WO2008128723A1 - Système implantable pour l'excitation de neurones - Google Patents

Système implantable pour l'excitation de neurones Download PDF

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Publication number
WO2008128723A1
WO2008128723A1 PCT/EP2008/003141 EP2008003141W WO2008128723A1 WO 2008128723 A1 WO2008128723 A1 WO 2008128723A1 EP 2008003141 W EP2008003141 W EP 2008003141W WO 2008128723 A1 WO2008128723 A1 WO 2008128723A1
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WO
WIPO (PCT)
Prior art keywords
implantable system
implantable
neurotransmitter
linker
neurotransmitters
Prior art date
Application number
PCT/EP2008/003141
Other languages
German (de)
English (en)
Inventor
Eberhart Zrenner
Martha Christina Lux-Steiner
David Fuertes Marron
Reto Weiler
Elke Guenther
Juergen Parisi
Elizabeth Von Hauff
Original Assignee
Eberhard-Karls-Universitaet Tuebingen
Helmholtz-Zentrum Berlin Für Materialien Und Energie Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eberhard-Karls-Universitaet Tuebingen, Helmholtz-Zentrum Berlin Für Materialien Und Energie Gmbh filed Critical Eberhard-Karls-Universitaet Tuebingen
Publication of WO2008128723A1 publication Critical patent/WO2008128723A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36046—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation of the eye
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0526—Head electrodes
    • A61N1/0543—Retinal electrodes

