MULTIPHASE NON-NEWTONIAN MICROFLUIDICS FOR DEVELOPMENT OF BIOMEDICAL DEVICES, THERAPEUTIC SYSTEMS AND NANOSEPARATION

Abstract

The use of non-Newtonian microfluidic systems, encompassing Herschel-Bulkley (H-B) and shear-thinning fluids (hydrogels), has recently gained attention for their potential in biomedical devices, therapeutic systems, research, and industrial applications. These systems exhibit unique non-Newtonian responses to shear stress, resulting in beneficial characteristics such as injectability, deformability, self-healing, and controllable degradation. Their applications in critical biomedical fields, including nanomedicine, drug delivery, tissue engineering, and 3D bioprinting, have been explored. However, the fluid dynamics and non-Newtonian behavior of these single-phase or multiphase (Eulerian-Eulerian and Eulerian-Lagrangian) microfluidic systems remain poorly understood and require further improvement and optimization to enable efficient and high-throughput clinical and industrial applications. In this dissertation, we focused on the extrudability and injectability of non-Newtonian Herschel-Bulkley hydrogels, which make them ideal materials for microfluidic systems, such as in-vivo/clinical injections and 3D printing. The existing approaches for selecting and tuning these hydrogels for specific end-use applications, as well as their synthesis for targeted functions, often involve time-consuming and ineffective trial and error methods. Furthermore, encapsulated cells, drugs, therapeutics, and proteins within these hydrogels may experience detrimental shear stress when injected via high gauge syringes and 3D printer nozzles with very small diameters. Designing H-B hydrogel injection systems to ensure needed cell and drug viability and protein functionality is currently approached through trial and error. To address these challenges, we first demonstrated the limitations of simplifying the behavior of Herschel-Bulkley hydrogels by neglecting yield stress and treating them solely as shear-thinning fluids for modeling purposes. We then developed an analytical model for the efficient design of hydrogel injectability, enabling the prediction of encapsulated cell and drug viability and injected protein functionality. Additionally, we introduced model-based Ashby-style plots for the design and selection of Herschel-Bulkley hydrogels. By integrating Ashby-style plots with a comprehensive understanding of the factors influencing injectability, our research provided a valuable framework for informed decision-making, streamlining the selection, tuning, and design process of Herschel-Bulkley hydrogels. Expanding on our achievements in modeling the single-phase fluid dynamics of Herschel-Bulkley hydrogels, we further investigated the multiphase flow of these fluids within flow focusing droplet generators. Although non-Newtonian hydrogel droplets have gained significant attention in various applications, the multiphase flow of Herschel-Bulkley droplets in flow focusing devices remains poorly understood. Our research successfully developed a 3D Computational Fluid Dynamics (CFD) model for non-Newtonian Eulerian-Eulerian multiphase flow in flow focusing droplet generators. This model provided valuable insights into the behavior and regimes of Herschel-Bulkley droplet generation and shape deformation, introducing novel parameters to quantify complex interfacial multiphase phenomena for the fabrication of spherical microgels. We introduced a conceptual framework to understand the interaction of Herschel-Bulkley droplets and their surrounding continuous phase by analyzing their relative motion. We identified and characterized two distinct regions: the Herschel-Bulkley multiphase layer (the fluidized zone) surrounding the droplet and the gel/solid-like core within the droplet itself. The conceptualization of the H-B multiphase layer is of significant importance as it provides insights into the dynamics of the H-B droplet and its immediate vicinity. This region, characterized by the fluidized zone, represents the area where the continuous phase interacts with the droplet surface, and the shear stress propagates into the hydrogel droplet. The presence of the H-B multiphase layer can influence the flow patterns and mass transfer processes occurring at the droplet interface. Understanding the behavior of this layer is crucial for various applications, such as emulsion stability and H-B droplet coalescence. Lastly, we explored the application of non-Newtonian multiphase flow as Lagrangian-Eulerian systems for separating and concentrating nano-scale particles, which holds promise for therapeutic and biomedical applications. We proposed an innovative microfluidic system leveraging the combined effects of shear-thinning behavior and Dean flow to overcome the limitations of current methods operating at very low flow rates of uL/hr. Our novel approach enabled significantly higher sample processing flow rates on the order of mL/min. By developing a 3D non-Newtonian Computational Fluid Dynamics (CFD) model of shear-thinning-assisted nanoparticle manipulation in Dean flow, we accurately captured the complex fluid dynamics governing the separation and concentration of nanoparticles. We also introduced normalized parameters to categorize nanoparticle manipulation as separation, concentration, and focus, offering a systematic framework for evaluating and optimizing nanoparticle manipulation strategies within microchannels. Investigating microchannel geometry, nanoparticle size, and non-Newtonian rheological behavior provided valuable insights into the dynamics of nanoparticle separation and concentration, contributing to the advancement of nanoparticle manipulation techniques within microfluidic systems. Overall, this dissertation significantly contributes to the field of non-Newtonian multiphase microfluidics by addressing critical challenges and presenting innovative solutions in the domains of injectable hydrogels, multiphase non-Newtonian CFD, droplet generation, and nanoparticle manipulation. The findings have practical implications for biomedical engineering, therapeutic manufacturing, and nanotechnology, particularly in drug discovery and delivery, 3D bioprinting, and biomedical device design. By expanding the fundamental understanding of non-Newtonian behavior and its applications, this research provides a solid foundation for future investigations and developments in these dynamic fields.