In treating epilepsy, the ideal solution is to act at a seizure's onset, but only in the affected regions of the brain. Here, an organic electronic ion pump is demonstrated, which directly delivers on-demand pure molecules to specific brain regions. State-of-the-art organic devices and classical pharmacology are combined to control pathological activity in vitro, and the results are verified with electrophysiological recordings.

Funding Agencies|European Union [602102]; A*MIDEX [A_M-AAP-ID-13-24-130531-16.31-BERNARD-HLS]; Swedish Innovation Office (VINNOVA); Swedish Research Council [621-2011-3517]; Knut and Alice Wallenberg Foundation [2012.0302]; National Science Foundation [DMR-1105253]; ANR [ANR-13-BSV5-0019-01]; Fondation pour la Recherche Medicale [DBS20131128446]; Fondation de lAvenir; Onnesjo Foundation; Region PACA; Microvitae Technologies; Orthogonal, Inc.; Marie Curie Fellowships

comprises materials and devices that can fulfill just this dual ionic-electronic capability. Iontronics utilize the coupling of electrical and ionic signals in conducing polymers, leading to, for example, organic electrochemical transistors (OECTs), [2] electrolyte-gated (also known as electric doublelayer capacitor-gated) organic field-effect transistors (EGOFETs), [3,4] organic electrochemical biosensors, [5,6] and iontronic delivery electrodes and devices. [7][8][9][10][11] In iontronic delivery devices (Figure 1), chemical gradients are created by controlled release of charged biomolecules (ions) at specific locations at specific times. [7,8,12] Ions are transported to these release sites through ionic conductors due to applied electric fields between electrodes. The ionic conductors form the foundation of iontronic resistors (organic electronic ion pumps, OEIPs), diodes, and transistors which can be combined into circuits for, for example, multiplexing, addressing, and signal processing. These iontronic circuits behave analogous to traditional electronics, but use ions as charge carriers rather than electrons, and allow for the development of fully chemical systems generating complex signal patterns at high spatiotemporal resolution and biochemical specificity.There are several other techniques for electronic control of substance release, drug delivery, or ion transport related to this form of iontronics. These include techniques such as microfluidic and microelectromechanical systems (MEMS) based micropumps, [13] iontophoresis, [14,15] and organic electronic redox-mediated controlled release. [11,16] In comparison to these technologies, iontronic drug delivery provides a means of simultaneously achieving high delivery precision, minimal (or zero) liquid transport that could interfere with fragile biochemical microenvironments, continuous resupply of the transported substance, and (in principle) exact control over delivered amounts, even at speeds on par with synaptic signaling. In addition, as they are based on well-established solid-state device manufacturing techniques, iontronic components and systems can be miniaturized, addressed, and integrated with complex electronic systems in a straightforward manner. These features of iontronics combine to enable the lowest dose possible. With other techniques for substance release and transport, larger doses are often distributed (usually in solution phase) with less control, which could result in unwanted side effects. Other technologies have their advantages primarily in potentially simpler device design, the ability to transport larger molecules (e.g., In contrast to electronic systems, biology rarely uses electrons as the signal to regulate functions, but rather ions and molecules of varying size. Due to the unique combination of both electronic and ionic/molecular conductivity in conjugated polymers and polyelectrolytes, these materials have emerged as an excellent tool for translating signals between these two realms, hence the field of organic bioelectroni...

Addressable organic electronic neurotransmitter delivery array with switching ~50 ms, approaching synaptic signaling speed.

The organic electronic ion pump (OEIP) has been developed as an "iontronic" tool for delivery of biological signaling compounds. OEIPs rely on electrophoretically "pumping" charged compounds, either at neutral or shifted pH, through an ion-selective channel. Significant shifts in pH lead to an abundance of H or OH, which are delivered along with the intended substance. While this method has been used to transport various neurotransmitters, the role of pH has not been explored. Here we present an investigation of the role of pH on OEIP transport efficiency using the neurotransmitter γ-aminobutyric acid (GABA) as the model cationic delivery substance. GABA transport is evaluated at various pHs using electrical and chemical characterization and compared to molecular dynamics simulations, all of which agree that pH 3 is ideal for GABA transport. These results demonstrate a useful method for optimizing transport of other substances and thus broadening OEIP applications.

