Electrical pulse generator and medical device for therapeutic treatment and therapeutic treatment method

Abstract

Electrical pulse generator and therapeutic treatment medical device and therapeutic treatment method. The invention relates to a generator for therapeutic treatment configured to be electrically coupled to an electric field application system inside the body, the generator comprising: - a housing, - a pulsed electric field source in the housing and configured to deliver a pulsed electric field through the electric field application system to a first treatment area, - a DC voltage source in the housing and configured to deliver a DC current to the electric field application system in order to cause objects capable of moving to follow a DC electric field in the body to migrate from a second treatment area to the first treatment area.- an electrical transmission circuit connected to the pulsed electric field generator and the DC voltage source, and configured to electrically couple the pulsed electric field generator and the two sources. Figure for the abbreviation: Fig. 1,

Description

Title of the invention: Electrical pulse generator and medical device for therapeutic treatment and method of therapeutic treatment

[0001] The present invention relates to an electrical pulse generator for the therapeutic treatment of an individual. It also relates to a medical device for therapeutic treatment and a corresponding therapeutic treatment method. technical field

[0002] Cancer is one of the leading causes of hospitalization and death worldwide.

[0003] However, many therapies used to treat cancer are either ineffective or poorly tolerated by patients. Effective treatment methods are needed that reduce the number of days of hospitalization and improve treatment efficacy.

[0004] Current treatment methods used for cancer include surgery, radiotherapy, chemotherapy, hormone therapy, and many others, including bone marrow replacement, biologic response modifiers, and gene therapy. Therapy often consists of a combination of these treatment methods. It is well known that these methods have side effects, including illness, pain, disfigurement, depression, cancer spread, and ineffectiveness, depending on the methods used, the individuals being treated, and the types of cancer.

[0005] Pulsed electric field technologies are relatively recent. They are non-thermal techniques used in many fields, particularly in cancer treatment. In this field, these techniques are known as electrochemotherapy, in connection with chemical treatment agents, or irreversible electroporation. Electrochemotherapy, through the application of a high-intensity pulsed electric field, increases the permeability of cell membranes, thereby improving the effect of chemotherapeutic agents on cells by facilitating their permeation into malignant cells and thus the treatment of cancers in areas where malignant cells proliferate.Irreversible electroporation, through the application of a high-intensity pulsed electric field, allows the destruction of cell membranes in a precise area and thus the destruction of malignant cells when localized in an area of ​​proliferation of this type of cell.

[0006] These technologies offer several advantages, notably that they are non-thermal and allow for localized cell treatment. Furthermore, they appear to spare blood vessels and bile ducts, which is important in certain types of cancer. However, these techniques are not yet used routinely in clinical practice due to the lack of consensus on an effective treatment protocol. Indeed, the precise conditions for effective treatment with these techniques, depending on the type of cancer, are not yet fully established, and clinical trials still need to be conducted.

[0007] These methods already allow for local reduction of tumor size after treatment, such as radiotherapy. However, the tumor often grows again shortly thereafter, requiring further treatment. Therefore, the approaches described above, as well as other prior approaches, are insufficient to meet the needs of real patients, particularly in terms of long-term treatment.

[0008] Such methods therefore present interesting potential in therapeutic treatment and there is a need to optimize their effectiveness and obtain effective treatment.

[0009] There is therefore a need to improve these technologies and methods, in particular to address the real problems of individuals in terms of treatment effectiveness. Description of the invention

[0010] The invention addresses this need by means of a therapeutic treatment generator configured to be electrically coupled to at least one electric field application system inside an individual's body, the generator comprising: - a housing, - a pulsed electric field source arranged in the housing and configured to deliver a pulsed electric field through the electric field application system to a first treatment area for localized cellular treatment in the first treatment area, - a direct voltage source arranged in the housing and configured to deliver a direct current to the electric field application system in order to cause objects capable of moving to follow a continuous electric field in the body to migrate from a second treatment area to the first treatment area by electrotaxy,- an electrical transmission circuit connected to the pulsed electric field source and the DC voltage source, and configured to electrically couple the pulsed electric field source and the DC voltage source to the electric field application system.

[0011] Having a direct current voltage source and a pulsed electric field source allows objects to be moved within the body towards a pulsed treatment zone, the first treatment zone, and then a pulsed electric field to be applied to the pulsed treatment zone to perform cellular treatment. Such a device allows for various types of treatment, particularly cancer treatment, including electrochemotherapy and irreversible electroporation. The ability to move objects upstream within the treatment zone allows them to be concentrated there, thus improving treatment efficacy.

[0012] The fact that the DC voltage source and the pulsed electric field source are housed in the same unit with a common electrical circuit allows for a single generator incorporating all the functionalities necessary for processing. Since both sources are integrated into the generator with a common transmission circuit, they can be controlled, notably by a microcontroller integrated into the generator as we will see later, sequentially relative to each other or independently. This allows for great versatility in processing with a single generator integrating both DC and pulsed field generation functionalities.

