Electrical stimulation device

Abstract

An electrical stimulation device includes an electrode assembly and an electrical stimulator. The electrical stimulator generates an electrical stimulation signal and is coupled to the electrode assembly. The electrical stimulation signal is transmitted to a target region of the organism via the electrode assembly. The electrical stimulation signal comprises a plurality of burst signals, the burst frequency range of the burst signals is between 0.1 Hz and 1,000 Hz, each burst signal comprises a plurality of pulses, and the pulse frequency range of the pulses is between 1 kHz (kHz) and 1,000 kHz. The electrical stimulation signal is used to reduce the cyclooxygenase-2 (COX-2) content of the organism.

Description

Technical Field

[0001] The present invention relates to an electrical stimulation technology, and more particularly to an electrical stimulation device. Background Art

[0002] Cyclooxygenase (COX) is an important enzyme involved in inflammatory reactions. When the tissues of an organism are stimulated and COX is activated, a large amount of ω-6 fatty acids on the cell membrane are converted into prostaglandins such as prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α) and thromboxane, causing redness, swelling, heat, pain and vasodilation. COX includes COX-1 and COX-2. Among them, COX-1 exists in various tissues of the organism and is responsible for regulating normal cell activities, such as protecting the stomach wall and platelet aggregation, while COX-2 is induced when the body is inflamed.

[0003] Analgesics can be divided into three categories according to their analgesic strength, from weak to strong, namely acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics. When inflammation occurs in the body, activated cyclooxygenase converts arachidonic acid into prostaglandins, which in turn produce more inflammatory factors, causing inflammation and pain. NASIDs mainly achieve anti-inflammatory, analgesic and / or antipyretic analgesic effects by inhibiting COX and blocking the process of COX converting arachidonic acid.

[0004] In addition, there are new analgesics that are NSAIDs that can selectively inhibit COX-2. At therapeutic doses, this drug does not affect COX-1. The advantage of this drug is that the incidence of gastrointestinal mucosal damage is low. However, although the drug can improve the symptoms of existing diseases, the accumulation of drug doses may also cause side effects and other problems. Summary of the invention

[0005] However, there is no electrical stimulation treatment method that can inhibit cyclooxygenase-2 (COX-2) without the side effects caused by drug dosage accumulation. In view of this, the present invention provides an electrical stimulation device that has the effect of reducing COX-2 without causing nerve damage.

[0006] In some embodiments, an electrical stimulation device includes an electrode assembly and an electrical stimulator. The electrical stimulator is coupled to the electrode assembly and generates an electrical stimulation signal. The electrical stimulation signal is transmitted to a target area of ​​a biological body via the electrode assembly. The electrical stimulation signal includes a plurality of burst signals, the burst frequency of the burst signals ranges from 0.1 Hz to 1,000 Hz, and each burst signal includes a plurality of pulses, the pulse frequency of the pulses ranges from 1 kHz (kilohertz) to 1,000 kHz. The electrical stimulation signal is used to reduce the cyclooxygenase-2 content of the biological body.

[0007] In some embodiments, the electrical stimulation signal reduces COX-2 levels by inhibiting COX-2 protein expression.

[0008] In some embodiments, the reduction in cyclooxygenase-2 levels in the organism occurs within 24 hours of the target area receiving the electrical stimulation signal.

[0009] In some embodiments, the electrical stimulator generates the electrical stimulation signal for a cumulative time that is less than or equal to 12 hours per day.

[0010] In some embodiments, the electrical stimulation signal is further used to reduce the content of brain-derived neurotrophic factor (BDNF) and / or substance P in the organism.

[0011] In some embodiments, the electrical stimulator utilizes an electrical stimulation signal to inhibit a neuroinflammatory response in a living organism.

[0012] In some embodiments, the electrical stimulation signal is used to suppress and / or relieve pain in at least a portion of the nerve conduction pathway to which the target area belongs.

[0013] In some embodiments, after the organism receives the electrical stimulation signal for less than or equal to 12 hours, the electrical stimulation signal relieves the organism's pain, relieves the organism's symptoms, reduces the organism's nerve sensitivity, or relieves the organism's overactive reaction, and lasts for at least 1 hour.

[0014] In summary, according to any embodiment, the electrical stimulation device or the electrical stimulation method has the effect of reducing COX-2 without causing nerve damage. The electrical stimulation device or the electrical stimulation method has the effect of reducing the content of brain-derived neurotrophic factor, reducing the content of substance P, inhibiting nerve inflammation, inhibiting and / or relieving pain, relieving symptoms, reducing nerve sensitivity, or relieving overreaction, and does not cause nerve damage. The electrical stimulation device or the electrical stimulation method has the effect of regulating nerves by regulating protein and protein gene expression. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1is a functional block diagram of an electrical stimulation device according to some embodiments.

[0016] Figure 2 for Figure 1 Schematic diagram of an exemplary electrical stimulation device.

[0017] Figure 3 for Figure 1 A schematic diagram of an exemplary use of an electrical stimulation device.

[0018] Figure 4 for Figure 1 Schematic diagram of another exemplary use of the electrical stimulation device.

[0019] Figure 5 for Figure 1 A schematic diagram of another exemplary use of the electrical stimulation device.

[0020] Fig. 6A for Figure 1 A schematic diagram of an example of an electrical stimulation signal generated by an electrical stimulator. Figure 6B for Figure 1 Schematic diagram of another exemplary embodiment of an electrical stimulation signal generated by an electrical stimulator.

[0021] Figure 6C for Figure 1 Schematic diagram of another exemplary embodiment of an electrical stimulation signal generated by an electrical stimulator.

[0022] Figure 7 It is a line graph of the results of the rat hind paw withdrawal threshold test.

[0023] Fig. 8A It is a histogram of the MBP content pixel density test results.

[0024] Figure 8B It is a histogram of the NF200 content pixel density test results.

[0025] Figure 8C It is a histogram of the test results of the percentage of MBP and NF200 positive cells.

[0026] Fig. 9 The figure shows the results of fluorescence staining test of MBP and NF200.

[0027] Fig.10 The figure is a histogram showing the percentage of BDNF-positive neurons.

[0028] Fig.11 This is a diagram showing the results of a fluorescent staining experiment of BDNF.

