Device for regenerative medicine

Abstract

Provided is a treatment device that can be used for treatment based on a treatment concept in which transient hypoxia induced by stress applied to microvascular tissue serves as a trigger.　This medical device comprises a warm air supply means that supplies warm air to microvascular tissue in an olfactory region of a nasal cavity to apply thermal stress thereto.

Description

Devices for regenerative medicine

[0001] The present invention relates to medical devices and treatment techniques.

[0002] Conventional regenerative medicine techniques mainly involve extracting culturable stem cells from the body, culturing and expanding them, and then returning them to the body. However, over the past decade or so, researchers from the Japanese Society of Cerebral Circulation and Metabolism, the Biochemical Society, and other related research institutions have published a series of new research reports on stroke and cerebral infarction regarding nerve cells. As a result, it has become clear that neurogenesis also occurs within the adult brain.

[0003] In particular, it has been discovered that neural stem cells that transform into neurons are expressed in pericytes (vascular pericytes) in cerebral blood vessels during cerebral infarction. Furthermore, it has been reported that even non-lethal blood flow arrest in these blood vessels for as little as five minutes can induce the emergence of neural stem cells (nestin expression) from these vascular pericytes, which have been named ischemia-induced pluripotent stem cells (iSC cells) (see Non-Patent Documents 4-8 and 20). This phenomenon is academically considered a type of hypoxia adaptation response (stress response), and when a small portion of a cell's blood vessel is briefly exposed to hypoxia, the hypoxic stress response is thought to regulate the expression of 800 genes, and in some cases, more than 2,000 genes (see Non-Patent Documents 3 and 63).

[0004] Conventional approaches have attempted to realize regenerative medicine by culturing iSC cells and transplanting them into patients using appropriate methods, but this has not yet been put to practical use due to the complexity of the process. In addition, a safe and appropriate method or mechanism for hypoxia in living tissues has yet to be discovered or invented.

[0005] Patent No. 6323894

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[0007] By applying physical stress (heat stress) to a few centimeters of the human microvascular tissue around olfactory cells, the dissolved oxygen in the blood flowing through the capillaries of the microvascular tissue is converted to O2 through the activation of the signaling complex between the TRP channel and NADPH oxidase. ・－ (superoxide) and then hydrogen peroxide H ２ O ２This disproportionation reaction leads to hypoxia in the capillary environment. Furthermore, the expression of NOX4 further activates TRP channels and NADPH oxidase, which in turn expresses the hypoxic stress response HIF-1α, promoting biochemical changes within the region and transforming some vascular pericytes into neural stem cells, which then dedifferentiate into neurons and other cells.

[0008] Specifically, by applying appropriate stress (heat) to microvascular tissues, neurogenesis is promoted through the production of hydrogen peroxide and hypoxia, and the hydrogen peroxide concentration in microvascular tissues during biochemical reactions is controlled using an appropriate method (appropriate mechanism). This process promotes the reprogramming of the mitochondrial genome in neurogenic cells, and is expected to lead to a new type of non-invasive neural metabolism aimed at repairing damaged or deteriorated tissues.

[0009] An object of the present invention is to provide an apparatus that can be used for treatment based on the above-mentioned treatment theory, which applies stress to microvascular tissue and triggers transient hypoxia.

[0010] The present invention solves the above problems as follows: [1] A medical device comprising a warm air supplying means for supplying warm air to microvascular tissue in the olfactory region of the nasal cavity to impart thermal stress.

[0011] [2] The medical device according to [1], wherein the hot air supply means is configured to supply hot air for 1 to 30 minutes.

[0012] [3] The medical device according to [1] or [2], comprising a hydrogen peroxide mist supplying means for supplying a mist of hydrogen peroxide to microvascular tissue in the olfactory region of the nasal cavity.

[0013] [4] The medical device according to [2] or [3], wherein the hydrogen peroxide concentration of the hydrogen peroxide solution is 600 μM or less.

[0014] [5] The medical device according to any one of [2] to [4], wherein the hydrogen peroxide mist supply means is configured to supply the hydrogen peroxide mist for 60 minutes or less.

[0015] [6] The device according to any one of [2] to [5], wherein the hydrogen peroxide mist supply means supplies a negatively charged hydrogen peroxide mist.

[0016] [7] The device according to any one of [1] to [6], configured to heat the nasal mucosa with the hot air and transiently heat the area around the internal olfactory region to between 39°C and 45°C by thermal conduction.

