Mortality due to cancer is a global health issue that can be improved through further development of diagnostic and prognostic tools. Recent advancements in technologies aiding cancer research have made significant strides, however a demand for a non-invasive clinically relevant point-of-care tools exists. To accomplish this feat, the desired instrument needs to be low-cost, easy-to-operate, efficient, and have rapid processing and analysis. Microfluidic platforms in cancer research have proven to be advantageous due to its operation at the microscale, which has low costs, favorable physics, high precision, short experimentation time, and requires minimal reagent and sample sizes. Label-free technologies rely on cell biophysical characteristics to identify, evaluate, and study biological samples. Biomechanical probing of cells through deformability assays provides a label-free method of identifying cell health and monitoring response to physical and chemical stimuli. Bioimpedance analysis is an alternative versatile label-free method of evaluating cell characteristics by measuring cell response to electrical signals. Microfluidic technologies can facilitate biomechanical and bioelectrical analysis through deformability assays and impedance spectroscopy. This dissertation demonstrates scientific contributions towards single-cell analysis and liquid biopsy devices focusing on cancer research. First, cell deformability assays were improved through the introduction of multi-constriction channels, which revealed that cells have a non-linear response to deformation. Combining impedance analysis with microfluidic deformability assays provided a large dataset of mechano-electrical information, which improved cell characterization and greatly decreased post-processing times. Next, two unique biosensors demonstrated improved throughput while maintaining sensitivity of single-cell analysis assays through parallelization and incorporating machine learning for data processing. Liquid biopsies involve studying cancer cells in patient vascular systems, called circulating tumor cells (CTCs), through blood samples. CTC tests reveal valuable information on patient prognosis, diagnosis and can aide therapy selection in a minimally invasive manner. This body of work presents two liquid biopsy devices that enrich murine and human blood samples and isolate CTCs to ease detection and analysis. Additionally, a microfluidic CTC detection biosensor is introduced to reliably count and identify cancer cells in murine blood, where an extremely low-cost version of the assay is also validated. Thus, the assays presented in this dissertation show promise of microfluidic technologies towards point-of-care systems for cancer research. / Doctor of Philosophy / Cancer is the second leading cause of death worldwide with approximately 2 million new cases each year in the just United States. Significant research development for diagnostic and prognostic tools have been conducted, however they can be expensive, invasive, time-consuming, unreliable, and not always easily accessible. Thus, a tool that is cheap, minimally invasive, easy-to-use, and robust needs to be developed to combat these issues. Typical cancer studies have primarily focused on biological and biochemical methods for evaluation; however, researchers have begun to leverage small-scale biosensors that utilize biophysical attributes. Recent studies have proven that these lab-on-a-chip technologies can produce meaningful results by exploiting these biophysical characteristics. Microfluidics is a science that consists of sub-millimeter sized channels which show a great deal of promise as they require minimal materials and can quickly and efficiently analyze biological samples. Label-free methods of studying cells rely on their physical properties, such as size, deformability, density, and electrical properties. These biophysical characteristics can be easily obtained at the single-cell level through microfluidic-based assays. Measuring and monitoring these attributes can provide valuable information to help understand cancer cell response to stimuli such as chemotherapeutic drugs or other therapies. A liquid biopsy is a non-invasive method of evaluating cancer patients by studying circulating tumor cells (CTCs) that exist in their blood. This dissertation reports a wide range of label-free microfluidic assays that evaluate and study biological samples at the single-cell level and for liquid biopsies. These assays consist of microfluidic channels with sensors that can rapidly obtain biophysical characteristics and process blood samples for liquid biopsy applications. Uniquely modifying microfluidic channel geometries and sensor configurations improved upon previously developed single-cell and CTC-based tools. The resulting devices were low in cost, easy-to-use, efficient, and reliable methods that alleviates current issues in cancer research while showing clinical utility.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/113064 |
| Date | 05 January 2023 |
| Creators | Ghassemi, Parham |
| Contributors | Electrical Engineering, Agah, Masoud, Baumann, William T., Jia, Xiaoting, Yi, Yang, Li, Liwu |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/x-zip-compressed |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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