in the computer-aided medical diagnostics and precision medicine fields, capable of complementing human operators in disease diagnosis and treatment but optimizing and streamlining medical image display. While incredibly powerful, images produced via Deep Learning or Artificial Intelligence should be analyzed critically in order to be cognizant of how the algorithms are producing the new image and what the new imagine is. One such opportunity arose in the form of a unique collaborative project: the technical development of an image assessment tool that would analyze outputs between DL-based and non DL-based Magnetic Resonance Imaging reconstruction methods.More specifically, we examine the operator input dependence of the existing reference method in terms of accuracy and precision performance, and subsequently propose a new metric approach that preserves the heuristics of the intended quantification, overcomes operator dependence, and provides a relative comparative scoring approach that may normalize for angular dependence of examined images. In chapter 2 of this thesis, we provide a background description pertaining to the two imaging science principles that yielded our proposed method description and study design. First, if treated naively, the examined linear measurement approach exhibits potential bias with respect to the coordinate lattice space of the examined image. Second, the examined DL-based image reconstruction methods used in this thesis warrants an elaborate and explicit description of the measured noise and signal present in the reconstructed images. This specific reconstruction approach employs an iterative scheme with an embedded DL-based substep or filter to which we are blinded. In chapters 3 and 4 of this thesis, the imaging and DL-based image reconstruction experiments are described. These experiments employ cardiac MRI datasets from multiple clinical centers. We first outline the clinical and technical background for this approach, and then examine the quality of DL-based reconstructed image sharpness by two alternative methods: 1) by employing the gold-standard method that addresses the lattice point irregularity using a ‘re-gridding’ method, and 2) by applying our novel proposed method inspired by radial MRI k-space sampling, which exploits the mathematical properties of uniform radial sampling to yield the target voxel counts in the ‘gridded’ polar coordinate system. This new measure of voxel counts is shown to overcome the limitation due to the operator-dependence for the conventional approach. Furthermore, we propose this metric as a relative and comparative index between two alternative reconstruction methods from the same MRI k-space.
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Title: DEVELOPMENT OF FULLY BIOCOMPATIBLE HYDROGEL NANOPARTICLE FORMULATIONS FOR CONTROLLED-RELEASE DELIVERY OF A WIDE VARIETY OF BIOMOLECULES
Creator: Borges, Fernando Tancredo Pereira
Date: 2020
Description: In recent years, our group has focused on the production of PEGDA-based hydrogel scaffolds and nanoparticles for drug delivery of small...
Show moreIn recent years, our group has focused on the production of PEGDA-based hydrogel scaffolds and nanoparticles for drug delivery of small molecules. However, with recent advances in modern therapeutic treatments, such as protein and genetic engineering, there is an increasing need for the development of drug delivery devices that would be able encapsulate larger molecules. Therefore, the goal of this thesis work was to develop a systematic way to produce fully biocompatible PEGDA-based hydrogel nanoparticle formulations that would be able to encapsulate any size molecule, ranging from small ionic molecules, to peptides and proteins, all the way to large nucleic acids, and deliver it in a controlled manner.The first of part of this work consisted of developing a stable and reproducible process for the production of hydrogel PPi-NPs. Initial studies were done in order to assess the influence of phosphate salts in the polymerization system and it was found that both monophosphate and polyphosphate salts significantly damper the NVP homo-polymerization kinetics, but do not affect the co-polymerization of NVP and PEGDA. Then, emulsion stability studies were done to determine whether phosphate salts affected the stability of the minimeulsion system used in the production of the nanoparticles. Cloud point measurements and droplet size screening measurements showed that by transitioning from a Pi-loaded emulsion system to a PPi-loaded emulsion system, the required HLB of the emulsion shifts by 1.5 points. Upon correction for that shift, a reproducible process for production of PPi-loaded nanoparticles was obtained. A parametric study was then performed to see how the different process parameters affected the different properties of the produced particles. The second part of the work consisted in developing a platform for encapsulation of large to very-large molecules within these hydrogel systems. A new set of equations was developed for better estimation of the interstitial space, available for encapsulation of molecules, of crosslinked polymers that used very high molecular weight crosslinkers and/or high amounts of crosslinker. Upon development of this new set of equations, hydrogel discs were made via photopolymerization in order to validate the equations. By introducing a third monomer, EGA, and varying the molecular weight and concentration of the crosslinker, hydrogels with a wide range of mesh dimensions from 25 to 700 were achieved. These gels were then used to encapsulate 4 different sample molecules of varying molecular weights and size. A new heuristic was developed for encapsulation of non-spherical molecules, where the aspect ratios of the molecule and of the polymer network are considered. By varying the size of the ratios of the dimensions of the hydrogel network to the dimensions of the molecule, significantly different release profiles of small molecules, peptides and oligonucleotides were obtained. Finally, in order to explore different administration routes, the process was transitioning into being fully biocompatible. The organic solvent previously used in the emulsion system was replaced by soybean oil and the surfactants were replaced by a food-grade surfactant, PGPR, to form Bio-Compatible Nanoparticle Emulsions (BCNEs). Qualitative release from the BCNEs was shown. A new method for quantitative measuring of release from BCNE was developed. Release from QK-BCNE was observed up to 46 days, which is unprecedented for sustained-release and revolutionary for the field. A BCNE spreadable ointment formulation was also developed.
