Bioelectronic neural pixel: Chemical stimulation and electrical

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    APPLIED PHYSICAL SCIENCES, NEUROSCIENCECorrection for Bioelectronic neural pixel: Chemical stimulationand electrical sensing at the same site, by Amanda Jonsson, SahikaInal, llke Uguz, Adam J. Williamson, Log Kergoat, JonathanRivnay, Dion Khodagholy, Magnus Berggren, Christophe Bernard,George G. Malliaras, and Daniel T. Simon, which appeared in issue34, August 23, 2016, of Proc Natl Acad Sci USA (113:94409445;first published August 9, 2016; 10.1073/pnas.1604231113).The authors note that, due to a printers error, the first name of

    the third author, Ilke Uguz, originally published with the firstletter as a lowercase letter l. This letter should instead appear asan uppercase letter i. The online version has been corrected.

    www.pnas.org/cgi/doi/10.1073/pnas.1615817113

    www.pnas.org PNAS | November 1, 2016 | vol. 113 | no. 44 | E6903

    CORR

    ECTION

    www.pnas.org/cgi/doi/10.1073/pnas.1615817113

  • Bioelectronic neural pixel: Chemical stimulation andelectrical sensing at the same siteAmanda Jonssona,1, Sahika Inalb,1, Ilke Uguzb,1, Adam J. Williamsonc,1, Log Kergoata,c, Jonathan Rivnayb,2,Dion Khodagholyb,3, Magnus Berggrena, Christophe Bernardc, George G. Malliarasb, and Daniel T. Simona,4

    aLaboratory of Organic Electronics, Department of Science and Technology, Linkping University, 60174 Norrkping, Sweden; bDepartment ofBioelectronics, cole Nationale Suprieure des Mines de Saint-Etienne, Centre Microlectronique de Provence, Microelectronique et Objects Communicants,13541 Gardanne, France; and cAix Marseille Universit, Institut de Neurosciences des Systmes, 13005 Marseille, France

    Edited by Zhenan Bao, Stanford University, Stanford, California, and accepted by Editorial Board Member John A. Rogers June 27, 2016 (received for reviewMarch 14, 2016)

    Local control of neuronal activity is central to many therapeuticstrategies aiming to treat neurological disorders. Arguably, the bestsolution would make use of endogenous highly localized andspecialized regulatory mechanisms of neuronal activity, and anideal therapeutic technology should sense activity and deliverendogenous molecules at the same site for the most efficientfeedback regulation. Here, we address this challenge with anorganic electronic multifunctional device that is capable of chemicalstimulation and electrical sensing at the same site, at the single-cellscale. Conducting polymer electrodes recorded epileptiform dis-charges induced in mouse hippocampal preparation. The inhibitoryneurotransmitter, -aminobutyric acid (GABA), was then actively de-livered through the recording electrodes via organic electronic ionpump technology. GABA delivery stopped epileptiform activity,recorded simultaneously and colocally. This multifunctional neuralpixel creates a range of opportunities, including implantable ther-apeutic devices with automated feedback, where locally recordedsignals regulate local release of specific therapeutic agents.

    organic electronics | controlled delivery | electrophysiology | epilepsy |therapy

    Recent estimates suggest neurological disorders affect up to 6%of the global population (1). The vast majority of treatmentsgenerally involve oral administration of pharmaceuticals. Whenthese fail, alternate therapies can include neurosurgery (e.g., inepilepsy) and electrical stimulation via implanted electrodes [e.g.,in Parkinsons disease (1)]. Pharmaceutical and basic research haveidentified promising targets and designed potentially efficient drugsfor multiple disorders, but such drugs havent reached patientsbecause of failure during (pre)clinical tests. There are multiplereasons for such failures. Drugs may be toxic in the periphery (2, 3),they may not cross the bloodbrain barrier or they may be pumpedback to the blood stream by multidrug transporters (4, 5). However,the critical factor is the fact that they may have deleterious sideeffects when they penetrate healthy regions, affecting physiolog-ical functions such as memory and learning (6, 7). In addition,because oral administration will lead to a dilution of the drug in thebody, there is often a mismatch between the dose necessary toobtain a therapeutic effect in the region to treat and the maximumdose that nonaffected body regions can support without side effects.Providing the drug past the bloodbrain barrier, where and

    when it is needed, constitutes the ideal solution. Such deliverywould solve all of the above-mentioned problems (bloodbrainbarrier crossing, peripheral toxicity, undesirable side effects inhealthy regions, and effective dose). Devices have been success-fully designed to deliver drugs locally (8). However, the whereand when issues remain to be addressed. Because clinicians mayhave several spatially distributed regions to treat, or if the volumeof the intended treatment region is large, it is important to havemultiple drug delivery sites, which would solve the where issue.The when issue is more difficult to address, as, ideally, a deliverysystem should act on demand, when needed (e.g., just before an