[0013] Furthermore, having a single generator means that only one connection is needed to the electric field application system to deliver the treatment, thus limiting the number of connections and disconnections required during treatment. This improves patient comfort.

[0014] Finally, having a single generator allows, in particular through its miniaturization, for portability and continuous connection to the electric field application system. This enables the physician to easily adapt the treatment, notably via telemetry as we will see later, without requiring the patient to be in the hospital for each stage of treatment. This allows at least part of the treatment to be administered at home, notably through programming or remote connection of the physician to the generator, as we will see later, thus reducing the length of hospital stays and improving patient comfort, thereby limiting the risk of depression. It also reduces the number of electrical components and lowers energy consumption, thereby extending battery life or the time between battery recharges.

[0015] Preferably, the generator is configured to be able to deliver a pulsed electric field from the pulsed electric field source simultaneously with a direct current field from the direct voltage source. This allows for the generation of either of the fields or both fields simultaneously in the body and offers greater treatment versatility.

[0016] Objects capable of movement may be cells sensitive to electrotaxy (or galvanotactica), in particular metastatic cells mentioned in the list below, or immune cells, in particular white blood cells.

[0017] Indeed, it is known that metastatic cancer cells move throughout the body, particularly under the influence of physiological electric fields by electrotaxy. This is, in fact, one of the reasons for cancer recurrence. It is difficult to identify all the individual metastatic cells that move throughout the body in order to eliminate them. The inventors have therefore invented a generator that does not identify cells dispersed near the tumor area, but rather retains or returns them to the tumor area and prevents them from moving out of it. The generator according to the invention is thus configured to generate, in an expanded area of ​​the body extending from the second treatment area to the first treatment area, a continuous electric field enabling movement by electrotaxy towards the first treatment area.Localized cell therapy in the first treatment area is preferably an irreversible electrochemotherapy or electroporation treatment, but it could be something else.

[0018] Alternatively, the objects capable of movement can be cell-treatment agents, in particular chemotherapeutic agents. Moving such agents from the second to the first treatment zone allows them to be concentrated in the treatment zone, thereby improving their treatment efficacy. Furthermore, the application of the pulsed electric field improves the efficacy of electrochemotherapy treatment by modifying cell permeability. Microcontroller

[0019] The generator is preferably configured to generate, via the electric field application system, either a direct current field, a pulsed electric field, or a combination of both. This allows for a high degree of versatility in the generator.

[0020] The generator includes a microcontroller configured to control the sources of direct voltage and pulsed electric field, in particular according to one or more received information and / or according to a pre-established operating sequence.

[0021] The generator can be configured to control the DC voltage and pulsed electric field sources independently of each other based on one or more received signals. The microcontroller can control the two sources according to independent operating sequences. For example, the DC voltage source can apply a continuous DC current field, and the microcontroller can trigger intermittently based on one or more signals. information received a predefined operating sequence of the pulsed electric field source.

[0022] Alternatively, the generator can be configured to control the DC voltage and pulsed electric field sources in relation to each other according to pre-established, interdependent operating sequences for the two sources, the two sequences being temporally linked. For example, the DC voltage source can apply a continuous DC current field except when the microcontroller triggers, based on one or more received signals, a predefined operating sequence for the pulsed electric field source. The generator can then control the DC voltage source to either decrease the intensity of the DC current field or shut down the DC voltage source.

[0023] The input information(s) may be initial information received prior to treatment or information obtained in real time from the physician via an external communication system, in particular by telemetry or by one or more sensors, in particular voltage and / or current sensors at the level of the electric field application system, and / or temperature sensor at the level of the first and / or second treatment area, in particular an electrical charge delivered by the continuous or pulsed field, and / or an electrical impedance for the purpose of assessing the integrity of the electrodes and for diagnostic purposes.

[0024] The input information may include information on the electric field application system, including the configuration of the electrodes and their implantation in the body, information on the type of treatment, including electrochemotherapy, irreversible electroporation or other, the properties of the first treatment area and / or the second treatment area, including the type of tumors, its stage or size, the properties of the treatment, including the amplitudes to be applied for each field, the control sequence of the two sources.

[0025] The microcontroller can be configured to control the application of the pulsed electric field and its parameters, including the pulse duration or amplitude, pulse frequency, or duration of pulsed electric field application, and / or the application of the direct current field and its parameters, including the DC voltage source and the DC field application duration. This control can be based on the input information(s) and / or according to the pre-established operating sequence. Pulsed electric field source

[0026] The pulsed electric field source may include a high-voltage source connected to at least one capacitor, in particular an electrolytic capacitor, configured to store sufficient electrical energy to generate several electrical pulses, including high voltage, through the electric field application system to the first treatment zone in order to generate the pulsed electric field.

[0027] The pulsed electric field source can be configured to emit positive polarity pulses and negative polarity pulses.

[0028] The capacitor can be configured to be continuously recharged by the high voltage source during the emission of the pulsed electric field.

