JP2008006128A - Orientation control unit - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a unit which can control the orientation of living body tissue and further control the orientation beneficial for the regeneration, analysis, etc., of the living body tissue. <P>SOLUTION: This orientation control unit controls the orientation of the living body tissue by supplying a magnetic field to an affected area. The orientation control unit comprises a magnetic-field supplying means 1 for supplying the magnetic field to the affected area, and a control means for controlling the magnetic field. The living body tissue is selected from a group which is composed of a bone, cartilage, a smooth muscle, a cardiac muscle, a skeletal muscle, skin, fat, a ligament, a tendon, a blood vessel, and a cell. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an orientation control device, and more particularly to an orientation control device using a magnetic field.

  At present, the use of regenerative medical technology makes it possible to regenerate huge bone defects that cannot be naturally cured. Conventionally, when joints and the like are highly destroyed, there are many operations for joint fixation, leg cutting, etc., but replacement with artificial joints has begun to spread.

  In addition, a treatment method that restores the function by regenerating a living tissue such as a hard tissue that has been destroyed has also been attempted, and the treatment method is intended for natural healing and helps the patient to return to society. It is very meaningful from the viewpoint.

  In order to achieve natural healing, for example, a noninvasive treatment apparatus using ultrasonic waves is known. Recently, it is possible to detect whether or not an ultrasonic wave is irradiated to an affected part during treatment, and a treatment apparatus that is safe and effective for a patient is known (Japanese Patent Laid-Open No. 10-085288).

  In particular, there is known a non-invasive electromagnetic therapy apparatus that treats biological tissue, biological cells, etc. using a pulsed electromagnetic field in order to give a stimulus for bone growth (Japanese Patent Laid-Open No. 6-233825). issue)

  As described above, various devices using ultrasonic waves and magnetism are used in the medical field.

JP-A-10-085288 JP-A-6-233825

However, those using the above ultrasonic waves are mainly used for natural healing of fractures and bone contusions. That is, natural healing is performed by applying an ultrasonic pulse having appropriate parameters (for example, ultrasonic frequency, pulse repetition period and pulse amplitude) at an appropriate position close to the affected area for an appropriate period, It does not control the orientation of in vivo tissues.

Moreover, what uses the said electromagnetic field is mainly used for the stimulus provision of a bone growth, and does not control the orientation of a biological tissue or a cell.

By the way, if regular orientation in a normal in-vivo tissue can be grasped, various analyzes can be performed based on information on the normal in-vivo tissue. However, the conventional method using an electromagnetic field merely provides stimulation, and does not use an electromagnetic field from the viewpoint of controlling orientation.

Further, it is known that during bone regeneration, the increase in bone mass precedes and fills the defect, and stress information from the outside is not transmitted at that time, so that the bone microstructure of the regeneration part is not repaired. Until now, there have been reports of cases where bone regeneration is accelerated by using a magnetic field, but this is thought to be caused by increased blood flow due to the magnetic field, which may actually lead to improvement in bone mass. Even if it is sexable, it does not lead to improvement of bone microstructure (bone quality). Given that bone microstructure dominates the mechanical function of actual bone, there is a need to improve bone microstructure simultaneously with bone regeneration. This is because it takes a very long time to improve the soundness of the bone microstructure once filled with bone. However, there has been no example of bone regeneration from the viewpoint of bone microstructure (bone quality).

In addition, polymer substances including in vivo tissues have magnetocrystalline anisotropy, and the anisotropy may affect some properties and functions. For example, collagen fibers are present in tendons and myocardium in addition to hard tissues, and the collagen fibers have orientation. If such orientation can be freely controlled, it is meaningful in fields such as regenerative medicine. However, there is no device for controlling such orientation.

  SUMMARY OF THE INVENTION An object of the present invention is to provide an apparatus capable of controlling the orientation of a tissue in a living body and thus controlling the orientation useful for regeneration and analysis of the tissue in the living body.

  In order to achieve the above-mentioned object, the inventors have paid attention to the orientation of the tissue in the living body and intensively studied the evaluation of the tissue in the living body. As a result, the inventors have found the orientation control device of the present invention.

  The orientation control device of the present invention is a device for supplying a magnetic field to an affected part and controlling the orientation of a tissue or a cell in a living body, a magnetic field supplying means for supplying the magnetic field to the affected part, and a control for controlling the magnetic field. And means.

  Further, in a preferred embodiment of the orientation control device of the present invention, the in vivo tissue is selected from the group consisting of bone, cartilage, smooth muscle, cardiac muscle, skeletal muscle, skin, fat, ligament, tendon, blood vessel, and cell. It is characterized by that.