[0029] Fig.12 The figure is a histogram showing the percentage of COX-2 positive neurons.

[0030] Fig.13 The figure is a histogram showing the percentage of c-Myc positive neurons.

[0031] Fig.14 The histogram is a test result of percentage of SP positive neurons.

[0032] Fig.15 The figure is a histogram showing the percentage of MEK-positive neurons.

[0033] Fig.16 The figure is a histogram showing the percentage of c-Fos positive neurons.

[0034] Wherein, the reference numerals are:

[0035] 10,10a,10b,10c: Electrical stimulation device

[0036] 11: Electrode assembly

[0037] 111: Electrode pair

[0038] 112: Electrode wire

[0039] 113: Ring electrode

[0040] 12: Electrical Stimulator

[0041] 20: Organisms

[0042] 21: Skin

[0043] B, B1, B2: burst signal

[0044] CH1, CH2: output terminal

[0045] ES,ES2: electrical stimulation signal

[0046] N: Target nerve

[0047] P: Pulse

[0048] P1, P3: positive phase pulse

[0049] P2, P4: Negative phase pulse

[0050] T: Target area

[0051] t: cycle time

[0052] T1: First ultra-high frequency electrical stimulation treatment

[0053] T2: Second ultra-high frequency electrical stimulation treatment

[0054] Vo: Voltage intensity

[0055] Wb, Wb2: Wave width

[0056] Wp, Wp1, Wp2: pulse width DETAILED DESCRIPTION

[0057] As used herein, the term "electrical stimulation signal" refers to an electrical signal transmitted from an electrical stimulator to a biological body through an electrode assembly. For example, the electrical stimulation signal may include voltage, current, electric field, power, joule energy, or other electrical measurement values.

[0058] The term "target region" refers to the neural tissue and / or non-neural tissue that receives the electrical stimulation signal. The neural tissue includes neurons. The non-neural tissue includes neuroglial cells, myelin sheath, immune cells, connective tissue, epithelial cells, cardiovascular cells and / or blood cells. Neuroglial cells include astrocytes, oligodendrocytes, ependymal cells, radial glial cells, Schwann cells, satellite cells, microglia and / or pituitary cells.

[0059] The term "organism" refers to an individual that receives the electrical stimulation signal, which may be a human or an animal, but is not limited thereto.

[0060] It should be understood that, unless clearly defined otherwise, the “one” or “one” mentioned herein is not intended to limit to only one, but may refer to a single one, any one of a plurality of ones, or one kind within a reasonable scope.

[0061] See also Figures 1 to 3. The electrical stimulation device 10 includes an electrode assembly 11 and an electrical stimulator 12. The electrical stimulator 12 is coupled to the electrode assembly 11 and generates an electrical stimulation signal ES. The electrode assembly 11 receives the electrical stimulation signal ES and transmits it to the target area T of the biological body 20. In other words, the electrical stimulation signal ES is transmitted to the target area T via the electrode assembly 11. In some embodiments, the electrical stimulation device 10 can be a transcutaneous, transcranial, partially invasive, minimally invasive or implantable type of electrical stimulation device 10. In some embodiments, the target area T is the area to be electrically stimulated by the electrical stimulation device 10, such as the central nervous system and its tissues, or the peripheral nervous system and its tissues. Among them, the central nervous system and its tissues include the brain, brainstem and spinal cord; the peripheral nervous system and its tissues include nerves, nerve roots and root ganglia outside the brain, brainstem and spinal cord. In some embodiments, peripheral nerves and their tissues are divided into the autonomic nervous system and the somatic nervous system according to their functions, including, for example, cranial nerves, vagus nerve, occipital nerve, trigeminal nerve, hypoglossal nerve, sphenopalatine ganglion, sacral nerves, lumbar nerves, pudendal nerves, sacral nerves and coccygeal nerves.

[0062] In some embodiments, the electrical stimulation device 10 can be an electrical stimulation device 10 such as a spinal cord stimulation (SCS) device, a transcutaneous electrical nerve stimulation (TENS) device, a peripheral nerve stimulation (PNS) device, a deep brain stimulation (DBS) device, or a vagus nerve stimulation (VNS) device.

[0063] In some embodiments, the electrode assembly 11 and the electrical stimulator 12 may be detachable components connected to each other or integrally formed. The detachable electrode assembly 11 and the electrical stimulator 12 are directly or indirectly coupled (e.g., snap-fit, pluggable, or electrically coupled) together.

[0064] In some embodiments, one or more electrical stimulation devices 10 may be installed on the target area T. For example, the user may use multiple electrical stimulation devices 10 to apply electrical stimulation to the same target area T at the same time. Of course, multiple electrical stimulation devices 10 may also be installed on the same biological body 20 to apply electrical stimulation to different target areas T.

[0065] In some embodiments, the electrodes included in the electrode assembly 11 may be in the form of paddles, cuffs, spirals, wires, thin probes, cylindrical electrodes, etc.; the electrode assembly 11 may be in the form of straight lines, spirals, patches, wires, or needles. Preferably, the electrodes of the electrode assembly 11 are close to the target nerves N in the target area T (see Figure 4 ), and the distance between the electrode of the electrode assembly 11 and the target nerve N is within 2 cm, or even within 1.5 cm or within 1 cm.

[0066] See also Figure 2 and Figure 3 In some embodiments, the electrical stimulation device 10 may be a transcutaneous electrical stimulation device 10a, and an electrode assembly 11 is embedded on one surface of the electrical stimulator 12. When in use, the electrical stimulator 12 is disposed on the skin 21 of the biological body 20, and the surface with the electrode assembly 11 is in contact with the skin 21. In other words, the electrical stimulator 12 and the electrode assembly 11 of the electrical stimulation device 10a are both located outside the body. The electrical stimulation signal ES generated by the electrical stimulator 12 stimulates the skin 21 and the superficial nerves under the skin 21 through the electrode assembly 11. In this embodiment, the target area T includes the skin 21 and the superficial nerves under the skin 21. The skin 21 may be the skin on the surface of the head, upper limbs, lower limbs, trunk or genitals, and the superficial nerves under the skin 21 refer to nerves with a depth of about 1, 2, 3, or 4 centimeters below the skin.