[0017] [8] The medical device according to any one of [1] to [7], wherein the warm air supplying means comprises: a heated warm air supplying unit; a flow path portion that forms a flow path for the warm air supplied from the heated warm air supplying unit; and a nose attachment portion that is provided at the distal end of the flow path portion and is attached to the nose to send the warm air into the nasal cavity through the flow path portion.

[0018] [9] The medical device according to [8], wherein the hot air supply means further includes a mist generating unit that generates a mist of water or hydrogen peroxide solution, and is configured to send the mist through the flow path together with the hot air supplied from the heated hot air supply unit.

[0019]

[10] A medical system comprising: a plurality of medical devices according to any one of [1] to [7]; and a server; wherein the medical devices are provided with a communication unit for communicating information with the other medical devices and the server.

[0020]

[11] The medical system according to

[10] , wherein the medical device is provided with an imaging means for taking pictures of the patient's condition, and the communication unit transmits the images taken by the imaging unit to the server.

[0021] According to the present invention, treatment based on the above-mentioned treatment theory becomes possible.

[0022] Explains the metabolism caused by the secretion of cytokine IL-1 in exercising muscles and the activation of neutrophils, and the effects of hydrogen peroxide and cell division in the human body. An example of transient phenomena caused by stress on microvascular tissue (computer diagram) is included, including excerpts from internet sources. An example of the interaction between cytokines and neutrophils and vascular endothelial cells is excerpted from Non-Patent Document 71, and an illustration of cytokines and neutrophils. An explanatory diagram of the molecular phylogenetic tree and temperature sensitivity of human TRP channels, excerpted from "Medical Progress, All About TRP Channels." An explanatory diagram of temperature-sensitive TRP channels and their activation temperature thresholds, excerpted from "Medical Progress, All About TRP Channels." A schematic diagram of the components and functions of NADPH oxidase. From "The Molecular Biological Basis of Neutrophil Active Oxygen Production and Its Activation Mechanism," IRYO Vol. 53 No. 4 (231-238) April 1999 (Internet source). A table of oxygen metabolism during the respiratory burst. IRYO Vol. 53 No. 4 (231-238) April 1999, from "The Molecular Biological Basis of Neutrophil Reactive Oxygen Production and Its Activation Mechanism" (Internet resource). Diagram of NOX Activation Mechanism and Epithelial Cell Migration, Biochemistry, Vol. 94, No. 1 (2022), from "The Control Mechanism of Cell Migration by the Reactive Oxygen Generating Enzyme NOX" (Internet resource). Cross-section of the brain showing the relative positions of the nasal cavity, olfactory bulb, hypothalamus, and hippocampus, predicting neurogenesis following heat stress to the olfactory bulb and olfactory region (Internet resource). Similarly, a diagram of the human head (Internet resource). The migration pattern of newborn neurons in mice is thought to be similar in humans. RIKEN (Internet resource). Diagram of the wiring of nerves and blood vessels. Excerpted from "The Control Mechanism of Stem Cell Maintenance and Differentiation Brought About by Neurovascular Cooperation," Biochemistry, Vol. 8, No. 3, pp. 384-390 (2019) (Internet resource). Diagram explaining the progression of cerebrovascular pericyte stem cells in the brain, excerpted from Cerebral Circulation and Metabolism, Vol. 30, No. 1 (Internet resource). Mechanism of SG formation by RNA-binding protein Nrd1, excerpted from materials from the Institute of Medical Science, University of Tokyo (Internet resource). Diagram explaining the inhibition of caspases and cell death (apoptosis) by the formation of liquid-liquid phase separators called "stress granules," excerpted from materials from the Institute of Medical Science, University of Tokyo (Internet resource). Diagram explaining the reprogramming of the mitochondrial genome in human cells by reactive oxygen species (ROS), excerpted from materials from the Institute of Physical and Chemical Research (Internet resource).Diagram illustrating the relationship between oxygen environment and cardiomyocyte proliferation. Materials from the Center for Interdisciplinary Research in Life Sciences, University of Tsukuba (online resource). Conceptual diagram of a regenerative medical device that applies short-term heat stress through the human nostrils and nasal cavity, followed by the inhalation of a micromist containing H2O2, promotes neurogenesis around the olfactory system, reprogramming the mitochondrial genome and promoting active neurogenesis. Examples of blood flow distribution, oxygen consumption, and oxygen concentration in biological tissues under physiological conditions in the human body at rest. Schematic diagram of the neurovascular unit and structural diagram of the blood-brain barrier, and in vitro reproduction of cerebral capillaries, excerpted from Japanese Journal of Pharmacology 143, 137-143 (2014). Basic diagram of the mechanism of action and operation of this invention. Diagram illustrating the molecular basis of TRPV2 activation mechanism and axonal elongation, excerpted from Medical Progress. An explanatory diagram of the regulation of epithelial cell function via temperature-sensitive ion channels in the skin and mucous membranes. Excerpted from Medical Progress. A diagram of Example 1 of the present invention. An explanatory diagram of the network of Example 1. A diagram of Example 2.