  In a preferred embodiment of the orientation control device of the present invention, the magnetic field to the affected part is given in a direction that minimizes the magnetocrystalline anisotropy energy with respect to the crystal orientation. .

In a preferred embodiment of the orientation control device of the present invention, the magnetic field to the affected part is applied in a direction of 90 ° ± 45 ° with respect to the traveling direction of the collagen fibers.

In a preferred embodiment of the orientation control device of the present invention, the crystal orientation is the c-axis direction of biological apatite.

In a preferred embodiment of the orientation control device of the present invention, the magnetic field to the affected part is given in a direction of 90 ° ± 45 ° with respect to the blood vessel running direction.

  In a preferred embodiment of the orientation control device of the present invention, the magnetic field to the affected area is applied in a direction of 90 ° ± 45 ° with respect to the stress load direction of the hard tissue.

  In a preferred embodiment of the orientation control device of the present invention, the magnetic field to the affected area is applied in a direction of 90 ° ± 45 ° with respect to the direction of bone near-centrifugation of the hard tissue.

  In a preferred embodiment of the orientation control device of the present invention, the magnetic field strength to the affected area is in the range of 1 to 20 (T).

  In a preferred embodiment of the orientation control device of the present invention, a magnetic field to the affected area is applied for 1 to 24 hours.

  Further, in a preferred embodiment of the orientation control device of the present invention, it is further characterized by further comprising evaluation means for evaluating the orientation of normal hard tissue crystals.

Further, in a preferred embodiment of the orientation control device of the present invention, the evaluation means includes an X-ray diffraction method, SEM-EBSP (Scanning Electron
TEM-DP (Transmission Electron), based on analysis of electron backscattered image of each crystal grain by Microscope-Electron Backscattering Pattern
It is provided by at least one selected from the group consisting of those obtained by analyzing electron diffraction patterns by a Microscope-Diffraction Pattern) method.

  According to the orientation control device of the present invention, it is possible to non-invasively control the orientation of a tissue in a living body, and thus, there is an advantageous effect that non-invasive treatment is possible.

Further, when the orientation control device of the present invention is applied to a hard tissue, there is an advantageous effect that bone filling, bone density increase and bone orientation recovery can be performed simultaneously. In addition, the use of a non-invasive magnetic field makes it possible to quickly realize a state in which the bone microstructure is close to a normal part. In the case of a fracture, shortening of the rehabilitation period is expected, and the bone disease part is expected to improve bone quality and mechanical function. Taking the case of hard tissue as an example, it is possible to regenerate bone while controlling the orientation in the present apparatus. That is, since the orientation can be controlled while taking advantage of the regenerative ability inherent in the living body, the regenerated hard tissue has the same bone density and bone quality as a normal hard tissue, and is extremely excellent. According to the present invention, such highly accurate reproduction can be provided.

  In addition, according to the orientation control device of the present invention, it is possible to reliably impart orientation to in vivo tissues while evaluating the regeneration process and disease formation of hard tissues. Expected to contribute to the fields of regenerative medicine and dentistry (especially orthopedics, brain surgery, dentistry) and basic medicine.

  An orientation control device according to the present invention is a device for supplying a magnetic field to an affected area and controlling the orientation of a tissue in a living body, a magnetic field supply means for supplying a magnetic field to the affected area, and a control means for controlling the magnetic field; . According to such an apparatus, it is possible to perform regeneration, etc., by applying to an in vivo tissue or a cell array lacking orientation according to the crystal magnetic anisotropy of normal in vivo tissue. . The magnetic field is generated in a specific direction or a specific plane direction, irradiated to the affected area, and controlled by changing an appropriate magnetic field size, magnetic field irradiation direction, and magnetic field irradiation time.

  In the present invention, the in vivo tissue is not particularly limited as long as it has crystal magnetic anisotropy. For example, bone, cartilage, smooth muscle, cardiac muscle, skeletal muscle, skin, fat, ligament , Tendons, blood vessels, cells and the like. That is, collagen fibers or biological apatites exist in hard tissues, tendons, and myocardium, and the collagen fibers or biological apatites have magnetic anisotropy. It was found that the running direction of the collagen fiber is one of the important factors that influence the properties of the tissue in vivo containing the collagen fiber, and it plays an important role in tissue regeneration by controlling the anisotropy. Turned out to play.

