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    • 专利摘要:
    A device (100) comprising a first electrode (104) provided at or in a source electrolyte (101), and at least one ion conductive channel (103), wherein said first electrolyte (101) is arranged at a first portion (201) of the ion conductive channel (103), and a second electrode (105) provided in a target electrolyte (102), wherein said target electrolyte (102) is arranged at a second portion (202) of the ion conductive channel (103), and wherein said first and second electrodes provides an electrical control of an ion flow through the ion conductive channel (103), wherein the device further comprises at least one controlled delivery electrode (114) arranged adjacent to or in the second portion of the ion conductive channel (103), wherein said first and second electrodes further are arranged to provide an electrical control of an ion flow through the controlled delivery electrode (114) to the target electrolyte (102), and wherein said controlled delivery electrode (114) is adapted to deliver ions from said ion conductive channel (103) to said target electrolyte (102), and wherein said controlled delivery electrode (114) comprising an electronically and ionically conductive material (107) and an electrical contact (106), wherein said controlled delivery electrode (114) is arranged in ionic contact with, and between, said ion conductive channel (103) and the target electrolyte (102), wherein said electrical contact (106) provides for an electrical control potential (V) over the controlled delivery electrode (114) to control an ion flow between the controlled delivery electrode (114) and the target electrolyte (102).Elected for publication: Fig. 1
    公开号:SE1650348A1
    申请号:SE1650348
    申请日:2016-03-15
    公开日:2017-09-16
    发明作者:Jonsson Amanda；Arbring Sjöström Theresia；Simon Daniel；Berggren Magnus
    申请人:Oboe Ipr Ab；
    IPC主号:
    专利说明:

    ION CONDUCTIVE DEVICE WITH CONTROLLED DELIVERY ELECTRODE Technical field The present invention relates to an ion conductive device for acontrolled delivery of ions to a target electrolyte such as tissue, body fluids orcells, and more specifically to enhanced spatial and temporal delivery in vitroor in v|vo.
    BackgroundDrugs typically have their therapeutic action at specific sites in the body, but are often administered systemically. This means that only a smallportion of the drug ends up where it is needed, and the rest may cause sideeffects elsewhere in the body. By delivering drugs locally, where and whenthey are needed, a much lower dose can be used, and hence side effectsmay be avoided. lndeed, many drugs that today fail in clinical trials becauseof their adverse effects due to high dosages could in fact be effective andwithout side effects if they were delivered locally and at very low doses.
    Neurological disorders, such as Parkinson's disease and epilepsyresult from perturbations to the nervous system. Treatments for neurologicaldisorders include administration of pharmaceuticals and electrical stimulationof the nerves. With electrical stimulation a very fast effect is achieved, but theeffect cannot target a certain nerve signaling pathway but rather effects allnearby nerve cells. Pharmaceutical treatment, on the other hand, is morespecific, but much slower since the drugs need to travel to the site of action.
    A drug delivery device, such as an implantable device that couldrelease drugs locally and on a millisecond timescale would have the benefitsof specificity that pharmaceutical treatment has, along with the fast responsetypical of electrical stimulation. Also, the side effects due to high dosage thatis associated with systemic administration of drugs, as well as side effectsassociated with electrical stimulation, such as muscle twitching andsensation, could be avoided.
    To be a good candidate for an implanted drug delivery device, thetechnology should exhibit a few important features. For many applications it isdesirable that the delivery rate can be controlled in time, so that the drug isdelivered only when it is needed, i.e. the passive leakage should be low,meaning that the device should exhibit a good ON/OFF function. Dependingon the application, it may be essential that the drugs can be delivered quicklywhen needed. This is specifically important in neurological disorders or ingeneral when interacting with the nervous system. For example in neuronalprostheses e.g. human-made electrical/technological connections to neuronsor neural tissue where the speed is essential. Neurons generallycommunicate with one another, and with their target tissue e.g. 2 neuromuscularjunctions, by transferring chemical signals e.g. vianeurotransmitters, in bursts lasting for ~10 milliseconds. For example, the finemotor motion of the hands and fingers requires this high speed ON/OFFchemical signaling; and a siower signaling could result, in e.g. continuousmuscle contraction.
    Furthermore, it is essential that any implantable device technologyhave a long lifetime. This means that the device should be stable inside thebody, not produce inflammation, and that enough drugs/therapeutic/signalingsubstances can be stored in the device. The latter requirement typicallyimplies that a reservoir needs to be coupled to the device. lt is of interest to control the amount of a drug that is released atseveral sites in the same fluid individually (each release site, or drug outlet,can be ON or OFF independently from the others). As an example, aprosthetic device that aims at connecting an arm with the brain (where theoriginal neuronal connections have been lost) may need to activate or inhibithundreds or thousands of different regions or nerve/muscle cells to achieveproper movements of the arm. The body fluid contains a significant quantity ofmobile ions, and is therefore ionically conducting. Therefore, it constitutes anelectrolyte by definition, and is herein also referenced as a target electrolyte.Prior art devices such as the Organic Electronic lon Pump (OEIP, see Fig. 18)delivers ions from a channel to a target. This pump must be combined withseveral other pumps to achieve several delivery points. Such a combineddevice would be large, and with many components that it would be difficult tomaintain sufficient robustness for implant applications.
    A technology with a single source electrolyte/reservoir is significantlymore desirable from both a practical perspective and based on eventualproduction costs.
    Likewise, a technology in which the addressability function of multiple,independent ON/OFF delivery sites does not add significant bulkiness orcomplexity is advantageous from the perspectives of practicality, e.g., ofproduction and deployment, cost, and possibly even regulatory issues, e.g.,specific requirements for medical implants.
