| 1. |
- Abrahamsson, Tobias, 1991-
(författare)
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Synthetic Functionalities for Ion and Electron Conductive Polymers : Applications in Organic Electronics and Biological Interfaces
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the search for understanding and communicating with all biological systems, in humans, animals, plants, and even microorganisms, we find a common language of all communicating via electrons, ions and molecules. Since the discovery of organic electronics, the ability to bridge the gap and communicate be-tween modern technology and biology has emerged. Organic chemistry pro-vides us with tools for understanding and a material platform of polymer electronics for communication. Such insights give us not only the ability to observe fundamental phenomenon but to actively design and construct materials with chemical functionalities towards better interfaces and applications. Organic electronic materials and devices have found their way to be implemented in the field of medicine for diagnostic and therapeutic purposes, but also in water purification and to help tackle the monumental task in creating the next generation of sustainable energy production and storage. Ultimately it’s safe to say that organic electronics are not going to replace our traditional technology based on inorganic materials but rather the two fields can find a way to complement each other for various purposes and applications. Compared to conventional silicon based technology, production of carbon-based organic electronic polymer materials are extremely cheap and devices can even be made flexible and soft with great compatibility towards biology. The main focus of this thesis has been developing and synthesizing new types of organic electronic and ionic conductive polymeric materials. Rational chemical design and modifications of the materials have been utilized to introduce specific functionalities to the materials. The functionalities serving the purpose to facilitate ion and electron conductive charge transport for organic electronics and with biological interface implementation of the polymer materials. Multi-functional ionic conductive hyperbranched polyglycerol polyelectrolytes (dendrolytes) were developed comprising both ionically charged groups and cross-linkable groups. The hyperbranched polyglycerol core structure of the material possesses a hydrophilic solvating platform for both ions and maintenance of solvent molecules, while being a biocompatible structure. Coupled with the peripheral charged ionic functionalities of the polymer, the dendrolyte materials are highly ionic conductive and selective towards cationic and anionic charged atoms and large molecules when implemented as ion-exchange membranes. Homogenous ion-exchange membrane casting has been achieved by the implementation of cross-linkable functionalities in the dendrolytes, utilizing robust click-chemistry for efficient micro and macro fabrication processing of the ion-ex-change membranes for organic electronic devices. The ion-exchange membrane material was implemented in electrophoretic drug delivery devices (organic electronic ion pumps), which are used for delivery of ions and neurotransmitters with spatiotemporal resolution and are able to communicate and be used for therapeutic drug delivery purposes in biological interfaces. The dendrolyte materials were also able to form free-standing membranes, making it possible for implementation in fuel cell and desalination purposes. Trimeric conjugated thiophene pre-polymer structures were also developed in the thesis and synthesized for the purpose of implementation of the material in vivo to form electrically conductive polymer structures, and in such manner to be able to create electrodes and ultimately to connect with the central nervous system. The conjugated pre-polymers being both water soluble and enzymatically polymerizable serve as a platform to realize such a concept. Also, modifying the trimeric structure with cross-linkable functionality created the capability to form better interfaces and stability towards biological environments.
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| 2. |
- Bliman, David, et al.
(författare)
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8-Bromination of 2,6,9-trisubstituted purines with pyridinium tribromide
- 2014
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Ingår i: Tetrahedron Letters. - : Elsevier Ltd. - 0040-4039 .- 1359-8562. ; 55:18, s. 2929-2931
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Tidskriftsartikel (refereegranskat)abstract
- 2,6,9-Trisubstituted purines are brominated in high yields using pyridinium tribromide as the brominating reagent. This procedure works excellently for electron-rich purines having electron-donating substituents at the 2- and 6-positions. The use of pyridinium tribromide, a crystalline alternative to elemental bromine, improves the bromination procedure for this type of substrate as the reagent is easy to handle and the work-up and purification procedures are simplified.
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| 3. |
- Bliman, David, et al.
