| 1. |
- Gällentoft, Lina, et al.
(författare)
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Impact of degradable nanowires on long-term brain tissue responses
- 2016
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Ingår i: Journal of Nanobiotechnology. - : Springer Science and Business Media LLC. - 1477-3155. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: A promising approach to improve the performance of neural implants consists of adding nanomaterials, such as nanowires, to the surface of the implant. Nanostructured interfaces could improve the integration and communication stability, partly through the reduction of the cell-to-electrode distance. However, the safety issues of implanted nanowires in the brain need to be evaluated and understood before nanowires can be used on the surface of implants for long periods of time. To this end we here investigate whether implanted degradable nanowires offer any advantage over non-degradable nanowires in a long-term in vivo study (1 year) with respect to brain tissue responses. Results: The tissue response after injection of degradable silicon oxide (SiOx)-coated gallium phosphide nanowires and biostable hafnium oxide-coated GaP nanowires into the rat striatum was compared. One year after nanowire injection, no significant difference in microglial or astrocytic response, as measured by staining for ED1 and glial fibrillary acidic protein, respectively, or in neuronal density, as measured by staining for NeuN, was found between degradable and biostable nanowires. Of the cells investigated, only microglia cells had engulfed the nanowires. The SiOx-coated nanowire residues were primarily seen in aggregated hypertrophic ED1-positive cells, possibly microglial cells that have fused to create multinucleated giant cells. Occasionally, degradable nanowires with an apparently intact shape were found inside single, small ED1-positive cells. The biostable nanowires were found intact in microglia cells of both phenotypes described. Conclusion: The present study shows that the degradable nanowires remain at least partly in the brain over long time periods, i.e. 1 year; however, no obvious bio-safety issues for this degradable nanomaterial could be detected.
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| 2. |
- Gällentoft, Lina, et al.
(författare)
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Size-dependent long-term tissue response to biostable nanowires in the brain.
- 2015
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Ingår i: Biomaterials. - : Elsevier BV. - 1878-5905 .- 0142-9612. ; 42, s. 172-183
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Tidskriftsartikel (refereegranskat)abstract
- Nanostructured neural interfaces, comprising nanotubes or nanowires, have the potential to overcome the present hurdles of achieving stable communication with neuronal networks for long periods of time. This would have a strong impact on brain research. However, little information is available on the brain response to implanted high-aspect-ratio nanoparticles, which share morphological similarities with asbestos fibres. Here, we investigated the glial response and neuronal loss in the rat brain after implantation of biostable and structurally controlled nanowires of different lengths for a period up to one year post-surgery. Our results show that, as for lung and abdominal tissue, the brain is subject to a sustained, local inflammation when biostable and high-aspect-ratio nanoparticles of 5 μm or longer are present in the brain tissue. In addition, a significant loss of neurons was observed adjacent to the 10 μm nanowires after one year. Notably, the inflammatory response was restricted to a narrow zone around the nanowires and did not escalate between 12 weeks and one year. Furthermore, 2 μm nanowires did not cause significant inflammatory response nor significant loss of neurons nearby. The present results provide key information for the design of future neural implants based on nanomaterials.
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| 3. |
- Lind, Gustav, et al.
(författare)
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Multiple implants do not aggravate the tissue reaction in rat brain.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Chronically implanted microelectrodes are an invaluable tool for neuroscientific research, allowing long term recordings in awake and behaving animals. It is known that all such electrodes will evoke a tissue reaction affected by its' size, shape, surface structure, fixation mode and implantation method. However, the possible correlation between tissue reactions and the number of implanted electrodes is not clear. We implanted multiple wire bundles into the brain of rats and studied the correlation between the astrocytic and microglial reaction and the positioning of the electrode in relation to surrounding electrodes. We found that an electrode implanted in the middle of a row of implants is surrounded by a significantly smaller astrocytic scar than single ones. This possible interaction was only seen between implants within the same hemisphere, no interaction with the contralateral hemisphere was found. More importantly, we found no aggravation of tissue reactions as a result of a larger number of implants. These results highlight the possibility of implanting multiple electrodes without aggravating the glial scar surrounding each implant.
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| 4. |
- Mohammed, Mohsin, et al.
(författare)
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Ice coating –A new method of brain device insertion to mitigate acute injuries
- 2020
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Ingår i: Journal of Neuroscience Methods. - : Elsevier BV. - 0165-0270. ; 343
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reduction of insertion injury is likely important to approach physiological conditions in the vicinity of implanted devices intended to interface with the surrounding brain. New methods: We have developed a novel, low-friction coating around frozen, gelatin embedded needles. By introducing a layer of thawing ice onto the gelatin, decreasing surface friction, we mitigate damage caused by the implantation. Results and comparison with existing methods: The acute effects of a transient stab on neuronal density and glial reactions were assessed 1 and 7 days post stab in rat cortex and striatum both within and outside the insertion track using immunohistochemical staining. The addition of a coat of melting ice to the frozen gelatin embedded needles reduced the insertion force with around 50 %, substantially reduced the loss neurons (i.e. reduced neuronal void), and yielded near normal levels of astrocytes within the insertion track 1 day after insertion, as compared to gelatin coated probes of the same temperature without ice coating. There were negligible effects on glial reactions and neuronal density immediately outside the insertion track of both ice coated and cold gelatin embedded needles. This new method of implantation presents a considerable improvement compared to existing modes of device insertion. Conclusions: Acute brain injuries following insertion of e.g. ultra-flexible electrodes, can be reduced by providing an outer coat of ultra-slippery thawing ice. No adverse effect of lowered implant temperature was found, opening the possibility of locking fragile electrode construct configurations in frozen gelatin, prior to implantation into the brain.
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| 5. |
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| 6. |
- Forni, Matilde, et al.