    impending seizure). Because electrophysiological signals can beused to predict incoming pathological events (9), electrical activityshould be measured at each delivery site to trigger drug delivery atthat specific location. Such local, real-time measurement, andprecision delivery, would pave the way for closed-loop, fully au-tomatic, therapeutic devices. Finally, because the size of the regionto treat may be smalldown to the scale of a single cellthetechnology should allow spatial resolution of delivery on the orderof micrometers.Interfacing malfunctioning neurological pathways with spatial

    resolution and signal specificity approaching those of the cell couldprovide significant advantages to future therapies. Microelectroderecordings of the field potentials generated by neurons (or evenneuronal firing itself) have become routine in investigations ofbrain function and dysfunction (10). Small size of recording sitesallows for recording of single neurons, and densely packed sites onminimally invasive electrodes enhance the sampling capacity of theprobe (11). Such densely packed probes can be accomplished usingconducting polymers, such as poly(3,4-ethylenedioxythiophene)doped with poly(styrenesulfonate) (PEDOT:PSS), without de-creasing the quality of the recordings. Conducting polymer elec-trodes exhibit inherently low impedance characteristics (more than

    Significance

    Electronically and ionically conducting polymers provide aunique means to translate electronic addressing signals intochemically specific and spatiotemporally resolved delivery,without fluid flow. These materials have also been shown toprovide high-fidelity electrophysiological recordings. Here, wedemonstrate the combination of these qualities of organicelectronics in multiple 20 20 m delivery/sensing electrodes.The system is used to measure epileptic activity in a brain slicemodel, and to deliver inhibitory neurotransmitters to the samesites as the recordings. These results show that a single-cell-scaleelectrode has the ability to both record and chemically stimulate,demonstrating the local effects of therapeutic treatment, andopening a range of opportunities in basic neuroscience as well asmedical technology development.

    Author contributions: A.J., S.I., I.U., A.J.W., L.K., J.R., D.K., M.B., C.B., G.G.M., and D.T.S.designed research; A.J., S.I., I.U., A.J.W., and L.K. performed research; A.J., S.I., I.U., A.J.W.,L.K., and C.B. analyzed data; and A.J., S.I., and D.T.S. wrote the paper.

    The authors declare no conflict of interest.

    This article is a PNAS Direct Submission. Z.B. is a Guest Editor invited by theEditorial Board.1A.J., S.I., I.U., and A.J.W. contributed equally to this work.2Present address: Electronic Materials and Devices Lab, Palo Alto Research Center, PaloAlto, CA 94304.

    3Present address: Neuroscience Institute, School of Medicine, New York University, NewYork, NY 10016.

    4To whom correspondence should be addressed. Email: daniel.simon@liu.se.

    This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1604231113/-/DCSupplemental.

    94409445 | PNAS | August 23, 2016 | vol. 113 | no. 34 www.pnas.org/cgi/doi/10.1073/pnas.1604231113

    http://crossmark.crossref.org/dialog/?doi=10.1073/pnas.1604231113&domain=pdfmailto:daniel.simon@liu.sehttp://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1604231113/-/DCSupplementalhttp://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1604231113/-/DCSupplementalwww.pnas.org/cgi/doi/10.1073/pnas.1604231113

  • one order of magnitude lower than bare Au, Pt, and Ir electrodesof similar dimensions at 1 kHz), with the low impedance beingattributed partly to the high porosity, giving an increased electro-chemical surface area (1214). Additionally, with their mixedelectronic and ionic conductivity and the soft mechanical proper-ties that match those of the neural tissue, conducting polymers areideally suited to obtain high signal-to-noise ratio recordings at theneural interface (15, 16). Recently, we have demonstrated micro-electrode arrays based on PEDOT:PSS electrodes for in vitro re-cordings of electrophysiological signals from rat brain slices (17).These microelectrodes, fabricated at small size and high density,have enabled a good match with the dimensions of neural networkswhile maintaining high-resolution neural recordings.We have also demonstrated substance delivery mimicking exo-

    cytotic release of neurotransmitters at the neuronal scale by meansof the organic electronic ion pump (OEIP) (18, 19). The OEIPuses conducting polymer electrodes to electrophoretically pumpneurotransmitters through a permselective membrane, enablinghigh spatiotemporal delivery resolution, without necessitatingliquid flow. OEIPs have been used in vitro to trigger cell signaling(18, 20) a