DE102012006953A1 - Apparatus for stimulating and / or detecting cell activity within a cell environment - Google Patents

Abstract

A device is described for stimulating and / or detecting time activities within a biological cell environment, with a biocompatible implant body temporarily or chronically implantable in the cell environment comprising at least one hollow channel connected or connectable directly or indirectly to a fluid pump on the proximal side, and Provides an opening on the distal side. The invention is characterized in that an optical means is provided on or in the hollow channel, via which light can be coupled into the hollow channel and / or decoupled therefrom, and / or that an electrically conductive means is provided on or in the hollow channel Anlgebar an electrical signal and / or can be tapped off.

Description

Technical area

The invention relates to a device for stimulating and / or detecting cell activities within a biological cell environment, preferably in the form of nerve cells, with a biocompatible implant body temporarily or chronically implantable in the cell environment comprising at least one hollow channel, the middle or proximal proximal is directly connected to a fluid pump or connectable and provides an opening on the distal side.

State of the art

Devices of the above type are used in the field of neuroscience gaining knowledge of biological cells, so in particular nerve or brain cells. In order to investigate the nature of individual cells or cell connections, cell-specific signals can be applied to a cell or a cell network to be examined with the aid of suitably designed, technical microinterfaces, whereby stimulation effects within the cell or the cell network can be produced. On the other hand, with the aid of suitably designed microinterfaces, it is possible to measure biosignals emitted by a cell or a cell network. In addition to electrical signals, optical signals as well as the application and detection of chemical substances which are present in liquid-dissolved form are used for stimulation as well as for detecting cell-specific activities within a biological cell environment.

From the US 2004/0224002 A1 describes a neural device for the modulation of neuronal activities, with which a cell or a cell composite with a, at least one bioactive substance-containing liquid is locally acted upon. For this purpose, the device provides a housing aperture into which a cell or a cell assembly to be examined can be positioned, adjoining a fluid reservoir on the inside of the housing, from which a predetermined amount of bioactive agent is applied to the cell with the aid of a flow regulator integrated within the housing or the cell composite can be applied. With the help of such or similar trained applicators, which have submillimeter rumbling structural dimensions, it is possible to apply chemical substances such as anti-inflammatory drugs, neurotransmitter-containing solutions, etc. locally to individual cells or cell networks. In the same way, it is possible to extract cell liquids locally, for example, to investigate the cell metabolism properties.

Representing a large variety of known measuring probes for the application as well as detection of bioelectric signals, reference is made to the publication, US 2007/0123765 A1 , which has an elongated, made of biocompatible material measuring body, on the surface of a plurality of individual contact electrode surfaces is distributed, which are connected via extending within the measuring body electrical connection lines with a signal generator and detector and each in contact with cells or cell areas brought are to elicit electrical cell stimulation as well as tapping cellular bioelectric signals.

As an extension to the above-described, implantable measuring probe for in vivo detection and delivery of bioelectric signals from and to cells, sees in the document, US 2011/0112591 A1 , implantable neuronal interface along an elongated biocompatible measuring body described both electrical contact surfaces, as well as an optical waveguide, which has a light exit opening in the region of the electrode surfaces distributed on the measuring body. With such a combination of optical fibers and measuring electrodes, it is possible to detect both the bioelectrical responsiveness of cells to optical stimulation events and the optical responsiveness of cells to electrical stimulation events. Such temporary or chronically implantable probes, which enable combined electrical and optical biosignal detection as well as stimulation, are already successfully used in the relatively new field of optogenetics.

From a post by Stieglitz, T., 2010, "Integration of micro fluidic capabilities into micromachined neural implants," International Journal of Micro-Nanocell Transport, 1 (2), pp. 139-158 , an implantable measuring device for receiving and delivering both bioelectrical signals and bioactive substances in liquid form emerges.