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Title: Development of Human Brain Atlas Resources
Creator: Qi, Xiaoxiao
Date: 2020
Description: Digital human brain atlases play an increasingly critical role and are widely used in neuroimaging studies such as developing biomarkers,...
Show moreDigital human brain atlases play an increasingly critical role and are widely used in neuroimaging studies such as developing biomarkers, training data for machine learning algorithms, functional connectivity analysis and so on. A brain atlas typically consists of brain templates of different imaging modalities that are representative of individual brains under study in a standard atlas space and semantic labels that delineate brain regions according to the characteristics of the underlying tissue.The IIT Human Brain Atlas project has developed the state-of-the-art diffusion tensor imaging (DTI) template, high angular resolution diffusion imaging (HARDI) template, and anatomical templates for the young adult brain in a standardized space. The probabilistic maps of gray matter (GM) labels and tissue segmentations were also constructed based on the anatomical information of the atlas. This thesis introduced an enhanced T1-weighted template that were developed by combining information from both diffusion and anatomical data. The GM labels and tissue segmentation maps in the standardized space were also improved. Existing white matter (WM) atlases typically lack specificity in terms of brain connectivity. A new approach named regionconnect was developed in this work based on precalculated average healthy adult brain connectivity information stored in standard space in a fashion that allows fast retrieval and integration. This thesis first generated and evaluated the white matter connectome of the IIT Human Brain Atlas v.5.0. Next, the new white matter connectome was used to develop multi-layer, connectivity-based labels for each white matter voxel of the atlas, consistent with the fact that each voxel may contain axons from multiple connections. The regionconnect algorithm was then developed to rapidly integrate information contained in the multi-layer labels across voxels of a white matter region and to generate a list of the most probable connections traversing that region. The regionconnect algorithm as well as the white matter tractogram and connectome, multi-layer, connectivity-based labels, and associated resources developed for the IIT Human Brain Atlas v.5.0 in this work are available at www.nitrc.org/projects/iit. Furthermore, it was well established that use of a young adult atlas in studies of older adults is inappropriate due to the age-related characteristic changes of the brain, resulting in an increasing demand of digital brain atlases for the older adults. To fulfill this demand, a function of fiber orientation distribution (fODF) template that is representative of older adults was developed in a standardized atlas space for studies of white matter of older adult human brains, which built a solid foundation for the development of the white matter resources for the older adults human brain atlas.
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Title: Development of Microfluidic Platform to Study Insulin Resistance
Creator: Tanataweethum, Nida
Date: 2020
Description: Insulin resistance, a precursor for the development of type 2 diabetes (T2D), propagates among heterologous tissues through dysregulated lipid...