[0067] In some embodiments, the electrode assembly 11 includes two electrodes or multiple electrodes, so that the electrical stimulation is bipolar or tripolar. In other embodiments, the electrode assembly 11 includes a working electrode and a reference electrode, so that the electrical stimulation is monopolar. Figure 2As shown, in a bipolar example, the electrode assembly 11 includes a pair of electrode pairs 111. In the electrical stimulation device 10a, this pair of electrode pairs 111 is arranged on the surface (i.e., on the shell) of the electrical stimulator 12. When in use, the electrical stimulation device 10a is attached to the skin 21 of the arm with the electrode pair 111, and is activated to output an electrical stimulation signal ES to the electrode pair 111, so as to electrically stimulate the skin 21 of the arm and the superficial nerves under the skin through the electrode pair 111. In some embodiments, the superficial nerve under the skin of the arm can be the musculocutaneous nerve located in the biceps brachii, the radial nerve located in the triceps brachii, the dorsal nerve of the penis (DPN) located on the male genitals, or the median nerve located near the wrist.

[0068] See also Figure 4 . In some embodiments, the electrical stimulation device 10 may be a minimally invasive electrical stimulation device 10b. After the electrode assembly 11 is implanted, one end thereof is wirelessly or wiredly connected to the electrical stimulator 12, and the other end is implanted in the organism 20. When in use, the electrical stimulator 12 is disposed on the skin 21 of the organism 20, and the electrode assembly 11 is at least partially implanted under the skin 21 of the organism 20 in a minimally invasive manner. In other words, the electrical stimulator 12 of the electrical stimulation device 10b is located outside the body, and the electrode assembly 11 of the electrical stimulation device 10b is located inside the body. The electrical stimulation signal ES generated by the electrical stimulator 12 stimulates the target nerve N near the terminal of the electrode assembly 11 (the end of the electrode assembly 11 not connected to the electrical stimulator 12) wirelessly or wired via the electrode assembly 11. In this embodiment, the target area T is the target nerve N near the terminal of the electrode assembly 11.

[0069] like Figure 4As shown, in one example, the electrical stimulation device 10b may be a peripheral nerve electrical stimulation device, and the electrode assembly 11 may be an electrode lead 112, and the electrode lead 112 includes a plurality of ring electrodes 113. In the electrical stimulation device 10b, the electrode lead 112 is wirelessly connected to the electrical stimulator 12. When in use, the electrical stimulation device 10b is attached to the skin 21 of a living organism 20 with the electrical stimulator 12, and the electrode lead 112 is micro-invasively implanted under the skin 21 of the living organism 20. The electrical stimulator 12 wirelessly outputs an electrical stimulation signal ES to the electrode lead 112, thereby electrically stimulating the nerve (i.e., the target nerve N) under the skin 21 of the living organism 20 and near the ring electrode 113 of the electrode lead 112 through the electrode lead 112. In some embodiments, one end of the electrode lead 112 may be implanted near the target nerve N, and the other end may be located subcutaneously so that the electrical stimulator 12 can be connected and powered wirelessly (e.g., Figure 4 In other embodiments, the other end of the electrode wire 112 may extend out of the surface of the skin 21 and be connected to the electrical stimulator 12, and be powered by wire.

[0070] In some embodiments, the target area T is a nerve or a nerve structure around the ring electrode 113 on the electrode lead 112. For example, the target area T is a target nerve N around the ring electrode 113 on the electrode lead 112.

[0071] Figure 5 for Figure 1 Another example of the use of the electrical stimulation device is shown in FIG. Figure 5, the electrical stimulation device 10 is an implantable electrical stimulation device 10c, such as a spinal cord electrical stimulation device or a sacral nerve electrical stimulation device, and the electrode assembly 11 can be an electrode wire 112, and the electrode assembly 11 is connected to the electrical stimulator 12. When in use, the electrical stimulator 12 and the electrode assembly 11 are both implanted in the biological body 20, and the ring electrode 113 of the electrode assembly 11 is located at the terminal of the electrode wire 112 (the end of the electrode assembly 11 not connected to the electrical stimulator 12), and the ring electrode 113 corresponds to the position of the target area T of the biological body 20. The electrical stimulation signal ES generated by the electrical stimulator 12 will stimulate the nerves near the ring electrode 113 through the ring electrode 113 on the electrode assembly 11. In other words, the electrical stimulator 12 can be implanted at any position around the target area T of the biological body 20 according to the placement position and length of the ring electrode 113 of the electrode wire 112. When the electrical stimulation device 10c is used, the electrical stimulator 12 is connected to one end of the electrode wire 112 and implanted in the epidural space of the spine or near the sacral nerve around the buttocks in the living body 20. Therefore, when the electrical stimulator 12 outputs the electrical stimulation signal ES to the electrode wire 112, the electrical stimulation signal ES can electrically stimulate the spinal cord of the living body 20 or the sacral nerve around the buttocks through the electrode wire 112.

[0072] In some embodiments, the electrical stimulation signal ES may be a biphasic electrical stimulation signal ES. In other embodiments, the electrical stimulation signal ES may also be a monophasic electrical stimulation signal ES.

[0073] Fig. 6A for Figure 1 A schematic diagram of an example of an electrical stimulation signal generated by an electrical stimulator. Fig. 6A In some embodiments, the waveform of the electrical stimulation signal ES generated by the electrical stimulation device 10 within the cycle time t is a biphasic, square wave, symmetric, charge balance electrical stimulation signal ES as an example. Of course, the waveform of the electrical stimulation signal ES may also be a monophasic signal, a triangular wave, a sine wave, an asymmetric signal, or a charge imbalance signal.

[0074] In some embodiments, the electrical stimulation signal ES includes a plurality of burst signals B, the burst frequency of these burst signals B is between 0.1 Hz and 1,000 Hz, and each burst signal B includes a plurality of pulses P, the pulse frequency of these pulses P ranges from 1,000 Hz to 1000 kHz (kilohertz). Preferably, the burst frequency of the burst signal B is between 0.1 Hz and 500 Hz, for example, 0.1 Hz to 400 Hz, 0.1 Hz to 200 Hz, 0.1 Hz to 100 Hz, or 0.1 Hz to 20 Hz. Preferably, the pulse frequency of the pulse P is between 1 kHz and 750 kHz, for example, 400 kHz to 600 kHz.