A permanently implantable measuring arrangement, which has both electrical, optical and a liquid interface, is in the dissertation of B. Rubehn, 2011, "Polymer-Based Microimplants for the Neurosciences", University of Freiburg , described, whose distal end portion in 2 is shown schematically. The substrate body is a shaft-shaped, formed of biocompatible polyimide implant body 1 , on the upper side in the distal region of a plurality of individual electrode surfaces 2 is attached, which can be brought intracorporeally into direct contact with a cell or a cell tissue composite. Every single electrode surface 2 is over a running within the implant body Connecting line with an electrical Signalgenerator- and evaluation unit (not shown).

Furthermore, at the top of the shaft-shaped implant body 1 an optical fiber 3 attached by means of an opaque adhesive to the surface of the shaft-shaped implant body 1 is added. The optical fiber 3 has an end-side light input and output surface 4 that are in close proximity to the electrode surfaces 2 whereby it is possible to detect bioelectrical cell signals which are caused by light-induced cell stimulation directly, ie in spatial proximity to the optical stimulation with the aid of the electrode surfaces.

In addition, within the shaft-shaped implant body 1 a hollow channel incorporated, which via a channel opening 5 has, on the surface of the shaft-shaped implant body 1 in close proximity to the electrode surfaces 2 empties. Proximal side to the implant body 1 the hollow channel is connected via a fluid adapter to a fluid reservoir from which fluid can be delivered through the hollow channel by means of a fluid pump.

Presentation of the invention

It is the object of the invention to provide a device for stimulating and / or detecting cell activities within a biological cell environment, preferably in the form of nerve cells, with a biocompatible implant body that temporarily or chronically implants the cell environment and comprises at least one hollow channel which has proximal side or is directly connected to a fluid pump or is connectable and provides an opening on the distal side, in such a way that, in addition to the application or uptake of a liquid substance through the hollow channel, it should also be possible to optically and / or electrically stimulate the cells or biooptically and / or detections make bioelectrical signals, the required design costs compared to known solutions to be simplified, reduced and made cheaper in terms of manufacturing costs. In addition, the system integrity is to be improved, so that the size of the device according to the invention significantly reduced d. H. miniaturized, can be.

The solution of the problem underlying the invention is specified in claim 1. The concept of the invention advantageously further-forming features are the subject of the dependent claims and the further description in particular with reference to the exemplary embodiments.

The solution according to the device for stimulating and / or detecting cell activities within a biological cell environment according to the features of the preamble of claim 1 is further developed such that a means is provided on or in the hollow channel, can be coupled via the light into the hollow channel and / or out of the hollow channel can be decoupled. As an alternative to the optical means or in combination with the optical means, an electrically conductive means is provided on or in the hollow channel, to which an electrical signal can be applied and / or tapped off.

The invention is based on the idea that the hollow channel whose previous function in generic devices is limited exclusively to the liquid transport, additionally as a light-conducting channel, d. H. as a light guide, and / or as an electrical signal transmitting channel is usable. The combined use of the hollow channel both as a fluid transport channel and as an optical waveguide and / or as an electrical signal conductor maximum system integrity is created, whereby the structural design of such a solution designed implant body using micromechanical manufacturing techniques, such as. From the field of semiconductor manufacturing known are significantly miniaturized. The elimination of the previous necessity of separately and individually on and in the implant body trainees structural components, each for an optical, electrical and / or chemical-material information exchange between a cell or a cell composite and a suitably designed implant body carries by the solution according measure or measures at a considerable cost savings in the production.

In a first embodiment, the optical means, via the light in the hollow channel can be coupled and ultimately auskoppelbar, as formed along the hollow channel coupling window formed, which consists of a light transparent material and optical signal light lossless as possible both sides of an external to Hollow channel provided light source coupled into the hollow channel, as well as optical biosignals, which originate from a cell or a cell network, decoupled from the side of the hollow channel to an externally provided to the hollow channel light detector. The coupling window can be formed separately from a light source and a light detector and be part of the light source and light detector.

Alternatively, it is also conceivable to provide light source and light detector within the hollow channel, for example, at its proximal end region, in order in this way to reduce light losses on the basis of the Coupling window unavoidably occurring coupling event to avoid.

