INTRODUCTION
Curing Alzheimer's disease (AD) or predicting the commercial viability of the next revolutionary drug molecule hinges on discovering how biomolecules flow and interact with their surroundings. The overarching goal of my research is to discover how fluid flow and interfacial interactions destabilize biomolecules, in the development of diseases in the body and in pharmaceutical drug manufacturing processes.
My expertise is in developing novel experiments that integrate techniques from engineering and biology to study transport phenomena in biological systems. My engineering training has incorporated aspects of experimental fluid mechanics, interfacial sciences, rheology, and microfluidics. I have also been trained in biological techniques from the fields of protein chemistry, cell culture, and neuroscience.
PROJECTS
Brain fluid flow and its role in Alzheimer’s disease and related dementias
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I am working towards deciphering the role of fluid flow in cleansing the brain during sleep and in neurodegeneration. The brain produces a significant amount of metabolic waste, such as proteins, which must be consistently removed to maintain brain health. Cerebrospinal fluid circulating in the brain plays a crucial role in washing away the waste, which can build up, turn toxic, and contribute to diseases like Alzheimer's and related dementias.
Combining advanced in vivo microscopy with traditional particle tracking methods and image processing in live mouse models, I’ve demonstrated that forces driving fluid into the brain arise from the pulsation of the brain’s arteries. I’m currently working towards investigating how these cleansing flows are altered because of aging, Alzheimer’s disease, and other neuropathological conditions. I’m also developing microscale devices that mimic these flows to assess their role in the pathology of diseases that affect the blood vessels in the brain.
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Related Publications:
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Trumbore, C. N. and Raghunandan, A. (2022). An Alzheimer’s Disease Mechanism Based on Early Pathology, Anatomy, Vascular-Induced Flow, and Migration of Maximum Flow Stress Energy Location with Increasing Vascular Disease. Journal of Alzheimer’s Disease, (in press).
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Raghunandan A., Ladron-de-Guevara, A., Tithof, J., Mestre, H., Nedergaard M., Thomas, J.H., Kelley D.H. (2021). Bulk flow of cerebrospinal fluid in periarterial spaces is not an artifact of injection. eLife 10: e65958.
Manuscripts in Preparation:
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Du, T.*, Raghunandan A.*, Luo, G., Mestre, H., Kelley, D.H., Nedergaard, M. (2022). Efflux of cerebrospinal fluid is reduced in aging and restored with Prostaglandin-2α. (in prep.) *Equal contribution
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Raghunandan, A., Chen, K., Kelley, D.H., McGrath, J.L.M. Microvascular Mimetic of perivascular transport and disease (in prep.)
Flow-driven aggregation of proteins
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Protein molecules like insulin adopt a certain structure to perform their function, regulating biophyical processes or binding to a specific target when administered as a drug. Under external forces like fluid flow or interfacial stresses, these molecules are forced to transform, change their structure, and aggregate. But in doing so, they lose their functionality which can lead to diseases in the body or failures during drug manufacturing.
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My graduate research led to the development and successful implementation of an experimental platform called the Ring-Sheared Drop (RSD) to study biophysics of protein aggregation aboard the International Space Station. The zero-gravity environment allows us to amplify and discover how fluid flow drives the aggregation of proteins at the air/water interface. Integrating protein specific bioanalytical technique in experiments on earth, I helped demonstrate that interfacial rheology could be used as a novel non-invasive probe to detect this aggregation. During the course of this project, I also had the unique experience of conducting proof-of-concept experiments in simulated microgravity (parabolic flights) to test the experimental hardware we developed for the space-based experiments.
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Related Publications:
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McMackin, P. M., Griffin, S. R., Riley, F. P., Gulati, S., Debono, N.E., Raghunandan, A., Lopez, J. M., Hirsa, A. H., (2020). Simulated microgravity in the ring-sheared drop. npj Microgravity, 6 (2).
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Balaraj, V. S., Zeng, P. C., Sanford, S. P., McBride, S. A., Raghunandan, A., Lopez, J. M., & Hirsa, A. H. (2017). Surface shear viscosity as a macroscopic probe of amyloid fibril formation at a fluid interface. Soft Matter, 13(9), 1780-1787. (Cover article)
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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, 29(1-2), 81-89.
Fluid dynamics during respiration
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Lung surfactants are essential to life; without them we cannot breathe. Small biomolecular films that line our lungs control and regulate respiration. Such molecules reside on top of the liquid lining in the alveloar sacs, at the air/liquid interface. Not only do they reduce the surface tension of the liquid lining (making it easier to breath), but also display highly variable fluid behaviours which are critical in preventing the lung from collapsing in on itself.
My graduate research focused on investigating this flow behavior of lung surfactant films at interfaces. With experiments and mathematical modeling, I showed that current measurement techniques offer limited understanding of their viscous properties. Using a flow field-based approach to interfacial rheology (as opposed to using commercial devices), I developed a new generalized model that predicts the flow of such interfacial films during breathing and in unexplored high-shear events like coughing, unifying disparate measurements in the literature. This research has direct applications to improving the success of artificial lung surfactant therapy, which is often given to premature infants born without lung surfactants.
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Related Publications:
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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, 121, 164502.
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Rasheed, F., Raghunandan, A., Hirsa, A. H., & Lopez, J. M. (2017). Oscillatory shear rheology measurements and Newtonian modeling of insoluble monolayers. Physical Review Fluids, 2(4), 044002.
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Raghunandan, A., Lopez, J. M., & Hirsa, A. H. (2015). Bulk flow driven by a viscous monolayer. Journal of Fluid Mechanics, 785, 283-300.