GB2560511A

GB2560511A - Electrotransfer device and uses thereof

Info

Publication number: GB2560511A
Application number: GB1703922.3A
Authority: GB
Inventors: Rachel Rajiah Ida
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-03-12
Filing date: 2017-03-12
Publication date: 2018-09-19
Also published as: GB201703922D0; WO2018167451A1

Abstract

An electrotransfer or electroporation device comprising first 18 and second 20 electrodes mounted to the distal end 12b of an elongate member 12 such that they are movable between a retracted position (Fig 2) and a deployed position (Fig 1). The first 18 and second 20 electrodes are preferably mounted on, and more preferably embedded within, flexible arms 14, 16 which together essentially define a tweezer or pincer shape. A third electrode 22, which preferably takes the form either a needle electrode or another mounted to an arm, may also be provided at the distal end 12b of the elongate member 12, and may be located at the mid-point between the first 18 and second 20 electrodes in a manner whereby the electrodes are arranged in a triangular configuration. The proximal end 12a of the elongate member is further provided with a connection means for operably connecting the electrodes to a controller comprising a single-pulse or multi-pulse generator and a multimeter.

Description

(71) Applicant(s):

Ida Rachel Rajiah

PO Box 744, Bury St Edmunds, Suffolk, IP33 9JU, United Kingdom (72) Inventor(s):

Ida Rachel Rajiah (74) Agent and/or Address for Service:

Ida Rachel Rajiah

PO Box 744, Bury St Edmunds, Suffolk, IP33 9JU, United Kingdom (51) INT CL:

A61N 1/32 (2006.01) (56) Documents Cited:

WO 2015/148445 A1 WO 2013/024437 A1 JP 2004041434 A US 20160096015 A1

US 20150328449 A1 (58) Field of Search:

INT CLA61B, A61N Other: WPI, EPODOC (54) Title of the Invention: Electrotransfer device and uses thereof

Abstract Title: An electrotransfer device comprising a pair of retractable electrodes (57) An electrotransfer or electroporation device comprising first 18 and second 20 electrodes mounted to the distal end 12b of an elongate member 12 such that they are movable between a retracted position (Fig 2) and a deployed position (Fig 1). The first 18 and second 20 electrodes are preferably mounted on, and more preferably embedded within, flexible arms 14, 16 which together essentially define a tweezer or pincer shape. A third electrode 22, which preferably takes the form either a needle electrode or another mounted to an arm, may also be provided at the distal end 12b of the elongate member 12, and may be located at the mid-point between the first 18 and second 20 electrodes in a manner whereby the electrodes are arranged in a triangular configuration. The proximal end 12a of the elongate member is further provided with a connection means for operably connecting the electrodes to a controller comprising a single-pulse or multi-pulse generator and a multimeter.

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Figure 4

ELECTROTRANSFER DEVICE AND USES THEREOF

FIELD OF INVENTION

The present invention relates to an electrotransfer device and uses thereof.

BACKGROUND OF INVENTION

Recent advances in nucleic acid based therapeutics have opened up new frontiers for medicinal chemists and contributed to a leap in clinical trials. However, safe delivery of these potent agents into cells of target tissues without loss of therapeutic efficacy remains a challenge. Virus based vectors have higher transfer efficiency compared to non-viral methods but the risk of immunogenicity, systemic and offtarget toxicity limit their clinical applications.

Current non-viral physical and chemical methods including electroporation, gene gun, ultrasound, magnetofection, liposomes, cationic polymers and peptides offer safety, versatility, low immunogenicity and large capacity for nucleic acids but lack therapeutic efficacy. Nevertheless, in-vivo electroporation has gained recognition in recent years as the most efficient non-viral strategy for delivery of therapeutic agents.

During electroporation, pores are formed in the cell membrane by electric pulses allowing for the uptake of extracellular molecules. Electroporation is ‘reversible’ when the induced transmembrane potential (AV_m) is within the critical value permitting cell recovery and viability. Conversely, when the critical value is exceeded, cell membrane disintegrates and electroporation becomes irreversible. Electroporation technology is adopted by more than fifty ongoing clinical trials including irreversible ablation of tumours, transfer of therapeutic drugs for electrochemotherapy (ECT) of solid tumours and transfer of DNA vaccines for activation of immune response against solid tumours and infections.

Despite clinical advancement in tissue electroporation for over a decade, a suitable device for electrogene therapy (EGT) of internal organs and tissues without surgical intervention does not exist. A clinical trial for electrochemotherapy of inoperable colorectal cancer using EndoVe® has been recently completed (Bourke M, Salwa S, Forde P. et al. Endoscopically targeted electrochemotherapy for the treatment of colorectal cancer. BASO - The Association for Cancer Surgery Scientific Conference 2012. Conference abstract. European Journal of Surgical Oncology, 2012). However, the modality of EndoVe® is irreversible electroporation based, which would be unsuitable for electrogene therapy wherein maximum cell viability is a prerequisite for therapeutic efficacy. Older strategies use a large array of electrodes to encompass a larger three dimensional pulsing zone but they are highly uncomfortable and limited by off-target pulsing, local burns and tissue damage.

