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Many drugs and environmental chemicals, such as antibiotics and chemotherapeutic agents, are nephrotoxic (toxic to the kidney) and are a common cause of acute kidney injury and chronic kidney disease. Conventional tissue models for assessment of drug-induced nephrotoxicity rely on animals or simple cell culture models, which lack tissue characteristics of the human kidney required to accurately predict a drug’s effect in clinical trials. Microfluidic kidney-on-chips can generate tissue with improved human relevance compared to traditional models, however, generally lack high-throughput and multiparametric data collection capabilities for evaluation of nephrotoxic drug exposures. Standard data collection techniques remain limited to fluorescent imaging or colorimetric assays that often focus on single endpoints, are invasive due to the addition of labels, and fail to capture dynamic changes in tissue function. Additionally, conventional toxicological readouts rely on bulk measures of injury, such as cell death, which are less sensitive than sub-lethal changes in cell function and morphology that occur prior to cell death. Due to the challenges above, there is a need for new measurement approaches that enable collection of kinetic, multi-parametric, and sub-lethal readouts of injury in kidney-on-chip systems. In this work, we developed and characterized several measurement approaches for evaluation of tissue function in kidney-on-chip systems and assessment of drug-induced nephrotoxicity. In chapter 2, we developed a novel optical-based oxygen sensing technique for measurement of sub-lethal mitochondrial dysfunction in an array of kidney-on-chips. In chapter 3, we investigated an approach for simultaneous transepithelial electrical resistance (TEER) sensing and flow control to enable near-continuous monitoring of tissue barrier function under different flow conditions. In chapter 4, we demonstrated the use of different data collection modalities, including multiple sensors, fluorescent imaging, and colorimetric-based assays, to generate multi-parametric readouts for evaluation of drug-induced nephrotoxicity in kidney-on-chips. / 2024-05-24T00:00:00Z

Multiphase flow in porous media is important in a wide range of industrial and environmental processes. It is well-known that the fluids’ relative affinity to the porous media (i.e., wettability) is a crucial factor controlling multiphase flow in porous media. Despite having a good understanding of multiphase flow in porous media under uniform wettability conditions, our knowledge of how fluids flow in mixed-wet porous media is more limited. Mixed-wet porous media (i.e., porous media with spatially heterogeneous wettability) is prevalent in nature, from groundwater aquifers to oil-bearing rocks. This Thesis aims to better understand the complexities of multiphase flow in mixed-wet porous media. The study begins with investigating fluid-fluid displacement in mixed-wet microfluidic flow cells. We performed experiments over a range of capillary numbers and mixed-wettability conditions, and our results show that the fluid-fluid interface in mixed-wet pores resembles an S shaped saddle with very low capillary pressure. In the next step, we derive analytical expressions for fluid-fluid interface evolution through mixed-wet pore throats. These analytical expressions are incorporated into a dynamic pore network model, which enables us to develop a numerical framework capable of simulating fluid-fluid displacement in mixed-wet porous media. Next, we leverage our model to simulate multiphase flow in simple mixed-wet porous micro-models consisting of distinct water-wet and oil-wet regions whose fractions are systematically varied to yield a variety of displacement patterns over a wide range of capillary numbers. Our simulations reveal that mixed-wettability impacts are most prominent at low capillary numbers, and it depends on the complex interplay between the wettability fraction and the intrinsic contact angle of the water-wet regions. We also investigate the dynamics of multiphase flow in mixed-wet porous media under quasi-static conditions and discover that it exhibits self-organized criticality (SOC). Finally, we determine the correlation between spatial and temporal aspects of this dynamical system. / Thesis / Doctor of Science (PhD)

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Laboratory test results are important in making decisions regarding a patient's diagnosis and response to treatment. These tests often measure the biomarkers found in biological fluids such blood, urine, and saliva. Immunoassay is one type of laboratory test used to measure the level of biomarkers using specific antibodies. Microfluidics offer several advantages such as speed, small sample volume requirement, portability, integration, and automation. These advantages are motivating to develop microfluidic platforms of conventional laboratory tests. I have fabricated polymer microfluidic devices and developed immunoassays on-chip for potential cancer markers. Silicon template devices were fabricated using standard photolithographic techniques. The template design was transferred to a poly(methyl methacrylate) (PMMA) piece by hot embossing and subsequently bonded to another PMMA piece with holes for reservoirs. I used these devices to perform microchip immunoaffinity electrophoresis to detect purified recombinant thymidine kinase 1 (TK1). Buffer with 1% methylcellulose acted as a dynamic coating that minimized nonspecific adsorption of protein and as sieving matrix that enabled separation of free antibody from antibody-TK1 complexes. Using this technique, I was able to detect TK1 concentration >80 nM and obtained separation results within 1 minute using a 5 mm effective separation length. Detection of endogenous TK1 in serum is difficult because TK1 is present at the pM range. I compared three different depletion methods to eliminate high abundance immunoglobulin and human serum albumin. Cibacron blue columns depleted abundant protein but also nonspecifically bound TK1. I found that ammonium sulfate precipitation and IgG/albumin immunoaffinity columns effectively depleted high abundance proteins. TK1 was salted out of the serum with saturated ammonium sulfate and still maintained activity. To integrate affinity columns in microfluidic devices, I have developed a fast and easy strategy for initial optimization of monolith affinity columns using bulk polymerization of multiple monolith solutions. The morphology, surface area, and porosity, were qualitatively assessed using scanning electron microscopy. This method decreased the time, effort, and resources compared to in situ optimization of monoliths in microfluidic devices. This strategy could be used when designing novel formulations of monolith columns. I have also integrated poly(ethylene glycol dimethacrylate-glycidyl methacrylate) monolith affinity columns in polymer microfluidic devices to demonstrate the feasibility of extracting human interleukin 8 (IL8), a cancer biomarker, from saliva. Initial results have shown that the affinity column (~3 mm) was successfully integrated into the devices without prior surface modification. Furthermore, anti-IL8 was immobilized on the surface of the monolith. Electrochromatograms showed that 1 ng/mL of IL8 can be detected when in buffer while 10 ng/mL was detected when IL8 was spiked in saliva. Overall, these findings can be used to further develop immunoassays in microfluidic platforms, especially for analyzing biological fluids.