  The orientation of collagen / apatite in living tissue is important because it is closely related to the mechanical function of hard tissue. However, for example, when bone regeneration is performed, normal stress transmission is not performed at the regeneration portion until the defect portion is filled and the bone density returns to normal, and as a result, the orientation is greatly recovered. There is a problem of being late. In particular, since the bone replacement speed after the regenerative portion is once filled decreases, it takes a long time to restore the orientation. Therefore, it is necessary to have a technique that enables bone filling, bone density increase, and bone orientation recovery at the same time. However, if the orientation control device of the present invention is used, such regeneration is possible. Is possible.

In addition, tissue having crystal magnetic anisotropy among in vivo tissues can be provided with anisotropy by a magnetic field. If the orientation control device of the present invention is used, non-invasive orientation provision can be realized.

In a preferred embodiment, the magnetic field to the affected part is applied in a direction that minimizes the magnetocrystalline anisotropy energy with respect to the crystal orientation. In particular, in the case of bioapatite, the direction that minimizes the magnetocrystalline anisotropy energy is preferably 90 ° ± 45 ° with respect to the crystal orientation.

  Typical examples of other substances are as follows.

  As is clear from Table 1, the direction of minimizing the magnetocrystalline anisotropy differs depending on the material. For example, in the case of HAp, the c-axis is perpendicular to the magnetic field, while fibrin is parallel to the magnetic field. Therefore, the orientation can be freely controlled according to the substance or as desired. In the present invention, desired orientation can be imparted based on the orientation information as described above. In addition, polyamino acids, DNA, viruses, various protein crystals, and the like are also known to be magnetically oriented.

  In particular, the principle of the present invention will be described as follows in the case where a hard tissue is used as a sample in vivo.

  FIG. 1 shows an outline of the principle of orientation by a magnetic field. In FIG. 1, Col indicates collagen fibers and BAp indicates biological apatite. Bone has an optimal collagen / apatite orientation depending on the site. Although it is only necessary that the orientation can be imparted outside the living body and it can be put into the living body, this is not possible with the current technology. For example, techniques for imparting orientation to the c-axis of apatite include those by heat treatment and those that apply a strong magnetic field, both of which require heat treatment to sinter the apatite. It has very different characteristics from in vivo apatite, and as a result, it has almost no bioabsorbability. In the present invention, the bone matrix (apatite + collagen is the main component in terms of quantity) is produced in vivo by bone cells (particularly osteoblasts that produce bone), and the produced collagen and apatite are non-contact and non-contact. It is generated by applying a strong magnetic field, which is an invasive method, and utilizing the magnetocrystalline anisotropy of both to provide orientation by a magnetic field. Orientation can be controlled not only in one direction, but also by controlling the direction and time in which the magnetic field is applied (changing the time and direction according to the degree and direction in which the magnetic field in one direction is desired to be oriented) It is. Due to the magnetocrystalline anisotropy, the energy is lower when the collagen travel direction (extension direction) is perpendicular to the magnetic field application, and the c-axis direction of the apatite crystal is perpendicular, so collagen elongation / apatite c Application can be made perpendicular to the axis. For example, in the case of a long bone with uniaxial orientation in the longitudinal direction of the bone, a magnetic field may be applied so that it is perpendicular to the long axis, so that it has a three-dimensional anisotropic orientation. In this case, the magnetic field can be applied three-dimensionally by changing the time.

  That is, according to the apparatus of the present invention, it is possible to control the orientation of virtually any substance as long as the relationship between the magnetocrystalline anisotropy and the magnetic field is clear.

  FIG. 2 shows the relationship between bioapatite (hereinafter also referred to as BAp) orientation and bone mechanical function. FIG. 2 shows a state in which the c-axis (crystal structure is hexagonal) of apatite is almost aligned along collagen fibers, taking an in vivo hard tissue as an example. Most in vivo hard tissues are composed of type I collagen and apatite crystallites. This collagen / apatite arrangement strongly depends on the hard tissue site. For example, in the case of a long bone such as a femur, the c-axis direction of collagen / apatite is preferentially arranged in the bone longitudinal direction. This is a tissue that appears as a result of a command sent by a cell that senses stress, and this arrangement exerts an optimal mechanical function on the site. This arrangement cannot be performed in a portion where a stress is not applied such as a bone regeneration portion or a diseased portion, and an optimal mechanical function cannot be exhibited. Since the c-axis of this collagen and apatite has crystal magnetic anisotropy, it is rotated perpendicularly to the direction of the magnetic field and rearranged for the purpose of reducing its energy by irradiating a relatively strong magnetic field. By utilizing this, the bone regeneration process and the diseased part with disordered bone quality are irradiated with a magnetic field to give appropriate bone quality (orientation, microstructure anisotropy) according to the site. As a result, the recovery of the mechanical function at an early stage is expected by the magnetic field irradiation.

