BEE 4530 - 2020 Student Papers

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    Designing and Optimizing a Protocol for Whole-Ovary Vitrification
    Scott, Mitchell Tyler; Chen, Dave; Cheng, Evan (2020-05)
    Ovarian tissue cryopreservation (OTC), a process to preserve human ovarian tissue by cooling to subzero temperature without ice formation, has been increasingly studied within the last 15 years. This is due to the growing scientific capabilities as well as more women who want the procedure for medical or elective reasons. For example, women at or below reproductive age who have to undergo radiological treatments might have to forfeit their fertility. However, if they cryopreserve part or all of their ovary, the ovaries can be reimplanted or in vitro fertilization (IVF) can occur to allow fertility options in the future. Other women have been undergoing OTC for more elective reasons such as delaying menopause so that they don’t have to live a majority of their life as postmenopausal. There are types of OTC; slow freezing and vitrification. Both require coupled mass and heat transfer. Slow freezing consists of low concentrations of cryoprotective agents (CPAs) which displace water to prevent freezing and a slow cooling rate of about 4∘C min−1. While this is the more thoroughly researched cryopreservation method, research suggests that vitrification is better in the long run, on cellular organelles. Vitirification consists of a higher amount of CPAs present and a cooling rate close to 150∘C min−1.While vitrificiation has many advantages, there is not a universally agreed-upon standard protocol for vitrification, especially not for the whole ovary. The advantages of OTC on the whole organ would be that upon reimplantation, the hormonal health is assumed to be easily maintained. In order to create a standard vitrification protocol, the criteria for vitirification have to be met (namely the ovary has 6M CPA and then is cooled to -150∘C), while then also maximizing the cellular viability. With higher concentration of CPAs especially in vitrification, there is an increase in cytotoxicity, so a cytotoxicity cost function was implemented in aiding the optimization. While creating a 3D computational model of the ovary, with a branched artery and six capillaries, we found that the mesh converged for both heat and mass transfer physics at around 200,000 elements. Using the optimization function, we were able to ascertain that the optimal conditions for the protocol were to submerge the ovary in 9.5 M dimethylsulfoxide (DMSO) for 6 hours and then placed in liquid nitrogen for around 60 seconds. This resulted in a cellular viability prediction of 29.07%, on par with current methods where only parts of the ovaries are cryopreserved. To test the robustness of our model, we varied some of the parameters to see the effect on the protocol. Future directions are analyzed to further improve our model.
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    Effect of Fibrotic Layer Formation on Oxygen Delivery to Pancreatic Cells in a (REDACTED) Cell Encapsulation Device
    Fibrosis is an immune response that handicaps the effectiveness of biomedical devices for individuals with type 1 diabetes. As an implant becomes encapsulated with connective tissue, forming a fibrotic layer, cells within a device may be unable to survive, leading to reduced performance. Recent studies have focused on fibrosis and its impact on insulin producing cells, but little research has explored the role fibrosis plays with regards to oxygen transfer. Oxygen transfer into a pancreatic cell encapsulation device was explored in this study. Specifically, this device contains (redacted) surrounded by an alginate hydrogel with cells. When implanted, a fibrotic layer forms around the device; in this study, various thicknesses, compositions, and percent coverages of this layer were analyzed to observe their impact on survivability of cells due to limited oxygen availability. In this study, oxygen transfer was explored within a (redacted) biomedical device with varying fibrotic layer thicknesses and percentages in order to observe the survival rate of insulin-producing cells within a hydrogel layer. The device used in this study contains an internal alginate hydrogel layer surrounded by a layer of fibrosis. The models were all built using COMSOL MultiphysicsⓇ Modeling Software and make use of oxygen diffusion from an external boundary condition and oxygen consumption based on Michaelis-Menten Kinetics. Under the 1D model, device oxygen levels were studied under varying severity of the fibrotic response and in several oxygen environments. Parameters including fibrotic layer thickness, seeding density within the hydrogel layer, and boundary oxygen concentration under full fibrotic layer coverage were varied. Results indicated that a higher seeding density results in lower concentration gradients, as more cells are present in the hydrogel and consuming more oxygen. Similarly, a thicker fibrotic layer results in less oxygen entering the hydrogel layer. Under the 3D model, the effects of various percentages and thickness of the fibrotic layer were studied, with coverages varying in intervals of 25%. In the scenario of 100% fibrotic layer coverage at 200μm thickness, the model indicates most cells in the hydrogel become necrotic due to the limited oxygen and high oxygen consumption from the fibrotic layer. Under a more idealized situation with 25% coverage of fibrotic tissue at 10μm thickness, oxygen concentration is still depleted but less egregiously, with little risk of necrosis. The sensitivity analysis indicates how the model is more sensitive to subtle changes in seeding density and surface oxygen concentration, as opposed to other parameters. Data obtained in the study was validated via comparisons with oxygen concentrations within the fibrotic layer from another existing 1D analytical model. Similarly, oxygen concentration in the hydrogel region of the 3D model was compared to data obtained from another study measuring oxygen concentration within a device encapsulated by fibrosis. Overall, the results emphasize the importance in eliminating any possible fibrotic encapsulation around a biomedical device.
