JP6652608B2 - Grouping and control of magnetically responsive bodies - Google Patents

Description

The present invention generally relates to the population and control of magneto-responsive entities. More specifically, the present invention relates to a technique for collecting a sensitive body at a convergence point in a predetermined three-dimensional space by controlling a magnetic field.

  In medical settings, it is highly desirable to use an operable sensitive body to deliver a therapeutic agent to a precise location in the body. Carrying therapeutic agents (radioisotopes, etc.) and diagnostic agents (contrast agents, etc.) by using a magnetically responsive body with a self-propelling function as a carrier (nano robot or magnetotactic bacterial carrier) and setting the direction of the magnetic field This is conventionally done, but it is difficult to do this in increasingly narrow blood vessels (eg, capillaries) or large areas (eg, stromal areas of tumors). In particular, it is very difficult to induce a propulsive force (traction force) to a carrier in a deep part of the body due to the small size of a sensitive body (for example, a magnetic carrier) and technical limitations. Therefore, in order to alleviate such a limitation, studies are being made on a magnetic susceptor as a carrier, referred to herein as an operable self-propelled body (SSPE).

  A patent assigned to Martel et al. (US Pat. No. 7,962,194) shows that ferromagnetic particles are controllably propelled in a patient by a nuclear magnetic resonance imaging (MRI) system. ing. Also, Martel (U.S. Patent Publication No. 2006/0073540) teaches the use of magnetotactic bacteria to control the orientation of microscopic objects in a two-dimensional space, for example, in a Petri dish. Such bacteria are capable of self-propulsion and swim in the direction of the magnetic field. One of the drawbacks of the known technique according to the above-mentioned U.S. Publication No. 2006/0073540 is that, in this technique, in a three-dimensional space such as a large blood vessel, an organ, or a tissue of a human body, an object is moved to a desired target point (target). ) Cannot be guided efficiently.

  Therefore, it is required to increase the amount of the therapeutic agent delivered to the target in the body by increasing the induction efficiency. Further, it is desired that the state be visually recognizable (detectable) using an image diagnostic method such as MRI. To achieve this, it is necessary to collect multiple SSPEs at desired locations. For this reason, there is a great demand for an apparatus, system, or method that can group SSPEs and control their displacement.

U.S. Pat. No. 7,962,194 US Patent Publication No. 2006/0073540

  Applicants have devised a novel apparatus and method for clustering and displacing a plurality of magnetically responsive bodies (operable self-propelled bodies or SSPEs) in three dimensions by using a time division multiplexing scheme. An apparatus for controlling SSPE population within a body comprises at least three sets of magnetic field sources arranged on three axes to generate a controllable magnetic field, the apparatus being connected to at least one of the magnetic field sources. And a control unit for generating a three-dimensional convergence point. The method of clustering sensitizers comprises using a first set and a second set of magnetic field sources to generate opposing gradient magnetic fields in each set, thereby clustering the magnetic sensitizers in two axes. The multiplexing process includes reversing the direction of the gradient magnetic field in the third axis according to a predetermined program.

  An apparatus according to an embodiment of the present invention controls the clustering of self-propelled magnetic susceptors inside a body, the apparatus comprising at least three axes arranged on three axes to generate a magnetic field. A set of magnetic field sources and a control unit connected to at least one of the magnetic field sources and generating a three-dimensional convergence point.

  In some embodiments, the first and second sets of magnetic field sources of the magnetic field sources each generate opposing gradient magnetic fields in the set to cause the magnetic susceptors to cluster in two axes, The control unit reverses the magnetic field directions of the third set of magnetic field sources on the third axis according to the first predetermined program, and the magnetic field source on the third axis switches two coils wired so as to flow current in the same direction. Further prepare.

  In some embodiments, the controller is configured to sequentially activate all combinations of the two sets of magnetic field sources according to a second predetermined program. In another embodiment, the at least one magnetic field source is located outside the body and comprises a permanent magnet.

  An apparatus according to another embodiment of the present invention is configured to guide a responsive body to a location within a body by moving a convergence point relative to a set of magnetic field sources. In another embodiment, the convergence point is moved using a positioning device for moving the magnetic field source. In another embodiment, the convergence point is moved by moving the platform on which the body rests.

  In an apparatus according to another embodiment of the present invention, the magnetic susceptor comprises a magnetotactic bacterium, and wherein the second predetermined program is that a portion of the magnetotactic bacterium realigns with the magnetic field according to a change in the magnetic field. Provide the frequency that you want.

  In an apparatus according to still another embodiment of the present invention, the control unit changes the size or shape of the convergence point (adjusts the amplitude for enlarging or reducing the clustering zone) to increase the path finding ability of the magnetic susceptor. It is configured to enhance.

  An apparatus according to yet another embodiment of the present invention further comprises a magnetic sensitive detector (such as an MRI machine) for detecting the position of the magnetic sensitive. In such an embodiment, the apparatus may further comprise a platform moving between a first station having a magnetically sensitive detector and a second station having a magnetic field source.

  According to yet another embodiment of the present invention, there is provided a method of clustering self-propelled magnetic sensitizers inside a body, the method comprising generating a magnetic field having a three-dimensional convergence point in the body, and forming the sensitizers. Moving toward the convergence point and clustering near the convergence point. In such an embodiment, a constant gradient magnetic field is maintained in two axes, and the direction of the gradient magnetic field is alternately switched in a third axis according to a first predetermined program.

  In some embodiments, the method further includes sequentially activating all combinations of the two opposing magnetic field sources according to a predetermined program.

It is physically impossible to concentrate all lines of the static magnetic field at one point in 3D space without using objects or surfaces that hinder progress. However, applicants have found that altering at least one axis using time division multiplexing can force the SSPE to move toward a point and form an aggregate of SSPEs. The three-dimensional convergence point (CP) in the magnetic field is an unbounded point in space, and is a point at which the responsive body that follows the direction of the magnetic field moves and clusters in the clustering zone (AZ). The magnetic field at the convergence point is substantially zero, surrounding the convergence point in AZ. Further, the effective magnetic field having a predetermined strength is directed from all directions to the convergence point. Since the magnetic field source is not a point source, by varying at least one magnetic field source over time, the sensible body can be moved toward the convergence point and remain near the convergence point.

  Thus, two axes (X, Y, or Z) are maintained to have a constant (static) magnetic field, and the direction of the magnetic field in the other axes is changed according to the two axes in which the magnetic field is kept constant. To generate a convergence point. Similarly, by keeping the magnetic field direction of one axis constant and changing the magnetic field directions of the other two axes simultaneously (synchronously) or stepwise (delayed) by time division multiplexing, A convergence point can be generated. In doing so, if the SSPE is a magnetotactic bacterium, the alteration is made at a frequency at which the SSPE responds appropriately, for example in the range of 0.1-5 Hz, more preferably at a frequency of about 0.5 Hz. The magnetic field directions of the three axes can be changed simultaneously or with a delay between the axes by a time division multiplexing method. All combinations are possible, but it is necessary to change the direction of the gradient magnetic field of at least one axis (X, Y or Z) by a time-division multiplexing method and adjust the switching speed at this time to the reaction time of the SSPE. It is.

  The invention will be better understood with reference to the following detailed description of embodiments of the invention and the accompanying drawings.