  As described above, according to the apparatus of the present invention, a sufficient dynamic function can be exerted on a site in a diseased part, a defect part, or the like by using a magnetic field instead of applying stress.

  As can be seen from FIGS. 1 and 2, the c-axis of the apatite and the fiber direction of the collagen fiber have the property of being arranged perpendicular to the magnetic field direction due to crystal magnetic anisotropy (magnetism anisotropy). Since the c-axis of biological apatite is crystallized in vivo in parallel with collagen fibers, it is desirable to irradiate a magnetic field for a time to be oriented in a direction perpendicular to the direction to be oriented. The higher the magnetic field, the higher the effect, but the magnetic field level that can be easily obtained at present is 10T. Although the adverse effect of the magnetic field on the living body is a concern, there are medical devices (MRI) around 6T at present, and the adverse effect on the bone against the magnetic field is considered low, so the problem is low. Moreover, since the magnetic field can be applied without touching the living body, it is not necessary to damage the skin or the like, which is advantageous as a non-invasive method.

  DESCRIPTION OF EXEMPLARY EMBODIMENTS Hereinafter, a preferred embodiment of the invention will be described in detail with reference to the accompanying drawings. One embodiment of the present invention includes a magnetic field supply means 1 and a unit 2 as shown in FIG.

The magnetic field supply means for supplying the magnetic field to the affected part is not particularly limited, and examples thereof include a permanent magnet, an electromagnet, a superconducting magnet, a water-cooled copper magnet, and combinations thereof. That is, the magnetic field supply means is not particularly limited as long as it can supply a magnetic field and the direction of the magnetic field B can be specified. This is because the collagen running direction and the c-axis direction of biological apatite have been found to be oriented substantially perpendicular to the magnetic field. This is because having the specific orientation is utilized in the present invention, and the orientation of the in vivo tissue can be controlled if the direction of the magnetic field B can be specified as the magnetic field supply means. As the magnetic field supply means, a permanent magnet, an electromagnet, a superconducting magnet, a water-cooled copper magnet, or a hybrid of both is preferable from the viewpoint that it is easy to generate a magnetic field in a specific direction.

In order to simplify the description, for example, a case where a tissue in a living body has unidirectional anisotropy (orientation) will be described. In one embodiment of the present invention, a magnetic field (B ) Direction 3 can be applied. FIG. 3 shows an example of a magnetic field application device for imparting orientation.

FIG. 3 shows a case where the magnetic field (B) is applied in a direction perpendicular to and parallel to the longitudinal direction of the rat tibia. That is, in FIG. 3, 4 indicates the case where the longitudinal direction of the rat tibia and the magnetic field are perpendicular, and 5 in FIG. 3 indicates the case where the longitudinal direction of the rat tibia and the magnetic field are parallel.

  The direction of the biological apatite c-axis and the running direction of the collagen fibers are parallel to the longitudinal direction of the rat tibia. Therefore, in order to orient the bioapatite c-axis direction or collagen fiber running direction in the same direction as the longitudinal direction of the tibia, a magnetic field is applied in a direction substantially perpendicular to the longitudinal direction of the tibia using the device of the present invention. Give it. By setting the magnetic field in a direction substantially perpendicular to the tibia, the biological apatite crystals and collagen fibers in the biological tissue are oriented in a state close to that of a normal tissue, and the tissue has anisotropy.

FIG. 3 is an example in which a magnetic field is applied in one direction, but the application direction (relative orientation with respect to a specific direction of the hard tissue) is three-dimensionally controlled along with the direction control of the irradiation unit (in this case, the rat tibia). It can be set as the apparatus which gives arbitrary orientation by changing and changing irradiation time.

  In a preferred embodiment of the orientation control device of the present invention, the magnetic field to the affected area is applied in the direction of 90 ° ± 45 ° with respect to the orientation direction of the crystal. In addition to the fact that it is impossible to set exactly perpendicularly, the stress direction and orientation direction of normal tissue may differ when an implant material is inserted. Although the range is ± 45 degrees, the range is not limited to this range depending on the degree of loss or the like, and the range can be appropriately set so as to exhibit the above-described original mechanical function. Therefore, depending on the case, it may be good when it is outside the range of 90 ° ± 45 °.

