Leveraging 3D printing to enhance mass spectrometry:A review

The use of 3D printing in the chemical and analytical sciences has gained a lot of momentum in recent years. Some of the earliest publications detailed 3D-printed interfaces for mass spectrometry, which is an evolving family of powerful detection techniques. Since then, the application of 3D printing for enhancing mass spectrometry has significantly diversified, with important reasons for its application including flexible integration of different parts or devices, fast customization of setups, additional functionality, portability, cost-effectiveness, and user-friendliness. Moreover, computer-aided design (CAD) and 3D printing enables the rapid and wide distribution of scientific and engineering knowledge. 3D printers allow fast prototyping with constantly increasing resolution in a broad range of materials using different fabrication principles. Moreover, 3D printing has proven its value in the development of novel technologies for multiple analytical applications such as online and offline sample preparation, ionization, ion transport, and developing interfaces for the mass spectrometer. Additionally, 3D-printed devices are often used for the protection of more fragile elements of a sample preparation system in a customized fashion, and allow the embedding of external components into an integrated system for mass spectrometric analysis. This review comprehensively addresses these developments, since their introduction in 2013. Moreover, the challenges and choices with respect to the selection of the most appropriate printing process in combination with an appropriate material for a mass spectrometric application are addressed; special attention is paid to chemical compatibility, ease of production, and cost. In this review, we critically discuss these developments and assess their impact on mass spectrometry

Mouse precision-cut liver slices as an ex vivo model to study drug-induced cholestasis

Drugs are often withdrawn from the market due to the manifestation of drug-induced liver injury (DILI) in patients. Drug-induced cholestasis (DIC), defined as obstruction of hepatic bile flow due to medication, is one form of DILI. Because DILI is idiosyncratic, and the resulting cholestasis complex, there is no suitable in vitro model for early DIC detection during drug development. Our goal was to develop a mouse precision-cut liver slice (mPCLS) model to study DIC and to assess cholestasis development using conventional molecular biology and analytical chemistry methods. Cholestasis was induced in mPCLS through a 48-h-incubation with three drugs known to induce cholestasis in humans, namely chlorpromazine (15, 20, and 30 µM), cyclosporin A (1, 3, and 6 µM) or glibenclamide (25, 50, and 65 µM). A bile-acid mixture (16 µM) that is physiologically representative of the human bile-acid pool was added to the incubation medium with drug, and results were compared to incubations with no added bile acids. Treatment of PCLS with cholestatic drugs increased the intracellular bile-acid concentration of deoxycholic acid and modulated bile-transporter genes. Chlorpromazine led to the most pronounced cholestasis in 48 h, observed as increased toxicity; decreased protein and gene expression of the bile salt export pump; increased gene expression of multidrug resistance-associated protein 4; and accumulation of intracellular bile acids. Moreover, chlorpromazine-induced cholestasis exhibited some transition into fibrosis, evidenced by increased gene expression of collagen 1A1 and heatshock protein 47. In conclusion, we demonstrate that mPCLS can be used to study human DIC onset and progression in a 48 h period. We thus propose this model is suited for other similar studies of human DIC

Solvent-dependent on/off valving using selectively permeable barriers in paper microfluidics

We report on a new way to control solvent flows in paper microfluidic devices, based on the local patterning of paper with alkyl ketene dimer (AKD) to form barriers with selective permeability for different solvents. Production of the devices is a two-step process. In the first step, AKD-treated paper (hydrophobic) is exposed to oxygen plasma for re-hydrophilization. 3D-printed masks are employed to shield certain areas of this paper to preserve well-defined hydrophobic patterns. In the second step, concentrated AKD in hexane is selectively deposited onto already hydrophobic regions of the paper to locally increase the degree of hydrophobicity. Hydrophilic areas formed in the previous oxygen plasma step are protected from AKD by wetting them with water first to prevent the AKD hexane solution from entering them (hydrophilic exclusion). Characterization of the patterns after both steps shows that reproducible patterns are obtained with linear dependence on the dimensions of the 3D-printed masks. This two-step methodology leads to differential hydrophobicity on the paper: (i) hydrophilic regions, (ii) low-load AKD gates, and (iii) high-load AKD walls. The gates are impermeable to water, yet can be penetrated by most alcohol/water mixtures; the walls cannot. This concept for solvent-dependent on/off valving is demonstrated in two applications. In the first example, a device was developed for multi-step chemical reactions. Different compounds can be spotted separately (closed gates). Upon elution with an alcohol/water mixture, the gates become permeable and the contents are combined. In the second example, volume-defined sampling is introduced. Aqueous sample is allowed to wick into a device and fill a sample chamber. The contents of this sample chamber are eluted perpendicularly with an alcohol/water mixture through a selectively permeable gate. This system was tested with dye solution, and a linear dependence of magnitude of the signal on the sample chamber size was obtained

3D-Printed Paper Spray Ionization Cartridge with Integrated Desolvation Feature and Ion Optics

In this work we present the application of 3D-printing for the miniaturization and functionalization of an ion source for (portable) mass spectrometry (MS). Two versions of a 3D-printed cartridge for paper spray ionization (PSI) are demonstrated, assessed, and compared. We first focus on the use of 3D-printing to enable the integration of an embedded electrostatic lens and a manifold for internal sheath gas distribution and delivery. Cartridges with and without a sheath gas manifold and an electrostatic lens are compared with respect to analytical performance and operational flexibility. The sensitivity and limit of detection are improved in the cartridge with an electrostatic lens and sheath gas manifold compared to the cartridge without (15% and over 6.5× smaller, respectively). The use of these focusing elements also improved the average spray stability. Furthermore, the range of potentials required for PSI was lower, and the distance to the MS orifice over which spray could be obtained was larger. Importantly, both setups allowed quantification of a model drug in the ng/mL range with single-stage MS, after correction for spray instability. Finally, we believe that this work is an example of the impact that 3D-printing will have on the future of analytical device fabrication, miniaturization, and functionalization

Liquid-infiltrated photonic crystals - enhanced light-matter interactions for lab-on-a-chip applications

Optical techniques are finding widespread use in analytical chemistry for chemical and bio-chemical analysis. During the past decade, there has been an increasing emphasis on miniaturization of chemical analysis systems and naturally this has stimulated a large effort in integrating microfluidics and optics in lab-on-a-chip microsystems. This development is partly defining the emerging field of optofluidics. Scaling analysis and experiments have demonstrated the advantage of micro-scale devices over their macroscopic counterparts for a number of chemical applications. However, from an optical point of view, miniaturized devices suffer dramatically from the reduced optical path compared to macroscale experiments, e.g. in a cuvette. Obviously, the reduced optical path complicates the application of optical techniques in lab-on-a-chip systems. In this paper we theoretically discuss how a strongly dispersive photonic crystal environment may be used to enhance the light-matter interactions, thus potentially compensating for the reduced optical path in lab-on-a-chip systems. Combining electromagnetic perturbation theory with full-wave electromagnetic simulations we address the prospects for achieving slow-light enhancement of Beer-Lambert-Bouguer absorption, photonic band-gap based refractometry, and high-Q cavity sensing.Comment: Invited paper accepted for the "Optofluidics" special issue to appear in Microfluidics and Nanofluidics (ed. Prof. David Erickson). 11 pages including 8 figure