[0029] The pulsed electric field source can be configured to emit pulses with an amplitude and voltage between 1 and 300 V, preferably between 10 V and 250 V. The pulsed electric field source can be configured to emit pulses with a duration between 1 ps and 200 ps, ​​preferably between 2 ps and 100 ps. The pulsed electric field source can be configured to emit one or more pulses, in particular between 1 and 10,000 pulses per treatment session, preferably between 10 and 1,000 pulses. In the case of multiple pulses, the pulsed electric field source can be configured to emit the pulses with a frequency between 1 Hz and 500 kHz. Such amplitudes, pulse durations, and frequencies allow for cell treatments by electrochemotherapy or irreversible electroporation.

[0030] The pulsed electric field source can be configured to emit single-phase or two-phase pulses. DC voltage source

[0031] The DC voltage source can be a voltage source configured to generate a constant electric field of between 0.5 V / cm and 5 V / cm, preferably between 0.7 and 1.2 V / cm, in the tissues between an anode in the first treatment zone and a cathode in the second treatment zone of the electric field application system.

[0032] The DC voltage source can be configured to generate an output voltage between 0.5V and 20V.

[0033] The DC voltage source may include a switching converter with a variable voltage output. Electrical transmission circuit

[0034] The electrical transmission circuit may include one or more high-voltage switches, in particular metal-oxide-semiconductor field-effect transistors (MOSFETs) or bipolar transistors, in particular insulated-gate (IGBTs), electrically connecting the pulsed electric field source, in particular the capacitor(s), to the electric field application system during the emission of a pulse sequence.

[0035] The switches can be configured to have a time accuracy of less than one microsecond.

[0036] The microcontroller can be configured to control the switch(s).

[0037] The electrical transmission circuit may include a hardware protection circuit between the high-voltage switches and the electric field application system configured to provide a hardware time limit to the duration of the pulsed electric field in the event of a software timing failure. Control Circuit

[0038] The generator may include a control circuit configured to receive one or more control information from the electric field application system and transmit it to the microcontroller.

[0039] The information(s) may be analog signals representing the voltage and current to the electric field application system or electrode temperature information. Telemetry

[0040] The generator may include an external communication system, in particular a hardware transmission system such as a connector, in particular USB or a memory card slot, integrated non-volatile memory, or a telemetry system. The telemetry system may include a transducer and an antenna for receiving and transmitting information, in particular transmitting control information and / or receiving processing parameters, in particular the amplitude and duration of pulses, the pulse frequency, the power of the DC field, the status of the battery and / or capacitors and / or the processing plan.

[0041] The telemetry system can be based on radio frequency or infrared communication. Battery

[0042] The generator may include a battery.

[0043] The battery can be rechargeable. The battery can be recharged by wired connection or by wireless connection, in particular it can include a dedicated antenna configured to recharge the battery by inductive coupling. Device

[0044] The invention also meets this need by means of a medical treatment device comprising the generator as described above and at least one system for applying an electric field inside the body, the generator being electrically coupled to the system for applying an electric field. Electric field application system

[0045] The electric field application system may include at least two electrodes, in particular an electrode array. One or more electrodes may be grounding electrodes spaced away from the first treatment zone, particularly at the periphery of the second treatment zone. Preferably, the electric field application system may include one or more electrodes delimiting the second treatment zone.

[0046] The electrode(s) may be made of a biocompatible metal, in particular a bioresorbable material, in particular a bioresorbable metal, for example zinc or aluminium, or a bioresorbable polymer.

[0047] The electric field application system may include a temperature detector with at least one electrode.

[0048] The electric field application system may include one or more voltage and / or current sensors in the electric field application system, in particular at at least one electrode.

[0049] The electric field application system may comprise a first series of one or more electrodes for applying the pulsed electric field to the first treatment zone and a second series of one or more electrodes for applying the direct current field. The first and second series of electrodes each include at least one common electrode in the first treatment zone. Treatment method

[0050] The invention also addresses this need by providing a method of therapeutic treatment by electrotherapy using a generator or device as described above, comprising: - the application of a direct current field between the second treatment zone and the first treatment zone by the direct voltage source in order to cause objects capable of moving within the individual's body to migrate following a continuous electric field within the body from a second treatment zone to the first treatment zone by electrotaxis, - the application of a pulsed electric field in the first treatment area by the pulsed electric field source for localized cellular treatment in the first treatment area.

[0051] The method may include the application of the direct current field and the application of the pulsed electric field according to a predetermined processing sequence controlled by the microcontroller.

[0052] The direct current field can be applied for a period of more than 1 minute, preferably more than or equal to 1 hour, even better more than or equal to 5 hours between at least two electrodes separated from the second set of electrodes.

[0053] The pulsed electric field may include a pulse or a train of pulses applied for a duration of between 1 ms and 10 s.

[0054] The direct current field and the pulsed electric field can be applied simultaneously by the electric field application system.

[0055] Alternatively, the direct current field is stopped when the pulsed electric field is applied.

[0056] The direct current field can be applied continuously, possibly outside of the applications of the pulsed electric field. The pulsed electric field can be applied periodically with a periodicity of between 1 day and 30 days.

