The mechanical stiffness of human cells can be a key parameter that reveals the disease state of the cell, for example, in various cancers and in malaria. However, for stiffness to be utilized in diagnostic settings, we will require methods for continuous monitoring of the stiffness of cells in high throughput. Although separation by other parameters, such as size or density, is commonly employed, methods are not currently available for separation by stiffness. The main goal of the proposed studies is to develop a microfluidic device capable of continuous separation and sorting of microscale elastic particles, synthetic microcapsules, and biological cells by their mechanical compliance. We will combine computational modeling and experimental studies to probe the movement of microscale compliant objects in microchannels with periodical constrictions and examine how the dynamical interplay between elastic deformation due to viscous flow and the channel geometry can be harnessed to provoke cell segregation. Our preliminary three dimensional computer simulations reveal that cells with dissimilar stiffness initially having identical lateral positions disperse to distinct lateral locations in a microchannel with diagonal constrictions and, in this way, can be effectively separated by their compliance. In the proposed studies, we will first develop a comprehensive computational model of elastic capsules and cells in a microfluidic environment. Our fluid structure interaction computational approach will capture the dynamic interactions among an elastic shell representing compliant capsules, complex geometry of microchannel, encapsulated fluid, and host solution. We will employ our numerical model to gain insight into the physics of compliant colloidal particles propelled through well defined solid constrictions and establish guidelines for designing robust and efficient microfluidic sorters with diagonal constrictions. We will formulate the optimal range of system parameters leading to the most efficient separation. These results will then guide our experimental studies. We will begin our experimental efforts by synthesizing well-defined capsules made from layer by layer deposition. The mechanical compliance can be reliably controlled by including additional layers to the wall of the capsule, with a negligible increase in particle diameter. We will assess particle stiffness with mechanics measurements based upon atomic force microscopy. We will implement the proposed microchannel design into an experimental microfluidic system composed of a rectangular poly (dimethylsiloxane) channel containing a pressure driven liquid flow. The top and bottom surface of the channel display skewed ridges with a defined vertical gap. We will employ the experimental setup to verify the predictions of our theoretical model and further examine the dynamics of microscopic particles in confined fluidic channels by tracking their trajectories. In our experiments, we will collect data on the effect of particle stiffness and channel geometry upon the particle movement, which is critical for designing robust sorters and establishing the accuracy of the proposed method.
Intellectual Merit: The proposed synergetic approach will enhance our basic knowledge on the dynamic interactions between compliant particles and microfluidic flows in constrained geometries and the role that elasticity plays in the complex particulate flows. The results of proposed studies could potentially transform our knowledge on the effect of elasticity in biological systems, including flows in blood vessels and the contribution of cell elasticity to development of various diseases. It will also yield useful computational and experimental tools for examining dynamic processes involving compliant particles and viscous flows.
Broader Impact: The results of our studies will establish the much needed guidelines for designing novel microfluidic devices for continuously analyzing and sorting of biological cells and synthetic microcapsules. Such microfluidic sorters could prove extremely valuable for rapid and inexpensive diagnostics of a large number of pathologies affecting the biomechanical properties of biological cells that could potentially save numerous human lives. In terms of educational outreach, the PI's will participate in CEISMC program to host a science teacher from the Atlanta Public School system. The teacher will recruit 2-3 high school students from underrepresented groups to work on site on a project in the framework of the proposed studies. The high-school students will then present their research results at the state science fair and the national Siemens science competition.
We have created a microfluidic device capable of continuous separation and sorting of microscale elastic particles, synthetic microcapsules, and biological cells by their mechanical compliance. We combined computational modeling and experimental studies to probe the movement of microscale compliant objects in microchannels with periodical constrictions and examine how the dynamical interplay between elastic deformation due to viscous flow and the channel geometry can be harnessed to provoke cell segregation. Our preliminary three-dimensional computer simulations reveal that cells with dissimilar stiffness initially having identical lateral positions disperse to distinct lateral locations in a microchannel with diagonal constrictions and, in this way, can be effectively separated by their compliance. We have experimentally demonstrated that stiff cells can be separated from soft cells, though they are identifical in other ways (size, stickiness, etc.). We have experimentally separated diseased cancer cells from blood cells, opening up the possibility of improved medical diagnostics. We are currently continuing the research to improve the separation of diseased cells from healthy cells. We have published 2 papers so far on this research and have trained 2 graduate students and 6 undergraduate students. These undergraduate students have gone on to further research training at a variety of institutions. We have also hosted 4 high school students from local high schools.