In a preferred embodiment, the magnetic field to the affected part is applied in a direction of 90 ° ± 45 ° with respect to the traveling direction of the collagen fiber. In addition to the fact that it is impossible to set exactly perpendicularly, the stress direction and orientation direction of normal tissue may differ when an implant material is inserted. Although the range is ± 45 degrees, the range is not limited to this range depending on the degree of loss or the like, and the range can be appropriately set so as to exhibit the above-described original mechanical function. Therefore, depending on the case, it may be good when it is outside the range of 90 ° ± 45 °.

In a preferred embodiment, the magnetic field to the affected area is applied in a direction of 90 ° ± 45 ° with respect to the blood vessel running direction. In addition to the fact that it is impossible to set exactly perpendicularly, the stress direction and orientation direction of normal tissue may differ when an implant material is inserted. Although the range is ± 45 degrees, the range is not limited to this range depending on the degree of loss or the like, and the range can be appropriately set so as to exhibit the above-described original mechanical function. Therefore, depending on the case, it may be good when it is outside the range of 90 ° ± 45 °.

  In a preferred embodiment of the orientation control device of the present invention, the magnetic field to the affected area is applied in the direction of 90 ° ± 45 ° with respect to the stress load direction of the hard tissue. In addition to the fact that it is impossible to set exactly perpendicularly, the stress direction and orientation direction of normal tissue may differ when an implant material is inserted. Although the range is ± 45 degrees, the range is not limited to this range depending on the degree of loss or the like, and the range can be appropriately set so as to exhibit the above-described original mechanical function. Therefore, depending on the case, it may be good when it is outside the range of 90 ° ± 45 °.

  In a preferred embodiment, the magnetic field to the affected area is applied in the direction of 90 ° ± 45 ° with respect to the bone near-distal direction of the hard tissue. Similar to the above, in addition to being impossible to set exactly vertically, the stress direction and orientation direction of normal tissue differ when implant materials are inserted. However, it is not limited to this range depending on the degree of deficiency, etc., but is appropriately set so that the above-described original mechanical function can be exhibited. Can be set. Therefore, depending on the case, it may be good when it is outside the range of 90 ° ± 45 °.

  In the orientation control device of the present invention, the intensity of the magnetic field to the affected area is preferably in the range of 1 to 20 (T) from the viewpoint that it can be generated relatively easily at the laboratory level. .

  In a preferred embodiment, the magnetic field effect on the affected area is applied for 1 to 12 hours from the viewpoint of efficiently reducing the time for hindering life. If the desired orientation can be obtained even in a short time, the application of the magnetic field may be stopped in a short time.

  Furthermore, the orientation control device of the present invention may include an evaluation means for evaluating the orientation of normal hard tissue crystals. If it is possible to evaluate the orientation of normal hard tissue crystals, the orientation can be controlled using the magnetic field in this device based on the orientation data corresponding to the evaluation result. it can.

The evaluation means includes X-ray diffraction, SEM-EBSP (Scanning Electron
TEM-DP (Transmission Electron), based on analysis of electron backscattered image of each crystal grain by Microscope-Electron Backscattering Pattern
Although at least one selected from the group consisting of those obtained by analysis of electron diffraction patterns by the Microscope-Diffraction Pattern method can be exemplified, there is no particular limitation as long as the orientation can be evaluated.

  From the viewpoint of being able to non-destructively measure a tissue in a living body, easily preparing and preparing a sample, and determining the orientation quantitatively, an X-ray diffraction method can be preferably used. From the viewpoint of more surely grasping the orientation from a small site, it is preferable that the analysis by the X-ray diffraction method is performed in a minute region. In general, it is more accurate to define the diameter of incident X-rays than to specify the range of a minute region. In other words, since the angle between the X-ray and the sample surface changes to some extent, it is difficult to rigorously measure the measurement area. On the other hand, the measurement range (the range of the minute region) is said to be about 3 to 5 times the incident X-ray diameter. Therefore, a preferable range can be determined using the incident X-ray diameter. From the viewpoint of accurately evaluating the orientation of a small part, the incident X-ray diameter is 10 μm to 1 mm, preferably 10 μm to 100 μm.

  The crystal orientation is not particularly limited as long as it can be specified to such an extent that it can be compared with normal in vivo tissues. Therefore, for example, when the orientation is examined by X-ray diffraction method, SEM-EBSP method, TEM-DP method, etc., the one with the largest peak may be used, or the second or third peak or those Other than these may be used. These orientations are specified by making appropriate changes and modifications according to the tissue properties, bone mass, disease severity, types of tissues in the body such as long bones, short bones, and flat bones, and various parts. Comparative analysis.

Therefore, although there is no particular limitation on the orientation direction, from the viewpoint of determining that the function is exerted compared with normal in vivo tissue, the orientation direction is the orientation of crystals in the in vivo tissue. The degree of orientation is preferably the maximum value or the maximum value of orientation.

