Cell therapy

Abstract

Based on combination therapy, we propose a cell therapy that can significantly enhance the therapeutic effect of treatment for cerebrovascular disease, ischemic heart disease, or traumatic cerebrospinal nerve injury in subjects compared to conventional methods. [Solution] A cell preparation containing microglia and / or monocytes, which have the ability to promote angiogenesis and axon extension, is administered to the subject. By repeatedly implementing a bidirectional biofeedback loop between the nervous system and the musculoskeletal system, the effect of improving the motor function of the subject's brain, nervous system, and muscular system is enhanced.

Description

Technical Field

[0001] The present invention relates to a cell preparation effective for the repair and regeneration of tissues damaged by, for example, cerebral infarction.

Background Art

[0002] Cerebral infarction refers to a cerebral dysfunction caused by ischemic necrosis in a local area of the brain, and is a disease that requires emergency treatment. It is one of the three major causes of death, along with cancer and heart disease. Cerebral infarction is classified into thrombotic, embolic, and hemodynamic types from the aspect of the mechanism of action, and is classified into atherosclerotic thrombotic cerebral infarction, cardiogenic cerebral embolism, lacunar infarction, etc. from the aspect of clinical findings.

[0003] Ischemia occurs when local cerebral blood flow is blocked due to cerebrovascular lesions such as arteriosclerosis or cardiogenic thrombus. In the central ischemic area, nerve cell death due to energy depletion is caused. After ischemia, nerve regeneration is poor, and it is difficult to recover symptoms in the chronic phase at present, and half of them cause some sequelae. As a process of nerve regeneration in the marginal area of the ischemic center, angiogenesis is assumed to be the trigger. Development of a treatment method targeting this is desired.

[0004] As the only therapeutic drug in the ultra-early stage of cerebral infarction, tissue plasminogen activator (t-PA) is known to have a dramatic effect. However, when more than 4.5 hours after onset, which is the treatable time, t-PA administration rather increases the risk of causing cerebral hemorrhage related to the prognosis of life. Therefore, development of a vascular protective drug to prevent the complication of cerebral hemorrhage is strongly desired.

[0005] Two molecules known to be involved in the complications of cerebral hemorrhage are the "bad" vascular endothelial growth factor (VEGF) and the "good" progranulin (PGRN). In addition to its vascular protective effect through the suppression of VEGF expression, PGRN exerts multifaceted neuroprotective effects, including neuroprotective effects through the maintenance of RNA (ribonucleic acid)-binding protein (TDP-43) function and anti-inflammatory effects through the secretion of inhibitory cytokinin (IL-10) from microglia. Furthermore, combination therapy with t-PA and PGRN shows promise in the treatment of cerebral infarction.

[0006] On the other hand, while rehabilitation alone has traditionally been insufficient for chronic stroke recovery, often resulting in residual disabilities, stem cell transplantation therapy has recently attracted attention, and clinical trials are underway.

[0007] For example, treatment for cerebral infarction using bone marrow-derived mesenchymal stem cells or MUSE cells has been proposed, but it has drawbacks: it requires bone marrow aspiration, which places a heavy burden on the patient; it requires amplification culture for 1-2 weeks to secure the number of transplantable cells, making it unsuitable for acute treatment; and it requires specialized facilities for culture, making it unsuitable for widespread use in general medical institutions.

[0008] Ideally, convalescent cell therapy should be applicable from the early stages after the onset of the disease, have no risk of cancer development like iPS cells, be less burdensome for the patient, and not require specialized facilities for cell culture.

[0009] Microglia, which express PGRN after ischemia-reperfusion and exhibit anti-inflammatory effects through IL-10 secretion, are examples of cells that satisfy the above requirements. Since microglia are naturally present in the brain and do not require genetic manipulation, there is no risk of them becoming cancerous. Furthermore, because they accumulate at the site of cerebral infarction, only a small number of transplanted cells are needed, eliminating the need for long-term culture and thus eliminating the need for specialized facilities for cell culture.

[0010] However, there are beneficial and harmful microglia; the former promote the regeneration of blood vessels and nerves, while the latter cause inflammation in the brain. More specifically, in the brain, when quiescent (M0) microglia are stimulated by LPS or IFN-γ, they become the harmful M1 type and produce harmful molecules such as IL-1β, IL-6, TNF-α, CCL2, and reactive oxygen species (ROS)-induced nitric oxide synthase.

[0011] On the other hand, when M0 microglia are stimulated by IL-4 or IL-13 and activated, they become the beneficial M2 type, producing protective molecules such as IL-4, IL-10, and arginase 1, exhibiting various neuroprotective effects such as anti-inflammatory, angiogenesis, and nerve regeneration. In cerebral infarction, the harmful M1 microglia are the main culprits.

[0012] Based on the idea that if these microglia can be converted to the M2 type (M2 conversion) outside the body, then transplanting the M2-converted microglia into patients could produce excellent neuroprotective effects in acute or chronic phase treatment after the hyperacute phase, an invention relating to a cell preparation has been proposed in which culture conditions for achieving M2 conversion have been diligently investigated (see Patent Document 1).

[0013] This Patent Document 1 describes how M2 microglia can be efficiently obtained by culturing microglia for 12 to 24 hours under conditions of low oxygen concentration (less than 1%) and low glucose concentration (OGD: Oxygen Glucose Deprivation) (less than 1.0 g / L), and how this can produce excellent therapeutic effects in the Corner test even when administered 7 days after cerebral ischemia, when symptoms usually stabilize, in animal models.

[0014] Thus, while the cell therapy described in Patent Document 1 is at least partially based on the discovery of specific culture conditions that enable M2 conversion of microglia in vitro, since microglia reside in the brain, in order to autotransplant the patient's own microglia, they must be collected from the patient's brain.

[0015] In practice, while it is easy to collect microglia that have migrated to the destroyed white matter surrounding the hematoma during hematoma removal surgery in patients with cerebral hemorrhage, it is not practical to collect the patient's own microglia in cases of cerebral infarction or other ischemic diseases.

[0016] Therefore, Patent Document 1 conceived the idea of ​​using monocytes that can become M2-type macrophages as a substitute for microglia, and by treating peripheral blood mononuclear cells (PMNCs) containing monocytes with OGD, PMNCs can be efficiently converted to M2 by culturing them for 12 to 24 hours under conditions of low oxygen concentration of less than 1% and low glucose concentration of 1.0 g / L or less (OGD), similar to microglia. When these cells are transplanted into an animal model, it is possible to achieve excellent therapeutic effects even when administered 7 days after cerebral ischemia. [Prior art documents] [Patent Documents]

[0017] [Patent Document 1] Patent No. 7089283 [Overview of the Initiative] [Problems that the invention aims to solve]

[0018] Incidentally, in recent years, numerous cases have been reported in which wearable motion assistance devices, which can control and assist movement based on bioelectric potentials associated with voluntary muscle activity in accordance with the subject's intentions, have been applied to the treatment and rehabilitation of subjects with functional impairments of the brain, nervous system, and body, resulting in improved function in these subjects.

[0019] Based on signals from the subject's own nervous system, the wearable movement assist device functions to move the body, which has impaired motor function. As a result, the subject moves their musculoskeletal system of their own volition, and sensory information flows from inside and outside the body to the nervous system, creating a bidirectional biofeedback loop between the nervous system and the musculoskeletal system.

[0020] It is believed that by repeating this process, synaptic connections in the brain, nervous system, and muscular system are strengthened, leading to relearning and functional regeneration, and thus promoting improvement in the physical function of subjects with brain, nervous system, or muscular system diseases.

[0021] It is expected that the combined therapy, when applied to a subject using such a wearable motion assist device while the subject is administered the cell preparation described in Patent Document 1 mentioned above, will further promote angiogenesis and axonal extension in the subject.

[0022] This invention has been made in consideration of the above points, and aims to propose a cell preparation that, based on combination therapy, can significantly improve the therapeutic effect of cerebrovascular disorders, ischemic heart disease, or traumatic cerebrospinal nerve disorders in subjects compared to conventional methods. [Means for solving the problem]

[0023] To solve these problems, the present invention provides a cell preparation containing microglia and / or monocytes, which has the ability to promote angiogenesis and axon extension. This preparation is produced by culturing a group of cells including microglia and / or monocytes under conditions of low oxygen concentration of less than 1% and low glucose concentration of 1.0 g / L or less for 12 hours or more but less than 24 hours. When administered to a subject, the preparation promotes the improvement of motor function of the subject's brain, nerve, and muscle systems by repeatedly implementing a bidirectional biofeedback loop between the brain and nervous system and the musculoskeletal system, which is constructed by correcting the difference between the movement commands from the brain and nervous system and the actual movement phenomena through repeated voluntary physical movements by the subject. This is intended for use in the treatment of cerebrovascular disorders, ischemic heart disease, or traumatic cerebrospinal nerve disorders in the subject.

[0024] While administering a cell preparation containing such microglia or monocytes treated with oxygen-glucose deprivation (OGD) to a subject, by improving the motor function of the brain, nerve, and muscle systems of the subject, based on combined therapy, the therapeutic effect on cerebrovascular disorders, ischemic heart diseases, or traumatic brain and spinal cord nerve disorders of the subject can be significantly enhanced.

[0025] Also in the present invention, while supplying vibrational energy of ultrasonic vibration or low-frequency vibration with a vibration frequency of 100 [Hz] or less from the outer surface of the head of the subject in a state where it is administered to the subject, the vibrational energy of ultrasonic vibration or low-frequency vibration is propagated throughout the target area in the brain of the subject.

[0026] While administering a cell preparation containing such microglia or monocytes treated with oxygen-glucose deprivation (OGD) to a subject, while improving the motor function of the brain, nerve, and muscle systems of the subject, a complex mechanism of action can be exerted in the brain, improving the microcirculation of the brain tissue, and further enhancing the therapeutic effect on cerebrovascular disorders, ischemic heart diseases, or traumatic brain and spinal cord nerve disorders of the subject.

[0027] Furthermore, in the present invention, a driving unit that applies power to the subject, a signal detection unit that detects the bioelectrical potential signal of the subject, a biosignal processing unit that acquires the neurotransmission signal and electromyogram signal of the subject from the bioelectrical potential signal detected by the signal detection unit, and a voluntary control unit that generates a command signal for generating power according to the will of the subject in the driving unit using the neurotransmission signal and electromyogram signal acquired by the biosignal processing unit, and based on the command signal generated by the voluntary control unit, a drive current generation unit that generates a current corresponding to the neurotransmission signal and a current corresponding to the electromyogram signal respectively and supplies them to the driving unit are used to perform voluntary body movements of the subject.

[0028] When the subject repeatedly performs voluntary movements using the motor function improvement device in this way, it becomes possible to improve the motor function of the brain, nerve, and muscle systems of the subject along with the correction of the difference between the movement command from the brain nervous system and the actual movement phenomenon.