[0023] In order to establish a treatment theory, the inventors needed to investigate a method for hypoxia in the microvascular tissue of the brain (a region of several centimeters). Specifically, they needed to discover and invent a method for blocking blood flow for a short period of time, or a method for achieving the same effect without blocking blood flow. To this end, they collected and analyzed epidemiological information and big data, and through repeated trial and error and extensive clinical experiments, discovered a method for partially inducing a transient state of hypoxia while maintaining blood flow in the microvascular tissue of the brain, and its mechanism of action.

[0024] When specific (thermal) stress is applied to microvascular tissue, a biochemical reaction occurs. Recent research has revealed that TRP channels respond to specific temperatures, chemicals, and mechanical stress. Research papers in this field also state that some TRP channels form complexes with NADPH oxidase. The safest and most controllable of these stresses is temperature, particularly heat. Therefore, targeting the olfactory cells and microvascular tissue of the olfactory region, which regenerate throughout life, heating the olfactory region to 39-45°C for one to several tens of minutes activates TRP channels, and simultaneously activates NADPH oxidase on the surface of neutrophils and on the vascular endothelium (through the signaling complex of TRP and NADPH oxidase). The action of this NADPH oxidase converts dissolved oxygen in the blood into reactive oxygen species (O2·-), which is then converted to hydrogen peroxide by the action of blood SOD. (NOX4 is O ２ Directly H ２ O ２ This dismutation reaction reduces the oxygen concentration in the blood, creating a transient hypoxic state. This hypoxia further activates TRP and NADPH oxidase, leading to the expression and activation of the hypoxic stress response HIF-1α.

[0025] This reaction is a contact reaction, and NADPH oxidase does not act uniformly on neutrophils and microvascular endothelium. Therefore, the dissolved oxygen in the blood vessels in the region drops to less than a few tenths, rapidly initiating the HIF-1α stress response, producing stress granules that protect cells from apoptosis due to transient hypoxia-induced activation of Casp3 / 7. Because stress granules do not have a membrane structure, they resolve within a few minutes once the stress is released. If this high-temperature, hypoxic condition continues for 15 minutes or more, apoptosis is accelerated, and the surrounding tissue is likely to die within 30 minutes. Therefore, the method of stress application (temperature and time) must be strictly controlled. The temperature should be between 39°C and 45°C, and the time should be within 60 minutes, more preferably between 1 and 30 minutes.

[0026] This reaction causes some of the pericytes in microvascular tissue to transform into stem cells (express nestin) through the action of HIF-1α, dedifferentiate into neurons, and migrate along the capillaries. This NADPH oxidase activity has attracted attention as it is involved in the worsening of stroke. According to a paper by the Institute of Physical and Chemical Research, if the concentration of hydrogen peroxide in blood plasma (around cells) is controlled at around 100 μM, the mitochondrial genome is initialized during cell division, changing from heteroplasmy to homoplasmy during the M phase of cell division. Autophagy (mitophagy) is enhanced in a low-oxygen environment, eliminating mutant mtDNA from mtDNA and leaving wild-type (healthy) mtDNA, thereby improving the quality of the mitochondria in dedifferentiated neural stem cells.

[0027] According to European Union risk assessment data, plasma hydrogen peroxide concentrations in six male researchers aged 30 to 35 ranged from 13 to 57 μM, and the tolerable concentration in plasma is 600 μM at 1 atmosphere (600 μM when water with a 100% oxygen concentration is converted to hydrogen peroxide). Therefore, by adding appropriate measures, it is possible to control the above-mentioned biochemical reaction to around 100 μM during the M phase, but only in the area around the olfactory system. (Without taking this additional measure, initialization of the mitochondrial genome in neurogenic cells generated from stem cells will not occur, but mitochondrial activity in neurogenic cells will remain appropriate for age due to mitophagy.)