Another obstacle for electrogene therapy in clinical medicine is lack of therapeutic efficacy of transferred agents. Therefore, existing protocols for electrotransfer require improvisation as outlined below:

First, pulse parameters tested in preclinical animal models would be incompatible within a clinical setting due to the animal’s limited ability to emulate the complex human physiology. With reference to Ohm's law, l_amp=V_Voit/ Rohm, tissue resistance or impedance (R) is a vital factor determining the physiological effects of current flow (I) through the tissue. Compared to the skin, organs such as muscle, nerves and blood vessels have lower resistance whereas tendon, bone and fat have higher resistance. Variation in age, gender, tissue characteristics and its milieu also impact tissue resistance. A wet tissue is far less resistant to current flow than its dry counterpart. For example, 20-100mA of current passing through wet skin can cause respiratory muscle paralysis and ventricular fibrillation (VF). (Raymond M. Fish, and Leslie A. Geddes. Conduction of Electrical Current to and Through the Human Body: A Review. Eplasty, 2009). In view of the numerous factors influencing tissue resistance, laboratory-based pulse parameters would be far from ideal whereas personalisation of pulse protocol would ensure safety and efficiency.

Second, use of high amplitude long duration pulses can compromise patient safety by inducing ventricular fibrillation. Since ventricular fibrillation threshold (VFT) is inversely proportional to the square root of the duration of current flow, current shock of 30mA (50-60Hz of AC) lasting a fraction of a second can still induce VF. Moreover, 1mA of alternating or direct current can induce VF if the circuit is established through the heart. Whilst lowering pulse amplitude and duration would raise VFT, it would also minimise electrotransfer efficiency. Therefore, a protocol that maximises electrotransfer without compromising patient safety is an urgent need.

Third, poor retention of transferred agents within electroporated cells is another causative factor for low transfer efficiency. Indeed, electrotransfer of large nucleic acid molecules across the plasma membrane into the cytoplasm and nucleus is a complex process. Actin, one of the main components of the cytoskeleton plays a vital role during the early stages of electrotransfer. Experimental evidences indicate that in addition to formation of pores in the cell membrane, actin polymerisation is a prerequisite for efficient electrotransfer. (Christelle Rosazza, Jean-Michel Escoffre, Andreas Zumbusch, and Marie-Pierre Rols The actin cytoskeleton has an active role in the electrotransfer of plasmid DNA in mammalian cells. Molecular Therapy, 2011; doi: 10.1038/mt.2010.303). However, small heat shock proteins (sHsps) inhibit actin polymerisation in response to heat induced stress. Joule heating of about 11,2K has been shown to occur following a rise in temperature from 37°C to 45°C during electroporation of myocardial tissue at 1.2kVcm'¹(500 V applied) for 6.7 milliseconds. (U.Pliquett. Joule heating during solid tissue electroporation. Medical & Biological Engineering & Computing, 2003; doi: 10.1007/BF02344892). Also, an increase in voltage by a factor of 10 has been shown to increase tissue heat energy by a factor of 100 when other parameters were equal. (Raymond M. Fish, and Leslie A. Geddes. Conduction of Electrical Current to and Through the Human Body: A Review. Eplasty, 2009). Hence, management of joule heating and prevention of sHsp induction is necessary to allow actin polymerisation. .

Last, cell death following electroporation is another factor for low therapeutic efficacy. During the post-electroporation phase, resealing of pores and reorganisation of cytoskeleton are crucial for preservation of cell membrane integrity. Despite the application of electric pulses within the critical value of AV_m, cell death may occur due to major cell membrane defects caused by the coalescence of pores generated during multiple pulsing. Addition of poloxamer 188 (8.4-kd), a water soluble, non-ionic surfactant has been shown to minimise electroporation induced cell death without reducing the number of electropores, (lana Tsoneva, Iordan lordanov, Annette J. Berger, Toma Tomov, Biliana Nikolova, Nikola

Mudrov, and Martin R. Berger. Electrodelivery of drugs into cancer cells in the presence of poloxamer 188. Journal of Biomedicine and Biotechnology, 2010; doi: 10.1155/2010/314213). However, poloxamer 188 can solubilise within the blood stream or may block the diffusion and active transport of molecules of physiological significance across the cell membrane. Recent reports of its deleterious effects on mechanically stressed membranes denotes its unsuitability for maximising cell survival during electrogene therapy in humans and warrants further research into its physical and chemical properties. (Rebecca L. Terry, Hannah M. Kaneb, Dominic J. Wells. Poloxamer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function. PLoS One, 2014; doi: 10.1371/journal.pone.0091221). Hence, a safe strategy is required to facilitate resealing of pores and preserve cell membrane integrity.

The present invention seeks to provide a safe device and efficient strategies for electrotransfer of therapeutic agents into internal as well as external tissues with or without surgical intervention. The electrotransfer device is one of two parts of a kit that also includes a tissue temperature regulation device. Collectively, the device and strategies seek to overcome obstacles in current practice, offer convenience to patients as the electrotransfer procedure can be performed in an out-patient facility and save time and resources for healthcare providers. The electrotransfer device and strategies also seek to overcome obstacles in veterinary medicine and cosmetic industry for safe and efficient electrotransfer of therapeutic or cosmetic agents into internal as well as external tissues.

SUMMARY OF INVENTION

An aspect of the present invention provides an electrotransfer device comprising an elongate member having a distal end and a proximal end, a first electrode and a second electrode proximate the distal end of the elongate member and connection means proximate the proximal end of the elongate member for operably connecting the first electrode and the second electrode to a controller comprising a single-pulse or multi-pulse generator and a multimeter, wherein the first electrode and the second electrode are movable between a retracted position and a deployed position relative to the elongate member and the single-pulse or multi-pulse generator supplies electric pulses to the first electrode and the second electrode when in the deployed position.

