CN101001665A - Device for transferring molecules to cells using an electric force - Google Patents

Device for transferring molecules to cells using an electric force Download PDF

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Publication number
CN101001665A
CN101001665A CNA2005800260718A CN200580026071A CN101001665A CN 101001665 A CN101001665 A CN 101001665A CN A2005800260718 A CNA2005800260718 A CN A2005800260718A CN 200580026071 A CN200580026071 A CN 200580026071A CN 101001665 A CN101001665 A CN 101001665A
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China
Prior art keywords
electrode
tissue
active component
generator
electrodes
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CNA2005800260718A
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Chinese (zh)
Inventor
伊夫斯·舍尔曼
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SPHERGEN
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SPHERGEN
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    • 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
    • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
    • 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
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis

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  • Health & Medical Sciences (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)
  • Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)
  • Electrotherapy Devices (AREA)

Abstract

The invention concerns a device and a method for optimal delivery of an active principle (36) into a human or animal tissue for chemotherapy or gene therapy, using an electric field or current. The device consists of electrodes connected to an electric current generator, providing better efficiency, reproducibility and safety which are achieved through use of adapted electrode devices and use of optimal current intensity.

Description

Utilize electric power that molecular transfer is arrived intracellular device
Technical field
The present invention relates to a kind of like this device: this device combines with physical method by the injection with active component and allows material to be administered in the tissue in vivo and be administered in the cell of these tissues to be improved.
Used physical method is applied electric fields or electric current.These electric fields and/or electric current have the effect of temporary transient penetration cell, also have the effect that improves active component infiltration in tissue.
Background technology
Electromigration or electro-osmosis relate to chemical molecular or nucleotide are expelled in the tissue, and simultaneously or applied electric fields and current impulse subsequently, these pulses can the penetration cell wall, promotes nucleotide to enter in the cell whereby, and can enter in the nucleus in some cases.
This is owing to electrophoresis or ionization to active component, utilizes this effect, and the molecule of active component is entrained in the tissue by electric convection or in fact is entrained in people, animal, plant or the bacterial cell.
In the present patent application, we should utilize electric field or electric current to improve active component to help application process to be called " electromigration " to the electricity of using and rendeing a service of biological tissue with this.We should will be called " field " in that the electric field that provides between two electrodes of different voltages and electromagnetic field and electric current are provided.
Anti-tumor chemotherapeutic is exactly an example, and the wherein infiltration of chemical molecular in tumor cell is necessary according to the therapeutic activity of " electrification is treated " method.
The electromigration of DNA, tissue permeability and the cell intrinsic permeability of these DNA have been improved, thereby make its can RNA or proteinic form express, if these DNA contain after promoter, the gene (this is known as the treatment expression cassette) before the polyadenylation sequence.
In the present patent application, " active component " is meant, any molecule that has beneficial effect or be used to analyze is such as all macromole of mirror image molecule, functional molecules, especially peptide or nucleic acid type.In nucleic acid, be preferred form by the synthetic plasmid that generates or linear DNA or RNA chain.The invention still further relates to the biomolecule of any nucleic acid, any protein, any sugar or any other genetic modification or the chemical modification that generate according to those skilled in the art's method or also have any complete synthesis molecule.
Electromigration especially can be used for coding DNA, plasmid or causes the genetic stocks (DNA, RNA etc.) of any other form of the expression of this gene outcome; this product is RNA or protein, especially structural RNA or the protein such as muscle, tumor, skin, nervous system or liver.
Electromigration needs the minimum device that is made of electric pulse generator and the device that has electrode.
US 5,273, and 525 have described a kind of syringe that comprises two injection needles (also as electrode).
US 6,055, and 453 have described the application order of utilizing one group of identification electrode selection electric field.
WO 03/086534 has showed and has a kind ofly had two needle electrodes and have the system of an injection needle at the center.
WO 02/098501 has described a kind of unordered needle electrode group, and one of these electrodes can make active component inject at skin surface.
US 2004/0092860 proposes a kind of group that is made of some needle electrodes that is used to inject, and wherein injection needle is positioned at the center.
US 5318514 has described the device that has electrode.
US 98/08183 has described some electrode network structural groupings.
US 2005/070841 has described a kind of device that comprises two injection needles (also as electrode).
US 2005/070841 has described a kind of device that comprises two injection needles (also as electrode).
US 2003/0009184 has described and has allowed tube electrode to be integrated in the electrode of the intrusive mood syringe needle form at center.
At last, the electric pulse generator of some types has had produce and market.
Providing of electric pulse with voltage difference is provided in the electromigration of DNA, this voltage difference a few tens of milliseconds magnitude during can surpass 30V.This causes seriously, even not endurable pain and muscle contraction, is the consequence that can not eliminate seriously, sometimes thereby can cause.Even muscle contraction also can take place in the anesthesia receptor.And in many cases, the weak state of receptor and age mean that anesthesia is incompatible.
Summary of the invention
The present invention proposes the device that has intrusive mood and non-intrusion type electrode, and make the method that electromigratory efficient and innocuousness are improved, toxicity reduces, the muscle contraction degree reduces.
The present invention also makes efficient be improved by the selection of electrode position and the electric field that is provided is provided." providing " or " transmission " of electric field mean in the present patent application, are generated by the generator that has potential difference between electrode, produce electric current and/or electric field thus between electrode.Chance has been created in the enhancing of efficient, thereby by reducing to cause the parameter of pain and muscle contraction to make harmfulness be reduced (if necessary).The present invention proposes a kind of casing bit that makes the device that has electrode grasp easily and electrode is electrically connected with generator.In the present patent application, " one group of electrode " means the group that is made of at least one electrode.
The present invention proposes following apparatus and method.
The present invention includes a kind of device that improves molecules of active components to the intracellular body intrinsic permeability of human or animal receptor tissue, it is characterized in that comprising:
Electric pulse generator,
The first electrode group, this first electrode group comprises at least one electrode that is electrically connected with the first terminal of electric pulse generator,
The second electrode group, this second electrode group comprises at least one electrode that is electrically connected with second terminal of electric pulse generator, and
Active component is expelled to in-house utensil.
Be that one of the present invention may feature be that the first electrode group comprises single electrode to the additional of above-mentioned feature.
More above-mentioned features are replenished, and one of the present invention may feature be that electrode is an intrusive mood.
More above-mentioned features are replenished, and one of the present invention may feature be the utensil that electrode has the injection active component.
More above-mentioned features are replenished, and one of the present invention may feature be that electrode is an injection needle.
More above-mentioned features are replenished, and one of the present invention may feature be, the utensil of injection active component is made of at least one integral type syringe needle, and close electrode is placed on the degree of depth place less than electrode depth.
More above-mentioned features are replenished, and one of the present invention may feature be: electrode also can be made of the sheathed catheter that is pierced by enough large-sized holes, thereby comes in contact by these holes between making syringe needle and organizing,
The intrusive mood syringe needle of electrode passes conduit along the conduit axis, and can slide along the conduit axis, can from conduit, regain,
In a single day conduit and syringe needle combine and just form the intrusive mood electrode, and these electrodes are called " by the electrode of non-conductive type duct portion ground covering " thereafter.
More above-mentioned features are replenished, of the present invention one may feature be electrode by constituting with lower member:
Conduit, this conduit is covered by the conductive surface that is connected with the respective terminal of pulse generator, is called " conductivity type catheter electrode " thereafter, and its surface is by roughly keeping the flexible material of conduit to form, and conduit can be used as the utensil of injecting active component,
The intrusive mood syringe needle, this syringe needle passes conduit along the conduit axis, and allows piercing tissue, can slide along the conduit axis, and can regain from conduit, and syringe needle also can be used as instrument used for injection.
More above-mentioned features are replenished, and one of the present invention may feature be that the intrusive mood electrode thrusts in-house top at it and is covered with by electrically insulating material.
More above-mentioned features are replenished, and one of the present invention may feature be, with at least one catheter electrode magnetization.
More above-mentioned features are replenished, and one of the present invention may feature be, the second electrode group comprises at least one non-intrusion type electrode, and this arrangement of electrodes comprises in covering on the tissue surface in zone of active component.
More above-mentioned features are replenished, and one of the present invention may feature be that at least one non-intrusion type electrode has the hole that allows the intrusive mood electrode to pass.
More above-mentioned features are replenished, and one of the present invention may feature be that this device also comprises the guider that the intrusive mood electrode axis is guided along predetermined direction.
More above-mentioned features are replenished, and one of the present invention may feature be that the second electrode group comprises an intrusive mood electrode.
More above-mentioned features are replenished, and one of the present invention may feature be that second group of electrode is the electrode that is covered by non-conductive type duct portion.
More above-mentioned features are replenished, and one of the present invention may feature be that second group of electrode is made of the conductivity type catheter electrode.
More above-mentioned features are replenished, and one of the present invention may feature be, first group of electrode is catheter electrode, and two syringe needles wherein are parallel, one, continuous by supporter.
More above-mentioned features are replenished, and one of the present invention may feature be, two intrusive mood electrodes be one, by means of supporter assemble, almost parallel and the degree of depth be roughly the same.
More above-mentioned features are replenished, and one of the present invention may feature be that the second electrode group comprises a plurality of intrusive mood electrodes.
More above-mentioned features are replenished, and one of the present invention may feature be, second group intrusive mood electrode roughly is positioned on the circle, and first group of electrode roughly forms the center of circle of this circle.
More above-mentioned features are replenished, and one of the present invention may feature be that second group intrusive mood sector electrode is made the zone of injection active component.