[0028] (Caution) H in blood ２ O ２There is no medical practice to measure hydrogen peroxide levels. Therefore, it is unlikely that testing is available at regular hospitals. While epidemiological information is scarce, as noted in Reference 22, when cancer cells divide in an environment where the combined concentration of hydrogen peroxide levels during the M phase of cell division reaches approximately 100 μM, the mitochondrial genome of the dividing cancer cells is initialized, potentially leading to the activation of the cancer cells (by giving them toughness). Such activated cancer cells may not be easily treated by the immune system. Cancer cells hypoxicate their surroundings, increasing the hydrogen peroxide concentration around the cancer cells. To prevent this from reaching approximately 100 μM, combined with the hydrogen peroxide concentration in the blood, it is recommended to maintain blood hydrogen peroxide levels at at least 50 μM or less by taking antioxidants such as vitamin C orally. Fortunately, antioxidants are inexpensive and should be used regularly. We also hope to develop a simple and relatively inexpensive device for measuring blood hydrogen peroxide levels, similar to blood glucose testing devices. (End of Warning)

[0029] Regarding the migration of stem cells and neurogenesis cells, research by the RIKEN Institute has shown that neurons move in chains along blood vessels (see Figure 10). The pathways are shown from the lateral ventricle to the olfactory region, and from the olfactory region to the hippocampus, and it is thought that the migration of neurons along these pathways contributes to the activation of hippocampal neurons, which have lost their vitality.

[0030] According to Non-Patent Documents 18 and 19, it takes about 60 minutes for cells to return to normal after exposure to hypoxia. Furthermore, stress granules are aggregates consisting of mRNA and RNA, and a deeper understanding of their function is needed. Furthermore, the convex curve of the hydrogen peroxide concentration in Figure 2 is due to the initial hypoxia, which activates NOX4 expression and reduces O2 levels. ２ is directly and efficiently H ２ O ２ This can also be seen as being due to the conversion into

[0031] The hypoxic stress response occurs not only in the brain but also in other organs. While organ metabolism is possible with optimal methods and control systems, this invention acts within the homeostatic range of the body and is limited to minute parts. Side effects may occur if the safe area of ​​action is exceeded. To expand the area of ​​action, it is necessary to divide the area of ​​action into minute parts, including individual organs, and repeat the same process at different times.

[0032] In this invention, we devised a method to apply heat stress to the olfactory system with the goal of promoting neurogenesis in the brain. This involves introducing hot air (approximately 41°C to 47°C) into the nasal cavity through a sealed nasal mask and expelling it through an open oral cavity. This method controls the temperature of the olfactory system to within 39-45°C and heats the system for 1 to 30 minutes. Furthermore, for the purpose of initializing the mitochondrial genome, we used a device that simultaneously aspirates a mist (approximately micron-sized) of hydrogen peroxide solution at 600 μM or less through the nasal cavity using the same system for up to 60 minutes.

[0033] The most important factors in reducing oxygen levels are the TRP channels and NADPH oxidase in the vascular endothelium. Moderate exercise induces metabolism, which secretes the pro-inflammatory cytokine IL-1 in the muscles, activating neutrophils and the vascular endothelium. Mechanical stress and elevated temperatures caused by exercise activate the TRP channels and NADPH oxidase (signal complex), converting some of the oxygen in the bloodstream into superoxide O2. ・－ This is converted to hydrogen peroxide by the action of SOD enzymes in the blood (or by the action of NOX4). This dismutation reaction lowers blood oxygen levels, causing a hypoxic stress response. Furthermore, hypoxia activates TRP channels and NADPH oxidase, and when the hydrogen peroxide concentration in the stressed area reaches approximately 100 μM, the mitochondrial genome is initialized during cell division, and the cells are metabolized into healthy, active cells. However, as shown in the example of oxygen concentrations in biological tissues at rest in Figure 18, during exercise, there is a possibility that the mitochondrial genome will be initialized in major muscles with appropriate exercise, but other parts, especially the head and brain, are in a relatively low-oxygen environment, and it is believed that this will not lead to the initialization of the mitochondrial genome during the generation of new neurons. (Nevertheless, mitophagy allows for healthy activity appropriate to age) (H in the blood２ O ２ H generated during hypoxic stress response HIF-1α ２ O ２ Concentration, estimated 20-30 μM < 100 μM)