The electrotransfer device may further comprise a third electrode disposed between the first electrode and the second electrode and operably connected to the controller, wherein the controller supplies electric pulses to the third electrode.

The electric pulses supplied to the first electrode and second electrode may be positive and the electric pulses supplied to the third electrode may be negative.

The electric pulses supplied to the first electrode and second electrode may be negative and the electric pulses supplied to the third electrode may be positive.

The first electrode and second electrode may be tweezer or pincer shaped. The length of the first electrode and second electrode may vary from 1mm to 100mm. The width of the first electrode and second electrode may vary from 1mm to 40mm. The length and width of the first and second electrodes may be further compromised as necessary.

The third electrode may be needle shaped. The length of the third electrode may vary from 1mm to 100mm. The diameter of the third electrode may vary from 0.1mm to 20mm. The length and diameter of the third electrode may be further compromised as necessary.

In another variation, the third electrode may be identical to the first and second electrode in both shape and size and may be mounted on a flexible arm or embedded within the flexible arm and disposed at mid-point between the first and second electrodes such that the three electrodes are in a triangular orientation.

In another variation, the first electrode, second electrode and third electrode may be needle shaped. The length of all three electrodes may vary from 1mm to 100mm. The diameter of all three electrodes may vary from 0.1mm to 20mm. The length and diameter of all three electrodes may be further compromised as necessary.

The first electrode, second electrode and third electrode may be moved from the retracted position to the deployed position by a lever mechanism.

In another variation, the first electrode, second electrode and third electrode may be electrically moved from the retracted position to the deployed position.

The first and second electrodes may have a first polarity and the third electrode may have a second polarity, different to the first polarity. The first polarity and the second polarity may be reversible.

The polarity of each electrode may be changed as necessary.

The controller may deliver alternating current or direct current pulses to all three electrodes.

The single-pulse or multi-pulse generator may deliver pulses of varying duration.

The multi-pulse generator may deliver a single pulse or multiple pulses.

The single-pulse or multi-pulse generator may deliver high amplitude or low amplitude pulses.

The single-pulse or multi-pulse generator may deliver square wave or exponential decay wave pulses.

In another variation, the controller may comprise a separate single-pulse or multipulse generator to deliver current pulses of varying amplitude and duration separately to each electrode.

Time lapses between pulses during multi-pulse delivery may be of variable length.

The elongate member may be insulated. The elongate member may be rigid or substantially flexible.

The electrotransfer device may further comprise one or more manually activated switches for activating the first electrode, second electrode and third electrode simultaneously or separately. The manually activated switch may be a foot switch, hand switch or voice-operated switch.

In another variation, the electrotransfer device may comprise one or more automatic switches for activating the first electrode, second electrode and third electrode simultaneously or separately.

In another variation, the switch for activating the first electrode, second electrode and third electrode may be located on a remote control unit. The switch on the remote control unit may be automatic or manually activated. The manually activated switch may be a foot switch, hand switch or voice-operated switch.

A further aspect of the present invention provides a tissue temperature regulation device comprising a compressed air source having an outlet, a vortex tube having an inlet and outlet, and a temperature regulator, wherein the inlet of the vortex tube is fluidly connected to the compressed air source and the outlet of the vortex tube is configured to be connectible to a surgical or non-surgical tool having an air port, and wherein the temperature regulator is configured to control the temperature of air exiting the outlet of the vortex tube.

The temperature regulator may maintain the temperature of air exiting the outlet of the vortex tube.

The electrotransfer device may be inserted on the surface of the body, orally, nasally, vaginally, anally or via a surgical incision with or without a surgical or nonsurgical tool.

The electrotransfer device may be used for improving delivery of therapeutic agents to all surface and internal organs and tissues accessible by the said device with or without a surgical or non-surgical tool.

A further aspect of the present invention provides a method of electrotransfer of therapeutic agents into internal tissues or organs using an electrotransfer device and a surgical or non-surgical tool comprising a working channel port for receiving the electrotransfer device and an air channel, the method comprising the steps of: a) inserting the tool into the patient; b) injecting one or more therapeutic agents into one or more sites on the target zone; c) inserting the electrotransfer device into the working channel of the tool; d) delivering single or multiple electric pulses to the target zone; and e) withdrawing the electrotransfer device from the target zone wherein the electrotransfer device comprises an elongate member having a distal end and a proximal end, a first electrode, second electrode and third electrode proximate the distal end of the elongate member and connection means proximate the proximal end of the elongate member for operably connecting the elongate member to a controller, wherein the first electrode, second electrode and third electrode are movable between a retracted position and a deployed position.

The surgical or non-surgical tool may be inserted orally, nasally, vaginally, anally or through a surgical incision.

The surgical or non-surgical tool may be an endoscope.

The current may be direct or alternating.

Pulses may be high amplitude or low amplitude pulses, square wave or exponential decay wave pulses

The target zone may be cooled or warmed using compressed air delivered through the air channel of the surgical or non-surgical tool either prior to pulsing, between multiple pulsing or post pulsing as necessary. The tissue temperature regulation device may be used for cooling or warming the target zone wherein the a compressed air source is connected to the inlet of a vortex tube and the outlet of the vortex tube is connected to the inlet of an air channel of a surgical or non-surgical tool while a temperature regulator connected to the vortex tube allows temperature of air exiting the outlet of vortex tube to be increased or decreased as required.

