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  • 1.
    Asplund, Maria
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Conjugated Polymers for Neural Interfaces: Prospects, possibilities and future challenges2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Within the field of neuroprosthetics the possibility to use implanted electrodes for communication with the nervous system is explored. Much effort is put into the material aspects of the electrode implant to increase charge injection capacity, suppress foreign body response and build micro sized electrode arrays allowing close contact with neurons. Conducting polymers, in particular poly(3,4-ethylene dioxythiophene) (PEDOT), have been suggested as materials highly interesting for such neural communication electrodes. The possibility to tailor the material both mechanically and biochemically to suit specific applications, is a substantial benefit with polymers when compared to metals. PEDOT also have hybrid charge transfer properties, including both electronic and ionic conduction, which allow for highly efficient charge injection.

     

    Part of this thesis describes a method of tailoring PEDOT through exchanging the counter ion used in electropolymerisation process. Commonly used surfactants can thereby be excluded and instead, different biomolecules can be incorporated into the polymer. The electrochemical characteristics of the polymer film depend on the ion. PEDOT electropolymerised with heparin was here determined to have the most advantageous properties. In vitro methods were applied to confirm non-cytotoxicity of the formed PEDOT:biomolecular composites. In addition, biocompatibility was affirmed for PEDOT:heparin by evaluation of inflammatory response and neuron density when implanted in rodent cortex.

     

    One advantage with PEDOT often stated, is its high stability compared to other conducting polymers. A battery of tests simulating the biological environment was therefore applied to investigate this stability, and especially the influence of the incorporated heparin. These tests showed that there was a decline in the electroactivity of PEDOT over time. This also applied in phosphate buffered saline at body temperature and in the absence of other stressors. The time course of degradation also differed depending on whether the counter ion was the surfactant polystyrene sulphonate or heparin, with a slightly better stability for the former.

     

    One possibility with PEDOT, often overlooked for biological applications, is the use of its semi conducting properties in order to include logic functions in the implant. This thesis presents the concept of using PEDOT electrochemical transistors to construct textile electrode arrays with in-built multiplexing. Using the electrolyte mediated interaction between adjacent PEDOT coated fibres to switch the polymer coat between conducting and non conducting states, then transistor function can be included in the conducting textile. Analogue circuit simulations based on experimentally found transistor characteristics proved the feasibility of these textile arrays. Developments of better polymer coatings, electrolytes and encapsulation techniques for this technology, were also identified to be essential steps in order to make these devices truly useful.

     

    In summary, this work shows the potential of PEDOT to improve neural interfaces in several ways. Some weaknesses of the polymer and the polymer electronics are presented and this, together with the epidemiological data, should point in the direction for future studies within this field.

  • 2.
    Asplund, Maria
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Hamedi, Mahiar
    Forchheimer, Robert
    Inganäs, Olle
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Wire electronics and woven logic, as a potential technology for neuroelectronic implantsManuscript (Other (popular science, discussion, etc.))
    Abstract [en]

    New strategies to improve neuron coupling to neuroelectronic implants are needed. In particular, to maintain functional coupling between implant and neurons, foreign body response like encapsulation must me minimized. Apart from modifying materials to mitigate encapsulation it has been shown that with extremely thin structures, encapsulation will be less pronounced. We here utilize wire electrochemical transistors (WECTs) using conducting polymer coated fibers. Monofilaments down to 10 μm can be successfully coated and weaved into complex networks with built in logic functions, so called textile logic. Such systems can control signal patterns at a large number of electrode terminals from a few addressing fibres. Not only is fibre size in the range where less encapsulation is expected but textiles are known to make successful implants because of their soft and flexible mechanical properties. Further, textile fabrication provides versatility and even three dimensional networks are possible. Three possible architectures for neuroelectronic systems are discussed. WECTs are sensitive to dehydration and materials for better durability or improved encapsulation is needed for stable performance in biological environments.

  • 3.
    Asplund, Maria
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Hamedi, Mahiar
    Inganäs, Olle
    Forchheimer, Robert
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Neural microcontacts with wire electrodes and woven logic2007Conference paper (Refereed)
  • 4.
    Asplund, Maria
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Nilsson, Mats
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Jacobsson, Anders
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Incidence of traumatic peripheral nerve injuries and amputations in Sweden between 1998 and 20062008In: Neuroepidemiology, ISSN 0251-5350, E-ISSN 1423-0208Article in journal (Refereed)
    Abstract [en]

    Background: To define the epidemiological pattern of nerve injuries and traumatic amputations in Sweden, 1998-2006, and investigate possible targets for emerging neural engineering and neuroprosthetic technologies.