[0075] The wave width Wb of the burst signal B is between 1 millisecond (ms) and 10 seconds, and the pulse width Wp of the pulse P is between 0.5 microseconds (μs) and 1 millisecond (ms). Preferably, the wave width Wb of the burst signal B is between 2 milliseconds and 500 milliseconds, for example, 10 milliseconds to 50 milliseconds. Preferably, the pulse width Wp of the pulse P is between 1 microsecond and 1 millisecond, for example, 1 microsecond to 100 microseconds.

[0076] In some embodiments, the current intensity of the electrical stimulation signal ES may be between 0.1 mA (milliampere) and 120 mA, and the voltage intensity Vo of the electrical stimulation signal ES may be between 0.05 V (volt) and 60 V. Preferably, the current intensity is between 6 mA and 40 mA. Preferably, the voltage intensity Vo is between 3 V and 20 V.

[0077] In some embodiments, the pulse P is a biphasic pulse, which is a continuous pulse with opposite polarities. The pulse P included in the biphasic pulse includes a positive phase pulse P1 and a negative phase pulse P2, the positive phase pulse P1 and the negative phase pulse P2 appear alternately, and preferably, the positive phase pulse P1 and the negative phase pulse P2 are charge balanced. In some embodiments, the pulse P can be a square wave, a sine wave, a triangle wave, or a combination thereof. In some embodiments, the burst signal B can be a square wave, a sine wave, a triangle wave, a symmetrical wave, an asymmetrical wave, or a combination thereof.

[0078] Figure 6B for Figure 1 Schematic diagram of another exemplary embodiment of an electrical stimulation signal generated by an electrical stimulator. Figure 6B In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 is an electrical stimulation signal ES2. The electrical stimulation signal ES2 is taken as an example having two interlaced burst signals B1 and B2, wherein the burst signal B1 and Fig. 6AThe same as the burst signal B in the example, and its waveform is indicated by a solid square, which is not described here; and the burst frequency of the burst signal B2 is also between 0.1Hz and 1,000Hz, preferably, the burst frequency of the burst signal B2 is less than or equal to the burst frequency of the burst signal B1. Here, the burst signals B1 and B2 appear alternately in a ratio of 1:1.

[0079] In some embodiments, the burst signal B2 includes a plurality of positive phase pulses P3 or a plurality of negative phase pulses P4. Figure 6B , the electrical stimulation signal ES2 includes two types of burst signals B2, the first type of burst signal B2 includes a plurality of positive phase pulses P3, and the second type of burst signal B2 includes a plurality of negative phase pulses P4, the two types of burst signals B2 have the same waveform but opposite phases. The pulse frequency range of the positive phase pulse P3 and the negative phase pulse P4 is between 1kHz and 1,000kHz, preferably, the pulse frequency range of the positive phase pulse P3 and the negative phase pulse P4 is between 1kHz and 300kHz. Preferably, the pulse frequency of the positive phase pulse P3 or the negative phase pulse P4 included in the burst signal B2 is less than the pulse frequency of the pulse P included in the burst signal B1. For example, the pulse frequency of the positive phase pulse P3 or the negative phase pulse P4 of the burst signal B2 is less than 1 / 3 times the pulse frequency of the pulse P of the burst signal B1.

[0080] In some embodiments, the width Wb2 of the burst signal B2 is also between 1 millisecond (ms) and 10 seconds. Preferably, the width Wb2 of the burst signal B2 is between 2 milliseconds and 500 milliseconds, such as 5 milliseconds to 100 milliseconds.

[0081] In some embodiments, the pulse widths Wp1 and Wp2 of the positive phase pulse P3 and the negative phase pulse P4 are also between 1 microsecond (μs) and 1 millisecond (ms). Preferably, the pulse widths Wp1 and Wp2 of the positive phase pulse P3 and the negative phase pulse P4 are between 3.3 microseconds and 1 millisecond, for example, 1 microsecond. The pulse frequencies and pulse widths Wp1 and Wp2 of the positive phase pulse P3 and the negative phase pulse P4 can be the same or different. Here, the same is taken as an example. Therefore, within a unit time, the charge of the positive phase pulse P3 will be equal to the charge of the negative phase pulse P4, which can achieve delayed charge balance and reduce the phenomenon of electrode corrosion (erosion) due to polarization.

[0082] In some embodiments, when the charge accumulated in a single phase of the positive phase pulse P3 or the negative phase pulse P4 of the burst signal B2 is greater than or equal to 20 μC (microcoulombs), it can be sensed by the organism 20 (the user using the electrical stimulation device 10), such as a jumping feeling, a shaking feeling, or a tingling feeling, so that the organism 20 can know that electrical stimulation is in progress.

[0083] Figure 6C for Figure 1 A schematic diagram of another exemplary embodiment of an electrical stimulation signal generated by an electrical stimulator. Figure 6C . In some embodiments, the electrical stimulation device 10 has two output terminals CH1 and CH2. In this embodiment, the two output terminals CH1 and CH2 respectively output the electrical stimulation signal ES2, and the electrical stimulation signal ES2 does not overlap in output time of the two output terminals CH1 and CH2 during each burst signal or each pulse on period within the cycle time t. For example, the on period of the burst signal B1 and the burst signal B2 of the output terminal CH1 does not overlap with the on period of the burst signal B1 and the burst signal B2 of the output terminal CH2. In this embodiment, the voltage or current interference of the two output terminals CH1 and CH2 when outputting the electrical stimulation signal ES2 is reduced, thereby avoiding unstable output of the two output terminals CH1 and CH2. For example, please refer to Figure 5 The electrical stimulation device 10c may include two electrode wires 112 ( Figure 5 Only one electrode wire 112 is shown, and the other electrode wire 112 is not shown), which corresponds to two output terminals CH1 and CH2 respectively, so as to output the electrical stimulation signal ES2 to the multiple ring electrodes 113 on the two electrode wires 112, and output the bipolar electrical stimulation signal ES2.

[0084] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 can reduce pain related neuropeptides, nerve inflammation information, and / or neuropathic pain signals in the biological body 20 .