[0057] In the case of electrochemotherapy, at least one remote electrode may be implanted near a site of administration of at least one chemotherapeutic agent, or at another site if the chemotherapeutic agent is administered systemically. The method may involve administering the (positively charged) chemotherapeutic agent, then applying a direct current field to migrate the chemotherapeutic agent to the first treatment area, and finally applying a pulsed electric field to enhance cell permeability to the chemotherapeutic agent. The pulsed electric field may be as described above. The pulsed electric field source may be configured to emit between 1 and 1000 pulses with an amplitude of 1 to 250 V and a voltage of 1 Hz to 500 kHz.It is also possible to reverse the polarity of the direct current field to disperse the chemotherapeutic agent in the second treatment area.

[0058] In the case of irreversible electroporation, the direct current field is configured to cause field-sensitive tumor cells, capable of moving along the electric field by electrotaxy, to migrate to the first treatment zone, and the pulsed electric field is configured to cause necrosis of the cells in the first treatment zone. In this case, the pulsed electric field source can be configured to emit between 1 and 1000 pulses with an amplitude of 1 to 300 V and a voltage of 1 Hz to 500 kHz. The field-sensitive tumor cells can be glioblastomas, metastatic cells of breast, lung, prostate, or ovarian cancer. This also applies to a wide range of other cancers and represents a fundamental property of malignant transformation or of reversion to a developmental program where this behavior may be innate.

[0059] Alternatively, the continuous electric field is configured to cause immune cells sensitive to the electric field and capable of moving along the electric field by electrotaxis to migrate to the first treatment area. In this case, the pulsed electric field can be deactivated.

[0060] The generator, device and method described above are envisaged for use in many types of malignant tumors (i.e. cancer) and benign tumors or as part of a stimulation of the individual's immune response. For example, the generator, devices, and methods described herein are considered for use in adrenocortical cancer, anal cancer, bile duct cancer (e.g., periphilic cancer, distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, benign and malignant bone cancer (e.g., osteoma), osteoid osteoma, osteoblastoma, osteochrondrome, hemangioma, chondromyxoid fibroma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma, giant cell bone tumor, chordoma, lymphoma, multiple myeloma), brain and central nervous system cancer (e.g., meningioma, astocytoma,oligodendrogliomas, ependymoma, gliomas, medullobastoma, ganglioglioma, schwannoma, germinoma, craniopharyngioma), breast cancer (e.g., ductal carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma, lobular carcinoma in situ, gynecomastia), Castleman disease (e.g., giant lymph node hyperplasia, angiofollicular lymph node hyperplasia), cervical cancer, colorectal cancer, endometrial cancer (e.g., endometrial adenocarcinoma, adenocanthoma, papillary serous adenocarcinoma, clear cell carcinoma), esophageal cancer, gallbladder cancer (mucinous adenocarcinoma, small cell carcinoma), gastrointestinal carcinoid tumors (e.g., choriocarcinoma, chorioadenoma) destruens), Hodgkin's disease, non-Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer (e.g., renal cell carcinoma), laryngeal and hypopharyngeal cancer, liver cancer (e.g.,hemangioma, hepatic adenoma, focal nodular hyperplasia, hepatocellular carcinoma), lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), mesothelioma, plasmacytoma, cancer of the nasal cavity and paranasal sinuses (e.g., esthesioneuroblastoma, median granuloma), nasopharyngeal cancer, neuroblastoma, cancer of the oral cavity and oropharynx, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, skin cancer (e.g., melanoma, non-melanoma skin cancer), stomach cancer, cancer of the, testicles (e.g., seminoma, non-seminomatous germ cell cancer), thymus cancer, thyroid cancer (e.g., follicular carcinoma, anaplastic carcinoma, poorly differentiated carcinoma, medullary thyroid carcinoma, thyroid lymphoma), vaginal cancer, vulvar cancer, and uterine cancer (e.g., uterine leiomyosarcoma).

[0061] The chemotherapeutic agent(s) may be selected from among chemotherapeutic agents carrying an electrical charge, in particular those which are ionized or which have ionic properties in biological environments, including cisplatin, doxorubicin, mitoxantrone, daunorubicin, bleomycin, vincristine, vinblastine, carboplatin, etoposide and irinotecan, or from chemotherapeutic agents which do not cross the blood-brain barrier or which must be administered locally or by breaching the blood-brain barrier, including methotrexate, cyclophosphamide, paclitaxel, temozolomide and 5-fluorouracil.

[0062] Individuals treated with the generators, devices, and methods described above can be any living being, but preferably a mammal such as, but not limited to, humans, monkeys, chimpanzees, rabbits, rats, horses, dogs, and cats. Individuals treated with the generators, devices, and methods described above can be of any age. In particular, they can be individuals with cancers, including the aforementioned cancers, autoimmune diseases, neurodegenerative diseases, epilepsy, or neuroendocrinological diseases. Brief description of the drawings

[0063] [Fig.1] schematically represents an example of a therapeutic treatment device,

[0064] [Fig.2] schematically represents an electric field application system,

[0065] [Fig.3] schematically represents a variant of an electric field application system,

[0066] [Fig.4] schematically represents a variant of an electric field application system,

[0067] [Fig.5] is a block diagram of a therapeutic treatment method according to the invention, and

[0068] [Fig.6] is a block diagram of a variant of a therapeutic treatment method according to the invention. Detailed description

[0069] Fig. 1 schematically illustrates a treatment device 5 comprising a generator 10 and an electric field application system in the body 70 electrically coupled to the generator 10.