    Methods: The Swedish Hospital Discharge Register was used as basis of information, including data from all public in-patient care, excluding out-patient data. ICD-10 codes were screened for nerve injuries and traumatic amputations of high incidence or in-patient care time. Selected codes, causing factors, age and gender distribution were discussed in detail, and potential targets for tailored solutions were identified.

    Results: Incidence rate was determined to 13.9 for nerve injuries and 5.21 for amputations per 100 000 person-yrs. The majority of injuries occurred at wrist and hand level although it could be concluded that these are often minor injuries requiring less than a week of hospitalization. The single most care consuming nerve injury was brachial plexus injury constituting, in average, 68 injuries and 960 hospital days annually. When minor amputations of fingers and toes were disregarded, most frequent site of amputation was between knee and ankle (24 patients / year).

    Conclusions: Based on analysis of incidence and care time, we find that brachial plexus injuries and lower leg amputations should be primary targets of these new technologies.

  • 5.
    Asplund, Maria
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Nyberg, Tobias
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Inganäs, Olle
    Electroactive polymers for neural interfaces2010In: Polymer chemistry, ISSN 1759-9954, Vol. 1, no 9, p. 1374-1391Article, review/survey (Refereed)
    Abstract [en]

    Development of electroactive conjugated polymers, for the purpose of recording and eliciting signals in the neural systems in humans, can be used to fashion the interfaces between the two signalling systems of electronics and neural systems. The design of desirable chemical, mechanical and electrical properties in the electroactive polymer electrodes, and the means of integration of these into biological systems, are here reviewed.

  • 6.
    Asplund, Maria
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Thaning, Elin
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Lundberg, J.
    Sandberg-Nordqvist, A. C.
    Kostyszyn, B.
    Inganas, O.
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Toxicity evaluation of PEDOT/biomolecular composites intended for neural communication electrodes2009Article in journal (Refereed)
    Abstract [en]

    Electrodes coated with the conducting polymer poly(3,4-ethylene dioxythiophene) (PEDOT) possess attractive electrochemical properties for stimulation or recording in the nervous system. Biomolecules, added as counter ions in electropolymerization, could further improve the biomaterial properties, eliminating the need for surfactant counter ions in the process. Such PEDOT/biomolecular composites, using heparin or hyaluronic acid, have previously been investigated electrochemically. In the present study, their biocompatibility is evaluated. An agarose overlay assay using L929 fibroblasts, and elution and direct contact tests on human neuroblastoma SH-SY5Y cells are applied to investigate cytotoxicity in vitro. PEDOT: heparin was further evaluated in vivo through polymer-coated implants in rodent cortex. No cytotoxic response was seen to any of the PEDOT materials tested. The examination of cortical tissue exposed to polymer-coated implants showed extensive glial scarring irrespective of implant material (Pt:polymer or Pt). However, quantification of immunological response, through distance measurements from implant site to closest neuron and counting of ED1+ cell density around implant, was comparable to those of platinum controls. These results indicate that PEDOT: heparin surfaces were non-cytotoxic and show no marked difference in immunological response in cortical tissue compared to pure platinum controls.

  • 7.
    Asplund, Maria
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Thaning, Elin
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Lundberg, Johan
    Sandberg-Nordqvist, Ann-Christin
    Kostyszyn, Beata
    Inganäs, Olle
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Biocompatibility of PEDOT/biomolecular composites intended for neural communication electrodesManuscript (Other (popular science, discussion, etc.))
    Abstract [en]

    Electrodes of the conjugated polymer poly(3,4-ethylene dioxythiophene) (PEDOT) have been shown to possess very attractive electrochemical properties for functional electrical stimulation (FES) or recording in the nervous system. Biomolecules already present in nervous tissue, added as counter ions in PEDOT electropolymerisation, could be a route to further improve the biomaterial properties of PEDOT, eliminating the need of surfactant counter ions like docedyl benzene sulphonate (DBS) or polystyrene sulphonate (PSS) in the polymerisation process. Such PEDOT/biomolecular composites using heparin, or hyaluronic acid, have been electrochemically investigated in a previous study and have been shown to retain the attractive electrochemical properties already proven for PEDOT:PSS.