[0085] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 reduces the COX-2 content of the organism 20. In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 suppresses the COX-2 content of the organism 20. In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 reduces the COX-2 content by suppressing the protein of COX-2 and the gene expression of the protein. In some embodiments, the reduction of the COX-2 content of the organism 20 occurs within 24 hours after the target area T receives the electrical stimulation signal ES. In some embodiments, the cumulative time that the electrical stimulator 12 generates the electrical stimulation signal ES is less than or equal to 12 hours per day, and the reduction of the COX-2 content of the organism 20 can be achieved.

[0086] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 reduces the content of brain-derived neurotrophic factor (BDNF) and / or substance P in the biological body 20 .

[0087] In some embodiments, the electrical stimulator 12 utilizes the electrical stimulation signal ES via the electrode assembly 11 to suppress the neural inflammatory response of the organism 20 .

[0088] In some embodiments, the electrical stimulator 12 uses the electrical stimulation signal ES to suppress and / or relieve pain in the organism 20. In some embodiments, the electrical stimulator 12 uses the electrical stimulation signal ES via the electrode assembly 11 to suppress and / or relieve the generation of neuropathic pain signals in the organism 20. In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 suppresses and / or relieves pain in at least a portion of the nerve conduction path to which the target area T belongs. In some embodiments, the pain in the organism 20 may be acute pain or chronic pain.

[0089] In some embodiments, the duration of the electrical stimulation signal ES generated by the electrical stimulation device 10 is at least 3 minutes to 60 minutes. In some embodiments, the duration of the electrical stimulation signal ES generated by the electrical stimulation device 10 is 5 minutes to 60 minutes, 5 minutes to 30 minutes, or 5 minutes to 20 minutes. Preferably, the duration of the electrical stimulation signal ES generated by the electrical stimulation device 10 is 15 minutes.

[0090] In some embodiments, the electrical stimulation device 10 generates the electrical stimulation signal ES for a cumulative time of less than or equal to 12 hours per day, preferably less than 10 hours, 8 hours, 6 hours, 4 hours, 2 hours or 1 hour, to achieve the effects of pain relief, symptom relief, desensitization of overactive nerves, or relief of overreaction. In other words, after the organism 20 receives the electrical stimulation signal ES for less than or equal to 12 hours, the electrical stimulation signal ES relieves the pain of the organism 20, relieves the symptoms of the organism 20, reduces the sensitivity of the overactive nerves of the organism 20, or relieves the overreaction of the organism 20.

[0091] In some embodiments, the electrical stimulator 12 utilizes the electrical stimulation signal ES to continuously suppress and / or relieve pain of the organism 20 for a specific time via the electrode assembly 11. In some embodiments, the specific time is at least one hour, one hour to five days, one hour to four days, at least one day, one day to five days, or one day to four days.

[0092] In some embodiments, the target region T is the dorsal root ganglion.

[0093] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 has the effect of inhibiting and / or relieving acute pain, chronic pain, local pain, spasticity, renal hypertension, overactive bladder, palmar hyperhidrosis, premature ejaculation (PE), or diseases or symptoms caused by nerve sensitization.

[0094] Experiment 1: Animal Experiment-Mechanical Allodynia Assessment Test

[0095] A. Test process:

[0096] (1) Establishment of rat CCI model

[0097] The sciatic nerve of the left hind paw of normal rats (Sprague Dawley, SD) was ligated with 5-0 nylon thread, and the controllable force (6g rope tension) was monitored by computer to establish a chronic constriction injury (CCI) model. The compressive neuropathy of the CCI model has significant and persistent mechanical allodynia and increased neuroinflammation. Among them, the CCI model treated with nerve injury is the CCI group, which is divided into CCI-UHF group and CCI+UHF group, with 6 mice in each group. The establishment of the CCI model can also refer to the literature of Chen et al. (Chen et al., 2020).

[0098] (2) First ultra-high frequency electrical stimulation treatment T1

[0099] 7 days after the establishment of the CCI model, an electrical stimulation device (StimOn GM2439; Gimer Medical Co., Ltd., Taiwan, China) was placed on the skin above the sciatic nerve of rats in the CCI+UHF group and treated with an ultra-high frequency electrical stimulation signal for 15 minutes. Among them, the electrode pads of the electrical stimulation device were firmly attached to the skin above the sciatic nerve (lesion site). The ultra-high frequency electrical stimulation signal includes multiple burst signals, and the burst signal includes multiple pulses. The burst frequency of the burst signal is 2Hz, the pulse frequency of the pulse is 500kHz, and the voltage intensity of the electrical stimulation signal is approximately ±6.6V. The duration of the electrical stimulation signal is 15 minutes. Rats in the CCI-UHF group did not undergo the first ultra-high frequency electrical stimulation treatment T1.

[0100] (3) Second ultra-high frequency electrical stimulation treatment T2

[0101] Four days after the first ultrahigh frequency electrical stimulation treatment T1, the rats in the CCI+UHF group received the second ultrahigh frequency electrical stimulation treatment T2. The treatment process was the same as the process of the first ultrahigh frequency electrical stimulation treatment T1 described above (2), and will not be repeated here. Among them, the rats in the CCI-UHF group did not receive the second ultrahigh frequency electrical stimulation treatment T2.

[0102] (4) Mechanical allodynia assessment test

[0103] The monofilament tactile allodynia test (von Frey test) was used to measure the threshold force (withdrawal threshold) required to cause the paw of rats in the CCI-UHF group and the CCI+UHF group to withdraw their paws to obtain the rats' plantar tolerance and to evaluate the mechanical allodynia state of normal rats. Semmes-Weinstein monofilament (SWM; North Coast Medical Inc., USA) was used to poke the underside of the rat's hind paw. During the test, each rat underwent two monofilament tactile allodynia tests, with an interval of at least 10 to 15 minutes between the two monofilament tactile allodynia tests.

[0104] A mechanical allodynia assessment test was performed on the rats in the CCI-UHF group and the CCI+UHF group before the establishment of the CCI model, 7 days after the establishment of the CCI model and before electrical stimulation, 30 minutes, 1 day, 2 days, 3 days, 4 days and 5 days after the first ultrahigh frequency electrical stimulation treatment T1, and 30 minutes, 1 day, 2 days, 3 days, 4 days and 5 days after the second ultrahigh frequency electrical stimulation treatment T2.

