Despite a range of available pain therapies, most patients report so-called “breakthrough pain.” Coupled with global issues like opioid abuse, there is a clear need for advanced therapies and technologies for safe and effective pain management. Here the authors demonstrate a candidate for such an advanced therapy: precise and fluid-flow-free electrophoretic delivery via organic electronic ion pumps (OEIPs) of the commonly used anesthetic drug bupivacaine. Bupivacaine is delivered to dorsal root ganglion (DRG) neurons in vitro. DRG neurons are a good proxy for pain studies as they are responsible for relaying ascending sensory signals from nociceptors (pain receptors) in the peripheral nervous system to the central nervous system. Capillary based OEIPs are used due to their probe-like and free-standing form factor, ideal for interfacing with cells. By delivering bupivacaine with the OEIP and recording dose versus response (Ca²⁺ imaging), it is observed that only cells close to the OEIP outlet (≤75 µm) are affected (“anaesthetized”) and at concentrations up to 10s of thousands of times lower than with bulk/bolus delivery. These results demonstrate the first effective OEIP deliveryof a clinically approved and widely used analgesic pharmaceutical, and thus are a major translational milestone for this technology.

The organic electronic ion pump (OEIP) is an on-demand electrophoretic drug delivery device, that via electronic to ionic signal conversion enables drug delivery without additional pressure or volume changes. The fundamental component of OEIPs is their polyelectrolyte membranes which are shaped into ionic channels that conduct and deliver ionic drugs, with high spatiotemporal resolution. The patterning of these membranes is essential in OEIP devices and is typically achieved using laborious micro processing techniques. Here, we report the development of an inkjet printable formulation of polyelectrolyte, based on a custom anionically functionalized hyperbranched polyglycerol (i-AHPG). This polyelectrolyte ink greatly simplifies the fabrication process, and is used in the production of free standing, OEIPs on flexible polyimide substrates. Both i-AHPG and the OEIP devices are characterized, exhibiting favorable iontronic characteristics of charge selectivity and ability to transport aromatic compounds. Further, the applicability of these technologies is demonstrated by transport and delivery of the pharmaceutical compound bupivacaine to dorsal root ganglion cells with high spatial precision and effective nerve-blocking, highlighting the applicability of these technologies for biomedical scenarios.

Body area networks (BANs), cloud computing, and machine learning are platforms that can potentially enable advanced healthcare outside the hospital. By applying distributed sensors and drug delivery devices on/in our body and connecting to such communication and decision-making technology, a system for remote diagnostics and therapy is achieved with additional autoregulation capabilities. Challenges with such autarchic on-body healthcare schemes relate to integrity and safety, and interfacing and transduction of electronic signals into biochemical signals, and vice versa. Here, we report a BAN, comprising flexible on-body organic bioelectronic sensors and actuators utilizing two parallel pathways for communication and decision-making. Data, recorded from strain sensors detecting body motion, are both securely transferred to the cloud for machine learning and improved decision-making, and sent through the body using a secure body-coupled communication protocol to auto-actuate delivery of neurotransmitters, all within seconds. We conclude that both highly stable and accurate sensing-from multiple sensors-are needed to enable robust decision making and limit the frequency of retraining. The holistic platform resembles the self-regulatory properties of the nervous system, i.e., the ability to sense, communicate, decide, and react accordingly, thus operating as a digital nervous system.

Highly controlled drug delivery devices play an increasingly important role in the development of new neuroengineering tools. Stringent - and sometimes contradicting - demands are placed on such devices, ranging from robustness in freestanding devices, to overall device miniaturization, while maintaining precise spatiotemporal control of delivery with high chemical specificity and high on/off ratio. Here, design principles of a hybrid microfluidic iontronic probe that uses flow for long-range pressure-driven transport in combination with an iontronic tip that provides electronically fine-tuned pressure-free delivery are explored. Employing a computational model, the effects of decoupling the drug reservoir by exchanging a large passive reservoir with a smaller microfluidic system are reported. The transition at the microfluidic-iontronic interface is found to require an expanded ion exchange membrane inlet in combination with a constant fluidic flow, to allow a broad range of device operation, including low source concentrations and high delivery currents. Complementary to these findings, the free-standing hybrid probe monitored in real time by an external sensor is demonstrated. From these computational and experimental results, key design principles for iontronic devices are outlined that seek to use the efficient transport enabled by microfluidics, and further, key observations of hybrid microfluidic iontronic probes are explained.

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 bodys 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 mu s 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 amp;lt;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.