     

    The aim of the present study is to evaluate biocompatibility of these PEDOT/biomolecular composites in vitro and also evaluate PEDOT:heparin biocompatibility in cortical tissue in vivo. Hereby, we also aim to identify a suitable test protocol, that can be used in future evaluations when further material developments are made.

     

    Material toxicity was first tested on cell lines, both through a standardised agarose overlay assay on L929 fibroblasts, and through elution tests on human neuroblastoma SH-SY5Y cells. Subsequently, a biocompatibility in vivo test was performed using PEDOT:heparin coated platinum probes implanted in the cerebral cortex of Sprague-Dawley rats. Tissue was collected at three weeks and six weeks of implantation and evaluated by immunohistochemistry.

     

    No cytotoxic response was seen to any of the PEDOT:biomolecular composites tested here. Furthermore, elution tests were found to be a practical and effective way of screening materials for toxicity and had a clear advantage over the agarose overlay assay, which was difficult to apply on other cell types than fibroblasts. Elution tests would therefore be recommendable as a screening method, at all stages of material development. In the in vivo tests, the stiffness of the platinum substrate was a significant problem, and extensive glial scarring was seen in most cases irrespective of implant material. However, quantification of immunological response through distance measurements from implant site to closest neuron, and counting of macrophage densities in proximity to polymer surface, was comparable to those of platinum controls. These results indicate that PEDOT:heparin surfaces were as compatible with cortical tissue as pure platinum controls.

  • 8.
    Asplund, Maria
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Inganäs, Olle
    Composite biomolecule/PEDOT materials for neural electrodes2008In: Biointerphases, ISSN 1559-4106, Vol. 3, no 3, p. 83-93Article in journal (Refereed)
    Abstract [en]

    Electrodes intended for neural communication must be designed to meet boththe electrochemical and biological requirements essential for long term functionality. Metallic electrode materials have been found inadequate to meet theserequirements and therefore conducting polymers for neural electrodes have emergedas a field of interest. One clear advantage with polymerelectrodes is the possibility to tailor the material to haveoptimal biomechanical and chemical properties for certain applications. To identifyand evaluate new materials for neural communication electrodes, three chargedbiomolecules, fibrinogen, hyaluronic acid (HA), and heparin are used ascounterions in the electrochemical polymerization of poly(3,4-ethylenedioxythiophene) (PEDOT). The resultingmaterial is evaluated electrochemically and the amount of exposed biomoleculeon the surface is quantified. PEDOT:biomolecule surfaces are also studiedwith static contact angle measurements as well as scanning electronmicroscopy and compared to surfaces of PEDOT electrochemically deposited withsurfactant counterion polystyrene sulphonate (PSS). Electrochemical measurements show that PEDOT:heparinand PEDOT:HA, both have the electrochemical properties required for neuralelectrodes, and PEDOT:heparin also compares well to PEDOT:PSS. PEDOT:fibrinogen isfound less suitable as neural electrode material.

  • 9. Gillies, P.
    et al.
    Marshall, I.
    Asplund, Maria L M
    KTH, School of Technology and Health (STH), Centres, Centre for Technology in Medicine and Health, CTMH.
    Winkler, P.
    Higinbotham, J.
    Quantification of MRS data in the frequency domain using a wavelet filter, an approximated Voigt lineshape model and prior knowledge2006In: NMR in Biomedicine, ISSN 0952-3480, E-ISSN 1099-1492, Vol. 19, no 5, p. 617-626Article in journal (Refereed)
    Abstract [en]

    Quantification of MRS spectra is a challenging problem when a large baseline is present along with a low signal to noise ratio. This work investigates a robust fitting technique that yields accurate peak areas under these conditions. Using simulated long echo time 1H MRS spectra with low signal to noise ratio and a large baseline component, both the accuracy and reliability of the fit in the frequency domain were greatly improved by reducing the number of fitted parameters and making full use of all the known information concerning the Voigt lineshape. Using an appropriate first order approximation to a popular approximation of the Voigt lineshape, a significant improvement in the estimate of the area of a known spectral peak was obtained with a corresponding reduction in the residual. Furthermore, this improved parameter choice resulted in a large reduction in the number of iterations of the least-squares fitting routine. On the other hand, making use of the known centre frequency differences of the component resonances gave negligible improvement. A wavelet filter was used to remove the baseline component. In addition to performing a Monte Carlo study, these fitting techniques were also applied to a set of 10 spectra acquired from healthy human volunteers.Again, the same reduced parameter model gave the lowest value for X2 in each case.