More above-mentioned features are replenished, and one of the present invention may feature be, two intrusive mood electrodes of the second electrode group basically with first group electrode alignment.
More above-mentioned features are replenished, and one of the present invention may feature be, it also comprises makes the utensil of electrode along the orientation that parallels to the axis.
More above-mentioned features are replenished, and one of the present invention may feature be, all electrodes be one, by means of supporter assemble, almost parallel and the degree of depth be roughly the same.
More above-mentioned features are replenished, and one of the present invention may feature be, this device also comprises the non-intrusion type electrode that at least one links to each other with one of terminal of generator.
More above-mentioned features are replenished, and one of the present invention may feature be:
Each intrusive mood electrode has the sleeve pipe that electrode is grasped easily and guarantee to be electrically connected between electrode and its generator terminal,
Sleeve pipe has shell, and this shell allows hold electrodes and the utensil of injection active component and the storage that contains active component.
More above-mentioned features are replenished, and one of the present invention may feature be:
A plurality of electrodes have a sleeve pipe that electrode device is grasped easily and guarantee to be electrically connected between the corresponding generator terminal of each electrode and its,
Sleeve pipe has shell, this shell hold electrodes and the utensil of injection active component and the storage that contains active component.
More above-mentioned features are replenished, and one of the present invention may feature be, sleeve pipe also comprises makes the utensil of electrode along the orientation that parallels to the axis.
More above-mentioned features are replenished, and one of the present invention may feature be:
Integral type electrode and their supporter have the sleeve pipe that electrode device is grasped easily and guarantee to be electrically connected between each electrode and its generator terminal,
Sleeve pipe has shell, and this shell holds the utensil of integral type electrode and supporter and injection active component and the storage that contains active component.
More above-mentioned features are replenished, and one of the present invention may feature be sleeve pipe:
Have and make electrode push the utensil of predetermined intermediate depth in the tissue continuously,
Has the utensil that the active component of making is injected at each stop position.
More above-mentioned features are replenished, and one of the present invention may feature be that the utensil that makes electrode push predetermined intermediate depth in the tissue continuously is made of at least one retainer.
More above-mentioned features are replenished, and one of the present invention may feature be that a plurality of intrusive mood electrodes that link to each other with generator are covered with by electrically insulating material on the top that it thrusts tissue.
More above-mentioned features are replenished, and one of the present invention may feature be that all intrusive mood electrodes that link to each other with generator are covered with by electrically insulating material on the top that it thrusts tissue.
More above-mentioned features are replenished, and one of the present invention may feature be, these two electrode groups comprise one group of non-intrusion type electrode, and these arrangement of electrodes comprise in covering on the tissue surface in zone of active component.
More above-mentioned features are replenished, and one of the present invention may feature be, electrode acts on single of the tissue that comprises active component, the electric field of propagating down with the tissue surface that allows to be provided at the electrode effect.
More above-mentioned features are replenished, and one of the present invention may feature be that the surface with the tissue of at least one non-intrusion type electrode contacts has the shape of essentially rectangular.
More above-mentioned features are replenished, and one of the present invention may feature be with the surface that the tissue of at least one non-intrusion type electrode contacts, to have the roughly shape of similar horseshoe.
More above-mentioned features are replenished, and one of the present invention may feature be that the surface of at least one non-intrusion type electrode is flexible.
More above-mentioned features are replenished, and one of the present invention may feature be that the non-intrusion type electrode has the smooth pointed shape in end.
More above-mentioned features are replenished, and one of the present invention may feature be that the non-intrusion type electrode forms the flexible sheath integral part.
More above-mentioned features are replenished, and one of the present invention may feature be that at least one non-intrusion type electrode is a wire.
More above-mentioned features are replenished, and one of the present invention may feature be, this device only comprises the non-intrusion type electrode of two wire, and these electrodes are along different axis.
More above-mentioned features are replenished, and one of the present invention may feature be that the surface with the tissue of at least one non-intrusion type electrode contacts has irregularly shaped.
More above-mentioned features are replenished, and one of the present invention may feature be that these non-intrusion type electrodes are asymmetrical.
More above-mentioned features are replenished, and one of the present invention may feature be that at least one non-intrusion type electrode is made up of the some non-intrusion type electrodes that are electrically connected to each other.
Following method adopts the device with above-mentioned these possibility features.The method is infiltrated in the histiocyte of human or animal's receptor to be improved molecules of active components in vivo; The method comprised as the next stage:
At least one electrode that is electrically connected with the first terminal of pulse generator and at least one electrode that is electrically connected with second terminal of pulse generator and tissue to be treated come in contact, and active component is expelled in the tissue regions to be treated;
Trigger generator then with the emission electric pulse, the function of electrical signal amplitude as distance between the electrode and tissue property calculated, so that produce electric field between electrode, this makes active component infiltrate in tissue and the infiltration cell.
More above-mentioned features are replenished, and one of this method may feature be active component to be expelled to the seal intracavity that comprises tissue to be treated and contain fluent material.
More above-mentioned features are replenished, and one of this method may feature be that active component is expelled in the synovial cavity.
More above-mentioned features are replenished, and one of this method may feature be, before electric field is provided:
To push tissue in proper order with one group of intrusive mood electrode that two terminals of generator link to each other and reach intermediate depth,
Utilize described electrode active component to be expelled in the tissue at degree of depth place in succession,
Before the providing of electric field is provided, all intrusive mood electrodes are pressed onto predetermined ultimate depth then.
More above-mentioned features are replenished, and one of this method may feature be, before electric field is provided:
The intrusive mood electrode that will link to each other with the first terminal of generator is incorporated into along same axis and reaches the same degree of depth in the tissue, and at the regional center place that comprises active component,
The intrusive mood electrode that will link to each other with second terminal of generator is introduced tissue along same axis, and arrive the identical degree of depth of intrusive mood electrode that links to each other with the generator the first terminal basically, roughly define the tissue regions that comprises active component, it is substantially the same with the distance of the regional center that comprises active component that these positioning of electrodes become, and around this center regular distribution.
More above-mentioned features are replenished, and one of this method may feature be, utilizes the electrode injection active component that links to each other with the generator the first terminal.
More above-mentioned features are replenished, and one of this method may feature be, before electric field is provided:
At least one catheter electrode is linked to each other with a terminal of generator,
At least one non-intrusion type electrode is linked to each other with another terminal of generator,
Each catheter electrode is pushed tissue, so that thrust body cavity; Make syringe needle slip into each catheter interior then, thereby in the process that catheter electrode moves and providing of electric field, do not damage body lumen wall in the process in body cavity,
Utilize at least one catheter electrode injection active component,
Each non-intrusion type electrode is placed on body cavity edge.
More above-mentioned features are replenished, and one of this method may feature be, at least one catheter electrode links to each other with a terminal of generator, and at least one catheter electrode links to each other with another terminal of generator, and before electric field is provided:
Each conduit that has electrode is pushed tissue, so that thrust body cavity; The syringe needle of each conduit is slided, thereby in the process that catheter electrode moves and providing of electric field, do not damage body lumen wall in the process in body cavity,
These catheter electrodes are pushed, so that make its almost parallel,
Utilize at least one catheter electrode injection active component.
More above-mentioned features are replenished, and one of this method may feature be that at least one non-intrusion type electrode also links to each other with these terminals of generator, and is placed on the tissue that defines body cavity.
More above-mentioned features are replenished, and one of this method may feature be, the non-intrusion type electrode is pressed in tissue, so that near each catheter electrode.
More above-mentioned features are replenished, and one of this method may feature be, at least one electrode is to be used for injecting active component, to get on except the conductivity type catheter electrode of syringe needle from conduit in advance.
More above-mentioned features are replenished, and one of this method may feature be to utilize at least one needle injection active component of catheter electrode.
More above-mentioned features are replenished, and one of this method may feature be, at least one electrode is the conductivity type catheter electrode, and the complete retracting needle from its corresponding conduit before that provides on the scene.
More above-mentioned features are replenished, and one of this method may feature be, injects active component when electrode pushes continuously.
More above-mentioned features are replenished, and one of this method may feature be to inject active component in continuous stages when electrode pushes.
More above-mentioned features are replenished, and one of this method may feature be, utilizes sleeve pipe to grasp at least one intrusive mood electrode, electrode is electrically connected with its generator terminal, and grasps electrode easily.
More above-mentioned features are replenished, one of this method may feature be, in case catheter electrode is introduced body cavity, just utilize a kind of utensil to adjust the angle of electrode axis so that obtain good collimation and the electrode avoiding linking to each other with the different terminals of generator between any contact danger takes place.
More above-mentioned features are replenished, and one of this method may feature be, in case catheter electrode is introduced body cavity, just physical unit is applied to the electrode tip that does not thrust tissue, so as the adjustment electrode separately angle and make it parallel.
More above-mentioned features are replenished, and one of this method may feature be, utilizes a kind of utensil to determine distance between the electrode tip, and makes the relative position of electrode suitable, so that obtain required electric field or electric current according to target tissue.
More above-mentioned features are replenished, and one of this method may feature be, utilizes a kind of utensil to determine distance between the electrode tip, and makes the programming of generator suitable, so that apply permission obtains required electric field or electric current according to target tissue voltage.
More above-mentioned features are replenished, one of this method may feature be, generator has the utensil of determining distance between the electrode tip continuously, and can dynamically adjust the programming of pulse, so that apply permission obtains required electric field or electric current according to target tissue parameter.