    There are several methods for local drug delivery already in use,including implanted pumps where the delivery rate can be controlled in time.When the drug is dissolved and delivered in a carrier fluid this dilutes theenvironment where the drug is delivered, and can lead to an increasedpressure if the drug is delivered into a confined compartment. Microfluidics isthe scaled down version of drug delivery in fluids, mostly used for in vitro lab-on-a-chip applications. Even though the volumes are much smaller, the sameproblem with increased pressure still exists. Furthermore, the amount ofdelivered drug is not controlled to a very high extent for either of these fluidictechniques. Other techniques used in practice are transdermal patches and 3 subdermal implants that exhibit passive delivery, meaning that drugs arecontinuously released at a predetermined rate. The delivery rate can thus notbe actively controlled in time with a sufficiently high degree of precision.
    A few techniques for local drug delivery utilize the fact that many drugsand neurotransmitters are, or can occur in, electrically charged form. Thisimplies that they can be controlled and measured electrically. Thesetechniques include drug release from conducting polymers and iontophoresis.lontophoresis, or electromotive drug administration (EMDA), is a method foradministering charged drugs through the skin with an applied electric field.This method is not very exact in terms of the amount of delivered drugs.Charged drugs have also been incorporated as counter ions into conductingpolymers, and when the charge of the polymer is altered as a function ofoxidation or reduction, the drug (counter ions) is expelled and released fromthe conducting polymer without any liquid flow (as shown in Fig. 17). Althoughmany research groups have successfully used this principle, it suffers fromhigh passive leakage, since ions of the electrolyte/body fluid are passivelyexchanged with the ionic drugs loaded in the conducting polymer, regardlessof the addressing voltage. Furthermore, only the drugs originally incorporatedinto the conducting polymer during the fabrication or pre-usage phase can bereleased, which limits the amount of drug that can be delivered.
    The OEIP is an alternative solution to deliver chargeddrugs/biomolecules from micrometer-sized outlets without any significant fluidflow. The delivery rate of drugs from an OEIP is controlled by the appliedcurrent, and can thus be tuned.
    With OElPs, several outlets in the same target can be separatelyaddressed if they all have separate source electrolytes and hence separatechannels. One source electrolyte can also be used to address several outletsif each outlet is located in a separate target electrolyte. As described inEP2068146 several target electrolytes may be used, since a waste electrolyteis introduced into the system. However, if the device is to be implanted, thesituation with multiple target electrolytes is not relevant at all, because thenthere is only one target electrolyte, e.g. the body fluid.
    One design of the OEIP enables millisecond-fast delivery, by making asmall, high aspect- ratio hole, i.e. high height to diameter ratio, to the targetelectrolyte so that delivery occurs out of the plane instead of in the plane ofthin films (100 nm scale). To increase the ON/OFF ratio during operation ofthis device, an ionic bipolar membrane diode (to be explained in the followingdescription) is incorporated, allowing only one direction of the ionic currentthrough the target outlet.
    However, the OEIP in any form, such as for instance described inEP1862799, WO2009/115103 A1 and WO2010118754 cannot be used toconstruct several individually controlled outlets in the same electrolyte if a 4 common source electrolyte is used. The reason why this is not possible isbecause the electrical potential of the electrolytes (the source, waste andtarget electrolytes) control the delivery currents and cannot distinguishbetween the different outlets. Therefore, if the geometry with several outlets isused with OElPs, the outlets will all be ON or all be OFF at the same time.
    There is thus a need for an ion transport device, which is preferablyan implantable device, where it is possible to individually control delivery ofcharged chemical species through one or several delivery sites in a commontarget electrolyte.
    Summarylt is an object of the present disclosure, to provide an improved ion conductive device, which eliminates or alleviates at least some of thedisadvantages of the prior art devices.
    The invention is defined by the appended independent claims.Embodiments are set forth in the appended dependent claims and in thefollowing description and drawings.
    According to a first aspect, there is provided a device comprising a firstelectrode provided at or in a source electrolyte, and at least one ionconductive channel, wherein said first electrode is arranged at a first portionof the ion conductive channel, and a second electrode provided in a targetelectrolyte, wherein said target electrolyte is arranged at a second portion ofthe ion conductive channel, and wherein said first and second electrodesprovides an electrical control of an ion flow through the ion conductivechannel, wherein the device further comprises at least one controlled deliveryelectrode (CDE) arranged adjacent to or in the second portion of the ionconductive channel, wherein said first and second electrodes further providesan electrical control of an ion flow through the controlled delivery electrode tothe target electrolyte, and wherein said controlled delivery electrode isadapted to deliver ions from said ion conductive channel to said targetelectrolyte, and wherein said controlled delivery electrode comprising anelectronically and ionically conductive material and an electrical contact,wherein said controlled delivery electrode is arranged in ionic contact with,and between, said ion conductive channel and the target electrolyte, whereinsaid electrical contact provides for an electrical control potential over thecontrolled delivery electrode to control an ion flow between the controlleddelivery electrode and the target electrolyte.
