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Approaches to studying collective migration, diffusion and integrated organ-on-a-chip technologies

  • Author(s): Lim, Han Liang
  • Advisor(s): Varghese, Shyni
  • et al.
Abstract

Cancer ranks amongst the most lethal diseases worldwide, partly due to there being more than 120 different types of cancer, each one different from the other. Even for cancers from the same organ, different mutations in different cells within the same tissue can give rise to different types of cancer, which may require completely different treatments. Due to advancements in medical and pharmacological sciences, different drug regiments for different types of cancer exist, which has contributed to improving the survival rates for many cancer patients. However, due to inherent patient-to-patient differences in genetic and epigenetic makeup, not every patient responds in the same manner to the same treatment. To this end, to provide a more comprehensive treatment for cancer patients, scientists and doctors are suggesting personalized medicine as the new paradigm in cancer treatments to tailor drug regiments for each patient. To realize this, drug testing platforms with cells derived from the patient should be used to obtain information about the specific patient’s sensitivity to different drugs. Here we demonstrate a proof-of-concept ‘you-on-a-chip’ integrated device that utilizes organ-on-a-chip systems to recapitulate the patient’s own physiological state outside of the human body. The organ-on-a-chip devices used here will consist of a ‘cancer-on-a-chip’ device containing the patient’s own cancer cells, integrated with the ‘liver-on-a-chip’, ‘heart-on-a-chip’ and ‘muscle-on-a-chip’ devices. Each chip will contain micro-tissues derived from the same patient’s own induced pluripotent cells. Here in this dissertation, I detail studies leading up to the development of this integrated organ-on-a-chip system, which we propose can be used as a personalized drug testing platform to tailor patients’ treatments. Furthermore, such devices can also be used as a drug testing platform by pharmaceutical companies to elucidate the most efficacious drug from thousands of drug candidates.

Chapter 1 is a literature review focusing on collective migration, diffusion and organ-on-a-chip technology. The first segment focuses on the mechanical regulation of collective migration, from the development of tools that allow us to elucidate these mechanical forces to the modern understanding of the different biological mechanism at play during collective migration. In the second segment, I cover studies that have examined diffusion of matter into cancer in many in vivo and in vitro platforms. Results from these studies show that there are multiple biological and physical barriers that can passively inhibit the diffusion of small molecules into tissue and into cancer cells. Lastly, in the final segment, I cover developments in the organ-on-a-chip field, such as the design and development of many different types of organ-on-a-chip platforms, as well as key studies that demonstrate integration of different organ-on-a-chips.

Collective migration is a key biological process that is involved in wound healing, morphogenesis, and cancer metastasis. In Chapter 2, using a protein-patterned platform, my colleagues and I study the mechanical interactions between two attached cells undergoing collective migration. Our results show that the role of the leading cell alternates between the two cells, as the pair migrates along the direction of the leading cell. We have also observed cooperativity between two cells in which the trailing cell mechanically softens itself to allow the leading cell to pull it along. Together, our observations show the two cells engaging in a mechanical “tug-of-war” where the trailing cell actively adjusts its own mechanical malleability to facilitate subtle movements of the cell pair.

Diffusion plays a key role in the transport of molecular agents into non-vascularized tumors. Past methods studying this have generalized the diffusivity within tumors by assuming its constant spatially in the tumor. However, recent studies have shown that microenvironmental factors, such as extracellular matrix rigidity, can play a role in affecting growth and packing within tumors, which we hypothesize can affect the spatial variation of diffusivity in the tumor. In chapter 3, I utilized a cancer-on-a-chip device as a platform to quantify the spatial variations in the diffusivity of a spheroid encapsulated within gelatin methacrylate hydrogels of different rigidities. Our results show that substrates of different rigidities can impact the diffusion of small molecules in the deepest regions of cancer spheroids, which may affect the efficacy of drugs administered.

Chapter 4 describes integrating the simplified cancer-on-a-chip device into an integrated system comprising cancerous, muscle, heart and liver tissues. Such platforms can be used to understand tissue-tissue or even organ-organ cross talk. They can also be used measure off-target side effects of anti-cancer agents on humans, thereby allowing us to bypass animal models to obtain more clinically relevant drug efficacy results. Here we show that we can build different organs in different devices, and then integrate them in a modular manner while sustaining viability in them for short periods of time. Our results also demonstrate the continual functionality of these organs through this time.

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