Show moreInsulin resistance, a precursor for the development of type 2 diabetes (T2D), propagates among heterologous tissues through dysregulated lipid flux, as well as dysregulated glucose production, and secretion of cytokines, adipokines and hepatokines. Although T2D is characterized by systemic insulin resistance, disruption of insulin signaling in the liver and adipose tissue recapitulates many aspects of T2D, including enhance endogenous glucose production as well as defects of insulin action. Mechanistic studies often aim to provide fundamental understanding of the observations from human and animal studies. Due to the complexity of animal models and the multifactorial character of T2D, there is a strong need to develop advanced experimental systems such as in vitro models that can enable the recapitulation of the complex physiology of the in vivo system and enable investigation of the pathological pathways as well as identify novel treatment options. The overall goal of this study was to develop insulin resistant models of adipose tissue and liver to study the metabolic function of each organ as well as to the organ-organ crosstalk. To accomplish this goal, four specific aims were pursued: (1) Establish adipose tissue on-a-chip to study the metabolic function of the adipocytes in flow culture; (2) Develop towards an insulin resistant adipose on-a-chip to study the metabolic function of adipocytes in setting of insulin resistance; (3) Develop insulin resistant liver on-a-chip to investigate the metabolic function of hepatocytes in setting of insulin resistance; (4) Develop adipose-liver on-a-chip in setting of insulin resistance to identify the metabolic interaction between organs.
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Title: ENLARGED PERIVASCULAR SPACES IN COMMUNITY-BASED OLDER ADULTS
Creator: Javierre Petit, Carles
Date: 2020
Description: Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function and vascular dementia...
Show moreEnlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function and vascular dementia. Furthermore, recent studies have investigated the links of EPVS with the glymphatic system (GS), since perivascular spaces are thought to play a major role as the main channels for clearance of interstitial solutes from the brain. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, more conclusive studies are needed to elucidate specific relationships between EPVS and neuropathologies. After demonstration of their neuropathologic correlates, detailed assessment of EPVS severity could provide as a potential biomarker for specific neuropathologies.In this dissertation, our focus was twofold: to develop a fully automatic EPVS segmentation model via deep learning with a set of guidelines for model optimization, and to evaluate both manual and automatic assessment of EPVS severity to investigate the neuropathologic correlates of EPVS, and their contribution to cognitive decline, by combining ex-vivo brain magnetic resonance imaging (MRI) and pathology (from autopsy) in a large community-based cohort of older adults. This project was structured as follows. First, a manual approach was used to assess neuropathologic and cognitive correlates of EPVS burden in a large dataset of community-dwelling older adults. MR images from each participant were rated using a semiquantitative 4-level rating scale, and a group of identified EPVS was histologically evaluated. Two groups of participants in descending order of average cognitive impairment were defined based and studied. Elasticnet regularized ordinal logistic regression was used to assess the neuropathologic correlates of EPVS burden in each group, and linear mixed effects models were used to investigate the associations of EPVS burden with cognitive decline. Second, a fully automatic EPVS segmentation model was implemented via deep learning (DL) using a small dataset of 10 manually segmented brain MR images. Multiple techniques were evaluated to optimize performance, mainly by implementing strategies to reduce model overfitting. The final segmentation model was evaluated in an independent test set and the performance was validated with an expert radiologist. Third, the DL segmentation model was used to segment and quantify EPVS. Quantified EPVS (qEPVS) were evaluated by combining ex-vivo MRI, pathology, and longitudinal cognitive evaluation. EPVS quantification allowed to study qEPVS both in the whole brain and regionally. Two different qEPVS metrics were studied. Elastic-net regularized linear regression was used to assess the neuropathologic correlates of qEPVS within each region of interest (ROI) under study, and linear mixed effects models were used to investigate the associations of qEPVS with cognitive decline. Finally, a preliminary study investigated the longitudinal associations of qEPVS with time. The DL segmentation model was re-trained using 4 in-vivo MR images. EPVS were segmented and quantified in a large longitudinal cohort where each participant was imaged at multiple timepoints. Factors that influenced segmentation performance across timepoints were evaluated, and linear mixed effects models controlling for these factors were used to investigate the associations of qEPVS with time.
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Title: Three-Dimensional Co-Culture Systems for Vascularization of Cardiac Tissue
Creator: Rodriguez Arias, Jessica A.
Date: 2023
Description: Myocardial Infarction (MI) is the partial or complete blockage of blood flow to the myocardial tissue resulting in damage and therefore loss...