[0070] The generator 10 comprises a housing 12 and includes several components. In particular, it includes a pulsed electric field source 20, a DC voltage source 30, and an electrical circuit 41 connected to the pulsed electric field source 20 and to the DC voltage source 30.

[0071] The pulsed electric field source 20 is arranged in the housing 12 and is configured to deliver a pulsed electric field through the electric field application system 70 to a first treatment zone ZI for localized cell treatment, in particular cell destruction treatment, electrochemotherapy, or stimulation of the immune response. This pulsed electric field source 20 includes a high-voltage source 22 and one or more capacitors 25, in particular high-voltage capacitors, which store sufficient electrical energy to generate one or more high-voltage pulses.

[0072] The pulsed electric field source 20 is configured to emit pulses of amplitude in voltage between IV and 300V, of duration between 2 ps and 100 ps, ​​and with a variable frequency.

[0073] The DC voltage source 30 is also arranged in the housing 12 and is configured to deliver a DC current field to the electric field application system 70 in order to move objects capable of following a DC electric field from a second treatment zone Z2 to the first treatment zone Z1 by electrotaxis. The DC voltage source may include a DC bias voltage source 32. The DC bias voltage source 32 is preferably of controllable voltage.

[0074] The DC voltage source 30 is configured to generate a constant electric field of between 0.5 V / cm and 5 V / cm in the tissues between an anode in the first treatment zone Z1 and a cathode in a second treatment zone Z2 of the electric field application system 70.

[0075] The electrical circuit 41 may include a hardware protection circuit 42 which ensures the safety of the system by protecting the components against overvoltages and other electrical anomalies.

[0076] The electrical circuit 41 may include switches 44, preferably metal-oxide-semiconductor field-effect transistors (MOSFETs) or bipolar transistors such as active-gate transistors (IGBTs). These switches electrically connect the pulsed electric field source 20, in particular the capacitor(s), to the electric field application system 70 during the emission of a pulse sequence. These switches 44 are preferably configured to achieve sub-microsecond timing accuracy. The voltage and current measurement circuit 46 is configured to receive one or more control signals from the electric field application system and transmit them to the microcontroller. These signals may include analog signals representing the voltage and current at the electric field application system or electrode temperature information, measured by the temperature sensor 75.

[0077] The generator 10 may include a microcontroller 40 configured to control the DC voltage and pulsed electric field sources 20 and 30, in particular according to one or more received inputs and / or a pre-established operating sequence. It may control the application of the pulsed electric field and its parameters, such as the duration or amplitude of the pulses, the pulse frequency, or the duration of application of the pulsed electric field, as well as the application of the DC current field and its parameters, including the voltage of the DC voltage source and the duration of application of the DC current field. The microcontroller 40 may be configured to control the emission of a pulsed electric field or a DC current field, or both simultaneously, according to the predetermined sequence or the received inputs.

[0078] The generator may include an external communication system 50. The external communication system may be a physical or telemetry connection system. It may include a USB port, a serial port, a memory card connection, or onboard non-volatile memory (FLASH). It may also include, as illustrated, a telemetry transducer 52 and a telemetry antenna 55 for receiving and transmitting information, including transmitting control information and / or receiving treatment parameters, such as pulse amplitude and duration, pulse frequency, DC field strength, battery and / or capacitor status, and / or the treatment plan. This allows for personalized treatment for each patient by enabling the reception of external information. The microcontroller can modify the treatment parameters in real time based on the information received.

[0079] Commands can be transmitted to an external communication system 50, in particular to the telemetry antenna 55 and the telemetry transducer 52, and then to the microcontroller 40. The information received can include the power delivered and sensory information from a tumor, such as tumor size, density, or chemical data (e.g., pH). Other embodiments include pressure measurements as the tumor 6 shrinks or grows, an index of tumor regression or proliferation, and an indication of electrode displacement. This type of information can be detected by The electric field application system 70 and specialized sensors, such as physical, impedance, pressure, optical, and chemical sensors, are used. The sensors can be designed to tolerate radio-ionization if radiotherapy is likely. The detected information is processed by the microcontroller 40 and can be used to control the generator 10 directly or transmitted via the external communication system 50. For example, the detection of excessive heat or gas buildup can cause treatment to be stopped until the tissues cool or the gas is reabsorbed. Other generator features may include defibrillation protection, the microcontroller 40 can gradually increase the voltage at the start of treatment, and a programmable timer to control the therapy duration and sequence.The entire device is preferably controlled by the microprocessor 40, although its simplicity may not require computer control. The microcontroller can be programmed according to several treatment sequences corresponding to different therapies depending on the required voltage and current levels. Certain parts of the device as a whole can operate in "standby" mode to save energy when not in use.

