The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Nerve reaction to self-sizing cuff electrode implantation and electrical stimulation : physiological and histological studies

Les objectifs de la simulation électrique fonctionnelle comprennent la restauration de fonctions déficientes et l’amélioration de la qualité de vie des patients. Les progrès de la recherche biomédicale et des micro-technologies ont permis d’augmenter le nombre de pathologies pouvant tirer bénéfice de cette technique. Dans le domaine des systèmes implantés, les électrodes à manchon spiral sont couramment utilisées. En effet, non invasives pour le nerf, elles permettent un confinement et un meilleur contrôle du courant. Cependant, deux désavantages en limitent l’usage. Premièrement, l’implantation de l’électrode provoque une réaction tissulaire. La fibrose qui apparaît au niveau de l’interface matériaux – tissu augmente la distance fibres nerveuses – contacts réduisant d’autant l’efficacité des électrodes. Deuxièmement, au cours des premières semaines qui suivent l’implantation, les paramètres électrophysiologiques sont instables. La reproductibilité des stimulations et/ou des enregistrements effectués peut ainsi en être altérée. La séquence des événements biologiques déclenchés dans le décours de l’implantation d’un tel système est en fait assez mal connue. Le but de cette thèse est d’acquérir une meilleure connaissance des processus impliqués dans ces deux phénomènes. Dans cette optique, un petit stimulateur implantable a été développé afin de permettre d’évaluer les changements affectant l’interface tissu-électrode au cours d’implantations chroniques. La littérature nous apprend que différents facteurs ou cytokines sont susceptibles d’intervenir. Les deux facteurs considérés dans cette thèse, l’oxyde nitrique (NO) et le ‘vascular endothelial growth factor’ (VEGF), exercent des rôles en partie connus dans la régulation du système vasculaire et dans les mécanismes de neuroprotection. L’implantation d’une électrode à manchon spiral, passive ou active, stimule leur expression dans l’épinèvre et dans l’endonèvre. Leur présence dans l’épinèvre est vraisemblablement associée aux remaniements vasculaires (vasoperméabilité, vasodilatation et angiogénèse) qui surviennent suite à une implantation. La chirurgie et une réaction inflammatoire aiguë provoquent un œdème en partie par leur biais. Cet œdème est associé à une faible impédance de l’électrode et à une rhéobase élevée. Par la suite, le dépôt d’un tissu fibreux remplace progressivement la réaction inflammatoire. A ce moment, on constate une inversion de la corrélation entre l’impédance d’électrode et l’aspect morphologique de l’épinèvre ; la rhéobase diminue progressivement, alors que l’impédance augmente. Le perinèvre est lui peu à peu renforcé par le dépôt de fibres qui tend à renforcer la protection de l’endonèvre. L’utilisation d’un pattern de stimulation caractérisé par de fortes densités de charges n’a pas permis d’induire des dommages axonaux en plus de ceux provoqués par les contraintes mécaniques. Nous avons néanmoins observé que l’expression des facteurs dans l’endonèvre était prolongée au-delà d’un mois après l’implantation. Les données de la littérature associées aux nôtres nous permettent de proposer que dans l’endonèvre, Nos et de VEGF agiraient dans le cadre d’un mécanisme de protection axonal. A partir d’un certain niveau d’expression, l’effet protecteur ne serait plus assuré. Au contraire, une certaine toxicité liée à des concentrations locales trop élevées pourrait contribuer à la dégénérescence axonale dont la traduction électrophysiologique est l’augmentation de la chronaxie. Qui plus est, le NO peut générer des activités électriques spontanées dans les nerfs périphériques et dans la moelle épinière. Ces dernières pourraient intervenir dans l’instabilité électrophysiologique enregistrée au cours des premières semaines qui suivent l’implantation. En résumé, suite à l’implantation d’une électrode à manchon spirale, le tissu nerveux exprime des cytokines et des agents responsables de remaniements morphologiques dont les conséquences, sur un plan électrophysiologique, ont été clairement établies. La découverte des mécanismes cellulaires et moléculaires locaux survenant dans le nerf dans le décours de l’implantation de ces électrodes devrait contribuer à élaborer de nouvelles stratégies de recherche dans le but d’en améliorer l’efficacitéThe goal of functional electrical stimulation (FES) is to restore function, improve health or counteract physiological disturbances and neurological damages. New developments in this field have increased the number of pathological conditions that might benefit from a neural prosthesis. Spiral cuff electrodes are currently used for such purpose because they allow a close contact between electrode and nerve. The electrical current is thus confined to the nerve and can be accurately controlled. However, the cuff implantation has two major drawbacks. First, the device implantation induces an inflammatory reaction which evolves towards fibrosis at the nerve-cuff interface. As a result, the electrode efficiency is reduced. Secondly, the first weeks after implantation are characterised by an electrophysiological instability resulting in a significant lack of reproducibility. The sequence of biological events and control mechanisms triggered by an electrode implantation are poorly known. The aim of this study is to gain more knowledge about the biological events leading to these phenomena. For this purpose, a fully implantable stimulator was developed in order to allow monitoring the electrode-tissue interface status during chronic experiments. Various cytokines can be suspected to play a role. The two factors, nitric oxide (NO) and vascular endothelial growth factor (VEGF), observed in this study have both partially known vasoactive and neuroprotective properties. They are up-regulated in the epineurial and in the endoneurial compartments in response to either passive or active cuff electrode implantation. Their presence in the epineurium is likely to be associated with the post-surgical vascular remodelling (oedema, vasodilation and angiogenesis). It is at least partially through these factors that the surgical procedure and the acute inflammatory reaction induce an oedema. This oedema is associated with low electrode impedance and high rheobase values. Gradually the initial inflammatory response evolves towards fibrosis. In the meantime, the correlation between the electrode impedance and the epineurium thickness reverses, the rheobase value decreases while the impedance increases. The perineurium is progressively reinforced by fibre deposits enhancing the protection of the endoneurium. Acute electrical stimulation with high charge densities did not result in more axonal damage than the occasional abnormalities induced by the mechanical stress due to the cuff itself. However, the various patterns of electrical stimulation prolong the expression of neuroactive factors in the endoneurial compartment for over one month after implantation. Considering data from the literature and our own results, we can suggest that endoneurial NOS and VEGF might contribute to an axonal protection mechanism. However, from a given level of expression on, the protection seems no longer effective. On the contrary, too high local concentrations might be toxic and lead to an axonal degeneration translated electrophysiologically in a prolonged chronaxie. Furthermore, NO can induce spontaneous electrical activity in peripheral nerves and in the spinal cord. This might be responsible for the electrophysiological instability observed during the first weeks after cuff implantation. In summary, immediately after cuff electrode implantation, the expression of cytokines and factors likely responsible for profound morphological changes are up-regulated in the nerve. This can, at least partially, explain the early electrophysiological instability that is usually reported. Our data provide new insights in the sequence of events and molecular pathways involved in the nerve reaction after spiral cuff electrode implantation. These findings should enhance our ability to improve the electrode efficiency.Thèse de doctorat en sciences biomédicales (neuroscience) (SBIM3) -- UCL, 200