    The device is thus based on the previously disclosed OrganicElectronic lon Pump (OEIP), however the inventive device comprises at least 5 three electrodes, i.e. the source, target and the at least one controlleddelivery electrode. Each controlled delivery electrode is arranged between itselectrical connection and its outlet, hence forming an ON/OFF switch enablingdelivery and preventing leakage by controlling the voltage of the controlleddelivery electrode with respect to the target electrolyte. Because there iselectronical conductivity in the controlled delivery electrode, very close to therelease site, ions can be released faster, i.e. with a fast switch-on speed, inthe millisecond range, from the application of a control potential. Thiselectrical switch-on is much faster compared to the switch-on speed ofprevious OEIP (seconds). The controlled delivery electrode thus forms anactive component for achieving a faster release of ions both from thecontrolled delivery electrode itself and from the ion conductive channel intothe target electrolyte. ln contrast to other types of electronically and ionically conductivematerials for delivery of ions, such as drugs, to a specific target electrolyte,e.g. a tissue or a nerve cell, the controlled delivery electrode, which may alsoserve as a storage of ions, may be continually refilled with ions from thesource electrolyte through the ion conductive channel. This may abolish theneed for an additional reservoir to be connected to the device. This may inturn allow for the creation of very small devices, for instance as smalleradhesive patches to be applied on a patient or in connection with nerves,brain or heart.
    This provides for an implantable device which can be used forcontinuously providing medicaments to a patient, as well as for deploying amedicament quickly when the need occurs, e.g. in a pulsed manner, butwhich does not need to be removed in order to be refilled. The electronicallyand ionically conductive material in the controlled delivery electrode may thusserve as a pre-loaded reservoir for ions, to be deployed into the targetelectrolyte at a specific time.
    The size of the controlled delivery electrode and its hole or interface tothe target electrolyte may be adapted for the desired rate of dischargeneeded, i.e. a larger controlled delivery electrode and a larger hole provides afaster discharge of ions into the target electrolyte.
    The electronically and ionically conductive material of the controlleddelivery electrode may be permselective for either cationic or anionic species.
    The material of the controlled delivery electrode may thus be adapteddepending on the type of ions to be delivered. The controlled delivery electrode is thus electronically as well as cationically (or anionically) conductive.The electronically and ionically conductive material may include a conducting polymer such as PEDOT.
    The electronically and ionically conductive material may be adapted fora charge being injected or extracted from the material.
    This provides for a material having a sufficiently high capacitance (forbeing able to store ion(s).
    The device may comprise at least two controlled delivery electrodes,and said at least two controlled delivery electrodes may be separated fromeach other with a ion conductive channel having a finite ion conductivity, tocontrol ion flow from the ion conductive channel into the target electrolytefrom each controlled delivery electrode separately.
    The at least two controlled delivery electrodes thus provide at least twospatially different delivery sites or outlets in said target electrolyte, which canbe individually controlled through the activation of the controlled deliveryelectrodes. This provides for a device which only has one source electrolyte,but where ions can be delivered at different locations in the target electrolyte.As the controlled delivery electrodes can be individually addressed it ispossible to precisely control the delivery to specific delivery sites or outlets, orfor instance cover a larger area, without having to use several differentdevices. The device may thus comprise at least four electrodes, i.e. a sourceand target electrode and at least two controlled delivery electrodes,controlling a respective outlet. Basically, by controlling the electric potentialsat the controlled delivery electrodes for each outlet, the ion delivery at multiplesites in a target electrolyte can be controlled individually, although thepotentials of the source, target and waste electrolytes are kept constant.
    The resistance between the controlled delivery electrode and the targetelectrolyte is preferably sufficiently high to enable the potential drop betweenthe contact of the controlled delivery electrode and the target electrolyte.
    The controlled delivery electrodes may be arranged on or in the sameor different ion conductive channel and the controlled delivery electrodes mayfurther be separated from each other with an ion conductive channel materialhaving a finite ion conductivity.
    By “finite ion conductivity” it is meant that the material has a sufficientlyhigh ionic resistance (ion conductive channel) to prevent so called crosstalkbetween outlets or the controlled delivery electrodes.
    A barrier layer or ion barrier may be arranged between the controlled delivery electrode and the target electrolyte.The ion barrier thus forms an ion diode together with the electronically and ionically conductive material in the controlled delivery electrode. Thebarrier provides a way of stopping passive leakage from the controlleddelivery electrode and the ion conductive channel to the target electrolyteespecially when combined with a small ionic current from the targetelectrolyte to the controlled delivery electrode.
    The barrier or ion barrier may comprise a material having a fixedconcentration of opposite charges with respect to the fixed charges of theelectronically and ionically conductive material of the controlled deliveryelectrode.
    The ion barrier thus provides an ion current rectification together withthe electronically and ionically conductive material in the controlled deliveryelectrode, since the two together form an ionic bipolar membrane diode. Thebarrier is not electronically conducting, but is merely a polycation or polyanionmaterial (or any other porous material with fixed charges opposite to theelectronically and ionically conductive material).
    The barrier may alternatively geometrically restrain ion flow.
    This may e.g. be a narrow passage or similar, which together with thepermselectivity of the controlled delivery electrode and ion conductivechannel materials results in ion current rectification. Hence it forms anothertype of ion diode.
    The device may further comprise at least two ion conductive channels,and multiple controlled delivery electrodes may be arranged in or on saidmultiple ion conductive channels, wherein said controlled delivery electrodesmay be in ionic contact with the same target electrolyte, and the controlleddelivery electrodes may be separated from each other by an ion conductivechannel having a finite ion conductivity.
    This provides for an even more versatile device in which there may beseveral delivery sites or outlets into the same target electrolyte, while stillhaving only one source electrolyte.
    The device may comprise at least one waste channel, and each wastechannel may comprise a waste electrolyte and a waste electrode.
    According to a second aspect there is provided a method of operatinga device according to the first aspect, comprising the steps of: a) providing a source electrolyte comprising the ions to be transported, b) providing a target electrolyte to where the ions are transported, c) bringing the source electrode of the device in contact with the sourceelectrolyte, d) optionally providing a waste and a waste electrolyte; e) bringing the target electrode in contact with the target electrolyte f) applying a potential to the source electrode, the target electrode andthe controlled delivery electrode, and optionally to the waste electrode,effecting ion transport from the source electrolyte, to the controlled deliveryelectrode, or optionally to the waste electrolyte; and g) altering the potential of the controlled delivery electrode to switch onion transport to the target electrolyte.
