CN117669662A

CN117669662A - Coil structure design method of magnetic nanoparticle targeted delivery diagnosis and treatment system

Info

Publication number: CN117669662A
Application number: CN202410129294.1A
Authority: CN
Inventors: 白石; 张晓丹; 李莎; 郭大可; 邹宇琪; 林禹熙; 刘志尧; 李克文; 富炎; 张九思; 史力伏
Original assignee: Liaoning Jiayu Technology Co ltd
Current assignee: Liaoning Jiayu Technology Co ltd
Priority date: 2024-01-31
Filing date: 2024-01-31
Publication date: 2024-03-08
Anticipated expiration: 2044-01-31
Also published as: CN117669662B

Abstract

A coil structure design method of a magnetic nanoparticle targeted delivery diagnosis and treatment system belongs to the technical field of medical magnetic auxiliary diagnosis, and solves the problems of fixed parameters, poor universality, suitability for body surface diagnosis and the like of the traditional external magnetic field. The method comprises the steps of obtaining required magnetic field parameters through theoretical calculation, and constructing an external magnetic field by adopting a mode that a plurality of hollow coils are coaxially and tightly arranged; the minimum height coil and the coil structure are designed according to the size and the position of the target area, and coil parameters such as the size of the hollow area of the coil structure, the axial height, the radial width and the like are designed according to the size of the detected body and the magnetic field intensity and gradient required by the targeted delivery of the magnetic particles. The method utilizes the coil structure form with the same ampere turns and gradient arrangement of heights, so that the magnetic field is smooth and excessive, and magnetic particles are better retained in a target area; the coil is turned off step by step, so that magnetic particles are precisely gathered at a tiny target area, and the targeted delivery of the magnetic particles and the gathering and detention of the magnetic particles in the target area are effectively realized.

Description

Coil structure design method of magnetic nanoparticle targeted delivery diagnosis and treatment system

Technical Field

The invention belongs to the technical field of medical magnetic auxiliary diagnosis, and particularly relates to a coil structure design method of a magnetic nanoparticle targeted delivery diagnosis and treatment system.

Background

The magnetic nano particles (Magnetic Nanoparticles, MNPs) are generally nano-scale due to small particle size, and the material is generally Fe which is nontoxic and harmless to human body ₃ O ₄ Or gamma-Fe ₂ O ₃ Therefore, the device is widely applied to the fields of biomedicine and other science, and is an effective tool for medical imaging, diagnosis and treatment. One of the main application modes is to realize targeted delivery under the action of an external magnetic field by utilizing the magnetism of the target, and the target is moved and accumulated and retained at the target.

At present, an external magnetic field mainly adopts a mode of externally adding a permanent magnet or an electromagnet at a target position of a detected body, so that magnetic nano particles are targeted to gather and precipitate at the target position. The magnet structure is generally divided into a monopolar type and a bipolar type, and a monopolar type structure is commonly adopted, namely, a magnetic pole is added on one side of a target part of a detected body. The magnet is arranged at the body surface of the object, a magnetic field with certain intensity and gradient is formed near the target, and when the magnetic nano particles are acted by an external magnetic field, directional movement is generated under the action of the magnetic field, and the magnetic nano particles are gathered and retained in the target.

However, the external magnetic field constructed by the permanent magnet or the electromagnet is influenced by the material, the size and the like of the permanent magnet, the strength and the gradient of the generated magnetic field are relatively fixed, the adjustment cannot be performed, and because the large permanent magnet is easy to strongly attract an externally-attached ferromagnetic object, accidents are easy to occur, and certain potential safety hazards exist. Moreover, most importantly, the intensity of the magnetic field generated by the magnetic field rapidly decays along with the increase of the distance, and the magnetic field can only be suitable for detection of the target area of the surface layer of the detected body. In addition, the magnetic field strength generated by the electromagnet is adjustable, but the overall size is smaller, due to the influence of the electromagnet structure, the energizing current, the size and the like.