(författare)
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A Caged Ret Kinase Inhibitor and its Effect on Motoneuron Development in Zebrafish Embryos
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Proto-oncogene tyrosine-protein kinase receptor RET is implicated in the development and maintenance of neurons of the central and peripheral nervous systems. Attaching activity-compromising photocleavable groups (caging) to inhibitors could allow for external spatiotemporally controlled inhibition using light, potentially providing novel information on how these kinase receptors are involved in cellular processes. Here, caged RET inhibitors were obtained from 3-substituted pyrazolopyrimidine-based compounds by attaching photolabile groups to the exocyclic amino function. The most promising compound displayed excellent inhibitory effect in cell-free, as well as live-cell assays upon decaging. Furthermore, inhibition could be efficiently activated with light in vivo in zebrafish embryos and was shown to effect motoneuron development.
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| 4. |
- Bliman, David
(författare)
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Purine and Pyrazolopyrimidine Derivatives: Design and Synthesis of Chemical Tools for Biological Applications
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Purines can be found in a multitude of naturally occurring compounds with a range of functions. This thesis describes the design and synthesis of purines and structurally related pyrazolopyrimidine derivatives intended for biological applications. Pyrazolopyrimidines are structurally related to purines and are used as scaffolds for ATP-competitive protein kinase inhibitors. A pyrazolopyrimidine based selective inhibitor of receptor tyrosine kinase REarranged during Transfection (RET), a protein kinase involved in cell development, was modified with a photolabile protecting group. The modification allowed for photocontrolled release of the inhibitor. Photodependent inhibition of RET was demonstrated in both a biochemical assay and in a cell based RET-assay. The utility of the caged inhibitor was demonstrated in transgenic zebrafish embryos by demonstrating the effect of photocontrolled RET-inhibition on motoneuron development. In addition, it was shown that the timing of irradiation was critical for motoneuron development. The purine structure is a key constituent of aminoacyl-adenosine monophosphate (aa-AMP), an intermediate in protein biosynthesis. Stable mimics of aa-AMP could have potential as inhibitors of protein biosynthesis, a mechanism identified as a target for antiinfectives. A series of 8-(triazolyl)purines was synthesized as aa-AMP mimics. In addition, their photophysical properties were studied to evaluate their potential as fluorescent probes. Unexpectedly, these compounds displayed very low quantum yields in contrast to previous data for similar structures. Protein-protein interactions (PPIs) are ubiquitously present in cells, have a central role in cell signaling and have been identified as interesting drug targets. The α-helix secondary structure has been identified as a central element in many PPIs. In this project, 2,6,9-substituted 8-(triazolyl)purines were evaluated as α-helix mimetics and inhibitors of the p53/MDM2 PPI. A series of compounds were synthesized and two of the compounds exhibited micromolar activity against MDM2. In addition, a bromination procedure for 8-bromination of purines was developed. Bromination with pyridinium tribromide at room temperature resulted in high yields for electron rich 2,6,9-substituted purines. The procedure is a convenient alternative to elemental bromine for this transformation. The fluorescent properties of the compounds were also measured. One of the compounds showed a high quantum yield of 51% and several compounds had quantum yields between 5-10%. The fluorescent properties could be useful for example to study intracellular localization of bioactive compounds.
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| 5. |
- Gerasimov, Jennifer, et al.
(författare)
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A Biomimetic Evolvable Organic Electrochemical Transistor
- 2021
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Ingår i: Advanced Electronic Materials. - : Wiley. - 2199-160X. ; 7:11
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Tidskriftsartikel (refereegranskat)abstract
- Biomimicry at the hardware level is expected to overcome at least some of the challenges, including high power consumption, large footprint, two-dimensionality, and limited functionality, which arise as the field of artificial intelligence matures. One of the main attributes that allow biological systems to thrive is the successful interpretation of and response to environmental signals. Taking inspiration from these systems, the first demonstration of using multiple environmental inputs to trigger the formation and control the growth of an evolvable synaptic transistor is reported here. The resulting transistor exhibits long-term changes in the channel conductance at a fixed gate voltage. Biomimetic logic circuits are investigated based on this evolvable transistor that implement temperature and pressure inputs to achieve higher order processes like self-regulation of synaptic strength and coincidence detection.