More above-mentioned features are replenished, and one of this method may feature be, the intrusive mood electrode be parallel, make one and be held in place by means of sleeve pipe, sleeve pipe grasps device easily and electrode is linked to each other with their generator terminals separately.
More above-mentioned features are replenished, and one of this method may feature be, the first electrode group comprises the intrusive mood electrode, at least one electrode in the second electrode group be non-intrusion type and be positioned on the tissue surface that comprises component.
More above-mentioned features are replenished, and one of this method may feature be, makes at least one intrusive mood electrode of the first electrode group pass organ, comprises the tissue regions of active component so that arrive, and need not to pass the non-intrusion type electrode.
More above-mentioned features are replenished, one of this method may feature be, promote the intrusive mood electrode along the axis that forms a surperficial occupied planar part that is arranged essentially parallel to described a plurality of non-intrusion type electrodes, these non-intrusion type electrodes contact with the tissue regions that comprises active component.
More above-mentioned features are replenished, one of this method may feature be, the top of at least one intrusive mood electrode is electric insulation, in order to avoid stray electrical current enters tissue volume by it, this tissue volume is on the one hand between electrode, on the other hand at skin surface and comprise between the tissue regions of active component.
More above-mentioned features are replenished, one of this method may feature be, the top of all intrusive mood electrodes all is electric insulation, in order to avoid stray electrical current enters tissue volume by it, this tissue volume is on the one hand between electrode, on the other hand at skin surface and comprise between the tissue regions of active component.
More above-mentioned features are replenished, one of this method may feature be, comprise the non-intrusion type electrode that has the first electrode group and the second electrode group on the tissue surface in zone of active component in covering, electrode is affacted on single of tissue, so that be provided at the electric field that the tissue surface of electrode effect is propagated down.
More above-mentioned features are replenished, and one of this method may feature be, one group of non-intrusion type electrode is pressed on the tissue surface that comprises active component, so that adjust their geometry, thus the tissue volume of increase between electrode.
More above-mentioned features are replenished, and one of this method may feature be, this generator is programmed, so that between every pair of approaching electrode, alternately launch electrical pulse sequence:
Thereby in comprising the organizing between each pulse of launching in institute's positioned area of active component, obtain interval at generator less than 50ms,
Between two pulses of an electrode pair, also have simultaneously interval greater than 100ms,
Thereby make the harmfulness of electric pulse littler.
More above-mentioned features are replenished, and one of this method may feature be, is transmitted into the persistent period between each electric pulse of pair of electrodes by generator, between 1ms to 50ms, to reduce the intensity of harmfulness and muscle contraction.
More above-mentioned features are replenished, and one of this method may feature be that the electric pulse of generator emission is unipolar and has square configuration.
More above-mentioned features are replenished, and one of this method may feature be:
Ratio between potential difference between each electrode and its distance between 10 volts/cm to 750 volt/cm,
The persistent period of electric pulse between 1 to 250ms,
Persistent period between two electric pulses between 1 to 1500ms,
The pulse number of each pulse train is between 1 to 1000.
More above-mentioned features are replenished, one of this method may feature be, the ratio that is applied to the volt/cm between the electrode is taken as 1.05 to 1.50 times of electric field optimum of target tissue, so that increase the tissue volume that comprises active component that electric field passed of best volt/cm numerical value.
More above-mentioned features are replenished, and one of this method may feature be to inject the tranquillizer before by means of the generator trigger impulse.
More above-mentioned features are replenished, and one of this method may feature be that used tranquillizer is an xylazine.
Description of drawings
Fig. 1 a and 1b illustrate the intrusive mood electrode and organize the mode that comes in contact.
Fig. 1 c and 1d illustrate the non-intrusion type electrode and organize the mode that comes in contact.
Fig. 1 e and 1f illustrate the electromigration method, and shown device has two electrodes, watches with section with from the top respectively.
Fig. 1 g illustrates the electromigration method, and wherein active component (is watched from the top) between electrode.
Fig. 2 a and 2b illustrate the zone that is covered by electric field, and wherein distance between electrodes is doubled in Fig. 2 a, and the ratio of v/cm is a constant.
Fig. 3 a, 3b and 3c illustrate an example of device, and wherein two electrodes have certain distance respectively, define active component and in the inside of active component at a distance of active component.
Fig. 4 a and 4b illustrate an example of device, one of them electrode is positioned at the center of active component, and with other electrode opposite in sign that defines active component, these two figure express the profile of the device that has 3 electrodes respectively, with the view of observing from the top that has 9 electrodes, the degree of depth of these electrodes is all identical.
Fig. 5 a and 5b express opposite in sign 2 (Fig. 5 a) or the electric field that is provided of the device of an electrode is provided between the individual electrode of 4 (Fig. 5 b).
The electric field that is provided is provided for Fig. 6 a, 6b, 6c and 6d, volt/cm respectively less than, equal, greater than, much larger than the optimum ratio of treated tissue kind.
Fig. 7 a and 7b express the device of being made up of two counter electrode electric field are provided, the ratio of volt/cm that these electrode pairs provide equate with the optimum ratio of tissue types to be treated (Fig. 7 a), than its big by 20% (Fig. 7 b).
Fig. 8 a and 8b express that (Fig. 8 a) or two device examples that (Fig. 8 b) injection needle is formed, wherein injection needle is positioned at the device center, at the intermediate depth place by 3 electrodes and one.
Fig. 9 a, 9b and 9c express the device example at center that electrode-injection needle is integrated in, active component is respectively, in case with electrode push tissue just provide (Fig. 9 a) perhaps is provided to intermediate depth (Fig. 9 b), with electrode by on shift protector (Fig. 9 c) onto.
Figure 10 .1 and 10.2 expresses an example of device, and it is electric insulation on a part that its 3 intrusive mood electrodes (being respectively central electrode) utilize plastic foil.
Figure 10 .3 expresses an example of device, and its outer electrode 10 is non-intrusion types, and it is electric insulation on a part that the center needle electrode utilizes plastic foil.
Figure 11 expresses the device example that has the one electrode, does not use under the telescopic situation for having.
Figure 12 a to 12c has proposed the example according to the several portions of constituent apparatus of the present invention, comprises sleeve pipe and stop system.
Figure 13 expresses the example of the injection sheet that is positioned at sleeve shell.
Figure 14 expresses the example that lock ring slides along closed sleeve pipe.
Figure 15 expresses the example of preparing to be applied to the locking device on the receptor.
Figure 16 a expresses the example of catheter electrode, the syringe needle of electrode in conduit, mobile slightly so that do not damage tissue or wall, and from conduit, regain.
Figure 16 b expresses the example of double needle conductivity type catheter electrode, and active component provides by conduit.
Figure 17 a-17c expresses the example of conductivity type catheter electrode.
Figure 18 a-18c expresses the use-case of device, and wherein the conductivity type catheter electrode is in body cavity.
Figure 18 d represent to send as an envoy to utensil example of two catheter electrode almost parallels.
Figure 18 e expresses the example of the electrode that is covered by non-conductive type duct portion.
Figure 19 illustrates the example of " rectangle " unipolar pulse.
Figure 20 a and 20b express the electric field line of propagating between the non-intrusion type electrode under tissue surface, this two width of cloth figure has wire or most advanced and sophisticated form respectively on plane and dish face electrode.
Figure 21 expresses the device example that is made of non-intrusion type electrode and intrusive mood electrode, and wherein tissue is passed on intrusive mood electrode edge and the axle that is positioned at structural non-intrusion type electrode plane almost parallel, so that arrive tissue regions.
Figure 22 expresses the device example that is made of non-intrusion type electrode and intrusive mood electrode, and wherein tissue is passed on intrusive mood electrode edge and the axle that is positioned at structural non-intrusion type electrode plane approximate vertical, so that arrive tissue regions.
Figure 23 expresses the device example that is made of non-intrusion type electrode and intrusive mood electrode, and wherein the intrusive mood electrode passes the non-intrusion type electrode by the hole, and the position of this electrode and needle shaft angle are guided by guider.
Figure 24 a and 24b express the example of non-intrusion type electrode, and it has dish and the Horseshoe that is pierced through by the hole of the center respectively.
Figure 24 c expresses the example of the non-intrusion type electrode of being made up of several non-integral plane electrodes.
Figure 24 d expresses the device example of being made up of two parallel wire electrodes, and wherein electrode is held in place by adhesive tape.
Figure 24 e expresses the device example of being made up of two wire electrodes, and wherein electrode is held in place by sheath.
Figure 24 f expresses the device example of being made up of one group of non-intrusion type electrode, and wherein arrangement of electrodes becomes checkerboard pattern and is held in place by sheath.
Figure 25 expresses the device example of forming by along the non-intrusion type wire electrode of not parallel axle.
Figure 26 expresses the device example of being made up of the non-intrusion type electrode, and electrode is pushed by the geometry that makes tissue and the tweezers that are out of shape are made one.
Figure 27 expresses the device example of being made up of two integrated non-intrusion type electrodes, these two electrodes link to each other with the same terminal of generator, be pressed against tissue, so that more close catheter electrode, and catheter electrode links to each other with the another terminal of generator and is arranged in body cavity.
The specific embodiment
The present invention make active component solution be expelled to animal or human, live body etc. the institute in a organized way in, especially in muscle, tumor, joint, corium and the epidermis, and in all organs (but except heart), especially bladder, stomach, kidney, lung, all head organs, especially comprise brain, ear, eyes, throat, the present invention also provides electric field, so that infiltration tissue and promotion active component are transferred in the cell.