[0080] The generator 10 may include a battery system 60, in particular one or more rechargeable batteries 65, and a power management circuit 62 for managing the power supply to the pulsed electric field and DC voltage sources 20 and 30. Battery 65 can be recharged via a wired connection or remotely by induction. To this end, the generator 10 may include a charging antenna 66 for wireless battery charging. The power management circuit 62 may include a remaining battery life detection system. The generator 10 may include an alarm device (not shown) that activates when the battery life falls below a certain threshold. The alarm device may be optical, haptic, or audible and may be controlled by the microcontroller 40 or integrated into the power management circuit 62.

[0081] The electric field application system 70 may include at least two electrodes E1 and E3, in particular an array of electrodes E1, E2, E3, and E4. One or more electrodes may be grounding electrodes E2 and E3 spaced from the first treatment zone Z1, in particular at the periphery of the second treatment zone Z2. Preferably, the electric field application system 70 may include one or more electrodes E3 delimiting the second treatment zone Z2.

[0082] The electrode(s) may be made of a biocompatible metal, in particular a bioresorbable material, in particular a bioresorbable metal, for example zinc or magnesium, or a bioresorbable polymer.

[0083] The electrodes can have various shapes depending on the treatment to be applied.

[0084] The electric field application system 70 may include a detector of temperature 75 at least one electrode, this detector can also be external to the electric field application system.

[0085] The generator 10 may include one or more voltage and / or current sensors 46 in the electric field application system 70, in particular at at least one electrode, in particular at an electrode El in the first treatment zone ZI.

[0086] As illustrated in Figures 2 to 4, the electric field application system may comprise a first series of one or more electrodes El or El and E2 for applying the pulsed electric field in the first treatment zone ZI and a second series of one or more electrodes El and E3 or E4 and E3 for applying the direct current field. The first and second series of electrodes may include at least one common electrode El in the first treatment zone, preferably the same electrodes.

[0087] Figures 2 to 4 show different variants of electric field application systems 70. The invention is not limited to the variants illustrated.

[0088] In [Fig. 2], the electric field application system 70 includes an electrode El for applying the pulsed electric field. The electrode El can be implanted in the treatment site, in particular a tumor or a cavity formed after tumor ablation. It can serve as an anode or a cathode for the emission of the pulsed electric field in the first treatment zone Z1, depending on the polarity of the pulses. The continuous electric field is generated between electrodes El and E3. The electrodes E3 can be positioned or implanted at the periphery of the second treatment zone Z2, from which the cells or agent of interest are to be migrated. The electrode El can be the anode or the cathode, and vice versa for electrode E3, depending in particular on the agent or cell to be migrated and its sensitivity to a direct current field in one direction or the other.

[0089] In [Fig. 3], the electric field application system 70 comprises electrodes E1 and E2 for the application of the pulsed electric field. The two electrodes E1 and E2 can be implanted in the first treatment zone Z1 or at the periphery of the first treatment zone Z1, in particular a tumor. They can each constitute an anode or a cathode for the emission of the pulsed electric field in the first treatment zone Z1, depending on the polarity of the pulses. Both can be cathodes, both can be anodes, or one can be an anode and the other a cathode. The direct current electric field is generated between electrodes E3 and E4. Electrodes E3 can be positioned or implanted at the periphery of the second treatment zone Z2, from which the cells or agents of interest are to migrate. Electrode E4 may be single or multiple and can be implanted in the first treatment zone Z1. It may be different from E1 and E2. Alternatively, E4 may be one or both electrodes E1 and E2. Electrodes E3 can be anodes or cathodes, and vice versa for electrode E4, depending on the agent or cell to be migrated and its sensitivity to a direct current field in one direction or the other.

[0090] In [Fig. 4], the electric field application system 70 comprises Electrodes E1 and E2 are used for applying the pulsed electric field. Electrode E1 can be implanted in the first treatment zone Z1, such as a tumor. The second electrode, E2, can form a trace surrounding the first treatment zone Z1. In this case, one of the electrodes, E1 and E2, is an anode and the other is a cathode, so that the pulsed electric field is established between the two electrodes, E1 and E2. The continuous electric field is generated between electrodes E1 and E3. Electrode E3 can be positioned or implanted at the periphery of the second treatment zone Z2 from which the cells or agents of interest are to migrate, for example, by surrounding it. Electrode E3 can be an anode or a cathode, and vice versa for electrode E1, depending on the agent or cell to be migrated and its sensitivity to a direct current field in one direction or the other.

[0091] The generator is configured so that each electrode can be an anode or a cathode, and the microcontroller can be configured to reverse the function of an electrode at any time depending on the treatment, in particular according to the pre-established treatment sequence or the information received. This can, in particular, allow the dispersion of immune cells or a chemotherapeutic agent in a peripheral treatment area. It is also possible to alternate the polarity of the direct current field to, in particular, optimize the distribution of immune cells or the chemotherapeutic agent in the area of ​​interest.