[0029] Furthermore, the present invention includes an action mechanism unit used to be integrated with the subject and having a drive unit that actively or passively drives in conjunction with the subject's physical movements; a signal detection unit that detects changes in ion current transmitted from the subject's brain and nervous system to the muscle system as biopotential signals appearing on the skin surface; a joint detection unit that detects physical quantities around the joints associated with the subject's physical movements based on the output signal from the drive unit; a voluntary control unit that controls the drive unit to produce a movement phenomenon that reflects the subject's intention to move, based on the biopotential signals and physical quantities around the joints; and a data storage unit that stores the reference parameters for each phase, which is a series of minimum movement units constituting the subject's movement patterns classified as tasks. By comparing the physical quantities around the joints with the reference parameters stored in the data storage unit, the phase of the subject's task is estimated, and power corresponding to that phase is supplied. An action function enhancement device is used, which includes an autonomous control unit that controls the drive unit to generate motion, and a synthesis control unit that stores the control ratios of the voluntary control unit and the autonomous control unit set for each task phase in a data storage unit, and synthesizes the control states of the voluntary control unit and the autonomous control unit so that the control ratio corresponds to the phase. The device performs voluntary physical movements of the subject, and the synthesis control unit compensates the physical impedance of the entire system consisting of the entire device and the subject based on physical quantities around the joints, in accordance with the physical characteristics of the entire system, including the subject's physical characteristics, and gravity. At the same time as correcting the difference between the subject's intention to move and the actual movement, the device also provides feedback adjustment to the synthesized control state, based on a bio-self-control loop interactively promoted between the subject's body and the motion mechanism, so as to minimize the difference between the subject's intention to move and the actual movement.

[0030] In this way, when a subject repeatedly performs voluntary movements using the movement mechanism of the motor function enhancement device, it becomes possible to improve the motor function of the subject's brain, nervous system, and muscular system by correcting the difference between the movement commands from the brain and nervous system and the actual movement phenomena.

[0031] Furthermore, in this invention, when forming a biological self-regulation loop, the smallest motor control unit for realizing voluntary movements generated by the subject's will is set as a minimal voluntary motor control unit consisting of the brain and nervous system, synaptic connections, and the muscular system. A biological self-regulation loop is then established for each minimal voluntary motor control unit that forms a coordinated bodily movement to realize the motor phenomenon, using a motion mechanism.

[0032] In this way, by explicitly incorporating the influence of disease site and disease cause into the functional improvement and treatment process based on the fundamental theory of the bio-self-regulation loop by the movement mechanism, the minimal voluntary movement control unit in the motor function improvement device will also be affected, and the coordination will progress in sync with the movement of the movement mechanism. In order to achieve the target movement, the function of each minimal voluntary movement control unit will be strengthened and adjusted in sync with the movement of the movement mechanism, thereby improving the function of the brain, nervous system, and muscular system.

[0033] Furthermore, in this invention, when supplying ultrasonic vibration or low-frequency vibration energy from multiple locations around the head of a subject, scattering of the ultrasonic vibration or low-frequency vibration is induced, and a phase difference is created between them.

[0034] In this way, multiple ultrasonic vibrations or low-frequency vibrations that penetrate the subject's brain can be propagated throughout the entire target area within the brain without resonance.

[0035] Furthermore, in this invention, the vibration energy of ultrasonic vibration or low-frequency vibration is set such that the vibration generation sound pressure is 0.1 to 1.5 [MPa], the irradiation time for a single use on the subject is set to a maximum of 20 minutes, and when repeated use is performed, the total irradiation time per day is set to a maximum of 60 minutes with an interval of 5 minutes between sessions.

[0036] In this way, by setting the sound pressure generated by ultrasonic or low-frequency vibration energy within a range that provides appropriate tissue amplitude to the brain, and by setting limits on the irradiation time for each use, as well as setting upper limits on the time interval when repeated and the total time per day, it becomes possible to sustain the effect of improving microcirculation in the brain tissue of the subject for a relatively long period after use.

[0037] Furthermore, in this invention, the vibrational energy of ultrasonic vibration or low-frequency vibration is diffused omnidirectionally while scattering from the supply direction, stimulating vascular cells with ultrasonic / low-frequency vibration and promoting the expression of eNOS, VEGF, and bFGF.

[0038] In this way, by scattering the vibrational energy of ultrasonic or low-frequency vibrations in all directions from the direction of irradiation, it becomes possible to enhance the expression of eNOS (endothelial nitric oxide synthase), VEGF (vascular endothelial growth factor), and bFGF (basic fibroblast growth factor), thereby improving the microcirculation of the brain tissue of the subject.

[0039] Furthermore, in this invention, vibrational energy of ultrasonic vibration or low-frequency vibration is sequentially supplied from multiple locations around the head of the subject at predetermined time intervals, and at the same time, each vibrational energy is supplied in a non-focused manner and diffused in an inverse tapered shape that gradually expands in the direction of radiation.

[0040] In this way, when non-focused vibrational energy is supplied sequentially from multiple locations, the irradiation or reflected wave of the non-focused vibrational energy generated from one location is attenuated, preventing excessive vibrational stimulation even if it overlaps with the non-focused vibrational energy generated from the next location, thus enabling the brain to receive appropriate tissue amplitude.

[0041] Furthermore, in this invention, the vibration energy of ultrasonic vibration or low-frequency vibration is supplied to the subject continuously for 15 to 60 minutes, with the angle of expansion of the expanding inverse tapered inclined surface being 50° to 100° and the vibration generation sound pressure being 0.1 to 1.5 [MPa].

[0042] In this way, by setting the angle of the expanding inverse tapered slope surface in the vibration energy of ultrasonic vibration or low-frequency vibration to a range that can be transmitted to the entire brain, and by setting the sound pressure generated by the vibration energy to a range that provides appropriate tissue amplitude to the brain, and by limiting the irradiation time for each use on the subject and repeating the process, it becomes possible to sustain the effect of improving microcirculation in the brain tissue of the subject for a relatively long period after use.

[0043] Furthermore, in this invention, the cell population containing monocytes is peripheral blood cells or their cell fraction, or a fraction containing mononuclear cells collected from peripheral blood, the hypoxia concentration is an oxygen concentration of 0.1-0.4%, and the culture time is approximately 18 hours.

[0044] Thus, with cell-based therapies, culturing under optimal conditions based on experiments can further promote angiogenesis and axonal extension, thereby enhancing the therapeutic effect. [Effects of the Invention]

[0045] According to the present invention, it is possible to realize a cell preparation that, based on combination therapy, can significantly enhance the therapeutic effect of treating cerebrovascular disorders, ischemic heart disease, or traumatic cerebrospinal nerve disorders in subjects compared to conventional methods. [Brief explanation of the drawing]

[0046] [Figure 1] This figure shows the mechanism of OGD pre-treated microglia transplantation after cerebral ischemia. [Figure 2] This is a conceptual diagram illustrating the basic theory of the biological self-regulation loop according to the present invention. [Figure 3] This is a conceptual diagram illustrating the minimal voluntary movement control unit. [Figure 4] This is a conceptual diagram showing the transition states when the basic theory of the biological self-regulation loop described above is applied to the subject. [Figure 5] This is a schematic diagram showing the external configuration of the motion function improvement device, including the waist-type motion mechanism, in this embodiment. [Figure 6] Figure 5 is a schematic diagram showing the main components of the device for improving operational functionality. [Figure 7] Figure 5 is a schematic diagram showing the operating state and range of motion of the device for improving the operational function. [Figure 8] Figure 5 is a block diagram showing the configuration of the control system for the device that enhances the operational function. [Figure 9] This is a conceptual diagram showing an example of each task and phase stored in the data storage unit. [Figure 10] This figure illustrates the functional improvement effect achieved by using a device that enhances operational function. [Figure 11] This figure illustrates the functional improvement effect achieved by using a device that enhances operational function. [Figure 12] This is an external perspective view showing the configuration of the condition improvement acceleration system according to this embodiment. [Figure 13] Figure 12 is a conceptual diagram showing the circuit configuration of the control system in the condition improvement acceleration system. [Figure 14] This is a conceptual diagram showing the circuit configuration of the control system in a state improvement acceleration device when the scattering induction unit of another embodiment is applied. [Figure 15] This is a conceptual diagram showing the circuit configuration of the control system in a state improvement acceleration device when the scattering induction unit of another embodiment is applied. [Modes for carrying out the invention]

[0047] An embodiment of the present invention will be described in detail below with reference to the drawings.

[0048] (1) Prerequisite cell preparation (Summary of the invention based on Japanese Patent Publication No. 7089283) In this embodiment, mononuclear cells, including microglia or monocytes treated with oxygen glucose deprivation (OGD), are administered intravascularly to the subject, making it possible to treat cerebral infarction by preventing worsening after the onset of cerebral infarction and promoting angiogenesis and axonal extension.

[0049] Experimental results using human PMNCs indicate that in order to confer the ability to promote angiogenesis and / or axonal extension to microglia and monocytes, it is sufficient to stimulate the cell population to approximate an ischemic state, and for this purpose, culturing the cell population under OGD conditions is most preferable.

[0050] Furthermore, experimental results using rats and human PMNCs show that monocytes that migrate from blood vessels to the brain parenchyma become microglia; therefore, a cell population containing monocytes, either in place of microglia or together with microglia, may be cultured under OGD conditions. If the cell population contains monocytes, it may be peripheral blood cells or their cell fractions, for example, a fraction containing mononuclear cells collected from peripheral blood.

[0051] Specifically, cell preparations that have the ability to promote angiogenesis and axonal extension are produced by culturing a cell population including microglia and / or monocytes under conditions of low oxygen concentration (less than 1%) and low glucose concentration (less than 1.0 g / L) for 12 to 24 hours.

[0052] Furthermore, the cell population containing monocytes consists of peripheral blood cells or their cell fractions, or a fraction containing mononuclear cells collected from peripheral blood. The hypoxia concentration is 0.1-0.4%, and the culture time is approximately 18 hours.

[0053] Figure 1 shows the mechanism of OGD-pretreated microglia transplantation after cerebral ischemia. OGD-pretreated microglia directly secrete VEGF, TGF-β, and MMP-9. These factors may be due to paracrine secretions from resident cells via remodeling factors secreted by OGD-pretreated microglia. These factors directly promote angiogenesis in the ischemic center. The ischemic center is defined as a MAP2-immuno-negative site, which consists of irreversible angiogenesis-negative ischemic centers and angiogenesis-positive ischemic centers that exhibit angiogenesis.

[0054] MMP-9 from microglia reduces the expression of CSPG, an axon extension inhibitor. This makes it easier to induce axon extension. In addition, VEGF, TGF-β, and MMP-9 may directly induce axon extension. Monocytes migrate from cerebral blood vessels through the blood-brain barrier (BBB) ​​to the brain parenchyma and differentiate into microglia. Since monocytes can be easily collected from peripheral blood, they can be obtained with less invasiveness than microglia.

[0055] Thus, cultures of cells containing microglia or monocytes treated with OGD are characterized by having the following physical properties compared to cultures treated under normal oxygen and glucose concentration conditions (or the same cell group before OGD treatment): (a) significantly higher secretion of VEGF, (b) significantly higher secretion of MMP-9, and (c) significantly higher secretion of TGF-β.

[0056] Since VEGF, MMP-9, and TGF-β have angiogenesis and axon extension promoting effects, administering OGD-treated cultures can induce regeneration of nerve tissue damaged or destroyed by ischemia or hemorrhage.

[0057] Furthermore, cultures of cells containing microglia or monocytes treated with OGD have the following additional properties compared to cultures treated under normal oxygen and glucose concentrations (or the same cell population before OGD treatment): (d) a significantly higher ratio of TGF-β secretion to TNF-α secretion, and / or (e) a significantly lower secretion of IL-6. In other words, by predominantly secreting anti-inflammatory cytokines compared to inflammatory cytokines, an anti-inflammatory effect can be achieved at the ischemic / hemorrhagic site.