[0034] Excessive exercise increases hydrogen peroxide concentrations, preventing the mitochondrial genome from being initialized (potentially resulting in the production of other types of reactive oxygen species), leading to apoptosis due to the effects of reactive oxygen stress granules. Ingesting large amounts of the antioxidant vitamin C during exercise prevents hydrogen peroxide concentrations from reaching approximately 100 μM, and the revitalizing effects of exercise cannot be expected to be significant. These findings have been academically reported. Comparing the brain neurogenesis achieved by exercise therapy with that achieved by the present invention, which does not occur naturally, it is estimated that the number of neurogenesis cells achieved in a single session is several times greater than that achieved by healthy exercise therapy. Because the therapy is non-invasive and easy to perform repeatedly, it is believed possible to generate high-quality neurogenesis cells in cumulative numbers of tens to hundreds of times more.

[0035] To determine the optimal intensity and duration of exercise therapy for each individual, it is ideal to measure intramuscular hydrogen peroxide levels by blood sampling before and after exercise. Temporal analysis of the biochemical response to stress applied to an area has shown that when effective thermal or mechanical stress is applied for approximately 30 seconds, hydrogen peroxide is produced, and hydrogen peroxide levels continue to rise even after 30 seconds, before decreasing after approximately 30 minutes. Based on this reaction, if hydrogen peroxide levels can be maintained at around 100 μM during the M phase of the cell cycle by appropriately adjusting the amount and intensity of aerobic exercise, the mitochondrial genome of dividing cells will be initialized, and together with the production of other physiologically active substances, metabolic activity will be improved, and the state of the cells' mitochondria will be rejuvenated.

[0036] Applying stress to the nasal cavity around the olfactory cells by hot air can induce cell division in the surrounding area in a short period of time, but the H around the microvascular tissue ２ O ２ Assuming that the blood concentration during daily life is 20-40 μM, the H produced by applying heat stress to the olfactory system ２ O ２If the oxygen concentration in the surrounding area is 4-5%, the concentration is at most 20 to 30 μM, totaling 40 to 70 μM, and does not reach about 100 μM during cell division. ２ O ２ If measures are taken to increase the risk of cancer cells in the body, there is a risk of their proliferation, so we have adopted a system limited to the olfactory part of the nasal cavity. That is, at the same time as applying short-term heat stress, a sealed nasal mask is used to inhale hydrogen peroxide solution of up to 600 μM in micron-sized mist from the nasal cavity in a controlled rhythm, and hydrogen peroxide reaches the olfactory area through the mucus in the nasal mucosa. ２ O ２ We adopted a system that aims to control the hydrogen peroxide concentration in the microvascular tissue around the olfactory region during cell division to around 100 μM by penetrating a fine mist containing hydrogen peroxide (or charged with negative ions) into the surrounding area.

[0037] The present invention was completed based on the above findings. The following describes in detail an embodiment of the present invention. The present invention is composed of an auxiliary control unit controlled by a microcomputer, related equipment, a power supply, etc. The stress applying unit is a heated air blower that filters the air in the room and generates warm air, and the fine mist supply unit of hydrogen peroxide that is linked to this is a built-in H ２ O ２ Using hydrogen peroxide solution with a concentration of 120 μM to 200 μM from a container (tank), a fine mist is generated using a high-voltage nozzle sprayer or ultrasonic atomizer, and then supplied to the device's external supply port using the conveying air from the heated air blower. All operations are controlled by the device's internal microcomputer and auxiliary peripherals. 120 μM hydrogen peroxide solution is supplied to the negative ion atomizer from a unitized 1- to 2-liter container, and is replaced and replenished on a unit-by-unit basis as it is used.

[0038] The present invention encompasses two embodiments, both of which involve the activation of TRP channels and NADPH oxidase, activation of HIF-1α hypoxia adaptive response and stress granules, and promotion of mitochondrial genome reprogramming.

