PRIORITY CLAIM

[QQQ1] This application claims the benefit of the filing date of U.S. Patent Application Serial No. 16/137,440, filed September 20, 2018, the disclosure of which is incorporated herein in its entirety by this reference.

FIELD

[0002] The application relates generally to the field of medical devices and associated treatments, and more specifically to precise bioelectrical stimulation of a subject’s tissue useful to control, manage, and/or modulate the subject’s blood pressure.

BACKGROUND

[0003] Blood pressure is simply the physical pressure of blood in the blood vessels. It is similar to the concept of air pressure m a car tire. A common blood pressure might he 120/80 (stated as“120 over 80”). These values are quoted in units known as millimeters of mercury (mm! lg). There are two numbers because the blood pressure varies with the heartbeat. The higher pressure (e.g., 120) represents the pressure in the arteries when the heart beats, pumping blood into the arteries. This pressure is called systolic pressure. The lower pressure (80) represents the pressure in the arteries when the heart is relaxed between beats. This pressure is called“diastolic pressure.”

[0004] Blood pressures differ between individuals. Some people have low', some average and some high blood pressure levels.

[0005] There are various definitions of high blood pressure, which is also known as hypertension, but most doctors consider blood pressures of 140/90 and greater to be high. The precise values that doctors might interpret as high blood pressure depend to an extent on individual circumstances. For example, in patients with diabetes, the definition of hypertension is considered by some to be pressures greater than 130/80.

[0006] Left unchecked, high blood pressure will over the years cause damage to the blood vessels of the subject’s heart and brain that leads to heart attacks and strokes. It also pl aces extra strain on the heart, causing thickening of the heart muscle and heart failure and it damages the kidneys and can lead to kidney failure. [0007! Hypertension is a large burden to patient health and health care costs. Despite various options, more 30% of patients do not respond sufficiently to medical treatment. Meehan oreceptors in the aortic arch relay blood pressure (BP) levels through vagal nerve (VN) fibers to the brainstem and trigger the baroreflex, lowering the BP. Selecti v e electrical stimulation of these nerve fibers reduced BP in rats.

[0008] More than 1 billion people suffer from high blood pressure worldwide. Blood pressure levels have been shown to be positively and continuously related to the risk for stroke and coronary heart disease. In some age groups, the risk of cardiovascular disease doubles for each increment of 20/10 mrnHg of blood pressure, starting as low as 115/75 mmHg. in addition to coronary heart diseases and stroke, complications of raised blood pressure include heart failure, peripheral vascular disease, renal impairment, retinal hemorrhage and visual impairment. Treating systolic blood pressure and diastolic blood pressure until they are less than 140/90 mmHg is associated with a reduction in cardiovascular complications.

DISCLOSURE

[0009] Described are a system and method that utilize bioelectric signaling to balance electrical potentials m a subject’s body via neuro-hormonal circuit loops, to increase elasticity of the subject’s arteries to promote protein release to dampen arterial blood pressure, and to change arterial electrical charges to reduce narrowing of the arteries.

[QQ1Q] The described system is designed to localize and stimulate the fibers inside the VN without inadvertent stimulation of non-baroreceptive fibers causing side effects like bradycardia and bradypnea. The system also controls release of specific proteins known to lower blood pressures including tropoelastin (known to increase elasticity in the aorta and other peripheral blood vessels).

[0011] Bioelectric stimulation as described herein is thought to address two known root causes of hypertension. First, loss of arterial compliance and, second, imbalance of electrical potentials within the body. The system and method are designed to reduce loss of arterial compliance by controlled release of a number of growth factors that promote increased elasticity in the arteries including tropoelastin, SDF-l , VEGF, IGF-1 , PDGF and HGF.

[0012] A theory exists that during a hypertension prophase episode, there may appear abnormal movement for cell membrane ions, the pathological electric potentials. This electrical abnormality of blood vessel signal controls may then be followed by the phenomena of slowed blood flow, small artery spasms, and increased blood vessel compliance resistance, finally leading to the rise of blood pressure

[0013] The bioelectric signals sequence for lowering blood pressure is designed to be applied to the subject’s body with its transmitted bioelectric signals intended to activate the bioelectric circuits in the body, changing abnormal current flow patterns back to normal. It is designed to directly adjust the pathological electrical ionic membrane potentials, arterial muscle cells, and relieve small artery spasm. The intent is also to strengthen red blood ceil surface repulsion to reduce blood magnetic viscosity, and thus lower vessel and blood stream flow resistance. The described system and method are designed to additionally then lead to continued regulation and integration in attempting to clear and dissolve cholesterol and neutral fat deposited on the tunica inti a of arteries to remove stasis in the blood vessels. Thus, system and methods are not only designed for acute decreases in blood pressure, but also to maintain a continuous effect for long term action m attempting to address the root causes of hypertension and thus many secondary to hypertension related cardiovascular diseases.

[0014] The described system and method are designed to address high blood pressure m a subject via three primary means.

[0015] First, bioelectric signaling to the brain’s blood pressure control center and send closed feedback loop real time. The stimulators of the system may he placed in any innervated area such as the forearm. Placed just under the skin, they are designed to activate bioelectrical signaling via the nervous system. The system’s stimulator(s) sense and send bioelectrical signals to modulate the subject’s blood pressure. The system emits very low- power, natural level, bioelectric stimulation sequences that communicate with the subject’s brain. These bioelectric signals travel to the hypothalamus midbrain, and the medulla; the signal has multiple pathways to the brain’s blood pressure control center. This bioelectric signaling in a closed feedback loop is designed to modulate and normalize blood pressure. The system is the only one known at this time that senses real time the needs of the subject, and then adjusts the bioelectric signaling to meet the individual’s needs for blood pressure control on a real time basis.

