Cell receptor and surface ligand density effects on dynamic states of adhering circulating tumor cells

Abstract

Dynamic states of cancer cells moving under shear flow in an antibody-functionalized microchannel are investigated experimentally and theoretically. The cell motion is analyzed with the aid of a simplified physical model featuring a receptor-coated rigid sphere moving above a solid surface with immobilized ligands. The motion of the sphere is described by the Langevin equation accounting for the hydrodynamic loadings, gravitational force, receptor-ligand bindings, and thermal fluctuations; the receptor-ligand bonds are modeled as linear springs. Depending on the applied shear flow rate, three dynamic states of cell motion have been identified: (i) free motion, (ii) rolling adhesion, and (iii) firm adhesion. Of particular interest is the fraction of captured circulating tumor cells, defined as the capture ratio, via specific receptor-ligand bonds. The cell capture ratio decreases with increasing shear flow rate with a characteristic rate. Based on both experimental and theoretical results, the characteristic flow rate increases monotonically with increasing either cell-receptor or surface-ligand density within certain ranges. Utilizing it as a scaling parameter, flow-rate dependent capture ratios for various cell-surface combinations collapse onto a single curve described by an exponential formula.

A microfluidic method for the selection of undifferentiated human embryonic stem cells and in situ analysis

“…Running collected cells through a second or multiple rounds of devices should be a straightforward method to improved capture efficiency. Control of the presentation of antibodies, such as their orientation, the amount of surface coverage, or selection of antibodies with greater affinity, can promote cell-antibody interactions and cell rolling Zheng et al 2011), ultimately leading to increased cell capture (Myung et al 2010). While we do partially control antibody orientation via Protein G, including some of the aforementioned modifications (e.g., flow control to induce mixing/increase cell-antibody interaction or increasing effective surface area with microposts) should boost the capture efficiency of our device.…”

Isolation of viable cancer cells in antibody-functionalized microfluidic devices

“…The characteristic shear rate was reported to increase with either increasing surface-ligand or cell-receptor density, 18 and error functions were empirically proposed to describe these functional relationships. 39 Hence, the characteristic shear rate dependency on both cell receptor and surface ligand densities can be described explicitly by a single empirical formula consisting of a product of two error functions given by…”

“…18 The cell motion is modeled as a rigid sphere, with receptors on its surface, moving under shear flow above a solid surface immobilized with counter-receptor ligands. The motion of the sphere can be described by the following Langevin equation: 37…”

“…The number of active bonds, contributing to the resultant adhesion force, depends on both membrane receptor and surface ligand densities. 18 Different functional properties of receptor/ligand combinations give rise to different dynamic states of adhering cells in shear flow; 19 several adhesion modes have been observed: firm adhesion, transient tethering, and rolling at reduced velocities. [20][21][22][23] Microfluidic systems provide a unique opportunity for cell sorting and detection; they have been applied for continuous size-based separation, flow cytometry, and adhesion-based separation.…”

“…33 We reported a characteristic shear rate controlling the fraction of cells captured under applied shear flow. 18 In this work, an empirical formula is proposed to explicitly describe the effect of receptor and ligand densities on the number of captured cells. The detection limit of rare target cells is explored, and the viability of captured cells is tested by culturing released cells.…”