    According to a third aspect there is provided the use of a deviceaccording to the first aspect, for delivering ions from a source electrolyte to atarget electrolyte through a controlled delivery electrode.
    Said target electrolyte may comprise any one of tissue, body fluids orcells both in vitro and in vivo.
    Brief Description of the DrawinqsEmbodiments of the present solution will now be described, by way ofexample, with reference to the accompanying schematic drawings.
    Fig. 1 is a schematic side view of the device comprising a single ionconductive channel and a single controlled delivery electrode device.
    Fig. 2 is a schematic side view of the device with an enlarged controlleddelivery electrode.
    Fig. 3 is a schematic side view of the device with a single ion conductivechannel and multiple controlled delivery electrodes placed in series.
    Fig. 4 is a schematic side view of the device with multiple ion conductivechannels, each having a controlled delivery electrode.
    Fig. 5 is a schematic side view of a controlled delivery electrode with a barrierlayen Fig. 6 is a schematic side view of a controlled delivery electrode with a barrierbased on geometry.
    Fig. 7 is a schematic side view of the device having multiple ion conductivechannels and multiple controlled delivery electrodes.
    Fig. 8 is a schematic top view of the device having a controlled deliveryelectrode, with multiple source electrolytes and a single target electrolyte. 9 Fig. 9 is a schematic top view of the device having controlled deliveryelectrodes, with a single source electrolyte and multiple target electrolytes.Fig. 10 is a schematic top view of the device having multiple controlleddelivery electrodes provided in parallel in the ion conductive channel.
    Fig. 11 is a schematic side view of the device comprising a controlled deliveryelectrode and a separate waste electrolyte.
    Fig. 12a is a schematic graph showing an aproximate potential path throughthe barrier.
    Fig. 12b is a schematic graph showing an aproximate potential path throughcontrolled delivery electrode to the waste.
    Fig. 13a shows a graph of a delivery pulse.
    Fig. 13b show that the target current is the sum of the source, waste andcontrolled delivery electrode currents.
    Fig. 14 is a graph showing delivery levels and delivery response time for astandard ion pump OEIP according to the dotted line and the solid lineaccording to the invention having a controlled delivery electrode.
    Fig. 15 is a schematic side view of a device system having one sourceelectrolyte and two encapsulated hoses/pipe-like struktures which both areconnected to a common waste electrolyte. The device having multiple ionconductive channels, each provided with one or more barrier equippedcontrolled delivery electrodes which are all in connection with a commontarget electrolyte.
    Fig. 16 shows a schematic top view of a device system having three ionconductive channels, each provided with a barrier equipped controlleddelivery electrode in connection with a target electrolyte and each channel inconnection to a common source electrolyte and a common waste electrolyte.Fig. 17 is a schematic side view of a prior art charged drug device.
    Fig. 18 is a schematic side view of the prior art Organic Electronic lon Pump(OEIP).
    Description of Embodiments Fig. 1 shows a device 100 or system according to the inventiondescribing the source electrolyte 101 comprising a first electrode 104, alsodenoted source electrode, a target electrolyte 102 which includes a secondelectrode 105, also denoted target electrode and a ion conductive channel103 having a first end 201 and a second end 202.
    The device 100 or system can either be constructed as a polyanionsystem or a polycation system depending on the fixed charges of the polymerof the permselective ion conductive channel.
    The ion conductive channel 103 should be designed or treated in sucha way as to minimize/reduce electronical conductivity, but preserve or provideionic conductivity, e.g. by a polystyrene sulfonate(PSS)-derivate or doping.
    Each respective controlled delivery electrode 114, 114a, 114b, see e.g.Fig. 1, Fig. 3, Fig. 4 or Fig. 10, comprises polymers having both electronicand ionic conductivity, connected to an electrical contact 106, 106a, 106b.The controlled delivery electrodes are separated by a portion of the ionconductive channel 103', 103a', 103b', see Fig. 3, Fig. 7 or Fig. 15.
    The ion conductive channel 103 and the controlled delivery electrodes114, 114a, 114b may be insulated from the electrolytes through anelectronically and ionically insulating layer 108, which also minimizestransport of water. On a plane surface, this insulation may consist of a wall, orin tissue, of pipe-like structure with openings through the insulation layer forthe respective controlled delivery electrode. lt is preferred that the potential VS over the source electrode and thetarget electrode is kept at a constant value. The ion conductive channel canthen be filled with ions by creating a potential over the channel e.g. by makinga difference in potential VCDEa and VCDEb between the respective controlleddelivery electrode and the target electrode see Fig. 3 for a given constantsource electrode potential. lf for example, the source electrode has a potentialof 10 volt, the target electrode 0 volt and the electrical contact of a controlleddelivery electrode -0.4 volt, then positive ions will be collected at thatcontrolled delivery electrode.
    To achieve delivery of ions, the electrical contact 106 of a controlleddelivery electrode is switched from negative to positive potential versus thetarget electrode 105. This will make the positive ions move into the targetelectrolyte. By quickly altering the internal state of the electronically andionically conductive material 107, a burst of ions will be quickly repelled fromthe electronically and ionically conductive material 107 and delivered to thetarget electrolyte. The electronically and ionically conductive material 107 canbe enlarged as seen in Fig. 2, to be able to increase the burst of ions see Fig.14. Hence a larged and well defined amount of ions or drugs can be quicklydelivered into the target electrolyte 102.