For the light pipe along the hollow channel, it is important to take into account the optical properties of the fluid flowing through the hollow channel. For successful transmission of light along the hollow channel filled with a liquid, it is firstly necessary to select liquids which have the highest possible optical transmission for the light coupled into or out of the hollow channel. Typically, crystal-clear liquids are used in which the chemical or medical active substances containing the chemical stimulation of the respective cells or cell composites are completely dissolved. Furthermore, it is necessary for a possible loss-free light pipe along the hollow channel of a suitable adjustment of the optical refractive index of the hollow channel inner wall with respect to the optical refractive index of the liquid flowing through the hollow channel. In order to avoid light losses through interactions with the light occurring along the hollow channel inner wall, it is necessary to create the prerequisite, so that the light is totally reflected along the hollow channel inner wall. For this purpose, it is necessary to choose the refractive index of the hollow channel inner wall smaller than the refractive index of the liquid flowing along the hollow channel. Since the liquids used have optical properties of water whose optical refractive index has the dimensionless size of 1.33, the optical refractive index of the hollow channel inner wall η is to be chosen smaller than 1.33.

Possible embodiments for realizing the optical coupling in and out of light signals into the hollow channel or out of the hollow channel are explained below with reference to specific exemplary embodiments.

A further embodiment for a solution according to the invention stimulation and / or detection of cell activities within a biological cell environment comprises an implant body, the at least one hollow channel is provided with an electrically conductive means on which an electrical signal can be applied or tapped from this. In a simplest embodiment, the electrically conductive means is designed as at least one pin-shaped or needle-shaped electrode body, which is preferably introduced in a proximal-side region of the hollow channel and connected to a signal generator and / or signal detector provided outside the hollow channel, preferably separately from the implant body. In order to be able to conduct electrical signals along the hollow channel for targeted cell stimulation, in a simplest embodiment the use of an electrically conductive liquid, in the form of an electrolyte liquid, which flows through the hollow channel or at least fills the hollow channel serves. With the aid of the pin-shaped or needle-shaped electrode, which is flowed over by the electrically conductive liquid along the hollow channel, the electrical signals applied to the electrode can be transmitted to the electrically conductive liquid for further transmission. Thus, the liquid serves as a guide medium for the electrical stimulation signals.

For coupling or decoupling of electrical signals along the hollow channel through which fluid flows, in addition to the already mentioned at least one pin-shaped or needle-shaped electrode which extends into the hollow channel, electrically conductive electrode surfaces which locally bound the hollow channel are also suitable. Such, the hollow channel at least locally enclosing, electrically conductive hollow channel inner wall surfaces have the advantage that electrical signals can be transmitted to or from the hollow channel flowing through the electrolyte liquid, without affecting the flow behavior sustainable.

Another alternative possibility for the supply and discharge of electrical biosignals along the hollow channel consists in the provision of longitudinally extending to the hollow channel inner wall, electrically conductive structures. Such an electrical conductor structure can be realized, for example, by direct deposition of electrically conductive material on the hollow channel inner wall, in the form of an elongated conductor track structure. The least one on the hollow channel inner wall along the hollow channel extending conductor track structure is connected to the proximal end of the hollow channel with an externally provided signal generator or detector. The electrical interconnect structure opens at the distal end to the hollow channel, preferably forming an electrode surface that is freely accessible to the cell or the cell assembly. In this case, it is not necessary for bioelectric signal transport to pass an electrically conductive liquid through the hollow channel. Of course, a plurality of distributed in the circumferential direction of the hollow channel, along the hollow channel extending such interconnect structures may be provided.

A further embodiment provides for the combination of all three information transmission techniques mentioned above by at least one hollow channel designed in accordance with the invention within the implant body, which is capable of transmitting optical, electrical and also chemical material biosignals. For this purpose, it is important to provide the provided within a implant body, provided for the liquid transport hollow channel with both an optical and with an electrical means, via the respective optical and electrical signals along the hollow channel can be coupled or decoupled.