[0016] Second, bioelectric signaling is delivered to improve the elasticity of arteries, especially the aorta, to improve blood pressure dampening. The bioelectric stimulator controls protein expressions, such as tropoelastin, SDF1, IGF1, EGF, C-X-C Motif Chemokine Ligand 5 (“CXCL5”), and folli statin, which improve elasticity of arteries.

[QQ17] Third, bioelectric signaling is applied to the subject to prevent artery flow narrowing and spasms. The bioelectric stimulator directs the release of proteins and bioelectric signals designed to inhibit plaque and blood clot formations and artery spasms which increase blood pressure and heighten the risk of a heart attack, stroke or limb amputation. The bioelectric signals for proteins such as PDGF, SDF1, VEGF, 1 11 F l a. CXCL5, EGF, HGF and eNOS also are designed to grow new blood vessels with mature healthy endothelium linings and dilate existing blood vessels, via eNOS expression, which also can serve to lower high blood pressure.

[0018] In certain embodiments, described is a system with control with selective vagal nerve stimulation.

[0019] Tire system and method are designed to be delivered via skin surface or low depth implantable ultra-low power signal sensors and signal generating processors.

[QQ2Q] The system and method are designed to control release of proteins that improve elasticity of the aorta and other peripheral vessels so that the blood pressure has a dampening relief system within the body as is found in normal healthy subjects.

[0021] In certain embodiments, the system and method utilize low depth, implantable ultra-low power signal sensors.

[0022] Tire system seeks to develop a method for selective vagus nerve stimulation to reduce high blood pressure (hypertension) without triggering bradycardia or bradypnea.

[QQ23] In certain embodiments, baroreceptor compound activity is localized using multiple non-mvasive bioelectric sensors with information sent to a microprocessor that then delivers a customized bioelectric signaling sequence via quad polar stimulation near the barofibers. Constant feedback loops adjust and vary the stimulation pulse, width, and duration.

[0024] In certain embodiments, the system is designed to lower high blood pressure by improving elastic compliance of the aorta and other arteries and bioelectric potentials balance management throughout the body.

[Q025] Certain embodiments of devices for use with the system and methods described herein preferably have the following features. Such a device has three primary components of blood pressure control therapy. First, wireless bioelectric signals for increasing arterial compliance via controlled release of growth factors such as tropoelastin. Second, wireless bioelectric signals to manage the control of blood pressure between the brain and hormonal glands. Third, bioelectric signals delivered via the nervous and cardiovascular system to manage total body electrical potentials balance.

[0026] Described is a bioelectric stimulator including: a power source (e.g , battery, capacitor, or other suitable source of electricity), and means for delivering an electrical signal to a subject’s tissue (e.g., via electrode(s) or wirelessly). The bioelectric stimulator utilizes the electrical signal to precisely control protein expression in the tissue on demand. Such a bioelectric stimulator preferably precisely controls release of SDF-l m the subject, without diminishing effect over time.

[QQ27] Also described is a method of usin the bioelectric stimulator to control a subject’s blood pressure, the method including: delivering selected electrical signals to the organ so as to precisely control protein expressions in the right sequence and volume for total or near total blood pressure control.

[0028] A preferred system includes: a bioelectric stimulator that controls/stimulates the release/production of SDFI, 1GF1, EGF, HGF, PDGF, eNOS, VEGF, follistatin, HIFla, and/or tropoelastin in a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 depicts a programmed bioelectric stimulator depicted alongside a U.S. quarter.

[0030] FIG. 2 depicts a device according to the description.

[0031] F1G. 3 depicts an image of the signal (voltage and frequency) associated with EGF at 10 V/'cm (5 V here), 500 Hz, pulse width 180 ps, square wave.

[QQ32] FIG. 4 depicts an image of the signal (voltage and frequency) associated with follistatin at 10 V/cm, 50 Hz, square wave.

[0033] FIG. 5 depicts an image of the signal (voltage and frequency) associated with HGF at 3.5 V, 10 second burst every 30 seconds, square wave.

[0034] FIG. 6 depicts an image of the signal (voltage and frequency) associated with IGF- 1 : 3.0 mV, 22 Hz, square w-ave.

[0035] FIG. 7 depicts an image of the signal (voltage and frequency) associated with PDGF 30%: 3 V/cm (100 mV here), 10 Hz, pulse width 200 ps, square wave.

[0036] FIG. 8 depicts an image of the signal (voltage and frequency) associated with PDGF 230%: 20 V/cm (7.0 V here), 100 Hz, pulse width 100 ps, square wave. [QQ37] FIG. 9 depicts an image of the signal (voltage and frequency) associated with SDF-1: 3.5 mV, 30 Hz, square wave.

[0038] FIG. 10 depicts an image of the signal (voltage and frequency) associated with tropoelastm: 60 mV, 50 Hz, square wave.

[0039] FIG. 11 depicts an image of the signal (voltage and frequency) associated with VEGF: 100 mV, 50 Hz, square wave.

[QQ4Q] FIG. 12 depicts an image of the signal (voltage and frequency) associated with SDF-1 (2 ^nd part): 0.25 mA (3.0 V shown here), 100 Hz, 100 ps pulse width, square wave.