Show moreMyocardial Infarction (MI) is the partial or complete blockage of blood flow to the myocardial tissue resulting in damage and therefore loss of heart function. In the U.S. every 40 seconds, someone will suffer from MI and the only available treatment is medication to treat the symptoms of heart function loss, but do not treat the underlying cause. Some attempts to treat the underlying cause have arisen in the last decades including cell-based therapies or tissue engineering therapies such as spheroid-based cardiac patches that have shown to be promising. Improvement in the mechanical properties to create suturable engineered tissues remain to be improved for ease of implantation purposes. Cell-laden hydrogel scaffolds can provide improved mechanical properties compared to biomaterial free cell-based therapies but need to allow for vascularization of the engineered tissue. Thus, the goal of this thesis is to provide preliminary studies for the use of a cell adhesive, proteolytically degradable PEG hydrogel scaffold that eventually would be used as an invitro model to evaluate engineered tissue vascularization for cardiac tissue engineering. To construct this model, important cell spheroid parameters on vascular invasion in 3D culture were investigated including the total number of cells/spheroid, the supporting cell for endothelial cells. In order to scale-up scaffolds to size of clinically relevant dimensions, a multilayered hydrogel construct visible light free-radical polymerization approach encapsulating vascular spheroids in multiple layers was also investigated. Results indicate that a total cell number of 5000 cells/spheroid aggregate were feasible due to cell sourcing. In addition, co-cultures of endothelial and mesenchymal stem cells led to maximized vascular invasion of the spheroids compared to fibroblast/endothelial co-culture and endothelial monoculture of spheroids in the hydrogel. Finally, the extent of vascularization of spheroids in each layer of the multilayered hydrogel constructs varied due to the observed differences in mechanical properties and swelling ratio of each layer due to incomplete polymerization of layers. This study demonstrated the importance of support cells and hydrogel mechanical properties in promoting vascularization of spheroid which serves as basis for building cell-laden hydrogel scaffolds for vascularization for cardiac tissues.
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Title: A MICROFLUIDIC INTESTINAL-MICROBIOTA PLATFORM TO STUDY DRUG METABOLISM
Creator: Wang, Chengyao
Date: 2020
Description: The intestine is the main site that orally administered drugs are primarily metabolized, absorbed, and distributed. The trillions of bacteria...
Show moreThe intestine is the main site that orally administered drugs are primarily metabolized, absorbed, and distributed. The trillions of bacteria that inhabit the intestine influence health and regulate important biochemical factors, such as the activity of enzymes pertinent to drug metabolism. However, this has not been systematically studied partly due to the challenges of recapitulating the unique and complex intestinal microenvironment that includes (1) the presence of mammalian and microbial cells and (2) a unique partitioned oxygenation proﬁle across the lumen to the subepithelial mucosa from anaerobic to the richly vascularized oxygenated. This thesis reports the development of a microfluidic device in which is integrated a membrane synthesized from a key element of mucosal basal lamina, collagen, and precisely controlled partitioned oxygen environment. The device enabled excellent cell viability and long-term function. More importantly, it enabled the coculture of intestinal epithelial cells and aerobic and anaerobic bacteria in the partitioned oxygen environment. These experiments on one hand allowed the measurement of cellular oxygen consumption rate under perfusion, which could be used to study microbial regulation of oxidative metabolism in epithelial cells. On the other hand, the device allowed a systematic examination of the role of different gut bacteria strains on the regulation of factors that are important in drug metabolism, namely, transporters and phase I enzymes. Our studies highlighted the importance of direct communication between the intestinal cells and the gut bacteria with major findings being that species-specific differences exist in the regulation of drug metabolism. This work will be useful for (1) the discovery of novel regulators of drug metabolizing enzymes, (2) developing new pharmacokinetic models, and (3) advancing precision medicine models for patients.
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Title: Intraoperative Assessment of Surgical Margins in Head And Neck Cancer Resection Using Time-Domain Fluorescence Imaging
Creator: Cleary, Brandon M.
Date: 2023
Description: Rapid and accurate determination of surgical margin depth in fluorescence guided surgery has been a difficult issue to overcome, leading to...