[0092] Figures 5 and 6 illustrate methods of electrotherapy treatment using a generator or device as described above, comprising - the application of a direct current field between the second treatment zone Z2 and the first treatment zone Z1 by the direct voltage source 30 in order to cause objects capable of moving to follow a continuous electric field in the body to migrate from the second treatment zone Z2 to the first treatment zone Z1 by electrotaxis, - the application of a pulsed electric field in the first treatment zone ZI by the pulsed electric field source 20 for localized cellular treatment in the first treatment zone Zl.

[0093] The application of the direct current field and the application of the pulsed electric field can be done according to a predetermined processing sequence controlled by the microcontroller 40, in particular according to the information received as input by the external communication system 50.

[0094] The direct current field can be applied for a period of more than 1 minute, preferably more than or equal to 1 hour, even better more than or equal to 5 hours between at least two electrodes separated from the second set of electrodes.

[0095] The direct current field and the pulsed electric field can be applied simultaneously by the electric field application system or the direct current field is stopped when the pulsed electric field is applied.

[0096] The direct current field can be applied continuously, possibly outside of the applications of the pulsed electric field. The pulsed electric field can be applied periodically with a periodicity of between 1 day and 30 days. The pulsed electric field can be applied for a duration of between 1 ms and 10 s.

[0097] The steps of electrochemotherapy are illustrated in [Fig. 5]. The therapy comprises three phases: a pretreatment phase (steps 1 to 3), a treatment phase (steps 4 to 6), and a tumor regression phase (steps 7 to 9). The pretreatment phase begins with an assessment of the patient's condition by the physician, including an evaluation of the parameters of the cells to be treated, which may also determine the initial setting of the electric field parameters (step 1). These parameters can be entered on a suitable user interface connected to the generator.

[0098] In step 2, the patient may undergo surgery, during which the tumor is removed at least partially if possible, and the electrodes are implanted on the tumor, or in the tumor resection cavity. The generator is also implanted during this step.

[0099] In step 3, a post-implantation evaluation is performed by the physician to verify that the patient has no adverse reaction to the implanted components. The initial diagnosis can be carried out during this period, such as measuring the electrode impedance to verify that the electrodes are in good electrical contact with the tissues.

[0100] After that, the processing phase begins with the activation of the DC field (step 4). The voltage of the DC field can be chosen to create a continuous electric field in The range is from 0.5 V / cm to 5 V / cm. This field is normally maintained throughout the therapy phase as well as during the tumor regression phase.

[0101] This is followed by the application of a pulsed electric field with sufficient amplitude and duration to induce reversible electroporation in the treatment area (step 5). The pulse amplitude can be selected from the range of 10 V to 250 V, the pulse duration from 1 ps to 200 ps, ​​the number of pulses from 1 to 10,000, and the pulse frequency from 1 Hz to 500 kHz.

[0102] This is immediately followed by the application of the electrochemotherapy agent (step 6) in one of the following three ways: 1. The electrochemotherapy agent can be immobilized on the surface of the electrodes before implantation, 2. The electrochemotherapy agent can be applied topically or 3. The electrochemotherapy agent can be applied systemically.

[0103] The duration of the pulsed field can be between 1 ms and 10 s.

[0104] Next, the tumor regression phase begins in step 7, where the direct current (DC) field is again applied to cause the migration of the desired species (cancer cells or electro-chemotherapy agent) to the first treatment area.

[0105] Tumor regression is then assessed by the physician in step 8 and if necessary, the DC field and pulsed field parameters can be readjusted in step 9.

[0106] The therapy can be repeated several times if necessary by returning to step 5.

[0107] In the event that the presence of cancer cells is no longer detected, the therapy may ending by switching off the electric fields or even by explanting the generator with the electrodes (step 10).

[0108] Irreversible electroporation therapy is similar to the electrochemotherapy described above. It differs in that it uses a higher voltage in a pulsed electric field to induce irreversible electroporation and in that it does not use an electrochemotherapeutic agent. The corresponding functional diagram is shown in [Fig. 6]. Irreversible electroporation therapy comprises three phases: the pretreatment phase (steps 1 to 3), the treatment phase (steps 4 to 5), and the tumor regression phase (steps 6 to 8). The pretreatment phase begins with an assessment of the patient's condition by the physician, who may also determine the initial settings of the electric field parameters (step 1). In step 2, the patient undergoes surgery, during which the tumor is removed if possible, and the electrodes are implanted on the tumor or in the tumor resection cavity.The generator is also implanted during this step. In step 3, the post-implantation evaluation is performed by the physician to verify that the... The patient experiences no adverse reactions to the implanted components. During this period, initial diagnostics can be performed, such as measuring electrode impedance to verify that the electrodes are in good electrical contact with the tissue. Next, the treatment phase begins with the activation of the DC field (step 4). The DC field voltage is selected to create an electric field in the range of 0.5 V / cm to 5 V / cm. This field is normally maintained throughout the therapy phase as well as during the tumor regression phase. This is followed by the application of a pulsed field of sufficient amplitude and duration to induce irreversible electroporation in the treatment area (step 5). The pulse amplitude can be selected from the range of 10 V to 300 V, the pulse duration can be selected from the range of 1 ps to 200 ps, ​​the number of pulses from 1 to 10,000 and the pulse frequency from 1 Hz to 500 KHz.The pulsed field duration can range from 1 ms to 10 s. The tumor regression phase then begins in step 6, where the DC field is reapplied to induce the migration of cancer cells to the initial treatment area. Tumor regression is then assessed by the physician in step 7, and if necessary, the DC and pulsed field parameters can be readjusted in step 8. The therapy can be repeated several times if needed by returning to step 5. If no cancer cells are detected, the therapy can be terminated by switching off the electric fields or even by removing the generator with electrodes (step 9).

