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MODELLING INTERACTION BETWEEN CD8+ T CELLS AND BETA CELLS IN PATHOGENESIS OF TYPE 1 DIABETES
Title
MODELLING INTERACTION BETWEEN CD8+ T CELLS AND BETA CELLS IN PATHOGENESIS OF TYPE 1 DIABETES
Creator
Xu, Qian
Date
2016, 2016-12
Description
Diabetes is one of the prevalent diseases in the USA, which affects the lives of millions of people. In 2010 only, there was a total of 234...
Show moreDiabetes is one of the prevalent diseases in the USA, which affects the lives of millions of people. In 2010 only, there was a total of 234,051 deaths linked to diabetes in the USA. Research related to preclinical and clinical assays are always costly and time consuming. Modeling is a helpful method to reduce the cost of clinical experiments and accelerates the discovery and improvement of new therapies. This research is focused on the development of a high performance agent-based model simulating the pathogenesis of Type 1 diabetes mellitus in pancreas. The whole immune response takes place in three compartments, pancreatic lymph node, circulation, and pancreas. A significant part of the complex interactions leading to Type 1 diabetes takes place in the pancreatic tissue. Therefore, the focus was placed on the islets of Langerhans in the pancreas, and the interaction of CD8+ T cells and Beta cells were modeled. T cell behavior was incorporated as rules in this model such as activation, migration, proliferation, apoptosis, and cytotoxicity. Likewise Beta cell death and regeneration under the T cell attack were modeled. The model is able to capture the trends of T cell and Beta cell variations during the disease progression and portrays the role of CD8+ T cells in the process. It is expected that, with the addition of other immune system and pancreatic tissue components, the model will be a valuable tool for the planning of clinical studies.
M.S. in Biomedical Engineering, December 2016
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A KINETIC MODEL TO ESTIMATE VASCULAR PERMEABILITY FROM FLUORESCEIN VIDEOANGIOGRAPHY DATA
Title
A KINETIC MODEL TO ESTIMATE VASCULAR PERMEABILITY FROM FLUORESCEIN VIDEOANGIOGRAPHY DATA
Creator
Hu, Shaoxian
Date
2017, 2017-05
Description
Diabetic retinopathy (DR) is a disease affecting the tissue of the retina through hemodynamics and vascular damage that is a side effect of...
Show moreDiabetic retinopathy (DR) is a disease affecting the tissue of the retina through hemodynamics and vascular damage that is a side effect of hyperglycemia. As such, markers of hemodynamic and vascular irregularity have been proposed as potential early indicators of the disease. However, conventional approaches to estimate these conditions are not sensitive enough, leading to indications that are too late, appearing only after irreversible vision problems have occurred. Indicator-dye-dilution tracer kinetic modeling is a decades-old methodology that can be used to quantify blood flow and vascular permeability based on the kinetics of a rapidly injected blood pool imaging agent. The methodology is able to track sensitive hemodynamic changes in stroke and heart disease patients, yet it has never been applied to blood flow and vascular permeability mapping of the retina. The purpose of my Master’s thesis was to adapt those tracer kinetic methods to fluorescein retinal videoangiography data collected in human to map both blood flow and vascular permeability so that in future work, changes in these parameters can be quantified at varying stages of the development of DR. Studies were carried out on simulated data, healthy and diabetic rats, and healthy and diabetic humans. While a robust validation of measures of blood flow and vascular permeability are still required, this first-of-its-kind study exposed many unique complications in applying the kinetic models to human fluorescein videoangiography data. Specifically, eye motion must be accounted for, both detector and fluorescein fluorescence quenching signal saturation must be avoided, and standard use of automatic gain control of imaging exposure should not be used (though corrections were developed for this); rather, data should be collected at a stable exposure throughout a measurement. Solutions were developed for all of these complications that were tested in rat models (optimal data collection in humans is ongoing). In rat study, average vascular permeability in the rat measured by the “extraction fraction”, the extraction fraction in control subject (n=3) 9.4e-4±1.3e-3, is lower than STZ-diabetic subjects (n=3) 5.5-2±5.17e-2 and VEGF group (n=3) 7.6e-2±5.1e-2. In healthy human volunteers, retinal extraction fraction was measured to be 5.0e-5 ± 6.1e-5 (n=2), whereas this was found to be elevated to 1.2e-3 ± 1.0e-3 in patients for diagnosed DR (n=3). These early results clearly demonstrated a statistically significant elevation in vascular permeability in all diabetic groups compared to controls (p<0.05). The human study was carried out on advanced cases of patients who were known to have DR as a test case; however, the sensitivity of the approaches is demonstrated by the eatly changes in extraction fraction observed at only 48 h after the onset of hyperglycemia in the rat experiments (well before irreversible damage to the retina had occurred). These results are promising for the adaptation of our modified kinetic modeling approach to measure hemodynamics and vascular permeability changes during the early onset of DR when preventative therapies could be most effective.