The device that has electrode according to the present invention comprises:
By the first electrode group 11 that at least one electrode is formed, these electrodes link to each other with a terminal of electric pulse generator 21,
By the second electrode group 10 that at least one electrode is formed, these electrodes link to each other with another terminal of electric pulse generator 21, so voltage is different with the first electrode group.
The utensil of injection active component 36.
The utensil of injection active component can be made up of one or more syringe needles.Also can be by well known to a person skilled in the art diaphragm (patch) or any other device, utilizing the utensil of under pressure, introducing active component such as compressor gun.
In the present patent application, " electrode " is meant the electrode of any kind of, the intrusive mood or the non-intrusion type electrode of especially solid or hollow." intrusive mood electrode " is meant the electrode of the design in order to thrust tissue." non-intrusion type electrode " is meant in order to be retained on the tissue surface and the electrode of design.
These two electrode groups 11,10 are made up of intrusive mood electrode and/or non-intrusion type electrode.
As by shown in the example among Fig. 1 a-1d, in the present patent application, " electrode is contacted with tissue to be treated " at first is meant: when electrode is intrusive mood electrode (9), just it is pushed in the tissue (50) of receptor.This electrode can be pushed in the tissue regions that must comprise active component, and also can be positioned at this tissue regions edge even close this zone.Otherwise, when electrode is non-intrusion type electrode (18), just be meant: electrode is placed on the related tissue surface (51).Also one deck conducting resinl can be inserted between electrode and the tissue (125), so that improve electric conductivity.In both of these case, electrode all electrically contacts with tissue.In the situation that a plurality of electrodes and tissue to be treated electrically contact, it can be pushed continuously or simultaneously in the tissue or be placed on the tissue surface according to the form of these electrodes.Electrode has hinted with contacting of tissue regions to be treated: can electrode with before tissue contact, while or inject active component afterwards.In the situation of a plurality of electrodes, can electrode with the tissue contact before, the while or all or part of afterwards injection active component.By electric wire (7) or well known to a person skilled in the art that any other device makes electrode link to each other with generator.
The electric pulse that is provided can be square, unipolar, ambipolar, exponential or other form.Generator is that every counter electrode produces one or more predetermined electrical pulse sequences, and this number is less than 100, and the preferred feature of each pulse is: following key element is different between two pulses, perhaps keeps the same within a single sequence:
The ratio of volt/cm (voltage/distance between two electrodes poor) between 10v/cm to 1500v/cm,
Voltage difference between every counter electrode is 1v-2500v,
The persistent period of pulse between 1 to 1000ms,
During between two pulses between 1 to 2000ms,
Distance between electrodes in the zone of injection active component is less than 10cm.
Cycle between two pulse train, sequence number was less than 25 less than 600 seconds.The intensity that is provided is less than 5 amperes.
Intrusion and non-intrusion type electrode are made with metal material, preferred rustless steel and medical grade.They can be solid or hollow, all syringe needles in this way.
The device example that has two intrusive mood electrodes 90,91 is described in Fig. 1 e and 1f to some extent.
For electromigratory optimum efficiency, active component must all be passed by electric field 12, so it is between electrode, shown in the device that has two intrusive mood electrodes 90,91 of Fig. 1 g.Shown in Fig. 2 a, because the obvious cause of geometry, central area 36 is covered than covering better by eccentric region 37 by electric field.Active component must be preferably located in the device center that has electrode.
Electromigratory efficient depends on electric field value, and this value determines that by the ratio of the distance 30 between the voltage between the electrode and the two poles of the earth (electrode) unit is volt/cm.This ratio must approach optimum, and this depends on the character of tissue, more specifically says so to depend on the cell size that constitutes tissue.In the present patent application, this value is known as " direct best electric field ".Represent with Dark grey in the accompanying drawings by the tissue 66 that electric field covers according to this ratio.Ratio is more little, and efficient is also tended to reduce gradually, and is too little because electric field force becomes.Ratio is big more, and gain is caused the super infiltration of the cell toxicity of cell death to be offset, so efficient is tended to reduce then., represent with light gray in the accompanying drawing of the present patent application by the tissue 65 that electric field covers according to this not too best ratio (thus owing to too big or too little volt/cm ratio).
The electric field 12 that provides between two electrodes has occupied such volume: this volume has the oval in shape of being roughly along the axle 68 that connects two electrodes.Electric field line is far away more apart from this axle, and the distance that is capped is just big more, and therefore volt/cm ratio reduces just manyly more.
In order not cause damage, distance between electrodes must be minimum.In fact, big distance means:
Voltage ratio between the electrode (90,91) increases, and can reach danger limit subsequently.
Electric current is more spreading on the large tracts of land.Shown in Fig. 2 a, voltage between the electrode and distance are the twices of Fig. 2 b.Electric current flows through more innerv surface, thereby causes more contraction, causes stronger pain reaction.
In order to have minimum distance 30 between electrode, although still will keep efficient (the active component maximum that electric field passed), electrode also must define the active component 36 of being injected.This is shown in Fig. 3 a to 3c, and accompanying drawing illustrates such device by means of example table: the injection needle 8 of active component is found and concentrates between two intrusive mood electrodes 90,91.
The present invention proposes a kind of like this device: the first electrode group 11 introduced within the active components, and the preferred heart therein, and surrounded by the second electrode group 10.Express an example in Fig. 4 a, it has the intrusive mood electrode.Distance between electrodes 30 is compared with the device (Fig. 3 b) of front and is reduced by half.If second group of electrode is non-intrusion type, the second electrode group is located on the tissue surface so, in the injection site of active component.
In a preferred form of the invention, if device is made of a more than intrusive mood electrode, the degree of depth of these intrusive mood electrodes is all identical so.
Transfer to intracellular efficient in order to improve active component, the necessary uniform distribution of the electrode of second group of 100-107, so that form a circle, and central electrode 11 forms its centers of circle.These electrodes therefore must be each other at a distance of fixed distance 31 (shown in Fig. 4 b).
Fig. 5 a and 5b are preferred forms of the present invention for intrusive mood or non-intrusion type electrode, and express and use: in this device as the electromigratory surface of lower device, the second electrode group is made up of two electrodes (100,101) and four electrodes (100-103) respectively.The electric field that is provided by back one device covers bigger area, approaches sphere.
With the optimum efficiency 66 and the regional position of handling, depend on the volt/cm ratio that is applied on the electrode pair with average efficiency 65:
In Fig. 6 a, the volt between the electrode/cm ratio is less than direct best electric field.
In Fig. 6 b, the volt between the electrode/cm ratio equals direct best electric field.
In Fig. 6 c, volt/cm ratio is a bit larger tham direct best electric field, and therefore handle with optimum efficiency 66 in the bigger zone between electrode, and adjacent domain is handled with average efficiency 65.
In Fig. 6 d, electric field is greater than direct best electric field, and their remarkable toxicity has been eliminated the electromigration effect to the tissue on the axle between two electrodes.
See thus, if put between the electrode volt/cm ratio with compare by direct best electric field being put on the result (illustration 7a) who obtains between the electrode, be a bit larger tham (for the ratio between 105% to 150%, also represent by means of the example among Fig. 7 b) direct best electric field, then obtain optimum efficiency.Yet, only with regard to innocuousness and toxicity, remaining receptor tolerable the time in the growth on volt/cm when electric field, this method can be used.
Have in some devices that the intrusive mood electrode are positioned at the same area (for the device with 2 counter electrode, illustrating by means of example table) in Fig. 7 a and 7b, pulse train can be continuously, simultaneously or provide overlappingly.
In the device situation that the second electrode group is made of at least two counter electrode, if electrode pair transmits electric field continuously, provide in the time of so with electric field and compare, efficient also is improved, and some is organized processed twice.
For the first electrode group accurately being positioned at the center of active component, the injection needle 8 of active component and electrode 11,100,101 can remain on separately the position by one or more intermediate plates 41, and these intermediate plates make their keep the geometry of regulation.For the device that is made of the intrusive mood electrode, this illustrates by the example among Fig. 8 a.
At the remainder of this description, unless otherwise indicated, otherwise the electrode of the first electrode group 11 is intrusive moods.These examples will be expressed whole device or comprise more multielectrode partial devices.The intrusive mood needle electrode of the first electrode group will be represented with single needle electrode 11 in the accompanying drawings.Be positioned at the device center and comprise first group of electrode of the utensil of injecting active component, be known as " first electrode " sometimes, second group of intrusive mood electrode is known as " external electrode " sometimes.
In order to make active component rightly between electrode, as by means of shown in the example among Fig. 8 a, on the device that has three intrusive mood electrodes, injection needle 8 must than central electrode and/degree of depth place that external electrode is shallow.Fig. 8 b illustrates the device with some injection needles 8 by means of example table, and these syringe needles are located in the face of center needle electrode 11, and are arranged in the degree of depth place more shallow than electrode regularly, so that active component is evenly distributed between the electrode.Can see that the injection needle that contacts with central electrode is also as virtual electrode.In this example, electrode and syringe needle are made one by supporter (41).
Central electrode also can be used as injection needle.Yet the defective of this device is, the some of them active component is dispersed in below the needle electrode of center, and (Fig. 9 a) no longer to pass electric field.The method that the present invention proposes is, active component 36 is injected at one or more intermediate depths place in the tissue (50).The device that has electrode 23 is deeper pushed tissue in each stage, so that the injection active component.In the end the stage, will shift protector on the electrode onto, and active component is not provided.This method makes active component be expelled in the zone of the best between electrode thus.This method illustrates by means of the example among Fig. 9 b and the 9c, and wherein device has intrusive mood electrode (100,101,11), and in the interstage of injecting all active components.
