(6er) Leveraging Soft Matter Flows across Length Scales to Improve Human Health

Across length scales, the flow of soft biological matter – within the human body or in biomanufacturing — has a profound effect on our health. To address grand challenges in disease diagnosis and drug development, my goal is to establish a leading research program that develops accurate predictive models describing nonlinear rheology, flow, interfacial interactions, and effects of hydrodynamic stresses on biomolecules.

Research Background and Expertise: My research training is in the areas of experimental fluid mechanics, rheology, and soft matter biophysics. My doctoral research at Rensselaer Polytechnic Institute (RPI), working with Prof. Amir Hirsa, focused on investigating interfacial shear rheology and coupled flow of biomolecular phospholipid films involved in human respiration. With experiments and mathematical modeling, I developed a predictive model to describe the flow of these films across the respiratory system during breathing and high-shear events like coughing. This new theoretical framework can be generalized to other 2-D soft matter systems that are confined to similar hydrodynamic environments. My graduate research led to the development and successful implementation of an experimental platform called the Ring-Sheared Drop (RSD) to study biophysics aboard the International Space Station.

As a postdoctoral researcher, I am collaborating with NASA to study flow-induced protein aggregation at hydrophobic interfaces -- the dominant mechanism in the pathology of neurodegenerative diseases -- both on Earth and in microgravity. Performing experiments in microgravity using the RSD allows for fluid containment by surface tension while amplifying the effects of air/liquid interfaces and flow. I have had the unique experience of conducting proof-of-concept experiments in simulated microgravity (parabolic flights).

Future Directions: Moving forward, I envision two thrusts in my research program:

Disease diagnosis in physiological flows: At the microscale, my focus will be to discover the fundamental role of hydrodynamics and rheology in the cause and progression of aging-related diseases such as dementia, Alzheimer's, and Parkinson's, which are leading causes of death today. The pathology of these debilitating maladies is often marked by the presence of soft biomaterial aggregates called amyloids that devastate the brain and the nervous system. The formation of such structures has been investigated primarily under quiescent conditions by changing their chemical and thermal environments. However, the important role of fluid flow has received little attention.

Combining my expertise in microscopy, flow visualization, and microrheology with a cadre of bioanalytical tools and microfluidics, my group will devise experiments and computations that mimic the flow of bodily fluids in tortuous environments like the brain. The goal will be to develop predictive models that relate effects of shear and extensional flows encountered in vivo to the rate, structure, and propensity of protein aggregate/amyloid formation in the body. Such studies will help explore why the popular amyloid hypothesis has proven insufficient to develop a potent cure for Alzheimer's and test alternative diagnoses. I foresee a strong collaboration with research groups that model protein misfolding, polymer rheology and clinical researchers in neuroscience. In the long term, the predictive models and technology developed will serve as a testing platform to aid drug development.

Biomolecular stability in manufacturing flows: At the macroscale, my focus will be to understand the stability of protein-based therapeutics like monoclonal antibodies (mABS) in pharmaceutical manufacturing flows and under post-manufacturing stresses. mABS are the fastest growing class of drugs and are expected to be the dominant modality to treat diseases in the coming decades. However, the complex architecture of these molecules confers a propensity to aggregate when subject to fluid flow. The presence of aggregates can significantly affect drug potency and often elicit adverse reactions during administration. Beginning with protein expression using cell cultures in bioreactors to the final filling in vials and administered syringes, these therapeutic biomolecules in solution are subject to a variety of hydrodynamic flows. Moreover, the molecules experience these hydrodynamic stresses at air/liquid and solid/liquid interfaces that contribute additional mechanisms for de-stabilization.

My goal in this thrust will be to devise experiments in tractable flow geometries that mimic the typical manufacturing processes and deconvolve the effects of flow and interfaces. The bulk rheology, interfacial rheology, and aggregation mechanisms will be investigated by combining experiments and flow computations with protein-specific in-situ fluorescence, light scattering and spectrophotometric tools. The proposed integrated approach will help develop state-of-the-art scale-down predictive models rooted in fundamental scientific principles that isolate the contributions of the myriad destabilizing forces. Adopting such physics-based scale-down models in lieu of ad hoc empirical models and makeshift solutions currently employed will improve manufacturing efficiency and reduce wastage, ultimately lowering the cost of bio-therapeutics. The pharmaceutical industry and consortiums like the National Institute of Innovation in Biopharmaceuticals (NIIMBL) will be significant partners and benefactors in this proposed endeavor.

Grants and Proposal Writing Experience:

• Conceived experiments to support science goals in microgravity and co-authored proposals to NASA (successful) and NSF-CASIS (under review) submitted by PI leading to $1,000,000+ in research funding
• Collaborated with pharmaceutical industry partners and developed short-term individual research contracts and proposals to NIIMBL (under review) as co-investigator

Teaching Interests:

My goal as a faculty member is to teach and inspire the next generation of problem solvers. I’m a strong proponent of experiential learning and aim to equip students with a deep physical intuition of the subject matter. I have served as Teaching Assistant in many Thermal-Fluid science classes and lab courses at RPI. In addition to guest lectures, I have prepared and graded exams, in-class and homework assignments. I've also conducted recitation sessions and lab demonstrations.

I am prepared to teach a variety of core 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 and Rheology of Complex Fluids. An integral part of the developed courses will be the integration of Microscopy, Flow Visualization, and Scattering techniques developed in my research program.

Mentorship and Outreach: In addition to teaching, I have mentored a number of graduate, undergraduate, and high school students from different engineering backgrounds, many of whom are co-authors on my research papers. My major K-12 outreach initiatives as a faculty member will be to develop/support a strong partnership with local high schools and establish regular workshops and lab-demonstrations to foster interest in STEM/STEAM fields.

As a faculty member, I will consistently strive to build a research group that is highly inclusive and brings together students from diverse cultures and socioeconomic backgrounds. It is my strong conviction that diversity can nurture creative solutions to grand challenges that confront us in the 21st century.

Selected Publications:

Raghunandan, A., Hirsa, A. H., Underhill, P. T., & Lopez, J. M. (2018). Predicting shear rheology of condensed-phase monomolecular films at the air-water interface. Physical Review Letters.

Rasheed, F.*, Raghunandan, A.*, Hirsa, A. H., & Lopez, J. M. (2017). Oscillatory shear rheology measurements and Newtonian modeling of insoluble monolayers. Physical Review Fluids.*Equal contribution

Gulati, S., Raghunandan, A., Rasheed, F., McBride, S. A., & Hirsa, A. H. (2017). Ring-Sheared Drop (RSD): microgravity module for containerless flow studies. Microgravity Science and Technology

Raghunandan, A., Lopez, J. M., & Hirsa, A. H. (2015). Bulk flow driven by a viscous monolayer. Journal of Fluid Mechanics.

Raghunandan, A., Middlestead, H.R., Riley, F., Lopez, J. M., & Hirsa, A. H. (2019). Flow-directed assembly of macroscale amyloid networks (in prep)

Debono, N.E., Raghunandan, A. , Middlestead, H.R., Lopez, J. M., & Hirsa, A. H. (2019). Kinetics of amyloid fibril formation in microgravity (in prep)