[0105] Among them, the retraction threshold measured before the establishment of the CCI model is the retraction threshold on day -7. The retraction threshold measured 7 days after the establishment of the CCI model and before the electrical stimulation treatment is the retraction threshold on day 0. The retraction threshold measured after the first ultra-high frequency electrical stimulation treatment T1 is the retraction threshold 30 minutes, 1 day, 2 days, 3 days, 4 days and 5 days after the first ultra-high frequency electrical stimulation treatment T1. The retraction threshold measured after the second ultra-high frequency electrical stimulation treatment T2 is the retraction threshold 30 minutes, 1 day, 2 days, 3 days, 4 days and 5 days after the second ultra-high frequency electrical stimulation treatment T2.

[0106] (5) Statistical analysis

[0107] The withdrawal thresholds between the groups were compared by Student's t test, and the groups were analyzed. The withdrawal thresholds were expressed as mean standard deviation, **** indicates that the CCI+UHF group was statistically significant compared with the CCI-UHF group, p<0.0001; ++++ indicates that the CCI+UHF group at different time points was statistically significant compared with the CCI+UHF group on day 0, p<0.0001.

[0108] B. Test results:

[0109] See also Figure 7 . On day -7, before the establishment of the CCI model, the withdrawal threshold of the CCI-UHF group was 5.77±1.39g, while that of the CCI+UHF group was 6.86±1.40g. On day 0, 7 days after the establishment of the CCI model and before the electrical stimulation, the withdrawal threshold of the CCI-UHF group was 0.45±0.068g, while that of the CCI+UHF group was 0.48±0.087g. 30 minutes after the first ultra-high frequency electrical stimulation treatment T1, the withdrawal threshold of the CCI+UHF group was 8.64±0.73g. 3 days after the first ultra-high frequency electrical stimulation treatment T1, the withdrawal threshold of the CCI+UHF group was 10.25±2.68g. 4 days after the first ultra-high frequency electrical stimulation treatment T1 (before the second ultra-high frequency electrical stimulation treatment T2), the withdrawal threshold of the CCI+UHF group was 0.55±0.20g. Then, 4 days after the first UHF electrical stimulation treatment T1, the second UHF electrical stimulation treatment T2 was performed, and 30 minutes after the second UHF electrical stimulation treatment T2, the withdrawal threshold of the CCI+UHF group was 8.53±0.89g. 5 days after the second UHF electrical stimulation treatment T2, the withdrawal threshold of the CCI+UHF group was 0.34±0.17g. On the other hand, the withdrawal threshold of the CCI-UHF group was maintained at about 0.45±0.068g for 2 weeks.

[0110] It can be seen that ultra-high frequency electrical stimulation can relieve mechanical allodynia caused by nerve injury. Moreover, the first ultra-high frequency electrical stimulation T1 can make the decreased retraction threshold last for 3 days, while the second ultra-high frequency electrical stimulation T2 can make the decreased retraction threshold last for 4 days. Ultra-high frequency electrical stimulation inhibits and / or relieves mechanical allodynia that lasts for at least about 4 days. The electrical stimulation signal generated by the electrical stimulator has the effect of relieving and / or inhibiting neuropathic pain caused by nerve injury.

[0111] Experiment 2: Animal experiment-neuronal damage experiment

[0112] A. Test process:

[0113] (1) First ultra-high frequency electrical stimulation treatment T1

[0114] Normal rats (Sprague Dawley, SD) without injury treatment were the control group (Ctrl group), which were divided into Ctrl-UHF group (4 rats) and Ctrl+UHF group (3 rats). The electrical stimulation device (StimOn GM2439; Gimer Medical Co., Ltd., Taiwan, China) was placed on the skin above the sciatic nerve of the rats in the Ctrl+UHF group and treated with ultra-high frequency electrical stimulation signals for 15 minutes. Among them, the electrode pads of the electrical stimulation device were firmly attached to the skin above the sciatic nerve. The ultra-high frequency electrical stimulation signal includes multiple burst signals, and the burst signal includes multiple pulses. The burst frequency of the burst signal is 2Hz, the pulse frequency of the pulse is 500kHz, the voltage intensity of the electrical stimulation signal is about ±6.6V, and the duration of the electrical stimulation signal is 15 minutes. The pulse is a symmetrical biphasic sine wave. In addition, the rats in the Ctrl-UHF group did not undergo the first ultra-high frequency electrical stimulation treatment T1.

[0115] (2) Second ultra-high frequency electrical stimulation treatment T2

[0116] Four days after the first ultrahigh frequency electrical stimulation treatment T1, the rats in the Ctrl+UHF group were subjected to the second ultrahigh frequency electrical stimulation treatment T2. The treatment process was the same as the process of the first ultrahigh frequency electrical stimulation treatment T1 described above (1), and will not be repeated here. Among them, the rats in the Ctrl-UHF group did not undergo the second ultrahigh frequency electrical stimulation treatment T2.

[0117] (3) Immunofluorescence staining test

[0118] 14 days after the first UHF electrical stimulation treatment T1, the middle segments of the sciatic nerves of the left hind paws of rats in the Ctrl+UHF and Ctrl-UHF groups were removed for immunofluorescence staining of myelin basic protein (MBP) and neurofilament-200 (NF200).

[0119] Immunofluorescence staining was performed according to the general immunofluorescence (IF) protocol. The staining reagents included mouse anti-neurofilament heavy polypeptide (1:200; Catalog No. N0142, Sigma-Aldrich, USA) and rabbit anti-MBP (1:200; Catalog No. GTX133108, GeneTex, USA) as primary antibodies, and goat anti-mouse IgG (1:200; GeneTex, Catalog No. GTX213111-05) as secondary antibody for NF200.

[0120] (4) Quantification of staining results

[0121] After staining, a fluorescence microscope (model BX61, purchased from Olympus, Japan) was used to observe and photograph, and the images were analyzed using ImageJ software (version 1.53s, NIH, USA) to obtain the protein content of MBP and NF200. ImageJ software calculates the fluorescence signal per pixel. Among them, MBP is used as a staining marker for Schwannn cells, and NF200 is used as a staining marker for mature axons.

[0122] (5) Statistical analysis

[0123] The content of MBP, the content of NF200, and the fluorescence staining results of MBP and NF200 were compared between the groups by Student's t test, and each group was analyzed. The content of MBP, the content of NF200, and the fluorescence staining results of MBP and NF200 were expressed as mean standard deviation (SD). ns indicates that there is no significant difference between the Ctrl+UHF group and the Ctrl-UHF group.