The method may further comprise repeating one or more of steps a) to e) as necessary with or without time interval between repeats.

The method may further compromise the sequence of steps a) to e) as necessary.

The method may further compromise omission of one or more steps a) to e) as necessary.

The method may be used to treat cancer. The cancer may be selected from tumours accessible by the electrotransfer device with a surgical or non-surgical tool.

The method may be used for improving delivery of therapeutic supplements into target tissues accessible by the electrotransfer device with a surgical or non-surgical tool in order to reduce tissue resistance to vaccines, sensitise tissues to radiation therapy, chemotherapy, photodynamic therapy and immunotherapy and thereby reduce side effects caused by the above therapies (Ida Rachel Rajlah. PARP-1 NTermlnal Fragment Down-regulates Endogenous PARP-1 Expression and Activity and Sensitises Cells to Oxidative Stress. Journal of Cell Science and Therapy, 2013; doi: 10.4172/2157-7013.1000138).

The method may be used treat non-cancerous, genetic and epigenetic diseases of tissues and organs on any part of the body accessible by the electrotransfer device with a surgical or non-surgical tool.

A further aspect of the present invention provides a method of electrotransfer of therapeutic agents to all tissues and organs accessible by the said device without a surgical or non-surgical tool, the method comprising: i) injecting one or more therapeutic agents into one or more sites on the target zone; ii) delivering single or multiple electric pulses to the target zone using the electrotransfer device; and iii) withdrawing the electrotransfer device from the target zone wherein the electrotransfer device comprises an elongate member having a distal end and a proximal end, a first electrode, second electrode and third electrode proximate the distal end of the elongate member and connection means proximate the proximal end of the elongate member for operably connecting the elongate member to a controller, wherein the first electrode, second electrode and third electrode are movable between a retracted position and a deployed position. The target zone may be cooled or warmed either prior to pulsing, between multiple pulsing or post pulsing as necessary. The tissue temperature regulation device may be used for cooling or warming the target zone wherein the outlet of a compressed air source is connected to the inlet of a vortex tube and compressed air exiting the outlet of vortex tube is directed to the target zone while a temperature regulator connected to the vortex tube allows temperature of air exiting the outlet of vortex tube to be increased or decreased as required.

The current may be direct or alternating. Pulses may be high amplitude or low amplitude pulses, square wave or exponential decay wave pulses.

The method may further comprise repeating one or more of steps i) to iii) as necessary with or without time interval between repeats.

The method may further compromise the sequence of steps i) to iii) as necessary.

The method may further compromise omission of one or more steps i) to iii) as necessary.

The method may be used to treat cancer. The cancer may be selected from tumours accessible by the electrotransfer device without a surgical or non-surgical tool.

The method may be used for improving delivery of therapeutic supplements into target tissues accessible by the electrotransfer device without a surgical or nonsurgical tool in order to reduce tissue resistance to vaccines, sensitise tissues to radiation therapy, chemotherapy, photodynamic therapy and immunotherapy and thereby reduce side effects caused by the above therapies.

The method may be used treat non-cancerous, genetic and epigenetic diseases of tissues and organs on any part of the body accessible by the electrotransfer device without a surgical or non-surgical tool.

A further aspect of the present invention provides an electrotransfer kit comprising an electrotransfer device comprising an elongate member having a distal end and a proximal end, a first electrode, second electrode and third electrode proximate the distal end of the elongate member and connection means proximate the proximal end of the elongate member for operably connecting the first electrode, second electrode and third electrode to a controller comprising a single-pulse or multi-pulse generator, wherein the first electrode and the second electrode are movable between a retracted position and a deployed position relative to the elongate member and the single-pulse or multi-pulse generator supplies electric pulses to all three electrodes when in the deployed position and a tissue temperature regulation device comprising a compressed air source having an outlet, a vortex tube having an inlet and outlet, and a temperature regulator, wherein the inlet of the vortex tube is fluidly connected to the compressed air source and the outlet of the vortex tube is configured to be connectible to a surgical or non-surgical tool having an air port, and wherein the temperature regulator is configured to control the temperature of air exiting the outlet of the vortex tube.

A further aspect of the invention provides an electrotransfer device comprising an elongate member having a distal end and a proximal end, a first electrode and a second electrode proximate the distal end of the elongate member, a third electrode disposed between the first electrode and second electrode and connection means proximate the proximal end of the elongate member for operably connecting the first electrode, second electrode and third electrode to a controller, wherein the first electrode and the second electrode are movable between a retracted position and a deployed position relative to the third electrode and the controller supplies electric pulses to the first electrode and the second electrode when in the deployed position.

The aspects of the invention may, in general, i) improve electrotransfer of therapeutic agents into internal and external tissues and organs with or without surgical intervention; ii) improve therapeutic efficacy of transferred agents without compromising on patient safety; iii) offer convenience to patients as the electrotransfer procedure can be performed in an out-patient facility; and iv) save time and resources for healthcare providers. In the field of veterinary medicine the aspects of the invention may improve electrotransfer of therapeutic agents into internal and external tissues of animals. The aspects of the invention may also improve electrotransfer of cosmetic agents into internal and external tissues.

FIGURES

Figure 1 shows an illustrative view of a first embodiment of the present invention in a deployed configuration.

Figure 2 shows the first embodiment of figure 1 in an undeployed configuration.

Figure 3 shows an illustrative end view of the first embodiment of figure 1.

