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An intra-cerebral drug delivery system for freely moving animals

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Abstract

Microinfusions of drugs directly into the central nervous system of awake animals represent a widely used means of unravelling brain functions related to behaviour. However, current approaches generally use tethered liquid infusion systems and a syringe pump to deliver drugs into the brain, which often interfere with behaviour. We address this shortfall with a miniaturised electronically-controlled drug delivery system (20 × 17.5 × 5 mm3) designed to be skull-mounted in rats. The device features a micropump connected to two 8-mm-long silicon microprobes with a cross section of 250 × 250 μm2 and integrated fluid microchannels. Using an external electronic control unit, the device allows infusion of 16 metered doses (0.25 μL each, 8 per silicon shaft). Each dosage requires 3.375 Ws of electrical power making the device additionally compatible with state-of-the-art wireless headstages. A dosage precision of 0.25 ± 0.01 μL was determined in vitro before in vivo tests were carried out in awake rats. No passive leakage from the loaded devices into the brain could be detected using methylene blue dye. Finally, the device was used to investigate the effects of the NMDA-receptor antagonist 3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid, (R)-CPP, administered directly into the prefrontal cortex of rats during performance on a task to assess visual attention and impulsivity. In agreement with previous findings using conventional tethered infusion systems, acute (R)-CPP administration produced a marked increase in impulsivity.

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Acknowledgments

This work was performed in the frame of the Information Society Technologies (IST) Integrated Project Neuro-Probes of the 6th Framework Program (FP6) of the European Commission (Project number IST-027017). The authors gratefully acknowledge funding support by the Wellcome Trust and MRC in the United Kingdom through support of the Behavioural and Clinical Neuroscience Institute (BCNI) at Cambridge University. We also acknowledge support from Karsten Seidl, Patrick Ruther, and the cleanroom facility of IMTEK, University of Freiburg, as well as the support from the cleanroom and the machine shop facilities at HSG-IMIT. The authors would like to thank Joachim Leicht, Bernd Ehrbrecht, Jürgen Merz, and Alexander Fabricius (all HSG-IMIT) for conception, assembly, and programming of the electronic control unit. Furthermore, the authors would like to thank Björn Samel and Göran Stemme of Royal Institute of Technology Stockholm for useful discussions and insights. The provision of microspheres from Expancel, Sundsvall, Sweden, TPE membranes from KRAIBURG TPE GmbH & Co. KG, Waldkraiburg, Germany, and COP plates from Zeon Corporation, Tokyo, Japan, is gratefully acknowledged.

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Authors and Affiliations

  1. Institut für Mikro-und Informationstechnik der Hahn-Schickard-Gesellschaft e.V. (HSG-IMIT), Wilhelm-Schickard-Str. 10, 78052, Villingen-Schwenningen, Germany

    Sven Spieth, Axel Schumacher, Rachid Nouna, Stephan Messner & Roland Zengerle

  2. Behavioural and Clinical Neuroscience Institute and Department of Experimental Psychology, University of Cambridge, Downing St, Cambridge, CB2 3EB, UK

    Tahl Holtzman, P. Dylan Rich, David E. Theobald & Jeffrey W. Dalley

  3. Janelia Farm Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA, 20147, USA

    P. Dylan Rich

  4. Department of Psychiatry, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, UK

    Jeffrey W. Dalley

  5. Laboratory for MEMS Applications, Department of Microsystems Engineering (IMTEK), University of Freiburg, Georges-Koehler-Allee 106, 79110, Freiburg, Germany

    Roland Zengerle

  6. BIOSS - Centre for Biological Signalling Studies, University of Freiburg, Hebelstr. 25, 79104, Freiburg, Germany

    Roland Zengerle

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  1. Sven Spieth
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  2. Axel Schumacher
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  5. David E. Theobald
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  7. Rachid Nouna
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  8. Stephan Messner
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  9. Roland Zengerle
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Correspondence to Sven Spieth.

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Spieth, S., Schumacher, A., Holtzman, T. et al. An intra-cerebral drug delivery system for freely moving animals. Biomed Microdevices 14, 799–809 (2012). https://doi.org/10.1007/s10544-012-9659-2

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