MODE(S) FOR CARRYING O UT THE IN VENTION

[0041] Referring now to FIG. 1, depicted is a human use bioelectric stimulator. Preferably, such a device is about the size of two quarters (available from QIG Greatbatch / Greatbatch, Inc. of Frisco, TX, US) and is programmable.

[Q042] A preferred device (FIG. 2) is about the size of a U. S. quarter dollar piece.

[QQ43] When arteries get stiff and hardened, the body loses its main natural blood pressure dampening system and high blood pressure sets in. Secondarily the bioelectric current potentials management between the brain, the hormonal gians of the body and arterial walls must be in balance for healthy blood pressure. The described device is designed to address multiple known root causes of hypertension.

[QQ44] There exists a close relationship between bioelectricity and hypertension. Bioelectric stimulation may address two known root causes of hypertension, i.e., the loss of arterial compliance and in-balance of electrical potentials within the body.

[0045] The described system and method are designed to reduce loss of arterial compliance by controlled release of a number of growth factors that promote increased elasticity' in the arteries including tropoelastin, SDF-1, VEGF, IGF-1, PDGF, and HGF.

[0046] While not intending to be bound by theory, the following might help explain the invention. A number of scientists propose the theory' that during the hypertension prophase episode, there may appear abnormal movement for cell membrane ions, the pathological electric potentials. This electrical abnormality of blood vessel signal controls may then be followed by the phenomena of slowed blood flow', small artery spasms, and increased blood vessel compliance resistance, finally leading to the rise of blood pressure. [0047! The bioelectric signals sequence described herein for lowering blood pressure is designed to be applied to the body with its transmitted bioelectric signals intended to activate the bioelectric circuits in the body changing abnormal current flow patterns back to normal. It is designed to directly adjust the pathological electrical ionic membrane potentials, arterial muscle cells, and relieve the small artery spasm. The intent is also to strengthen red blood cell surface repulsion to reduce blood magnetic viscosity , and thus lower vessel and blood stream flow resistance. The described system and method are designed to additionally then lead continued regulation and integration in attempting to clear and dissolve cholesterol and neutral fat deposited on the tunica intima of arteries to remove stasis m the blood vessels. Thus, the described syste and method are not only designed for acute decreases in blood pressure, but also to maintain a continuous effect for long term action in attempting to address the root causes of hypertension and thus many secondary to hypertension related cardiovascular diseases.

[0048J In certain embodiments, the disclosure includes a method of controlling blood pressure in a subject, the method comprising: delivering selected bioelectric signals to the subject’s tissue so as to enhance the release and/or expression of proteins that reduce the subject’s blood pressure. In such a meth, the proteins preferably comprise proteins selected from the group consisting of stromal cell-derived factor 1 (“SDF1”), vascular endothelial growth factor (“VEGF”), insulin-like growth factor 1 (‘ ^‘ IGFF’), platelet-derived growth factor (“PDGF”), tropoelaslin, hepatocyte growth factor (“TTGF”), and any combination thereof. The proteins may further include protein(s) selected from the group consisting of IGF i, epidermal growth factor (“EGF”), CXCL5, hypoxia-inducible factor 1 -alpha (“HIFla”), endothelial NOS (“eNOS”), follistatin, and a combination of any thereof. In certain embodiments, the subject’s tissue to be treated preferably comprises fiber inside the vagus nerve. Preferably, the subject’s tissue does not comprise non-baroreceptor fibers.

[0049] Generally, the system hereof involves a bioelectric stimulator controlling release of SDF-1 , IGF-l, HGF, EGF, VEGF, PDGF, eNOS, follistatin, and tropoelaslin. Optionally, other proteins and/or hormones may be included.

[QQ5Q] SDF-1 is generally for recruiting stem cells and maturing blood vessels. IGF-l is for DNA repair. FIGF is for tissue regeneration and reduces arrhythmias in the case of heart. EGF grows tissue. VEGF grows blood vessels. PDGF is a second stem cell homing factor and helps tissue regeneration especially heart. eNOS dilates blood vessels. Follistatin promotes muscle growth. Tropoelastin increases elasticity of all tissues especially arteries. skin, heart, aorta.

[0051] The micro voltage signal generator may be produced utilizing the same techniques to produce a standard heart pacemaker well known to a person of ordinary skill in the art. An exemplary microvoltage generator is available (for experimental purposes from Cal-X Stars Business Accelerator, Inc. DBA Leonhardt’s Launchpads or Leonhardt Vineyards LLC DBA Leonhardt Ventures of Salt Lake City, UT, US). The primary difference is the special electrical stimulation signals needed to control, e.g., precise follistatin release on demand (which signals are described later herein). The leading pacemaker manufacturers are Medtronic, Boston Scientific Guidant, Abbott St. Jude, BioTronik and Sorin Biomedica.

[0052] Construction of the electric signal generators and pacemakers, are known in the art and can be obtained from OEM suppliers as well as their accompanying chargers and programmers. The electric signal generators are programmed to produce specific signals to lead to specific protein expressions at precisely the right time for, e.g., optimal organ treatment or regeneration.

[0053] The pacing infusion lead may be constructed or purchased from the same suppliers that build standard heart pacemaker leads. Pacing infusion leads may be purchased from a variety' of OEM vendors. The pacing infusion lead may, for example, be a standard one currently used in heart failure pacing studies in combination with drug deliver}'.

[0054] An infusion and electrode wide area pitch may be constructed by cutting conduction polymer to shape and forming plastic into a flat bag with outlet ports in strategic locations.