[0058] Therefore, cell preparations containing cultures of cells including microglia or monocytes treated with OGD can be used to treat ischemic cerebrovascular disease or ischemic heart disease, and are expected to promote angiogenesis and have anti-inflammatory effects. This ischemic cerebrovascular disease refers to so-called cerebrovascular disorders, and includes not only cerebral infarction (cerebral thrombosis, cerebral embolism) but also hemorrhagic encephalopathy (intracranial hemorrhage, subarachnoid hemorrhage). Cerebral infarction is a preferred indication. Cell preparations containing cultures of cells including monocytes treated with OGD can also be used for ischemic diseases such as ischemic heart disease (e.g., myocardial infarction). Alternatively, they can be used for traumatic cerebrospinal nerve injuries.

[0059] Methods for delivering cell preparations to the affected area of ​​a subject include, for example, local transplantation by surgical means, intravenous administration, local injection administration, subcutaneous administration, intradermal administration, intraperitoneal administration, intramuscular administration, intracerebral administration, intraventricular administration, or intra-arterial administration.

[0060] Cell transplantation by injection into a subject can be performed, for example, when used to repair the nervous system. The cells to be transplanted are suspended in artificial cerebrospinal fluid or saline solution and stored in a syringe. The damaged nerve tissue is then exposed through surgery, and the cells are directly injected into the damaged area using a needle. Alternatively, the cells may be transplanted near the damaged area, and injection into the cerebrospinal fluid can also be effective. Furthermore, intravenous injection can also be effective.

[0061] (2) Basic theory of bio-self-regulation loops using functional enhancement devices While medical research focuses on elucidating information processing in the brain as a method to improve the motor function of the brain, nervous system, and muscular system of subjects, brain research alone is insufficient to target physical motor function because it separates the motor system from the brain.

[0062] The human motor system consists of the central nervous system (brain and spinal cord), the peripheral nervous system, and the musculoskeletal system. While these systems form an interconnected information transmission system when dealing with the flow of efferent nerve information that travels from the central nervous system to the periphery, this alone is not sufficient to achieve proper motor control.

[0063] In other words, while efferent nerve information is transmitted to muscle fibers involved in muscle contraction, information after contraction is not returned to the brain, even though it is transmitted from the brain through the spinal cord to the muscle fibers via motor nerves. For this reason, simply analyzing the "motor unit" composed of motor nerves and muscle fibers makes it virtually impossible to elucidate the mechanisms of improving motor function or to create technologies for improving motor control.

[0064] For this reason, some research attempts to improve function by using robotic technology to move the joints and muscles of the legs and hands through external motion input. However, it has also been reported that simply applying external force to move the joints and muscles of the legs and hands does not lead to functional improvement.

[0065] In this invention, using an action mechanism (the main mechanism of the motion function improvement device 10 shown in Figure 5, described later) having a drive unit that is actively or passively driven in conjunction with the subject's physical movements, we demonstrate that when a subject performs a specific action, as shown in Figure 2, command signals (efferent nerve signals) that attempt to move according to the intention to move, and sensory signals (afferent nerve signals) generated by being able to move, travel back and forth between the central system (brain and spinal cord) and the peripheral system (motor nerves, muscular system, and sensory nerves), thereby improving and reconstructing the physical functions necessary for voluntary movement.

[0066] The method for improving the function of the operating mechanism according to the present invention includes a voluntary control step for causing the operating mechanism to move in accordance with the subject's intention to move, an autonomous control step for generating a preset ideal power, and an impedance control step (including gravity compensation control) for reducing the feeling of difficulty in movement due to the load and viscous friction of the operating mechanism itself. As a result, the subject can feel as if the operating mechanism is an extension of their own body, and a functional fusion and integration between the subject and the operating mechanism can be achieved.

[0067] Furthermore, in this method for improving operational function, the synthesis control step, which synthesizes control states from voluntary control steps and autonomous control steps to achieve a control ratio corresponding to the phase of the task, not only executes the impedance control step described above, but also, based on a bio-self-regulation loop interactively promoted between the subject's body and the motor mechanism, corrects the difference with movement commands from the brain and nervous system, while simultaneously providing feedback adjustment to the synthesized control state, so as to minimize the difference between the subject's intention to move and the actual movement.

[0068] This biological self-regulation loop is formed when, in sync with the transmission of nervous system commands from the brain through the spinal cord to muscle fibers via motor nerves, causing muscle contraction, proprioceptors called muscle spindles and tendon spindles in the muscles and tendons are activated. This activation information is then fed back to the central nervous system (spinal cord and brain) via sensory nerves as information about muscle contraction, and this feedback information is used to strengthen and regulate synaptic connections between nerves and between nerves and muscles. This cycle is repeated, forming the loop.

[0069] In this way, in the method for improving motor function, when the subject repeatedly performs voluntary movements using the motor mechanism, it becomes possible to improve the motor function of the subject's brain, nerve, and muscle systems by correcting the difference between the motor commands from the brain and nervous system and the actual motor phenomena.

[0070] One of the features of the present invention is that, in forming a biological self-regulation loop, a minimal voluntary motor control unit consisting of the cranial nervous system (brain and spinal cord), synaptic connections (synaptic connections between nerves and synaptic connections between nerves and muscles), and the muscular system (muscle fibers (extrafusal muscle fibers to which α motor neurons connect and intrafusal muscle fibers to which γ motor neurons connect), tendon fibers, muscle spindles, tendon spindles, etc.) can be configured as the smallest motor control unit for realizing voluntary movements that arise from a person's will in order to establish a biological self-regulation loop.

[0071] In other words, the minimal voluntary movement control unit is the control unit that realizes the smallest voluntary movement, formed through pathways such as the cranial nervous system (brain, spinal cord, motor nerves), muscle fibers, movement (response), muscle spindles / tendon spindles, and the cranial nervous system (sensory nerves, spinal nerves, brain), as shown in Figure 3.

[0072] Multiple minimal voluntary movement control units, each forming a specific joint movement, are configured in conjunction with other minimal voluntary movement control units that interact with the aforementioned unit, thereby achieving the desired overall movement.

[0073] In this process, the synaptic connections between nerves and between nerves and muscles within the minimal voluntary movement control units are adjusted and strengthened within the overall regulatory system, such as the group of minimal voluntary movement control units related to the target overall movement, and the unconscious adjustment of postural balance.

[0074] Furthermore, by using the movement mechanism (such as the lower limb type, single-joint type, waist type, hand type, and finger type described later) in joint movements driven by muscle groups (so-called flexion and extension muscle groups) composed of minimal voluntary movement control units (units), and in more complex and coordinated movements composed of each joint system, it becomes possible to accommodate everything from the smallest units to higher-order complex body systems, thereby achieving functional improvements in the brain, nervous system, and muscular system.

[0075] In fact, when the minimal voluntary movement control unit is considered a unit that promotes synaptic plasticity, neural plasticity, and muscle plasticity—basic neural functions for improving the function of the brain, nervous system, and muscular system—the process of activating the subject's self-healing ability according to the disease or symptoms (such as flaccidity, stiffness, tremors, rigidity, ataxia, and co-contraction) will differ for each of these minimal voluntary movement control units.

[0076] Therefore, the unit components of the minimal voluntary movement control unit for improving motor function of the brain, nerve, and muscular systems differ for each disease or symptom, and the relevant parts and ranges of other minimal voluntary movement control units that the said minimal voluntary movement control unit is involved in also differ. Thus, by using it as the smallest unit when making various adjustments to the movement mechanism section 20 (Figures 5 to 7 described later) in the motor function improvement device 10 according to the subject's condition (such as tuning parameters to realize movement according to the subject's intention to move and establish a biological self-control loop), it becomes possible to construct a treatment control strategy.

[0077] In the method for improving motor function according to the present invention, by detecting signals originating from the nervous system that are linked to voluntary will obtained from pathways affected by the disease site and cause of the disease, the method focuses on the minimal voluntary motor control units involved in those pathways and performs functional improvements on each minimal voluntary motor control unit that constitutes the target overall voluntary movement.

[0078] For voluntary movement to be achieved in humans, the starting point is the expression of the intention to move voluntarily in the cerebrum. The neural signals of this intention are transmitted from the brain to the spinal cord, motor nerves, and muscle fibers, ultimately resulting in the achievement of the target movement. However, this flow is too broad, from the expression of intention to the generation of movement. Therefore, it is difficult to explicitly grasp the influence of disease sites and causes on voluntary movement, from the brain and nervous system through synaptic connections to the muscular system, including sensory nerves in muscle fibers and muscle spindles and the gamma loop formed by gamma motor neurons. It is also difficult to explicitly perform treatment that takes the influence of disease sites and causes into account. For this reason, in actual clinical practice, training is limited to the repetition of simple movements.

[0079] Therefore, by explicitly incorporating minimal voluntary movement control units that reflect the influence of the disease site and cause into the functional improvement treatment process based on the basic theory of the biological self-regulation loop by the movement mechanism unit 20 (Figures 5-7), the effects extend to other minimal voluntary movement control units, causing them to work in sync with the movement of the movement mechanism unit 20. To achieve the target movement, each minimal voluntary movement control unit strengthens and adjusts the function of its unit components in sync with the movement of the movement mechanism unit, thereby enabling functional improvement of the brain, nervous system, and muscular system as a new method different from conventional approaches.

[0080] Figures 4(A) to 4(E) show the transition states when the basic theory of the biological self-regulation loop described above is applied to the subject. Starting from the state before treatment when the movement mechanism 20 is not attached (Figure 4(A)), in the initial stages of treatment, sensory nerve information from the musculoskeletal system is fed back to the central nervous system (brain and spinal cord) through joint movement using the movement mechanism 20 (Figure 4(B)).

[0081] Subsequently, in the state without the motor mechanism 20 after initial treatment (Figure 4(C)), some feedback sensation from sensory nervous system information remains. However, by continuing treatment using the motor mechanism 20 (Figure 4(D)), the difference between the subject's intention to move and the actual movement phenomenon, based on a bio-self-regulation loop interactively promoted between the subject's body and the motor mechanism 20, is corrected by movement commands from the central nervous system.

[0082] Furthermore, even when the motor mechanism 20 is not attached after continuous treatment, the motor function of the subject's brain, nerve, and muscular systems can be improved by correcting the difference between the motor commands from the central nervous system and the actual motor phenomena, thereby activating the subject's self-healing ability (Figure 4(E)).

[0083] (3) Configuration of the device for improving the operation function in this embodiment (3-1) Configuration of the operating mechanism (waist type: hardware) Figures 5(A) and (B) show the motion function improvement device 10, including the waist-type motion mechanism 20 in this embodiment. Figures 6(A) and (B) show the main components of the motion mechanism 20, excluding the thigh cuff, belt, etc. The motion function improvement device 10 is a device that assists the work and movements of a subject, and it detects bioelectric potential signals, the motion angle of the subject's hip joint, and the absolute angle of the torso, and operates by applying driving force from the drive unit based on these detected signals.

[0084] When a subject wearing the motion function enhancement device 10 lifts and carries a relatively heavy object of their own volition, the bioelectric potential signals on the skin surface of the latissimus dorsi or gluteus maximus muscles and the driving torque corresponding to the movement angle of the subject's hip joint are applied as assisting force from the motion mechanism 20. Therefore, the subject can lift and carry the object using the combined force of their own muscle strength and the driving torque from the drive mechanism (actuator).