  • 10. Inganäs, Olle
    et al.
    Asplund, Maria
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Hamedi, Mahiar
    Forchheimer, Robert
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Neural Contacts with Conjugated Polymers in Fibre Geometries2007Conference paper (Refereed)
  • 11.
    Maria, Asplund
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Thaning, Elin
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Inganäs, Olle
    Biomolecular and Organic Electronics IFM, and Center of Organic Electronics, Linköping University, SE-581 83 Linköping, Sweden.
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Electroactive Polymers for Neural Interfaces: New Materials2007Conference paper (Refereed)
  • 12.
    Thaning, Elin
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Asplund, Maria
    KTH, School of Technology and Health (STH).
    Nyberg, Tobias
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Inganäs, Olle
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Stability of PEDOT materials intended for implantsManuscript (Other (popular science, discussion, etc.))
    Abstract [en]

    This study presents a set of experiments designed to study the stability over time of the conducting polymer poly(3,4-ethylene dioxythiophene) (PEDOT), under simulated physiological conditions. Especially, the influence of switching the counter ion used in electropolymerisation, from surfactant polystyrene sulphonate (PSS) to heparin, was investigated. Electropolymerised PEDOT was exposed to different solutions at 37 °C over a 5-6 weeks study period. Two methods were used to study changes over time, spectroscopy and cyclic voltammetry. Phosphate buffer solution (PBS) and diluted hydrogen peroxide (H2O2) (0.01 M) were used to simulate in vivo environment. Some PEDOT electrodes in PBS were also subject to voltage pulsing to further stress the material.

     

    The vast part of the samples of both types lost both electroactivity and optical absorbance within the study period, when exposed to H2O2. An overall slightly higher stability of PEDOT:PSS compared to PEDOT:heparin could be seen. The time dependence of the decline also differed, with a linear decrease of electroactivity for PEDOT:heparin while for PEDOT:PSS a comparably stable appearance initially, followed by a marked decrease after 8-15 days.

     

    Polymers were relatively stable in PBS throughout the study period, with around 80% of electroactivity remaining after five weeks. Disregarding a slight drop in electroactivity during the first day, voltage pulsing in PBS did not increase degradation (tested over 11 days). Delamination of PEDOT exposed to PBS was however a significant problem, especially for polymer on ITO substrates.

     

    PEDOT is sensitive to oxidising agents, also in the dilute concentrations used here, and counter ion influences the time course of degradation. Even without oxidising agents, some decline in electroactivity can be expected and it is unclear whether this decrease will continue over time, or if the polymer will stabilise. Such stabilisation was however not seen within the five weeks studied here. Delamination of polymer is likely to be a problem on implantation, especially with unwisely chosen substrates, and might be an even more serious threat to long term applications than degradation in biological fluids.

  • 13.
    Thaning, Elin M.
    et al.
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Asplund, Maria
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Nyberg, Tobias
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Inganäs, Olle W.
    Biomolecular and Organic Electronics, IFM, Linköping University.
    von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701).
    Stability of Poly(3,4-ethylene dioxythiophene) Materials Intended for Implants2010In: Journal of Biomedical Materials Research - Part B Applied Biomaterials, ISSN 1552-4973, Vol. 93B, no 2, p. 407-415Article in journal (Refereed)
    Abstract [en]

    This study presents experiments designed to study the stability of the conducting polymer poly(3,4-ethylene dioxythiophene) (PEDOT), under simulated physiological conditions using phosphate-buffered saline (PBS) and hydrogen peroxide (H2O2) (0 01M) at 37 degrees C over a 5- to 6-week period Voltage pulsing in PBS was used as an additional test environment The influence of switching the counter ion used in electropolymerization from polystyrene sulphonate (PSS) to heparin was investigated Absorbance spectroscopy and cyclic voltammetry were used to evaluate the material properties Most of the samples in H2O2 lost both electroactivity and optical absorbance within the study period, but PEDOT.PSS was found slightly more stable than PEDOT heparin. Polymers were relatively stable in PBS throughout the study period, with around 80% of electroactivity remaining after 5 weeks, disregarding delamination, which was a significant problem especially for polymer on indium tin oxide substrates Voltage pulsing in PBS did not increase degradation. The counter ion influenced the time course of degradation in Oxidizing agents.

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