Meanwhile, the permanent magnet or the electromagnet for constructing the external magnetic field has the characteristics of relatively smaller magnetic field strength, larger attenuation in the depth direction of the detected body, small effective coverage depth, inconvenient adjustment of field intensity and gradient and the like under the premise of considering the safety. In addition, the target size is directly related to the size, shape, configuration, etc. of the magnet, which in turn directly determines the magnetic field size and coverage of the magnetic field. To obtain a precise micro target area, the size or shape of the magnet should be matched to the effective area of the structure, but the magnetic field coverage area and the magnetic field strength formed by the smaller magnet size are relatively smaller. Therefore, the target size is not compatible with the magnetic field strength and the magnetic field coverage for both permanent magnets and electromagnets. In addition, in order to improve the magnetic field effect, magnetic shoes of different shapes are generally adopted to contact with the object; when the magnetic nano particles are delivered to the detected bodies in different shapes in a targeted mode, different magnetic shoe shapes, magnet sizes, magnet materials or structures are designed according to specific conditions to meet different diagnosis and treatment requirements, so that the whole system is poor in universality and narrow in application range, basically belongs to customized products, and is only suitable for targeted delivery of the magnetic nano particles on the detected body surfaces or near body surfaces. Therefore, the structure of the existing magnetic nanoparticle targeted delivery diagnosis and treatment system needs to be improved.

Disclosure of Invention

The invention aims to: the invention aims to provide a coil structure design method of a magnetic nanoparticle targeted delivery diagnosis and treatment system, which enables magnetic nanoparticles to rapidly move towards a target area of a designated place, so that the concentration of the magnetic nanoparticles in the target area is obviously improved, the concentration of the magnetic nanoparticles in other areas is obviously reduced, the magnetic nanoparticles are gathered and detained in the target area, and the size of a gathering area of the magnetic nanoparticles can be adjusted and controlled; not only can the targeted delivery of the magnetic nano particles in the body surface and near-surface layer area of the detected body be realized, but also the targeted delivery of the magnetic nano particles at the deep structure can be realized.

The technical scheme of the invention is as follows: a coil structure design method of a magnetic nanoparticle targeted delivery diagnosis and treatment system comprises the following steps:

step 1, determining the position and the size of a target in advance;

step 2, calculating magnetic field parameters required by targeted delivery of the magnetic nanoparticles according to the selected magnetic nanoparticle parameters and the attribute of the detected body;

step 3, designing the height and structure of the minimum-height coil according to the target size determined in the step 1;

step 4, designing a structural form of a coil combination system according to the target position determined in the step 1;

Step 5, designing the size of a hollow area of the coil structure according to the body surface size of the target area of the detected body and the maximum body surface size of a path required by the coil structure from outside the detected body to the target area;

step 6, designing the axial height, the radial width, the heights of other coils, the energizing current and the number of coils of the coil structure according to the magnetic field parameters determined in the step 2, so that the magnetic field intensity and gradient generated by the coil structure meet the magnetic nanoparticle targeted delivery requirement;

step 7, assembling a coil structure, placing a detected body in a hollow area of a coil combination system, aligning a target area of the coil combination system to the target area determined in the step 1, and injecting magnetic nano particles into the detected body;

step 8, electrifying the coil combination system to generate an in-vitro targeting delivery magnetic field of the magnetic nanoparticles, so that the magnetic nanoparticles generate directional movement under the action of the in-vitro targeting delivery magnetic field; when the equal-height coil combined structure is adopted, the coil is matched with a step-by-step turn-off mode, so that the magnetic nano particles are precisely gathered at the micro target area in the most efficient targeted delivery mode.

And step 1, diagnosing a detected body by adopting an imaging diagnosis and treatment means, and determining the specific position and the specific size of a target.