    Fig. 12, Fig. 13 and Fig. 14 show the potential profile and currents atdifferent parts of the device 100 when the control voltage is applied. Fig. 12aand Fig. 12b show approximate potential profiles along two pathways in thedevice. Fig. 12a shows the potentials ions would experience in travelling fromthe source electrolyte to the target electrolyte and to the waste electrolyte. Acontrolled delivery electrode that is ON will have a negative potential gradientfrom the controlled delivery electrode 114 through the barrier 110 to the targetelectrolyte, meaning that the diode is forward biased, which makes cationsmove from the electronically and ionically conductive material 107 to thetarget electrolyte and anions from the target electrolyte into the electronicallyand ionically conductive material 107. For a controlled delivery electrode thatis OFF, the potential gradient from the electronically and ionically conductive 11 material 107 to the target electrolyte is instead positive, which attracts cationstoward the electronically and ionically conductive material 107 and cationstoward the polycation in polyanion/polycation interface, thus the diode isreverse-biased and the interface is depleted of ions, leading to a low current.
    Fig. 13 shows measured currents isource, iwaste, iCDE and the calculatediTarget when switching from reverse to forward bias in a one second longdelivery pulse (iTarget = isource + iwaste + iCDE) from a single controlled deliveryelectrode. The voltage of the electronically and ionically conductive material107 is switched between 10.5 V, relative to the target potential. A diodebehavior can be noted (high target current in forward bias, and low in reversebias). ln reverse bias, the controlled delivery electrode is refilled with ionsfrom the source.
    Fig. 14 shows the current of intended molecules to be delivered, notthe overall current. For example, if a substance in a prior art ion pump(dashed line) is to be delivered, there will be a delay of t' before the moleculemakes it to the delivery site. Even if the channel is prefilled, there will still be arise time due to some passive diffusion at the very tip (i.e., same dashedcurve shape even if t'=0). The solid line is the “burst” achieved from acontrolled delivery electrode according to the invention.
    A physical or functional barrier layer 110 as illustrated in Fig. 5,improves the functionality by allowing individual addressing with highlyreducedleakage.
    The barrier may be based on an oppositely charged material,compared to the charge of the permselective ion conductive channel and thenet charge of the material in the controlled delivery electrode.
    The barrier 110' may also comprise a small-area hole, as illustrated byFig. 6, or a hole with a high height-to-area aspect ratio. ln either case, theeffect of the barrier or barrier layer is to minimize the reverse current neededto prevent leakage, which prevents local depletion of cations at the deliverysite. The barrier can also be constructed using previously known ionic diodes.
    The device 100 or device system can be extended to include a wasteportion comprising a waste channel 111 leading to a waste electrolyte 112and a waste electrode 113, see as illustarted in Fig. 11, Fig.15 or Fig. 16. Thewaste is used to carry away ions and to provide the means of a constant flowof ions through the ion conductive channels and controlled deliveryelectrodes. This facilitates the filling of the ion conductive channel. The wastethus increases the speed with which the controlled delivery electrode is filledwith ions.
    When an alternating current is applied as VCDE a serial burst effect isachieved.
    The device 100 or system may be used with a common targetelectrolyte but different source electrolytes as illustated in Fig. 8, and where 12 the different source electrolytes include different substances or medical drugsto be delivered.
    Alternatively, the device 100 or system can be used with a commonsource electrolyte but with different target electrolytes, see Fig. 9, and wherethe target electrolytes are located at different places to receive the same typeof substance or medical drug.
    Fig. 17 shows a schematic side view of a prior art charged drug device.Charged drugs have been incorporated as counter ions into conductingpolymers. The drug (counter ions) is expelled and released from theconducting polymer 115 when the charge of the polymer is altered as afunction of oxidation or reduction, Definitions used in the descriptionliThe term “ion” as used herein encompasses not only positively or negatively charged monovalent or multivalent ionic species of atomicelements, but also other molecular species carrying a net positive or negativecharge. Hence, in an embodiment of the invention it is intended to transportcharged biologically active molecules or macromolecules such as chargedamino acids, vitamins, peptides, neurotransmitters, hormones, andsubstances e.g. pharmaceuticals or endogenous substances. ln oneembodiment of the invention, the ions that may be transported are cations, forexample metal ions, such as potassium or calcium ions. ln anotherembodiment of the invention the ions that may be transported are anions. lonic contact A first and a second material are in ionic contact when a substantialamount of ions comprised in the first material can move from the first materialto the second material, possibly via a third material. The ionic movement maybe caused by diffusion or by an applied electric field.
    A material which provides an ionic connection between a first and asecond material, is a material which is ionically conductive, thus electricallyconductive (distinguished from being electronically conductive), and in ioniccontact with both said first and said second material.
    Directlv or indirectlv attached Two parts which are directly attached to each other are in directphysical contact with each other. With respect to this invention, when a firstpart is directly attached to a second part, which second part is directlyattached to a third part, said first and third parts are referred to as beingindirectly attached to each other. Similarly, when said third part is directly 13 attached to a fourth part, said first and fourth parts are referred to as beingindirectly attached to each other.
    Semi-solid material The term semi-solid material refers to a material, which at thetemperatures at which it is used has a rigidity and viscosity intermediatebetween a solid and a liquid. Thus, the material is sufficiently rigid such that itdoes not flow or leak. Further, particles/flakes in the bulk thereof aresubstantially immobilized by the high viscosity/rigidity of the material. ln a preferred case, a semi-solid material has the proper rheologicalproperties to allow for the ready application of it on a support as an integralsheet or in a pattern, for example by conventional printing methods. Afterdeposition, the formulation of the material should preferably solidify uponevaporation of solvent or because of a chemical cross-linking reaction,brought about by additional chemical reagents or by physical effect, such asirradiation by ultraviolet, infrared or microwave radiation, cooling etc.