It is a figure showing a magnetotactic bacterium (magnetic responsive body) concerning an embodiment of the present invention. FIG. 3 is a diagram showing a magnetic field in an XZ plane (FIG. 2A) and a YZ plane (FIG. 2B), and the strength of the magnetic field is proportional to the length of the arrow. FIG. 3 shows the distance of the convergence point from the center point between two opposing coils as a function of the current ratio in Maxwell coils. FIG. 4B illustrates a flat magnetic field velocity vector (FIG. 4A) generated from a 2D Maxwell pair and the absolute magnetic field generated by two opposing Maxwell coil pairs in the x and y axes. As shown in FIG. 4B, the field lines are strongest at the four upper (dark) ends, the gradient of which is the center (convergence point) where the magnetic field strength is (almost) zero (towards the minimum). , Shown below as dark areas). FIG. 3 is a diagram showing a cube in which each vertex is numbered to facilitate understanding of a direction in which a current flows. It is a figure which shows typically various adjustment modes for improving a path | route discovery ability. It is a figure which shows typically various adjustment modes for improving a path | route discovery ability. 1 is a diagram showing an embodiment of a coil configuration for implementing a magnetotactic system according to the present invention. FIG. 4 shows the distance of the convergence point from the center point as a function of the current ratio in two opposing Helmholtz coils and the displacement value of the Maxwell field. FIG. 4 schematically illustrates a portable configuration having one internal magnetic field source, which is configured to “surround” a convergence point for clustering and controlling the magnetically responsive bodies. FIG. 3 is a diagram showing a hybrid configuration having one internal magnetic field source and one external magnetic field source for grouping and controlling magnetic responsive bodies. It is the figure which modeled the sensitive body which does not have a route finding ability (FIG. 12A), and the sensitive body which has a route finding ability (FIG. 12B). Directivity mode applied to two magnetically sensitive objects that have pathfinding capability (or may not have pathfinding capability if the angle from an obstacle is large enough), indicating the limitations of the method FIG. FIG. 4 is a diagram schematically illustrating the directivity mode (D mode) control of the magnetic sensitive body, and the arrow in the figure indicates the approximate direction of the gradient magnetic field. FIG. 15B is a diagram schematically illustrating a grouping mode used for target setting (FIG. 15A), and is a diagram illustrating an example in which a grouping zone (or size of a convergence point) is reduced in order to improve target setting efficiency (FIG. 15B). ). FIG. 4 is a schematic diagram of a collective target mode (T mode) control of the magnetic responsive body. It is a schematic diagram of the grouping division mode (S mode) control of a magnetic sensitive body. It is a schematic diagram of the grouping continuous mode (C mode) control of a magnetic sensitive body. FIG. 4 illustrates time division multiplexing in a set of opposing coils located on the X, Y, and Z axes. FIG. 19A shows a first predetermined program, and FIG. 19B shows a second different predetermined program, both programs for generating a three-dimensional convergence point.

  An actuatable self-propelled body (SSPE) or a magnetically responsive body is here an entity that is not bound by another, and whose propulsion source, ie the system causing the displacement of the same, is the same itself. Is defined as being part of, adhering to, or embedded in the sensitizer itself. Operable self-propelled vehicles include groups of objects or microorganisms and biological or hybrid systems. The system includes a micro-nano system or micro-nano structure composed of biological and / or synthetic (chemical, artificial, etc.) materials and / or elements. In addition, the operable self-propelled body has a moving direction in which a directional magnetic field (for example, by a permanent magnet) or an electromagnetic field (in the present specification, a magnetic field is generated by a current flowing through a conductor) orientated in a predetermined direction. (Including an electromagnetic field). In the present specification, the magnetotactic property means that the moving direction of the SSPE is affected by a directional magnetic field (if necessary, the SSPE may be functionalized and added to another structure). Examples of the above SSPE include flagellated magnetotactic bacteria (MTB) in single or group (swarms, clumps, aggregates, etc.) or are self-migrating and are affected by directional control by a directional magnetic field Other bacteria or microorganisms include but are not limited to. These bacteria and microorganisms may have been partially modified in advance by various methods. Such methods include, but are not limited to, using culture parameters and genetics. In addition, other objects modified such that these bacteria and microorganisms can be controlled by magnetotaxis ("control" in the present specification refers to affecting the movement, displacement, behavior, etc. of the object). For example, it may be attached to or embedded in other cells (such as red blood cells). Alternatively, it may be mounted on a composite structure that can be affected by a directional magnetic field or a directional magnetic field gradient. Also, by attaching micro- or nano-components to bacteria, cells, or other microorganisms, the direction of movement of structures, including hybrid (having biological and synthetic components) tissue, can be magnetically driven. The magnetic compass may be configured so as to be able to respond to a directional magnetic field that can control the direction of the needle of the nano-sized magnetic compass.

  Each SSPE must have at least a propulsion system and a directional control system. Here, the direction control system is influenced by torque caused by magnetic field lines of a directional magnetic field generated by an appropriate coil (or permanent magnet) means (part of a magnetotactic system) (magnetism control). System.

MC-1 type magnetotactic bacteria are an example of biological SSPE, where the flagellar bundles play a role in the propulsion system. In addition, a series of membrane-based nanoparticles (crystals) called magnetosomes embedded in cells function like a small magnetic compass needle that is oriented in accordance with a directional magnetic field, thereby providing a direction control system. Has been realized.

  FIG. 1 is a schematic diagram showing an MC-1 magnetotactic bacterium 13 functioning as an SSPE (or a magnetic sensitizer) existing in nature, which comprises two flagella 12 for propulsion and a series for directional control. Of the magnetosome 14. Bacteria 13 are directed to the magnetic field lines by the magnetosome 14, and the pole 16 is searched. That is, the combination of orientation and propulsion forces bacteria to be directed toward pole 16.

  Basic Principle and Main Intent: The main intent behind a magnetotaxis system is to use the magnetic field primarily for directional control (no intention to apply a displacement force to the navigable sensible body). Therefore, this system is designed primarily for the SSPE as defined herein. The magnetic field from the magnetotaxis system is for directional control only, not for providing propulsion or traction (although there may be non-negligible small traction). Thus, the required magnitude (intensity) of the magnetic field is much lower, which makes it technically possible to navigate a smaller SSPE with very little power.

In practice, direction control is performed by applying a directional magnetic field B and generating a torque T in a predetermined direction, as shown by the following equation.

  For a sensitive body having the same volume and the same amount of magnetization, the magnitude of the magnetic field required to generate a torque in a predetermined direction (directional torque) is compared with a displacement force (traction force) in a predetermined direction. Very small. Therefore, in operation under the same environment (condition), the power required for controlling the direction of the sensitive body having self-propulsion (driving force) is extremely small.

By adopting a special coil configuration and changing the magnitude of the current flowing in each coil in a predetermined direction in various ways to change the combination, not only the direction control of the SSPE becomes possible, but also the By performing directional control, these SSPEs can be clustered into a particular "center" position (which can be shifted in the desired direction). The ability to cluster SSPEs in this way is very important and essential in many medical interventions. For example, when delivering a drug to a tumor, the overall size of each SSPE must be reduced so that the SSPE can pass through the microvasculature or small openings. Using smaller overall size SSPEs also reduces the amount of therapeutic delivered by each SSPE. Thus, controlling the population of SSPEs allows for a greater and, more sufficient, amount of therapeutic agent to be delivered in a medical intervention as described above. Another reason that the system should have the ability to cluster SSPEs is to prevent SSPE distribution. In fact, it is not possible to control each SSPE simultaneously and individually using coils placed outside the patient, but it is possible to control these SSPEs as a group as a whole. Therefore, when using a system that allows only directional control and does not have a function of grouping SSPEs, the initial grouping process usually differs depending on the speed difference of each SSPE and / or each SSPE. It disperses due to other perturbations or forces acting. When such dispersion occurs, the density of the aggregate decreases and MR detection and tracking become difficult or impossible. Furthermore, the direction control in this case is performed only for the entire group within the control range of the magnetotaxis system. For this reason, for example, if the scale of dispersion increases beyond the distance between adjacent branch points, each reaching a different target, many SSPEs become uncontrollable.