The organic electronic ion pump (OEIP) is an emerging bioelectronic technology for on-demand and local delivery of pharmacologically active species, especially targeting alkali ions, and neurotransmitters. While electrical control is advantageous for providing precise spatial, temporal, and quantitative delivery, traditionally, it necessitates wiring. This complicates implantation. Herein, we demonstrate integration of an OEIP with a photovoltaic driver on a flexible carrier, which can be addressed by red light within the tissue transparency window. Organic thin-film bilayer photovoltaic pixels are arranged in series and/or vertical tandem to provide the 2.5-4.5 V necessary for operating the high-resistance electrophoretic ion pumps. We demonstrate light-stimulated transport of cations, ranging in size from protons to acetylcholine. The device, laminated on top of the skin, can easily be driven with a red LED emitting through a 1.5-cm-thick finger. The end result of our work is a thin and flexible integrated wireless device platform.npj Flexible Electronics (2019) 3:14 ; https://doi.

Current neural interfaces rely on electrical stimulation pulses to affect neural tissue. The development of a chemical delivery technology, which can stimulate neural tissue with the body's own set of signaling molecules, would provide a new level of sophistication in neural interfaces. Such technology should ideally provide highly local chemical delivery points that operate at synaptic speed, something that is yet to be accomplished. Here, the development of a miniaturized ionic polarization diode that exhibits many of the desirable properties for a chemical neural interface technology is reported. The ionic diode shows proper diode rectification and the current switches from off to on in 50 µs at physiologically relevant electrolyte concentrations. A device model is developed to explain the characteristics of the ionic diode in more detail. In combination with experimental data, the model predicts that the ionic polarization diode has a delivery delay of 5 ms to reach physiologically relevant neurotransmitter concentrations at subcellular spatial resolution. The model further predicts that delays of <1 ms can be reached by further miniaturization of the diode geometry. Altogether, the results show that ionic polarization diodes are a promising building block for the next generation of chemical neural interfaces.

On-demand local release of biomolecules enables fine-tuned stimulation for the next generation of neuromodulation therapies. Such chemical stimulation is achievable using iontronic devices based on microfabricated, highly selective ion exchange membranes (IEMs). Current limitations in processability and performance of thin film IEMs hamper future developments of this technology. Here we address this limitation by developing a cationic IEM with excellent processability and ionic selectivity: poly(4-styrenesulfonic acid-co-maleic acid) (PSS-co-MA) cross-linked with polyethylene glycol (PEG). This enables new design opportunities and provides enhanced compatibility with in vitro cell studies. PSSA-co-MA/PEG is shown to out-perform the cation selectivity of the previously used iontronic material.

The b-adrenergic response is impaired in failing hearts. When studying b-adrenergic function in vitro, the half-maximal effective concentration (EC 50 ) is an important measure of ligand response. We previously measured the in vitro contraction force response of chicken heart tissue to increasing concentrations of adrenaline, and observed a decreasing response at high concentrations. The classical interpretation of such data is to assume a maximal response before the decrease, and to fit a sigmoid curve to the remaining data to determine EC 50 . Instead, we have applied a mathematical modeling approach to interpret the full dose-response curve in a new way. The developed model predicts a non-steady-state caused by a short resting time between increased concentrations of agonist, which affect the dose-response characterization. Therefore, an improved estimate of EC 50 may be calculated using steady-state simulations of the model. The model-based estimation of EC 50 is further refined using additional timeresolved data to decrease the uncertainty of the prediction. The resulting model-based EC 50 (180-525 nM) is higher than the classically interpreted EC 50 (46-191 nM). Mathematical modeling thus makes it possible to reinterpret previously obtained datasets, and to make accurate estimates of EC 50 even when steady-state measurements are not experimentally feasible. DatabaseThe mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database, and may be accessed at http://jjj.bio.vu.nl/database/nyman.