Definitions

  • the present invention relates to an implantable system for stimulating neurons in a mammal and to its use.
  • Neurons are cells of the nervous system in humans, or higher organisms in general, specialized on excitation processing and conduction, which are connected via synapses with other nerve cells or recipient cells. Neurons can generate and transmit pulses due to their conductivity and electrical excitability, whereby electrical or chemical Synapses transmit the excitement of nerve or sensory cells to downstream cells.
  • the chemical synapse consists of a presynaptic "transmitter cell” which contains neurotransmitters and empties them into the synaptic cleft via the presynaptic membrane after previous excitement. Opposite them lies the postsynaptic membrane of the "recipient cell”, which is equipped with receptors to which the neurotransmitters released by the presynaptic membrane through intraneural signaling bind. Between the two membranes lies the synaptic cleft, which is filled with an extracellular solution in which the various substances can move more or less freely.
  • This synapse thus provides an interface in which information can be chemically transferred to another cell by neurotransmitters.
  • glutamate which is the major excitatory neurotransmitter of the nervous system, is known to be the most abundant messenger in the vertebrate retina in transmitting sensory cell information to neurons.
  • Certain eye diseases (macular degeneration, retinitis pigmentosa), which can lead to partial or total blindness, are caused by degenerated photoreceptors in the retina, while the downstream nerve cells are still active. Therefore, of the synapse, which serves the signal transmission from sensory cell to neuron, only the receptor side is functional. Therefore, the replacement of the degenerate photoreceptors in the retina by technical implants is a possible approach for the therapy of such diseases, since the implantable systems can then serve, for example, as artificial synapses.
  • the second approach mimics the natural neuronal connection that is based on the exchange of specific neurotransmitters, where the exchange is triggered, for example, by electrical impulses (see, for example, B. Vastag, "Future eye implants focussed on neurotransmitters ", JAMA 288 (2002) page 1833).
  • an implant of a silicon chip having densely packed micro-photodiodes and electrode pads is implanted under the retina (see, for example, Zrenner, "Will retinal implants restore vision?", Science, (2002) , 295: 1022-1025).
  • the ambient light may not be sufficient to produce stimuli of sufficient amplitudes greater than the stimulus threshold of the retina to be stimulated. Therefore, in another approach, a subretinal implant has been proposed (see DE 197 05 988 A1) which is provided with a photovoltaic layer and contains electronic amplifiers.
  • the implant described in this publication further comprises a substrate with through-holes intended to improve the supply of nutrients to the retina. However, this substrate has only mechanical functions and does not interact with the photovoltaic layer.
  • Peterman et al. (“Towards a neurotransmitter-based retinal prosthesis using an inkjet printhead", Biomedical Microdevices 5 (2003): 195-199) describe another way of implementing the "chemical" approach, where a localized ejection of glutamate by the use of an inkjet Such a printer head has a multiplicity of small holes, which in one Distance of about 200 microns are arranged. In this approach, a voltage pulse is necessary, which drives the device.
  • WO 2006/034377 describes a device which, for example, can be used as a retina implant. This has a solar cell which provides sufficient energy to actuate an electro-active thin film, which in turn is coupled to a thin membrane of a substrate. By the pressure of the electro-active thin film, the membrane moves mechanically, so that, for example, via this mechanical movement neurotransmitters can be ejected, which are also stored in the implant.
  • a disadvantage of the artificial synapses or implants known hitherto in the state of the art is that in most cases an electric current must be used to actuate them, as a result of which its surroundings can be heated up. Further, in the chemical approaches, there is a continuing problem that the neurotransmitter stored in the implants is released at each incoming stimulus, and therefore the amount of neurotransmitters continuously decreases until it is emptied. As a result, the functionality of such implants is severely limited, or the neurotransmitter reservoirs must be refilled regularly.
  • the object of the present invention is therefore to provide an alternative implant with which the disadvantages of the prior art can be overcome, and in particular the concentration of neurotransmitters in a synaptic cleft can be controlled in a targeted manner.
  • an implantable system having a photosensitive or piezoelectric element for generating an electrical potential, as well as having a surface which conducts the electrical potential, and releasable by the implantable system neurotransmitters and / or neuromodulators, further on at Surface a linker is provided, via which the neurotransmitters and / or neuromodulators at the implanting Baren system by external excitation electrostatically fixable and / or releasable and, if necessary, again be fixed again.
  • the system according to the invention it is possible to replace the function of defective presynaptic elements.
  • a system equipped with a photosensitive element use is made of the fact that, when the light is incident, the photosensitive element provided in the system generates an electrical potential which is passed on via the surface.
  • the neurotransmitter connected to the system via the linker is then released by electrostatic interactions triggered by the electrical potential and, if necessary, fixed again after a change in the potential.
  • incident light can be exploited as an energy source, so that no power must be supplied.
  • the concentration of the neurotransmitters is thus adjustable as a function of the potential difference produced by the incidence of light in the photosensitive element or by the pressure in the piezoelectric element.
  • the external excitation is therefore in the case of equipped with photosensitive elements systems, by electromagnetic waves, so for example by infrared radiation, visible light or UV radiation.
  • electromagnetic waves so for example by infrared radiation, visible light or UV radiation.
  • a light incidence can cause the adsorption of the neurotransmitters to the linker and an incoming darkness a desorption, or vice versa.
  • the external excitation is by pressure
  • Both systems have in common that the neurotransmitters can be released or refixed by electrostatic interactions.
