Dynamic Tracking and Modification of Cell Forces during Guided Migration

Description

Cell traction force is fundamental to many cellular processes, including cell migration,proliferation, and differentiation. The localized cellular force acts on the extracellular matrix(ECM) through focal adhesions (FAs). It has been shown that cells can sense physicalsurrounding, such as rigidity and surface topography. Based on their surroundings, cellsexpress different biochemical proteins that can influence cell migration. However, there aretwo aspects of this process with limited knowledge which still need to be investigated. Ascellular force during migration is evolved dynamically in a cyclic manner from the leading tothe trailing regions of cells, it is important to track the real-time development of cellular forcein order to have a better understanding of the cell-ECM interactions and differentiate criticalcell migration steps. Furthermore, the ECM provides migrating cells with three dimensional(3D) physical complexities ranging from micro- to nanometer. In order to understand factorsthat affect cellular force during cell migration, it is essential to create a 3D microenvironmentwith physical properties that resemble realistic tissue. Hence the dynamic tracking of thelocalized cellular force with microsensors in a 3D platform is essential to gain insight in cellbehaviors.Aside from physical clues of ECM, the presence of external force also changes thecellular behavior and biological processes as well. Therefore, cell migration and cellularfunctions can be manipulated by applying external force at the localized cellular area.However, there are some challenges in external force stimulation. As the cellularmechanosensing system is able to resolve the physical deviation in nanometer range, it isimportant to develop the ability to actuate the external force with high spatial resolution. Bypatterning the microposts that could serve as both the force sensor and actuator, it is possibleto control the cell behavior and its migration path.The proposed 3D platform with cellular force microsensors for guided cell migrationprovides a number of advantages and unique capabilities including: 1) The nanotechnologydeveloped for stacking the 3D platform with high aspect ratio microsensors allows flexibledesigns with precise control in dimensions and layouts to mimic a realistic ECM. It will bethe first demonstration of tracking cellular force in real time for cell migration across 3Dvertical planes over multiple levels; 2) Cell confinement and guiding topography will beintegrated in the 3D platform. The cell traction force measurements can be performed in aconfined microenvironment that better resembles how cells move in tissue; 3) Thenanostructures patterned on top of the microposts allow the localized surface energy andeffective cell contact area to be regulated. This feature is a new approach to control the cellmigration path by selectively patterning the microposts with and without the nanostructures;4) The proposed platform will be the first demonstration of magnetically actuatedmicroposts to exert external, localized force on cells, while at the same time measuring thecell traction force distribution as that force is applied; and 5) This 3D cell migration platformwith microsensors and microactuators to apply localized control in guiding topography, cellconfinement, surface energy, and external force will provide significant insights into cell-ECM interactions and cell migration dynamics.We propose to develop a 3D cell migration platform with microsensors andmicroactuators to apply localized control in guiding topography, cell confinement, surfaceenergy, and external force. Dynamic changes in the cellular force distribution will be trackedby real time confocal imaging. The results will provide momentous insights into the dynamicsof cell migration and a better understanding of the cell-ECM interactions. The long-termimpact of this project will be profound since this project will lead to the development of amicrosystem for controlling cell migration path and cell screening, which will be essential forfast and accurate diagnosis, prevention, and treatment of various diseases.