Of course, embodiments are also conceivable in which the implant body has at least one hollow channel through which both chemically material substances in the way of a fluid flow as well as bio-optical signals in the manner described above can be guided or directed. Separate from the hollow channel within the implant body consisting of biocompatible material electrical conductor structures which end in the distal region of the implant body in the form of freely accessible electrode surfaces and the proximal side to the implant body by means of suitable connection structures with an electrical signal generator or detector are connected.

The electrode surfaces arranged on the distal region of the implant body are mounted as close as possible to the hollow channel opening in order to be able to pick up bioelectrical signals in the immediate vicinity of the cell region, which has been stimulated by means of optical and / or materially chemical stimuli.

In the same way, it is possible with the aid of such an implant body arrangement by the application of bioelectrical excitation signals by means of the freely accessible electrode surfaces within the cell to be able to derive biooptical as well as biochemical signals via the hollow channel for further investigation.

The biocompatible implant body is preferably made of a biocompatible polymer, such as polyimide or polydimethylsiloxane, and is also transparent to diagnostic X-rays, IR radiation or visible light, so as not to produce spurious artifacts on images generated by standard diagnostic methods can be obtained from tissue or cell areas.

The novel implant body is preferably suitable as temporary or chronic, d. H. permanently implantable neuronal prosthesis and is able to gently allow investigations on the central and peripheral nervous system for purposes of neuronal stimulation applications. With the help of the novel implant body, it is not only possible to make bioelectrical activity checks on the central nervous system and in particular in peripheral and central brain areas, by the possibility of combined use of the hollow channel, for example, for purposes of optical and chemical material signal transmission, concentration analysis of neurotransmitter materials can be made beyond which are delivered from the side of individual cells or cell clusters by optical and / or electrical stimulation of the cells or cell clusters. Furthermore, it is possible to detect optical biosignals emitted by the cells by artificial stimulation as a result of bioelectrical or materially chemical excitation as a function of the local electrical potential prevailing at the location of the cell.

Brief description of the invention

The invention will now be described by way of example without limitation of the general inventive idea by means of embodiments with reference to the drawings. Show it:

1a , b representations of an implant body with hollow channel, which is designed both for a liquid transport and for optical waveguide,

2 Representation of a known implant body for the optical, electrical and chemical stimulation of a cell,

3a , b representations of a hollow channel designed in accordance with the invention with electrode surfaces arranged in the distal region,

4 Longitudinal view through an implant body with optical coupling window,

5 schematic representation of an implant body with a hollow channel, along which both a flow of material as well as optical and electrical signals can be passed and

6 Schematic representation of the distal end portion of an implant body with a variety of existing hollow channels.

Ways to carry out the invention, industrial usability

1a shows an implant body consisting of biocompatible polymeric material 1 , a hollow channel 6 encloses, the hollow channel opening 5 at the top of a distal side on the implant body 1 attached extension 1' empties. Proximal side to the implant body 1 is the hollow channel 6 via a suitably designed fluid adapter 7 with a fluid pump 8th connected, the one inside a fluid reservoir 9 stored fluid along the hollow channel 6 dosed to promote. Likewise, the fluid pump 8th an analysis unit 10 downstream, with which it is possible to analyze chemical substances within the fluid flow.

Furthermore, in the proximal region of the implant body is an optical means 11 provided, via the light L an external to the implant body 1 attached light source 12 along the otherwise rectilinear hollow channel 6 can couple.