Two-way communication for programming and measurement in a miniature implantable stimulator.

Implantable stimulators are needed for chronic electrical stimulation of nerves and muscles in experimental studies. The device described exploits the versatility of current microcontrollers for stimulation and communication in a miniature implant. Their standard outputs can provide the required selectable constant-current sources. In this device, pre-programmed stimulation paradigms were selected by transcutaneous light pulses. The potential of a programmable integrated circuit (PIC) was thus exploited. Implantable devices must be biocompatible. A novel encapsulation method that require no specialised equipment and that used two classical encapsulants, silicone and Teflon was developed. It was tested for implantation periods of up to four weeks. A novel way to estimate electrode impedance in awake animals is also presented. It was thus possible to follow the evolution of the nerve-electrode interface and, if necessary, to adjust the stimulation parameters. In practice, the electrode voltage at the end of a known constant-current pulse was measured by the PIC. The binary coded value was then indicated to the user as a series of muscle twitches that represented the binary value of the impedance measurement. This neurostimulator has been successfully tested in vitro and in vivo. Thresholds and impedance values were chronically monitored following implantation of a self-sizing spiral cuff electrode. Impedance variations in the first weeks could reflect morphological changes usually observed after the implantation of such electrodes

Time course of tissue remodelling and electrophysiology in the rat sciatic nerve after spiral cuff electrode implantation.