  Basic configuration and principle of magnetotaxis system: The form of the magnetotaxis system may be a platform, a portable system or a portable tool, or may be a hybrid type. Platform-based magnetotaxis systems are designed to surround a patient's entire or partial body. That is, the patient, or a portion of the body to be treated, is designed to be located within the inner diameter of the magnetotactic system. In portable systems, the inner diameter of the system, such as the coil structure, does not surround the patient or the part of the body to be treated, but surrounds the treatment area. That is, the magnetic source structure is designed to be applied directly to the target site to be treated. Therefore, the target site must be a site physically accessible by the magnetotactic system. An example of this is a rectal tumor accessible from the rectum, or an area of the body that can be accessed using open surgery or other techniques, including non-invasive techniques such as laparoscopy. The hybrid type is a combination of the above two types.

  Various configurations can be envisioned as the magnetic field source, but it is important to consider that, in addition to performing directional control using magnetotaxis, a magnetic field capable of focusing on a target in 3D space. That is, it has the ability to use it to group SSPEs.

For example, a converging gradient magnetic field (magnetic gradient field) can be generated by passing currents in opposite directions through a plurality of magnetic coils, but the direction of the magnetic field is determined by the current circulating through each coil. Will always be directed to the position determined by the value of. Thus, SSPEs, such as magnetotactic bacteria (MTB), which have the property of going in the direction of the magnetic field, are guided towards the above-mentioned positions.

  The size of the target area depends on the strength of the current circulating in the coil and the sensitivity of the SSPE to the direction of the magnetic field generated by the coil of the magnetotactic system. For example, MC-1 type MTBs respond to very weak magnetic fields. We estimated magnetic sensitivity by counting the number of bacteria as a function of the spatially varying gradient magnetic field. As a result, it was found that MTB was distributed in a 0.3 Gauss equipotential circle, and almost half of the MTB was distributed in a 0.1 Gauss equipotential circle (not shown). Thus, not only can the size of the AZ be changed by increasing or decreasing the amount of current circulating in the coil, but the outer boundary of the AZ depends on the percentage of MTB deemed sufficient in the AZ or target zone. , Can be arbitrarily selected to have a predetermined equipotential (for example, 0.1 or 0.3 gauss) (provided that the MTB is not preselected).

  MC-1 type magnetotactic bacteria are spatially distributed within the equipotential zone, and MTB has normal variations in magnetotactic sensitivity. What is needed is a system that can guide the SSPE toward the point of convergence, a magnetic guidance system referred to herein as a magnetotactic system. This problem can be solved by using a simple electromagnet. However, the convergence point or target point is limited to an area on the surface (closer to the magnetic field source) and it is not possible to set a convergence point on the side of a deep organ or area. By using a magnetotactic system based on a 3D magnetic coil, the SSPE can be guided to a deep target region by appropriately selecting a surface on which the SSPE converges.

FIG. 2A shows the direction of the magnetic field in the XZ plane, and FIG. 2B shows the YZ plane (the strength of the magnetic field is proportional to the length of the arrow). The magnetic field converges to a single point in the XZ plane shown in FIG. 2A, but not to a single point in 3D space, but to a 2D convergence area 23 in a 2D clustering area 25. Actually, the y component of the magnetic field (see FIG. 2B) exists, and the component becomes more important near the convergence point. It should be noted that the direction of the arrow pointing outward in FIG. 2B (the direction of the magnetic field,
Is shown). As can be seen from FIG. 2, a static magnetic field cannot guide SSPE to a given target in 3D space. Therefore, it is necessary to invert the magnetic field back and forth at a specific frequency by employing an appropriate coil configuration using the time division multiplexing method. By incorporating this approach into the magnetotactic system described above, targeting using a focused magnetic field is achieved. This is functionally equivalent to being able to use the magnetic tip on any surface (not only the surface close to the magnetic tip), and also to be performed in a deep part of the body where the magnetic tip cannot be carried. Can be.

  This approach leads to basic remarks about possible coil hardware configurations in magnetotactic systems. For example, when four coils are used, a reverse current flows through each pair of two coils, and there is a mathematical relationship between the current flowing through these coils and the position of the convergence point. When six coils are used, the two additional coils can minimize the y component of the magnetic field (see FIG. 2B) and improve controllability in 3D space. Instead of adjusting the current value in the coil generating the gradient magnetic field, a set of Helmholtz coils can be used to change the position of the convergence point. The advantage of this approach is that the magnetic field gradient can always be the same (or nearly the same), which is not possible with other configurations. The configuration using Helmholtz coils is relatively complicated, but if it is important to always make the gradient the same (or almost the same), it can be said to be one of useful configurations.

  The focusing magnetic field is centered at what is called the convergence point. Arrows indicate the direction of the magnetic field. As shown in the figure, the strength of the magnetic field represented by the length of the arrow becomes weaker as approaching the convergence point or away from the coil used to generate the magnetic field. The circle surrounding the convergence point indicates the outer boundary of AZ. The adjustment of AZ can be adjusted by changing the intensity of the current flowing through the coil. Usually, the larger the current, the smaller the AZ.

  Main basic configuration: A simple example of the configuration of a magnetotaxis system consists of two sets of coils, one set of which is used for SSPE clustering and the other set of coils directing this group in the desired direction. Used to move to However, a more complicated configuration or a simple configuration may be adopted.

  FIG. 3 shows that when the current value in one coil of the Maxwell pair is changed, the position of the magnetic field convergence point moves from the center. However, the linearity of the gradient is lost.

  In fact, although many variations are possible, one possible basic embodiment is a three-axis Maxwell coil configuration (referred to as an M (Maxwell) configuration). With the Maxwell configuration, the SSPE that follows the lines of magnetic force is captured at the center of the coil configuration. The operation control of the SSPE is performed by changing the current ratio between the coils of the same set. To obtain a linear gradient, the current through each coil of the Maxwell pair must be the same. If the current value is different in each coil of the same pair, the gradient will be non-linear. The relationship between the ratio between I1 and I2 (the current in each coil of the Maxwell pair) and the position of the zero magnetic field, also called the magnetic field convergence point, is plotted in FIG.

ここで、Ｉ１（Ａ）およびＩ２（Ａ）は、マクスウェルペアの各コイルにおける電流を示しており、ｒ（ｍ）は、コイルの半径を示しており、ｄ（ｍ）はコイル間の距離を示しており、ｚ（ｍ）は、所望の位置を示している。 There are several ways to change the current value, but one simple method is to set one current value to the maximum value according to the side to be displaced and set the other current value according to the desired position. Something to change. The mathematical relationship between the position of the convergence point and the current ratio is expressed as:

Here, I1 (A) and I2 (A) indicate the current in each coil of the Maxwell pair, r (m) indicates the radius of the coil, and d (m) indicates the distance between the coils. And z (m) indicates a desired position.

  Main power-up sequence for SSPE clustering in 3D space: the magnetic fields generated by Maxwell pairs (currents in opposite directions in each coil of the same pair) are shown in FIGS. , Two orthogonal pairs. FIG. 4A shows a flat magnetic field velocity vector generated from a 2D Maxwell pair. FIG. 4B shows the magnetic field magnitudes generated by the two Maxwell coil pairs in the x and y axes. The field lines are towards the center (convergence point) where the field strength is (almost) zero (ie towards a minimum). Note that a convergence point in a three-dimensional space can be generated even if the coil has a non-orthogonal geometric structure.