[0039] The first method involves applying appropriate thermal stress to the olfactory region surrounding regenerating olfactory cells in order to promote the regeneration of brain function and neurogenesis. As shown in Figures 17 and 23, warm air at approximately 41°C to 47°C is introduced into the nasal cavity using a closed-type nasal mask for 1 to 30 minutes and then expelled through the open oral cavity. This method allows heat transfer through the nasal mucosa, briefly raising the temperature around the olfactory region to 39°C to 45°C, thereby inducing a biochemical reaction. The amount of heat transferred varies depending on the amount of air injected into the nasal cavity and the flow rate. Prior to treatment, an otolaryngologist or other specialist uses an endoscope to confirm the absence of tumors or cancers along the pathway from the nasal cavity to the pharynx and oral cavity, as shown in Figure 9. (If there are any problems, the present invention will be provided after treatment.) Furthermore, simultaneously with the application of this thermal stress, H ２ O ２ The system is used to inhale the fine mist and measure its penetration from the skin surface of the olfactory area of ​​the nasal mucosa, bringing the hydrogen peroxide concentration around the olfactory area to approximately 100 μM. The concentration of hydrogen peroxide used at this time is set to 120 to 180 μM, with 120 μM hydrogen peroxide being the default concentration.

[0040]

[0041]

[0042] <Example 1> Figure 23 is an explanatory diagram of Example 1 of the present invention. First, the user is examined in advance by a specialist such as an otolaryngologist to check for the possibility of cancer or other problems in the passages from the nasal cavity to the respiratory tract, and to confirm that there are no problems. This device is broadly divided into two parts. It consists of a Windows-based computer (here, a laptop) that controls the entire device, the regenerative medicine device main body containing various interface boards, devices, and power units controlled by this computer, and the cables (LAN, USB, etc.) connecting them. The basic operation involves injecting a fine mist of hydrogen peroxide and heated warm air into the nose through a sealed nasal mask, then expelling it through the oral cavity by opening the mouth. Breathing is performed through the mouth during treatment.

[0043] The laptop computer is equipped with IoT-related software and is connected to the Internet. (Optionally, 4G and 5Gn LTE mobile communication systems are also available.) First, regarding the device's operation and function, reference numeral 1 in Figure 23 denotes a sealed nasal mask worn against the nose. It can be secured at the back of the head with a band. Reference numeral 2 denotes the tubes for the passage of heated air and fine mist of hydrogen peroxide connected to reference numeral 1, reference numerals 3 and 4 are relay connections, and reference numeral 5 denotes a two-way switching valve for this fluid (heated air), an electromagnetic switching valve with a built-in precision temperature sensor. The temperature sensor signal is sent to a computer, and the switching of the solenoid valve is controlled by the computer. Reference numeral 8 denotes an artificial nasal cavity, a simulating nasal cavity, used when heated air is not being introduced to the nasal cavity. It is either discharged indoors or connected to the flow path referenced 9a or 9b to evaluate the characteristics of time-series temperature changes due to contact of heated air with the nasal mucosa and the penetration characteristics of hydrogen peroxide mist into the nasal mucosa. Each test takes about 10 minutes to analyze and evaluate the samples, and the temperature settings, quantity, quality and spray pattern of the hydrogen peroxide mist are evaluated and used to set up the computer.

[0044] Second, if the temperature sensor (7) detects that the temperature exceeds the set upper limit for some reason during treatment, the computer controls the solenoid valve to switch, releasing the heated air into the room. The computer then lowers the temperature setting of the precision heating device (17) by an appropriate temperature (usually 2°C). Once the temperature sensor (7) reaches a safe level, the solenoid valve (5) redirects the heated air toward the nasal cavity again, and treatment continues. (It operates for a set time and then stops as instructed by the computer.) Reference numeral 11 denotes a hydrogen peroxide solution container, storing 1 to 2 liters of approximately 150 μM hydrogen peroxide solution. This hydrogen peroxide solution is sent to the electrostatic atomizer (12), where the fine mist is negatively ionized and pushed into the passage (tube) (6) by the heated air (16). The inner surface of the flow path tube is coated with or made of an insulating material. When the negatively ionized hydrogen peroxide solution mist is introduced into the nasal cavity, it is easily adsorbed by the nasal mucosal surface (conductor).