[Q055] Micro stimulators may be purchased or constructed m the same manner heart pacemakers have been made since the 1960’s. The programming computer can be standard laptop computer. The programming wand customary' to wireless programming wands may be used to program heart pacers.

[0056] In certain embodiments, the bioelectric signals are delivered via skin surface or low' depth implantable ultra-low power signal sensors and signal generating processors. The system is designed to control release of proteins that improve elasticity' of the aorta and other peripheral vessels so that the blood pressure has a dampening relief system within the body as is found in normal healthy subjects.

[0057] In certain embodiments, described is a method for selective vagus nerve stimulation to reduce high blood pressure (hypertension) without triggering bradycardia or bradypnea. [QQ58] A wireless, single lumen infusion pacing lead or infusion conduction wide array patch may all be used to deliver the regeneration signals and substances to the organ of interest to be treated or they may be used m combination.

[0059 J A re-charging wand for use herein is preferably similar to the pacemaker re charging wand developed by Alfred Mann in the early 1970’s for recharging externally implantable pacemakers. In certain embodiments, described is a bioelectric stimulator for controlling blood pressure in a subject, wherein the bioelectric stimulator is configured to generate bioelectric signals responsive to a programmed process, which bioelectric signals are adapted to stimulate target tissue of the subject to express and/or release stromal cell- derived factor 1 (“SOFT”), vascular endothelial growth factor (“VEGF”), insulin-like growth factor 1 (“IGF-l”), platelet-derived growth factor (“PDGF”), tropoelastin, and hepatocyte growth factor (“HGF”).

[0060] Bioelectric signals that exhibit (within 15%) the following characteristics enhance the expression and/or release of SDF-I : (a) 0.1 V applied at a frequency of 50 Hz, square wave, (b) 0.25 mA, 3.0 V, 100 Hz, 100 ps pulse width, square wave, or (c) 3.5 mV, 30 Hz, square wave.

[0061] A preferred bioelectric signal for expressing and/or releasing SDF-i may exhibit the following characteristics (within 15%): 30 pulses per second with a voltage of 3.5 mV, and successively alternating currents of 700 to 1500 pi coamps for one minute, and again with 700 to 1500 picoamps for one minute, plus stimulated with a current of 0.25 mA, pulse duration of 40 pulses per second, pulse width of 100 its, and frequency of 100 Hz, each signal for 40 minutes to 8 hours a day.

[QQ62] A bioelectric signal for expressing and/or releasing VEGF may exhibit the following characteristics (within 15%): 0.1 V appli ed at a frequency of about 50 Hz, square wave, with a duration of about three (3) minutes.

[0063] A bioelectric signal for expressing and/or releasing IGF-l may exhibit the following characteristics (within 15%): 3 mV with a frequency of about 22 Hz, square wave, and a current of about 1 mA for about fifteen (15) minutes and 3 mA for about fifteen (15) minutes (duration 5 minutes).

[QQ64] A bioelectric signal for expressing and/or releasing PDGF may exhibit the following characteristics (within 15%): 3 V/cm, 10 Hz, 2 pA (0.000002 amps), and pulse duration of 0.2 ms, or 20 V/cm, 100 Hz, 0.25 mA (2.5e-7 amps), and pulse duration of 40 pulses/s, width of 100 ps. [Q065] A bioelectric signal for expressing and-' or releasing tropoelastin may exhibit the following characteristics (within 15%): 0.06 V with 50 Hz, square wave, alternating electrical field and a current of about 1 mA for about fifteen (15) minutes and 3 raa for about fifteen (15) minutes (duration 2 minutes).

[00661 A bioelectric signal for expressing and/or releasing HGF may exhibit the following characteristics (within 15%): 3.5 V stimulation in 10 second bursts, 1 burst every 30 seconds at a frequency of about 50 Hz, square wave, (duration 5 minutes).

[Q067] The bioelectric stimulator may be further configured to generate bioelectric signals responsive to a programmed process, which bioelectric signals are adapted to stimulate target tissue of the subject to express and/or release epidermal growth factor (‘HGF”), wherein the bioelectric signal for expressing and/or releasing EGF exhibits the following characteristics (within 15 %) : 5 V/cm or 10 V/'cm, pulse-width 180 ps, 500 Hz, square wave, (duration nine (9) minutes).

[QQ68] The bioelectric stimulator may be further configured to generate bioelectric signals responsive to a programmed process, which bioelectric signals are adapted to stimulate target tissue of the subject to express and/or release endothelial NOS (“eNOS”), wherein the bioelectric signal for expressing and/or releasing eNOS exhibits the following characteristics (within 15%): alternating high-frequency and medium-frequency signals, symmetric, biphasic, trapezoid pulses, with 400-ps pulse duration and 1.5/1 -s ramp-up/ramp- down duration, respectively.

[QQ69] The bioelectric stimulator may be further configured to generate bioelectric signals responsive to a programmed process, which bioelectric signals are adapted to stimulate target tissue of the subject to express and/or release follistatin, wherein the bioelectric signal for expressing and/or releasing follistatin exhibits the following characteristics (within 15%): 10 V at 50 Hz, square wave, and 100 Hz for about 12 hours each (duration 1 minute).

[0070] The bioelectric stimulator may include an electrode or electrodes for delivering bioelectric signal(s) to the subject.

[QQ71] The bioelectric stimulator may include a transducer and/or transceiver, wherein the transducer and/or transceiver is configured for delivering bioelectric signal(s) wirelessly to the subject.

