Recent work has demonstrated the pervasive role of mechanics in biology. The most prominent examples include matrix stiffness influencing stem cell lineage and tumor progression, axonal tension regulating presynaptic vesicle clustering, and stiffness gradients guiding migrating cells. Mechanotransduction, the mechanism underlying these cellular responses to mechanical stimuli, has been studied in detail for the past decade and offers a new paradigm for directing the form and function of integrated cellular systems.
Over the past 5 years, we developed various microfluidic platforms for mimicking the three dimensional microenvironment and investigating the role of mechanical stimuli, such as interstitial flow, cyclic strain, and ECM stiffness gradients, on cellular processes including cell migration, angiogenesis, and differentiation.
Recently, we have drawn upon our understanding of mechanobiology to direct the function of multicellular systems. For example, we extended our angiogenesis model to build functional vascular networks in vitro, and we directed stem cell differentiation into cardiomyocytes by applying cyclic strain. As we increase the complexity of synthetic modules toward building biological machines, mechanics will play a more significant role, particularly in the engineering of neurons and myocytes for sensing and actuation. We will employ mechanical engineering as a tool to address this complexity while simultaneously extending our understanding of mechanotransduction.
Investigators: Sebastien Uzel, Vivek Sivathanu, Jordy Whisler.
Formation of new blood vessel from an existing branch, by a regulated process known as angiogenesis, governs vascular patterning in the body and determines the distribution of nutrients and oxygen supply. Angiogenesis has essential roles in development, reproduction and repair but also occurs in tumor formation and in a variety of diseases [1, 2]. Our lab studies the angiogenic process by computational modeling across multiple scales [3, 4] and by in vitro microfluidic experiments that mimics in vivo biophysical and biochemical microenvironment. We showed that angiogenic endothelial cells seeded in contact with collagen gel can be induced to form nascent angiogenic sprouts in microfluidic which later develop into a vascular network [5, 6, 7].
To understand the single cell decisions in angiogenesis at the signaling level, we model individual cell as a decision making entities and follow individual cell as they make decisions in angiogenic conditions . In collaboration with the Lauffenburger lab at MIT, we attempt to elucidate how such single cell decision might be governed by an intracellular signaling by measuring the intracellular changes in signaling activities upon stimulating cells with potent factors that induce and suppress sprout formation .
Investigators: Michelle Chen, Jordy Whisler, Ran Li, Vivek Sivathanu, Anya Burkart
We developed a microfluidic system for investigating the role of interstitial flow in tumor cell migration (Figure 2). Tumor cells exposed to interstitial flow preferentially migrated along streamlines, and the relative percentage of cells migrating upstream and downstream is a function of chemokine receptor activity and cell density.
We applied the known commercially-viable manufacturing methods to a cyclic olefin copolymer (COC) material to fabricate a microfluidic device with controlled surface properties and improved potential to serve high-volume applications. Culture of cells in the new hard plastic device indicated no adverse effects of the COC material. Therefore, this transition of platform demonstrates a capability of using microfludic devices for 3D cell culture across the range from the scientific research to applications with broad clinical impact.
Investigators: Ran Li, Michelle Chen, Emad Moeendarbary, Tohid Pirbodhagi, Alexandra Boussommier-Calleja, Anya Burkart.
Investigators: Michael Mak, Andrea Malandrino.
To understand better the remarkable behavior of filamentous actin, we investigate the mechanochemistry and dynamics of actin regulatory proteins using optical microscopy and force spectroscopy. Specifically, we are interested in learning how these proteins use mechanical signals to regulate the polymerization/de-polymerization of actin filaments at the single-molecule level.
Amyloids are fibrous protein aggregates that are the basis for many diseases such as Alzheimer’s, type 2 diabetes, Parkinsons, Huntington’s, and scrapie, among many others. It has been found however, that there are many instances of functional amyloids that are used by biology for structural purposes, such as the E. coli curli proteins and spider silk; for sensing, such as HET-s from P. anserina; or as part of a system to adapt to new environments, such as the yeast prions, eg: [PSI] (sup35).
A great deal of work has been done to characterize amyloids biochemically, genetically, and biophysically, but there is still quite a lot that is still unknown regarding the mechanisms involved in assembly of amyloid fibers and the structure of the constituent proteins in the amyloid state. We are using applied force via optical tweezers as a probe to better understand the organization of the monomers within the amyloid fibril, and to gain insight into the structure of the monomers within the fiber. The overarching goal of this project is to determine if amyloids have similar mechanical properties, and thus potentially similar organizations of the proteins within amyloid fibers.
Investigators: Ted Feldman, Bill Hesse.