[0085] Furthermore, the motion enhancement device 10 can assist not only with transport tasks such as lifting an object and walking, but also with tasks such as ascending and descending stairs while the subject is carrying luggage.

[0086] In the motion mechanism section 20 of the motion function enhancement device 10, a lumbar frame 30 is attached to the posterior side of the subject's waist, extending in the left-right direction. The lumbar frame 30 is, for example, a hollow member made of CFRP (carbon fiber reinforced plastic) and has a rounded shape that conforms to the shape of the posterior and both sides of the human waist.

[0087] The lumbar frame 30 is configured such that a first lumbar frame 30A, which is attached to the back of the subject's lumbar region from left to right, and a second lumbar frame 30B, which is attached above the first lumbar frame 30A and also extends from left to right, are connected via a support column 31.

[0088] The first lumbar frame 30A and the second lumbar frame 30B are attached to the subject's waist by attachment belts 32 and 33 that are passed across the subject's ventral side. When attached, the first lumbar frame 30A and the second lumbar frame 30B are attached in a forward-leaning posture such that both ends are lower than the back side, that is, both ends are positioned lower than the longitudinal center (the part located on the back side of the subject).

[0089] Left-side frame 40 and right-side frame 41 are fixed to both ends of the first lumbar frame 30A and the second lumbar frame 30B.

[0090] Furthermore, on the outer side opposite to the mounting side of the operating mechanism unit 20, a battery 42 is detachably housed in the central part of the first waist frame 30A, and wiring connected to the battery 42 is inserted into the internal space.

[0091] The support column 31 is a member that connects the longitudinal center of the first waist frame 30A and the longitudinal center of the second waist frame 30B in the vertical direction. The support column 31 is, for example, a hollow member made of reinforced resin, and sensor wiring is inserted through its interior. A control device 80 (Figure 8, described later) that controls the operation of the operating mechanism 20 is also provided inside the support column 31.

[0092] The support column 31 holds the various components constituting the first waist frame 30A and the second waist frame 30B in place, preventing them from rotating, thereby ensuring the strength of the monocoque structure. In addition, a mounting belt 32 corresponding to the first waist frame 30A and a mounting belt 33 corresponding to the second waist frame 30B are attached to the support column 31, respectively.

[0093] The left-side frame 40 is fixed by joining the left end of the first lumbar frame 30A and the left end of the second lumbar frame 30B on the left side of the subject's hip joint. The right-side frame 41 has a structure that is substantially symmetrical to the left-side frame 40 and is fixed by joining the right end of the first lumbar frame 30A and the right end of the second lumbar frame 30B.

[0094] The left side frame 40 houses an actuator and a brake mechanism (neither shown), and is provided with a minus button 43 for inputting a reduction in the driving force of the actuator. This minus button 43 lights up when the power supply of the function enhancement device is turned on.

[0095] The right-side frame 41 houses an actuator and a brake mechanism (neither shown), and is provided with a plus button 44 for inputting an increased driving force for the actuator, and a power button 45 for switching the power of the performance enhancement device 10 on and off. The plus button 44 and power button 45 light up when the power of the performance enhancement device 10 is turned on.

[0096] In this way, the lumbar frame (first lumbar frame 30A and second lumbar frame 30B), the support column 31, and the side frames (left side frame 40 and right side frame 41) are assembled to form a single integrated structure, thereby realizing a monocoque structure in which the frame itself bears the stress.

[0097] In Figures 6(A) and (B), the thigh fixation part 50 consists of a left thigh fixation part 50L that fixes the left thigh of the subject and a right thigh fixation part 50R that fixes the right thigh of the subject.

[0098] The left thigh fixing portion 50L consists of a stay portion 51L connected to an actuator in the left side frame 40 and a belt portion 52L attached to the stay portion 51L, and is rotatably mounted relative to the left side frame 40 in a side view.

[0099] Furthermore, the right thigh fixing portion 50R is composed of a stay portion 51R connected to an actuator in the right side frame 41 and a belt portion 52R attached to the stay portion 51R, and is provided so as to be rotatable in a side view relative to the right side frame 41.

[0100] In addition, in the left thigh fixing section 50L and the right thigh fixing section 50R, the stay sections 51L and 51R are designed to be of an optimal length based on the average length of a human thigh, and the subject's thigh is fixed by the belt sections 52L and 52R.

[0101] The attachment belt 32 is an attachment belt that is passed across the ventral side when attaching the first lumbar frame 30A to the subject, and serves as the main attachment point for the operating mechanism 20 to the waist of the human body.

[0102] The attachment belt 33 is an attachment belt that is passed across the abdominal side when attaching the second lumbar frame 30B to the subject. The attachment belt 33 is used to fix the motion mechanism 20 to the human body above the attachment belt 33 in order to efficiently transmit the reaction force generated by the leg movement to the subject's abdomen or waist when the subject wearing the motion mechanism 20 lifts a relatively heavy object from a bent-knee position.

[0103] The battery 42 is located on the outside of the central part of the first waist frame 30A, on the side opposite to the mounting side of the operating mechanism 20, and supplies power to the control device, actuator, brake mechanism (not shown), minus button 43, plus button 44, and power button 45.

[0104] The biosignal detection unit 60, which has a biopotential sensor, is attached to the back of the subject's lower back and is a detection unit that detects biopotential signals associated with muscle activity when the subject tries to raise their torso or when they try to maintain the angle of their torso.

[0105] The bioelectric potential sensors of the biosignal detection unit 60 are connected to the ends of wiring that extends from holes in the support column 31 to the outside of the support column, and there are three of them. The bioelectric potential sensors are attached to the back of the subject's lower back to detect bioelectric potential signals generated when the subject moves the muscles of their trunk.

[0106] The biopotential signal detected by the biosignal detection unit 60 is input to the control device. The biopotential sensor may be attached to the subject's back using tape or the like, or it may be attached using gel or the like. One of the three sensors is used to measure the reference signal, and the remaining two sensors are used to measure the biopotential signal.

[0107] In fact, in the motion function improvement device 10, the motion mechanism 20 is attached to the subject's waist from the rear. The motion function improvement device 10 is a device that generates assisting force to help the movement of the thighs relative to the waist when the subject stands up from a bent-over position (half-crouching posture) as shown in Figure 7(A) to a standing position as shown in Figure 7(B). Such movements of the subject include, for example, standing up from a half-crouching posture, lifting an object from a half-crouching posture, and movements during transfer assistance.

[0108] Figure 7(C) is a diagram (left side view) showing the range of motion of the motion mechanism 20 in the motion function improvement device 10. The left thigh fixing part 50L can rotate 130° clockwise and 30° counterclockwise from the reference position shown in Figure 7(C), with the left side frame 40 as the center of rotation. Through this movement, the motion function improvement device 10 generates an assisting force to support the movement of the thigh relative to the waist when the subject moves from a bent-over position as shown in Figure 7(A) to a standing position as shown in Figure 7(B). The range of motion of the right thigh fixing part 50R is similar.

[0109] In this embodiment, the waist-type motion function enhancement device 10 has a control system 70 as shown in Figure 8, which will be described later. As a result, the motion function enhancement device 10 also functionally includes a voluntary control step for performing actions according to the subject's intention to move, an autonomous control step for generating a preset ideal power, and an impedance control step (including gravity compensation control) for reducing the feeling of difficulty in movement due to the load and viscous friction of the motion mechanism 20 itself.

[0110] As a result, in the waist-type motion function improvement device 10, the subject can feel as if the motion mechanism 20 is an extension of their own body, making it possible to achieve functional fusion and integration between the subject and the motion mechanism 20.

[0111] In fact, the motion function improvement device 10 can generate an assisting force to support the movement of the thighs relative to the waist when the subject moves from a crouched position as shown in Figure 7(A) to a standing position as shown in Figure 7(B). This assisting force is generated when the drive unit (actuator) is driven based on bioelectric potential signals, which are detected by the biosignal detection unit 60, and are associated with muscle activity when the subject tries to raise their trunk or maintain the angle of their trunk.

[0112] Therefore, it is possible to provide a highly convenient motor function improvement device 10 that can provide the necessary assistive force in the necessary direction according to the subject's will. Furthermore, it is possible to provide a motor function improvement device 10 that can minimize the amount of power (muscle strength) that the subject must generate themselves, and that can prevent situations that impair the subject's convenience.

[0113] Furthermore, the control device 80 (Figure 8) is configured to determine that the subject is walking if it determines that the signal levels of the biological signals in the subject's left and right thighs are not equal, while determining that the subject is stationary if it determines that the signal levels are equal.

[0114] Furthermore, when the control device 80 determines that the subject is in a stationary state, if it determines that both the left and right hip joint angles are greater than a predetermined specified angle, it determines that the subject is walking. Conversely, if it determines that the angles are less than or equal to the specified angle, it determines that the subject is in a posture with their upper body lowered forward.

[0115] Furthermore, in the motion function enhancement device 10, the synthesis control step, which synthesizes the control states from the voluntary control step and the autonomous control step to achieve a control ratio corresponding to the phase of the task, not only executes the impedance control step described above, but also, based on a bio-self-control loop interactively promoted between the subject's body and the motion mechanism, corrects the difference with motion commands from the brain and nervous system, and simultaneously provides feedback adjustment to the synthesized control state, so as to minimize the difference between the subject's intention to move and the actual movement.

[0116] As a result, with the motor function improvement device 10, when a subject repeatedly performs voluntary movements using the motor mechanism 20, it becomes possible to improve the motor function of the subject's brain, nerve, and muscle systems by correcting the difference between the movement commands from the brain and nervous system and the actual movement phenomena.

[0117] Furthermore, in the motor function improvement device 10, when forming a biological self-control loop, the smallest motor control unit for realizing voluntary movements generated by the subject's will is set as a minimal voluntary motor control unit consisting of the brain and nervous system, synaptic connections, and the muscular system. The motor mechanism unit 20 is used to establish a biological self-control loop for each minimal voluntary motor control unit that forms a coordinated bodily movement to realize a motor phenomenon.

[0118] As a result, in the motor function improvement device 10, by explicitly incorporating the influence of disease site and disease cause into the process of functional improvement and treatment based on the basic theory of the bio-self-regulation loop by the motor mechanism, the effect extends to other minimal voluntary movement control units, causing them to work in sync with the operation of the motor mechanism 20. This strengthens and adjusts the function of each minimal voluntary movement control unit in sync with the operation of the motor mechanism to achieve the target movement, thereby improving the function of the brain, nervous system, and muscular system.

[0119] (3-2) Control system in the device for improving operational function Figure 8 is a block diagram showing the configuration of the control system 70 of the motion function improvement device 10. As shown in Figure 8, the control system 70 of the motion function improvement device 10 includes a control device 80 that is in charge of overall control of the entire system, a data storage unit 81 in which various data are stored in a database that can be read and written according to the commands of the control device 80, and drive units 82L and 82R that are driven actively or passively in conjunction with the lower limb movements of the subject.

[0120] Furthermore, the control system 70 is equipped with a joint detection unit 90 having a potentiometer 83, an absolute angle sensor 84, and a torque sensor 85, which detects physical quantities around the joints associated with the subject's body movements based on output signals from the drive units 82L and 82R.