  Regardless of the position of the SSPE before the magnetic field is applied, after the magnetic field is applied, all the SSPEs are directed to the center (convergence point). Located within the operable range of the system). Also note that even in relatively high magnetic fields, the SSPE behaves unfavorably, causing the outer boundary to exist. This plot is for the 2D case. To apply a Maxwell magnetic field in 3D space, temporal multiplexing is required. In fact, each coil has a longitudinal component of the magnetic field (the component needed for SSPE capture) and a transverse magnetic field. The transverse magnetic field from one coil is opposite to the longitudinal component of the transverse coil. Since the vertical component has a higher amplitude than the horizontal component, the resulting magnetic field is high enough to capture the SSPE. However, if the three pairs are powered at the same time, each direction adds four transverse components to the longitudinal component, causing a situation where the longitudinal magnetic field is almost canceled. Therefore, in order to apply a Maxwell magnetic field in 3D, it is conceivable to perform a power-on sequence of the coil by a time-division multiplexing method. This is based on the premise that there is no obstacle to suppress the “dispersion” of the SSPE in at least one direction. This is the basic principle of a magnetotactic system. The coil may be powered by a group of two pairs of possible sequences. Since there are three different combinations, each coil group must typically be powered for 1/3 of the time period. Alternatively, power may be continuously supplied to the two pairs of Maxwell coils, and the direction of the magnetic field lines generated by the remaining Maxwell pairs may be reversed using a time division multiplexing method. As described above, other sequences may be used. The same idea as the time division multiplexing sequence may be applied to other configurations. In the following examples and the embodiments shown in FIGS. 5 to 8, the X, Y, and Z planes are defined as follows.

FIG. 5 shows a cube with vertices numbered to aid in understanding the flow of the directional current. The X axis is defined by the axis through the coils arranged in the 1375 and 2486 configurations. 1375 defines one face (square) of the cube represented by the vertices 1, 3, 7, and 5. As shown in FIG. 6, if the currents in the X sets of coils (X1 and X2) are in the same direction (both X1 and X2 are in direction D1), the current will be It can be seen that they flow in the directions of 1, 3, 7, 5, and 1, and in the virtual coil of X2, they flow in the directions of 2, 4, 8, 6, and 2. This configuration creates a coil resembling a Helmholtz or Maxwell coil, and creates a constant magnetic field in one plane across the sides of cubes 1375 and 2486. On the other hand, with everything else in the same state and reversing the current in the coil of X2 (flow 2684 instead of 2486), the magnetic field generated by the reverse current in the coils of X1 and X2 is directed to the midpoint. Become. In such a state, the current is said to be in the opposite direction.

  The Y axis is defined by the axis through the coils arranged in the 1243 and 5687 configurations. 1243 defines one face (square) of the cube represented by the corners of 1, 2, 4, and 3. If the currents in the Y sets of coils (Y1 and Y2) are in the same direction (both Y1 and Y2 are in direction D1), the currents will be 1, 2, 4,. It flows in the directions 3 and 1 and in the virtual coil of Y2 it flows in the directions 5, 6, 8, 7 and 5. As will be appreciated by those skilled in the art, if the current is in the same direction and both coils are reversed, the direction of the magnetic field will change. The same can be said for other planes.

  The Z axis is defined by the axis through the coils arranged in the 1265 and 3487 configurations. 1265 defines one side (square) of the cube represented by the corners of 1, 2, 6, and 5. If the currents in the Z sets of coils (Z1 and Z2) are in the same direction (both Z1 and Z2 are in direction D1), the currents will be 1, 2, 6,. Flows in the directions 5 and 1 and in the virtual coil of Z2 flows in the directions 3, 4, 8, 7 and 3. As will be apparent to those skilled in the art, AZ is formed by the action of two opposing magnetic field sources in two planes. In the following example, AZ is formed by the action of opposing magnetic field sources in the X and Y planes. Due to the action of the X and Y sources, the sensitizers cluster in two axes (X, Y) but do not "cluster" in the third axis (Z). For example, in this case, forming a "circular" clustering zone in the X and Y planes results in a "cylindrical" three-dimensional AZ. This is because the responders do not cluster on the Z axis.

  Other configurations can be employed. For example, the patient (patient move (PM) configuration) and / or the coil (coil move (CM) configuration) may be physically moved to avoid non-linearities. In this case, it is necessary to cope with the above movement by enlarging the inner diameter of the coil configuration. Therefore, it is necessary to increase the electric energy in order to achieve the same result (generation of torque for SSPE) as in the above-described configuration. Other variations are possible. For example, a combination of a three-axis Helmholtz coil 85 and a three-axis Maxwell coil 86 (referred to as an HM configuration) can be implemented as shown in FIG. In this combination, the three-axis Helmholtz coil 85 (shown in a light dot pattern and only one of the two opposing coils in each axis is shown with a code) is replaced by a three-axis Maxwell coil 86 (a dark dot pattern). (Only one of the two opposing coils in each axis is shown with a reference numeral) controls the position of the magnetic field convergence point generated by the same. With this control, as shown in FIG. 9, a linear (or quasi-linear) relationship is established between the current flowing through the Helmholtz coil and the position of the convergence point generated in the Maxwell pair.

In FIG. 8, the control unit 81 receives an input from the user interface 80 and transmits an output to each of the three coil driving units. The coil drive unit includes an X coil drive unit 82 that independently controls two opposed coils on the X axis, a Y coil drive unit 83 that independently controls two opposed coils on the Y axis, and a Z axis There is a Z-coil drive unit 84 that independently controls the two opposing coils in, and these drives allow each coil to generate a gradient magnetic field and function as a magnetic field source. For the sake of simplicity, the coil driving units 82, 83, 84 are drawn so as to control only the Maxwell coil, but the control unit can also control the Helmholtz coil 85 if necessary. Needless to say. The control unit 81 is configured to control the position of the convergence point 10. This control is performed by controlling the current of each coil shown in FIG. 8 according to a predetermined program (see FIG. 19). The coil drivers 82, 83, 84 can control the amount and direction of the current in each of the two opposing coils to control the position of the convergence point 10. In some embodiments, the coil drives 82, 83, 84 control the position of the convergence point 10 using a positioning device (not shown) incorporated in these drives. This positioning device is configured to receive an input from the control unit 81 and move the coil with respect to a platform 88 disposed in a three-axis coil (the platform 88 is located outside the coil for simplicity). Is shown). In use, the patient lies on the platform 88. This platform is either pre-positioned in the triaxial coil or moved into the triaxial coil after the patient lays down. In other embodiments, the magnetic field source (ie, the coil) is stationary and moving the platform 88 moves the convergence point 10 to a different location within the body. The controller 81 can receive an input from the detector 87 regarding the position of the magnetically responsive body in the body. This detector is, for example, an MRI machine or a PET scan machine.