[0124] B. Test results:

[0125] See also Fig. 8A , Figure 8B , Figure 8C as well as Fig. 9 There were no significant differences in the content of MBP, the content of NF200, and the fluorescence staining results of MBP and NF200 between the Ctrl+UHF group and the Ctrl-UHF group.

[0126] It can be seen that the number of myelinated axons in the uninjured nerves of rats treated with ultra-high frequency electrical stimulation is not significantly different from that of the uninjured nerves of rats not treated with ultra-high frequency electrical stimulation. Ultra-high frequency electrical stimulation does not damage axons and Schwann cells in uninjured nerves.

[0127] Experiment 3: Animal experiment-neuromodulation experiment

[0128] A. Test process:

[0129] (1) Establishment of rat CCI model

[0130] The sciatic nerve of the left hind paw of normal rats (Sprague Dawley, SD) was ligated with 5-0 nylon thread, and the controllable force (6g rope tension) was monitored by computer to establish a chronic constriction injury (CCI) model. The compressive neuropathy of the CCI model has significant and persistent mechanical allodynia and increased neuroinflammation. Among them, the CCI model treated with nerve injury is the CCI group, and the normal rats without injury treatment are the control group (Ctrl group). The CCI group is divided into CCI-UHF group and CCI+UHF group. The Ctrl group is the Ctrl-UHF group. The establishment of the CCI model can also refer to the literature of Chen et al. (Chen et al., 2020).

[0131] (2) Ultra-high frequency electrical stimulation

[0132] 7 days after the establishment of the CCI model, an electrical stimulation device (StimOn GM2439; Gimer Medical Co., Ltd., Taiwan, China) was placed on the skin above the sciatic nerve of rats in the CCI+UHF group and treated with an ultra-high frequency electrical stimulation signal for 15 minutes. Among them, the electrode pads of the electrical stimulation device were firmly attached to the skin above the sciatic nerve (lesion). The ultra-high frequency electrical stimulation signal includes multiple burst signals, and the burst signal includes multiple pulses. The burst frequency of the burst signal is 2Hz, the pulse frequency of the pulse is 500kHz, and the voltage intensity of the electrical stimulation signal is about ±6.6V. The duration of the electrical stimulation signal is 15 minutes.

[0133] Rats in the CCI-UHF and Ctrl-UHF groups were not treated with UHF electrical stimulation.

[0134] (3) Immunofluorescence staining test

[0135] On the day after the CCI model was established, the left L4-L5 dorsal root ganglion (DRG) of rats in the Ctrl-UHF group (without nerve injury or electrical stimulation) was removed for immunofluorescence staining.

[0136] Seven days after the establishment of the CCI model, the left L4-L5 DRG of rats in the CCI-UHF group (within nerve injury but not electrical stimulation) were removed for immunofluorescence staining.

[0137] One day after the UHF electrical stimulation, the left L4-L5 DRG of the rats in the CCI+UHF group was removed for immunofluorescence staining, which was the CCI+UHF1-day group. Five days after the UHF electrical stimulation, the left L4-L5 DRG of the rats in the CCI+UHF group was removed for immunofluorescence staining, which was the CCI+UHF5-day group.

[0138] The immunofluorescence staining experiment was carried out according to the general immunofluorescence staining (IF) experiment process. The staining reagents included rabbit anti-c-FOS antibody (purchased from GeneTex), rabbit anti-brain-derived neurotrophic factor (BDNF) antibody (purchased from Elabscience), rabbit anti-COX-2 antibody (purchased from Elabscience), rabbit anti-c-Myc antibody (purchased from GeneTex), guinea pig anti-SP antibody (purchased from GeneTex) and rabbit anti-MEK antibody (purchased from GeneTex) as primary antibodies, and goat anti-guinea pig IgG antibody (purchased from GeneTex) as secondary antibodies for SP and goat anti-rabbit IgG antibody (purchased from GeneTex) as secondary antibodies for BDNF, COX-2, c-Myc, MEK and c-FOS. antirabbit IgG antibody, purchased from GeneTex).

[0139] After staining, a fluorescence microscope (model BX61, purchased from Olympus, Japan) was used to observe and photograph, and the images were analyzed using ImageJ software (version 1.53s, NIH, USA) to obtain the content ratios of pain-related neuropeptides BDNF, c-Myc, and COX-2, as well as neuroinflammatory information SP, MEK (Mitogen-activated protein kinase (MAPK) kinase) and c-Fos. The stronger the fluorescence signals of c-Fos, BDNF, COX-2, c-Myc, SP, and MEK, the neurons were positively labeled by the antibodies corresponding to these proteins. The higher the proportion of positive neurons for c-Fos, BDNF, COX-2, c-Myc, SP, and MEK to the total neurons, the higher the content of c-Fos, BDNF, COX-2, c-Myc, SP, and MEK.

[0140] (5) Statistical analysis

[0141] The experimental data between the groups were compared by Student's t test, and the experimental data were analyzed for each group. The experimental data were expressed as mean standard deviation (SD), * indicates p < 0.05; ** indicates p < 0.01, *** indicates p < 0.001, **** indicates p < 0.00001, and ns indicates no significant difference.

[0142] B. Test results:

[0143] See also Fig.10 and Fig.11 , the percentage of BDNF-positive neurons in the CCI-UHF group was 29.98%±3.79%, that in the CCI+UHF1-day group was 12.95%±1.71%, and that in the CCI+UHF5-day group was 24.66%±13.85%.

[0144] That is to say, nerve injury treatment significantly increases BDNF content, and after ultra-high frequency electrical stimulation treatment, the BDNF content of the CCI+UHF1-day group decreased significantly. The BDNF content of the CCI+UHF5-day group returned to the BDNF content of the group that had undergone nerve injury but not electrical stimulation treatment (CCI-UHF group), and there was no significant difference from the CCI-UHF group.