To the light pipe along the hollow channel 6 coupled light L requires an optical adjustment of the refractive index of the hollow channel inner wall with respect to the refractive index of the through the hollow channel 6 flowing fluid flow in such a way, so that the realization of a total reflection of the light L at the hollow channel inner wall, the refractive index of the hollow channel inner wall is dimensioned smaller than the refractive index of the through the hollow channel 6 flowing fluid. This requirement can be fulfilled either by the material from which the implant body 1 and thus the hollow channel 6 surrounding hollow channel inner wall itself has a refractive index which is smaller than the refractive index of the through the hollow channel 6 is flowing fluid flow. Alternatively, it is possible, the hollow channel inner wall with a suitably selected material coating 13 to provide, see cross-sectional view according to 1b ,

On the surface of the distal shaft-shaped extension 1' of the implant body 1 , please refer 1a , are in close proximity to the hollow channel opening 5 electrode surfaces 2 attached to the delivery as well as recording bioelectric signals. Every single electrode surface 2 is with one inside the implant body 1 integrated extending electrical supply and discharge connected. The illustration of a signal generator or detector required for feeding or also detecting bioelectric signals is dispensed with.

The arrangement of the freely accessible electrode surfaces 2 at the distal end of the implant body 1 can those in the 3a and 3b assume removable layout geometries. 3a shows laterally to the hollow channel opening 5 attached electrode surfaces 2 . 3b shows immediately around the hollow channel opening 5 attached electrode surfaces 2 ,

About the distal side of the implant body 1 distributed electrode surfaces 2 For example, bioelectric signals for cell stimulation can be emitted as well as bioelectric signals generated by the cells and removed accordingly for further evaluation. Due to the spatially close arrangement of the electrode surfaces 2 relative to the hollow channel opening 5 For example, high-precision cell examinations can be performed in which cell-specific response signals delivered by the cell in the form of bioelectric, bio-optical or biochemical signals in response to corresponding artificially applied stimulation events can be detected and examined.

In 4 is a longitudinal sectional view through an implant body 1 shown in which a possibility for coupling and decoupling optical signals in and out of the hollow channel 6 is realized.

The hollow channel 6 passes through the implant body 1 However, substantially rectilinear in the proximal region of the implant body 1 a channel bend of 90 °. For coupling the externally mounted light source 12 emitted light L along the hollow channel 6 serves a light transparent coupling window 14 in the longitudinal section through the implant body 1 is mounted in the region of the curved channel running at 90 °. The coupling window 14 is centrally mounted in the area of the rectilinear channel axis A in the curvature region, so that the light L is outside the composite body 1 provided light source 12 directly axially along the hollow channel 6 can be coupled. In the light beam path between the light source 12 and docking windows 14 Furthermore, a semitransparent mirror S is introduced, via which out of the hollow channel 6 passing through the coupling window light onto a light-detecting unit 15 is directed through the hollow channel 6 can detect light signals originating from the side of a cell.

At the proximal area of the implant body 1 90 ° downwardly directed hollow channel close over the fluid adapter 7 in the 1a explained components.

5 schematically shows an implant body 1 , a hollow channel 6 surrounds, through which both optical, biochemical and bioelectric signals can be passed. For this purpose, the hollow channel 6 in the same way as explained above, see 1a , B, formed for guiding the light wave, ie, the hollow channel inner wall has a refractive index which is smaller than the refractive index of a through the hollow channel 6 passed through fluid flow.

By way of an optical means, light is coupled into or out of the hollow channel, for example comparable to the embodiment 4 , the light source shown schematically 12 as well as light detector 15 should clarify this.

In addition, in the proximal region of the hollow channel 6 provided an electrical means, preferably in the form of a pin or needle-shaped electrode 16 is formed locally in the hollow channel 6 protrudes. The electrode 16 is suitable with a signal generator as well signal detector 17 connected, which generates electrical signals and detects bioelectric signals.

About the already explained fluid adapter 7 becomes one in the fluid reservoir 9 stocked electrolyte fluid by means of the fluid pump 8th metered introduced. By flushing the electrode 16 With electrolyte fluid, electrical signals are made along the hollow channel filled with electrolyte fluid 6 to one at the hollow channel opening 5 adjacent cell area slides that lead to cell stimulation.

The implant body shown in highly schematic form in FIG 1 is thus able to transmit both optical, electrical and also chemical material signals through the hollow channel, both for purposes of artificial stimulation of neuronal signals and for their detection.