By the deeper injection of active component, especially be expelled to big mammal or people's intramuscular, electric field 120 also spreads in the tissue of not sheltering any active component.This is shown in Fig. 9 c.But this causes toxicity and contraction or the pain helpless and unhelpful to patient.The present invention proposes electrically insulating material 15 is put on syringe needle 100,101,11 top (as by means of shown in the example among Figure 10 .1, wherein device has 3 intrusive mood electrodes), and this has limited the magnitude of current that flows through tissue greatly.This insulant also has the insulating beneficial effect of the electrode pair of making skin surface, just propagates under receptor skin 51 to avoid electric field.Only make the insulating fact of syringe needle that links to each other with the single terminal of generator, will only reduce the some of them stray electrical current, shown in the example among Figure 10 .2, wherein device has 3 intrusive mood electrodes.Usefulness also has, and for the device that comprises one or more non-intrusion type electrodes, makes the top insulation (example of device is shown in Figure 10 .3) of central electrode.
Syringe needle and intrusive mood or non-intrusion type electrode are made one, and with rigidity or flexible a little supporter (41) clamping.Make the intrusive mood parts parallel then.Such example is shown in Figure 11, and wherein device has intrusive mood syringe needle (100,101), and electrode and needle electrode pass electric insulation piece 41, and simultaneously also through electric wire 7a, 7b directly links to each other with generator 21.
Consider disposable economical electrode, this device also can comprise the sleeve pipe 3 that electrode is linked to each other with generator.This sleeve pipe will allow to handle easily the ground extracting and have the device of electrode, and make operator and electrical insulation.This sleeve pipe can also make the utensil and the storage 1 thereof of injection active component become one.And, can also be pushed into desired depth such as the device that utilizes retainer to make to have electrode.Each stage outside stage in the end also allows a part of active component of injection, and this part component will be distributed in (perhaps at not between the insulated part of electrode) between the electrode equably.The device example that has disposable electrode 23 and sleeve pipe 3 is shown in Figure 12 a, 12b and the 12c, and its middle sleeve 3 has the system that comprises retainer 20-22.The method that this example of sleeve pipe and electrode and retainer thereof is assembled is shown in Figure 13-15.
The intrusive mood electrode must be fit to the treatment of brittle zone, so that in the muscle contraction process that causes owing to providing of electric field, avoids damaging handled zone (comprising these tissues that the electrode that defines tissue and wall 77 are passed) with syringe needle.In fact, some tissues and wall itself seldom or not can be recombinated, so step must carry out, so that at positioning of electrode with active component is injected and the providing in the process of electric field, avoid these tissues and wall are caused damage.Device of the present invention is known as " catheter electrode ", and its example is shown in Figure 16 a, 16b, the 17a-17c, and this device can be avoided this danger.Figure 17 c describes out all parts of catheter electrode 75.This device is fit to institute in a organized way, muscle especially, and refer in particular to and be used to comprise the organ that seals body cavity 78, comprise fluid even viscous fluid in the body cavity.This device refers in particular to and is used to handle the synovial cavity in any joint that body weight surpasses all mammals (comprising the people) limbs of 2 kilograms.
Catheter electrode is the intrusive mood electrode, is made up of the intrusive mood syringe needle 71 that conduit 70 covers.Conduit is to use the pipe that the compression stress along it is had thin flexible material (for example siloxanes) formation of greater or lesser resistance.By the syringe needle 71 that is positioned at conduit conduit is introduced tissue.Make the catheter surface conduction, also preserve flexibility to a certain degree simultaneously.In case catheter electrode is in tissue, syringe needle just part is drawn back, even regains from device fully.Conduit 70 is damaging tissue no longer then.If tissue is a fluid, conduit can be pushed, be to push in some cases along its direction of adjusting.
In modification of the present invention, active component is introduced in the several electrodes that comprises this device simultaneously, as by shown in the example among Figure 16 b, this example is a double needle conductivity type catheter electrode, and active component provides by conduit, and two electrodes are one.
In modification of the present invention, catheter electrode is made up of several syringe needles and conduit.These catheter alignment are arranged to the circle form or arrange with any alternate manner.An example is shown in Figure 17 a, wherein two conduits each link to each other with the different terminals of generator, supporter 41 concentrates in together electrode and is non-conductive, syringe needle is independently.
In order to conduct electricity, conduit must cover with film or metal wire or any other conductive material 72.Any way that electric wire is arranged to those skilled in the art will know that (braiding, parallel, silk screen etc.).
If device is made of a plurality of catheter electrodes, electrode can link to each other with a supporter or independently so.
In by the method shown in the example among Figure 18 a-18d,, therefore device can be introduced in the body cavity a little owing to the intrusive mood syringe needle of regaining subsequently 71.Inside by conduit 70 is expelled to active component in the body cavity then.Progressively inject active component in the time of can be in electrode pushes body cavity.In the situation of synovial cavity, flexible conduit allows arthrogryposis, so that active component is distributed satisfactorily.
Active component can provide once or several times, perhaps provide simultaneously in conduit pushes tissue the time.
In modification of the present invention, make the syringe needle 71 of each conduit 70 mobile slightly, so that no longer can contact again with body lumen wall.Yet syringe needle is retained in the conduit, so as to make its push endoceliac the time harder.In this case, utilize syringe needle 71 to inject active component gradually.In case assemble in placely, syringe needle 71 just can be regained before electric field provides.
When generator provided electric pulse, electric current just flow through the metal surface of conduit.
Conduit covers (shown in the example among Figure 17 b-18d) with electrically insulating material 15 at an upper portion thereof, so that electric field is only propagated in body cavity.Under these conditions, if body lumen wall does not innervate, receptor is in fact just experienced less than pain so, only experiences slight muscle contraction, and has tangible voltage to be provided.
Catheter electrode can be used on all types of tissues.At the nonfluid tissue, especially on muscle, on will installing, shift onto before the required ultimate depth, need not to remove syringe needle.
If device is to be made of at least two sleeve pipes that link to each other with the different terminals of generator, so preferably, these telescopic axles are parallel.Sleeve pipe is by supporter or utilize sleeve pipe to make one.Yet the use of integral duct electrode is difficult for the tissue that is difficult to arrive.In case first electrode is in place, just can utilize the protector that forces second electrode parallel: protector is applied to overflowing on the part of the syringe needle that pushed, so that the electrode below the guiding is by another hole of protector.This principle can be applicable to the intrusive mood syringe needle of any kind.
Many method and apparatus all allow the distance between the electrode tip (74) to obtain accurately determining.This available medical image system shows.Another technology is the non-intrusion type needle electrode to be inserted inside pipe casing, and utilize them as electrode, so that launch slight pulse by its needle point of process outside sleeve pipe.This makes that the resistance between the electrode is determined, and determines distance thus.
In order to adjust collimation, also can utilize a kind of device.Such as, utilize the device that constitutes by rigid rod 760,761, in the rigid rod lead-in bushing so that make sleeve pipe orientation (as by shown in the example among Figure 18 d), perhaps with suitable device by on the outer end that is pressed in electrode 763,764 (76).Also can utilize sleeve pipe, sleeve pipe also can provide between catheter electrode and generator and electrically contact.
Generator can be controlled the strength grade that electric field provides in the process to be launched, and whereby with the epiphase of former record than or with first pulsion phase ratio of being launched, indicate the successful degree of operation.
This device can comprise one or more non-intrusion type electrodes of refill conduit electrode, and these non-intrusion type electrodes are positioned on the tissue surface that defines body cavity, links to each other with a terminal of generator, and this moment, at least one catheter electrode linked to each other with another terminal.This electrode can be non-intrusion type (for example being positioned at the dish on the knee).This device can comprise the intrusive mood electrode (for example arriving buttocks syringe needle all around) of refill conduit electrode, the only approaching tissue regions that comprises active component of this intrusive mood electrode, and do not pierce through this zone.In a kind of situation in back, this syringe needle can cover with electrically insulating material in its end.If device comprises several counter electrode, the pulse between so every counter electrode can simultaneously or provide continuously.
Catheter electrode can also be pierced through by the hole on the wall of conduit (70) (78), and this no longer needs conductive cap.An example is shown in Figure 18 e.In this case, be syringe needle (71) owing to take place directly to contact by hole and tissue and guarantee and the electrically contacting of pending (treatment) tissue.Utilize such electrode, because innocuousness also is recommended in and triggers electric field before in the mobile slightly syringe needle of catheter interior.In this manual, such electrode is known as: the electrode that covers with non-conductive type duct portion.
In this manual, term " catheter electrode " is meant all types of catheter electrodes, especially electrode and the conductivity type electrode that covers with non-conductive type duct portion.
The remainder of description is considered all types of electrodes and electrode assemblie.
Generator was launched the purposes of low-voltage, short time test of pulse and popularize before the treatment pulse is provided, to comprise all types of electrodes.These pulses are by analyzing the current intensity generated and consider tissue property and the geometry of electrode, and make distance between electrodes controlled.This also makes pulse sequence program be recomputated.Sequencer program provides at electric field and also can utilize data method makeup to put in real time in the process to recomputate, so that the remainder of correction sequence.If owing to muscle contraction changes, this is useful so such as the space between the electrode.