[0045] Regarding computer software and networks, Windows IoT Enterprise is a typical example. However, the system described here does not require 1-msec real-time control; a delay of approximately 1 second poses no control problems. However, the multi-language capabilities and wide range of applications provided by Windows are beneficial. This system was constructed by installing a dedicated app and equipping related IoT devices. Reference numeral 23 denotes the regenerative medicine device itself, which contains all components except the computer and has maintenance access panels (screwed) reference numerals 21 and 22. The power is plugged into outlet 19, the PC is placed in the installation area, and the power cable, LAN cable, and USB cable are connected to reference numeral 18. Next, the medical professional turns on the power switch reference numeral 23 and the PC to enter standby mode. A startup message appears on the PC screen, and the medical professional enters the set password to begin all startup. A start-up video begins playing on the touch panel in the specified language, showing how to use the regenerative medicine device and how to care for patients. Next, enter the ID (identification number) of the medical professional and the patient. Next, the device's core settings will appear, displaying options such as how long the hot air will last and what temperature it will be.

[0046] After selecting the treatment options and explaining the procedure to the patient and placing a nasal mask on them, the start button on the computer screen is pressed. The treatment then follows a predetermined sequence, completing the selected time (usually 20 to 30 minutes). With the patient's consent, a short video recording is automatically performed using a high-performance webcam (with tracking function). This includes the interview, the patient's condition during and after treatment, and the patient's facial expressions. These are recorded on the computer and, with the consent of both the medical staff and the patient, automatically transmitted via the internet to a server at a separate information center. Through follow-up observations over one to four weeks, the patient's image data is used to determine changes in the patient's condition over time in response to this regenerative therapy for various neurological disorders. Data from each site is aggregated and processed using AI statistical processing, providing feedback to each site and contributing to the rapid development of treatment technologies. Two temperature settings are automatically adjusted based on the elapsed time: one temperature for dedifferentiating neural stem cells from pericytes in the olfactory region of the nasal cavity, and another temperature for maintaining this effect (usually 1 to 2°C lower). Also, although not shown in the drawing, the built-in temperature sensor recommends a room temperature of 20°C. If the temperature exceeds 25°C, the computer screen will display a message indicating that the room temperature needs to be adjusted, and the system is programmed to prevent patient treatment. In an abnormal situation, a warning message will appear on the screen and a voice message will be played. Although no display is shown, data from the attached sensor is recorded in the main unit and, if necessary, automatically transmitted to the information center server. Furthermore, as long as a patient has a valid ID, they can continue treatment at another location after their previous treatment. However, since each patient is assigned a single closed-type nasal mask and are not shared, they must bring their own closed-type nasal mask (reference number 1). Although mass-market (commercially available) closed-type nasal masks are used, for patients who simply cannot fit them, it is possible to create a model of the patient's nose using the 3D scanner shown at the top of Figure 23 and then modify the commercially available mask to fit the patient's shape.

[0047] As for the crucial temperature setting of the heated air, the initial setting (one week after the start of treatment) is a nasal cavity surface temperature of 42 to 43°C, a heated air temperature of 44°C, and a time of about one minute. The subsequent maintenance temperature for stem cell dedifferentiation is a nasal cavity surface temperature of 39°C or higher, a heated air temperature of 41°C, and a total nasal suction time of 20 to 30 minutes, which is the initial setting. After one week or six treatments, the progress is analyzed and the settings are reset. The computer also has an internet connection, so it is possible to exchange information with each other outside of treatment hours by using email replies from the user list sent from the information center (this can also be done using a smartphone).

[0048] Example 2 Figure 24 illustrates Example 2 of the present invention. This is a small, simplified regenerative medicine device, and operation is manually controlled except for the sequence control for sequential operation. Operation begins when the simplified regenerative medicine device is powered on and the main switch is turned on. An adjustable blower draws air from the room through an air filter, then sends it to a heater (adjustable) that heats the air to a set temperature. The ultrasonic humidifier then passes through an ultrasonic atomizer containing hydrogen peroxide solution (not water) at a concentration of 120 μM to 150 μM. The heated, fine mist-like air passes through a temperature sensor and is delivered to a sealed nasal mask. The illustrated equipment is built into the device. The control switches on the top allow for adjustment of the volume and temperature of the heated air, the output of the ultrasonic atomizer, and the ON-OFF timing of the intermittent control. When the switch is turned on, the blower, heater, and ultrasonic atomizer are activated in a delayed sequence; when a stop command is issued, they are delayed and stopped in the reverse sequence. The thermometer has a digital display, and when the optimal temperature (target temperature) is reached, an alarm sounds and a green indicator light will alert. If the temperature exceeds the set upper limit, the device is programmed to sound a buzzer and light up a red indicator light to alert. There is a slight delay between activation and the warm air reaching the appropriate temperature. Fluctuations in various factors can also affect the temperature of the warm air. The user (patient, medical professional) waits until the green light comes on before connecting the sealed nasal mask to the connector to begin treatment. After the set time has elapsed, an end sound will sound and the device will automatically shut down. This treatment takes approximately 30 minutes. During the latter half of activation, the temperature of the heated warm air is set to a target nasal temperature of 39°C to 40°C. As a medical device, the simplified regenerative medical device's medical management is managed under the direction of a medical professional (doctor).