Figure 4 shows an enlarged partial view of figure 1.

Figure 5 shows an illustrative view of a second embodiment of the invention.

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DETAILED DESCRIPTION

Referring to the figures, an embodiment of the present invention comprises a cable type member 12 having a lumen therethrough (not shown). The cable type member 12 has a proximal end 12a and a distal end 12b. The cable type member 12 is made from medical grade rubber, silicone rubber or polyisoprene and may be electrically insulated and waterproof. The material of cable type member may be further compromised as necessary. Depending on its use with or without a surgical tool the cable type member 12 may be rigid or substantially flexible. The outer diameter of the cable type member 12 may vary from 1,5mm to 50mm and the inner diameter of the lumen may vary from 1,2mm to 49mm depending on its use with or without a surgical or non-surgical tool. A wire (not shown) passes through the lumen of the cable type member 12 and is connected to a controller comprising a single-pulse or multi-pulse generator (not shown) and a multimeter (not shown) proximate the proximal end 12a of the cable type member 12. The wire may be a conductor, semiconductor or superconductor and made of graphene, tungsten, copper, silver, gold, chromium or nickel or an alloy of any of these metals or stainless steel, chromel, chromel-alumel, gold-platinum, platinum-palladium, chromel-gold/iron alloy. The material of the wire may be further compromised as necessary.

First and second flexible arms 14, 16 are disposed proximate the distal end 12b of the cable type member 12. The first and second flexible arms 14, 16 are generally pincer or tweezer shaped. The first and second flexible arms are generally made of glass, glass-mica, PVC, polyvinyl, Kapton or fluorinated ethylene propylene(FEP). The length of the first and second flexible arms 14, 16 may vary fromlmm to 100mm. The width of the first and second flexible arms may vary from 1 mm to 40mm. An end of each of the first and second flexible arms 14, 16 is inserted into the cable type member 12. The other end of each of the first and second flexible arms 14, 16 is unrestrained and mounts respective first and second electrodes 18,

20. The material, length and width of the flexible arms 14, 16 may be further compromised as necessary.

The first and second electrodes 18, 20 are pincer or tweezer-shaped. The first and second electrodes 18, 20 may be conductors, semiconductors or superconductors and made of graphene, tungsten, copper, silver, gold, chromium or nickel or an alloy of any of these metals or stainless steel, chromel, chromel-alumel, gold-platinum, platinum-palladium, chromel-gold/iron alloy. The length of the first and second electrode 18, 20 may vary from 1mm to 100mm. The width of the first and second electrodes 18, 20 may vary from 1mm to 40mm. The material, length and width of first and second electrodes 18, 20 may be further compromised as necessary.

In another variation, the first and second electrodes 18, 20 may be embedded within the flexible arms 14 and 16 (not shown).

The first and second flexible arms 14, 16 are mounted to a common plate (not shown) at the distal end 12b of the cable type member 12 such that the first and second flexible arms 14, 16 may be moved in unison relative to the cable type member 12.

A third, needle shaped electrode 22 is disposed between the first and second electrodes 18, 20. The third electrode 22 may be a conductor, semiconductor or superconductor and made of graphene, stainless steel, tungsten, copper, silver, gold, nickel or made of graphene, tungsten, copper, silver, gold, chromium or nickel or an alloy of any of these metals or stainless steel, chromel, chromel-alumel, goldplatinum, platinum-palladium, chromel-gold/iron alloy. The length of third electrode 22 may vary from 1 mm to 100mm and the diameter may vary from 0.1 mm to 20mm. The material, length and diameter of the third electrode 22 may be further compromised as necessary.

In another variation, the first electrode 18 and second electrode 20 may also be needle shaped and identical in length and diameter to the third electrode 22 (not shown).

In another variation, the third electrode 22 may be identical to the first and second electrodes18, 20 in both shape and size and may be mounted on a flexible arm or embedded within the flexible arm and disposed at mid-point between the first and second electrodes 18, 20 such that the three electrodes 18, 20 and 22 are oriented in a triangular orientation.

The common plate at the distal end 12b of cable type member 12 is operably connected to a lever 24 which penetrates through the cable type member 12 and into the lumen therethrough. The lever 24 is movable between a first position in which the first and second flexible arms 14, 16 are in a retracted configuration relative to the cable type member 12 and a second position in which the first and second flexible arms 14, 16 are in a deployed configuration relative to the cable type member 12.

Operation of the lever 24 increases the diameter about the first and second flexible arms 14, 16 as the lever 24 is moved into the second position to deploy the first and second electrodes 18, 20 and decreases the diameter about the first and second flexible arms 14, 16 as the lever 24 is moved into the first position to retract the first and second electrodes 18, 20.

In another variation, the first electrode 18, second electrode 20 and third electrode 22 may be electrically movable between a retracted and a deployed position (not shown).

In another variation, the common plate at the distal end 12b of the cable type member 12, may be fixed to the cable type member 12 or may be removable.

The first and second electrodes 18, 20 have a first polarity and the third electrode 22 has a second polarity, different to the first. The polarity of the first and second electrodes 18, 20 and third electrode 22 may be reversed so long as the polarity of the first and second electrodes 18, 20 is different to the polarity of the third electrode 22. The polarity of each of the electrode may be changed as necessary.

The controller comprises a single-pulse or multi-pulse generator to deliver pulses of alternating current or direct current to the first electrode 18, second electrode 20 and third electrode 22. The pulses may be of variable duration. The pulses may be configured to be high amplitude or low amplitude pulses, square wave or exponential decay wave pulses. The pulses may comprise of single or multiple pulses. Time interval between pulses may be of variable length.