  Clustering zone: During operation, SSPE is captured (bound) in an area that exists between Maxwell coils and accumulates in this area. The size of this region, referred to herein as the convergence point 10, is determined by the strength (magnitude) and sensitivity of the magnetic field (i.e., the torque applied to the SSPE to provide proper directional control (magnetotactic control). (The minimum intensity of the required directional magnetic field (gradient)). The sensitivity to the magnetic field depends on the magnetic moment, which can vary from SSPE to SSPE. When the convergence point 10 is reached, the SSPE is relatively free to move in all directions, and eventually reaches a directional magnetic field with enough strength that the SSPE can return to the AZ. Thus, as described above, the convergence point 10 is defined as a negligible amount of torque applied to the SSPE used or selected for target setting (not enough to induce proper directional control) Degree) of the magnetic field strength. The Helmholtz coil is capable of linearly (or quasi-linear) offset of the AZ formed by the Maxwell magnetic field in all directions in space. Because the clustering zone 20 is larger than the convergence point 10, the magnetic field at AZ20 tends to pull the SSPE in the direction of CP10.

  Other configurations: As described above, other configurations may be adopted. For example, according to the above configuration using a pair of Maxwell coil and Helmholtz coil, the same result as moving the magnetic tip below a plane and moving the aggregate of SSEPs within the same plane can be obtained. The magnetic field gradient in this case is linear, but when the configuration is simplified using only Maxwell coils, the magnetic field gradient is non-linear. For medical interventions, the methods proposed herein perform various techniques (e.g., permanent magnets or electromagnets) to perform similar functions as magnetic tips (permanent or electromagnets) that can be placed inside the body or on any plane of the workspace. , Time division multiplexing).

  Other variations are possible. Various variations are conceivable, especially when the target is accessible or exposed. In the latter case, a magnetic field may be generated at an end of a predetermined tool such as a rod-shaped member or a similar device (for example, a catheter), depending on a target region. However, even in the latter case, setting the target deep from the accessible surface may be limited, unlike using a coil configuration surrounding the target. This can occur if the convergence point is too deep and lies further than the lower side of the coil configuration.

Where to place a magnetotactic system relative to a magnetic resonance navigation (MRN) or MRI system should be considered when performing MRN manipulation or MR imaging during medical intervention. Ideally, when used as an auxiliary system in an MRN (MRI) system, to facilitate patient registration and movement between the two platforms, including reduced travel time, The magnetotactic system should be located close enough to the MRN or MRI system. In practice, however, the highly uniform field strength in the MRN or MRI system, SSPE because it can not work properly, by disposing the magnetic run of the system with respect to B ₀ field, sufficiently distant, proper operation of SSPE It is essential that they are not disturbed. On the other hand, a directional control system built into the SSPE (eg, a superparamagnetic magnetosome of MC-1 bacteria) can be used to track (or locate) the SSPE, such as in MRI techniques. Thus, ideally, the magnetotactic system should be located close enough to the MRN or MRI system to facilitate patient movement (eg, to increase the range of movement of the sliding table on which the patient is lying). desirable. This makes it possible to monitor the moving state of the SSPE using the MRI technique and to facilitate the above-described positioning. Alternatively, by passing a large current to a particular coil, as long as it can compensate or correct the effects of B ₀ field can further reduce the distance between the magnetic run of the system and MRN system. Another option is to add a single coil, multiple coils, or shields (typically between the two platforms) to reduce the effect of the _B0 field in the working zone of the magnetotactic system. Elimination or reduction is conceivable. In some instances, the influence of B ₀ field is available in the design of magnetic run of the system (this time, adjust the parameters by changing the intensity of the current in the particular coil magnetic run of the system , controls the influence of the B ₀ field and toward or away from the magnetic run property system MRN system). With respect to all of the configurations described above, and other configurations having similar functionality, other configurations of the magnetotactic system can be realized by replacing one or more coils with permanent magnets.

  Portable and hybrid configurations: There are two examples that can cause errors in the accuracy of the convergence point location process in a particular target zone (eg, tumor area), with the potential for patient alignment and movement. Problem. To avoid such problems, a portable magnetotactic system is desirable. Provided that such devices are accessible to the targeted area. Two examples where portable systems such as those described above can be used include the use of techniques such as laparoscopic, for use on target areas in the body made accessible by surgical incisions, and in some cases Has been used for colorectal cancer and colorectal, but this is just one example. For example, in the latter case, a portable magnetotactic system can be inserted into the rectum 108, as shown in FIG. The advantage of this approach is that the instrument (local coil or magnet) can be placed near or very close to the target area after SSPE injection, so it is less susceptible to problems such as patient alignment and movement. That is. This injection can be performed using an injector implanted in the same device or a separate device. The local coil of the magnetotactic device may be designed to be variable in shape and radius to better fit the shape of the tumor. Also, a set of various magnetotactic tools having different diameters can be provided. FIG. 10 shows a form of a portable magnetotactic system having a magnetotactic probe 102 at the end of a tether 106. In this example, the probe 102 is inserted through the rectum 108 to reach the target site of the tumor 104. After the probe 102 reaches the tumor 104, a magnetic field is generated to direct the magnetic susceptor to the tumor 104 or to a convergence point 10 located therein.

  FIG. 11 illustrates an embodiment in which the magnetotactic system targets deeper by using an external source of magnetic field, such as an external coil 114. Arrows indicate the direction of the magnetic field, and two arrows in opposite directions indicate that the operation is in the time division multiplex mode. In this embodiment, the magnetotactic probe 112 and tether 106 are inserted as portable components, but rather than “surrounding” the tumor with the probe 112, the opposing magnetic field source (external coil 114) is Is located as close as possible to the target site on the skin surface 116.

  If access is restricted, for example, for colorectal cancer treatment and the target area is deep in the rectum, it is more preferable to use a magnetotactic platform. This is because placing a portable magnetic field source at the target site is difficult, if not impracticable, given the distance traveled, the rectum diameter and the weight of the coil. Thus, indicia for alignment purposes, for example, indicia on the tip of the catheter, can be used with a magnetotactic platform (via a real-time imaging modality such as X-ray or CT).

Path finding capability: The operating mode to be used depends on whether the magnetic susceptor or SSPE 126 has the route finding capability. FIG. 12 shows a very simple example of this. An SSPE 126 that does not have route discovery capability is shown in FIG. 12A. This is typically the case for artificial or synthetic SSPE 126 (but not for bio-mimetic artificial SPE 126).
The SPE 126 can have some degree of route discovery capability). When a directional gradient magnetic field 128 (or a sequence of gradient fields) is used to indicate the desired direction of movement of SSPE 126 (eg, the direction in which the target is located), the SSPE was generated with that directional magnetic field. Moves under the influence of induced torque. When the SSPE reaches a sufficiently wide obstruction 124 (the wall as shown in FIG. 12A), the SSPE 126 will typically turn in a white circle shown in FIG. 12A until the direction of the directional gradient magnetic field 128 changes. Stay in the position represented. In this case, it is assumed that there is no route discovery capability, that is, 0%. However, in order to know when and in which direction the field lines must be changed, the minimum feedback information required for that must be collected for SSPE 126. For example, if the destination of the SSPE 126 is a target location 122 indicated by a circled T on the right, the SSPE 126 needs to be navigated along a predetermined path following this particular target location 122. . Thus, FIG. 12A shows that SSPE 126 without pathfinding capability is stagnated after being guided in the direction of obstacle 124 (thick white arrows indicate the direction of the induced magnetic field or directional torque). Is shown). Note that, as will be apparent to those skilled in the art, the SSPEs 126 are actually a plurality of SSPEs grouped at the convergence point 10.

  FIG. 12B shows that the SSPE 126 having the path finding capability “searches” for a path leading to the direction of the directional gradient magnetic field 128 without stagnation. In this case, as shown in FIG. 12A, unlike the case of the SSPE 126 having no path finding capability, the target channel position 122 (indicated by a circled T) can be reached without changing the direction of the magnetic field. there is a possibility.

