Deliverables
An 8-channel stimulator for the application of arbitrary shaped stimulation pulses was developed. The options of constant current and constant voltage amplitudes have been implemented. The system is computer controlled via a graphical used interface. The control program runs on any PC, the stimulator has been designed and developed as a stand-alone version with RS 232 link to the PC.
The stimulator is able to give arbitrary physiological stimulation impulses. Within this stimulation system it allows preliminary investigations to define new clinical stimulation effects. This can lead to a development of new medical implants for selective blocking and selective stimulation. The areas of application are deep brain stimulation, pain therapy and incontinence.
The main advantage of the new stimulation system is an efficiently stimulation because of the arbitrary impulses and therefore a lower adaptation of the nerve system which results in a better physiological tolerance.
Within the REBEC project it was possible to develop two animal models representing almost the same conditions of bladder dysfunction as in humans with an unstable bladder for the first time. In the acute cystitis model it has been possible to induce bladder instabilities with a fast onset in the Göttinger minipig model as well as in the rabbit model by means of formalin instillations into the bladder. Therefore a special method of anaesthesia had to be developed as normal anaesthesia suppresses involuntary bladder contractions. In the chronic cystitis model within rats, mustard oil was used to induce a chronic inflammation of the bladder without the need for this special anaesthesia.
The acute models provide a fast onset of involuntary bladder contractions within several minutes to one hour with a duration time of up to 5 hours. At this, the concentration of formalin instilled into the bladder can induce hyperactive bladder syndrome without acute inflammation process (like interstitial cystitis) or, using higher concentration, induce symptoms of acute cystitis with inflammation signs and concomitant bladder instabilities. The chronic cystits model within rats provides a much slower onset of involuntary bladder contractions after 24hours and duration for several days. The chronic cystitis model therefore allows investigations on awake rats under normal life conditions if needed.
These two animal models allow scientific investigations under almost the same inflammatory and pathophysiological conditions of overactive bladder syndrome as in humans. Pharmacological investigations as well as investigations on neuromodulation effects and scientific investigations on the neurophysiological and neuroanatomical conditions due to overactive bladder conditions can thus be conducted. These models therefore provide the basis for scientific research on all kinds of treatment methods for overactive bladder in a reliable animal model.
One of the main goals within the REBEC project was to improve the efficacy of neuromodulation therapy. One of the research topics dealing with this issue was to develop and evaluate optimised stimulation signals for neuromodulation and neurostimulation treatment using newly developed arbitrary stimulation generators.
The newly developed signals enable selective stimulation (neuromodulation) of unmyelinated nerve fibres within e.g. the sacral nerve bundles. These signals have proven to be more effective in the inhibition of bladder instabilities in the animal model than the standard rectangular signals used in conventional stimulation generators. They seem to affect mainly the sensory afferent nerve fibres and allow higher stimulation amplitudes without undesirable motor responses and therefore can allow a significant increase of the responder rate to neuromodulation therapy.
Furthermore these signals could also improve other neurostimulation and neuromodulation techniques as e.g. deep brain stimulation in parkinsons disease and should be evaluated in further scientific studies. However, these signals could not be implemented in conventional stimulators, as they require different electronics and tripolar stimulation electrodes. As long as no certified implantable system is available this technique cannot be tested in humans. But REBEC provides the basics and information for the use of this new neurostimulation technique in other clinical fields also.
Hybrid Cuff Electrodes for the stimulation and recording from the sacral nerves have been designed in a tripolar electrode arrangement in different diameters. This medical device were subjected to an intensive biocompatibility study according to the requirements of the ISO 10993 series and passed all tests of standards concerning biocompatibility testing of medical devices.
Based on the results of the series of biocompatibility tests performed on the raw materials and the ETO sterilized finished product, consequently no bioincompatibilites arising from the materials and the product can be expected during clinical application.
Documentations for clinical trial in humans have been prepared according ISO 14971:2000 and ISO 14155:2003 including risk analysis, clinical investigation plan and investigator brochure. Additionally in vivo tests in pigs showed the manageability and functionality of the Hybrid Cuff Electrodes.
We have developed an electronic system for detecting when the urinary bladder of a person with a spinal cord injury begins to contract involuntarily and used these signals to activate the stimulation of sensory sacral nerves, which then immediately suppresses the contraction. This so-called conditional neuromodulation, involving electronic processing circuitry to provide the feed-back pathway, is able to significantly increase bladder capacity and reduce the incidence of urinary incontinence.
We have demonstrated that conditional neuromodulation can be used both as a relatively non-invasive technique and, more appropriately, as a hybrid technique by applying the stimulation through an implanted posterior (sensory) nerve root stimulator.
It is the ultimate intention in future development to combine sensing and conditional stimulation through the posterior nerve roots with sacral anterior root stimulation for bladder emptying so as to provide patients with complete control over their lower urinary tract. Such control would be the ideal long-term management for people with spinal cord injuries and hopefully have a significantly good impact on their quality of life.
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