The signaling dynamics in neuronal networks includes processes ranging from lifelong neuromodulation to direct synaptic neurotransmission. In chemical synapses, the time delay it takes to pass a signal from one neuron to the next lasts for less than a millisecond. At the post-synaptic neuron, further signaling is either up- or down-regulated, dependent on the specific neurotransmitter and receptor. While this up- and down-regulation of signals usually runs perfectly well and enables complex performance, even a minor dysfunction of this signaling system can cause major complications, in the shape of neurological disorders. The field of organic bioelectronics has the ability to interface neurons with high spatiotemporal recording and stimulation techniques. Local chemical stimulation, i.e. local release of neurotransmitters, enables the possibility of artificially altering the chemical environment in dysfunctional signaling pathways to regain or restore neural function. To successfully interface the biological nervous system with electronics, a range of demands must be met. Organic bioelectronic techniques and materials are capable of reaching the demands on the biological as well as the electronic side of the interface. These demands span from high performance biocompatible materials, to miniaturized and specific device architectures, and high dose control on demand within milliseconds.

The content of this thesis is a continuation of the development of organic bioelectronic devices for neurotransmitter delivery. Organic materials are utilized to electrically control the dose of charged neurotransmitters by translating electric charge into controlled artificial release. The first part of the thesis, Papers 1 and 2, includes further development of the resistor-type release device called the organic electronic ion pump. This part includes material evaluation, microfluidic incorporation, and device design considerations. The aim for the second part of this thesis, Papers 3 and 4, is to enhance temporal performance, i.e. reduce the delay between electrical signal and neurotransmitter delivery to corresponding delay in biological neural signaling, while retaining tight dosage control. Diffusion of neurotransmitters between nerve cells is a slow process, but since it is restricted to short distances, the total time delay is short. In our organic bioelectronic devices, several orders of magnitude in speed can be gained by switching from lateral to vertical delivery geometries. This is realized by two different types of vertical diodes combined with a lateral preload and waste configuration. The vertical diode assembly was further expanded with a control electrode that enables individual addressing in each of several combined release sites. These integrated circuits allow for release of neurotransmitters with high on/off release ratios, approaching delivery times on par with biological neurotransmission.

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.

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 bioelectronics. Since organic bioelectronics relies on the electron-mediated transport and compensation of ions (or the ion-mediated transport and compensation of electrons), a great deal of effort has been devoted to the development of so-called "iontronic" components to effect precise substance delivery/transport, that is, components where ions are the dominant charge carrier and where ionic-electronic coupling defines device functionality. This effort has resulted in a range of technologies including ionic resistors, diodes, transistors, and basic logic circuits for the precisely controlled transport and delivery of biologically active chemicals. This Research News article presents a brief overview of some of these "ion pumping" technologies, how they have evolved over the last decade, and a discussion of applications in vitro, in vivo, and in plantae.

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 LEMs 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 acidco-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 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.

Technologies that restore or augment dysfunctional neural signaling represent a promising route to deeper understanding and new therapies for neurological disorders. Because of the chemical specificity and subsecond signaling of the nervous system, these technologies should be able to release specific neurotransmitters at specific locations with millisecond resolution. We have previously demonstrated an organic electronic lateral electrophoresis technology capable of precise delivery of charged compounds, such as neurotransmitters. However, this technology, the organic electronic ion pump, has been limited to a single delivery point, or several simultaneously addressed outlets, with switch-on speeds of seconds. We report on a vertical neurotransmitter delivery device, configured as an array with individually controlled delivery points and a temporal resolution of 50 ms. This is achieved by supplementing lateral electrophoresis with a control electrode and an ion diode at each delivery point to allow addressing and limit leakage. By delivering local pulses of neurotransmitters with spatiotemporal dynamics approaching synaptic function, the high-speed delivery array promises unprecedented access to neural signaling and a path toward biochemically regulated neural prostheses.

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.

The beta-adrenergic response is impaired in failing hearts. When studying beta-adrenergic function in vitro, the half-maximal effective concentration (EC50) 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 EC50. Instead, we have applied a mathematical modeling approach to interpret the full dose–response curvein 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 EC50 may be calculated using steady-state simulations of the model. The model-based estimation of EC50 is further refined using additional time resolved data to decrease the uncertainty of the prediction. The resulting model-based EC50 (180–525 nM) is higher than the classically interpreted EC50 (46–191 nM). Mathematical modeling thus makes it possible to reinterpret previously obtained datasets, and to make accurate estimates of EC50 even when steady-state measurements are not experimentally feasible.