An intra-cerebral drug delivery system for freely moving animals
- 517 Downloads
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.
KeywordsDrug delivery Micropump Silicon microprobes Microfluidics Five-choice serial reaction time task Impulsivity (R)-CPP Infralimbic cortex Neuroscience
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.
- Akzo Nobel, Eine technische Präsentation der Expancel® Mikrosphären, Technische Information Nr. 40 (2006)Google Scholar
- M. Carli, M. Baviera, R.W. Invernizzi, C. Balducci, Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 31(4), 757–767 (2006)CrossRefGoogle Scholar
- H. Domininghaus, P. Elsner, P. Eyerer, T. Hirth, Kunststoffe: Eigenschaften und Anwendungen, 7th edn. (Springer, Berlin, 2008)Google Scholar
- G. Lacey, Microelectrophoresis and Pressure Ejection Methods, in Neuroscience Methods: A Guide for Advanced Students, ed. by R. Martin (Harwood Academic Publishers, Amsterdam, 1997), pp. 80–84. Chap. 12Google Scholar
- S. Musa, M. Welkenhuysen, R. Huys, W. Eberle, K. Kuyck, C. Bartic, B. Nuttin, G. Borghs, Planar 2D-Array Neural Probe for Deep Brain Stimulation and Recording (DBSR), in Proc. 4th Eur. Conf. of the IFMBE, IFMBE Proceedings, vol. 22 (Springer, Berlin, 2009), pp. 2421–2425Google Scholar
- H.P. Neves, G.A. Orban, M. Koudelka-Hep, T. Stieglitz, P. Ruther, Development of modular multifunctional probe arrays for cerebral applications, in Proc. 3rd Int. IEEE EMBS Conf. on Neural Eng., pp. 104–109 (2007)Google Scholar
- P. Ruther, A. Aarts, O. Frey, S. Herwik, S. Kisban, K. Seidl, S. Spieth, A. Schumacher, M. Koudelka-Hep, O. Paul, T. Stieglitz, R. Zengerle, H. Neves, The NeuroProbes project – Multifunctional probe arrays for neural recording and stimulation. Biomed. Techn. 53(Suppl. 1), 238–240 (2008)Google Scholar
- S. Spieth, A. Schumacher, K. Seidl, K. Hiltmann, S. Haeberle, R. McNamara, J.W. Dalley, S.A. Edgley, P. Ruther, R. Zengerle, Robust microprobe systems for simultaneous neural recording and drug delivery, in Proc. 4th Eur. Conf. of the IFMBE, IFMBE Proceedings, vol. 22 (Springer, Berlin, 2009), pp. 2426–2430Google Scholar
- S. Spieth, A. Schumacher, S. Messner, T. Holtzman, P.D. Rich, J.W. Dalley, R. Zengerle, A miniaturized on-demand drug delivery system for neural research, in Proc. 6th Int. Conf. on Microtechn. in Med. and Biol., pp. 62–63 (2011)Google Scholar
- S. Spieth, A. Schumacher, S. Messner, R. Zengerle, The NeuroMedicator - A micropump integrated with silicon microprobes for drug delivery in neural research. J. Micromech. Microeng., in press (2012)Google Scholar