[0072] Bioelectric stimulation can be done with a microstimulator having, e.g., a pacing infusion lead with a corkscrew lead placed/attached in or on the subject’s tissue. Alternatively, wireless delivery may be accomplished.

[QQ73] In certain embodiments (not shown), the bioelectric stimulator takes the form of a wrist watch (or is incorporated into a so-called‘"smart watch”), and the bioelectric signals are delivered (e.g., wirelessly) to a subject wearing the wrist watch.

[00741 The microstimulator is actuated and runs through programmed signals to signal the release of, e.g., SDF-1. Described is a method of activating a tissue to differentiate a stem cell or to stimulate the tissue to produce a protein. The protein is selected from the group consisting of insulin-like growth factor 1 (“IGF1”), epidermal growth factor (“EGF”), hepatocyte growth factor (“HGF”), platelet-derived growth factor (“PDGF”), endothelial NOS (“eNOS”), vascular endothelial growth factor (“VEGF”), tumor necrosis factor alpha (“TNF A”), follistatin, hypoxia-inducible factor 1 -alpha (“HIFla”), and tropoelastin, the method including: stimulating the, e.g., human tissue with an electrical signal appropriate for the protein and tissue.

[QQ75] In such a method, when the electrical signal includes (within 15%): 0.1 V applied at a frequency of about 50 Hz with a duration of about three (3) minutes (wherein the electrical signal is as measured three (3) mm deep into the tissue), the protein produced is VEGF.

[0076] In such a method, when the electrical signal includes (within 2%): 200 picoamps for about 10 seconds for about one (1) hour and the pulse has an amplitude of about 5 volts and a width of about 0.5 milliseconds for about I hour, with a duration of about one (1) minute (wherein the electrical signal is as measured three (3) mm deep into the tissue), stem cells differentiate.

[QQ77] In such a method, when the electrical signal includes (within I 5%): 10 V at 50 Hz and 100 Hz for about 12 hours each (duration 1 minute) (wherein the electrical signal is as measured three (3) mm deep into the tissue), the protein produced is follistatin.

[0078] In such a method, when the electrical signal includes (within 15%); 3.5 V stimulation in 10 second bursts, 1 burst every 30 seconds at a frequency of about 50 Hz (duration 5 minutes) (wherein the electrical signal is as measured three (3) mm deep into the tissue), the protein produced is HGF.

[QQ79] In such a method, when the electrical signal includes (within 15%); 3 mv with a frequency of about 22 Hz, and a current of about 1 mA for about fifteen (15) minutes and 3 ma for about fifteen (15) minutes (duration 5 minutes) (wherein the electrical signal is as measured three (3) mm deep into the tissue), the protein produced is IGF-l. [QQ8Q] In such a method, when the electrical signal includes (within 15%): 0.06 V with 50 Z alternating electrical field and a current of about 1 ma for about fifteen (15) minutes and 3 ma for about fifteen (15) minutes (duration 2 minutes) (wherein the electrical signal is as measured three (3) mm deep into the tissue), the protein produced is tropoelastin.

[OOSlf l ⁿ such a method, when the electrical signal includes (within 15%): alternating high-frequency (HF) and medium-frequency signals (MF), symmetric, bi phasic, trapezoid pulses, with 400-ps pulse duration and 1.5/1 -s ramp-up/ramp-down duration, respectively (wherein the electrical signal is as measured three (3) mm deep into the tissue), the protein produced is eNOS. In such a method, when the HF consists of about 75 Hz pulses with six (6) seconds on and 21 seconds off for about fi fteen (15) minutes. In such a method, when the MF consists of about 45 Hz pulses with 5 seconds on 12 seconds off for about fifteen (15) minutes followed by stimulation duration set as 20 minutes. In such a method, when the electrical signal includes (within 15%): 1 Hz stimulation, stimulation applied for about nine (9) seconds, followed by a one (1) second silent period, a total of about 1080 stimulations for about 20 minutes. In such a method, when the electrical signal includes (within 15%): 20 Hz stimulation, stimulation applied for about two (2) seconds, followed by silent period for about 28 seconds, a total of about 1600 stimulations for about 20 minutes (duration 2 minutes).

[0082] In such a method, when the electrical signal includes (within 15%): 10 V/cm, pulse-width 180 ps, 500 Hz (duration nine (9) minutes) (wherein the electrical signal is as measured three (3) mm deep into the tissue), the protein produced is EGF.

[QQ83] For example, upregulation of IGF-l, VEGF, and SDF-1 w¾s achieved in cardiomyocytes using such signals. Upregulation of SDF-1 was achieved in pig heart. Upregulation of VEGF, endothelial NOS (“eNOS”), and HIFla was achieved in eye cells.

[0084] Also described is a method of activating a tissue to produce stromal cell- derived factor 1 (“SDF1”), the method including: stimulating the (e.g., human) tissue with an electrical signal, wherein the electrical signal includes (within 15%): 30 pulses per second with a voltage of about 3.5 mV, and successively alternating currents of about 700 to 1500 picoamps for about one minute, and again w ith 700 to 1500 pi coamps for about one minute and stimulated with current of about 0.25 mA, pulse duration of about 40 pulses/s, pulse width of about 100 ps, wherein the electrical signal is as measured three (3) mm deep into the tissue. [QQ85] Further described is a method of activating a tissue to attract a stem cell the method including: stimulating the (e.g., human) tissue with an electrical signal, wherein the electrical signal includes (within 2%): fifteen (15) mV and a current of about 500 picoamps at 70 pulses per minute for about three (3) hours and 20 pulses per minute, a pulse amplitude of from about 2.5-6 volts, and a pulse width of from about 0.2-0.7 milliseconds for about three (3) hours for about three (3) minutes, wherein the electrical signal is as measured three (3) mm deep into the tissue.