(författare)
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Sustained and potent analgesia with negligible side effects enabled by adaptive individualized granular stimulation in rat brainstem
- 2023
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Ingår i: Journal of Neural Engineering. - 1741-2560. ; 20:3
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. To clarify if an adaptive current stimulation protocol, in which current amplitude is modulated during continuous stimulation, provides better efficacy than constant current stimulation protocol with respect to analgesia caused by individualized stimulation in rat periaqueductal gray matter (PAG) /dorsal raphe nuclei (DRN). Approach. Ultrathin microelectrodes adapted for recording (n = 6) and stimulation (n = 16) were implanted in rat primary somatosensory cortex and PAG/DRN, respectively. In each animal included (n = 12), a subset of PAG/DRN microelectrodes (n = 1-3 per animal) was selected that on simultaneous stimulation blocked nociceptive withdrawal reflexes in awake unrestrained animals without noticeable side effects. Analgesic effects were subsequently assessed from both nociceptive withdrawal reflexes and intracortical pain-related responses on CO2 laser hind paw stimulation. The analgesic effects of adaptive current PAG/DRN stimulation comprising incremental increases of 5 μA/microelectrode (initial median current 30 μA/microelectrode) when effects declined were compared to the effects of constant current stimulation. Behavioral effects and brain state related changes were analyzed using quantitative movement analysis and electrocorticography (recorded on top of the dura mater), respectively. Tissue reactions and probe placement in PAG/DRN were assessed with immunohistochemistry. Main results. Powerful and sustained (4 h) analgesia was achieved with the adaptive current protocol within a rather wide area of PAG/DRN. Analgesic after-effects were seen for up to 30 min. Behavioral and brain state related side effects were minimal. Moreover, 6 weeks after implantation, there were no traces of bleedings, only small glial reactions and small but not statistically significant loss of neurons nearby indicating that the microelectrode stimulation employed is biocompatible. Significance. The results indicate that sustained and powerful analgesia with minimal side effects can be achieved by granular and individualized stimulation in PAG/DRN using an adaptive current stimulation protocol. This microelectrode technology and stimulation paradigm thus has the potential of providing a highly efficient and safe pain therapy.
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| 7. |
- Gällentoft, Lina
(författare)
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Nanowires and Neural interfaces. Biocompatibility in the brain
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic neural interfaces that are able to record or stimulate neurons in the CNS are valuable instruments in use today and they hold great promise for the future both within neuroscience research and in the clinic. However, a major obstacle is that they show a decline in performance over time. Many different approaches to improve the interface designs are gradually evaluated in hope of overcoming this obstacle. One approach is to enhance the biomaterials ability to integrate with the surrounding tissue by manipulating the surface structure. One way of doing this is to construct a nanostructured electrode surface. A nanostructured electrode surface, in this case nanowires, has the potential to improve the electrical properties of the neural interface a well as to improve the interface biocompatibility and tissue integration. However, before nanowires can be used as an electrode surface structure it is crucial to investigate the safety aspects of exposing the brain tissue to nanowires. Nanowires share morphological features with asbestos fibers and if some of the nanowires were to break off from the electrode surface a possible asbestosis-like pathology might develop. To address this issue we assessed the inflammatory tissue response and neuronal survival following injection of biostable nanowires of different lengths (paper I). Furthermore, we also evaluated the tissue response following injection of short degradable nanowires (paper II). We found that short biodegradable or biostable nanowires did not cause a significant tissue response or neuronal loss. However, we found that debris from degradable nanowires as well as intact biostable nanowires remained in the brain one year post injection. Suggesting that nanoparticle clearance from the brain is a very slow process.A neural interface with a nanostructured surface needs to be protected from damage during the implantation procedure. In paper III, we showed that embedding the nanowire substrate in a temporary protective and stiffening matrix, consisting of gelatin and glycerol, preserved the majority of the nanowires during implantation into agar.In paper IV, we showed that implanting multiple wire bundles in the brain does not result in an increased glial response to each individual implant. This implies that it is feasible to interface and interact with several brain structures in parallel without the confounding factor of an over all cumulatively increased glial response.In summary, this thesis has provided key knowledge about how to design and implant a nanowire structured neural interface. The development of a seamlessly integrating neural interface would have immense implications in neuroscience research as well as in clinical settings.
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| 8. |
- Witteveen, Jolanda, et al.
(författare)
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Gelatin/glycerol coating to preserve mechanically compliant nanowire electrodes from damage during brain implantation
- 2010
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Ingår i: Journal of Vacuum Science and Technology B. - : American Vacuum Society. - 1520-8567. ; 28:6, s. 6-16
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Tidskriftsartikel (refereegranskat)abstract
- Chronically implanted neural implants are of clinical importance. However, currently used electrodes have several drawbacks. Some weeks after implantation in the brain, a glial scar forms around the electrode, causing decreased electrode functionality. Nanostructures, and in particular nanowires, are good candidates to overcome these drawbacks and reduce glial scar formation. Using a mechanically compliant substrate with protruding nanowires could further decrease the glial scar formation by reducing the mechanical mismatch between the tissue and the electrode. However, flexible substrates require strengthening upon brain implantation. One solution consists of embedding the implant in a gelatin-based matrix, which is resorbable. In the case where nanostructures are present at the surface of the implant, it is crucial that the embedding matrix also preserves the nanostructures, which can be challenging considering the forces involved during the drying phase of gelatin. Here, the authors show that freestanding gallium phosphide nanowires coated with hafnium oxide (HfO2), titanium (Ti), and gold (Au) were preserved in a gelatin-glycerol embedding matrix with subsequent implantation in 1% agar, which is a model for brain implantation. (C) 2010 American Vacuum Society. [DOI: 10.1116/1.3498764]
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| 9. |
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