  In a preferred embodiment, the in-vivo tissue is a bone slice. The bone section is not particularly limited, but can be obtained by one selected from the group consisting of bone biopsy needles, bone saws, bones only, duel, sharp blades, cutting tools, etc. Can do. Bone biopsy needles have been widely used for the analysis of hard tissues in the past, and incorporating a bone section collected using the bone biopsy needle into the present invention is a preferred embodiment for quick and precise evaluation. is there.

  In the present invention, the power of the evaluation method can be exhibited particularly when the axial direction to be measured is not clear. Therefore, in addition to the case of bone biopsy, even in the case of a bone slice in which the axial direction to be measured is unclear, it is possible to quickly and accurately evaluate the in vivo tissue by applying this evaluation means. is there.

  Of course, if the purpose is to perform a more precise analysis, it is desirable to determine a plurality of the above orientation orientations and perform a comparative analysis, respectively. However, when speediness is required such as surgery, at least one orientation orientation is desired. If this can be specified, it is advantageous in that it is possible to quickly evaluate the tissue in the living body only by analyzing the orientation direction.

  In a preferred embodiment of the in vivo tissue evaluation means, the orientation direction can be determined by analyzing in-plane anisotropy of the in vivo tissue. In this method, the orientation orientation is swiftly specified by continuously measuring the in-plane orientation by rotating the sample.

  Usually, the degree of orientation parallel to a specific axis, for example, a bone axis direction is high. Therefore, for example, when a bone section is collected using a bone biopsy needle as described above, since the bone axis is perpendicular to the bone biopsy direction, it is 360 degrees with the direction of the extraction axis of the collected sample as the central axis. It can be installed on a rotatable jig and the continuous profile of diffraction information can be analyzed by X-ray diffraction. If the detector is two-dimensional and can be detected simultaneously, the analysis time will be accelerated. However, analysis time is required for the 0th and 1st dimensions, but analysis is possible. Further, the case of using the X-ray diffraction method will be described. In order to make the rotation axis of the sample coincide with the incident X-ray, the rotary jig can be fixed on a movable stage and the axis can be aligned. . Then, while rotating 180 degrees, the maximum orientation orientation is determined, the orientation degree at that position is precisely measured, and compared with a database (orientation) showing the degree of disease progression, the degree of disease and disease It is also possible to determine the part. Using a two-dimensional PSPC (detector) enables analysis within one hour and enables quantitative orientation analysis before surgery.

Further, in a preferred embodiment of the evaluation means, the in-plane anisotropy analysis is performed in an in-plane difference on a plane parallel to the bone axis direction of the in-vivo tissue or a plane within the range of the bone axis direction ± 90 degrees. This is done by analyzing the direction. First, by analyzing the in-plane orientation, the orientation direction can be quickly identified, which is preferable from this viewpoint. Further, when the shape of the sample is indefinite (when it is not cylindrical), it is possible to determine an axis and rotate the axis to detect a highly oriented orientation in the plane of rotation.

  In a preferred embodiment, analysis can be performed by determining the diffraction intensity of the crystal by X-ray diffraction. For example, the diffraction intensity can be obtained based on the orientation with respect to the a-axis, the c-axis, and / or other orientations. As an analysis condition, a Bragg angle (which means an angle formed by incident X-rays and diffracted X-rays with respect to the diffraction surface to satisfy the diffraction conditions) is determined so that the orientation of the a-axis and the c-axis can be determined. For example, the angle between the incident direction of the line and the sample surface can be set and the sample can be swung.

  That is, it is possible to evaluate the state of the regenerated tissue or the diseased tissue by comparing the diffraction intensity of the crystal of normal in vivo tissue with the diffraction intensity of the crystal of the regenerated tissue or the like. This is based on the fact that in the evaluation method of the present invention, the orientation of crystals of in vivo tissues, for example, hard tissues, varies greatly depending on the types of bones such as long bones, short bones, and flat bones, and various parts. It is a thing.