  • the system according to the invention, or the utilization of electrostatic interactions generated by external excitation furthermore ensures that the neurotransmitter released into the synaptic gap is again fixed on the implantable system and can thereby be reused.
  • the system is thus, to a certain degree, independent of a "supply" of spent neurotransmitter, which - unused - otherwise degrades after a certain time.
  • the system according to the invention also has the advantage over the "electrical" approaches that it can be based on photovoltaics and does not necessarily require an externally flowing current as a decisive parameter for controlling the system.
  • an additional pulse generator is provided in the system, with which a continuous alternating current for generating different pulse lengths and pulse heights is generated.
  • the linker is a layer on the surface of the implantable system via which the neurotransmitter and / or neuromodulator is connected to the surface.
  • the linker layer has a highly structured surface.
  • the surface comprises electrodes that are coupled to the photosensitive element.
  • the electrical potential generated by the photosensitive element upon incident light is applied to electrodes, preferably metal electrodes. Electrodes, which are coupled to the photosensitive element. On the electrodes is a linker layer through which the glutamate is coupled to the implantable system. The electrical potential transmitted to the electrodes by the photosensitive element causes electrostatic interactions between the linker layer and the neurotransmitter molecules bound thereto, thereby causing the adsorption or desorption of the molecules.
  • the linker layer may consist, for example, of an organic polymer material, preferably of a conjugated polymer, or of low molecular weight organic molecules whose HOMO-LUMO transitions are energetically adapted to the external excitation, such as, for example, phthalocyanines.
  • an organic polymer material preferably of a conjugated polymer
  • low molecular weight organic molecules whose HOMO-LUMO transitions are energetically adapted to the external excitation such as, for example, phthalocyanines.
  • the photosensitive layer is a photovoltaic layer, and in particular a semiconductor layer which comprises the surface.
  • This embodiment has the advantage that as the photosensitive elements semiconductor materials can be used which develop surface photo voltages under the action of light.
  • the presence or absence of surface potential in, for example, exposure to light / darkness directly influences the electrostatic interactions between linker and neurotransmitter via the linker.
  • the photovoltaic layer can also be arranged on a biocompatible substrate and form a photosensitive electrode.
  • the linker layer comprises at least one inorganic heterogeneous material, such as, for example, nitrides, oxides, carbides, and in particular, for example, titanium nitrite, titanium dioxide or titanium carbide. In this case, it is generally preferred if it is a further semiconductor material.
  • inorganic heterogeneous material such as, for example, nitrides, oxides, carbides, and in particular, for example, titanium nitrite, titanium dioxide or titanium carbide.
  • the linker layer comprises at least one amorphous material, preferably amorphous silicon or amorphous carbon.
  • the semiconductor material comprises elemental semiconductors of group IV of the periodic table of the elements.
  • the photosensitive element is a photovoltaic element, and is preferably formed from an organic or inorganic biocompatible semiconductor material.
  • the photovoltaic element may comprise a solar cell or a photodiode, or a photosensitive diode structure, preferably a homodiode, for example a pn semiconductor contact, a heterodiode, for example a semiconductor metal contact, or a Schottky diode, for example a semiconductor insulator -Metal contact.
  • the device can also have a layer with a number of microchannels which serve as a reservoir for the neurotransmitter or modulator.
  • the layer in this case has a thickness in the nm to the micron range, and the microchannels may be spaced apart in the micron range and have a diameter in the range of a few nm to a few hundred nm.
  • the photosensitive element is located at the bottom of a microchannel and may be a semiconductor layer, a pn junction, a photodiode or a solar cell or a pressure-sensitive element.
  • the channels can also be at least partially led into the photosensitive element, or this also completely penetrate.
  • the photosensitive element is formed as an electrode with a layer having a multiplicity of microchannels
  • a layer is applied to the photosensitive element and then microchannels, for example by means of ion bombardment, are introduced into this layer. After a subsequent etching treatment, the channels are insulated from each other.
  • the photosensitive member can also be formed by the so-called focused ion beam (FIB) method in which needle-like / cylindrical-form photosensitive material is grown on a substrate to form the photosensitive member, and insulating inorganic or organic material for filling the voids between the needle-shaped structures separates.
  • FIB focused ion beam
  • the photosensitive element can also be spatially separated and drive via individual electrodes for neurotransmitter or neuromodulator release.
  • the neurotransmitter / neuromodulator is selected from the group comprising amino acids, biogenic amines, acetylcholine, purine derivatives or peptides.
  • neurotransmitter encompasses any substance or biochemical substance which, on the basis of its property as a chemical messenger, transmits information from one nerve cell to another via the contact point of the nerve cells, that is, synapses.
  • neuromodulator is understood to mean any substance that can influence the functioning of the nervous system, in which a neuromodulator may be a substance produced by the body itself or else substances that are externally supplied to the body and directly or indirectly influence synapses.
  • the neurotransmitter and / or neuromodulator is selected from the group comprising glutamate, glycine, aspartate, gamma-aminobutyrate, dopa, dopamine, norepinephrine, adrenaline serotonin and histamine.
  • the concentration of the neurotransmitter that is necessary in the system according to the invention for triggering an irritation will depend on the nature of the neurotransmitter to be used and its functional effect on the synapse. It goes without saying that the concentration must be kept as high as possible so as not to lose too much neurotransmitter into the extracellular space or distant target sites. For this purpose, it is provided to occupy the surface of the system according to the invention maximally with the neurotransmitter, so that, for example, for glutamate up to 10 15 molecules per mm 2 can be bound. Further, to maintain concentration, the neurotransmitter is stored in microchannels already described above.