    The semi-solid or solidified material preferably comprises an aqueousor organic solvent-containing gel, such as gelatin or a polymeric gel.
    Electrochemicallv active material With respect to this invention the term electrochemically active materialrefers to a material which is capable of being oxidized or reduced when it is incontact with an electrolyte, or another ionically conductive material, and avoltage is maintained across it. Examples of such electrochemically activematerials include electrically conductive polymers, as will be described below,and certain metal oxides, such as indium tin oxide (ITO) and tungsten oxide(WO3).
    ElectrolyteThe device may comprise three different electrolytes. lt is important to distinguish between the three (source, target, and waste): the sourceelectrolyte contains the ions to be delivered and should not contain a highextent of other ionic species with the same charge (positive or negative) asthe ion to be delivered. The target electrolyte may be the body fluid or the cellculture medium, or whatever media needed for the application. Thus, thecontent of this electrolyte can often not be controlled, but it must bedetermined from the application of the device. The waste electrolyte servesas a waste for the ions that are transported from the source, and those ionsmust thus be soluble in this electrolyte.The electrolyte for use with the device or method of the present invention must be based on a solvent that permits ionic conduction in theelectrolyte, i.e. that allows for the dissociation of ionic substances such as 14 salts, acids, bases, etc. The solvent and/or the ionic Substance maycontribute nucleophiles. Possible electrolytes for use in combination with theinventive device are solutions of salts, acids, bases, or other ion-releasingagents in solvents that support the dissociation of ionic species, thus allowingionic conductivity. ln applications where it is required, the target electrolytemay comprise buffer solutions, such as buffer solutions suitable for use withliving organisms or biomolecules, such as proteins. Examples of such buffersinclude NaHPO4 and sodium acetate. As other non-limiting examples ofpossible electrolytes, mention can be made of: aqueous solutions ofpotassium acetate, calcium acetate, NaCl, Na2SO4, H3PO4, H2SO4, KCI,RbNOg, NH4OH, CsOH, NaOH, KOH, H2O2; organic solvents such asacetonitrile, pyridine, DMSO, DMF, dichloromethane, etc., in combination withsuitable salts, such as lithium perchlorate and tertiary ammonium salts, e.g.tetra-butyl ammonium chloride; inorganic solvents such as hypercritical C02,liquid S02, liquid NH3, etc., in combination with salts that dissociate in thesesolvents; solvents displaying auto-dissociation, which results in the formationof ionic species, such as water, formic acid and acetic acid.
    The term electrolyte also encompasses solutions comprising chargedbiologically active molecules or macromolecules such as charged aminoacids, proteins, vitamins, peptides or hormones. An electrolyte may alsocomprise cell culturing media or ingredients thereof, such as proteins, aminoacids, vitamins and growth factors.
    The electrolyte may also be in a semi-solid or solidified form, preferablycomprising an aqueous or organic solvent-containing gel as described above.However, solid polymeric electrolytes are also contemplated and fall withinthe scope of the present invention. Furthermore, the term electrolytes alsoencompasses liquid electrolyte solutions soaked into, or in any other wayhosted by, an appropriate matrix material, such as a paper, a fabric or aporous polymer.
    Electrodes in the electrolvtes The source, target and optionally the waste electrodes that control thepotential of the three respective electrolytes may each comprise a material ora combination of materials which is capable of electron-to-ion conversion, i.e.they need to enable charge transfer between the electrode and its contactand the electrodes must be so called non-polarizable electrodes.
    The electrodes of the inventive device may preferably comprise anelectrochemically active material, for example Ag/AgCl. Said electrodematerial may also be an organic material, for example an electricallyconductive polymer. Electrically conductive polymers suitable for use in thedevice of the invention, are preferably selected from the group consisting ofpolythiophenes, polypyrroles, polyanilines, polyisothianaphthalenes, polyphenylene vinylenes and copolymers thereof such as described by J CGustafsson et al. in Solid State lonics, 69, 145-152 (1994); Handbook ofOligo- and Polythiophenes, Ch 10.8, Ed D Fichou, Wiley-VCH, Weinhem(1999); by P Schottland et al. in Macromolecules, 33, 7051-7061 (2000);Technology Map Conductive Polymers, SRI Consulting (1999); by M Onodain Journal of the Electrochemical Society, 141, 338-341 (1994); by M Chandrasekar in Conducting Polymers, Fundamentals and Applications, aPractical Approach, Kluwer Academic Publishers, Boston (1999); and by A JEpstein et al. in Macromol Chem, Macromol Symp, 51, 217-234 (1991). Thethe electrically conductive polymer may preferably a polymer or copolymer ofa 3,4-dialkoxythiophene, in which said two alkoxy groups may be the same ordifferent or together represent an optionally substituted oxy-alkylene-oxybridge. lt is particularly preferred that the polymer is a polymer or copolymerof a 3,4-dialkoxythiophene selected from the group consisting of poly(3,4-methylenedioxythiophene), poly(3,4-methylenedioxythiophene) derivatives,poly(3,4-ethylenedioxythiophene), poly(3,4-ethylenedioxythiophene)derivatives, poly(3,4-propylenedioxythiophene), poly(3,4-propylenedioxythio-phene) derivatives, poly(3,4-butylenedioxythiophene), poly(3,4-butylenedioxy-thiophene) derivatives, and copolymers therewith.
