Gardeniers, Johannes G.E.

Lüttge, Regina

van den Berg, Albert

Vrouwe, E.X.

English

This paper presents a microneedle array sampler interfaced to a capillary electrophoresis (CE) glass chip with integrated conductivity detection electrodes. A solution of alkali ions was electrokinetically loaded through the microneedles onto the chip and separation was demonstrated compared to a diluted blood sample. This method shows therefore feasibility for clinical relevant analytics

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MICRONEEDLE ARRAY INTERFACE TO CE ON CHIP R. Luttge, J.G.E. Gardeniers, E.X. Vrouwe, and A. van den Berg BIOS The Lab-on-a-Chip Group, MESA’ Research Institute, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands, e-mail: r.l~~tt~eiii,ufniente.nl Abstract This paper presents a microneedle array sampler interfaced to a capillary electrophoresis (CE) glass chip with integrated conductivity detection electrodes. A solution of alkali ions was electrokinetically loaded through the microneedles onto the chip and separation was demonstrated compared to a diluted blood sample. This method shows therefore feasibility for clinical relevant analytics. Keywords: Microneedles, Point-of-care, CE, Conductivity detection, Blood 1. Introduction Point-of-care testing has a number of advantages, like rapid turn around times, high degree of automation and improved quality of life [l]. Miniaturization strategies allow performing more and faster tests from smaller blood volmes being sampled off-clinic at ever-lower costs. Off-clinical diagnostics also reduces the risk of sample exchange or cross-contamination making a test result more reliable. Therefore, we envision a microneedle array sampler as an interface to diagnostics resulting in high patient’s compliance. In this paper, we focus on an analytical device that uses micromachined hollow microneedles in combination with capillary electrophoresis on chip [2]. Out-of- plane needle arrays provide a large needle density, while the fact that the needles are backed witha flat thin plate of a few mm’ making integration in a small card-type device or a patch possible (Fig. 1) [3], [4]. Figure 1. 450 pm high silicon needles with 555 urn pitch (left) [4], needle array approaching finger tip giving an impression of the blood sampler (right). 7th lnternat~onal Conference on Miniaturized Chemical and Blochemlcal Analysts Systems October 5-9, 2003, Squaw Valley, Callfornla USA O-974361 1-0-0/~TAS2003/$15.0IXZ003TRF 511 The silicon needle array fabrication consists of a sequence of Deep Reactive Ion Etching, anisotropic wet etching and conformal thin film deposition, and allows needle shapes with different, lithography-defined tip curvature [4]. Feasibility of these needles, which were fabricated at MESA’ Research Institute, is presented here for liquid transport and alkali ion diagnostics. 2. Fluidic transport through microneedles An experiment was performed to characterize the flow of fluorescent dye through the needles. The process of diffusion was captured with a CCD camera at a rate of 1 frame/s. Figure 2 shows the passive flow of the dye diffusing horn the needle tips into the buffer at the needle backside, achieved with the set up described in the figure. It was observed that non-uniform fluid flow occurred, although all needles were observed to be open before the test. Partial blockage could have been caused by air bubble or dust particle trapping. ~lu~res~~in in buffer at pti 6.4 Silicon needle Figure 2. Set-up to characterize the flow through a microneedle array (left). Microscope images of fluorescent dye transported through needles (right). 3. Microneedle sampler for CE Figure 3 shows a schematic of the set-up as used for interfacing the needle array to a glass CE chip of 2 cm separation length with a channel cross section of 6Q pm x 6 pm with end-cohnnn integrated electrodes for conductivity detection. The silicon needle chip was clamped onto the CE sample inlet via a PDMS seal. A calibrated solution of alkali ions containing 10 mM K+, Na’ and Lif and a 10 times diluted blood sample were electrokinetically loaded through the microneedles into the chip. A standard pinching procedure was applied to define and inject a sample plug, which was subsequently separated by Capillary Zone Electrophoresis (CZE). 20 mM MES-His was used as the background electrolyte. Details on the CZE procedure were described earlier [5]. 7th lnternat~onal Conference on Miniaturized Chemical and Blochemlcal Analysts Systems October 5-9, 2003, Squaw Valley, Callfornla USA 512 Figure 3. Measurement set-up for silicon microneedle array, coupled to a capillary electrophoresis chip. Figure 4. Electropherograms of separation results performed in set-up of Figure 3. Insert shows the same calibration compared to blood being sampled through the needles. 7th lnternat~onal Conference on Miniaturized Chemical and Blochemlcal Analysts Systems October 5-9, 2003, Squaw Valley, Callfornla USA 513 Figure 4 shows resulting electropherograms, which are achieved without and with the microneedle sampler for the 10 mM calibration solution and obtained with identical voltage schemes. In both experiments the concentration (peak area} and migration time of the alkali ions are nearly the same, indicating that no dilution occurs after transport through the needles and confirms that the needle array does not constitute a restriction to ionic transport. The insert shown in Figure 4 compares the same calibration graph for sampling through the needles with a measurement in blood. Here, two peaks were detected and can be identified as potassium and sodium. The ratio of peak areas of IS+ and Na+ in whole blood becomes approximately 1:l for samples when cell lysis occured during sample preparation. 4. Conclusions The characterization of the diffusion process through microneedles shows fast passive transport, leading to capillary electrophoresis experiments, in which sampling was achieved through the microneedles without diluting the sample by the loading procedure (note chip inlet and needle volume in Figure 3 not drawn to scale). A calibration solution of 10 mM K’, Na”, and Li+ was successfully sampled by the microneedle method and baseline separated. Performing the sampling method with diluted blood two peaks were identified. It is therefore assumed that due to the fast diffusion the concentration being sampled into the loading channel represents the concentration of the sample positioned onto the needle array. Acknowledgements The authors would like to acknowledge the financial support for this research by NanoPass Ltd. and specifically thank Y. Yeshurun and M. Hefetz of NanoPass Ltd. for fruitful discussions. References 1. D.D. Cunningham, Fiuidics and sample handling in clinical chemical analysis, Analytica Chimica Acta 429,2001, pp. l- 18. 2. Patent pending by NanoPass Ltd, Israel. 3. B.Stoeber and D. Liepmann, Design, Fabrication and Testing of a MEMS Syringe, Techn. Digest Solid-State Sensor Act. Workshop, Hilton Head NC, June 2-6, 2002, pp. 77-80. 4. J.G.E. Gardeniers et al. Silicon micromachined hollow microneedles for transdermal liquid transport, Proc. MEMS Workshop, Las Vegas, Jan. 20-24,2002, pp. 141-146. 5. E.X. Vrouwe et al. Measuring lithium in whole blood using capillary electrophoresis, Proc. uTAS 2002 Symp., Nara, Japan, Nov. 3- 7, 2002, Eds. Y. Baba, S. Shoji, and A. van den Berg, pp. I78- 180. 7th lnternat~onal Conference on Miniaturized Chemical and Blochemlcal Analysts Systems October 5-9, 2003, Squaw Valley, Callfornla USA 514 

Microneedle Array Interface to CE on Chip

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Microneedle Array Interface to CE on Chip

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