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| 6. |
- Gerasimov, Jennifer Yevgenia, 1985-, et al.
(författare)
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Rational Materials Design for In Operando Electropolymerization of Evolvable Organic Electrochemical Transistors
- 2022
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Ingår i: Advanced Functional Materials. - : John Wiley and Sons Inc. - 1616-301X .- 1616-3028. ; 32
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Tidskriftsartikel (refereegranskat)abstract
- Organic electrochemical transistors formed by in operando electropolymerization of the semiconducting channel are increasingly becoming recognized as a simple and effective implementation of synapses in neuromorphic hardware. However, very few studies have reported the requirements that must be met to ensure that the polymer spreads along the substrate to form a functional conducting channel. The nature of the interface between the substrate and various monomer precursors of conducting polymers through molecular dynamics simulations is investigated, showing that monomer adsorption to the substrate produces an increase in the effective monomer concentration at the surface. By evaluating combinatorial couples of monomers baring various sidechains with differently functionalized substrates, it is shown that the interactions between the substrate and the monomer precursor control the lateral growth of a polymer film along an inert substrate. This effect has implications for fabricating synaptic systems on inexpensive, flexible substrates. © 2022 The Authors.
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| 7. |
- Hjort, Martin, et al.
(författare)
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In situ assembly of bioresorbable organic bioelectronics in the brain
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Bioelectronics can potentially complement classical therapies in nonchronic treatments, such as immunotherapy and cancer. In addition to functionality, minimally invasive implantation methods and bioresorbable materials are central to nonchronic treatments. The latter avoids the need for surgical removal after disease relief. Self-organizing substrate-free organic electrodes meet these criteria and integrate seamlessly into dynamic biological systems in ways difficult for classical rigid solid-state electronics. Here we place bioresorbable electrodes with a brain-matched shear modulus-made from water-dispersed nanoparticles in the brain-in the targeted area using a capillary thinner than a human hair. Thereafter, we show that an optional auxiliary module grows dendrites from the installed conductive structure to seamlessly embed neurons and modify the electrode's volume properties. We demonstrate that these soft electrodes set off a controlled cellular response in the brain when relaying external stimuli and that the biocompatible materials show no tissue damage after bioresorption. These findings encourage further investigation of temporary organic bioelectronics for nonchronic treatments assembled in vivo. Temporary bioelectronics can complement classical therapies in non-chronic treatments. Here, the authors describe the minimally invasive implantation of bioresorbable electrodes in the brain that form in situ from water-dispersed nanoparticles and show no tissue damage after bioresorption.
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| 8. |
- Mousa, Abdelrazek H., et al.
