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Date of Award

2025

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering (PhD)

Administrative Home Department

Department of Chemical Engineering

Advisor 1

Caryn L. Heldt

Committee Member 1

Michael E. Mullins

Committee Member 2

Lei Pan

Committee Member 3

Loredana Valenzano-Slough

Abstract

Millions of lives and significant productivity are lost globally each year to vaccine-preventable illnesses. For example, seasonal influenza alone causes millions of cases and tens of thousands of deaths annually in the United States. While vaccines offer effective protection, manufacturing deficiencies, particularly in adapting downstream purification to continuous processing, limit their impact. Traditional methods like ultracentrifugation and chromatography struggle with continuous operation and often yield less than 30% for viral particles. Aqueous two-phase systems (ATPS) present a promising solution: they adapt naturally to continuous processing, achieve high yields and purity, and can reduce capital and operating costs by an order of magnitude compared to chromatography-based processes.

Despite their potential, two barriers prevent the industrial adoption of ATPS: unpredictable separations and poor understanding of scale-up. This dissertation addresses both challenges. First, a comprehensive literature review of current experimental, statistical, and mechanistic approaches to optimizing biomolecule separations in aqueous two-phase systems is presented. This review emphasizes the need to replace the existing norm of iterative optimization with more universal predictive models and highlights artificial neural networks and molecular dynamics as key drivers of this transition. Importantly, the discussion closes by considering how predictive models, once developed, may be leveraged by flowcharts to optimize separations with minimal experiments. Second, to facilitate ATPS scale-up for continuous manufacturing, a microfluidic method is developed to inform a two-resistance mass transport model. Predicting the mass flux of products and contaminants across the ATPS interface will inform the design of mixer-settler or column contactor systems to maximize recovery and minimize processing time. Finally, a study of protein and virus aggregation in ATPS used for viral separations connects these two investigations, exploring how aggregation and non-equilibrium behavior contributes both to separations and mass transfer. Collectively, this work bridges critical gaps, moving ATPS closer to industrial implementation and ultimately aiming to reduce costs and enable the production of better, more effective vaccines.

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