The step 2 is specifically implemented as follows:

step 21, according to the magnetic nanoparticle targeting delivery efficiency required during actual targeting delivery, bringing the movement speed of the magnetic nanoparticles into a fluid viscous resistance equation, and calculating fluid viscous resistance, wherein the fluid viscous resistance equation is as follows:

F _s = 3πηd _H v _p

wherein,F _s is fluid viscous resistance;ηis the viscosity of the fluid in the subject;d _H hydrodynamic diameter of the magnetic nanoparticles;v _p is the movement speed of the magnetic nano particles;

step 22, when the magnetic nanoparticles do uniform motion, the magnetic field force is equal to the fluid viscous resistance, so that the magnetic field strength and gradient required by targeted delivery of the magnetic nanoparticles can be obtained by bringing the fluid viscous resistance into a magnetic field force calculation formula, and the magnetic field force equation is as follows:

F _s =F _m =V _p M·▽B

wherein,F _m is magnetic field force;V _p is the volume of the magnetic nano particles;Mmagnetization in units of volume of magnetic nanoparticles; (V)BIs a magnetic field gradient;

to maximize the magnetic field force, the magnetic nanoparticles are in a saturated magnetization state, and the magnetic field strength required for targeted delivery of the magnetic nanoparticles can be calculated from the saturation magnetization and magnetic susceptibility of the magnetic nanoparticles:

M=χ _p H

wherein χ is _p Magnetic nano particle magnetic susceptibility;His the magnetic field strength.

In the step 3, the minimum height coil is placed opposite to the target area, and when the size of the target area in the axial direction of the coil structure is smaller than 8.5mm, a single coil can be used as the minimum height coil, and the number of the minimum height coils is the same as that of the minimum height coil n ₁ When the size of the target area in the coil axial direction is greater than 8.5mm, a plurality of equal-height coils may be used instead of a single coil as the minimum-height coil of the whole coil combination system, and at this time, the overall height of the plurality of equal-height coils is still the height of the minimum-height coil in the coil combination system;

height of minimum height coilhThe method comprises the following steps:

h=（c+1.58）/0.67

wherein,cthe dimension of the target area in the axial direction of the coil structure is in mm;

number of coils of minimum height coiln ₁ The method comprises the following steps:

。

step 4, when a plurality of target areas exist in the object and/or the size of the target areas is larger than 20mm, the structural form of the coil combination system is designed into a coil combination structure with equal height, and the height of each coil in the coil combination system is the minimum height coil heighthThe method comprises the steps of carrying out a first treatment on the surface of the Step 8 is shown in detail in a mode of gradually switching off the coils;

when the target area is positioned at the upper/lower edge of the detected body, the structural form of the coil combination system is designed into a height gradual change type coil combination structure, the coil with the minimum height is placed over against the target area, and the heights of the other coils are gradually increased in sequence, and the step 63 is shown in detail; the height of each coil from top to bottom of the coil structure is gradually increased or gradually reduced;

When the target area is positioned at the middle part of the detected body, the structural form of the coil combination system is designed into a central symmetrical coil combination structure, the coil with the minimum height is arranged in the middle of the coil combination system, and the heights of the other coils at the upper side and the lower side are symmetrically distributed and are larger than the height of the coil with the minimum height, and the specific details are shown in the step 63;

when the target area is located in the upper center or lower center of the object, the coil combination system is designed into a center-offset coil combination structure, namely, the coil with the smallest height in the center-symmetrical coil combination structure is offset to one side of the target area.

Step 5 of measuring the body surface diameter of the target region of the subjectaAnd maximum diameter of body surface of the subject on the necessary path from outside of the subject to reach the target regionbTaking the following formula, and calculating to obtain the size of the hollow area of the coil structure;

wherein phi is the diameter of the hollow area of the coil structure, and the unit is mm;athe body surface diameter of the target area of the detected body is in mm;bthe maximum diameter of the body surface of the subject in mm is necessary for the coil structure to reach the target region from outside the subject.

The step 6 is specifically implemented as follows:

step 61, designing the axial height of the coil structure; the axial height of the coil combination system should ensure that the effective magnetic field generated by the coil combination system covers the whole object, and the magnetic field intensity and gradient generated by the coil structure meet the requirement of the step 2;