  For large channels (eg, blood vessels with large diameters), image data can be collected, but for small channels or blood vessels, the image data cannot be collected due to spatial resolution limitations in medical imaging devices. Therefore, the conventional navigation control technique cannot be used. This is because such a method cannot collect necessary image information and cannot define a route or a trajectory.

In such a case, an SSPE (for example, MC-1 magnetotactic bacterium (MTB) as an example) having a route finding ability can be considered instead. Using the constant directional gradient magnetic field 128 of FIG. 12B, the SSPE typically does not stagnate and reach the obstacle 124 in the direction of the magnetic field (or SSPE) as shown in FIG. 12B. However, if it is south-directional rather than north-directional, it "searches" for a path leading the SSPE (in the direction opposite to the magnetic field). In this particular example, which has perfect symmetry and state on both sides, when the SSPE goes to the desired target location 122 or hits an obstacle 124, the unique characteristics of the SSPE allow it to be in a particular direction (eg, The likelihood of proceeding in the direction of rotation of the flagella, etc. (or whether there is a tendency to proceed in a particular direction) is one-fifth. In any case, this leads to a specific behavior of the SSPE. Behavioral navigation control (BNC) as defined herein, or behavioral control for short (
BC) is to control the SSPE 126 to a specific target in consideration of the above-mentioned actions (including the path finding ability).

  Directional versus clustering modes: Given the complexity of many navigable networks, especially in environments such as microvasculature and angiogenic networks, relying solely on the behavior of SSPEs with pathfinding capabilities Not enough. In order to prevent or reduce the risk that the SSPE will follow the wrong path and eventually reach a location other than the target area, the directional field alone can be changed without clustering. FIG. 13 shows a method called a directional mode in this specification. In this simple example, targeting using directional mode is very effective in many cases, but the effect is highly time dependent and is affected by the spatial distribution and velocity of the SSPE Indicates a possibility. This is also the case when real-time tracking and path imaging are possible (not when operating on the microvasculature). An example is shown below.

  In the example illustrated in FIG. 13, among the two SSPEs 126 having the route discovery capability, SSPE A starts from a position 131 and SSPE B starts from a position 136. Both SSPEs follow the same directional gradient field 128 (indicated by the thick white arrow), so that SSPE A goes to the intermediate target channel at location 132. When SSPE A reaches location 132, the direction of the magnetic field changes and directs SSPE A to its final target, indicated by a circled T. In this particular example, SSPE B is slightly faster than SSPE A, so SSPE B is at position 137 when the direction of the magnetic field changes. In this case, only SSPE A reaches the target location 122. This is because, in this particular example, SSPE B enters the next channel. FIG. 13 illustrates the limitations of the above method, applying the directional mode to two SSPEs with pathfinding capabilities (or without pathfinding capabilities if the angle from obstacle 124 is too large). Here is an example of the case.

  In another attempt, a change in the directional magnetic field can be made later to correct the direction of the magnetic field by a small angle. In this case, as shown in FIG. 13, it is considered that SSPE A exists at the position 133 and SSPE B exists at the position 138. In this case, SSPE B reaches the target and SSPE A reaches the adjacent channel that is to the left of the target channel. By slightly extending the waiting time, SSPE A reaches position 134 and SSPE B reaches position 139 before changing the direction of the directional gradient magnetic field 128 has the same result as the above attempt. Due to the initial location of each SSPE, the geometric or environmental characteristics of the path (obstacle 124), and the speed differences between the SSPEs, in this particular example, even with real-time visual feedback, Is only 50%. This number may be higher or lower in other cases, but nonetheless, this simple example may be indicative of the limitations of the directional mode.

  FIG. 14 is a highly schematic diagram of directivity mode (D mode) control for a plurality of magnetic sensators 151 or SSPEs that exhibit a normal distribution with respect to “dispersion”. The white arrows indicate the approximate direction of the gradient magnetic field for guiding the plurality of magnetic responsive bodies 151. It can be seen that the variance increases until the SSPE reaches the obstacle 124, after which the SSPE regroups / groups and then re-distributes, eventually reaching the AZ 20.

In order to eliminate or ameliorate the above-mentioned problem that causes the limitation of the directional mode, the area where the path finding (PF) can be performed by the SSPE is defined as AZ20 above, that is, all (or almost) May be reduced (restricted) to the region where the SSPEs 126 converge and cluster first. This "grouping mode" is shown in FIGS. FIG. 15A illustrates the use of a clustering mode for targeting, and FIG. 15B illustrates an example of reducing the AZ 20 to increase the efficiency of targeting. As shown in FIG.
Both PEs converge toward position A, but convergence to this position is not possible only in the directional mode. First, before the AZ 20 (the center or convergence point 10 converges into a circular area indicated by the four hatched arrows), the two SSPEs cause the convergence of the You are guided to point 10. The strength of the magnetic field at this time (in FIG. 15, indicated by an arrow larger than the hatched arrow around AZ) is higher than the sensitivity of the SSPE to the directional torque. Outside the perimeter of the clustering zone 20, the two SSPEs move linearly or nearly linearly toward the point of convergence. Beyond the periphery of the AZ 20, the directional torque is weakened and the SSPE cannot be directed to the convergence point 10 of the AZ 20. As a result, the SSPE performs a “random”, ie, non-linear, uncontrollable behavior (displacement) within the AZ 20. If sufficient time is taken, all SSPEs reach the AZ20, so unlike the case of the directional mode, factors such as the dependence of the SSPE on time, the speed difference, and the initial position are different from each other. Have no or very little effect. For example, in this case, even if the convergence point of the AZ 20 is changed to the position indicated by T in FIG. 15A, the target arrival rate is 100%.

  In consideration of the above, the size of the AZ 20 (for example, when the AZ 20 is symmetric, its diameter) needs to be appropriately adjusted in some cases. For example, in the example of FIG. 15B, the AZ 20 has a diameter similar to that of FIG. 15A, but does not achieve the same target reach. In this case, some SSPEs in the AZ will be directed to the wrong channel and will reach another target location 153 instead of the target location 122. In order to avoid this, for example, the size of the AZ may be reduced with respect to the geometric characteristics of the environment (for example, the width of the channel and the distance between the channels). This is shown as a small circle drawn by a solid line in FIG. 15B. This circle is surrounded by four hatched arrows, which point to the center of the circle. Even for this new small clustering zone 155, 100% target reach can be achieved in this example. However, this requires higher power for the magnetotactic system.

  In FIG. 15B, the AZ used for the later target is larger than that before. In this case, there is no need to reduce the size of the subsequent AZ because the movement of the SSPE is limited by obstacles 124 (such as walls) and other geometrical elements. In a specific region, the exact state of the geometric element is not known, but if the boundary or range is known, the size of the AZ is usually appropriately adjusted accordingly.

  Grouping modes: There are three basic grouping modes, as shown in FIGS. The first mode is the simplest, called the target mode or T mode, and is shown in FIG. In the T mode, the AZ 20 is maintained at the target position 122 throughout the entire operation until a predetermined amount or a predetermined percentage of the SSPE 126 reaches the target site. The target location 122 may be, but need not be, the convergence point 10 within the AZ 20. In some situations, the SSPE 126 may reach a point where it cannot move along the magnetic field. This is the case, for example, when the SSPE becomes lodged in a blood vessel smaller than its diameter. In such a case, it is not necessary to form AZ20. Further, in some cases, the target position 122 may be the convergence point 10, but is not necessarily limited to this as in the above-described example.

