Attractive Design: An Elution Solvent Optimization Platform for Magnetic-Bead-based Fractionation Using Digital Microfluidics and Design of Experiments

Abstract

There is great interest in the development of integrated tools allowing for miniaturized sample processing, including solid phase extraction (SPE). We introduce a new format for microfluidic SPE relying on C18-functionalized magnetic beads that can be manipulated in droplets in a digital microfluidic platform. This format provides the opportunity to tune the amount (and potentially the type) of stationary phase on-the-fly, and allows the removal of beads after the extraction (to enable other operations in same device-space), maintaining device reconfigurability. Using the new method, we employed a design of experiments (DOE) operation to enable automated on-chip optimization of elution solvent composition for reversed phase SPE of a model system. Further, conditions were selected to enable on-chip fractionation of multiple analytes. Finally, the method was demonstrated to be useful for online cleanup of extracts from dried blood spot (DBS) samples. We anticipate this combination of features will prove useful for separating a wide range of analytes, from small molecules to peptides, from complex matrices.

Pre-concentration by liquid intake by paper (P-CLIP): a new technique for large volumes and digital microfluidics

“…20 While surface-binding on magnetic microparticles can be a versatile pre-concentration technique, a disadvantage is the risk of clogging when used with microchannel systems. 21 "Open"-format microfluidic systems such as those powered by digital microfluidics (DMF) eliminate the problem of clogging and have proven particularly useful for handling magnetic micro-particles 22 for the analysis of small molecules, 23,24 proteins, [25][26][27][28][29][30][31] and nucleic acids. 32,33 In the most common DMF device format, discrete droplets of liquid are sandwiched between two plates: the bottom plate comprises an array of electrodes that is covered by an insulating dielectric layer and a hydrophobic layer, and the top plate comprises a ground electrode that is covered with a hydrophobic layer.…”

“…In this two-plate format, droplets cannot be manipulated in the z-axis but are unrestricted by any walls or barriers in the xy-plane. 34 Despite its proven utility in handling magnetic microparticles, [22][23][24][25][26][27][28][29][30][31][32][33] DMF is limited in its ability to effect preconcentrations of significant magnitude. Specifically, the difference between the smallest and largest volumes that can be (practically) manipulated on most DMF devices is often quite smalle.g., in the devices used here, this range runs from ∼0.9 μL (a "unit" droplet covering one electrode) to ∼9 μL (a droplet covering 10 electrodes; volumes larger than this are impractical to use).…”

“…More generally, the new technique should be incorporated in any DMF assay relying on functionalized magnetic microparticles. [22][23][24][25][26][27][28][29][30][31][32][33]…”

Recent advances in magnetic digital microfluidic platforms

“…To overcome this limitation, M. Nelson et al. [108] designed an elution solvent miniplate based on magnetic beads for SPE (see Fig. 7), where magnetic beads (1 μm in diameter) covered with C18 alkyl moieties are used as solid sorbent beds, and a permanent magnet fixed on a 3D stepping motor sliding table is used to mobilize magnetic beads.…”

Single-Layered Microfluidic Network-Based Combinatorial Dilution for Standard Simplex Lattice Design

“…In addition to platforms using pneumatically isolated chambers or continuously flowing microfluidic networks, electrowetting-based digital microfluidic platforms could be well-suited for the creation of on-demand combinatorial mixtures or dilutions [ 31 ]. Recently, Wheeler’s group implemented a full factorial DOE [ 32 ] and a mixture DOE [ 33 ] using discrete droplets of liquid on the surface of an insulated two-dimensional array of electrodes. Although such a digital microfluidic format enables better droplet manipulation for combinatorial chemistry, it still requires an advanced integration of electrowetting-based microfluidics and electronics.…”