    The electrically conductive polymer may be poly(3,4-ethylenedioxythiophene) (PEDOT). The electrodes may further comprise apolyelectrolyte compound, more preferably said polyelectrolyte compound ispoly(styrene sulfonic acid) or a salt thereof. One especially preferred materialfor use in the electrodes of the device of the invention is poly(3,4-ethylenedi-oxythiophene) with a poly(styrene sulfonate) polyanion (in the followingreferred to as PEDOT:PSS). The electrodes may be present in the form of athin layer of PEDOT:PSS deposited on a solid substrate.
    The electrodes may alternatively be Ag/AgCl, painted on the device, ordipped into the electrolytes.
    The source, target and waste electrodes of the inventive device mayfurther comprise a hydrogel. The hydrogel is preferably based on polymersselected from the group consisting of polyacrylates, such as poly(2-hydroxyethyl methacrylate) and poly(acrylamide), polyelectrolytes, such aspoly(styrene sulfonic acid) (PSS) and poly(acrylic acid) (PAA),polysaccharides, such as agarose, chitosan and dextran, gelatin, polyvinylalcohol, polyvinyl pyrrolidone and polyethylene glycol.
    The electrodes are preferably arranged in a common plane on a solidsubstrate or dipped into the electrolyte. The electrodes can be additivelypatterned onto said substrate, e.g., by spincoating, painting, printing, orlamination techniques, or subtractively patterned, e.g., by etching.
    At least the target electrode should be biocompatible, since it may bein contact with body fluid or cell culture medium. The term biocompatible is 16 used herein to characterize a material or a surface allowing cultivation of cellsthereon or in close association therewith, or the lack of a bodilyimmunoresponse or similar upon implantation. Cultivation of cells refers toattachment, maintenance, growth and/or proliferation of said cells. Anexample of an electrode material according to the invention that provides abiocompatible surface is PEDOT:PSS. The biocompatibility of an electrodeallow for studies of cellular activities in cells cultivated on or in closeassociation with the electrode.
    The Controlled Deliverv Electrode ln order to control the delivery of ions to or from each outlet 109, thedevice comprises at least one controlled delivery electrode (CDE) 114 whichis arranged at or in connection with each delivery site/outlet 109 as illustratedin Fig. 1. The controlled delivery electrode comprises an electronically andionically conductive material 107, such as an electronically and ionicallyconductive polymer, and an electrical contact 106. The electronically andionically conductive material may be PEDOT as described above but alsoporous metals and supercapacitors.
    The electrical contact may be a metal or other conductive material.
    The potential from the source to the target is kept constant, but thepotential at each controlled delivery electrode may be varied to control thedelivery from each outlet respectively.
    The electronically and ionically conductive material 107 in combinationwith a barrier 110 can be seen as an ion diode, where one portion 107 of thediode that is contacted by the electrical contact 106 is electronically as well ascationically (or anionically) conducting. The other part 110 of the diode (theportion that contacts the target electrolyte) is not electronically conducting, butis merely a polycation or polyanion (or any other porous material with fixedcharges opposite to the fixed charges of the other half of the diode) and thusacts as a barrier as shown in Fig. 5. The diode does not necessarily consist oftwo oppositely charged materials, but can also be formed by the conductingpolymer/polyelectrolyte blend (or other conducting material with an excess offixed charges positive or negative) and a small hole with high aspect ratio.
    The potential across the controlled delivery electrode and the targetelectrolyte sets the diode in forward or reverse bias and determines whetherions can pass through it and be delivered to the outlet in the target electrolyte. 17 Reference list 100 device or device system 101 source electrolyte 102 target electrolyte 103 ion conductive channel 103' ion conductive channel between the controlled delivery electrodes104 first electrode or source electrode 105 second electrode or target electrode 106 electrical contact 107 electronically and ionically conductive material108 electronically and ionically insulating layer109 delivery site/outlet 110 barrier 110' barrier based on geometry 111 waste channel 112 waste electrolyte 113 waste electrode 114 controlled delivery electrode (CDE) comprising electrical contact 106 andelectronically and ionically conductive material 107115 conducting polymer (in prior art) 201 first end of ion conductive channel 103 202 second end of ion condutive channel 103
    权利要求:
    Claims (15)
    [1] 1. A device (100) comprising a first electrode (104) provided at or in asource electrolyte (101), and at least one ion conductive channel (103),wherein said first electrolyte (101) is arranged at a first portion (201) of the ionconductive channel (103), and a second electrode (105) provided in a targetelectrolyte (102), wherein said target electrolyte (102) is arranged at a secondportion (202) of the ion conductive channel (103), and wherein said first andsecond electrodes provides an electrical control of an ion flow through the ionconductive channel (103) characterized inthat the device further comprises at least one controlled delivery electrode(114) arranged adjacent to or in the second portion of the ion conductivechannel (103), wherein said first and second electrodes further are arrangedto provide an electrical control of an ion flow through the controlled deliveryelectrode (114) to the target electrolyte (102), and wherein said controlleddelivery electrode (114) is adapted to deliver ions from said ion conductivechannel (103) to said target electrolyte (102), and wherein said controlleddelivery electrode (114) comprising an electronically and ionically conductivematerial (107) and an electrical contact (106), wherein said controlled deliveryelectrode (114) is arranged in ionic contact with, and between, said ionconductive channel (103) and the target electrolyte (102), wherein saidelectrical contact (106) provides for an electrical control potential (VCDE) overthe controlled delivery electrode (114) to control an ion flow between thecontrolled delivery electrode (114) and the target electrolyte (102).
    [2] 2. A device (100) as claimed in claim 1, wherein said electronically andionically conductive material (107) of the controlled delivery electrode (114) ispermselective for either cationic or anionic species.
