Novel method for investigating structure and rheology of complex fluid interfaces with biotherapeutic applications
Date
2022
Authors
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Publisher
University of Delaware
Abstract
Complex fluid interfaces commonly exist in a broad range of materials, including biological systems, food, and other consumer products, as well as in multiphase fluid systems. Such complex fluid interfaces encompass proteins, polymers, particles, and surfactants that are drawn to fluid-fluid and air-fluid interfaces and often have microstructures that exhibit complex rheological behaviors. A longstanding challenge in interfacial sciences has been to establish relationships between the microstructure and strain-induced, or flow, properties of these interfacial systems. Addressing this challenge is difficult as it requires measuring the interfacial material response that is often inherently coupled with the corresponding bulk systems; furthermore, traditional methods are unable to perform interfacial deformations with pure kinematics (e.g., pure shear and pure dilation/compression). Thus, the overarching goal of this thesis was to investigate complex material functions at the air-liquid interface through the development of a novel, multifunctional instrument capable of controlling interfacial kinematics to measure material responses under well-defined kinematics, both rheological and microstructural. To this end, significant contributions and findings were made in this thesis to address previously unresolved scientific questions surrounding complexities in model, but complex interfacial systems, as well as to pave the way forward with methodologies to overcome challenges existing in current industrial practice. ☐ The Quadrotrough was developed with the unique ability to investigate the rheology and microstructure of complex fluid interfaces by enabling combinations of pure shear strain and dilation/compression that had previously not been possible. This instrument works as a standalone instrument, where the implementation of pure strain deformations consequently allows us to directly measure surface pressure responses that are proportional to rheological properties through constitutive relationships. The combination of the Quadrotrough with structural techniques is a critical step toward understanding the length scale of structural features associated with interfacial deformation and mechanical response. Combination with in situ Brewster angle microscopy provides detailed mesostructural (e.g., micron-scale) in-plane measurements, and the implementation of the Quadrotrough on the neutron reflectometer (Rheo-MAGIK) provides in situ nanostructural, out-of-plane measurements of these complex fluid interfaces. In this thesis, we provide the methodology framework using the Quadrotrough to investigate these process-dependent properties using various deformation protocols that can be performed on the same interfacial system. ☐ Using this Quadrotrough, we clarified previously unresolved material behaviors of a model, insoluble fatty acid interface. Generalized relationships between the structure and rheological material properties are based on the specific surface phases. Measurements of d-stearic acid on pure water demonstrated how isotropic compressions could create trapped stresses that manifest as delayed buckling and as long stress relaxations. For the more complex interface of d-stearic acid on the aqueous aluminum nitrate solution, the trapped stresses upon isotropic compression manifest as metastable structures that can be relaxed by subsequent shearing, which demonstrates sensitivity to deformation history. Additionally, the primary phase transition that demarcates these interfacial properties are identified relative to equilibrium monolayer state, which was not so easily identifiable by traditional surface pressure measurements for the complex, viscoelastic interface. ☐ Another significant contribution provided in this thesis is addressing the complexities associated with interfacial stability of monoclonal antibody (mAbs) therapeutics. While monoclonal antibodies (mAbs) have been used as biotherapeutics to treat numerous human ailments, the molecules are inherently unstable and have a natural tendency to aggregate in solution, impacting drug formulation stability. One source of instability for mAbs occurs at the air-water interface; their propensity to adsorb at this interface stems from their amphiphilic structure. Thus, a robust understanding of mAb and surfactant behavior under competitive adsorption and both dilatational and shear strained-induced effects at air-water interfaces is necessary to evaluate overall interfacial stability and elucidate surface-mediated protein aggregation in solution. In this work, we investigate a well-defined NIST reference mAb with and without surfactant poloxamer 188. Using the unique ability of the Quadrotrough in tandem with structural techniques, we can form robust structure-property relationships of protein-surfactant pairings to pinpoint the interfacial origins of formulation instability and provide guidance in designing stabilized formulations through excipient addition. ☐ The instrument development and findings discussed in this thesis ultimately pave the way forward in establishing generalized relationships between structural and rheological material properties for complex fluid interfaces to advance the overall field of interfacial science.
Description
Keywords
Biotherapeutics, Complex fluid interfaces, Instrument development, Interfacial rheology, Neutron reflectometry