Organic Electronics toward Artificial Neurons

Conducting Polymer Devices Regulate Mammalian Sensory Functions

  • Fig. 1: The organic electronic ion pump (OEIP)
  • Fig. 2: Transport results for the planar OEIP. (a) Ca2+ imaging of HCN-2 cells on delivery of K+. (b) Comparison of delivered K+ vs. total transported charge indicating nearly 1:1 ratio of K+ to electrons. (c) Ca2+ imaging of SH-SY5Y cells on delivery of ACh, the numbers to the right of the voltage pulses are the duration in seconds. Panel reproduced with permission from refs. [4, 6].
  • Fig. 3: The encapsulated OEIP. The electrolytes are contained in the tubes, and charged species are released from the tip (orange arrow).
  • Fig. 4: Application in vivo. (a) Device mounted on the RWM, with the two ion channels visible as dark blue strips on the transparent substrate. The dotted lines indicate the obscured shape of the device. (b) Experimental scheme. The dotted line indicates a slice through the cochlea, expanded below. The gray arrow indicates diffusion of ions through the RWM. (c) Hearing attenuation as a function of recording frequency at 15 min (dashed bars) and 60 min (solid bars) into delivery of Glu (blue) and H+ (yellow). Error bars indicate s.d. (d) Histology demonstrating selectivity of the device: only inner hair cells are effected (asterisks indicate dendrite damage). Reproduced with permission from ref. [7].
  • Prof. Agneta Richter-Dahlfors, Swedish Medical Nanoscience Center, Karolinska Institutet
  • Daniel T. Simon, PhD, Linköping University and Swedish Medical Nanoscience Center, Karolinska Institutet

When nerve cells are exposed to chemical stimuli, an electric potential is triggered. Migrating along the axon, the signal reaches the synapse, where it is converted into the release of neurotransmitters. This mode of cell-to-cell communication inspired us to develop an artificial nerve cell based on conducting polymers. Its use for precise stimulation of nerve cells in vivo illustrates its potential as an implantable device for automated correction of malfunctioning signaling pathways in pathophysiological conditions.

Introduction


With increasing understanding of nerve cell signaling, there is a growing demand for human-made systems that can interface with the nervous system. To fulfill this "machine-to-brain" demand, techniques involving electrical stimulation of nerve cells are often used. While established therapeutically, they suffer from drawbacks, e.g., an inability to distinguish specific between cell types. Until now, no technology has demonstrated behavior analogous to a nerve cell: electrically triggered release of neurotransmitters.

A major challenge is to bridge the gap between the signal carriers of the nervous system (ions, neurotransmitters) and those of conventional electronics (electrons). Organic conjugated polymers [1] have been proposed to resolve this disparity. Unlike most plastics, these materials can conduct electricity similarly to conventional semiconductors. However, unlike other conductors, their electrical conductivity is highly dependent on the presence of charged molecules. In this way, electronic signals can be transduced directly into ionic/molecular signals, and vice versa [2, 3].

Recently, we reported an organic electronic ion pump (OEIP) which simultaneously utilizes the electronic and ionic conduction of conjugated polymers [4] (fig. 1). The device is based on poly(3,4-ethylenedioxythiophene) combined with the polyelectrolyte poly(styrenesulfonate) (PEDOT:PSS) [5]. A PEDOT:PSS film is patterned into two electrodes separated by an ionically conducting but electrically insulating "ion channel" (a salt bridge). Voltage applied across the electrodes causes redox reactions within the PEDOT:PSS, and positively charged biomolecules, in contact with the source electrode, are thus electrophoretically transported through the ion channel.

With dosage determined by precise electrochemistry, these biomolecules can be delivered to a biological system in contact with the ion channel or the target electrode. The electronic control of the circuit allows the delivery rate to be adjusted or turned on/off and due to the electrophoretic transport, no fluid is delivered into the target system. Similar to a neuron, the OEIP is thus capable of converting addressing signals (here, voltage) into the diffusive release of neurotransmitters.