The controller further comprises a multimeter to measure impedance or resistance value and temperature of target tissue (not shown). Using the tissue impedance or resistance value a personalised pulse protocol may be designed and programmed onto the single-pulse or multi-pulse generator.

The single-pulse or multi-pulse generator is activated using a manually operable switch (not shown) such as a hand switch, foot switch or voice-operated switch. The individual electrodes 18, 20 and 22 may be activated simultaneously using a single switch or separately using separate switches.

In another variation, the device may comprise an automatic switch or switches for simultaneous or separate activation of the first electrode 18, second electrode 20 and third electrode 22.

In another variation, the switch for activating the first electrode 18, second electrode 20 and third electrode 22 may be located on a remote control unit. The switch may be automatic or manually activated. The manually activated switch may be a foot switch, hand switch or voice-operated switch.

In another variation, the controller may comprise a separate single-pulse or multipulse generator to deliver electric pulses of varying amplitude and duration separately to the first electrode 18, second electrode 20 and third electrode 22.

The electrotransfer device may be used with or without a surgical or non-surgical tool. The tool may be an endoscope.

In preparation for the electrotransfer procedure with the aid of a surgical or nonsurgical tool, for example, an endoscope, the insertion tube of the tool, 26 is inserted through an appropriate natural orifice which may be nasal, oral, rectal or vaginal or via a surgical incision. The distal end or bending section of an insertion tube 26 is positioned close to the zone of interest within the target organ or tissue using angulation controls on the tool 26. One or more therapeutic agents may be injected into one or more sites on the target zone either directly or using syringe and needle accessory inserted through the working channel 28 of the tool 26.

Subsequently the electrotransfer device according to embodiments of the present invention may be inserted through the working channel 28 of the tool 26. The distal end 12b of the cable type member is deployed to a target zone.

Following pulsing, distal end 12b of the cable type member is withdrawn from the target zone. While monitoring temperature changes using the multimeter, the target tissue is either cooled or warmed. The tool 26 is then carefully withdrawn from the patient.

The target tissue may be cooled or warmed prior to pulsing, between multiple pulsing or after pulsing as necessary using compressed air delivered through the air channel of the tool.

For cooling or warming the target tissue, compressed air is delivered to the target zone through the air channel 30 of the tool 26. A compressed air source 32 is connected to an inlet to the air channel 30 by a vortex tube 34. An inlet 36 to the vortex tube 34 is connected to the compressed air source 32 and an outlet 38 from the vortex tube 34 is connected to the inlet to the air channel 30. An outlet from the air channel 30 delivers the compressed air directly to the target zone. Temperature of the compressed air is regulated by a temperature regulator 42 such that the temperature of the compressed air can be increased or decreased as required. The tool 26 has a camera 44 for display of target zone on a visual display unit and a light 46 for illuminating the target zone.

In preparation for the electrotransfer procedure without the aid of a surgical or nonsurgical tool, one or more therapeutic agents may be injected into one or more sites on the target zone. Subsequently the distal end 12b of the cable type member of the electrotransfer device according to embodiments of the present invention may be inserted into the target zone. Following pulsing, the distal end 12b of cable type member is withdrawn from the target zone. While monitoring temperature changes using the multimeter, the target zone is either cooled or warmed. The cable type member of the electrotransfer device may be inserted onto the surface of the body or through an appropriate natural orifice which may be nasal, oral, rectal or vaginal or via a surgical incision. The target tissue may be cooled or warmed prior to pulsing, between multiple pulsing or after pulsing as necessary. The tissue may be cooled or warmed using compressed air exiting the outlet 38 of vortex tube 34 whilst regulating the temperature of the compressed air using the temperature regulator 42.

Claims

1. An electrotransfer device comprising an elongate member having a distal end and a proximal end, a first electrode and a second electrode proximate the distal end of the elongate member and connection means proximate the proximal end of the elongate member for operably connecting the first electrode and the second electrode to a controller comprising a single-pulse or multi-pulse generator and a multimeter, wherein the first electrode and the second electrode are movable between a retracted position and a deployed position relative to the elongate member and the single-pulse or multi-pulse generator supplies electric pulses to the first electrode and the second electrode when in the deployed position.

2. An electrotransfer device according to claim 1, further comprising a third electrode disposed between the first electrode and second electrode and operably connected to the controller, wherein the single-pulse or multi-pulse generator supplies electric pulses to the third electrode.

3. An electrotransfer device according to claim 1 or claim 2, wherein the first electrode and second electrode are mounted on flexible arms extending from the distal end of the elongate member.

4. An electrotransfer device according to claim 3, wherein the flexible arms are tweezer or pincer shaped.

5. An electrotransfer device according to claim 3 or claim 4, wherein the length of the flexible arms is between 1 mm and 100mm and the width of the flexible arms is between 1mm to 40mm.

6. An electrotransfer device according to any preceding claim, wherein the length of the first electrode and second electrode is between 1mm and 100mm and the width of the first electrode and second electrode is between 1mm and 40mm.

7. An electrotransfer device according to any of claims 3 to 5, wherein the first and second electrodes are embedded within their respective flexible arms.

8. An electrotransfer device according to claim 2, wherein the third electrode is needle shaped.

9. An electrotransfer device according to claim 8, wherein the length of the third electrode is between 1mm and 100mm and the diameter of the third electrode is between 0.1mm and 20mm.