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    Modeling of Primary Freeze Drying Phase of Lyophilization of Ebola Virus Disease Vaccine
    Adams, Abby; Flood, Donovan; Ganesan, Sandhya; Koga, Maho (2020-05)
    Lyophilization, or freeze-drying, is a commonly used technique to extend the shelf life and increase the stability of various pharmaceuticals by removing excess water from the product. The process can be energy and time-intensive, but it is often required for approval of widely used pharmaceuticals, including the Ebola Virus Disease vaccine. The process can be broken down into three phases: freezing, primary drying (sublimation), and secondary drying. The focus of this model was on the primary drying phase, which is the longest and most critical of the three stages. The success of the lyophilization process largely depends on the result of the primary drying phase, making it crucial to optimize key parameters that characterize this stage. Therefore, the main objectives of this study were to develop a model to form a better understanding of the sublimation reaction that occurs during primary drying and to optimize key process parameters to increase the efficiency of the process. COMSOL Multiphysics was used to develop a computational model of the lyophilization process to achieve these objectives. A 2-D axi-symmetric geometry was used to construct the vial in which the pharmaceutical product was placed during lyophilization. Three different COMSOL physics interfaces were chosen to model the primary drying phase for a duration of 20 hours for the Ebola virus disease vaccine. Whereas most prior models use a moving sublimation boundary, this model employed a non-equilibrium sublimation front formulation to simulate the behavior. From our sensitivity analysis, it was determined that permeability is a critical factor affecting sublimation. Increasing permeability not only increased the amount of sublimation but also allowed for sublimation to occur more evenly throughout the domain. This was due to the increased vapor flow throughout the domain, driving the pressure gradient powering sublimation. Other parameters, including the heat transfer coefficient, chamber pressure, and sublimation reaction constant, primarily affected sublimation at the boundary rather than throughout the entire domain. Increasing the heat transfer coefficient and sublimation reaction constant while decreasing the lyophilization chamber pressure increased sublimation at the vial edge. This model elucidated key insights into the sublimation process. Pressure buildup into the vial was specifically identified as the main limiting factor of sublimation, and this can be improved in future studies by adjusting various parameters including those analyzed in a sensitivity analysis. This key finding provides further insight into the physics and mechanism that drives the phase change and provides a foundation for further research and optimization. Furthermore, while this study focused on the Ebola Virus Disease vaccine, this computational model can be customized with the properties and process parameters for other vaccines of interest, making it a valuable tool for many pharmaceutical manufacturers.