[0121] The joint detection unit 90 detects the absolute angle, rotation angle, angular velocity, angular acceleration, and drive torque between the rotor-side frame and the stator-side frame of the drive units 82L and 82R in the operating mechanism unit 20 as physical quantities around the joint.

[0122] The potentiometer 83 is located coaxially with the output shaft of the actuator in the drive units 82L and 82R, and detects the joint angle corresponding to the lower limb movement of the subject by detecting the rotation angle of the output shaft.

[0123] The absolute angle sensor 84 is mounted on the side frame (left side frame 40 and right side frame 41) and measures the absolute angle of the subject's thigh relative to the vertical direction. This absolute angle sensor 84 consists of an accelerometer and a gyroscope and is used in sensor fusion, a method of extracting new information using data from multiple sensors.

[0124] To calculate the absolute angle of the thigh, a first-order filter is used to remove the effects of translational motion and temperature drift in each sensor. This first-order filter is calculated by weighting and adding the values ​​obtained from each sensor.

[0125] If θabs(k) is the absolute angle of the thigh with respect to the vertical, ω is the angular velocity obtained by the gyro sensor, dt is the sampling period, and α is the acceleration obtained by the accelerometer, then θabs(t) can be expressed as shown in equation (1) below.

number

[0126] Furthermore, the torque sensor 85 detects the current value supplied to the drive units 82L and 82R, and detects the drive torque by multiplying this current value by a torque constant specific to the actuator.

[0127] A biosignal detection unit 60, equipped with biopotential sensors (electrode groups), is positioned on the body surface of the subject (mainly the body surface of the thigh) based on the joints associated with the subject's lower limb movements. This unit detects changes in ion current transmitted from the subject's brain and nervous system to the muscle system as biopotential signals appearing on the skin surface.

[0128] The biosignal detection unit 60 is a detection unit that measures nerve action potentials emitted from the brain to the legs to move the subject's legs, and muscle action potentials generated when skeletal muscles generate muscle force, and has electrodes that detect weak potentials generated at the periphery of the body system. In this embodiment, the biopotential sensor is attached so as to be detachably attached to the surface of the subject's skin by means of, for example, an adhesive seal that covers the area around the electrodes.

[0129] The data storage unit 81 stores data necessary for performing various calculations in the control device 80. Bioelectric potential signals detected by the biosignal detection unit 60 are stored in the data storage unit 81. Joint angle (θknee, θhip) data detected by the absolute angle sensor 84 of the joint circumference detection unit 90 is input to the data storage unit 81.

[0130] The control device 80 is composed of, for example, a CPU (Central Processing Unit) chip with memory, and includes a discretionary control unit 100, an autonomous control unit 101, and a composite control unit 102.

[0131] The voluntary control unit 100 controls the drive units 82L and 82R based on bioelectric signals and physical quantities around the joints, so that the movement phenomena reflect the subject's intention to move. Specifically, the voluntary control unit 100 supplies a command signal to the current control unit 105 corresponding to the detection signal from the biosignal detection unit 60.

[0132] The discretionary control unit 100 generates a command signal by applying a predetermined command function f(t) or gain P to the biosignal detection unit 60. This gain P is a preset value or function and can be adjusted by an external input.

[0133] The knee joint angle data detected by the potentiometer 83, the absolute angle data of the thigh relative to the vertical direction detected by the absolute angle sensor 84, the drive torque detected by the torque sensor 85, and the bioelectric potential signal detected by the biosignal detection unit 60 are input to the data storage unit 81.

[0134] The autonomous control unit 101 stores the reference parameters for each phase, which is a series of minimum operating units that constitute the operation pattern of the subject classified as a task, in the data storage unit 81. By comparing the physical quantities around the joints with the reference parameters stored in the data storage unit 81, it estimates the phase of the subject's task and controls the drive unit to generate power corresponding to that phase.

[0135] The autonomous control unit 101 compares the knee joint angle data detected by the joint detection unit (potentiometer 83) 90 with the knee joint angle of a reference parameter stored in the data storage unit 81, and estimates the phase of the subject's movement based on the comparison result.

[0136] Then, when the autonomous control unit 101 obtains the control data for the estimated phase, it generates a command signal corresponding to the control data for this phase and supplies this command signal to the current control unit 105 to generate power in the drive units 82L and 82R.

[0137] Furthermore, the autonomous control unit 101 receives a gain adjusted by an external input, generates a command signal corresponding to this gain, and outputs it to the current control unit 105. The current control unit 105 controls the current that drives the actuators of the drive units 82L and 82R, thereby controlling the magnitude of the actuator torque and the rotation angle, and thus applying an assisting force from the actuators to the knee joint of the subject.

[0138] In this way, the autonomous control unit 101 identifies phases corresponding to the subject's task based on the physical quantities detected by the joint detection unit (potentiometer 83, absolute angle sensor 84, and torque sensor 85) 90, and generates power corresponding to each phase in the drive units 82L and 82R.

[0139] The combined control unit 102 combines the control signals from the voluntary control unit 100 and the autonomous control unit 101, and the current control unit 105 amplifies the drive current corresponding to the combined control signal and supplies it to the actuators of the drive units 82L and 82R. The torque of these actuators is transmitted to the knee joint of the subject as an assist force via the lumbar frame 30.

[0140] Figure 9 shows an example of each task and phase stored in the data storage unit 81. Tasks that classify the subject's movements include, for example, Task A, which has data on standing up from a seated position to a standing position; Task B, which has data on walking after the subject has stood up; Task C, which has data on sitting up from a standing position to a seated position; and Task D, which has data on climbing stairs from a standing position to going up and down stairs. These tasks are stored in the data storage unit 81.

[0141] Furthermore, each task has multiple phase data sets. For example, task B, which involves walking, has phase B containing motion data (such as joint angles, trajectory of the center of gravity, torque fluctuations, and changes in bioelectric signals) when swinging the right leg forward from a standing position with the center of gravity on the left leg; phase B containing motion data when landing and shifting the center of gravity from a position with the center of gravity on the right leg; phase B containing motion data when swinging the left leg forward from a standing position with the center of gravity on the right leg; and phase B containing motion data when landing and shifting the center of gravity from a position with the left leg in front of the right leg.

[0142] Thus, by analyzing typical human movements, it becomes clear that typical movement patterns, such as the angles of each joint and the movement of the center of gravity, are determined for each phase. Therefore, for each phase that constitutes numerous basic human movements (tasks), typical joint angle displacements and center of gravity movement states are empirically determined and stored in the data storage unit 81. In addition, multiple assist patterns are assigned to each phase, and different assists are provided for the same phase depending on the assist pattern.

[0143] In the above configuration, the function enhancement device 10 detects changes in ion current transmitted from the subject's brain and nervous system to the muscle system as bioelectric potential signals appearing on the skin surface using the biosignal detection unit 60, and operates to apply driving force from the drive units (actuators) 82L and 82R based on these detected signals.

[0144] When a subject wearing the motion mechanism 20 attempts to perform lower limb movements of their own volition, the motion mechanism 20 provides a driving torque as an assisting force corresponding to the bioelectric potential signals generated. In other words, the assisting force is a force that generates torque acting around each joint in the frame mechanism of the motion mechanism 20 (corresponding to the subject's knee and hip joints, respectively) as the axis of rotation.

[0145] Therefore, the subject can perform walking movements while supporting their weight with the combined force of their own muscle strength and the driving torque from the drive units 82L and 82R. In addition to walking, the motion function improvement device 10 can also assist with movements that correspond to the subject's will, such as when the subject stands up from a seated position in a chair, or sits down in a chair from a standing position, and when the subject goes up or down stairs. In particular, when muscle strength is weak, it is difficult to go up stairs or stand up from a chair, but a subject wearing the motion mechanism unit 20 can perform these movements without worrying about muscle weakness because driving torque is applied according to their will.

[0146] The composite control unit 102 stores the control ratios of the discretionary control unit 100 and the autonomous control unit 101 set for each phase of each task in the data storage unit 81, and combines the control states of the discretionary control unit 100 and the autonomous control unit 101 so that the control ratio corresponds to the phase.

[0147] In other words, when a subject attempts to move their body, their intention to move is transmitted as a weak ionic current from the brain to the spinal cord, nerves, muscle spindles, and muscles, causing the musculoskeletal system, which has joints, to move. At that time, when a weak bioelectric signal is detected from the surface of the subject's skin, the voluntary control unit 100 controls the actuators to move the joints according to the subject's intention.

[0148] Furthermore, since the motion mechanism 20 is fastened in close contact with the subject's leg (biological part), the driving force of the drive units 82L and 82R is transmitted to the subject as an assisting force to rotate the joint. As a result, the subject's body moves due to the assisting force of the motion mechanism 20, and signals from Ia afferent neurons from muscle spindles return to the brain via nerves and the spinal cord.

[0149] As a result, an interactive biofeedback system is established between the subject, the brain, and the motor function enhancement device 10, consisting of two signal transmission systems: "brain → spinal cord → motor nerves → [musculoskeletal system + motor mechanism unit 20]" and "motor mechanism unit 20 → musculoskeletal system (muscle spindles) → sensory nerves → spinal cord → brain". This is bidirectional voluntary control from the brain and the motor mechanism unit 20, making it possible to further enhance the effectiveness of neurorehabilitation-based training for restoring the function of the nervous system.

[0150] Thus, the motor function enhancement device 10 is configured to sense bioelectric potential signals from the brain to the periphery after decision-making regarding movement and utilize them for actuator control. It attempts to capture bioelectric potential signals corresponding to brain activity from the periphery, specifically muscle activity. This makes it possible to provide real-time feedback to the brain and nervous system sensed in the periphery. Therefore, by performing rehabilitation with the subject wearing the motor mechanism unit 20, functional recovery in the bidirectional signal transmission system can be promoted.

[0151] Furthermore, in cases of severe motor dysfunction, where bioelectric signals cannot be detected, voluntary control does not function. Therefore, the control ratio is switched to enable autonomous control, which controls the drive units 82L and 82R based on a phase-by-phase control program derived from the analysis results of basic human movement patterns and operating mechanisms.

[0152] In this hybrid control system, where voluntary and autonomous control coexist, the amplitude and characteristics of bioelectric signals change according to the state of motor function, even in cases of complete paralysis or the progression of neuromuscular diseases. Therefore, rehabilitation can be effectively carried out for these conditions as well.

[0153] Furthermore, the synthesis control unit 102 compensates for the physical impedance of the entire system, including the entire apparatus and the subject, based on the physical quantities around the joints, in accordance with the physical characteristics of the entire system, including the human characteristics of the subject, and gravity.

[0154] In other words, the synthesis control unit 102 constructs the target equation of motion in the calculation environment using the equation of motion data (Mi) and known parameters (Pk) read from the data storage unit 81, and is configured to allow the input of the estimated drive torque (Te), the estimated joint torque (ΔT), and the joint angle θ into the equation of motion.

[0155] Here, the equation of motion data (Mi) is used to construct the equation of motion for the entire system consisting of the motion function improvement device 10 and the subject, while the known parameters (Pk) consist of dynamic parameters such as the weight of each part of the motion function improvement device 10, the moment of inertia around the joints, the viscosity coefficient, and the Coulomb friction coefficient.

