Magnetophoretic circuits for digital control of single particles and cells

Abstract

The ability to manipulate small fluid droplets, colloidal particles and single cells with the precision and parallelization of modern-day computer hardware has profound applications for biochemical detection, gene sequencing, chemical synthesis and highly parallel analysis of single cells. Drawing inspiration from general circuit theory and magnetic bubble technology, here we demonstrate a class of integrated circuits for executing sequential and parallel, timed operations on an ensemble of single particles and cells. The integrated circuits are constructed from lithographically defined, overlaid patterns of magnetic film and current lines. The magnetic patterns passively control particles similar to electrical conductors, diodes and capacitors. The current lines actively switch particles between different tracks similar to gated electrical transistors. When combined into arrays and driven by a rotating magnetic field clock, these integrated circuits have general multiplexing properties and enable the precise control of magnetizable objects. O ne of the main goals of lab-on-a-chip research is to develop generic platforms for manipulating small fluid droplets, colloidal particles and single cells with the flexibility, scalability and automation of modern-day computer circuits. Single-cell arrays represent one high impact application of lab-on-a-chip tools, which are increasingly being adopted to evaluate rare biological responses in small-cell subsets that are overlooked by the ensemble averaging approaches of traditional biology. Improved understanding of these rare cellular responses can profoundly impact the development of vaccines and pharmaceuticals for curing infectious diseases and cancer 1,2 ; however there are few existing techniques with the scale and flexibility to unmask single-cell heterogeneity and pave the way for new medical breakthroughs 3-7 .In particular, there is an urgent need for tools to organize large arrays of single cells and single-cell pairs, evaluate the temporal responses of individual cell and cell-pair interactions over long durations, and retrieve specific cells from the array for follow-on analyses. The desired capabilities of single-cell arrays bear strong resemblance to random access memory (RAM) computer chips, including the ability to introduce and retrieve single cells from precise locations of the chip (writing data), and query the biological state of specified cells at future time points (reading data). Existing particle handling tools based on hydrodynamic 8-11 , optic 12-18 , electric [19][20][21][22] and magnetic [23][24][25][26][27][28][29][30][31][32][33][34][35][36] trapping forces can achieve parts of this desired functionality; however, no single technique to our knowledge encompasses the scalability, flexibility and automation that allows single-cell chips to perform with the level of integration of computer circuits.Our approach has significant similarities with magnetic bubble memory technology 37 , which was originally developed to store memory and implement lo...

Micromagnet arrays for on-chip focusing, switching, and separation of superparamagnetic beads and single cells

“…This experiment demonstrated the transport of individual cells from one area of the chip to another by simply adjusting the orientation of rotation of the external magnetic field for a pre-programmed magnetisation angle on the MMA. This feature may be incorporated in more complex networks of micromagnets to direct magnetically-labelled cells to specific regions of the chip, for subsequent biochemical analysis, and may be integrated with recently reported trapping stations 23 to create functional biosensors.…”

“…The combination of MMA and rotating fields has been used for on-chip cell manipulation. [22][23][24] Using engineered microstructures, the controlled transport, assembly, and isolation of both labelled and non-labelled cells have been recently demonstrated.…”

Single Cell Manipulation Technology

“…In order to instead of permanent magnets and ease to control the particles, an electromagnet was assembled to generate a constant magnetic gradient for DNA manipulation by Haber [56]. After that, based on the general circuit theory and magnetic bubble technology, Lim demonstrated that a class of integrated circuits for executing sequential and parallel timed operations on an ensemble of single particles and cells [57]. In single cell manipulation field, Liu reported a simple and straightforward approach to fabricate magnetic nanofiber segments for cell manipulation.…”

Concentric manipulation and monitoring of protein-loaded superparamagnetic cargo using magnetophoretic spider web

“…26 The sense of the field rotation was adjusted by applying a phase difference of ± 90°between the orthogonal coils with field magnitudes ranging from 0 to 15.9 kA m − 1 . The motion of the superparamagnetic particles on the pattern was tracked via video microscopy using an IMC-1040FT camera (IMI Tech, Anyang, South Korea) connected to a computer.…”

“…Thus, the magnetic particle trajectory can be precisely controlled by shifting the energy minima across the substrate. [26][27][28] Similarly, the lateral asymmetry pathway causes lateral differences in the field distribution, where particles move through ellipses and continuous edges of sawtooth, 29,30 and magnetic conductor patterns, 21,[31][32][33] directionally controlled by the rotating field directions. Although the massive linear transportation of biofunctionalized particles was achieved by parallel pathways in our previous report, 26 there has yet to be more precise transport of particles to a concentric point, and also there is still no magnetic architecture available for controlling low-density biocarriers as well as overcoming the low diffusion transport of biomolecules toward the sensing region.…”