On-demand generation and mixing of liquid-in-gas slugs with digitally programmable composition and size

Chen, Yi‐Chun; Liu, Kan; Shen, Che-Kun James; Dam, R. Michael van

doi:10.1088/0960-1317/25/8/084006

Cited by 6 publications

(3 citation statements)

References 47 publications

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“…(The loading process would need to be slightly modified to ensure that the sample chamber is closed while still under pressurized conditions.) Another possible approach to add volume flexibility is to introduce several microvalves along the sample chamber to allow the length of the chamber to be dynamically adjusted (in discrete steps) [64], as was done in the chip designed in this study (i.e. either ~2 or ~4 nL injection volume; see Supporting Information, Figure S-2).…”

Section: Resultsmentioning

confidence: 99%

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Novel volumetric method for highly repeatable injection in microchip electrophoresis

Jones

et al. 2017

Analytica Chimica Acta

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A novel injector for microchip electrophoresis (MCE) has been designed and evaluated that achieves very high repeatability of injection volume suitable for quantitative analysis. It eliminates the injection biases in electrokinetic injection and the dependence on pressure and sample properties in hydrodynamic injection. The microfluidic injector, made of poly(dimethylsiloxane) (PDMS), operates similarly to an HPLC injection valve. It contains a channel segment (chamber) with a well-defined volume that serves as an “injection loop”. Using on-chip microvalves, the chamber can be connected to the sample source during the “loading” step, and to the CE separation channel during the “injection” step. Once the valves are opened in the second state, electrophoretic potential is applied to separate the sample. For evaluation and demonstration purposes, the microinjector was connected to a 75 µm ID capillary and UV absorbance detector. For single compounds, a relative standard deviation (RSD) of peak area as low as 1.04% (n=11) was obtained, and for compound mixtures, RSD as low as 0.40% (n=4) was observed. Using the same microchip, the performance of this new injection technique was compared to hydrodynamic injection and found to have improved repeatability and less dependence on sample viscosity. Furthermore, a non-radioactive version of the positron-emission tomography (PET) imaging probe, FLT, was successfully separated from its known 3 structurally-similar byproducts with baseline resolution, demonstrating the potential for rapid, quantitative analysis of impurities to ensure the safety of batches of short-lived radiotracers. Both the separation efficiency and injection repeatability were found to be substantially higher when using the novel volumetric injection approach compared to electrokinetic injection (performed in the same chip). This novel microinjector provides a straightforward way to improve the performance of hydrodynamic injection and enables extremely repeatable sample volume injection in MCE. It could be used in any MCE application where volume repeatability is needed, including the quantitation of impurities in pharmaceutical or radiopharmaceutical samples.

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Section: Resultsmentioning

confidence: 99%

“…To increase volume flexibility, valve-based approaches where the volume or length of the chamber is dynamically adjusted can be readily incorporated [54,64]. The separation channel can be incorporated in a hybrid fashion as was done here (i.e.…”

Section: Discussionmentioning

confidence: 99%

Novel volumetric method for highly repeatable injection in microchip electrophoresis

Jones

et al. 2017

Analytica Chimica Acta

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“…While parameters like temperature and reagent flow rates can be readily studied in a high-throughput manner, others, such as reaction solvent or the conditions for the drying/activation of the [ 18 F]fluoride, cannot. Another optimization platform used a polydimethylsiloxane (PDMS) microfluidic chip to prepare ultra-small batches (~ 100 nL each) for screening of aqueous protein radiolabeling conditions but was limited to varying reagent ratios and pH 22 , 23 .…”

Section: Introductionmentioning

confidence: 99%

Microliter-scale reaction arrays for economical high-throughput experimentation in radiochemistry

Ríos

Holloway

Chao

et al. 2022

Sci Rep

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The increasing number of positron-emission tomography (PET) tracers being developed to aid drug development and create new diagnostics has led to an increased need for radiosynthesis development and optimization. Current radiosynthesis instruments are designed to produce large-scale clinical batches and are often limited to performing a single synthesis before they must be decontaminated by waiting for radionuclide decay, followed by thorough cleaning or disposal of synthesizer components. Though with some radiosynthesizers it is possible to perform a few sequential radiosyntheses in a day, none allow for parallel radiosyntheses. Throughput of one or a few experiments per day is not well suited for rapid optimization experiments. To combat these limitations, we leverage the advantages of droplet-radiochemistry to create a new platform for high-throughput experimentation in radiochemistry. This system contains an array of 4 heaters, each used to heat a set of 16 reactions on a small chip, enabling 64 parallel reactions for the rapid optimization of conditions in any stage of a multi-step radiosynthesis process. As examples, we study the syntheses of several 18F-labeled radiopharmaceuticals ([18F]Flumazenil, [18F]PBR06, [18F]Fallypride, and [18F]FEPPA), performing > 800 experiments to explore the influence of parameters including base type, base amount, precursor amount, solvent, reaction temperature, and reaction time. The experiments were carried out within only 15 experiment days, and the small volume (~ 10 μL compared to the ~ 1 mL scale of conventional instruments) consumed ~ 100 × less precursor per datapoint. This new method paves the way for more comprehensive optimization studies in radiochemistry and substantially shortening PET tracer development timelines.

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Advantages of Radiochemistry in Microliter Volumes

Keng

Sergeev

Dam

2016

Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy

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Positron emission tomography (PET) provides quantitative 3D visualization of physiological parameters (e.g., metabolic rate, receptor density, gene expression, blood flow) in real time in the living body. By enabling measurement of differences in such characteristics between normal and diseased tissues, PET serves as vital tool for basic research as well as for clinical diagnosis and patient management. Prior to a PET scan, the patient is injected with a short-lived tracer labeled with a positron-emitting isotope. Safe preparation of the tracer is an expensive process, requiring specially trained personnel and high-cost equipment operated within hot cells. The current centralized manufacturing strategy, in which large batches are prepared and divided among many patients, enables the most commonly used tracer (i.e., [ 18 F]FDG) to be obtained at an affordable price. However, as the diversity of tracers increases, other strategies for cost reduction will become necessary. This challenge is being addressed by the development of miniaturized radiochemistry instrumentation based on microfluidics. These compact systems have the potential to significantly reduce equipment cost and shielding while increasing diversity of tracers produced in a given facility. The most common approach uses "flow-through" microreactors, which leverage the ability to precisely control reaction conditions to improve synthesis times and yields. Several groups have also developed "batch" microreactors which offer significant additional advantages such as reduced reagent consumption, simpler purifications, and exceptionally high specific activity, by reducing operating volumes by orders of magnitude. In this chapter, we review these "batch" approaches and the advantages of using small volumes, with special emphasis on digital microfluidics, in which reactions have been performed with volumes as low as~1 μL.

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On-demand generation and mixing of liquid-in-gas slugs with digitally programmable composition and size

Cited by 6 publications

References 47 publications

Novel volumetric method for highly repeatable injection in microchip electrophoresis

Novel volumetric method for highly repeatable injection in microchip electrophoresis

Microliter-scale reaction arrays for economical high-throughput experimentation in radiochemistry

Advantages of Radiochemistry in Microliter Volumes

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