ERI: Investigating How Tissue Stiffness and Fluid Flow Coordinate to Regulate Lymphatic Capillary Growth and Function

Worcester Polytechnic Institute, Worcester MA

Investigators

Abstract

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). This Engineering Research Initiation (ERI) award will advance fundamental knowledge about lymphatic vessels. The results will positively impact future strategies for addressing lymphatic disorders. Lymphatic vessels drain fluid from tissues and transport immune cells throughout the body. When vessels are compromised, consequences include fluid buildup in tissues, weakened immune function, and/or disease progression. There are limited effective treatments. This is in part because the response of these vessels to changes in the surrounding tissues is incompletely understood. Plenty of information is known about how fluid flow affects vessel growth and function. However, less is known about how tissue stiffness plays a role. This is surprising because changes in stiffness occur in many disorders. This work will study the combined effects of fluid flow and tissue stiffness on vessel growth and function. Experimental models will be used to study variable stiffness and controlled fluid flow, and their combination, to reveal how lymphatic vessel behavior is regulated. Results from this work will enhance the ability to make informed decisions about studying lymphatic disorders and developing treatment strategies. The project approach combines multiple aspects of engineering and biology. It will provide opportunities for advanced training and workforce development across disciplines. Research training and mentorship will also broaden participation of underrepresented groups in research and engage an even broader population through community and educational outreach. Despite extensive research on lymphatics and fluid-induced biomechanical forces, lymphatic mechanobiology as it relates to tissue stiffness is not well understood. There is an overall gap in knowledge around how extracellular matrix stiffness in tissues factors into lymph vessel regulation. This gap is significant since matrix remodeling and progressive tissue stiffening are critical to normal and disease processes, and many lymphatic disorders lack curative treatments. The objective is to combine a microfluidic chip with a responsive biomaterial to systematically apply fluid flow, pressure, and progressive extracellular matrix stiffening to lymphatic endothelial cells. The project will use progressive matrix stiffening to establish a role for changing tissue stiffness in regulating mechanosensors in lymph capillaries. The research team will then apply a combination of mechanical inputs—fluid flow, pressure, and stiffness—to link their interactions with specific mechanosensing targets and functional outcomes. Results will identify mechanosensory complexes that are regulated by coordinated mechanical inputs and expand perspectives on what drives lymph capillary regulation and dysregulation. The knowledge gained will advance an understudied area of lymphatic mechanobiology and enhance the ability to make informed decisions about how lymphatic disorders are studied and treated. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.