[0156] The joint detection unit 90 includes not only the potentiometer 83, absolute angle sensor 84, and torque sensor 85 mentioned above, but also a relative force detection unit 110, a joint torque estimation unit 111, and a muscle torque estimation unit 112. The relative force detection unit 110 detects the relative force (ΔF) acting on the operating mechanism (frame mechanism) 20, that is, the force determined relatively by the relationship between the force generated by the drive units 82L and 82R and the muscle strength of the subject.

[0157] The joint torque estimation unit 111 estimates the joint moment (ΔT) around each joint of the subject from the difference between the relative force data (ΔF) detected by the relative force detection unit 110 multiplied by a preset coefficient and the drive torque (Te) detected by the torque sensor 85. Since the resultant force of the drive torque (Te) of the drive units 82L and 82R and the subject's muscle torque (Tm) acts as the joint moment (ΔT) on the subject's leg, the subject can move their leg with less muscle force than when the motion mechanism unit (frame mechanism) 20 is not attached.

[0158] The muscle torque estimation unit 112 estimates the muscle torque (Tm) due to the subject's muscle force based on the drive torque (Te) detected by the torque sensor 85 and the joint moment (ΔT) estimated by the joint torque estimation unit 111. The muscle torque (Tm) is determined to enable parameter identification even when the subject is generating muscle force, and is advantageous when performing parameter identification in the subject's operating state.

[0159] The synthesis control unit 102 performs calculations that take into account the drive torque (Te), joint data (θ), and joint moment (ΔT) obtained from the joint detection unit 90, as well as muscle torque (Tm), to identify unknown dynamic parameters (Pu) such as the weight of each part of the subject, the moment of inertia around each joint, the viscosity coefficient, and the Coulomb friction coefficient, and then averages these parameters after repeating the process multiple times (for example, 10 times).

[0160] Next, the synthesis control unit 102 reads the estimated ratio of muscle torque (Tm) to biopotential (Tm / BES) and a predetermined setting gain (Gs) from the data storage unit 81. If the setting gain (Gs) is outside the acceptable error range (Ea), it corrects the biopotential (BES) to obtain a corrected biopotential (BES') and makes the ratio of muscle torque (Tm) to corrected biopotential (BES') (Tm / BES') approximately equal to the setting gain (Gs).

[0161] As a result, it is possible to prevent a decrease in the accuracy of identifying the unknown dynamic parameters (Pu) of the subject, as well as to prevent situations where the assist force generated by the drive units 82L and 82R is too small or too large.

[0162] The synthesis control unit 102 is configured to read control method data (Ci) from the data storage unit 81, drive torque (Te), joint torque (ΔT), and joint angle θ obtained from the joint detection unit 90, as well as identification parameters (Pi) which are the result of identifying unknown dynamic parameters (Pu), and corrected biopotential (BES').

[0163] Furthermore, the composite control unit 102 uses control method data (Ci) to configure a predetermined control unit on the computing environment, and by reflecting the drive torque (Te), joint torque (ΔT), joint angle θ, identification parameter (Pi), and biopotential (BES') in this composite control unit 102, it is possible to send a control signal Ur for driving control of the drive units 82L and 82R. The current control unit 105 drives the drive units 82L and 82R in accordance with the control signal Ur from the composite control unit 102.

[0164] Furthermore, the motion enhancement device 10 is designed to control the assist force based on impedance adjustment in order to eliminate the constraints on natural control caused by the physical characteristics of the device itself, namely the viscoelasticity around the joints and the inertia of the frame. In other words, the motion enhancement device 10 calculates the parameters of the joints and compensates for the moment of inertia, viscosity, and elasticity with the drive units (actuators) 82L and 82R, thereby improving the assist rate in walking motion and reducing discomfort for the subject.

[0165] In this way, the motion enhancement device 10 makes it possible to indirectly change and adjust the characteristics of the subject by changing the characteristics of the entire system, including the subject in the device itself. For example, by adjusting the drive torque so as to suppress the influence of the inertia term and viscous friction term of the entire system, it becomes possible to maximize the subject's ability to perform agile movements such as reflexes. Furthermore, it is also possible to suppress the influence of the subject's own inertia term and viscous friction term, making it possible to make the subject walk faster than their original period or move more smoothly (with less viscous friction) than before the device was attached.

[0166] Furthermore, the performance enhancement device 10, while attached to the subject, can identify the subject's unique dynamic parameters using the composite control unit 102, and control the drive units 82L and 82R using the control device 80 based on the equation of motion obtained by substituting the identified dynamic parameters. Therefore, it can exert effects according to the control method used by the control device 80, regardless of individual differences or fluctuating factors such as the subject's physical condition.

[0167] Furthermore, since the control device 80 can control the drive units 82L and 82R based on the equation of motion which also incorporates the muscle torque (Tm) estimated by the joint detection unit 90, dynamic parameters can be identified even when muscle force is being generated by the subject, and the above effects can be achieved without requiring the subject to wait for the identification of these dynamic parameters.

[0168] By adjusting the gain between the bioelectric potential (BES) detected by the bioelectric signal detection unit 60 and the muscle torque (Tm) detected by the joint detection unit 90 to a preset gain (Gs), it is possible to prevent situations in which the detection results from the bioelectric signal detection unit 60 have poor or excessive sensitivity.

[0169] As a result, it is possible to prevent a decrease in the accuracy of identifying the subject's dynamic parameters, as well as to prevent situations where the assist force generated by the drive units 82L and 82R is too small or too large. Moreover, with the motion function improvement device 10 of this embodiment, calibration can be performed even when the subject is generating muscle force, and the subject does not need to wait for the calibration to be performed.

[0170] Since the control device 80 can be subjected to at least one of gravity compensation and inertia compensation using dynamic parameters identified by the composite control unit 102, it is possible to prevent situations where the weight of the device itself becomes a burden on the subject, or where the inertia of the device itself causes discomfort to the subject during operation.

[0171] In addition, the synthesis control unit 102, based on a biological self-regulation loop interactively facilitated between the subject's body and the motion mechanism unit 20, corrects the difference with motion commands from the brain and nervous system, and simultaneously provides feedback adjustment to the synthesized control state, so as to minimize the difference between the subject's intention to move and the actual movement.

[0172] As a result, with the motor function improvement device 10, when a subject repeatedly performs voluntary movements using the motor mechanism 20, it becomes possible to improve the motor function of the subject's brain, nerve, and muscle systems by correcting the difference between the movement commands from the brain and nervous system and the actual movement phenomena.

[0173] Furthermore, in the motor function improvement device 10, when forming a biological self-control loop, the smallest motor control unit for realizing voluntary movements generated by the subject's will is set as a minimal voluntary motor control unit consisting of the brain and nervous system, synaptic connections, and the muscular system. The motor mechanism unit 20 is used to establish a biological self-control loop for each minimal voluntary motor control unit that forms a coordinated bodily movement to realize a motor phenomenon.

[0174] As a result, in the motor function improvement device 10, by explicitly incorporating the influence of disease site and disease cause into the process of functional improvement and treatment based on the basic theory of the bio-self-regulation loop by the motor mechanism, the effect extends to other minimal voluntary movement control units, causing them to work in sync with the operation of the motor mechanism 20. This strengthens and adjusts the function of each minimal voluntary movement control unit in sync with the operation of the motor mechanism 20 in order to achieve the target movement, thereby improving the function of the brain, nervous system, and muscular system.

[0175] For example, in subjects with progressive diseases (slowly progressive neuromuscular diseases), motor function normally gradually declines over time, but using the motor function improvement device 10 yields a functional improvement effect that was previously unthinkable (Figure 10). Furthermore, while it is generally accepted that normal daily life and conventional exercise therapy cause muscle breakdown, leading to an increase in blood CK levels, an indicator of muscle breakdown in the blood, the motor function improvement device 10 actually results in a decrease in CK levels (Figure 11).

[0176] With the above configuration, a cell preparation containing microglia and / or monocytes, which has the ability to promote angiogenesis and axon extension, is produced by culturing a group of cells including microglia and / or monocytes under conditions of low oxygen concentration of less than 1% and low glucose concentration of 1.0 g / L or less for 12 to less than 24 hours. When this cell preparation is administered to a subject, the motor function enhancement device 10 is used to repeatedly perform voluntary physical movements by the subject, thereby correcting the difference between the motor commands from the brain and nervous system and the actual motor phenomena. This repeatedly creates a bidirectional biofeedback loop between the brain and nervous system and the musculoskeletal system, thereby promoting the effect of improving the motor function of the subject's brain, nerve, and muscle systems. Based on this combined therapy, the therapeutic effect of treating cerebrovascular disorders, ischemic heart disease, or traumatic cerebrospinal nerve disorders in the subject can be significantly enhanced.

[0177] (4) Configuration of a condition improvement acceleration system using the operational function improvement device according to this embodiment (4-1) Conceptual Structure of a System for Promoting Condition Improvement Figure 12 is a schematic external view of the condition improvement promotion system 120 according to this embodiment. This condition improvement promotion system 120 includes a pair of vibration energy supply units 130 that are attached to the outer surface of the subject's head to perform low-intensity pulsed ultrasound therapy (LIPUS), a control unit 140 for driving and controlling each of the vibration energy supply units 130, and a motion function improvement device 10 that promotes the effects of the subject's physical movement based on the repetition of a bidirectional biofeedback loop established between the nervous system and the musculoskeletal system.

[0178] A pair of vibration energy supply units 130, a control unit (vibration control unit) 140, and an action function enhancement device 10 are connected to each other via wired or wireless communication. When the control unit 140 drives and controls the vibration energy supply units 130, it is configured to reflect the effect of the subject's physical movement on the action function enhancement device 10.

[0179] The pair of vibration energy supply units 130 consist of piezoelectric resonators (such as piezoelectric ceramic resonators, piezoelectric single crystal resonators, polymer piezoelectric film resonators, etc.) or magnetostrictive resonators (such as ferrite magnetostrictive resonators) that generate ultrasonic vibrations and low-frequency vibrations with a vibration frequency of 100 Hz or less.

[0180] Each of these pair of vibration energy supply units 130 is equipped with a scattering induction unit 150 at the contact point with the outer surface of the subject's head to induce scattering of ultrasonic vibrations and low-frequency vibrations generated from each piezoelectric transducer (or magnetostrictive transducer) (Figure 13, described later).

[0181] The subject attaches a pair of vibration energy supply units 130 in the condition improvement promotion system 120 to the left and right temporal bones (temples), which are the thinnest parts of the skull, so that the scattering induction units 150 are in contact with each other. By selecting the temporal bones (temples) as the contact site with the outer surface of the head, it is possible to relatively improve the efficiency of transmission of ultrasonic vibrations and low-frequency vibrations to the brain.

[0182] The scattering induction unit 150 consists of a thin, plate-like encapsulated body containing fine particles made of ultrasonic scatterers having predetermined scattering characteristics, dispersed in a liquid (e.g., water), gel, or polymer medium.

[0183] Here, scattering refers to the phenomenon where, when ultrasonic waves are incident on an irregular interface or a minute reflector, the reflected waves spread out in all directions. The ultrasonic scatterer can be any fine particle capable of inducing forward scattering of ultrasonic vibrations and low-frequency vibrations generated from the vibration energy supply unit (piezoelectric transducer or magnetostrictive transducer), and can be of various sizes, shapes, and materials.