10. An electrotransfer device according to any of claims 2 to 9, wherein the third electrode is identical to the first and second electrodes in shape and size and is mounted on a flexible arm or embedded within the flexible arm and disposed at a mid-point between the first and second electrodes such that each of the first, second and third electrodes are oriented in a triangular orientation.

11. An electrotransfer device according to any preceding claim further comprising a common plate at the distal end of the elongate member, wherein the common plate is fixed to the elongate member.

12. An electrotransfer device according to any preceding claim, wherein the common plate is removable.

13. An electrotransfer device according to any of claims 2 to 12, wherein the first electrode, second electrode and third electrode are moved from the retracted position to the deployed position by a lever mechanism.

14. An electrotransfer device according to any of claims 1 to 13, wherein the first electrode, second electrode and third electrode are moved electrically from the retracted position to the deployed position.

15. An electrotransfer device according to any of claims 2 to 14, wherein the first and second electrodes have a first polarity and the third electrode has a second polarity, different to the first polarity.

16. An electrotransfer device according to claim 15, wherein the first polarity and second polarity are selectively reversible.

17. An electrotransfer device according to any preceding claim, wherein the elongate member is insulated.

18. An electrotransfer device according to any preceding claim, wherein the elongate member is rigid.

19. An electrotransfer device according to any of claims 1 to 17, wherein the elongate member is substantially flexible.

20. An electrotransfer device according to any preceding claim, wherein the controller comprises respective single-pulse or multi-pulse generators, each singlepulse or multi-pulse generator configured to deliver current pulses to electrode respective one of the first, second or third electrode.

21. An electrotransfer device according to claim 20, wherein each single-pulse or multi-pulse generator is configured to deliver alternating current or direct current pulses to a respective one of the first, second and third electrodes.

22. An electrotransfer device according to claim 20 or claim 21, wherein the single-pulse or multi-pulse generator is configured to deliver high amplitude or low amplitude pulses.

23. An electrotransfer device according to any of claims 20 to 22, wherein each single-pulse or multi-pulse generator is configured to deliver square wave or exponential decay wave pulses to a respective one of the first, second and third electrodes.

24. An electrotransfer device according to any of claims 20 to 23, wherein each single-pulse or multi-pulse generator is configured to deliver pulses of variable duration.

25. An electrotransfer device according to any of claims 20 to 24, wherein each multi-pulse generator is configured to deliver multiple pulses with variable length of time lapses between pulses.

26. An electrotransfer device according to any of claims 2 to 25, further comprising an automatic or manually activated switch for activating one or more of the first, second and third electrodes.

27. An electrotransfer device according to claim 26, wherein the switch is a manually activated hand switch, foot switch or voice-operated switch.

28. An electrotransfer device according to claim 26 or claim 27, wherein the switch may be located on a remote control unit.

29. An electrotransfer device according to any preceding claim, wherein the controller further comprises a multimeter configured to determine the impedance or resistance value and temperature of a target zone.

30. An electrotransfer device substantially as described with reference to, and/or as shown in, the drawings.

31. A tissue temperature regulation device comprising a compressed air source having an outlet, a vortex tube having an inlet and outlet, and a temperature regulator, wherein the inlet of the vortex tube is fluidly connected to the compressed air source and the outlet of the vortex tube is configured to be connectible to a surgical or non-surgical tool having an air port, and wherein the temperature regulator is configured to control the temperature of air exiting the outlet of the vortex tube.

32. A method of electrotransfer of therapeutic agents into a tissue, the method comprising:

i) injecting one or more therapeutic agents into one or more sites on a target zone;

ii) delivering single or multiple electric pulses to the target zone using the electrotransfer device according to claims 1 to 29; and iii) withdrawing the electrotransfer device from the target zone.

33. A method of electrotransfer of therapeutic agents into a tissue according to claim 32 further comprising the method step of cooling or heating the target zone after injection of one or more therapeutic agents into the target zone.

34. A method of electrotransfer of therapeutic agents into a tissue according to claim 32 or claim 33 further comprising the method step of cooling or heating the target zone between application of single or multiple electric pulses to the target zone.

35. A method of electrotransfer of therapeutic agents into a tissue according to any of claims 32 to 34 further comprising the method step of cooling or heating the target zone following withdrawal of the electrotransfer device from the target zone.

36. A method of electrotransfer of therapeutic agents into a tissue according to any of claims 32 to 35, wherein the electrotransfer device is inserted into the patient orally, nasally, vaginally, anally or via surgical incision.

37. A method of electrotransfer of therapeutic agents into a tissue according to any of claims 32 to 35, wherein the electrotransfer device is positioned external to the patient.

38. A method of electrotransfer of therapeutic agents into a tissue, the method comprising:

a) inserting a surgical or non-surgical tool according to claim 31 into the patient;

b) injecting one or more therapeutic agents into one or more sites on a target zone;

c) cooling or warming the target zone using compressed air delivered through an air channel of the surgical or non-surgical tool;

d) inserting an electrotransfer device according to claims 1 to 30 into a working channel of the surgical or non-surgical tool;

e) delivering single or multiple electric pulses to the target zone using the electrotransfer device with cooling or warming between pulses using compressed air delivered through the air channel of the surgical or non-surgical tool; and

f) cooling or heating the target zone using compressed air delivered through the air channel of the surgical or non-surgical tool.