  In a preferred embodiment of the present invention, the analysis includes c-axis / a-axis, c-axis / (orientation other than a-axis and / or c-axis), c-axis / (a-axis, and / or c-axis). This is performed by obtaining at least one diffraction intensity or diffraction integral intensity ratio selected from the group consisting of various orientations. That is, as long as the numerator is the c-axis, any denominator may be used. Specifically, c axis / (a axis + c axis), c axis / {a axis + (another direction other than a axis and c axis)}, c axis / {c axis + (a axis and c axis) Azimuth other than axis)}, c axis / (other azimuth other than a axis and / or c axis), c axis / (a axis, c axis, and other azimuth other than these), etc. Can do. When it is desired to evaluate a tissue in a living body more quickly, for example, the evaluation is performed by determining only the diffraction intensity based on the orientation with respect to the a-axis, the c-axis and / or other orientations without obtaining the diffraction intensity ratio. You may go. For the case of using the X-ray diffraction method, for example, in addition to the diffraction intensity ratio of (002) / (310), when taking (002) / {(211) + (112) + (300)}, Orientation by measuring and mapping only (002) diffraction three-dimensionally at the same location (in this case, normalize the average diffraction intensity of all three dimensions to 1 and take its maximum intensity and half-value width) The direction may be determined. In particular, when performing rapid evaluation of tissue in a living body, only (002) diffraction may be performed. In this case, although it is extremely simplified, it is possible to obtain a generally good evaluation.

To supplementarily explain the relationship between the diffraction intensity and the orientation, for example, among the X-ray profiles obtained under the same conditions, the diffraction intensity or diffraction integrated intensity from the (002) and (310) planes is the a-axis and the c-axis, respectively. In order to show the strength of orientation, relative orientation can be analyzed by taking the ratio. Further, by comparing with the intensity of other diffraction lines, it is possible to evaluate the orientation with respect to the a-axis, c-axis and / or other directions. Using these diffraction intensities and orientation properties, it is possible to evaluate in vivo tissues.

  By applying the X-ray diffraction method to living tissue, regenerated tissue, and diseased tissue, (1) orientation of crystallites such as hydroxyapatite, (2) determination of crystal structure and identification of constituent crystal components, (3) crystal (4) Evaluation of the three-dimensional texture of crystallites. Regarding (1), it is possible to analyze the orientation by measuring the intensity of a specific diffraction surface from the above-mentioned X-ray profile and taking the ratio. Regarding (2), the crystal structure can be determined and the constituent crystal components can be identified by comparing the angle at which the diffraction line appears (Bragg angle) and the intensity of each. Regarding (3), the crystallinity can be evaluated by measuring the half width of each diffraction line. The half width is the width of a diffraction peak at a position where the intensity is halved, and is a unit of angle. A larger width means lower crystallinity. The crystallinity is determined by the size of the crystallite and the lattice strain. When the crystallite is small and the lattice strain is large, the crystallinity is lowered (half-value width is increased). Regarding (4), it can be performed by changing the sample orientation to be evaluated three-dimensionally and the X-ray incident angle, and measuring the diffraction intensity of a specific diffraction line from multiple orientations. When it is desired to know the orientation of the c-axis, a diffraction angle of about 26 ° may be used when the Bragg angle (2-seater) uses Cu-Kα characteristic X-rays as incident X-rays.

  Crystal orientation usually means that unit structures (microcrystals) constituting a polymer solid are arranged in a certain direction. For orientation, the plane orientation found in polyethylene films (for example, the c-axis is in the plane of the film and there is no other orientation), uniaxial orientation (the c-axis is oriented in the fiber direction). , Spiral orientation found in cotton and hemp (the c-axis has a certain inclination with the fiber orientation), and double orientation (one crystal plane parallel to a certain plane including the fiber axis). . Therefore, it is possible to evaluate the in vivo tissue by examining the orientation of normal in vivo tissue and the orientation of regeneration and / or diseased tissue, and comparing both.

  For example, the hard tissue can be evaluated by examining the orientation of hydroxyapatite, which is a typical component of the hard tissue, and comparing the normal one with the diseased one during regeneration.

  In addition, in the evaluation of hard tissues, bone mass, observation of tissue samples, composition analysis, infrared absorption (IR) analysis, evaluation of mechanical properties such as hardness / fracture stress, elastic modulus, etc. should be performed in combination. Can do. By using conventional evaluation means such as bone mass and tissue specimen observation in combination with the above evaluation method, it is possible to evaluate a dense hard tissue with higher accuracy.

Here, although one Example of this invention is described, this invention is limited to the following Example and is not interpreted. Moreover, it cannot be overemphasized that it can change suitably, without deviating from the summary of this invention.
Example 1
In the examples, magnetic field application was performed using rat tibia, which is a kind of long bone. First, a bone defect was given to the rat tibia (longitudinal bone), and a magnetic field (10T) perpendicular and parallel to the bone long axis direction was given. Specifically, a 10-week-old SD rat female tibia (uniaxially oriented parallel to the bone axis) was given a cortical bone defect of 2 mmφ, and a 10 T (unit: Tessler) magnetic field was applied perpendicularly and parallel to the tibia. Irradiation was performed only for 2 hours a day, and the formation of trabecular bone was observed. Since the orientation of collagen / apatite is generally shown in the direction of trabecular extension, the direction of trabecular extension was examined.