[0184] As a result, in the condition improvement promotion system 120, when the subject wears the vibration energy supply unit 130 on their head, the scattering induction unit 150, which is interposed between the vibration energy supply unit 130 and the contact area of ​​the outer surface of the head, is made of a relatively flexible material, thereby reducing discomfort to the subject's head.

[0185] In this way, the condition improvement promotion system 120 works by having the subject wear the vibration energy supply unit 130 on their head via the scattering induction unit 150, and by scattering ultrasonic vibrations or low-frequency vibrations to propagate vibration energy throughout the target area in the brain. At the same time, by reflecting the effects of the subject's physical movement using the motor function improvement device, peripheral blood vessels, mainly in the head, are dilated and blood flow is improved, allowing a complex mechanism of action to work in the brain and improve microcirculation of brain tissue.

[0186] (4-2) Drive control method for a pair of vibration energy supply units Figure 13 shows the circuit configuration of the control system in the condition improvement acceleration system 120. The condition improvement acceleration system 120 has a control unit 140 which contains a control unit 140, a control unit 160 which is in charge of controlling the entire device and consists of an MCM (Multi-Chip Module) equipped with a CPU (Central Processing Unit) and memory, and a storage unit 161 which reads and writes various data under the control of the control unit 160.

[0187] The central control unit 160 drives and controls each vibration energy supply unit 130 so that the vibration energy of ultrasonic vibrations and low-frequency vibrations is propagated throughout the entire target area in the subject's brain.

[0188] According to the experiment, the vibration energy conditions for the ultrasonic vibrations and low-frequency vibrations generated by the vibration energy supply unit 130 were set as follows: vibration generation sound pressure of 0.1 to 1.5 [MPa], a maximum irradiation time of 20 minutes per use for the subject, and, in the case of repeated use, a maximum of 60 minutes of irradiation per day with a 5-minute interval between uses.

[0189] In this way, the condition improvement promotion system 120 sets the sound pressure generated by the piezoelectric vibrator (or magnetostrictive vibrator) in the vibration energy supply unit 130 to a range that provides appropriate tissue amplitude to the brain, and also sets an upper limit on the time interval for repeated use and the total time per day. This makes it possible to sustain the effect of improving microcirculation in the brain tissue of the subject and the effect of suppressing the decline of cognitive function for a relatively long period of time, more than 3 months after use.

[0190] The function of promoting condition improvement by irradiating with ultrasonic vibrations and low-frequency vibrations generated by the vibration energy supply unit 130 is that the vibration energy of the ultrasonic vibrations and low-frequency vibrations is scattered from the irradiation direction and diffused omnidirectionally, and the ultrasonic and low-frequency vibrations stimulate vascular cells in the subject's brain, thereby promoting the expression of eNOS (endothelial nitric oxide synthase), VEGF (vascular endothelial growth factor), and bFGF (basic fibroblast growth factor).

[0191] In this way, the condition improvement promotion system 120 makes it possible to improve the expression of eNOS (endothelial nitric oxide synthase), VEGF (vascular endothelial growth factor), and bFGF (basic fibroblast growth factor) by diffusing the vibrational energy of ultrasonic vibrations and low-frequency vibrations in all directions while scattering from the direction of irradiation, thereby improving the microcirculation of the brain tissue of the subject and improving dementia.

[0192] Furthermore, in the condition improvement acceleration system 120, the central control unit 160 drives and controls the ultrasonic vibrations and low-frequency vibrations from the pair of vibration energy supply units 130 so that a phase difference is created between them, thereby enabling the vibration energy that penetrates the subject's brain to propagate throughout the entire target area of ​​the brain without resonance.

[0193] Furthermore, the condition improvement promotion system 120 is provided with a vibration receiving unit 162 located near a pair of vibration energy supply units 130, which receives ultrasonic vibrations and low-frequency vibrations transmitted through contact points with the outer surface of the subject's head.

[0194] The central control unit 160 constantly monitors the vibration energy intensity of the ultrasonic vibrations and low-frequency vibrations received by the vibration receiving unit 162 to maintain it below a predetermined level, while driving and controlling the vibration energy supply unit 130 if the intensity is above a predetermined level.

[0195] As a result, the condition improvement promotion system 120 can ensure safety by constantly monitoring to prevent excessive vibrational energy from the ultrasonic vibrations and low-frequency vibrations transmitted into the subject's brain, thereby preventing adverse effects on the subject's brain caused by the application of this device.

[0196] Furthermore, while the vibration energy of ultrasonic vibrations and low-frequency vibrations from the pair of vibration energy supply units 130 is being irradiated, the control unit 160 may, when the intensity of the vibration energy of ultrasonic vibrations and low-frequency vibrations received by the vibration receiving unit 162 is above a predetermined level, constantly monitor and drive the vibration energy supply units 130 to keep it below that predetermined level, and at the same time appropriately change the phase difference between the ultrasonic vibrations and low-frequency vibrations for both vibration energy supply units 130.

[0197] (5) Role of the operational function improvement device in the condition improvement acceleration system of the present invention In the state improvement promotion system 120 of this embodiment, with the subject wearing the vibration energy supply unit 130 on their head, ultrasonic low-frequency vibrations are transmitted to the entire target area in the brain, thereby activating a complex mechanism of action in the brain and improving the microcirculation of brain tissue.

[0198] In this condition improvement promotion system 120, when the control unit (vibration control unit) 140 drives and controls the vibration energy supply unit 130, the subject repeatedly performs voluntary movements using the movement mechanism unit 20 of the motion function improvement device 10. This corrects the difference between the movement commands from the brain and nervous system and the actual movement phenomena, thereby improving the motor function of the subject's brain, nerve, and muscle systems. As a result, the subject can obtain the effects of physical movement, such as dilation of peripheral blood vessels, mainly in the head, and improved blood flow.

[0199] In this way, the condition improvement promotion system 120 reflects the effect of the subject's physical movement using the motion function improvement device 10, dilating peripheral blood vessels mainly in the head to improve blood flow. When the vibration energy of the ultrasonic and low-frequency vibrations generated by the vibration energy supply unit 130 is scattered from the supply direction and diffused in all directions, it becomes possible to further promote the expression of eNOS (endothelial nitric oxide synthase), VEGF (vascular endothelial growth factor), and bFGF (basic fibroblast growth factor) when vascular cells are stimulated by the ultrasonic and low-frequency vibrations.

[0200] Furthermore, in this condition improvement promotion system 120, irradiation with low-power pulsed ultrasound enhances the expression of eNOS (endothelial nitric oxide synthase) through a mechanism involving physical stimulation of the caveolin-1 / β-integrin complex present in the vascular endothelial cell membrane. As a result, downstream processes such as reduction of amyloid-β accumulation, suppression of microglial activity, angiogenesis, and remyelination are induced, making it possible to suppress cognitive decline through a complex mechanism of action.

[0201] Therefore, the condition improvement promotion system 120 can improve microcirculation in the brain by utilizing the vibrational energy of ultrasound and low-frequency vibrations propagated throughout the target area, while reflecting the effects of the subject's physical movement using the motor function improvement device 10. Since the subject can simultaneously experience both the propagation effect of vibrational energy from ultrasound and low-frequency vibrations acting on their head and the improvement effect of motor function through lower limb movements, it is possible to obtain a synergistic effect that combines both effects.

[0202] In fact, when a subject is administered a cell preparation containing microglia or monocytes treated with the aforementioned hypoxia-low glucose (OGD) regimen, the condition improvement enhancement system 120 can be used to improve the motor function of the subject's brain, nerve, and muscular systems. In addition to the effect of the motor function enhancement device 10 in improving motor function, by supplying vibrational energy of ultrasonic vibrations or low-frequency vibrations with a vibration frequency of 100 Hz or less from the external surface of the subject's head, and propagating the vibrational energy of ultrasonic vibrations or low-frequency vibrations throughout the target area in the subject's brain, a complex mechanism of action can be activated in the brain to improve microcirculation of brain tissue, and the therapeutic effect of the subject's cerebrovascular disease, ischemic heart disease, or traumatic cerebrospinal nerve injury can be further enhanced.

[0203] (6) Other embodiments In the above-described embodiment, the scattering induction unit 150 that induces the scattering of ultrasonic low-frequency vibrations generated from the vibration energy supply unit 130 was described in which a thin plate-shaped encapsulated body containing fine particles made of ultrasonic scatterers having predetermined scattering characteristics is scattered in a liquid, gel, or polymer medium. However, the present invention is not limited to this, and in short, various scattering induction units may be applied as long as they can be propagated throughout the entire target area in the subject's brain and have a structure that can be attached to the contact area with the outer surface of the subject's head.

[0204] For example, as shown in Figure 14, where the corresponding parts in Figure 13 are denoted by the same reference numerals, the scattering induction unit 170 consists of a thin plate-shaped encasing body containing point-like scattering bodies 171, which are made up of bubbles, scattered in a liquid medium. The central control unit 160 adjusts the scattering characteristics of ultrasonic vibrations and low-frequency vibrations by controlling either the arrangement and / or distribution state of the point-like scattering bodies 171 in the scattering induction unit 170 to a desired state.

[0205] As a result, the condition improvement promotion system 120 can adjust the scattering characteristics of the scattering induction part 170, which comes into contact with the contact area on the outer surface of the subject's head, to a desired state, thereby optimizing the propagation state of vibrational energy throughout the target area in the brain.

[0206] As another example, as shown in Figure 15, where the corresponding parts in Figure 13 are denoted by the same reference numerals, the scattering induction unit 180 consists of a thin plate-shaped encasing filled with magnetic fluid 181. The central control unit 160 adjusts the scattering characteristics of ultrasonic vibrations and low-frequency vibrations by controlling either or both of the arrangement and distribution state of the ferromagnetic fine particles contained in the magnetic fluid 181 in the scattering induction unit 180 to a desired state.

[0207] Magnetic fluid 181 is a colloidal solution in which magnetic iron oxide nanoparticles are extremely stably dispersed in a liquid. It is a composite material consisting of magnetic nanoparticles (e.g., magnetite (Fe3O4) or maghemite (γ-Fe2O3)) as the dispersed phase (solute), a solvent as the dispersion medium (solvent), and ions or surfactants as dispersants.

[0208] The magnetic fluid 181 has the property that, in the absence of an external magnetic field, the orientation of the magnetic moments of the magnetic particles rotates randomly in the liquid, canceling each other out and resulting in no magnetization of the fluid as a whole. However, in the presence of an external magnetic field, the magnetic moments of each nanoparticle are oriented in the direction of the magnetic field lines, causing it to behave as if it were magnetized.

[0209] Taking advantage of these magnetic fluid properties, the central control unit 160 controls the particle size, particle size distribution, shape, and aggregate size of the ferromagnetic microparticles contained in the magnetic fluid 181 in the scattering induction unit 180, thereby controlling either or both of the arrangement and distribution state of the ferromagnetic microparticles to a desired state, and adjusting the scattering characteristics of ultrasonic vibrations and low-frequency vibrations.

[0210] As a result, the condition improvement promotion system 120 can adjust the scattering characteristics of the scattering induction unit 180, which comes into contact with the contact area on the outer surface of the subject's head, to a desired state, thereby optimizing the propagation state of vibrational energy throughout the target area in the brain.