In order to reduce the harmfulness of device, the use of the tranquillizer such as xylazine (for example xylazine of 7mg/ml), reduced the muscle contraction and the pain reaction that are caused by providing of electric field, and corresponding to another kind of mode very bigly, especially constituted incompatible the time at anesthetis.
Pulse train defines with following feature and parameter:
Pulse shape: rectangle (by the one pole shown in the example among Figure 19), sine curve, bipolar, exponential etc.
Poor, the number of pulse 133 of the voltage 130 between the electrode, the persistent period of each pulse 132.
Interval between each pulse 131.
The inventor finds, the use of the short time interval (between 1-100ms) between two electric pulses is compared with the value (greater than 100ms) that habituation is used, and the muscle contraction and the pain reaction that are caused by providing of electric field have been provided very consumingly.In muscle contraction and the obviously this minimizing aspect the pain reaction, hour improve gradually at spacing of cut.
The test that Canis familiaris L. and cat are finished demonstrate following some:
The use of tranquillizer causes pain and muscle contraction to reduce very significantly,
The use of 1-50ms interval causes pain and muscle contraction to reduce very significantly, and this minimizing becomes more obvious when the persistent period reduces.
Yet very Duan interval can cause reducing of electromigration efficient.Secondly utilize the device that has several counter electrode, this device is mutually close, parallel or staggered with the generator that alternately triggers each pulse.In the present patent application, pulse will be known as " superimposed pulse ".
More than making the electrode pair number that is adopted in the whole level utilization of tissue regions can simulate two times between the pulse divides.Recommend to utilize the persistent period that equate to blanking time between the pulse of being divided by by the electrode pair number, make pulse interlacing.An electrode can link with the several electrodes that is connected on the generator another terminal, to produce several counter electrode.For example, in the situation of the device that has 3 electrodes (for example Fig. 4 a, 5b), every counter electrode is corresponding to coupling: central electrode (one of external electrode).
In optimal way of the present invention, whole or some electrodes in the second electrode group are non-intrusion types, and are arranged in covering (or approaching) and comprise on the tissue surface in zone of active component.
Non-intrusion type electrode and intrusive mood electrode become one, or independently.These two electrode groups constitute with intrusive mood and/or non-intrusion type electrode, and the non-intrusion type arrangement of electrodes comprises in covering on the tissue surface in zone of active component.
These two electrode groups also can only constitute with the non-intrusion type electrode.
In this case, in optimal way of the present invention, electrode affacted on single of the tissue 51 that comprises active component, so that allow electric field 12 under the tissue surface that electrode 9 effects are arranged, to propagate.The electric field that is provided is propagated between electrode by one deck intermediate structure (skin, fat etc.), and pass the tissue that comprises active component (as by among Figure 20 a and the 20b example exemplified).
These non-intrusion type electric pole type one or independently; They can perhaps be reused only with once.
The present invention proposes a kind of like this device: this device comprises the one or more intrusive mood electrodes that link to each other with the first terminal of generator, and the one or more non-intrusion type electrodes that link to each other with second terminal of generator, and these electrodes are not one.The intrusive mood electrode can pass tissue 50, so that arrive the zone that comprises active component.An example is shown in Figure 21, and wherein the axle of intrusive mood electrode 17 is arranged essentially parallel to the surface of non-intrusion type electrode 78 or the plane of organizing 51 surface to follow.An example is shown in Figure 22, and wherein the axle of intrusive mood electrode 17 is approximately perpendicular to the surface of non-intrusion type electrode or the plane 18 that tissue surface is followed.In a preferred form of the invention, protector 49 makes the place that the intrusive mood electrode must piercing tissue and/or the angle that pierces through of intrusive mood electrode axis 69 accurately be located (shown in the example among Figure 23).
Can be any type of in the moment that electric field provides with the surface of organizing each the non-intrusion type electrode 18 that contacts.It can be any geometry: (shown in the example among Figure 24 d) of rectangle, triangle, circle (shown in the example among Figure 24 a), semicircle, circular arc, dish, Horseshoe (shown in the example of Figure 24 b), ellipse, wire, symmetry or asymmetric etc.Each electrode can have hole 43 (example is shown in Figure 24 a and the 24b), thereby allows the intrusive mood electrode to pass this hole.Figure 24 c expresses the non-intrusion type electrode example of being made up of the plane electrode of several non-one.
The non-intrusion type electrode can replenish the device that comprises intrusive mood electrode and catheter electrode.
Can be virtually any size in the moment that electric field provides with the surface of organizing each the non-intrusion type electrode that contacts.It can be very little, smooth slightly tip, all ends in this way.It can be bigger, such as allowing obviously to cover the tissue surface that comprises active component, perhaps covers bigger surface.
Each non-intrusion type electrode is rigidity or flexibility.Each intrusive mood electrode is smooth or crooked slightly, so that follow the shape on target tissue surface.
Each non-intrusion type electrode can keep organizationally by sleeve 5, sleeve pipe, resilient sleeve 94 (an one example is shown in Figure 24 e and the 24f), binder, viscosity bar 92 (an one example is shown in Figure 24 d).Figure 24 e expresses the example of the wire electrode that forms circle.These adnexaes also are used for electrode is connected on parts 7,7a and the 7b, and these parts are used for electrode is linked to each other with the corresponding terminal of generator.
In preferred embodiment of the present invention, the non-intrusion type electrode can be symmetric or asymmetric or even irregular device.At electrode is line 44a, the form of 44b and be in the situation of non-intrusion type, and these electrodes can be followed not parallel axis (an one example is shown in Figure 25).
The non-intrusion type electrode can be by being pressed on the tissue 50, so that revise its geometry, thereby increases the tissue volume between the electrode (as by shown in the example among Figure 26, wherein electrode support is the tweezers forms).
The non-intrusion type electrode also can be by being pressed on the tissue 50, to reduce these electrodes and other distance between electrodes (as by shown in the example among Figure 27, wherein having bipolar electrode) that is connected on the generator another terminal.This especially can be near introducing endoceliac intrusive mood syringe needle.
The detailed description of the embodiment of the invention
The application is meant the preferred embodiment of describing among Figure 12 a, 12b and the 12c of the present invention herein.This device is made up of following two major parts:
Especially " the injection sheet " 23 that electrode, instrument used for injection and supporter is concentrated in together,
The shell 2 of injection sheet is called " sleeve pipe ".
Sleeve pipe is made up of two semicircular cylinders 3, and whole fixing with ring 22.Injection sheet 23 is made of three alignment electrodes parallel to each other and at the same depth place, and wherein central electrode 11 is positioned at two equidistance places between the external electrode 100,101, and makes active component be injected.The hole is used to receive the syringe that will comprise active component, and active component will be injected by first electrode (11).
Syringe needle utilizes one or two clamping disk 41 to keep together.The electrical insulating film 15 that will comprise the thin-walled made from synthetic material is applied on the electrode below the clamping disk 41.
Sleeve pipe is as the shell of injection sheet 23.It also as and the injection electric terminal of sheet 2 and being electrically connected of electric wire 7, electric wire 7 be used for electromigratory electricity (pulse) generator 21 and link to each other.Two electrodes 100,101 that are positioned at injection sheet periphery link to each other with the same terminal of generator, and first electrode links to each other with another terminal.Sleeve pipe is formed by one or more, thereby in case assembles the just easy grabbing device of realizing.The contact is to use the metallic forms 38 that is pressed on the electrode by spring or flexure strip to produce, and perhaps also available flexible metal sheet generates.Also as the shell of the syringe 1 that comprises active component 36, active component will be injected between two external electrodes of injection sheet 23 sleeve pipe.Stop system 20 makes the parts of winning be pushed into desired depth.Figure 13 expresses and has the device of injecting sheet, and the injection sheet is made up of syringe, and the injection sheet that assembles is positioned at its shell.
The definition pulse sequence program is perhaps selected the program of record in advance, this program specifically defined interval between the number of each pulse and persistent period, the pulse, sequence synchronously and put on voltage between the electrode.
Syringe and biologically active prod thereof and electrode pad set are fitted together, and place them in the telescopic corresponding shell, then two semicircular cylinders are assembled, with sleeve pipe locking (Figure 14), insert retainer 20 (Figure 15) by on locking cylinder 22, sliding then subsequently.Electric terminal 7 is linked to each other with electric pulse generator 21, the cap of protection syringe needle 5 is removed.Device is assembled (Figure 15), implant then in the tissue of receptor, adopt usual medical practice and the motion of using, so that implant the syringe needle that is equipped with syringe.The locking cylinder is locked in predetermined intermediate depth with device.The injection active component is removed retainer, and sleeve pipe upwards is pushed into protector.
Start the pulse train of programming in advance now.
Then sleeve pipe is opened, with disposable: syringe 1, injection sheet 23 and head protector 5 thereof discard.
Industrial applicibility of the present invention
Aspect using by means of the nucleotides of electric field many industrial applicibilities are being arranged. According to the present invention Device especially can be used for people's medicine (especially based on DNA medicine) and veterinary drug Use.
Treatment application in the human or animal specifically comprises (but not being unique obviously) tumour The generation for the treatment of and hemalbumin.
The generation of blood protein relates to, and by the inherence generation of erythropoietin(EPO), treats blood Friend's disease, growth disorder, myopathy, common lysosome and metabolic disease, chronic kidney function deficiency And β-thalassemia. Other application comprises new Angiogenesis, atherosclerotic, profit With the use of the protection effect of cell factor (for example IT-10), inoculation, ASON, Perhaps also have by cisplatin, by the electromigration of the plasmid coding of neurotrophin bring out outside Neuropathic prevention of week. What stress in particular is mainly to be in rheumatoid arthritis and general at present Application on the logical inflammation pathology, utilize IT-10, anti-TNF or other cell factor in addition Protection effect. The application of growth factor also is enriched in neurodegeneration and the sex change disease in joint potentially Sick (arthritis).