[0109] Furthermore, the two processes described above can generate, in addition to what is described, a migration of immune cells to the treatment area, which can improve the treatment and stimulate the immune response by the body.

[0110] The invention is not limited to a particular type of electrode. The generator can be interfaced with a large number of different electrodes, and the treatment parameters can be adapted by the user according to the electrodes. For example, it is possible to use two interdigitated flexible electrodes implanted on the surface of the tumor with a unipolar pulsed electric field for irreversible electroporation therapy applied once a day for 4 days. The pulsed electric field in this case can consist of 8 pulses of amplitude 150 V, each lasting 100 ps, ​​and spaced 1 s apart. Such therapy enabled infiltration of the innate immune system within hours of the first application of the pulsed electric field. Tumor regression was observed 5 days after the first day of treatment.

Claims

Demands

1. A generator for therapeutic treatment configured to be electrically coupled to at least one electric field application system (70) inside the body, the generator (10) comprising: - a housing (12), - a pulsed electric field source (20) arranged in the housing (12) and configured to deliver a pulsed electric field through the electric field application system (70) to a first treatment area for localized cellular treatment in the first treatment area, - a direct voltage source (30) arranged in the housing (12) and configured to deliver a direct current to the electric field application system (70) in order to migrate objects capable of moving to follow a continuous electric field in the body from a second treatment area to the first treatment area by electrotaxy,- an electrical transmission circuit (41) connected to the pulsed electric field generator (20) and the DC voltage source (30) and configured to electrically couple the pulsed electric field source (20) and the DC voltage source (30) to the electric field application system (70).

2. Generator according to claim 1, comprising a microcontroller (40) configured to control the DC voltage sources (30) and pulsed electric field (20), in particular as a function of one or more received information and / or according to a pre-established operating sequence.

3. Generator according to claim 2, wherein the microcontroller (40) is configured to control the application of the pulsed electric field and its parameters, including the duration or amplitude of the pulses, the frequency of the pulses or the duration of application of the pulsed electric field, and / or the application of the direct current field and its parameters, including the voltage of the direct voltage source (30) and the duration of application of the direct current field.

4. Generator according to any one of claims 2 and 3, comprising a control circuit (41) configured to receive one or more control signals from the application system electric field (70) and transmit them to the microcontroller (40), the information being in particular analog signals representing the voltage and current to the electric field application system (70) or temperature information of the electrode.

5. Generator according to any one of the preceding claims, wherein the pulsed electric field source (20) comprises a high voltage source (22) connected to at least one electrolytic capacitor (25) configured to store sufficient electrical energy to generate several pulses, including high voltage pulses, through the electric field application system (70) to the first treatment zone in order to generate the pulsed electric field.

6. Generator according to any one of the preceding claims, wherein the pulsed electric field source (20) is configured to emit pulses of amplitude in voltage between IV and 300V, better between 10V and 250V, of duration between 1 ps and 200 ps, ​​better between 2 ps and 100 ps and with a frequency between 1 Hz and 500 KHz.

7. Generator according to any one of the preceding claims, wherein the DC voltage source (30) is a voltage source configured to generate a constant electric field of between 0.5 V / cm and 5 V / cm, more preferably between 0.7 and 1.2 V / cm, in the tissues between an anode in the first treatment zone and a cathode in the second treatment zone of the electric field application system (70).

8. Generator according to any one of the preceding claims, wherein the electrical transmission circuit (41) comprises one or more high-voltage switches (44), in particular metal-oxide-semiconductor field-effect transistors (MOSFETs) or bipolar transistors, in particular insulated-gate (IGBTs), electrically connecting the pulsed electric field source (20), in particular the capacitor(s) (25), to the electric field application system (70) during the emission of a pulse sequence.

9. Generator according to claim 8, wherein the switches (44) are configured to have a time accuracy of less than one microsecond.

10. Generator according to any one of the preceding claims, comprising a telemetry system (50), the telemetry system comprising a transducer (52) and an antenna (55) for receiving and transmitting information, in particular transmitting control information and / or receiving processing parameters, in particular the amplitude and duration of pulses, the pulse frequency, the DC current field power and / or the processing plan.

11. Generator according to any one of the preceding claims, comprising a rechargeable battery (65).

12. Medical treatment device comprising the generator (10) according to any one of the preceding claims and at least one electric field application system (70) inside the body, the generator (10) being electrically coupled to the electric field application system (70).

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