The state of magnetic field irradiation is shown in FIG. As a result, the bone microstructure in the initial stage of bone regeneration showed anisotropy, and the trabecular direction was perpendicular to the magnetic field. This indicates that a bone microstructure anisotropy similar to that of normal bone can be imparted from the early stage of bone regeneration.

  Further, FIG. 5 shows the formation of new bone trabeculae after 2 weeks of regeneration. As a result, even when a strong magnetic field was applied perpendicularly or parallel to the bone axis (longitudinal direction of bone), trabecular extension (collagen / apatite orientation) was observed perpendicular to the magnetic field direction. Therefore, it is possible to give the desired orientation by controlling the direction of the magnetic field and the application time. The bone is controlled by stress sensors (cells called osteosites) present in the bone, whereas this device proved to be an epoch-making device that enables this by using a magnetic field. did.

  As described above, bones having anisotropy of the bone microstructure close to the normal part by irradiating while considering the direction of the magnetic field using a relatively high magnetic field during bone regeneration or for bone diseases It became possible to acquire a regenerative part or recover the fine structure of the diseased part. As used in MRI, magnetic fields have little effect on the human body and can work on bone microstructures in a non-invasive and non-contact manner. The bone extracellular matrix can be produced by bone cells in vivo, and this arrangement can be controlled by a magnetic field.

According to the present invention, it can be expected to contribute to the treatment of diseases in in vivo tissues such as hard tissues, the field of regenerative medicine and dentistry (particularly orthopedics, brain surgery, dentistry) and basic medicine.

FIG. 1 is a diagram showing an outline of the principle of orientation by a magnetic field. FIG. 2 is a diagram showing the relationship between bioapatite orientation and bone mechanical function. FIG. 3 is a diagram illustrating an example of a magnetic field application device for imparting orientation. FIG. 4 is a diagram showing a state in which magnetic field irradiation is performed using an animal model. FIG. 5 is a diagram showing the influence of strong magnetic field irradiation on defect portion regeneration.

Claims (12)

An apparatus for controlling the orientation of a tissue or cell in a living body by supplying a magnetic field to an affected area, comprising: a magnetic field supplying means for supplying a magnetic field to the affected area; and a control means for controlling the magnetic field. apparatus.   2. The control apparatus according to claim 1, wherein the in vivo tissue is selected from the group consisting of bone, cartilage, smooth muscle, cardiac muscle, skeletal muscle, skin, blood vessel, fat, ligament, tendon, blood vessel, and cell.   3. The apparatus according to claim 1, wherein the magnetic field to the affected part is applied in a direction that minimizes the magnetocrystalline anisotropy energy with respect to the orientation direction of the crystal. The apparatus according to any one of claims 1 to 3, wherein a magnetic field to the affected part is applied in a direction of 90 degrees ± 45 degrees with respect to a traveling direction of the collagen fibers. The apparatus according to any one of claims 1 to 4, wherein an orientation direction of the crystal is a c-axis direction of biological apatite.   The apparatus according to any one of claims 1 to 5, wherein a magnetic field to the affected part is applied in a direction of 90 degrees ± 45 degrees with respect to a main blood vessel traveling direction.   The apparatus according to any one of claims 1 to 6, wherein a magnetic field to the affected part is applied in a direction of 90 degrees ± 45 degrees with respect to a stress load direction of the hard tissue.   The apparatus according to any one of claims 1 to 7, wherein a magnetic field to the affected part is applied in a direction of 90 degrees ± 45 degrees with respect to the bone near-distal direction of the hard tissue.   The device according to any one of claims 1 to 8, wherein the intensity of the magnetic field to the affected area is in the range of 1 to 20 (T).   The device according to any one of claims 1 to 9, wherein a magnetic field to the affected area is applied for 1 to 10 hours.   Furthermore, the apparatus of any one of Claims 1-10 provided with the evaluation means to evaluate the orientation of the crystal | crystallization of normal hard tissue. The evaluation means is an X-ray diffraction method, SEM-EBSP (Scanning Electron Microscope-
Electron
TEM-DP (Transmission Electron), which is based on analysis of electron backscattering image of each crystal grain by Backscattering Pattern
The apparatus according to claim 11, which is provided by at least one selected from the group consisting of those obtained by analysis of electron diffraction patterns by a Microscope-Diffraction Pattern) method.

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