[QQ86] In some cases, SDF-1 recruits via a presumed homing signal new reparative stem cells to the damaged organ. VEGF causes new ⁷ nutrient and oxygen producing blood vessels to grow into the area being treated. IGF-1 repairs damaged cells, tissues and organs. Follistatm repairs damaged muscle. Tropoelastin adds elasticity to treated tissues making them more compliant. HGF aides in ail repair processes and in the specific case- of the heart regeneration reduces the risk of arrhythmias. All of these proteins work together to fully regenerate an organ over time.

[QQ87] What follows are preferred signals from the stimulator. For example, described are two PDGF expression control signals, one low voltage and one higher voltage. The test tissue is sheep heart tissue. The test cells are mesenchymal stem cells.

[0088] 30% PDGF increase > 3 V/cm, 10 Hz, 2 micro amps (0.000002 amps) and the pulse duration 0.2 ms.

[0089] 230% PDGF increase > 20 V/cm 100 Hz, 0.25 mA (2.5e-7 amps) and pulse duration of 40 pulses/s, width of 100 ps.

[0090] 40-minute treatment cycles 2 times a week for 4 weeks and then 3 times a week for 12 weeks.

[0091] PDGF Signal: 20 V for 1 minute, 20 MV s for 10 minutes, current of 0.25 mA, pulse duration of 40 pulses/s, pulse width of 100 ps, and frequency of 100 Hz for 5 minutes followed by 528 Hz for 3 minutes and 432 Hz for 3 minutes and 50 Hz for 3 minutes.

[0092] VEGF - Blood vessel sprouting growth: 0.1 V applied at a frequency of 50 Hz. Duration 3 minutes.

[0093] SDF-1 - Stem cell recruiting signal: 30 pulses per second with a voltage of 3.5 mV, and successively alternating currents of 700 to 1500 picoamps for one minute, and again with 700 to 1500 picoamps for one minute and stimulated with current of 0.25 mA, pulse duration of 40 pulses/s, pulse width of 100 ps, and frequency of 100 Hz - each signal for 40 minutes to 8 hours a day for 2 to 36 months as needed for ideal results. Duration 7 minutes. [00941 Stem ceil differentiation signals to become muscle: 200 picoamps for 10 seconds for 1 hour and the pulse has an amplitude of 5 volts and a width of 0.5 milliseconds for 1 hour. Duration 1 minute.

[0095] Another method is to reverse polarity and drop the voltage.

[0096] Fol!istatm - (muscle growth) production signal: 10 V at 50 Hz and 100 Hz 0.25 mA. Duration 1 minute.

[0097J HGF - Hepatocyte growth factor (arrhythmia reduction) signal: 3.5 V stimulation in 10 second bursts, 1 burst every 30 seconds at frequency 50 Hz. Duration 5 minutes.

[0098] IGF-i: 3 mv with electric frequency of 22 Hz, and electric current of 1 mA for 15 minutes and 3 ma for 15 minutes. Duration 5 minutes.

[0099] Tropoe!astin: 0.06 V with 50 Z alternating electrical field and electric current of 1 ma for 15 minutes and 3 ma for 15 minutes. Duration 2 minutes.

[0100] eNOS: Alternating high-frequency (HF) and medium-frequency signals (MF): Symmetric, biphasic, trapezoid pulses, with 400-ps pulse duration and 1.5/1-s ramp- up/ramp-down duration, respectively. HF consisted of 75 Hz pulses with 6 seconds on-21 seconds off for 15 minutes. MF consisted of 45 Hz pulses with 5 seconds on-12 seconds off for 15 minutes. Followed by stimulation duration set as 20 minutes for both 1 Hz and 20 Hz stimulations. For 1 Hz stimulation, stimulation is applied for 9 seconds, followed by a 1 second silent period, a total of 1080 stimulations for 20 min. For 20 Hz stimulation, stimulation is applied for 2 seconds, followed by silent period for 28 seconds, a total of 1600 stimulations for 20 min. Duration 2 minutes.

[0101] EGF - 10 V/cm, pulse-width 180 ps, 500 Hz. Duration 9 minutes.

[0102] FIGS. 3-12 are images of the corresponding signals with the name, voltage, and frequency of each signal written on each image. eNOS and differentiation signals were omitted due to of complexity or lack of frequency parameters. The signals are to be further defined in terms of current and frequency, not voltage and frequency as shown. The voltage delivered to the cells wall be different for each tissue type, but with current all of the signals can be kept constant regardless of tissue type. The device should have a current driven signal (instead of voltage driven like most other devices).

