Dried Blood Spot Analysis by Digital Microfluidics Coupled to Nanoelectrospray Ionization Mass Spectrometry

Abstract

Dried blood spot (DBS) samples on filter paper are surging in popularity as a sampling and storage vehicle for a wide range of clinical and pharmaceutical applications. For example, a DBS sample is collected from every baby born in the province of Ontario, Canada, for quantification of approximately one hundred analytes that are used to screen for 28 conditions, including succinylacetone (SA), a marker for hepatorenal tyrosinemia. Unfortunately, the conventional methods used to evaluate DBS samples for newborn screening and other applications are tedious and slow, with limited options for automated analysis. In response to this challenge, we have developed a method to couple digital microfluidics (DMF) to nanoelectrospray ionization mass spectrometry (nESI-MS) for SA quantification in DBS samples. The new system is formed by sandwiching a pulled glass capillary emitter between the two DMF substrates such that the capillary emitter is immobilized without external seals or gaskets. Moreover, we introduce a new feedback control system that enables high-fidelity droplet manipulation across DBS samples without manual intervention. The system was validated by application to on-chip extraction, derivatization, and analysis of SA and other analytes from DBS samples, with comparable performance to gold-standard methods. We propose that the new methods described here can potentially contribute to a new generation of analytical techniques for quantifying analytes in DBS samples for a wide range of applications.

A programmable droplet-based microfluidic device applied to multiparameter analysis of single microbes and microbial communities

“…This high level of integration enables device architectures capable of executing thousands of predefined "unit cell" reactions in parallel, with applications ranging from protein structure (4) and interaction studies (7,8) to single-cell analysis and genomics (2,9,10). Two-phase flow systems that manipulate picoliter (pL) volume droplets in closed channels have been shown to be ideally suited to high-speed serial analysis for use in high-throughput screening applications (11) and sample preparation for genomics (12), while the programmable manipulation of nanoliter (nL) volume droplets using electrostatic forces has received increasing attention as a potential platform for sample processing automation in proteomics and medical diagnostics (13).…”

A Low-Cost and High-Resolution Droplet Position Detector for an Intelligent Electrowetting on Dielectric Device

“…There are several studies directed at using an air environment to actuate the liquids by using smaller electrodes and more hydrophobic surfaces. 22 If the contact angle of the droplet on the electrode is large enough in air, then the oil environment can be avoided. Pumping and collecting the droplets are also required for the staining experiment.…”

Direct Analysis of Dried Blood Spot Samples

“…Further refinements to the technique, including simplified chip fabrication and improved liquid actuation, have recently been reported that are specifically aligned with optimising DBS direct analysis. This work compared newborn screening of succinylacetone (a marker for hepatorenal tyrosinemia) in DBS samples using a conventional manual extraction technique and DMF and demonstrated no significant difference in the two sets of data (111) . …”