The second grouping mode is called the split mode or the S mode, and is shown in FIG. This mode takes into account the path discovery level of the SSPE and the assumed path geometry. In this mode, one (at a different point in time) between the injection site or initial population zone 171 of the SSPE (or the site where this mode becomes operational) and the target AZ 20 (or the site where this mode ends) Intermediate AZs of level 1 split mode or S1 mode or multiple (level 2 or S2 mode or higher split modes) are used. Normally, the position of the middle AZ is changed to the next position when all SSPEs (or most SSPEs) reach that AZ. The last AZ 20 is the AZ at the target position 122. This mode can be used when the distance traveled is relatively long, the route is irregular or complex, and as a result there is a significant risk of losing a very high percentage of SSPE during travel, or This is useful when compared to the target mode when there is a significant risk of clogging in one place due to the structure. As an example of avoiding the latter case, there is a case where a C-mode is used for MC-1MTB which plays a role of SSPE in a microfluidic channel. As shown in FIG. 17, the grouping zones move in the order of 1, 2, 3, 4, and 5, and sections between the grouping zones are indicated by S1 to S4. In this mode, the clustering zones do not overlap each other, and the SSPE may not be able to detect the gradient magnetic field at some point in the sections (S1 to S4) between the zones. This method is useful in some embodiments. For example, when moving within a large blood vessel, the SSPE can be moved along the blood vessel only by the blood flow.

  The third clustering mode is called continuous mode or C mode and is shown in FIG. In this mode, the AZ containing the SSPE will be at a low enough speed to maintain the SSPE in the AZ, and the initial zoning zone 171 (or the site where this mode will be operational) and the target AZ 20 (or this (The part where the mode ends). The AZ moves sequentially from 1 to 12 (target grouping zone), but unlike the division mode shown in FIG. 17, the moving zones sequentially overlap so that the SSPE always senses a predetermined gradient magnetic field.

  In all cases, it is also possible to use a combination of the above modes. In addition, SSPE having a pathway finding ability, such as MC-1 bacteria, can perform directional operation more freely when the influence of induction of directional torque on a series of magnetosomes embedded in cells is small. it can. Therefore, when operating in the continuous mode or in the AZ, as compared with the case of operating outside the AZ, the efficiency of route finding may be affected.

  Coordination mode: SSPEs have different levels of path discovery capabilities. For example, the pathfinding capability of a simple virtual artificial sphere having a propulsion system and a direction control system and passively oriented by directional torque from a directional magnetic field would be 0%. On the other hand, using only T mode for SSPEs with 100% path finding capability results in 100% target reach regardless of the complexity and geometric features of the path leading to the target area. Unfortunately, 100% route discovery capability is not feasible at this time, and in practice, SSPEs with route discovery capabilities are less than 100%. Thus, in order to navigate the SSPE in problematic paths, taking into account the channel geometry and the speed and behavior of the SSPE for a particular field strength, the magnetic field must be adjusted It is very important to improve the delivery efficiency. For example, as shown in FIG. 15, MC-1 bacteria behave differently in the vicinity of an obstacle, so that the efficiency of inducing a target may be improved. The strength of the magnetic field also affects the behavior of the SSPE and may need to be taken into account when selecting the appropriate tuning mode and its associated settings.

  However, due to the geometry of the path between the current location of the SSPE and the target AZ, the level of the path finding capability of the SSPE is insufficient to reach the AZ, or at that level. If it is not possible to achieve a sufficiently high target reach, one or more adjustment modes may be used in addition to the above-described clustering mode.

There are four basic adjustment modes: an amplitude adjustment (AM) mode, an offset adjustment (OM) mode, a frequency adjustment (FM) mode, and a shape adjustment (SM) mode, and each mode is different. Operable with frequency. As mentioned above, these four basic adjustment modes typically operate with at least one of the four basic clustering modes described in the previous section.

  For example, in the T-AM mode, the diameter of the AZ is amplitude-modulated at a specific frequency (period) (ie, the overall size of the AZ is alternately enlarged and reduced). Here, it is necessary to specify not only the amplitude or change in the size of the AZ, but also the frequency at which these changes occur. Typically, two sizes are used, but more sizes can be used in this mode.

  Although FIG. 6 is not to scale, as shown, a higher slope or higher current amplitude can be used to create a smaller convergence point 60 (or AZ). This adjustment method is controlled by the control unit 81, so that the bacteria or the SSPE 126 can avoid the obstacle 124. As a result, it is possible to increase the target arrival rate by using the path finding capability unique to the SSPE 126. In order to avoid the obstacle 124, when the convergence point must move to the left side coil (X1) side and be at the position shown as the dashed circle area 61, the control unit 81 determines whether X1, X2, Y1, and The convergence point 10 is moved to the dashed circle 61 by controlling the current, direction, and activation of the four coils indicated by Y2.

  The same applies to other modes. For example, in the T-OM mode, the AZ convergence point located at the target shifts between the center of the target zone and one or more shift positions at a specific distance and a specific frequency. For the T-FM mode, the current in the magnetotactic system is simply turned on and off at a specific frequency. Finally, in the T-SM mode, for example, the shape of the convergence point is changed between the shape of the convergence point 10 and the first shape 71 or the second shape 72 at a specific frequency. An example is shown in FIG.

  The basic concept of the various types of adjustment modes is to slightly change the direction of the SSPE to avoid obstructions blocking the path of the SSPE. Magnetotactic bacteria can swim around obstacles, but in the case of some types of obstacles, unless we let the little support help us find an exit, These obstacles cannot be avoided. This support is provided by the above adjustments. These adjustment modes can be applied, for example, according to knowledge (or a model) obtained a priori regarding a capillary network or the like. When the size of the AZ is changed, the direction of the magnetic force lines converging to the convergence point is slightly changed, which is the amplitude adjustment. Instead of changing the overall size of the AZ, its shape can also be changed, resulting in a slight change in the direction towards the convergence point, which is a shape adjustment. Further, when the convergence point is displaced, the convergence line of magnetic force of the directivity is changed. This is offset adjustment. In the case of frequency adjustment, the system is turned on and off at a specific frequency. When the system is off (when no current is flowing through the coil), no directional torque is applied to the series of magnetosomes when using magnetotactic bacteria as the SSPE. Thus, the bacteria can move randomly and escape from a vascular deadlock. Then, when the system is turned on again, the SSPE can be directed toward the tumor or other target before leaving the path significantly. All of these modes of regulation can also be combined to improve control over SSPE targeting, population, and route discovery.

FIG. 19 illustrates a predetermined program (for example, time division multiplexing) for generating a convergence point using a set of opposing coils arranged on the X, Y, and Z axes. FIG. 19A shows a first predetermined program, and FIG. 19B shows a second different predetermined program, both programs for generating a three-dimensional convergence point 10. As can be seen from FIG. 19A, with respect to the X-axis coil, a set of coils that generate a gradient magnetic field in the X-axis, and that use the terminology shown in FIG. The set is configured such that a specific current flows through each coil (X1 and X2) and a current in the opposite direction (D1 and D2) flows through each coil. With respect to the Y-axis coil, a coil set that generates a gradient magnetic field in the Y-axis, and is opposed to and substantially parallel to each other, has a specific current flowing through each coil (Y1 and Y2). It is configured such that currents in opposite directions (D1 and D2) flow through each coil. Finally, the set of coils facing each other in the Z axis is configured such that a specific current flows in both coils in the same direction (only D1), and this direction is reversed in both coils according to a predetermined frequency. .