[0103] Specifically, FIG. 3 depicts an image of the signal (voltage and frequency) associated with EGF at 10 V/cm (5 V here), 500 Hz, pulse width 180 ps, square wave. FIG. 4 depicts an image of the signal (voltage and frequency) associated with foihstatin at 10 V/cm, 50 Hz, square wave. FIG. 5 depicts an image of the signal (voltage and frequency) associated with HGF at 3.5 V, 10 second burst ever' 30 seconds, square wave. FIG. 6 depicts an image of the signal (voltage and frequency) associated with IGF-1 : 3.0 mV, 22 Hz, square wave. FIG. 7 and FIG. 8 relate to PDGF signals. FIG. 9 depicts an image of the signal (voltage and frequency) associated with SDF-l : 3.5 mV, 30 Hz, square wave. FIG. 10 depicts an image of the signal (voltage and frequency) associated with tropoelastin: 60 mV, 50 Hz, square wave. FIG. 11 depicts an image of the signal (voltage and frequency) associated with VEGF: 100 mV, 50 Hz, square wave. FIG. 12 depicts an image of the signal (voltage and frequency) associated with SDF-l (2 ^nd pari): 0.25 rnA (3.0 V shown here), 100 Hz, 100 ps pulse width, square wave.

[01041 The system is designed to address high blood pressure via three primary means.

[0105] First, bioelectric signaling to the brain’s blood pressure control center in a sense and send closed feedback loop real time. The system stimulators may be placed in any innervated area such as the forearm. Placed j ust under the skin they are designed to activate bioelectrical signaling via the nervous system. The system stimulator senses and sends bioelectrical signals to modulate blood pressure. The system emits very low-power natural level bioelectric stimulation sequences that communicate with the brain. These bioelectric signals travel to the hypothalamus midbrain, and the medulla; the signal has multiple pathways to the brain’s blood pressure control center. This bioelectric signaling in a a closed feedback loop is designed to modulate and normalize blood pressure. The system device is the only one known at this time that senses real time the needs of the body and then adjusts the bioelectric signaling to meet the individual’s needs for blood pressure control on a real time basis. The system device is the only one known at this time that senses real time the needs of the body and then adjusts the bioelectric signaling to meet the individual’s needs for blood pressure control on a real time basis.

[0106] Second, bioelectric signaling to improve elasticity of arteries, especially the aorta, to improve blood pressure dampening. The system bioelectric stimulator controls protein expressions such as tropoelastin, SDF1, IGF1, EGF, CXCL5 and Follistatin known to improve elasticity of arteries.

[0107] Third, bioelectric signaling to prevent artery flow narrowing and spasms.

[0108] The system’s bioelectric stimulator release bioelectric signals designed to inhibit plaque and blood dot formations and artery spasms which increase blood pressure and heighten the risk of a heart attack, stroke or limb amputation. The bioelectric signals used to produce, e.g., PDGF, SDF1, VEGF, FIIFla, CXCL5, EGF, HGF, and eNOS also are designed to grow new blood vessels with mature healthy endothelium linings and dilate existing blood vessels, via eNOs expression, which also can serve to lower high blood pressure.

[0109] In certain embodiments, a subject’s organ(s) and/or tissue(s) are first scanned or analyzed with a device to determine what Ins or her needs may be before treatment begins. The scanning / analysis can be by, e.g., generating mechanical vibrations at position adjacent the location to be an analyzed as described in, e.g., U.S. 2003/0220556 Al to Porat et al. (the contents of which are incorporated herein by this reference) and/or by measuring transmembrane voltage potential of a cell (see, e.g., Chernet & Levin, ‘Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in a Xenopus model,” Dis. Models and Mech. 6, pp. 595-607 (2013); doi: l0.1242/dmm.0l0835, the contents of which are also incorporated herein by this reference. See, also, Brooks et al.‘ ^‘ Bioelectric impedance predicts total body water, blood pressure, and heart rate during hemodialysis in children and adolescents,” J. Ren. Nutr., 18(3) ; 304- 311 (May 2008); doi: l0. l053/j.jm.2007. T1.008, the contents of which are incorporated herein by this reference, describing the use of bioelectric impedance to evaluate the variability of blood pressure, systolic blood pressure, etc.

[0110] As used herein,“scanning” means measuring bioelectrical electrical activity of organs, sometimes by placement of a bion coil reader and transmitter in the organ, and direct that information to a computer. The computer stores the bioelectrical read measurements of diseased organs and healthy organs and makes a comparative exam classifying the organ into one category or another, which is much like a doctor using information to make a diagnosis.

[0111] Presently, the best approach for whole body and individual organ scanning is to use a combination of: (a) 31) Body Scannint, (b) Quantum Magnetic Resonance Scanning, (c) Biofeedback scanning, (d) Bioelectric scanning, (e) Bion implant scanning, (f) Nervous system scanning, and (g) Light-activated cell reaction reading.

[0112] Scanners such as the Ina’Chi scanner, the Quantum Magnetic Resonance Analyzer (QMRA), the 3D Quantum Health Analyzer Scan whole body organ health 2, BodyScan® scanner, and the“BIONic muscle spindle” are also useful. tric Signals Can Be Used to Detect Early Cancer,” Tufts News, http://now.tufts.edu/news-releases/bioelectric-signals-used- detect- early-cancer (Feb. 1, 2013) reported that scientists had discovered a bioelectric signal that can identify cells likely to develop into tumors, and that they could lower the incidence of cancerous ceils by manipulating the electrical charge across cell membranes. After the subject’s needs in this regard are determined, then treatment (e.g., enhanced tissue growth or regeneration) may be initiated as needed and/or desired, preferably with the same device.

[Q114] In an alternative embodiment, the analysis conducted by the device comprises (or further includes) detecting minute energy fields around the human body with, e.g., a“SQUID magnetometer” (SQUID is an acronym for“Superconducting Quantum Interference Device”), able to detect biomagnetic fields associated with physiological activities in the subject’s body. A quantum resonant magnetic analyzer analyzes such fields.