[0211] Furthermore, in the above-described embodiment, as a method for controlling the drive of the vibration energy supply unit 130 by the central control unit 160 in order to bring about an improvement effect on the microcirculation of the brain tissue of the subject in the condition improvement promotion system 120, multiple vibration energy supply units 130 are mounted so as to be arranged around the head of the subject, and scattering induction units 150, 170, and 180 are attached to the contact parts of the vibration energy supply unit 130 with the outer surface of the subject's head to induce scattering of ultrasonic and low-frequency vibrations, and the central control unit 160 drives and controls each vibration energy supply unit 130 so as to create a phase difference in the ultrasonic and low-frequency vibrations, the present invention is not limited to this, and various drive control methods may be applied as long as it is possible to propagate the vibration energy that passes through the brain to the entire target area in the brain without resonance.

[0212] For example, multiple vibration energy supply units 130 may be mounted around the head of the subject, and the control unit 160 may drive and control each vibration energy supply unit 130 so that each unit supplies ultrasonic vibration or low-frequency vibration energy in a non-focused manner and diffuses in an inverse taper shape that gradually expands in the direction of radiation, and so that the energy is supplied sequentially between the multiple vibration energy supply units 130 at predetermined time intervals.

[0213] As a result, in the condition improvement promotion system 120, when unfocused vibration energy is sequentially supplied between multiple vibration energy supply units 130, the irradiation wave or reflected wave of unfocused vibration energy generated from one vibration energy supply unit is attenuated, so that even if it overlaps with the unfocused vibration energy generated from the next vibration energy supply unit, it does not result in excessive vibration stimulation, making it possible to provide the brain with an appropriate tissue amplitude and treat dementia.

[0214] In this case, the vibration energy of ultrasonic vibration or low-frequency vibration supplied by the vibration energy supply unit 130 is such that the angle of the expanding inverse tapered inclined surface is 50° to 100°, and the vibration generation sound pressure is 0.1 to 1.5 [MPa], and is supplied continuously to the subject for 15 to 60 minutes.

[0215] As a result, the condition improvement promotion system 120 sets the angle of the expanding inverse tapered inclined surface in the vibration energy of the ultrasonic vibration or low-frequency vibration supplied from the vibration energy supply unit 130 to a range that can be transmitted to the entire brain, and sets the sound pressure generated by the piezoelectric vibrator to a range that provides an appropriate tissue amplitude to the brain. By setting a limit on the irradiation time for each use on the subject and repeating the process, it becomes possible to sustain the effect of improving microcirculation in the brain tissue and suppressing the decline of cognitive function in the subject for a relatively long period after use.

[0216] Furthermore, in this embodiment, we have described a case in which the left and right temporal regions (temples) are selected as contact points with the outer surface of the subject's head in the condition improvement promotion system 120, and vibration energy supply units 130 are attached to each of them. However, the present invention is not limited to this, and the number of vibration energy supply units 130 can be freely set to one, three or more, not just two. For example, in addition to the left and right temporal regions (temples), the boundary between the occipital region and the crown (foramen magnum) may also be selected as a contact point with the outer surface of the subject's head.

[0217] Furthermore, although the above-described embodiment described the case in which a waist-type motion mechanism 20 was applied as the motion function improvement device 10, the present invention is not limited to this, and can be broadly applied to motion function improvement devices equipped with motion mechanisms adapted to the joint area where the subject's body can move, such as those equipped with a lower body (lower limb type) motion mechanism or a single-joint type motion mechanism.

[0218] For example, a device for improving motor function may be configured that includes a hand-type motion mechanism and a control system equipped with the functional configuration of the basic theories of the voluntary control step, autonomous control step, impedance control step, and bio-self-regulation loop described above. This hand-type motion mechanism may be configured to be directly attached to the subject's hand or to be fixed to a table.

[0219] Furthermore, even if the device does not have a detailed configuration like the motion function improvement device 10 in this embodiment, a motion function improvement device with a relatively simple configuration may be used, as long as it has a motion mechanism adapted to the joint area of ​​the subject's body that is capable of movement.

[0220] For example, a simple operational function improvement device (not shown) may be applied, comprising: a drive unit that provides power to a subject; a signal detection unit that detects the subject's bioelectric potential signal; a biosignal processing unit that acquires the subject's nerve transmission signal and myoelectric potential signal from the bioelectric potential signal detected by the signal detection unit; a voluntary control unit that uses the nerve transmission signal and myoelectric potential signal acquired by the biosignal processing unit to generate a command signal for the drive unit to generate power according to the subject's will; and a drive current generation unit that generates a current corresponding to the nerve transmission signal and a current corresponding to the myoelectric potential signal, respectively, based on the command signal generated by the voluntary control unit, and supplies them to the drive unit. [Explanation of symbols]

[0221] 10...Motion function improvement device, 20...Motion mechanism unit, 30...Waist frame, 30A...First waist frame, 30B...Second waist frame, 31...Support column, 32, 33...Mounting belt, 40...Left side frame, 41...Right side frame, 42...Battery, 43...Minus button, 44...Plus button, 45...Power button, 50...Thigh fixing unit, 50L...Left thigh fixing unit, 50R...Right thigh fixing unit, 51L, 51R...Stay unit, 52L, 52R...Belt unit, 60...Biosignal detection unit, 70...Control system, 80...Control device, 81...Data storage unit, 82L 82R...Drive unit, 83...Potentiometer, 84...Absolute angle sensor, 85...Torque sensor, 90...Joint circumference detection unit, 100...Voluntary control unit, 101...Autonomous control unit, 102...Composite control unit, 105...Current control unit, 110...Relative force detection unit, 111...Joint torque estimation unit, 112...Muscle torque estimation unit, 120...Condition improvement promotion system, 130...Vibration energy supply unit, 140...Control unit, 150, 170, 180...Scattering induction unit, 160...Overall control unit, 161...Memory unit, 162...Vibration receiving unit, 171...Point scattering body, 181...Magnetic fluid.

Claims

1. A cell preparation containing microglia and / or monocytes, which is produced by culturing a cell population including microglia and / or monocytes under conditions of low oxygen concentration of less than 1% and low glucose concentration of 1.0 g / L or less for 12 hours or more but less than 24 hours, and which has the ability to promote angiogenesis and axon extension, This drug is used for the treatment of cerebrovascular disorders, ischemic heart disease, or traumatic cerebrospinal nerve disorders in a subject. It is administered to the subject and, while the subject is performing voluntary physical movements, it repeatedly creates a bidirectional biofeedback loop between the nervous system and the musculoskeletal system, correcting the difference between the movement commands from the nervous system and the actual movement phenomena. This process promotes the improvement of the motor function of the subject's brain, nerves, and muscles. A cell preparation characterized by the following features.

2. While administered to the subject, the vibrational energy of ultrasonic vibrations or low-frequency vibrations with a vibration frequency of 100 Hz or less is supplied from the outer surface of the subject's head, and the vibrational energy of ultrasonic vibrations or low-frequency vibrations is propagated throughout the target region in the subject's brain. The cell preparation according to feature 1.

3. A drive unit that provides power to the subject, A signal detection unit for detecting the bioelectric potential signal of the subject, A biosignal processing unit that acquires the nerve conduction signals and electromyographic signals of the subject from the biopotential signals detected by the signal detection unit, A voluntary control unit that uses nerve transmission signals and electromyographic signals acquired by the biosignal processing unit to generate command signals for generating power in the drive unit according to the subject's will, A drive current generation unit generates a current corresponding to the nerve transmission signal and a current corresponding to the electromyographic signal, respectively, based on the command signal generated by the voluntary control unit, and supplies them to the drive unit. Using a motion function enhancement device equipped with the above, the subject performs voluntary physical movements. A cell preparation according to claim 1 or 2.

4. An operating mechanism unit used to be integrated with the subject and having a drive unit that is driven actively or passively in conjunction with the physical movements of the subject, A signal detection unit that detects changes in ion current transmitted from the brain and nervous system to the muscle system of the subject as a biopotential signal appearing on the skin surface, A joint detection unit detects physical quantities around the joints associated with the body movements of the subject based on the output signal from the drive unit, A voluntary control unit controls the drive unit based on the bioelectric signal and the physical quantities around the joint, so as to produce a movement phenomenon that reflects the subject's intention to move. An autonomous control unit stores reference parameters for each phase, which is a series of minimum operating units constituting the operating pattern of the subject classified as a task, in a data storage unit, estimates the phase of the subject's task by comparing the physical quantities around the joint with the reference parameters stored in the data storage unit, and controls the drive unit to generate power corresponding to that phase. The data storage unit stores the control ratios of the discretionary control unit and the autonomous control unit set for each phase of each task, and a synthesis control unit combines the control states of the discretionary control unit and the autonomous control unit to achieve a control ratio corresponding to the phase. Using a motion function enhancement device equipped with the above, the subject performs voluntary physical movements, The aforementioned synthesis control unit, Based on the physical quantities around the joints, the physical impedance of the entire system, consisting of the entire apparatus and the subject, is compensated to match the physical characteristics of the entire system, including the human characteristics of the subject, and gravity. To minimize the difference between the subject's intention to act and the actual movement, the system provides feedback adjustments to the synthesized control state based on a bio-self-regulation loop interactively facilitated between the subject's body and the movement mechanism, while simultaneously correcting the difference with movement commands from the brain and nervous system. A cell preparation according to claim 1 or 2.

5. In forming the aforementioned biological self-regulation loop, the smallest motor control unit for realizing voluntary movements generated by the subject's will is defined as a minimal voluntary motor control unit consisting of the brain and nervous system, synaptic connections, and the muscular system. Using the aforementioned operating mechanism, the bio-self-control loop is established for each of the minimum voluntary movement control units that form coordinated body movements to realize the aforementioned motor phenomenon. The cell preparation according to feature 4.

6. When supplying vibrational energy of the ultrasonic vibration or low-frequency vibration from multiple locations around the head of the subject, scattering of the ultrasonic vibration or low-frequency vibration is induced, and at the same time, a phase difference is created between them. The cell preparation according to feature 2.

7. The vibration energy of the ultrasonic vibration or low-frequency vibration shall be set such that the vibration generation sound pressure is 0.1 to 1.5 [MPa], the irradiation time for a single use on the subject shall be a maximum of 20 minutes, and when used repeatedly, the total irradiation time per day shall be limited to 60 minutes with a 5-minute interval between uses. The cell preparation according to feature 6.

8. The vibrational energy of the ultrasonic vibration or low-frequency vibration is scattered omnidirectionally from the supply direction, stimulating vascular cells and promoting the expression of eNOS, VEGF, and bFGF. The cell preparation according to feature 7.

9. The vibrational energy of the ultrasonic vibration or the low-frequency vibration is sequentially supplied from multiple locations around the head of the subject at predetermined time intervals, and at the same time, the vibrational energy is supplied in a non-focused manner and diffused in an inverse tapered shape that gradually expands in the direction of radiation. The cell preparation according to feature 2.

10. The vibration energy of the ultrasonic vibration or low-frequency vibration is supplied to the subject continuously for 15 to 60 minutes, with an angle of expansion of the expanding inverse tapered inclined surface of 50° to 100° and a vibration generation sound pressure of 0.1 to 1.5 [MPa]. The cell preparation according to feature 9.

11. The cell population containing monocytes is peripheral blood cells or a cell fraction thereof, or a fraction containing mononuclear cells collected from peripheral blood, the hypoxia concentration is an oxygen concentration of 0.1 to 0.4%, and the culture time is approximately 18 hours. A cell preparation according to claim 1 or 2.

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