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    Effect of Layout and Shape to the Drug Delivery of Intratumoral Implant
    Xue, Zhengxing; Cai, Yalu; Fuchs, Matthieu (2020-05)
    Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. In 2015, about 90.5 million people had cancer. About 14.1 million new cases occur a year.[1] It caused about 8.8 million deaths (15.7% of deaths).Abdominal cancer is a particular type of cancer that occurs when there is an uncontrolled growth of abnormal cells anywhere in the abdomen. It is one of the most pernicious types of cancer.[2] Since the abdomen consists of many organs, including the stomach, intestines, liver, gallbladder, and pancreas, abdominal cancer is more difficult to detect and treat. [3-5] Currently the most curative treatment option for abdominal cancers is surgical resection followed by adjuvant chemotherapy or radiation therapy to minimize the risk of recurrence [6]. Many cancers respond well to this treatment strategy, but many patients are not eligible for surgical resection due to a variety of reasons. For example, cancer of the liver is difficult to treat with resection because more than one liver lobe may be involved and the possibility of a coexisting liver condition (e.g., cirrhosis) [7]. Abdominal cancers, such as those of the pancreas and stomach, also have low resection success rates and poor overall patient survival [9]. Treatment of unresectable tumors has been supplemented in recent years by the development of minimally invasive interventions, such as laser, microwave, and radiofrequency (RF) ablation. [10] RF ablation in particular has shown improved efficacy, where approximately 80% of tumors cannot be surgically removed. However, despite its success, RF ablation is restricted by limited effective ablation volume that can be created with a single treatment as well as the risk of tumor recurrence around the boundary. [11-12] Biodegradable polymer implants, termed polymer millirods, have been designed to deliver chemotherapeutic agents to the RF treated region to kill residual tumor cells and prevent tumor recurrence. [8] These implants have been studied systematically in non-ablated and ablated liver tissues, and initial studies using doxorubicin-containing implants to treat tumors have indicated their potential benefit. Currently, the major challenge in effectively treating tumors with polymer millirods has been the limited drug penetration distance into the surrounding tissue. Although several changes to implant design have already been described, how these changes would affect local drug delivery and antitumor efficacy is still not known. In “Modeling doxorubicin transport to improve intratumoral drug delivery to RF ablated tumors”, the researchers built a mathematical model to provide an ideal strategy to optimize intratumoral drug delivery implants to supplement radiofrequency (RF) ablation for tumor treatment [8].They focused on the drug diffusion process in both a one-dimensional (1-D) simulation model and a more complex three-dimensional (3-D) simulation model. According to their experiment data and modeling analysis, they estimated the diffusion coefficient and drug elimination rate in ablated and non-ablated tumors. They found that RF ablation facilitates intratumoral drug delivery in tissue by reducing normal elimination processes and increasing diffusion. Also, they suggested that computational modeling approach has great advantages to design and rapidly prototype new implant treatment strategies. In "Polymer implants for intratumoral drug delivery and cancer therapy”, Weinberg et al. examined different designs of tumor implants to provide optimal drug release kinetics [7]. They examined the delivery goals for the implants and the methods to modulate local drug pharmacokinetics. They used three-dimensional (3-D) modeling to study the effect of using one central implant versus four peripheral implants on the drug diffusion process inside the tumor. The different layouts of the implants can maximize drug coverage of the tumor periphery, but also need to maintain a reasonable number of implants and total drug dose, which needs further exploration. These studies, we are going to create a more realistic model that replicates ablating a tumor in the liver and then delivering a chemotherapy drug, Doxorubicin, intratumorally. While previous research focused on the simplified spherical geometry, we constructed a more realistic three-dimensional (3-D) tumor simulation from a CT scan of the actual tumor. This will provide us with more accurate insight in our exploration of the optimal implant drug delivery.
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    Heat Transfer in Penguin Huddles
    Karben, Samson; Kim, Glenn; Purwamaska, Ivanakbar; Tormey, Caitlin (2020-05)
    Emperor penguins have several adaptations that allow them to survive the extreme Antarctic winter. Some of these adaptations are behavioral, such as huddling to reduce exposure and preserve body heat. While previous research has been done to estimate the metabolism of individual emperor penguins, these birds often group together, and thus less heat is lost than the equation suggests. The paper will focus on modeling a full penguin huddle where the penguins are exposed to ambient temperature and wind typical of Antarctica to see what spacing is necessary to maintain a typical body temperature and where the best place to stand in the huddle is. The numerical solver used in this report is COMSOL, a multiphysics modeling software that allows for a high degree of flexibility and accuracy. Each penguin is modeled as a 2-D circle with heat generation and insulation parameters determined by previous research. The penguin was copied 6,000 times to form a hexagonal huddle. The physics modeled are fluid flow and heat transfer in fluids and solids. We found that a spacing of between 0.8cm and 0.951cm allows the penguins in the penguin huddle to maintain the average body temperature of 38.2°C, the typical penguin body temperature (Le Maho, 1976). In addition, the optimal location of minimal heat loss was determined to be the middle towards the back. This simulation could allow for new insights and methods into research of how the huddling of the penguins preserves body heat and how changing conditions, due to climate change, could affect penguin behavior and survival in such a hostile environment.