And, also relate to all pathology that benefit from the local expression of secreted protein, this A little all arthritic anti-inflammatory protein that are used for the treatment of if any in the joint, secreting of albumen, or use Anti-angiogenic proteins matter in the treatment cancer. Equally, the joint of growth factor generates and is considered to Can be used for treating arthritis. Merocrine angiogenin protein is at treatment periphery arthritis prescription The purposes of face also obtains paying attention to.
Also relate to active and passive inoculation, the generation of vaccine and the life of antibody of people and animal Become, especially in the pathology framework relevant with bio-terrorism (bioterrorism). Must Must treating in addition of explanation use, use for these, the cell inner expression of protein is necessary , such as many neuromuscular diseases (myopathy), tumour etc.

Claims (81)

1, a kind of device that improves the body intrinsic permeability of molecules of active components in the histiocyte of human or animal's receptor is characterized in that comprising:
Electric pulse generator (21),
The first electrode group, the described first electrode group comprises at least one electrode (9) that is electrically connected with the first terminal of electric pulse generator,
The second electrode group, the described second electrode group comprises at least one electrode (9) that is electrically connected with second terminal of electric pulse generator, and
Active component is expelled to in-house utensil (8).
2, device according to claim 1 is characterized in that, the first electrode group comprises single electrode (11).
3, device according to claim 2 is characterized in that, described electrode (11) is an intrusive mood.
4, device according to claim 3 is characterized in that, described electrode (11) has the utensil of injection active component.
5, device according to claim 4 is characterized in that, described electrode (11) is injection needle (8).
6, device according to claim 5 is characterized in that, the utensil of injection active component is made of at least one integral type syringe needle (8), and close electrode is placed on the degree of depth place less than electrode depth.
7, device according to claim 5 is characterized in that,
Electrode also is made of the sheathed catheter (70) that pierces through by enough large-sized hole (78), thereby comes in contact by these holes between allowing syringe needle and organizing,
The intrusive mood syringe needle of electrode (71) passes conduit along the conduit axis, and can slide along the conduit axis, also can from conduit, regain,
In a single day conduit and syringe needle combine and just form the intrusive mood electrode, and these electrodes are called " by the electrode of non-conductive type duct portion covering " (75) thereafter.
According to each described device of claim 4-6, it is characterized in that 8, described electrode (11) is by constituting with lower member:
Conduit (70), described conduit is covered by the conductive surface (72) that is connected with the respective terminal of pulse generator, is called " conductivity type catheter electrode " thereafter, and its surface is by roughly keeping the flexible material of conduit to form, this conduit can be as the utensil of injection active component
Intrusive mood syringe needle (71), described syringe needle passes conduit along the conduit axis, and allows piercing tissue, can slide along the conduit axis, and can regain from conduit, and syringe needle can also be used as instrument used for injection.
According to each described device of claim 3-8, it is characterized in that 9, described intrusive mood electrode thrusts in-house top at it and is covered with by electrically insulating material (15).
10, according to each described device of claim 7-9, it is characterized in that, at least one catheter electrode magnetization (75).
According to each described device of claim 3-10, it is characterized in that 11, the second electrode group comprises at least one non-intrusion type electrode (18), described non-intrusion type arrangement of electrodes comprises in covering on the tissue surface in zone of active component.
12, device according to claim 11 is characterized in that, at least one non-intrusion type electrode (18) has the hole (43) that allows intrusive mood electrode (11) to pass.
13, device according to claim 12 is characterized in that, described device also comprises the guider (49) of the orientation of its axis predetermined direction that makes intrusive mood electrode (11).
According to each described device of claim 3-10, it is characterized in that 14, the second electrode group comprises single intrusive mood electrode (10).
15, device according to claim 14 is characterized in that, the electrode of the second electrode group is the electrode that is partly covered by non-conductive type conduit (75).
16, device according to claim 14 is characterized in that, the electrode of the second electrode group is made of conductivity type catheter electrode (75).
According to claim 14 or 15 described devices, it is characterized in that 17, the electrode of the first electrode group is catheter electrode (75), and described two syringe needles wherein are parallel, one and continuous by supporter.
18, according to each described device of claim 15-16, it is characterized in that, two intrusive mood electrodes (10,11) be one, utilize supporter (41) to assemble, the almost parallel and the degree of depth are roughly the same.
According to each described device of claim 4-10, it is characterized in that 19, the second electrode group comprises a plurality of intrusive mood electrodes (10).
20, device according to claim 19 is characterized in that, the intrusive mood electrode of second group (10) roughly is positioned on the circle, and the electrode of the first electrode group (11) roughly forms the center of circle of this circle.
According to claim 19 or 20 described devices, it is characterized in that 21, second group intrusive mood sector electrode is made the zone of injection active component (36).
According to each described device of claim 19-21, it is characterized in that 22, two intrusive mood electrodes (100,101) of the second electrode group are aimed at first group electrode (11) basically.
According to each described device of claim 14-16,19-22, it is characterized in that 23, described device also comprises makes the utensil (764,763) of electrode along the orientation that parallels to the axis.
24, according to each described device of claim 20-22, it is characterized in that, all electrodes (10,11) be one, utilize that supporter (41) assembles, almost parallel and the degree of depth be roughly the same.
According to each described device of claim 14-24, it is characterized in that 25, described device also comprises the non-intrusion type electrode that at least one links to each other with one of terminal of generator.
26, according to each described device of claim 4-16,19-23, it is characterized in that,
Each intrusive mood electrode can have the sleeve pipe (2) that electrode is grasped easily and guarantee to be electrically connected between the terminal of electrode and its generator (21),
Described sleeve pipe (2) has shell, and described shell allows hold electrodes and the utensil of injection active component and the storage (1) that contains active component.
27, according to each described device of claim 4-16,19-23, it is characterized in that,
A plurality of electrodes have the single sleeve pipe (2) that electrode device is grasped easily and guarantee to be electrically connected between the terminal of the corresponding generator of each electrode and its (21),
Described sleeve pipe (2) has shell, and described shell allows hold electrodes and the utensil of injection active component and the storage (1) that contains active component.
According to claim 23 or 27 described devices, it is characterized in that 28, described sleeve pipe also comprises makes the utensil of electrode along the orientation that parallels to the axis.
29, according to claim 18 or 24 described devices, it is characterized in that,
Described integral type electrode and their supporter have the sleeve pipe (2) that electrode device is grasped easily and guarantee to be electrically connected between the terminal of each electrode and its generator (21),
Described sleeve pipe (2) has shell, the storage (1) that described shell holds the utensil of described integral type electrode and supporter and injection active component and contains active component.
30, according to each described device of claim 26-29, it is characterized in that described sleeve pipe:
Have the utensil that electrode (11) is pushed in succession reach in the tissue predetermined intermediate depth,
Has the utensil that active component is injected at each stop position.
31, device according to claim 30 is characterized in that, makes electrode (11) push the utensil of extremely predetermined intermediate depth in the tissue in succession, is made of at least one retainer (20).
According to each described device of claim 2-31, it is characterized in that 32, a plurality of intrusive mood electrodes that link to each other with generator are covered with by electrically insulating material (15) on the top that it thrusts tissue.
According to each described device of claim 2-32, it is characterized in that 33, all intrusive mood electrodes that link to each other with generator are covered with by electrically insulating material (15) on the top that it thrusts tissue.
34, device according to claim 1 is characterized in that, described two electrode groups comprise one group of non-intrusion type electrode (18), and described non-intrusion type arrangement of electrodes comprises in covering on the tissue surface in zone of active component.
35, device according to claim 34 is characterized in that, described electrode acts on single of the tissue (51) that comprises active component, the electric field of propagating down with the tissue surface that allows to be provided at the electrode effect.
According to claim 1,11-13,25,34,35 each described devices, it is characterized in that 36, the surface with the tissue of at least one non-intrusion type electrode (18) contacts has the shape of essentially rectangular.
According to claim 1,11-13,25,34,35 each described devices, it is characterized in that 37, the surface with the tissue of at least one non-intrusion type electrode (18) contacts has the roughly shape of similar horseshoe.
38, according to claim 1, each described device of 11-13,25,34-37, it is characterized in that the surface of at least one non-intrusion type electrode (18) is flexible.
39, according to claim 1,11-13,25,34,35 each described devices, it is characterized in that non-intrusion type electrode (18) has the smooth pointed shape in end.
According to claim 1, each described device of 34-39, it is characterized in that 40, the non-intrusion type electrode forms the integral part of flexible sheath (94).
According to claim 1,11-13,25,34,35 each described devices, it is characterized in that 41, at least one non-intrusion type electrode (18) is a wire.
According to claim 1,34,35,41 each described devices, it is characterized in that 42, described device only comprises the non-intrusion type electrode (18) of two wire, these electrodes are along different axis.
According to claim 1,11-13,25,34,35,38,40 each described devices, it is characterized in that 43, the surface with the tissue of at least one non-intrusion type electrode (18) contacts has irregularly shaped.
44, according to claim 1, each described device of 11-13,25,34-43, it is characterized in that described non-intrusion type electrode (18) is asymmetrical.
