(4ac) Leveraging Soft Matter Transport and Biomolecular Interactions to Transform Human Health

Curing Alzheimer's disease or predicting whether the next revolutionary drug molecule can be manufactured relies on unraveling the mechanisms governing the transport and interactions of biomolecules with their surroundings. My Transport and Biomolecular Interactions (TBI) laboratory will use experiments, flow computations, and theory to address such grand challenges in physiological fluid transport, disease diagnostics, and pharmaceutical manufacturing. My research training is in the fields of interfacial sciences, experimental and physiological fluid mechanics, soft matter biophysics, rheology, microfluidics, and mouse models of disease. Building on these foundations, my research group will engineer micro and macroscale systems to study diseases caused by protein aggregation, test new treatments, and develop a biophysics-informed framework to predict the manufacturing success of protein-based drug molecules. My interdisciplinary research group will leverage these insights to create a transformative impact on human health. I envision two thrusts in my research program:

1. Disease diagnosis in physiological systems: At the microscale, my group will focus on the critical roles of physiological fluid transport and protein-cell interactions in devastating diseases caused by protein aggregation, such as Alzheimer's and Cerebral Amyloid Angiopathy. My group will develop microfluidic and tissue-on-a-chip systems that capture the fluid flow and cellular interactions experienced by neurotoxic proteins in the body. We will use such in vitro disease-on-a-chip models to predict how physiological flows and age-related changes in the cellular microenvironment trigger "hot spots" of protein deposition in the brain. Such studies could bring new insight into the mechanisms that cause Alzheimer's disease and related dementias. In the long term, the predictive models and technology developed will also serve as a testing platform for new therapies that restore cellular function.

2. Biomolecular stability in manufacturing systems: At the macroscale, my research group will focus on predicting the aggregation and stability of protein-based therapeutics, such as monoclonal antibodies (mAbs), in pharmaceutical manufacturing processes. Aggregated mAbs can significantly affect drug potency and elicit adverse reactions during administration. My group will engineer scaled-down models of typical pharmaceutical unit operations to discover how fluid and interfacial stresses destabilize mAbs. We will investigate the bulk rheology, interfacial rheology, and aggregation mechanisms of mAbs solutions by combining experiments and flow computations with protein-specific in-situ fluorescence, light scattering, and spectrophotometric tools. My research group will use this integrated approach to develop state-of-the-art predictive mechanistic models that isolate the contributions of the different destabilizing forces. Adopting such biophysics-based models to predict stability, instead of ad-hoc solutions currently employed by the industry, will help reduce wastage and improve manufacturing efficiency, ultimately lowering the cost of bio-therapeutics.

Relevant Publications (out of 10):

• Raghunandan, A., et al. "Cervical lymphatic efflux of cerebrospinal fluid is compromised in aged mice and restored with Prostaglandin-2α" (under review)
• Raghunandan, A., et al. "Bulk flow of cerebrospinal fluid observed in periarterial spaces is not an artifact of injection." eLife 10 (2021): e65958.
• Raghunandan, A., et al. "Predicting steady shear rheology of condensed-phase monomolecular films at the air-water interface." Physical Review Letters 16 (2018): 164502.

Teaching Interests:

My goal as a faculty member is to teach and inspire the next generation of problem solvers. I am a strong proponent of experiential learning and aim to equip students with a deep physical intuition of the subject matter. At the undergraduate level, I am prepared to teach various foundational engineering courses, with a preference for Transport Phenomena and Engineering Laboratory courses. At the more advanced level, I am interested in teaching courses that cover the principles of Soft Matter, Colloids and Interfacial Sciences, Transport in Non-Newtonian Fluids, Rheology of Complex Fluids, and Biological Fluid Mechanics.