  FIG. 19B shows an alternative time division multiplexing program for generating a three-dimensional convergence point using two sets of coil combinations (eg, X and Y) simultaneously. At this time, the third set (eg, Z) does not operate (ie, the magnetic field source does not generate a gradient magnetic field in the Z axis). It will be appreciated that the combinations of the two sets of magnetic field sources in X, Y and Z are all (X, Y), (X, Z), (Y, Z).

  The Maxwell coil can be understood to be formed by three parallel coils in a virtual sphere, where R is the radius of the central coil, each outer coil has a radius of the square root of (4/7) R, and It has a distance of (3/7) R from the plane. In embodiments of the coil configuration in which a set of parallel coils separated by a predetermined distance are arranged, the currents flowing through the coils "opposite" with each other must be flowing in opposite (or opposite) directions, and for this purpose Can be understood to be to create a gradient magnetic field that clusters the SSPEs at a particular "central" position where there is almost no magnetic field force. In the Helmholtz configuration, a linear magnetic field gradient in one direction is generated in two substantially opposed and substantially parallel coils by making currents flowing in these coils have the same direction. On the other hand, in the Maxwell configuration, the convergence point depending on the current flowing through each coil is generated at a certain position between the coils by making the current flowing in the two substantially opposite and substantially parallel coils opposite directions. I do.

  In this specification, the term “body” should be interpreted in a broad sense. In some embodiments, the body is a human body, and in other embodiments, the body is an animal body or physical object that would benefit from the population (and guidance to a target) of the magnetically responsive body. The apparatus and method of the present invention are also useful when used on a cadaver for training, research and development, and the like.

  In some embodiments, the magnetic susceptors are clustered at specific locations on the human body to make a diagnosis. This is because some diagnostic compounds are more effective by local and extremely specific transport, and some are toxic at high concentrations.

As will be apparent to those skilled in the art, in some embodiments, the body may be located within a magnetic field source, or the magnetic field source may be located around the body. While a platform for mounting the patient and securing it to the magnetic field source is preferred, it is also possible to secure the magnetic field source to the body without using a plot form. For example, there is a mode in which a person or a body stands in a magnetic field source. A positioning system that determines the position of the magnetic field source relative to the body is advantageous. In some cases, the source of the magnetic field may be moved, and in other cases the body (located on the platform or elsewhere) may be moved. In any case, aligning the body with respect to the magnetic field source is advantageous for guiding the sensitive body to a particular convergence point. If the magnetic field source is a coil (or coils), the coil must be of sufficient size to place a human body in the coil. Thereby, it is possible to set the convergence point at any position in the human body including the head. In some embodiments, the device for placing the patient includes various means, such as mechanical means, for example, means for arranging the coil around the body, and means for releasing the body from the coil. Including. In other embodiments, after placing the patient or body on a platform (chair, wheeled stretcher, bed), the platform is moved into the device. In yet another embodiment, the platform is already located in the device, and the device is provided with means for placing the patient or body on the platform.

  Although the present invention has been described based on various specific embodiments, it is needless to say that the embodiments can be further modified. This application is intended to generally cover any modifications, uses, or adaptations of the principles of the invention. In addition, the present application includes those which can be modified from the above disclosure by a method known or commonly used in the art to which the present invention pertains. The present application is intended to cover modifications obtained by applying the essential features disclosed in the present specification or described in the following claims.

Claims (24)

A device for controlling the grouping of self-propelled magnetically responsive bodies inside the body,
At least three magnetic field sources arranged on three axes to generate a magnetic field;
A control unit connected to at least one of the magnetic field sources and configured to generate a three-dimensional convergence point, wherein the responsive body moves to the three-dimensional convergence point by following the direction of the magnetic field. Moving and grouping, surrounding the convergence point, the effective magnetic field is from all directions toward the convergence direction, comprising a control unit,
At least one of the at least three magnetic field sources changes in time to move the responsive body toward the convergence point and stay near the convergence point;
The control unit includes:
While any two of the three axes maintain a constant magnetic field, the magnetic field direction of the other one of the three axes is changed according to the two axes maintaining the magnetic field constant. Change,
While maintaining the magnetic field direction of one of the three axes constant, the magnetic field directions of the other two axes of the three axes are simultaneously changed or time-delayed by a time division multiplexing method. And changing the magnetic field directions of the three axes simultaneously or with a delay between the axes by a time-division multiplexing method,
Do one of the following,
The apparatus wherein a direction of a magnetic field gradient of at least one of the three axes is changed by a time division multiplexing method at a switching speed adapted to a reaction time of the self-propelled magnetic sensitive body.   The first and second magnetic field sources among the magnetic field sources generate gradient magnetic fields facing each other in the respective magnetic field sources to group the magnetically responsive bodies into two axes, and the control unit includes a first predetermined magnetic field source. The apparatus according to claim 1, wherein the direction of the gradient magnetic field of the third magnetic field source in the third axis is reversed according to a program.   3. The apparatus of claim 2, wherein the magnetic field source in the third axis further comprises two coils wired to conduct current in the same direction. The apparatus according to claim 2, wherein the control unit is configured to sequentially activate all combinations of the two magnetic field sources according to a second predetermined program.   Apparatus according to any one of claims 2 to 4, wherein the first and second magnetic field sources comprise two coils in each of which a current flows in opposite directions.   Apparatus according to any of the preceding claims, wherein at least one magnetic field source is located outside the body.   Apparatus according to any one of the preceding claims, wherein one or more of the at least three opposing magnetic field sources comprises a permanent magnet.   The device according to any one of claims 1 to 7, wherein the control unit is further configured to control the magnetic field source to displace the magnetically responsive body.   Apparatus according to any of the preceding claims, wherein the axes are orthogonal to one another.   The controller according to claim 1, wherein the controller is configured to move the convergence point with respect to the magnetic field source so as to guide the responsive body to a position inside the body. An apparatus according to one.   The apparatus according to any one of claims 1 to 9, further comprising a positioning device for the magnetic field source, wherein a position of the convergence point is changed by moving the magnetic field source.   The device according to any one of claims 1 to 9, further comprising a platform for supporting the body, wherein a position of the convergence point is changed by moving the platform.   The apparatus according to claim 10, wherein the guidance is performed by combining a directional mode and a grouping mode.   The apparatus according to claim 10, wherein the guidance includes one of a continuous movement and a sequential movement of the convergence point.   5. The device according to claim 4, wherein the magnetic susceptor comprises a magnetotactic bacterium.   16. The apparatus of claim 15, wherein the first and second predetermined programs provide a frequency at which a portion of the magnetotactic bacterium realigns with the magnetic field according to a change in the magnetic field.   17. The apparatus according to claim 16, wherein said frequency is in the range of 0.1-5 Hz.   17. The apparatus of claim 16, wherein said frequency is about 0.5 Hz.   19. The device according to any one of claims 15 to 18, wherein the magnetic susceptor is linked to an anti-cancer agent.   20. The device according to any one of the preceding claims, wherein the convergence point is a tumor in the body.   The apparatus according to any one of claims 1 to 20, wherein the control unit is configured to change a size of the convergence point to enhance a path finding ability of the magnetic susceptor.   The apparatus according to any one of claims 1 to 20, wherein the control unit is configured to change a shape of the convergence point to enhance a path finding ability of the magnetic susceptor.   23. The apparatus according to any one of claims 1 to 22, further comprising a magnetic sensitive detector for detecting a position of the magnetic sensitive.   24. The apparatus of claim 23, wherein the magnetically sensitive detector is one of a magnetic resonance imaging machine and a positron emission tomography machine.

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