[0049] This invention will revolutionize regenerative medicine, replacing stem cell culture transplantation in the development and treatment of brain function. It will provide new and essential treatment opportunities for many neuropsychiatric disorders, including developmental disorders such as dementia and attention-deficit hyperactivity disorder. Furthermore, by sharing information between each center, it is expected that global expansion will be possible regardless of region, and that the ability to adapt to changes over time will be improved for rapid treatment of patients with various neurological disorders.

[0050] 1. Sealed nasal mask (with head restraint band) 2. Heated air (tube) passage to the sealed nasal mask 3. Connection between tubes 4. Connection with electromagnetic distribution valve 5. Two-way electromagnetic switching valve with built-in temperature sensor; 5 is always 8-way, 4-way during treatment 6. Heated air passage (tube) containing negatively ionized hydrogen peroxide mist 7. Precision temperature sensor 8. Passage (tube) from the switching valve to the outside 9a. Device for evaluating fine hydrogen peroxide mist, for evaluating the quantity and quality of the fine mist in imitation of an artificial nasal cavity 9b. Device for evaluating the heat conduction from the nasal surface of heated warm air, for evaluating the heat conduction from the mucosal surface in imitation of an artificial nasal cavity 10. Adjustable exhaust path (via tube) from the electromagnetic distribution valve, discharged into the room 11. Container of hydrogen peroxide solution (120-μM), 1-2 L 12. Electrostatic atomizer for hydrogen peroxide solution 13. Variable speed blower, air supplier 14. Precision heating device, 15 Path from the air supply device to the heater 16 Path to the electrostatic atomization device 17 Handle for transporting the regenerative medicine device main body 18 Interface between the device and computer, containing LAN, USB, computer power terminals, etc. 19 Power outlet for the device and system (connects to an indoor outlet and a cable) 20 Carry for transporting the device (with stopper) 21. 22 Lids for internal maintenance (screwed) 23 Regenerative medicine device main body, with an interface board between the computer and the device installed inside

Claims

1. A medical device comprising a warm air supply means for supplying warm air to microvascular tissue in the olfactory region of the nasal cavity to impart thermal stress.

2. The medical device according to claim 1, wherein the hot air supply means is configured to supply hot air for a period of 1 to 30 minutes.

3. The medical device according to claim 1, further comprising a hydrogen peroxide mist supply means for supplying a mist of hydrogen peroxide to the microvascular tissue in the olfactory region of the nasal cavity.

4. The medical device according to claim 3, wherein the hydrogen peroxide solution has a hydrogen peroxide concentration of 600 μM or less.

5. The medical device according to claim 3, wherein the hydrogen peroxide mist supply means is configured to supply the hydrogen peroxide mist for a period of 60 minutes or less.

6. The device according to claim 3, wherein the hydrogen peroxide mist supply means supplies a negatively charged hydrogen peroxide mist.

7. The device according to claim 1, wherein the warm air is configured to heat the nasal mucosa and to transiently heat the area around the internal olfactory area to within 39°C to 45°C by thermal conduction.

8. A medical device according to any one of claims 1 to 7, wherein the warm air supply means comprises: a heated warm air supply unit; a flow path unit that forms a flow path for the warm air supplied from the heated warm air supply unit; and a nose attachment unit that is provided at the distal end of the flow path unit and is attached to the nose to supply the warm air to the nasal cavity through the flow path unit.

9. A medical device according to claim 8, wherein the hot air supply means further comprises a mist generating unit that generates a mist of water or hydrogen peroxide solution, and is configured to send the mist through the flow path together with the hot air supplied from the heated hot air supply unit.

10. A medical system comprising a plurality of medical devices according to any one of claims 1 to 7 and a server, wherein the medical devices are provided with a communication unit for communicating information with other medical devices and the server.

11. The medical system according to claim 10, wherein the medical device is provided with an imaging means for taking images of the patient's condition, and the communication unit transmits the images taken by the imaging unit to the server.

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