Results and Discussion

Bio-Signaling by Metal Ion Delivery

Since the PEDOT:PSS surfaces of the OEIP are biocompatible [4], cells can be cultured directly on the electrodes, enabling cell-signaling studies in vitro. An ideal ion to demonstrate such functionality is K+. High extracellular [K+] results in opening of membrane-bound ion channels and influx of Ca2+. When K+ is delivered to cells cultured on the target electrode, intracellular [Ca2+] can be measured as readout for K+-mediated membrane depolarization. This study was realized by microscopy-based real-time single-cell Ca2+ imaging of human cortical neurons [4] (fig. 2a). In addition, the adjustable electrical current through the device can be used to directly determine the K+ delivery rate (fig. 2b).

Bio-Signaling by Neurotransmitter Delivery
The repertoire of species capable of transport through the OEIP was recently expanded to include positively charged neurotransmitters such as acetylcholine (ACh), glutamate (Glu), aspartate and GABA [6, 7]. Microscopy-based Ca2+ imaging demonstrates how pulsed ACh delivery can be used to induce an oscillatory Ca2+ response in human neuroblastoma cells, where the voltage pulse duration (the dosage) determines the magnitude of the response (fig. 2c).

Neurotransmitter Delivery in vivo
The above results illustrate the OEIP's feasibility as the basis of an "artificial neuron": electrical input signals are converted into the controlled diffusive release of neurotransmitters, which selectively activate cells expressing the appropriate receptor. The OEIP was therefore redesigned from its original open planar geometry to a fully encapsulated, syringe-like form, allowing its use in vivo [7]. This was achieved by "folding" the device in half, so that the ion channel comes into direct contact with the target system. To demonstrate the OEIPs efficacy in a living animal, the hearing organ of guinea pigs was used. In the cochlea, sound waves of various frequencies are transduced predominantly by the inner hair cells. These cells utilize Glu as the primary neurotransmitter, and accordingly, express the Glu receptor. The OEIP was mounted on the round window membrane (fig. 4a, b), an established point of diffusive access to the cochlea. As shown in figure 4c, delivery of Glu resulted in significant change in hearing sensitivity as compared to delivery of H+ (control). Histological analysis indicated that by delivering a particular neurotransmitter, the OEIP was able to target a specific cell type within the cochlea (fig. 4d).

Conclusion

Many prominent neurological disorders, e.g., epilepsy and Parkinson's disease, occur as a result of malfunctioning signal-transduction pathways. The "artificial nerve cell" offers a unique possibility to precisely translate electronic signals into chemical messengers and represents the establishment of a system where endogenous signaling substances - e.g., ions and neurotransmitters - can be delivered to restore the activity of signaling pathways. Our hope is that this technique will aid in increasing our understanding of pathophysiology in neurological diseases, and eventually, that it can be used as an implantable, automated delivery system for treatment of these disorders.

References

[1] Heeger A.: Rev. Mod. Phys. 73, 681-700 (2001)
[2] Kittlesen G.P. et al.: J. Am. Chem. Soc. 106, 7389-7396 (1984)
[3] Nilsson D. et al.: Advanced Materials 14, 51-54 (2002)
[4] Isaksson J. et al.: Nature Materials 6, 673-679 (2007)
[5] Groenendaal L. et al.: Advanced Materials 12, 481-494 (2000)
[6] Tybrandt K. et al.: Advanced Materials (2009)
[7] Simon D.T. et al.: Nature Materials 8, 742-746 (2009)

Authors:

Daniel T. Simon, PhD

Postdoctoral researcher with joint position at Linköping University, Department of Science and Technology, and the Swedish Medical Nanoscience Center, Karolinska Institutet, Department of Neuroscience
Karin C. Larsson, MSc
Doctoral student at the Swedish Medical Nanoscience Center, Karolinska Institutet, Department of Neuroscience
Magnus Berggren, PhD
Önnesjö Professor in Organic Electronics at Linköping University, Department of Science and Technology, and
director of the Strategic Research Center in Organic Bioelectronics
Agneta Richter-Dahlfors, PhD
Professor and director of the Swedish Medical Nanoscience Center, Karolinska Institutet, Department of Neuroscience and co-director of the Strategic Research Center in Organic Bioelectronics.

 

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