Implantation of nerve cuff electrodes induces inflammatory cell infiltration and loose connective tissue accumulation. Along with time, morphological changes evolve towards a thicker epi/perineurium as part of mechanisms that protect nerve functionality when a foreign body is wrapped around it. The rise in electrode impedance is linked to the nature of the epineurial tissue. Changes involve an increased expression of neuroprotective factors that is stronger in the endoneurium with axonal degeneration. Our data indicate that epineurial and endoneurial changes after electrode cuff implantation are part of axonal protection mechanisms. Their control is important to improve the yield of FES applications

Nitric oxide synthases II and III and vascular endothelial growth factor are up-regulated in sciatic nerve after spiral cuff electrode implantation

Nerve cuff electrodes, commonly used in functional electrical stimulation systems, induce local morphological changes that can affect nerve functionality. Nitric oxide (NO) and vascular endothelial growth factor (VEGF) have both neural and vascular effects. We investigated the time-dependent regulation of nitric oxide synthases (NOS) and of VEGF after implantation of spiral cuff electrode around rat sciatic nerve. NOSIII as well as VEGF were up-regulated in both epineurial and endoneurial compartments in cuff-implanted animals along with microvascular changes. Our results suggest that VEGF and NO are implied in morphological and functional alterations occurring in the early time after cuff implantation. (C) 2005 Elsevier B.V. All rights reserved

Biocompatibility of platinum-metallized silicone rubber: in vivo and in vitro evaluation.

Silicone rubber is commonly used for biomedical applications, including implanted cuff electrodes for both recording and stimulation of peripheral nerves. This study was undertaken to evaluate the consequences of a new platinum metallization method on the biocompatibility of silicone rubber cuff electrodes. This method was introduced in order to allow the manufacture of spiral nerve cuff electrodes with a large number of contacts. The metallization process, implying silicone coating with poly(methyl methacrylate) (PMMA), its activation by an excimer laser and subsequent electroless metal deposition, led to a new surface microtexture. The neutral red cytotoxicity assay procedure was first applied in vitro on BALB/c 3T3 fibroblasts in order to analyze the cellular response elicited by the studied material. An in vivo assay was then performed to investigate the tissue reaction after chronic subcutaneous implantation of the metallized material. Results demonstrate that silicone rubber biocompatibility is not altered by the new platinum metallization method

Cuff electrode implantation around the sciatic nerve is associated with an upregulation of TNF-alpha and TGF-beta 1

Epineurial fibrosis, fiber loss, limited reproducibility of recordings and variability of stimulation conditions have been documented after extraneural cuff electrode implantation. These morphological and electrophysiological modifications could be due to the local release of cytokines. We report the expression of two cytokines, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) in the rat sciatic nerve after 'cuff' implantation for 18 h, 7 days and 1 month. Immunohistochemical and Western blot analyses showed a transient upregulation of TNF-alpha, during the first week, and a prolonged increase of TGF-beta1, over the 1-month period duration of this study. Considering the known pro-inflammatory roles of TNF-alpha and the pro-fibrotic action of TGF-beta, our results strongly suggest that these cytokines may contribute to nerve alterations occurring within the acute and sub-acute phases after cuff electrode implantation

Drug-eluting nanowires array

The present invention relates to a a nanowire array for electrically-controlled elution of a therapeutic composition comprising a plurality of nanoscopic-sized wires, nanowires, attached to an electrically conducting solid support, said nanowires formed from electroactive conjugated polymer containing or doped with said therapeutic composition coated over a plurality of nanoscopic sized electrically conducting protrusions. It also relates to a method for preparing a nanowire array and an electrode