Axial height of coil assemblyLExpressed as:L≥p/1.18；

wherein,Lthe axial height of the coil combination system is in mm;pthe length of the detected body in the axial direction of the coil structure is in mm;

when (when)L=p1.18, satisfying the requirement of effective magnetic field to cover the whole subject, if the magnetic field strength and gradient are not satisfiedThe axial height of the coil combination system can be increased to meet the requirement of the step 2L>p1.18, until the magnetic field meets the requirements; specific axial height of coil structureLThe value determination is detailed in step 65;

step 62, designing the radial width of the coil structure; according to the required magnetic field intensity, designing the radial width of the coil structure, wherein the radial width of each coil in the coil structure is consistent; for a conventional subject, the width of the coil in the radial direction is less than 200mm;

step 63, designing the heights of the rest coils; the coil combination system is characterized in that other coils except the coil with the minimum height are all other coils;

for a coil combination structure with equal height, the heights of the rest coils are equal to the height of the coil with the minimum heighthI.e. the heights of all coils in the coil assembly system areh；

For the height gradient coil combination structure, the heights of the other coils are distributed in an equal-difference array, and the difference value range is 5-30 mm;

For the central symmetry type coil combination structure, when the heights of the other coils on the upper side and the lower side of the coil with the minimum height are equal, the heights of the other coils are 5mm higher than those of the coil with the minimum height; when the heights of the other coils on the upper side and the lower side of the coil with the minimum height are changed, the heights of the other coils on the single side are distributed in an equal-difference array, the difference value range is 5 mm-30 mm, and the heights of the coils on the outer side are large;

for the central offset type coil combination structure, the heights of the other coils on the upper side and the lower side of the coil with the minimum height are consistent with the arrangement mode of the heights of the other coils in the central symmetry type coil combination structure, and the number of coils on the outer side of the central offset type coil combination structure is less than that of the coils on the opposite side of the central offset type coil combination structure;

step 64, designing a coil structure to electrify current; the energizing current is the maximum safe current allowed to pass through by the wire diameter used in winding the coil structure so as to ensure the magnetic field strength; in addition, care should be taken to ensure that the ampere-turns of each coil in the coil structure are the same, so that the magnetic field between the coils is excessive smoothly;

step 65, designing the number of coils; number of coilsNFor all coils in a coil-combination systemNumber including the minimum height coil numbern ₁ And the number of the other coilsn ₂ The method comprises the steps of carrying out a first treatment on the surface of the The number of coils is designed by combining the axial height, the minimum height coil height, the coil structure form and the rest coil heights of the coil combination system, and meanwhile, the requirements of the step 2 on the magnetic field intensity and the gradient are met;

N=n ₁ +n ₂

Minimum height coil countn ₁ See step 3 for details of the determination of (c);

number of remaining coilsn ₂ Is determined by:

(1) if the axial height of the coil assembly systemLSubtracting the minimum height coil heighthThe number of the other coils is less than or equal to 0n ₂ Is 0;

(2) otherwise, subtracting the coil former thickness delta from the difference, and subtracting the remaining coil height adjacent to the coil with the minimum height determined according to the coil structurea _i If the difference is less than or equal to 0, the number of the other coilsn ₂ =n ₂ +1, finally obtaining the number of the other coils asn ₂ The method comprises the steps of carrying out a first treatment on the surface of the If the difference is greater than 0, the number of the other coilsn ₂ =n ₂ +1, and continuing to repeat the operation judgment of (2) until the difference is less than or equal to 0;

if the magnetic field generated by the coil combination system does not meet the requirement, the number of the other coils is continuously increased until the magnetic field generated by the coil combination system meets the requirement;

axial height of coil combination system adjusted according to number of coilsLThe final validation was:

。

the step 7 is specifically implemented as follows:

step 71, coaxially arranging all coils according to a coil structure form, only keeping the thickness of a coil framework between adjacent coils, and wiring according to the winding direction of each coil so that the magnetic field directions generated by each coil are the same;

Step 72, placing the detected body in a hollow area of the coil combination system, and aligning the axial center position of the coil with the minimum height to the center of the target area determined by the imaging diagnosis and treatment means in the step 1;

step 73, injecting magnetic nanoparticles into the subject.