[0145] See also Fig.12 and Fig.13In addition to BDNF, c-Myc and COX-2 also have the same trend. Nerve injury treatment significantly increases the levels of c-Myc and COX-2, while ultra-high frequency electrical stimulation treatment can significantly reduce the levels of c-Myc and COX-2 and can last for at least 4 days. Figures 14 to 16 In addition, substance P(SP), MEK and c-Fos also showed similar trends. After nerve injury, substance P(SP), MEK and c-Fos levels increased significantly, while after UHF electrical stimulation, the levels of substance P(SP), MEK and c-Fos in the CCI+UHF1-day group decreased significantly, and the decrease could continue at least until 5 days after UHF electrical stimulation.

[0146] The percentage of positive neurons of c-Myc, COX-2, substance P (SP), MEK and c-Fos in each group is shown in Table 1 below and will not be described in detail here.

[0147] Table 1

[0148]

[0149] It can be seen that ultra-high frequency electrical stimulation can reduce the levels of pain-related neuropeptides BDNF, COX-2 and c-Myc and can last for at least 4 days. Ultra-high frequency electrical stimulation can reduce the levels of neuroinflammatory information SP, MEK and c-FOS and can last for at least 5 days.

[0150] The electrical stimulation signals generated by the electrical stimulator have the effect of reducing pain-related neuropeptides and improving inflammatory information, which can improve neuropathic pain.

[0151] Among them, BDNF is essential for neuronal survival, differentiation, and regulation of synaptic strength, and is involved in the mechanism of inflammatory pain. BDNF is considered a neuromodulator and plays an important role in spinal plasticity. In addition, the levels of BDNF and its downstream signaling proteins (such as MEK, c-Myc, and c-FOS) are downregulated after ultra-high frequency electrical stimulation. The electrical stimulation signal generated by the electrical stimulator can inhibit and / or neuroinflammation and inhibit and / or relieve neuropathic pain by regulating the BDNF / MAPK-mediated pain conduction pathway.

[0152] COX-2 levels are related to the occurrence and maintenance of neuropathic pain. Prostaglandins synthesized by COX-2 are involved in the pathogenesis of inflammatory reactions and neuropathic pain. The electrical stimulation signal generated by the electrical stimulator can inhibit and / or relieve pain, or inhibit and / or relieve inflammatory reactions by inhibiting the production of COX-2. Among them, the reduction in COX-2 content is not limited to the site of DRG, but anywhere that COX-2 content can be detected, such as blood, saliva, urine, feces, cerebrospinal fluid, and other sampleable biological samples. The detection method may include ELISA (enzyme-bound immunosorbent assay), immunofluorescence staining, or other immunological methods.

[0153] SP can bind to its specific receptor neurokinin-1 (NK-1), sensitizing neurons and producing pain. The electrical stimulation signal generated by the electrical stimulator can inhibit and / or relieve pain by inhibiting SP production.

[0154] This experiment proves that the neuropeptides BDNF, c-Myc, and COX-2, which increase in content due to pain or inflammation, and the nerve inflammation information SP, MEK and c-Fos, can cause a significant decrease in content after 15 minutes of ultra-high frequency electrical stimulation. This has a similar effect to general anti-inflammatory drugs or analgesics, and becomes an electronic medicine, and should be related to the regulation of BDNF / MAPK (Mitogen-activated protein kinase). Moreover, some nerve information (SP, MEK and c-Fos) can be suppressed for up to five days even after only one 15-minute ultra-high frequency electrical stimulation. In this way, it is possible to reduce the use of analgesics by using the electrical stimulation device or electrical stimulation method of any embodiment, thereby reducing the side effects of taking medicine and even the risk of dialysis.

[0155] In summary, according to any embodiment, the electrical stimulation device or the electrical stimulation method has the effect of reducing COX-2 without causing nerve damage. The electrical stimulation device or the electrical stimulation method has the effect of reducing the content of brain-derived neurotrophic factor, reducing the content of substance P, inhibiting nerve inflammation, relieving and / or inhibiting pain, relieving symptoms, reducing nerve sensitivity, or relieving overreaction, and does not cause nerve damage. The electrical stimulation device or the electrical stimulation method has the effect of reducing protein content by regulating protein and protein gene expression to achieve the effect of regulating nerves.

[0156] Of course, the present invention may have many other embodiments. Without departing from the spirit and essence of the present invention, technicians familiar with the field may make various corresponding changes and deformations based on the present invention, but these corresponding changes and deformations should all fall within the scope of protection of the claims of the present invention.

Claims

1. An electrical stimulation device, characterized in that: Include: Electrode assembly; as well as an electrical stimulator, coupled to the electrode assembly and generating an electrical stimulation signal; The electrical stimulation signal is transmitted to the target area of ​​the organism via the electrode assembly, the electrical stimulation signal comprises a plurality of burst signals, the burst frequency of the plurality of burst signals ranges from 0.1 Hz to 1,000 Hz, each of the burst signals comprises a plurality of pulses, the pulse frequency of the plurality of pulses ranges from 1 kHz (kilohertz) to 1,000 kHz, and the electrical stimulation signal is used to reduce the cyclooxygenase-2 content of the organism.

2. The electrical stimulation device according to claim 1, characterized in that The electrical stimulation signal reduces the COX-2 level by inhibiting the COX-2 protein expression.

3. The electrical stimulation device according to claim 1, characterized in that The reduction in the cyclooxygenase-2 level in the organism occurs within 24 hours after the target area receives the electrical stimulation signal.

4. The electrical stimulation device according to claim 1, characterized in that The cumulative time that the electrical stimulator generates the electrical stimulation signal is less than or equal to 12 hours per day.

5. The electrical stimulation device according to claim 1, characterized in that The electrical stimulation signal is further used to reduce the content of brain-derived neurotrophic factor (BDNF) and / or substance P (substance P) in the organism.

6. The electrical stimulation device according to claim 1, characterized in that The electrical stimulator utilizes the electrical stimulation signal to inhibit the neural inflammatory response of the organism.

7. The electrical stimulation device according to claim 1, characterized in that The electrical stimulation signal is used to suppress and / or relieve pain in at least a portion of the nerve conduction pathway to which the target area belongs.

8. The electrical stimulation device according to claim 1, characterized in that After the organism receives the electrical stimulation signal for less than or equal to 12 hours, the electrical stimulation signal relieves the pain of the organism, relieves the symptoms of the organism, reduces the nerve sensitivity of the organism, or relieves the overreaction of the organism, and lasts for at least 1 hour.

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