Platform with Cell Guidance, Switches, and Confined Microwells to Control Natural Killer Cell Cytotoxicity

Description

It is important to understand and control the movement and interactions of cells sincethey influence various biological processes, including the formation of cancers. Thisknowledge is critical for the development of interventions to promote wound healing,appropriate inflammatory responses, and to prevent tumour invasion or metastasis.Establishing a platform that mimics a key biological microenvironment would provideprofound insights into controlling cellular interactions such as cell spreading, cell motility,migration directionality, and selective screening. While previous studies have controlled cellmigration using external force, biochemical, or biomarker labeling, as outlined in thisproposal, we will develop a label free technology that has minimal damage or changes on thebiological functionalities of the cells. In this nanofabricated platform, we also provideprecise control in the placement, confinement, and mixing ratio of selected cells, chemicals,and nutrients that can be used to tune the immune cell cytotoxicity against cancer cells.Natural killer (NK) cells are one of the important immune cell lines against tumours.NK cells can attack cancer cells by releasing chemokines to increase the immune response orby cytotoxic contact with the targeted cancer cells. NK cell mediated therapy shows diverseeffects on different tumour tissues, which indicates that NK cell activities can be tuned by itssurrounding microenvironment. But little is known about the elements that control the NKcell cytotoxicity. To gain a better understanding of interaction dynamics between NK cellsand cancer cells, we propose to design and develop a nanofabricated platform that canprovide precise control of cell density, cell type, cell guidance and switching, as well as therelease of nutrients, chemokines, and drugs in the tunable microenvironment. This will be thefirst demonstration of such biosystem with injection ports, cell guidance topography,microchannels, and microwells, which has the capability to allow dynamic tuning of the NKcell cytotoxicity. A platform of such unprecedented control elements will provide significantperceptiveness into the NK and cancer cell interactions, ultimately providing the basis fordeveloping effective cancer therapy.Our objectives include the following: (1) design and develop a cell guidance platformwith cell switches to precisely position NK and cancer cells; (2) screen and sort cells basedon designed topography to selectively guide different types of cancer cells to desiredlocations; (3) measure cell traction force on substrates with guidance patterns usingmicropost arrays to formulate design rules for cell guidance topography; (4) integratemicrowells with connecting microchannels in platform to study influence of adjacentmicrowells and chemical diffusion on target cell lysis; and (5) tune NK cell cytotoxicity inconfined microwells with adjustable cell density, mixing ratio, and migration path to analyzethe dynamics of NK and MCF7 cell interactions.The proposed integrated platform provides the high precision control of cell migrationand cell switching using designed topography for cell guidance and screening. The guidancepatterns will be developed based on mapping the cellular force distribution during migration,as measured using a micropost array. This biosystem provides a controlled microenvironmentto dynamically tune the interactions between NK cells and target cells by adjusting the celldensity, mixing ratio, microwell confinement, and microchannel connection. The results willprovide momentous insights into the dynamics of immune cell interactions with cancer cells,which will enable tuning of NK cell cytotoxicity to selected target cells. The long-termimpact of this project will be profound since the control of cell migration and screening, aswell as the understanding of the NK and cancer cell interactions, could lead to rapid andefficient diagnosis, prevention, and treatment of cancer related illnesses.