M.S. in Biomedical Engineering, May 2017
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MECHANICAL AND BIOCHEMICAL FACTORS INFLUENCING INITIAL PLATELET ADHESION TO COLLAGEN: IMPORTANT ROLE FOR SLIDING AND ROLLING IN ACCELERATED AGGREGATE FORMATION
Title
MECHANICAL AND BIOCHEMICAL FACTORS INFLUENCING INITIAL PLATELET ADHESION TO COLLAGEN: IMPORTANT ROLE FOR SLIDING AND ROLLING IN ACCELERATED AGGREGATE FORMATION
Creator
Au, Bonnie
Date
2015, 2015-05
Description
Injury at the vessel wall leads to exposure of collagen to which platelets initially adhere, grow into aggregates and eventually thrombotic...
Show moreInjury at the vessel wall leads to exposure of collagen to which platelets initially adhere, grow into aggregates and eventually thrombotic masses which can occlude the vessel lumen. This process underlies the disorders of heart attack and stroke. The initial phase of platelet aggregation governs the extent of thrombus formation. We have investigated initial platelet attachment to collagen-coated surfaces under mechanical and biochemical conditions in a parallel plate flow reactor. A simple algorithm has been developed to simulate the effects of platelet sliding/rolling on the surface with respect to the development of surface aggregate formation. Platelets are hypothesized to stop such movement once they collide with a neighboring platelet in their pathway (due to platelet coherence that strengthens the overall adhesive forces due to platelet-platelet bonding). We and others have observed microscopically that platelets will either attach firmly onto the surface, roll and slide or detach completely from the surface. Platelet behavior was investigated for overall adhesion and the translocation dynamics on overall adhesion on temperature, flow conditions, C-reactive protein (CRP), and coffee consumption. Our findings indicate that temperature, shear force, and CRP promote platelet adhesion and the intake of coffee impedes platelet adhesion.
M.S. in Biomedical Engineering, May 2015
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IMAGING TISSUE SCAFFOLDS WITH X-RAY PHASE CONTRAST IMAGING
Title
IMAGING TISSUE SCAFFOLDS WITH X-RAY PHASE CONTRAST IMAGING
Creator
Doe, Frederick
Date
2014, 2014-12
Description
A major challenge in tissue engineering is imaging within scaffolds. Biomaterials commonly used in tissue engineering have similar x-ray...
Show moreA major challenge in tissue engineering is imaging within scaffolds. Biomaterials commonly used in tissue engineering have similar x-ray absorption properties to native tissue, so they provide poor contrast in radiography. X-ray phase contrast imaging (XPCI) is an imaging modality that measures light/matter interactions other than absorption. By providing insight into these interactions, x-ray phase contrast imaging has the potential to allow imaging of materials used in biomedical applications. In this thesis, a technique for imaging explanted poly(ethylene glycol) (PEG) hydrogels is presented. PEG is a highly biocompatible polymer with widespread use in biomedical applications. Porous PEG hydrogels were synthesized with 100-150 μm pore size through a salt-leaching technique and loaded with fibrin, a natural protein known to stimulate vascularized tissue formation. The hydrogels were formed in the shape of disks and implanted subcutaneously in the backs of rodent animal models for 1, 2 and 3 weeks. The hydrogels and surrounding tissue were harvested at 1, 2, and 3 weeks. After explanation, the hydrogels were placed in formaldehyde and imaged at the National Light Source at Brookhaven National Laboratory using a multiple image radiography (MIR) technique. Five hundred angles were captured of each sample over 180°, and computed tomography was performed. The samples were compared to histological stains to identify specific tissue features that could be identified in the XPCI images. XPCI allowed imaging of hydrogels and identification of interfaces between native tissue and the PEG material. In addition, tissue invasion into the pores of the scaffold could be identified and could be used to quantify the depth of invasion. Muscle tissue could also be seen, and within muscle fibers were visible. With computed tomography, 3D volumes were constructed, enabling analysis throughout the samples.
M.S. in Biomedical Engineering, December 2014
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