Show moreRapid and accurate determination of surgical margin depth in fluorescence guided surgery has been a difficult issue to overcome, leading to over- or under-resection of cancerous tissues and follow-up treatments such as ‘call-back’ surgery and chemotherapy. Current techniques utilizing direct measurement of tumor margins in frozen section pathology are slow, which can prevent surgeons from acting on information before a patient is sent home. Other fluorescence techniques require the measurement of margins via captured images that are overlayed with fluorescent data. This method is flawed, as measuring depth from captured images loses spatial information. Intensity-based fluorescence techniques utilizing tumor-to-background ratios do not decouple the effects of concentration from the depth information acquired. Thus, it is necessary to perform an objective measurement to determine depths of surgical margins. This thesis focuses on the theory, device design, simulation development, and overall viability of time-domain fluorescence imaging as an alternative method of determining surgical margin depths. Characteristic regressions were generated using a thresholding method on acquired time-domain fluorescence signals, which were used to convert time-domain data to a depth value. These were applied to an image space to generate a depth map of a modelled tissue sample. All modeling was performed on homogeneous media using Monte Carlo simulations, providing high accuracy at the cost of increased computational time. In practice, the imaging process should be completed within a span of under 20 minutes for a full tissue sample, rather than 20 minutes for a single slice of the sample. This thesis also explores the effects of different thresholding levels on the accuracy of depth determination, as well as the precautions to be taken regarding hardware limitations and signal noise.
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Title: Retrospective Quantitative T1 Imaging to Examine Characteristics of Multiple Sclerosis Lesions
Creator: Young, Griffin James
Date: 2024
Description: Quantitative MRI plays an essential role in assessing tissue abnormality and diseaseprogression in multiple sclerosis (MS). Specifically, T1...
Show moreQuantitative MRI plays an essential role in assessing tissue abnormality and diseaseprogression in multiple sclerosis (MS). Specifically, T1 relaxometry is gaining popularity as elevated T1 values have been shown to correlate with increased inflammation, demyelination, and gliosis. The predominant issue is that relaxometry requires parametric mapping through advanced imaging techniques not commonly included in standard clinical protocols. This leaves an information gap in large clinical datasets from which quantitative mapping could have been performed. We introduce T1-REQUIRE, a retrospective T1 mapping method that approximates T1 values from a single T1-weighted MR image. This method has already been shown to be accurate within 10% of a clinically available reference standard in healthy controls but will be further validated in MS cohorts. We also further aim to determine T1-REQUIRE’s statistical significance as a unique biomarker for the assessment of MS lesions as they relate to clinical disability and disease burden. A 14-subject comparison between T1-REQUIRE maps derived from 3D T1 weighted turbo field echoes (3D T1w TFE) and an inversion-recovery fast field echo (IRFFE) revealed a whole-brain voxel-wise Pearson’s correlation of r = 0.89 (p < 0.001) and mean bias of 3.99%. In MS white matter lesions, r = 0.81, R2 = 0.65 (p < 0.001, N = 159), bias = 10.07%, and in normal appearing white matter (NAWM), r = 0.82, R 2 = 0.67 (p < 0.001), bias = 9.48%. Mean lesional T1-REQUIRE and MTR correlated significantly (r = -0.68, p < 0.001, N = 587) similar to previously published literature. Median lesional MTR correlated significantly with EDSS (rho = -0.34, p = 0.037), and lesional T1-REQUIRE exhibited xiii significant correlations with global brain tissue atrophy as measured by brain parenchymal fraction (BPF) (r = -0.41, p = 0.010, N = 38). Multivariate linear regressions between T1- REQUIRE NAWM provided meaningful statistical relationships with EDSS (β = 0.03, p = 0.027, N = 38), as well as did mean MTR values in the Thalamus (β = -0.27, p = 0.037, N = 38). A new spoiled gradient echo variation of T1-REQUIRE was assessed as a proof of concept in a small 5-subject MS cohort compared with IR-FFE T1 maps, with a whole brain voxel-wise correlation of r = 0.88, R2 = 0.77 (p < 0.001), and Bias = 0.19%. Lesional T1 comparisons reached a correlation of r = 0.75, R2 = 0.56 (p < 0.001, N = 42), and Bias = 10.81%. The significance of these findings means that there is the potential to provide supplementary quantitative information in clinical datasets where quantitative protocols were not implemented. Large MS data repositories previously only containing structural T1 weighted images now may be used in big data relaxometric studies with the potential to lead to new findings in newly uncovered datasets. Furthermore, T1-REQUIRE has the potential for immediate use in clinics where standard T1 mapping sequences aren’t able to be readily implemented.
