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Organic electronics for precise delivery of neurotransmitters
Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Organic electronic materials, that is, carbon-based compounds that conduct electricity, have emerged as candidates for improving the interface between conventional electronics and biological systems. The softness of these materials matches the elasticity of biological tissue better than conventional electronic conductors, allowing better contact to tissue, and the mixed ionic-electronic conductivity can improve the signal transduction between electronic devices and electrically excitable cells. This improved communication between electronics and tissue can significantly enhance, for example, electrical stimulation for therapy and electrical recording for diagnostics.

The ionic conductivity of organic electronic materials makes it possible to achieve ion-specific ionic currents, where the current consists of migration of specific ions. These ions can be charged signalling substances, such as neurotransmitters, that can selectively activate or inhibit cells that contain receptors for these substances. This thesis describes the development of chemical delivery devices, where delivery is based on such ion-specific currents through ionically and electronically conducting polymers. Delivery is controlled by electrical signals, and allows release of controlled amounts of neurotransmitters, or other charged compounds, to micrometer-sized regions.

The aims of the thesis have been to improve spatial control and temporal resolution of chemical delivery, with the ultimate goal of selective interaction with individual cells, and to enable future therapies for disorders of the nervous system. Within the thesis, we show that delivery can alleviate pain through local delivery to specific regions of the spinal cord in an animal model of neuropathic pain, and that epilepsy-related signalling can be suppressed in vitro. We also integrate the delivery device with electrodes for sensing, to allow simultaneous electrical recording and delivery at the same position. Finally, we improve the delay from electrical signal to chemical delivery, approaching the time domain of synaptic signaling, and construct devices with several individually controlled release sites.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , p. 108
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1817
National Category
Textile, Rubber and Polymeric Materials Condensed Matter Physics Biomedical Laboratory Science/Technology Materials Chemistry Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-133164DOI: 10.3384/diss.diva-133164ISBN: 978-91-7685-616-1 (print)OAI: oai:DiVA.org:liu-133164DiVA, id: diva2:1055273
Public defence
2017-01-11, Kåkenhus sal K3 (Önnesjösalen), Linköpings Universitet, Norrköping, 10:00 (English)
Opponent
Supervisors
Available from: 2016-12-12 Created: 2016-12-12 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Therapy using implanted organic bioelectronics
Open this publication in new window or tab >>Therapy using implanted organic bioelectronics
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2015 (English)In: Science Advances, ISSN 2375-2548, Vol. 1, no 4, article id e1500039Article in journal (Refereed) Published
Abstract [en]

Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug’s spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics. Keywords

Place, publisher, year, edition, pages
American Association of the Advances of Science, 2015
Keywords
pain, neuromodulation, in vivo, organic electronics, bioelectronics
National Category
Textile, Rubber and Polymeric Materials Medical Materials Other Medical Biotechnology
Identifiers
urn:nbn:se:liu:diva-117968 (URN)10.1126/sciadv.1500039 (DOI)000216593600006 ()
Projects
OBOE miljö
Funder
VINNOVA, 2010-00507
Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2018-03-09
2. Controlling Epileptiform Activity with Organic Electronic Ion Pumps
Open this publication in new window or tab >>Controlling Epileptiform Activity with Organic Electronic Ion Pumps
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2015 (English)In: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095, Vol. 27, no 20, p. 3138-3144Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-VCH Verlag, 2015
Keywords
Organic Bioelectronics, Organic Electronic Ion Pump, PEDOT:PSS, Neuroengineering
National Category
Neurology
Identifiers
urn:nbn:se:liu:diva-119247 (URN)10.1002/adma.201500482 (DOI)000354823600002 ()25866154 (PubMedID)
Note

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

Available from: 2015-06-15 Created: 2015-06-12 Last updated: 2017-11-22
3. Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site
Open this publication in new window or tab >>Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 34, p. 9440-9445Article in journal (Refereed) Published
Abstract [en]

Local control of neuronal activity is central to many therapeutic strategies aiming to treat neurological disorders. Arguably, the best solution would make use of endogenous highly localized and specialized regulatory mechanisms of neuronal activity, and an ideal therapeutic technology should sense activity and deliver endogenous molecules at the same site for the most efficient feedback regulation. Here, we address this challenge with an organic electronic multifunctional device that is capable of chemical stimulation and electrical sensing at the same site, at the single-cell scale. Conducting polymer electrodes recorded epileptiform discharges induced in mouse hippocampal preparation. The inhibitory neurotransmitter, γ-aminobutyric acid (GABA), was then actively delivered through the recording electrodes via organic electronic ion pump technology. GABA delivery stopped epileptiform activity, recorded simultaneously and colocally. This multifunctional “neural pixel” creates a range of opportunities, including implantable therapeutic devices with automated feedback, where locally recorded signals regulate local release of specific therapeutic agents.

Place, publisher, year, edition, pages
National Academy of Sciences, 2016
National Category
Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:liu:diva-130851 (URN)10.1073/pnas.1604231113 (DOI)000381860800035 ()27506784 (PubMedID)
Note

Funding agencies:We thank Gaelle Rondeau and the staff of the clean room in Centre Microelectronique de Provence (CMP) for technical support during fabrication. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under Grant Agreement 602102 (EPITARGET) and Initiative of Excellence Aix-Marseilles project MIDOE (A_M-AAP-ID-13-24-130531-16.31-BERNARD-HLS). Funding was also provided by the Swedish Innovation Office (2010-00507), the Swedish Research Council (621-2011-3517), and the Knut and Alice Wallenberg Foundation (KAW Scholar, 2012.0302). The authors also thank the National Science Foundation Grant DMR-1105253 for partial support of this work, the French National Research Agency (ANR) through the project PolyProbe (ANR-13-BSV5-0019-01), Fondation pour la Recherche Medicale under Grant Agreements DBS20131128446 and ARF20150934124, Fondation de l'Avenir, the Onnesjo Foundation, the Region Provence-Alpes-Cote d'Azur, and Microvitae Technologies. J.R. and L.K. acknowledge support from Marie Curie Fellowships. The fabrication of the device was performed, in part, at CMP.

Available from: 2016-08-26 Created: 2016-08-26 Last updated: 2017-11-21Bibliographically approved
4. Chemical delivery array with millisecond neurotransmitter release
Open this publication in new window or tab >>Chemical delivery array with millisecond neurotransmitter release
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2016 (English)In: Science Advances, ISSN 2375-2548, Vol. 2, no 11, article id e1601340Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Washington: American Association for the Advancement of Science (A A A S), 2016
National Category
Atom and Molecular Physics and Optics Computer Engineering Other Engineering and Technologies not elsewhere specified Biomedical Laboratory Science/Technology Signal Processing
Identifiers
urn:nbn:se:liu:diva-133161 (URN)10.1126/sciadv.1601340 (DOI)000391267800033 ()27847873 (PubMedID)
Available from: 2016-12-12 Created: 2016-12-12 Last updated: 2018-01-13Bibliographically approved

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