The magnetic frequency and energy of a subject’s organ(s) and/or tissue(s) are collected by appropriately positioning the sensor with respect to the portion of the subject’s organ(s) and/or tissue(s) to be analyzed, and after amplification of the signal by the instrument, the data are compared with standard quantum resonant spectrum of diseases, nutrition, and other indicators/markers to determine whether the sample waveforms are irregular using a Fourier approach.

[0115] Tire invention is further described with the aid of the following illustrative

Examples.

EXAMPLES

[0116] EXAMPLE !

[0117] Low voltage pulsed electrical stimulation device for controlling expression of follistatin, a muscle formation promotion protein, from tissues.

[0118] Epicardial stimulation is especially useful for heart regeneration.

[0119] In one embodiment, the system stimulates the controlled production/release of follistatin, a known myostatin inhibitor, thus promoting the formation of new muscle and repair of damaged or weakened muscle including heart muscle post heart attack. Follistatin- like 1 (FSTL1) is a protein that encourages the growth of healthy cells, contractile muscle tissue and even blood vessels, helping supply the newly created muscle tissue with oxygen and nutrients. This therapy was originally designed to reduce or eliminate scarring of the heart following a heart attack and reversing heart failure, hut may also be applicable to treating other organs suffering from muscle loss or degradation.

[0120] The electrical stimulation device promotes the reliable controlled release of follistatin with practical, safe, low voltages. The version of the system described in this Example includes the following components: Micro voltage signal generator (micro- stimulator from QIG Greatbatch); pacing and infusion lead; corkscrew tip; conductive polymer bandage wrap or patch; signal programmer; and external batter _} charging wand.

[9121] Relationship Between The Components:

[0122] The micro voltage signal generator is attached to the pacing infusion lead with, e.g., a corkscrew tip or conductive polymer bandage or patch to the tissue or organ to be treated. An external signal programmer may be used to program the micro voltage signal generator with the proper signals for treatment including the follistatin producing signal. The device battery may be re-chargeable with an external battery charging wand.

[0123] In use, the signal generator sends a signal to the target tissue organ that causes the genes within the DNA of that tissue to start the follistatin synthesis process on demand. The signal generator sends a signal to the target tissue organ that causes the genes within the DNA of that tissue to start releasing follistatin on demand. The follistatin - (muscle growth) production signal is preferably 10 V at 50 HZ and 100 HZ 0.25 mA alternating back and forth. A 3 V signal is being developed.

[0124] The system not only controls the DNA to build ribosomes and proteins, but also controls the gates of the cell membranes opening and closing correctly to promote regeneration.

[0125] The essential elements are the micro voltage signal generator and the means for delivering the signal to the target tissue.

[0126] The signal generator may be external or internal. The transmission of the signal may be wireless, via liquid and'or via wires.

[0127] The tissue contact interface may be a patch or bandage or may be via electrodes or leads.

[0128] The described system produces follistatin under precise dosing control at safe and comfortable low voltages.

[0129] The signal generator programmed with the follistatin release signal is directed via a lead, bandage of patch to the target organ tissue in need of muscle repair or build up. As the signal is in stimulation mode the tissue releases follistatin and muscle is built or repaired as needed until full function resumes or the desired enhanced function is reached.

[0130] EXAMPLE II

[0131] A human subject’s blood pressure is monitored. The device of FIG. 2 (or FIG. 1) is utilized to deliver bioelectric signals to fibers in the subject’s vagal nerve. These bioelectric signals include the signals for the subject’s tissue to enhance the control and/or release of tropoelastin, SDF-1, VEGF, IGF-1, PDGF, and HGF. The subject’s blood pressure is controlled.

[0132] EXAMPLE III

[0133] Bioelectric signaling is used to balance electrical potentials in a subject’s body via neuro-hormonal circuit loops, increase elasticity promoting protein release to dampen blood pressure in arteries and changing arterial electrical charges to reduce artery narrowing.

[0134] Bioelectric stimulation is thought to address two known root causes of hypertension (1) loss or arterial compliance and (2) in-balance of electrical potentials within the body. The bioelectric stimulator is to reduce loss of arterial compliance by controlled release of a number of growth factors that promote increased elasticity' in the arteries including tropoelastin, SDF-1, VEGF, IGF-1, PDGF and HGF.

[0135] While not intending to be bound by theory, during the hypertension prophase episode, there may appear abnormal movement for cell membrane ions, the pathological electric potentials. This electrical abnormality' of blood vessel signal controls may then be followed by the phenomena of slowed blood flow, small artery spasms, and increased blood vessel compliance resistance, finally leading to the rise of blood pressure. The selected bioelectric signals sequence for lowering blood pressure is designed to be applied to the subject’s body with its transmitted bioelectric signals intended to activate the bioelectric circuits in the subject’s body changing abnormal current flow patterns back to normal. It is designed to directly adjust the pathological electrical ionic membrane potentials, arterial muscle cells, and relieve the small artery' spasm. The intent is also to strengthen red blood cell surface repulsion to reduce blood magnetic viscosity, and thus lower vessel and blood stream flow resistance.

[0136] The system is designed to additionally then lead continued regulation and integration in attempting to clear and dissolve cholesterol and neutral fat deposited on the tunica intima of arteries to remove stasis in the blood vessels. Thus, the system is not only designed for acute decreases in blood pressure, but also to maintain a continuous effect for long term action in attempting to address the root causes of hypertension and thus many secondary to hypertension related cardiovascular diseases.

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