Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Engineering (ENAS)
First Advisor
Mak, Michael
Abstract
Physical cues are ubiquitous in biological systems, from the formation of molecules to the activities of living organisms. While bioprocessing requires functional and efficient biophysics, anomalies in biophysics also present medical challenges. My research integrated biophysical phenotyping and bioinformatics to investigate the physical cues in cancer and sickle cell disease. Cancer is one disease with a wide range of physical challenges. Numerous internal and environmental factors contribute to the heterogeneity of the tumor population. The development of tumor results in numerous physical stresses, which compress tumor cells. In addition, some aggressive tumor cells can migrate through the dense pores in the ECM and initiate metastasis, which is responsible for more than 90% of cancer-related deaths. We developed an integrated biophysical phenotyping and bioinformatics analytical system to further the understanding of the physical cues of cancer. In Chapter 2, we investigated the phenotypes of highly aggressive MDA-MB-231 cells in a single cell and cell doublet forms in confined microenvironments. We elucidated the underlying morphological and subcellular features associated with different single cell and cell doublet phenotypes and the impact of invasion through confined geometry on cell behavior. In Chapter 3, we applied the analytical system to analyze the biophysical data of MDA-MB-231 cells during their spontaneous migration through confined environments. Our approach elucidates phenotypic heterogeneity in cancer cells under confined microenvironments at single-cell resolution. In Chapter 4, we apply an integrative approach to investigate the impact of compression on melanoma cells. Our findings indicate that volumetric compression is a double-edged sword for melanoma progression and drives tumor evolution. In order to further validate the biophysical-informatics system's functionality in addressing other diseases, we subsequently adapted it to a microfluidic-informatics analytical system for sickle cell disease. Sickle cell disease is a genetic condition that causes abnormalities in hemoglobin mechanics. Those affected are at high risk of vaso-occlusive crisis. The vaso-occlusive crisis is a life-threatening condition that causes pain and stroke, reducing the life expectancy of patients to less than 50 years. In Chapter 5, we applied the microfluidic-informatics analytical system to quantify sickle cell occlusion. We demonstrated the device as an easy-to-use assay for quick occlusion information extraction with a simple setup and minimal additional instruments. We also validated the system as a platform for testing the effectiveness of potential therapeutic strategies in reducing sickle cell disease severity.
Recommended Citation
Zhang, Xingjian, "Biophysical Signatures in Cancer and Sickle Cell Disease" (2022). Yale Graduate School of Arts and Sciences Dissertations. 726.
https://elischolar.library.yale.edu/gsas_dissertations/726