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Title: NON-DESTRUCTIVE CANCER DETECTION IN LYMPH NODE USING PAIRED-AGENT MOLECULAR IMAGING
Creator: Li, Chengyue
Date: 2020
Description: Identification of cancer spread to tumor-draining lymph nodes through lymph node dissection and histology offers critical information for...
Show moreIdentification of cancer spread to tumor-draining lymph nodes through lymph node dissection and histology offers critical information for guiding treatment in many cancer types, including breast, melanoma, head and neck, lung and gynecologic cancers, as the lymphatic system serves as the primary route for metastasis. Lymph node biopsy involves localization of tumor-draining lymph nodes, followed by their surgical removal and histological assessment. However, the procedure is associated with overtreatment concerns and some considerable morbidity, including lymphedema, seroma formation, and restricted arm movement. Moreover, conventional histological analyses are time-consuming and laborious, yet pathologists generally examine less than 1% of the volume of each lymph node, leading to undetected micrometastasis (tumor clusters 0.2-2mm in diameter) in 30-60% of cases. In response to these limitations in standard lymph node dissection protocol, there is a significant need for the development of lymph node imaging strategies that are capable of identifying metastatic cancer as a means of staging a patient’s cancer without the need for invasive and time-intensive conventional pathology. Paired-agent imaging molecular imaging protocols have been spearheaded by our group and entail co-administration of a control imaging agent with a molecular targeted agent as a way to account for nonspecific uptake and retention. The overall goal of my thesis was to methodically design, optimize and evaluate the clinical utility of a paired-agent lymph node imaging protocol to achieve levels of sensitivity and specificity in nodal staging not possible with current conventional methods, less invasively and at a fraction of the time and cost.
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Title: IMPACT OF DATA SHAPE, FIDELITY, AND INTER-OBSERVER REPRODUCIBILITY ON CARDIAC MAGNETIC RESONANCE IMAGE PIPELINES
Creator: Obioma, Blessing Ngozi
Date: 2020
Description: Artificial Intelligence (AI) holds a great promise in the healthcare. It provides a variety of advantages with its application in clinical...
Show moreArtificial Intelligence (AI) holds a great promise in the healthcare. It provides a variety of advantages with its application in clinical diagnosis, disease prediction, and treatment, with such interests intensifying in the medical image field. AI can automate various cumbersome data processing techniques in medical imaging such as segmentation of left ventricular chambers and image-based classification of diseases. However, full clinical implementation and adaptation of emerging AI-based tools face challenges due to the inherently opaque nature of such AI algorithms based on Deep Neural Networks (DNN), for which computer-trained bias is not only difficult to detect by physician users but is also difficult to safely design in software development. In this work, we examine AI application in Cardiac Magnetic Resonance (CMR) using an automated image classification task, and thereby propose an AI quality control framework design that differentially evaluates the black-box DNN via carefully prepared input data with shape and fidelity variations to probe system responses to these variations. Two variants of the Visual Geometric Graphics with 19 neural layers (VGG19) was used for classification, with a total of 60,000 CMR images. Findings from this work provides insights on the importance of quality training data preparation and demonstrates the importance of data shape variability. It also provides gateway for computation performance optimization in training and validation time.
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Title: Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Creator: Kaczmarek, Julia A.
Date: 2023
Description: The loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment...
Show moreThe loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment. An effector molecule of the disease, amyloid-beta (Aβ), has been observed to interact with lipid membranes, but its relevance to mitochondrial membranes containing CL remained elusive. The present study investigated if the presence of CL modulated the insertion of adsorbed helical amyloid beta (Aβ14-40) into model mitochondrial membranes, and if this effect was more pronounced for its N-terminus or C-terminus. I conducted a coarse-grained computer simulation using well-tempered metadynamics to traverse the free energy landscape that maps the translocation of Aβ14-40. Insertion into CL-containing bilayers created larger local membrane deformations and modulated the location of the transition path but had an inconclusive impact on the free energy cost of translocation. Since the generation of toxic calcium-permeable pores depends on the insertion of Aβ into the bilayer, the loss of CL seen in AD may prime the inner mitochondrial membrane for pore formation, but more research is needed to pursue this hypothesis.
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