According to claim 1, each described device of 11-13,25,34-44, it is characterized in that 45, at least one non-intrusion type electrode is made up of the some non-intrusion type electrodes that are electrically connected to each other.
46, a kind of method of carrying out in according to the described device of aforementioned each claim, being used to improve the body intrinsic permeability of molecules of active components in the histiocyte of human or animal's receptor comprised as the next stage:
At least one electrode (9) that is electrically connected with the first terminal of pulse generator (21) and at least one electrode (9) of being electrically connected with second terminal of pulse generator (21) come in contact with tissue to be treated, and active component (36) is expelled in the tissue regions to be treated;
Trigger the electric pulse emission of generator (21) then, the function of electrical signal amplitude as distance between the electrode and tissue property calculated, so that produce electric field (12) between electrode, this makes active component infiltrate in tissue and the infiltration cell.
47, according to the described method of claim 46, it is characterized in that, active component is expelled to comprises tissue to be treated and contain in the fluidic sealing body cavity (78).
48, according to the described method of claim 48, it is characterized in that, active component is expelled in the synovial cavity (78).
49, according to each described method of claim 46-48, it is characterized in that, before electric field is provided:
One group of intrusive mood electrode (11,10) order that will link to each other with described two terminals of generator pushes tissue and reaches intermediate depth,
Utilize described electrode (11) active component to be expelled in the tissue at degree of depth place in succession,
Before the providing of electric field is provided, all intrusive mood electrodes are pushed into predetermined ultimate depth then.
50, according to claim 46 or 49 described methods, it is characterized in that, before electric field is provided:
The intrusive mood electrode that will link to each other with the first terminal of generator (11) is incorporated into along same axis and reaches the same degree of depth in the tissue, and in the center in the zone that comprises active component (36),
The intrusive mood electrode (10) that will link to each other with second terminal of generator is introduced tissue along same axis, and arrive the identical degree of depth of intrusive mood electrode that links to each other with the first terminal of generator (11) basically, roughly define the tissue regions that comprises active component, it is substantially the same with the distance of the regional center that comprises active component (36) that described positioning of electrode becomes, and around this center regular distribution.
51, according to each described method of claim 46-51, it is characterized in that, utilize the electrode injection active component (36) that links to each other with the first terminal of generator (11).
52, according to each described method of claim 47-48, it is characterized in that, before electric field is provided:
At least one catheter electrode (75) is linked to each other with a terminal of generator,
At least one non-intrusion type electrode (18) is linked to each other with another terminal of generator,
Each catheter electrode is pushed tissue, so that thrust body cavity; Make syringe needle (71) slip into each catheter interior then, thereby in the process that catheter electrode moves in body cavity and at the wall that does not damage body cavity (77) in the process that provides of electric field,
Utilize at least one catheter electrode injection active component,
Each non-intrusion type electrode is placed on body cavity edge.
According to each described method of claim 47-51, it is characterized in that 53, at least one catheter electrode (75) links to each other with a terminal of generator, at least one catheter electrode (75) links to each other with another terminal of generator, and before electric field is provided:
Each conduit that has electrode is pushed tissue, so that thrust body cavity (78); The syringe needle of each conduit is slided, thereby in the process that catheter electrode moves and providing of electric field, do not damage body lumen wall in the process in body cavity,
These catheter electrodes (75) are pushed, so that its almost parallel,
Utilize at least one catheter electrode injection active component.
According to the described method of claim 53, it is characterized in that 54, at least one non-intrusion type electrode (18) also links to each other with the terminal of generator, and is placed on the tissue that defines body cavity (51).
55, according to claim 52 or 54 described methods, it is characterized in that, the non-intrusion type electrode is pressed in tissue, so that near each catheter electrode.
According to each described method of claim 52-55, it is characterized in that 56, at least one electrode is to be used for injecting active component and to have got on except the conductivity type catheter electrode of syringe needle from conduit in advance.
57, according to each described method of claim 52-56, it is characterized in that, utilize at least one syringe needle (70) injection active component of catheter electrode.
According to each described method of claim 52-57, it is characterized in that 58, at least one electrode is the conductivity type catheter electrode, and the complete retracting needle (71) from its corresponding conduit (70) before that provides on the scene.
59, according to each described method of claim 52-58, it is characterized in that, when electrode pushes, inject active component continuously.
60, according to each described method of claim 52-59, it is characterized in that, when electrode pushes, inject active component in each stage in succession.
61, according to each described method of claim 46-60, it is characterized in that, grasp at least one intrusive mood electrode (10,11,75), electrode is electrically connected with the terminal of its generator (21), and grasps electrode easily with sleeve pipe.
62, according to each described method of claim 53-61, it is characterized in that, in case catheter electrode is introduced body cavity (78), just utilize a kind of utensil to adjust the angle of electrode axis (69), so as to obtain good collimation and the electrode avoiding linking to each other with the different terminals of generator between any contact danger takes place.
63, according to the described method of claim 62, it is characterized in that,, physical unit be applied to the electrode tip (76) that does not thrust tissue in case catheter electrode is introduced body cavity (78), so as to adjust electrode separately angle and make it parallel.
64, according to each described method of claim 50-63, it is characterized in that, utilize a kind of utensil to determine distance between the end of electrode (74), and make the relative position of electrode suitable, so that obtain required electric field or electric current according to target tissue.
65, according to each described method of claim 53-63, it is characterized in that, utilize a kind of utensil to determine distance between the end of electrode (74), and make the programming of generator (21) suitable, so that apply permission obtains required electric field or electric current according to target tissue voltage.
66, according to each described method of claim 53-63, it is characterized in that, generator has the utensil of distance between the end of determining electrode (74) continuously, and can dynamically adjust the programming of pulse, so that use the parameter that allows to obtain according to target tissue required electric field or electric current.
67, according to each described method of claim 46-52,54-61, it is characterized in that intrusive mood electrode (10,11,75) be parallel, make one and utilize sleeve pipe to be held in place, described sleeve pipe grasps device easily and electrode is linked to each other with their generator terminals (21) separately.
According to each described method of claim 46-48, it is characterized in that 68, the first electrode group comprises the intrusive mood electrode, at least one electrode in the second electrode group is non-intrusion type (18) and is positioned on the tissue surface that comprises component.
69, according to the described method of claim 69, it is characterized in that, make at least one intrusive mood electrode (11) of the first electrode group pass organ, comprise the tissue regions of active component so that arrive, and need not to pass non-intrusion type electrode (18).
70, according to the described method of claim 69, it is characterized in that, axis (69) along the substantially parallel planar part in the formation and the surperficial occupied plane of described a plurality of non-intrusion type electrodes promotes intrusive mood electrode (11), and these non-intrusion type electrodes contact with the tissue regions that comprises active component.
71, according to each described method of claim 46-70, it is characterized in that, the top of at least one intrusive mood electrode is electric insulation, in order to avoid stray electrical current (120) enters tissue volume by it, described tissue volume is positioned at the surface of skin (51) on the other hand and comprises between the tissue regions of active component (36) on the one hand between electrode.
72, according to each described method of claim 46-11, it is characterized in that, the top of all intrusive mood electrodes all is electric insulation, in order to avoid stray electrical current (120) enters tissue volume by it, described tissue volume is positioned at the surface of skin (51) on the other hand and comprises between the tissue regions of active component (36) on the one hand between electrode.
73, according to each described method of claim 46-48, it is characterized in that, comprise the non-intrusion type electrode that has the first electrode group and the second electrode group on the tissue surface in zone of active component in covering, described electrode is affacted on single of tissue, so that be provided at the electric field (121) that propagate down on the surface of the tissue (51) of electrode effect.
74, according to the described method of claim 73, it is characterized in that, one group of non-intrusion type electrode (18) is pressed on the tissue surface that comprises active component (51), so that adjust their geometry, thus the tissue volume of increase between electrode.
According to each described method of claim 46-74, it is characterized in that 75, described generator (21) is programmed to alternately launch electrical pulse sequence between every pair of approaching electrode:
Thereby between each pulse that generator is launched, obtain interval less than 50ms in the zone of organizing the place that comprises active component,
Between two pulses (131) of an electrode pair, also have simultaneously interval greater than 100ms,
Make the harmfulness of electric pulse littler.
76, according to each described method of claim 46-75, it is characterized in that, be transmitted into the persistent period (131) between each electric pulse of pair of electrodes by generator (21), between 1ms to 50ms, to reduce the intensity of harmfulness and muscle contraction.
According to each described method of claim 46-75, it is characterized in that 77, the electric pulse of generator (21) emission is unipolar and has square configuration.
78, according to each described method of claim 46-77, it is characterized in that,
Ratio between potential difference between each electrode and its distance between 10 volts/cm to 750 volt/cm,
The persistent period of electric pulse (132) between 1 to 250ms,
Persistent period between the electric pulse (131) between 1 to 1500ms,
The pulse number of each pulse (133) sequence is between 1 to 1000.
79, according to each described method of claim 46-78, it is characterized in that, be applied to electrode (10,11,18,75) ratio of the volt/cm between is taken as 1.05 to 1.50 times of electric field optimum of target tissue, so that increase the volume of the tissue that comprises active component that electric field passed of best volt/cm numerical value.
80, according to each described method of claim 46-79, it is characterized in that, before utilizing generator (21) trigger impulse, inject the tranquillizer.
81,0 described method according to Claim 8 is characterized in that used tranquillizer is an xylazine.
CNA2005800260718A 2004-06-24 2005-06-24 Device for transferring molecules to cells using an electric force Pending CN101001665A (en)

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