  • a dielectric plate may be provided with channel-like holes in which the glutamate is electronically translated between the plate (below) and the top of the channel (cell membrane).
  • the invention relates to a method for producing an implantable system with a photosensitive or piezoelectric element for generating an electrical potential, as well as with a surface that transmits the electrical potential, and connected via a linker layer with the implantable system and electrostatically releasable neurotransmitters and / or neuromodulators, which method comprises the step of generating a linker layer on an electrode, wherein the linker layer is generated from a solution containing the neurotransmitter and a polymer.
  • the present invention further relates to the use of the implantable system for stimulating neurons in the central and / or peripheral nervous system of a mammal.
  • the system is used to treat neurological diseases selected from the group consisting of seizure disorders, neurodegenerative diseases, neuromotor and neurosensory disorders.
  • the implantable system is used as an artificial retinal implant or as an artificial cochlear implant. It is understood that in the former a photosensitive element is used in order to use the incident light in the eye as an energy source can.
  • a cochlear implant pressure sensors are used which generate or control electrical potentials by pressure. With the system according to the invention and the controlled release of neurotransmitters, therefore, defective synapses in the retina or in the ear can be rendered functional again.
  • the system according to the invention offers the possibility of not only releasing neurotransmitter molecules by the electrostatic interactions, but also of fixing them to the system again.
  • the sensor part of the transmitter-releasing part may be spatially separated, with a signal transmitting connection between the two parts.
  • FIG. 1a the schematic representation of an intact synapse
  • Fig. Ib is a schematic representation of an embodiment of the system according to the invention.
  • Fig. Id is a schematic representation of a human eye
  • Fig. Ia the operation of an intact and functional synapse is shown schematically, which is generally designated 10.
  • the reference numerals 12 and 14 respectively show the presynaptic and postsynaptic elements.
  • a neurotransmitter 16 is released from the presynaptic element 12 into the region of the existing or former synaptic gap 20 upon receipt of a corresponding stimulus and bound by corresponding receptors 18 to the postsynaptic element 14.
  • ion therapy Ie 22 opened, which allows the exchange of ions between the extracellular space in the downstream cell.
  • the information transmitted by the stimulus is forwarded.
  • the photoreceptors so the "presynaptic elements" are defective, so that the stimuli can not be passed to the downstream bipolar cells.
  • the implant has an element that is photosensitive or piezoelectric, and a linker layer in which, for example, glutamate is embedded as a neurotransmitter via electrostatic interactions.
  • An electric potential is generated by a stimulus striking the sensor element, for example a solar cell, and passed on to the surface, which in turn changes the electrostatic interactions between the linker layer and glutamate.
  • this is, for example, released, diffused into the synaptic gap 20 and binds to specific receptors 18 of the postsynaptic element 14.
  • Fig. Ib an embodiment of the system according to the invention is shown, wherein in this embodiment at 20 an artificial synapse device is designated, which identifies the (neuro) transmitter / modulator releasing part, and with a photo- or pressure-sensitive Element 22 is in contact via corresponding connections 24.
  • the part 20 has a surface via which neurotransmitters and / or neuromodulators on the implantable system can be electrostatically fixed or released by external excitation, namely via linkers (not shown in FIG. 1).
  • the photo / pressure sensitive element 22 can be directly connected to the transponder. mid-modulator-releasing member 20, or form part of it.
  • the photo / pressure sensitive element 22 may be, as in the embodiment in Fig. Ic, a semiconductor, a solar cell, a photodiode or two pn junction forming layers.
  • the connection 24 between the two parts 20 and 22 may be any suitable electrical conductor, such as wires, etc.
  • Fig. Ic in which the same elements as in Fig. 1 are provided with the same reference numerals, shows a further embodiment of the inventive system, wherein the photo / pressure sensitive element 22 and the transmitter / modulator releasing member 20 directly to each other are in contact, or the transmitter / modulator-releasing member 20 is formed as a layer on the photo / pressure-sensitive element 22.
  • the system in FIG. 1c has a multiplicity of microchannels 30 via whose surface 25 neurotransmitter or neuromodulator molecules can be electrostatically fixed or released by means of linkers on the implantable system by external excitation.
  • the power source is preferably any suitable AC power source.
  • FIG. 1 d shows a schematic representation of an eye 30 of a person in which the system according to the invention, designated 32 in its entirety, was implanted. Briefly described, in Fig. Id the retina is designated 34, the vitreous body 35 and the sclera 36.
  • the system according to the invention is implanted, for example, between pigment epithelium (not shown) and retina 34 (subretinally) peripherally from the fovea centralis 38 , Attempts to produce an embodiment of the implantable system according to the invention
  • polypyrrole films have been formed on electrically conductive substrates into which glutamate has been embedded.
  • polypyrrole films were deposited in solutions of pyrrole monomers and a glutamate-containing electrolyte.
  • the glutamate concentration in the final deposited polymer layer was determined by scintillation measurements on radioactively labeled glutamate.
  • smaller amounts (microliters) of H 3 labeled L-glutamate were added.
  • H 3 labeled glutamate and "cold" glutamate were incorporated into the polymer film.
  • the dissociation of H 3 labeled glutamate in the polymer layer was quantified by liquid scintillation, thereby calculating the exact amount of glutamate in the polymer layer.
  • FIG. 2 shows a diagram showing the number of glutamate molecules in the film which are incorporated in the polymer layer over a certain period of time.
  • infrared spectra of the solutions were measured in the ATR method on electrically contacted germanium crystals.
  • infrared spectra of the solutions in ATR method measured on electrically contacted germanium (Ge) crystals.
  • iw-5 / ru measurements were carried out, in which a constant electric potential was adjusted at the electrode during a time interval of 6 min and at the same time infrared spectra at the interface to a glutamate solution (100 mM) were measured.

