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Organic Bioelectronics for Neurotransmitter Release at the Speed of Life
Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2020. , p. 77
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 2104
National Category
Electrical Engineering, Electronic Engineering, Information Engineering Polymer Technologies Medical Engineering
Identifiers
URN: urn:nbn:se:liu:diva-171789DOI: 10.3384/diss.diva-171789ISBN: 9789179297558 (print)OAI: oai:DiVA.org:liu-171789DiVA, id: diva2:1507188
Public defence
2021-01-13, Online and K1 (kåkenhus) Please contact Jennie Jordenlöv, jennie.jordenlov@liu.se to get the Zoom link, Campus Norrköping, Norrköping, 14:00 (English)
Opponent
Supervisors
Available from: 2020-12-07 Created: 2020-12-07 Last updated: 2021-01-18Bibliographically approved
List of papers
1. Cross-Linked Polyelectrolyte for Improved Selectivity and Processability of lontronic Systems
Open this publication in new window or tab >>Cross-Linked Polyelectrolyte for Improved Selectivity and Processability of lontronic Systems
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2017 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 9, no 36, p. 30247-30252Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
Keywords
ion exchange membranes; iontronics; organic bioelectronics; microfabrication; neurotransmitter release
National Category
Other Materials Engineering
Identifiers
urn:nbn:se:liu:diva-142182 (URN)10.1021/acsami.7b05949 (DOI)000411043600002 ()28831798 (PubMedID)
Note

Funding Agencies|Knut and Alice Wallenberg Foundation (KAW) [2012.0302]; Swedish Research Council (Vetenskapsradet) [621-2011-3517]; Swedish Innovation Office (VINNOVA) [2010-00507]; Onnesjo Foundation

Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2020-12-07
2. Design and Operation of Hybrid Microfluidic Iontronic Probes for Regulated Drug Delivery
Open this publication in new window or tab >>Design and Operation of Hybrid Microfluidic Iontronic Probes for Regulated Drug Delivery
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2021 (English)In: Advanced Materials Technologies, E-ISSN 2365-709X, Vol. 6, no 2, article id 2001006Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Hoboken, New Jersey: John Wiley & Sons, 2021
Keywords
bioelectronics, drug delivery, iontronics, microfluidics, organic electronics
National Category
Medical Materials
Identifiers
urn:nbn:se:liu:diva-172686 (URN)10.1002/admt.202001006 (DOI)000607538700001 ()
Conference
2021/01/18
Funder
Swedish Foundation for Strategic Research Knut and Alice Wallenberg FoundationVinnovaSwedish Research CouncilEU, European Research Council, 2018
Note

Additional Funding agencies: FLAG‐ERA. Grant Number: JTC2017; EPIGRAPH. Grant Number: ANR‐17‐GRF2‐0001; Swedish Government Strategic Research Area in Materials Science on Advanced Functional Materials at Linköping University. Grant Number: 2009‐00971; A*MIDEX ION. Grant Number: 2IONXXID/REID/ID17HRU208

Available from: 2021-01-18 Created: 2021-01-18 Last updated: 2025-02-09Bibliographically approved
3. 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, E-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 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: 2025-02-10Bibliographically approved
4. Miniaturized Ionic Polarization Diodes for Neurotransmitter Release at Synaptic Speeds
Open this publication in new window or tab >>Miniaturized Ionic Polarization Diodes for Neurotransmitter Release at Synaptic Speeds
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2020 (English)In: Advanced Materials Technologies, E-ISSN 2365-709X, Vol. 5, no 3, article id 1900750Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
WILEY, 2020
Keywords
bioelectronics; controlled release; ion diodes; iontronics; neurotransmitters
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:liu:diva-162499 (URN)10.1002/admt.201900750 (DOI)000497801400001 ()
Note

Funding Agencies|Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research; Knut and Alice Wallenberg foundationKnut & Alice Wallenberg Foundation; Swedish Government Strategic Research Area in Materials Science on Advanced Functional Materials at Linkoping University [2009-00971]

Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2022-09-15

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Arbring Sjöström, Theresia

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