(författare)
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Method Matters: Exploring Alkoxysulfonate-Functionalized Poly(3,4-ethylenedioxythiophene) and Its Unintentional Self-Aggregating Copolymer toward Injectable Bioelectronics
- 2022
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Ingår i: Chemistry of Materials. - : American Chemical Society (ACS). - 0897-4756 .- 1520-5002. ; 34:6, s. 2752-2763
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Tidskriftsartikel (refereegranskat)abstract
- Injectable bioelectronics could become an alternative or a complement to traditional drug treatments. To this end, a new self-doped p- type conducting PEDOT-S copolymer (A5) was synthesized. This copolymer formed highly water-dispersed nanoparticles and aggregated into a mixed ion-electron conducting hydrogel when injected into a tissue model. First, we synthetically repeated most of the published methods for PEDOT-S at the lab scale. Surprisingly, analysis using high-resolution matrix-assisted laser desorption ionization-mass spectroscopy showed that almost all the methods generated PEDOT-S derivatives with the same polymer lengths (i.e., oligomers, seven to eight monomers in average); thus, the polymer length cannot account for the differences in the conductivities reported earlier. The main difference, however, was that some methods generated an unintentional copolymer P(EDOT-S/EDOT-OH) that is more prone to aggregate and display higher conductivities in general than the PEDOT-S homopolymer. Based on this, we synthesized the PEDOT-S derivative A5, that displayed the highest film conductivity (33 S cm(-1)) among all PEDOT-S derivatives synthesized. Injecting A5 nanoparticles into the agarose gel cast with a physiological buffer generated a stable and highly conductive hydrogel (1-5 S cm(-1)), where no conductive structures were seen in agarose with the other PEDOT-S derivatives. Furthermore, the ion-treated A5 hydrogel remained stable and maintained initial conductivities for 7 months (the longest period tested) in pure water, and A5 mixed with Fe3O4 nanoparticles generated a magnetoconductive relay device in water. Thus, we have successfully synthesized a water-processable, syringe-injectable, and self-doped PEDOT-S polymer capable of forming a conductive hydrogel in tissue mimics, thereby paving a way for future applications within in vivo electronics.
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| 9. |
- Padinhare, Harikesh, et al.
(författare)
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Organic electrochemical neurons and synapses with ion mediated spiking
- 2022
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Ingår i: Nature Communications. - : Nature Portfolio. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Future brain-machine interfaces, prosthetics, and intelligent soft robotics will require integrating artificial neuromorphic devices with biological systems. Due to their poor biocompatibility, circuit complexity, low energy efficiency, and operating principles fundamentally different from the ion signal modulation of biology, traditional Silicon-based neuromorphic implementations have limited bio-integration potential. Here, we report the first organic electrochemical neurons (OECNs) with ion-modulated spiking, based on all-printed complementary organic electrochemical transistors. We demonstrate facile bio-integration of OECNs with Venus Flytrap (Dionaea muscipula) to induce lobe closure upon input stimuli. The OECNs can also be integrated with all-printed organic electrochemical synapses (OECSs), exhibiting short-term plasticity with paired-pulse facilitation and long-term plasticity with retention >1000 s, facilitating Hebbian learning. These soft and flexible OECNs operate below 0.6 V and respond to multiple stimuli, defining a new vista for localized artificial neuronal systems possible to integrate with bio-signaling systems of plants, invertebrates, and vertebrates. The integration of artificial neuromorphic devices with biological systems plays a fundamental role for future brain-machine interfaces, prosthetics, and intelligent soft robotics. Harikesh et al. demonstrate all-printed organic electrochemical neurons on Venus flytrap that is controlled to open and close.
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| 10. |
- Pettersson, Mariell, 1984, et al.
(författare)
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8-Triazolylpurines: Towards Fluorescent Inhibitors of the MDM2/p53 Interaction
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Small molecule nonpeptidic mimics of alpha-helices are widely recognised as protein-protein interaction (PPIs) inhibitors. Protein-protein interactions mediate virtually all important regulatory pathways in a cell, and the ability to control and modulate PPIs is therefore of great significance to basic biology, where controlled disruption of protein networks is key to understanding network connectivity and function. We have designed and synthesised two series of 2,6,9-substituted 8-triazolylpurines as alpha-helix mimetics. The first series was designed based on low energy conformations but did not display any biological activity in a biochemical fluorescence polarisation assay targeting MDM2/p53. Although solution NMR conformation studies demonstrated that such molecules could mimic the topography of an alpha-helix, docking studies indicated that the same compounds were not optimal as inhibitors for the MDM2/p53 interaction. A new series of 8-triazolylpurines was designed based on a combination of docking studies and analysis of recently published inhibitors. The best compound displayed low micromolar inhibitory activity towards MDM2/p53 in a biochemical fluorescence polarisation assay. In order to evaluate the applicability of these compounds as biologically active and intrinsically fluorescent probes, their absorption/emission properties were measured. The compounds display fluorescent properties with quantum yields up to 50%.
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