Date of Award

Fall 12-2021

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor

Scott D. Collins

Second Committee Member

Rosemary L.Smith

Third Committee Member

Gregory A. Cox

Additional Committee Members

Paul J. Millard

Carl P. Tripp

Abstract

Cellular microenvironment or cell niche plays an important role in developmental biology and disease pathophysiology. Physical or chemical signals in microenvironment drive the cellular activity. These signaling molecules are generated from the surrounding cells/tissues as part of intercellular communication; a fundamental property of a cell. Dynamic profile of these signaling molecules in the microenvironment plays a pivotal role in transfer of molecular information from cell to cell in disease proliferation or fate determination. Recapitulating these signaling cues in an in vitro study is difficult to achieve using standard cell culture techniques. However microfluidic systems are capable of addressing these issues, due to their ability to precisely control the microenvironment.

The first study focuses on developing a microfluidic system capable of differentiating MNs in a 3D microenvironment (similar to in vivo) and perform a drug assay to identify the therapeutic concentration range. Using this microfluidic device, ALS (amyotrophic lateral sclerosis) motor neurons were differentiated (in 3D) and ideal concentration of rapamycin in rescuing motor neurons from degeneration was identified.

In the second study, a gradient generating coculture system capable of culturing two distinct types of tissues (in 3D) (muscle and motor neurons) in spatially distinct chambers which were interconnected by microchannels for intercellular communications (chemical signal and axon transport) was designed and fabricated. This microfluidic device offers us an ability to understand and evaluate the effects of coculturing muscle cells with motor neurons in defining the motor neuron columnar identity.

Thus, the current microdevice will be a useful platform not only in understanding the developmental processes but also to study and model rare degenerative diseases. Due to its ability to create a concentration gradient, this device can also be a unique platform for scientists to perform a high throughput screening for drug activity and drug toxicity using patient specific cells.

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