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  • Health & Medical Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Prostheses (AREA)

Abstract

L'invention concerne un système implantable servant à exciter des neurones chez un mammifère et comprenant un élément piézoélectrique ou sensible à la pression pour la génération d'un potentiel électrique. Le système selon l'invention présente une surface qui transmet le potentiel électrique, ainsi que des neurotransmetteurs et/ou neuromodulateurs qui peuvent être libérés par le système implantable. Sur la surface se trouve un système de liaison grâce auquel les neurotransmetteurs et/ou neuromodulateurs peuvent être fixés au système implantable et peuvent être libérés électrostatiquement par une excitation externe et éventuellement à nouveau fixés.
PCT/EP2008/003141 2007-04-19 2008-04-18 Système implantable pour l'excitation de neurones WO2008128723A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE200710020305 DE102007020305A1 (de) 2007-04-19 2007-04-19 Implantierbares System zur Anregung von Neuronen
DE102007020305.7 2007-04-19

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Publication Number Publication Date
WO2008128723A1 true WO2008128723A1 (fr) 2008-10-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109524545A (zh) * 2018-11-16 2019-03-26 河北大学 一种基于二维Ti3C2材料的神经仿生器件及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002710A2 (fr) * 2001-06-29 2003-01-09 The Board Of Trustees Of Leland Stanford Jr. University Interface de puce de synapse artificielle pour prothese de la retine
WO2006034377A2 (fr) * 2004-09-22 2006-03-30 The Board Of Trustees Of The University Of Illinois Microactionneur alimente par la lumiere, distributeur de microfluide et prothese retinienne
WO2006076008A2 (fr) * 2004-04-26 2006-07-20 Massachusetts Institute Of Technology Dispositif de stimulation neurale utilisant la stimulation chimique renouvelable
EP1743665A1 (fr) * 2005-07-15 2007-01-17 Interuniversitair Micro-Elektronica Centrum Stimulation de neurones à l'aide de neurotransmetteurs avec rétroaction des capteurs

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19705988C2 (de) 1996-10-23 2002-04-11 Univ Eberhard Karls Retina-Implantat

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002710A2 (fr) * 2001-06-29 2003-01-09 The Board Of Trustees Of Leland Stanford Jr. University Interface de puce de synapse artificielle pour prothese de la retine
WO2006076008A2 (fr) * 2004-04-26 2006-07-20 Massachusetts Institute Of Technology Dispositif de stimulation neurale utilisant la stimulation chimique renouvelable
WO2006034377A2 (fr) * 2004-09-22 2006-03-30 The Board Of Trustees Of The University Of Illinois Microactionneur alimente par la lumiere, distributeur de microfluide et prothese retinienne
EP1743665A1 (fr) * 2005-07-15 2007-01-17 Interuniversitair Micro-Elektronica Centrum Stimulation de neurones à l'aide de neurotransmetteurs avec rétroaction des capteurs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109524545A (zh) * 2018-11-16 2019-03-26 河北大学 一种基于二维Ti3C2材料的神经仿生器件及其制备方法

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