39. A method of electrotransfer of therapeutic agents into a tissue according to claim 38, wherein the surgical or non-surgical tool is inserted, orally, nasally, vaginally, anally or via a surgical incision.

40. An electrotransfer device according to any of claims 2 to 30, wherein the first, second and third electrodes are selected from the materials including graphene, tungsten, copper, silver, gold, chromium or nickel or an alloy of any of these metals or stainless steel, chromel, chromel-alumel, gold-platinum, platinum-palladium, chromel-gold/iron alloy.

41. A tissue temperature regulation device comprising a compressed air source having an outlet, a vortex tube having an inlet and outlet, and a temperature regulator, wherein the inlet of the vortex tube is fluidly connected to the compressed air source and the outlet of the vortex tube is configured to be connectible to a surgical or non-surgical tool having an air port, and wherein the temperature regulator is configured to control the temperature of air exiting the outlet of the vortex tube.

Intellectual

Property

Office

Mr Geraint Davies

9 August 2017

41. An electrotransfer device according to any of claims 3 to 30, wherein the flexible arms of the first electrode, second electrode and third electrode are selected from the materials including glass, glass-mica, PVC, polyvinyl, Kapton or fluorinated ethylene propylene.

42. An electrotransfer device comprising an elongate member having a distal end and a proximal end, a first electrode and a second electrode proximate the distal end of the elongate member, a third electrode disposed between the first electrode and second electrode and connection means proximate the proximal end of the elongate member for operably connecting the first electrode, second electrode and third electrode to a controller, wherein the first electrode and the second electrode are movable between a retracted position and a deployed position relative to the third electrode and the controller supplies electric pulses to the first electrode and the second electrode when in the deployed position.

43. An electrotransfer device according to claim 42, wherein the electric pulse supplied to the first and second electrode is positively charged and the electric pulse supplied to the third electrode is negatively charged.

44. An electrotransfer device according to claim 42, wherein the electric pulse supplied to the first and second electrode is negatively charged and the electric pulse supplied to the third electrode is positively charged.

Amendement to the claims have been filed as follows

31 01 18

1. An electrotransfer device comprising an elongate member having a distal end and a proximal end, a first electrode and a second electrode proximate the distal end of the elongate member and connection means proximate the proximal end of the elongate member for operably connecting the first electrode and the second electrode to a controller comprising a single-pulse or multi-pulse generator, a multimeter and a thermistor, wherein the first electrode and the second electrode are movable between a retracted position and a deployed position relative to the elongate member and the single-pulse or multi-pulse generator supplies electric pulses to the first electrode and the second electrode when in the deployed position.

31 01 18

23. An electrotransfer device according to any of claims 20 to 22, wherein each single-pulse or multi-pulse generator is configured to deliver square wave or exponential decay pulses to a respective one of the first, second and third electrodes.

31 01 18

27. An electrotransfer device according to claim 26, wherein the switch is a manually activated hand switch, foot switch, voice-operated switch or neural control interface.

30. An electrotransfer device according to any preceding claim, wherein the controller further comprises thermistors with audio and visual alarms configured for inrush current limiting, voltage regulation and tissue temperature sensing.

31. An electrotransfer device substantially as described with reference to, and/or as shown in, the drawings.

32. An electrotransfer device for transfer of agents into a tissue according to any preceding claim, wherein the electrotransfer device is inserted into the person orally, nasally, vaginally, anally or via surgical incision.

33. An electrotransfer device for transfer of agents into a tissue according to any preceding claim, wherein the electrotransfer device is positioned external to the person.

34. An electrotransfer device for transfer of agents into a tissue according to any preceding claim wherein the electrotransfer device is used with a surgical or nonsurgical tool wherein the surgical or non-surgical tool is inserted, orally, nasally, vaginally, anally or via a surgical incision.

35. An electrotransfer device according to any of claims 2 to 31, wherein the first, second and third electrodes are selected from the materials including graphene, tungsten, copper, silver, gold, chromium or nickel or an alloy of any of these metals

31 01 18 or stainless steel, chromel, chromel-alumel, gold-platinum, platinum-palladium, chromel-gold/iron alloy.

36. An electrotransfer device according to any of claims 3 to 31, wherein the flexible arms of the first electrode, second electrode and third electrode are selected from the materials including glass, glass-mica, PVC, polyvinyl, Kapton or fluorinated ethylene propylene.

37. An electrotransfer device comprising an elongate member having a distal end and a proximal end, a first electrode and a second electrode proximate the distal end of the elongate member, a third electrode disposed between the first electrode and second electrode and connection means proximate the proximal end of the elongate member for operably connecting the first electrode, second electrode and third electrode to a controller, wherein the first electrode and the second electrode are movable between a retracted position and a deployed position relative to the third electrode and the controller supplies electric pulses to the first electrode and the second electrode when in the deployed position.

38. An electrotransfer device according to claim 37, wherein the electric pulse supplied to the first and second electrode is positively charged and the electric pulse supplied to the third electrode is negatively charged.

39. An electrotransfer device according to claim 37, wherein the electric pulse supplied to the first and second electrode is negatively charged and the electric pulse supplied to the third electrode is positively charged.

40. A tissue temperature regulation device comprising a compressed air source having an outlet, a vortex tube having an inlet and outlet, and a temperature regulator, wherein the inlet of the vortex tube is fluidly connected to the compressed air source and the temperature regulator is configured to control the temperature of air exiting the outlet of the vortex tube.