Of course it is possible the implant body 1 with a plurality of such hollow channels 6 form, as in the embodiment according to 6 is illustrated. In the exemplary embodiment shown, three hollow channels are located separately next to each other within an implant body, of which each individual hollow channel can be filled with a different liquid. Such a design allows a broadband investigation of individual cells or cell networks with different chemical stimulants.

Of course, it is possible the above concrete embodiments, in the 1 . 3 to 5 have been explained to combine arbitrarily with each other. For example, suppose that over several channels 6 having implant body 1 each for the coupling and decoupling of electrical signals in the individual hollow channels integrated electrical means 16 (not shown), in addition, are on the surface of the distal extension 1' of the implant body 1 extra electrode surfaces 2 attached, via which an additional tap of bioelectric signals or a separate electrical stimulation of cell areas is possible.

LIST OF REFERENCE NUMBERS

1

implant body

1'

Distal extension, extension

2

electrode surfaces

3

optical fiber

4

Light input and output surface

5

Hollow channel opening

6

hollow channel

7

fluid adapter

8th

fluid pump

9

fluid reservoir

10

analysis unit

11

Optical means

12

light source

13

Optical coating

14

coupling window

15

light detector

16

electrode

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 2004/0224002 A1 [0003]
• US 2007/0123765 A1 [0004]
• US 2011/0112591 A1 [0005]

Cited non-patent literature

• Stieglitz, T., 2010, "Integration of micro fluidic capabilities into micromachined neural implants", International Journal of Micro-Nanocell Transport, 1 (2), pp. 139-158 [0006]
• B. Rubehn, 2011, "Polymer-Based Microimplants for the Neurosciences", University of Freiburg [0007]

Claims (13)

Apparatus for stimulating and / or detecting cell activity within a biological cell environment, comprising a biocompatible implant body temporarily or chronically implantable in the cell environment, comprising at least one hollow channel directly or indirectly connected or connectable to a fluid pump on the proximal side and an opening distally provides, characterized in that on or in the hollow channel, an optical means is provided, can be coupled via the light into the hollow channel and / or auskoppelbar, and / or that on or in the hollow channel, an electrically conductive means is provided on the one electrical signal can be applied and / or tapped off. Apparatus according to claim 1, characterized in that the optical means is a directly the hollow channel, at least locally delimiting window element, connected to the outside of the hollow channel, a light source and / or a light detector directly or indirectly via a photoconductive element or connect. Apparatus according to claim 2, characterized in that the window element is part of the light source and / or the light detector. Apparatus according to claim 1, characterized in that the optical means is a light source and / or a light detector, which is mounted within the hollow channel. Device according to one of claims 1 to 4, characterized in that the hollow channel is internally coated at least partially with a material having an optical refractive index η, for which applies: η <1.33 Device according to one of claims 1 to 5, characterized in that the hollow channel has a linear, the opening passing through channel axis, and in that the hollow channel has at least one curved channel region on the proximal side, in which the optical means is mounted. Device according to one of claims 1 to 6, characterized in that the implant body in the region of the opening outside the hollow channel has at least one freely accessible electrode surface which is connected via an internal body extending in the implant body, electrical connection line with a proximally provided to the implant body signal unit or connectable , Apparatus according to claim 7, characterized in that a plurality of electrode surfaces is provided on the implant body in the region of the opening, which are spatially distributed evenly distributed around the opening. Device according to one of claims 1 to 8, characterized in that the electrical means is at least one electrode surface within the hollow channel, which surrounds the hollow channel at least partially inside wall. Device according to one of claims 1 to 9, characterized in that the electrical means is designed as at least one electrode body which protrudes on the proximal side along the hollow channel in this. Device according to one of claims 1 to 10, characterized in that the fluid pump is connected to a liquid reservoir and / or connected to a chemical analysis unit or connectable. Apparatus according to claim 11, characterized in that in the liquid reservoir, a light-conducting and / or electrically conductive liquid is contained. Device according to one of claims 1 to 12, characterized in that the biocompatible implant body consists of a material which is transparent to diagnostic X-rays, IR radiation or visible light.

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