    [3] 3. The device (100) as claimed in any one of claims 1 or 2, wherein theelectronically and ionically conductive material (107) includes a conductingpolymer such as PEDOT. 19
    [4] 4. The device (100) as claimed in claim 1, wherein said electronicallyand ionically conducting material (107) is adapted to act as a reservoir forions being injected to, or extracted from the material.
    [5] 5. The device (100) as claimed in any one of the preceding claims,wherein said device comprises at least two controlled delivery electrodes(114a, 114b), and wherein said at least two controlled delivery electrodes(114a, 114b) are separated from each other with an ion conductive channel(103') having a finite ion conductivity, to control ion flow from the ionconductive channel (103) into the target electrolyte (102) from each controlleddelivery electrode separately.
    [6] 6. The device (100) as claimed in any one of the preceding claims,wherein a resistance between the controlled delivery electrode (114) and thetarget electrolyte (102) is sufficiently high to enable the potential dropbetween the contact (106) of the controlled delivery electrode and the targetelectrolyte.
    [7] 7. The device (100) as claimed in claim 5, wherein the controlleddelivery electrodes (114a, 114b) are arranged on or in the same or differention conductive channels (103, 103a, 103b, 103') and wherein the controlleddelivery electrodes (114a, 114b) are separated from each other with amaterial having a finite ion conductivity.
    [8] 8. The device (100) as claimed in any one of the preceding claims,wherein an ion barrier (110) is arranged between the controlled deliveryelectrode (114) and the target electrolyte (102).
    [9] 9. The device (100) as claimed in claim 8, wherein the ion barrier (110)comprises a material having a fixed concentration of opposite charges withrespect to the fixed charges of the controlled delivery electrode (114).
    [10] 10. The device (100) as claimed in any one of claims 8 or 9, whereinthe barrier (110') is adapted to geometrically restrain or limit an ion flow.
    [11] 11. The device (100) as claimed in any one of the preceding claims,wherein the device comprises at least two ion conductive channels (103a,103b), and wherein multiple controlled delivery electrodes (114a, 114b) arearranged in or on said multiple ion conductive channels (103), wherein saidcontrolled delivery electrodes are in ionic contact with the same targetelectrolyte (102), and wherein the controlled delivery electrodes (114a, 114b)are separated from each other by an ion conductive channel (103') having afinite ion conductivity.
    [12] 12. The device (100) as claimed in any one of the preceding claims,wherein the device comprises at least one waste channel (111), and whereineach waste channel comprises a waste electrolyte (112) and a wasteelectrode (113).
    [13] 13. A method of operating a device (100) as claimed in any one ofclaims 1 to 12, comprising the steps of: a) providing a source electrolyte (101) comprising the ions to betransported, b) providing a target electrolyte (102) to where the ions aretransported, c) bringing the source electrode (104) of the device in contact with thesource electrolyte, d) optionally providing a waste electrode (113) and a waste electrolyte(112); e) bringing the target electrode (105) in contact with the targetelectrolyte (102); f) applying a potential to the source electrode (104), the targetelectrode (105) and the controlled delivery electrode (114), and optionally tothe waste electrode (113), effecting ion transport from the source electrolyte(101), to the controlled delivery electrode (114), or optionally to the wasteelectrolyte (112); and g) altering the potential of the controlled delivery electrode (114) toswitch on ion transport to the target electrolyte (102).
    [14] 14. Use of a device as claimed in any one of claims 1 to 12, fordelivering ions from a source electrolyte (101) to a target electrolyte (102)through a controlled delivery electrode (114). 21
    [15] 15. Use according to claim 14, wherein said target electrolytecomprises any one of tissue, body fluids or cells.
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    同族专利:
    公开号 | 公开日
    EP3429660A1|2019-01-23|
    SE540063C2|2018-03-13|
    US20190111251A1|2019-04-18|
    CA3017545A1|2017-09-21|
    WO2017157729A1|2017-09-21|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    SE526873C2|2003-12-02|2005-11-15|Acreo Ab|Wettability switch comprising an electrochemically active element with interchangeable surface wetting properties, process for its manufacture and its use in various applications|
    EP1862799B1|2006-06-02|2012-04-11|Oboe Ipr Ab|Electrically controlled ion transport device|
    EP2068146A1|2007-12-03|2009-06-10|Oboe Ipr Ab|Electrically controlled ion transport device|
    EP2265325A1|2008-03-20|2010-12-29|Oboe Ipr Ab|Electrically controlled ion transport device|
    WO2010118754A1|2009-04-14|2010-10-21|Oboe Ipr Ab|Selective ion transport device|SE1951545A1|2019-12-20|2021-06-21|Oboe Ipr Ab|Selective drug delivery in an ion pump through proton entrapment|
    SE2050204A1|2020-02-24|2021-08-25|Oboe Ipr Ab|A system and method for releasing a species|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    SE1650348A|SE540063C2|2016-03-15|2016-03-15|Ion conductive drug delivery device with controlled deliveryelectrode|SE1650348A| SE540063C2|2016-03-15|2016-03-15|Ion conductive drug delivery device with controlled deliveryelectrode|
    CA3017545A| CA3017545A1|2016-03-15|2017-03-08|Ion conductive device with controlled delivery electrode|
    US16/085,380| US20190111251A1|2016-03-15|2017-03-08|Ion conductive device with controlled delivery electrode|
    PCT/EP2017/055385| WO2017157729A1|2016-03-15|2017-03-08|Ion conductive device with controlled delivery electrode|
    EP17709938.9A| EP3429660A1|2016-03-15|2017-03-08|Ion conductive device with controlled delivery electrode|
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