Step 8, all coils of the coil combination system are electrified to generate an in-vitro magnetic field required by targeted delivery of the magnetic nanoparticles; however, when the structural form of the coil combination system adopts a constant-height coil combination structure, after all coils are electrified to effectively gather magnetic nano particles in the current target area, the coil electrifying current is turned off one by one from the position far away from the target area by adopting a mode of gradually turning off the coils until only the smallest-height coil electrifying at the target area is reserved at last (from outside to inside or from left to right or from right to left), so that the size of the target area of the magnetic targeting coil structure is gradually reduced, the magnetic nano particles are precisely gathered in the position of the tiny target area in the most efficient targeting delivery mode, and the dynamic change of the target area range of the coil structure and the rapid and precise gathering of the magnetic nano particles in the tiny target area are realized.

The invention has the beneficial effects that: a coil structure design method of a magnetic nanoparticle targeted delivery diagnosis and treatment system adopts a plurality of hollow narrow coils to be coaxially arranged, only the thickness of a coil skeleton is reserved between adjacent coils, the size and the position of a target area are determined through an imaging diagnosis and treatment means, a minimum height coil and a coil structure form are designed, and the mode of designing the size of the hollow area, the axial height, the radial width, the heights of other coils, the electrifying current and the number of coils of the coil structure according to the size of a detected object and the magnetic field intensity and gradient required by the targeted delivery of the magnetic nanoparticles is designed, so that an effective magnetic field generated by the coil structure not only meets the magnetic field parameter condition required by the targeted delivery of the magnetic nanoparticles, but also can effectively cover the detected object, thereby realizing the targeted delivery of the magnetic nanoparticles in the detected object and aggregation and detention in the target area. And, still have following advantage:

(1) Through the height of the coil with the minimum height, the design of the size of the magnetic nanoparticle aggregation area can be realized, and the accurate correspondence of the size of the target area of the coil structure and the size of the target area of the detected body can be easily realized.

(2) The heights of the other coils adopt an arrangement mode of an arithmetic progression, so that the heights of the coils in the coil structure sequentially decrease towards the coil direction with the minimum height. The excitation mode that the ampere turns of each coil are the same is matched, so that the magnetic field intensity generated by the coil structure is slowly increased towards the direction of the coil with the minimum height, and the magnetic field gradient is gradually reduced. Therefore, the magnetic field force borne by the magnetic nano particles is effectively reduced, the magnetic nano particles are better retained in the target area, the size of the aggregation area of the magnetic nano particles increased due to the inertia effect is reduced, the aggregation and retention effects of the magnetic nano particles in the micro target area are better, and the position and the size of the aggregation area of the magnetic nano particles are more consistent with those of the target area.

(3) By adopting a coil structure form design mode that the magnetic field distribution characteristics are more consistent with the motion track of the magnetic nanoparticles in the detected body, the magnetic nanoparticles can rapidly move towards target areas at different positions, and the targeting delivery efficiency is improved.

(4) The constant-height coil combined structure is matched with a coil to be turned off step by step, so that the size of the target area of the magnetic targeting coil structure can be gradually reduced, the magnetic nanoparticles can be precisely gathered at the micro target area in the most efficient targeting delivery mode, and the dynamic change of the target area range of the coil structure and the rapid and precise gathering of the magnetic nanoparticles in the micro target area are realized.

(5) The hollow coil structure is utilized to place the object to be examined in the coil structure, so that the coil structure form is simplified, the coil structure is easier to manufacture, operate and use, and the coil combination system can be easily moved and aligned to the target area from the outside of the object to be examined.

(6) The radial magnetic field in the hollow area of the coil structure is slowly attenuated, so that the targeted delivery of the magnetic nanoparticles in the deep area of the detected body can be effectively realized, and the limitation that the external magnetic field can only perform the targeted delivery of the magnetic nanoparticles on the surface or near-surface area of the detected body due to the overlarge magnetic field gradient in the traditional magnetic nanoparticle delivery means is avoided.

(7) The coil structure has high universality, and the coil structure is only required to be designed with the minimum height or rearranged in structural form for different detected bodies (the same detected body shape, different target area sizes/positions and different detected body shapes but the same body surface maximum diameter size), and the whole height of the coil structure and the number of coils can be increased or decreased according to the detected body size. The whole coil structure is not required to be redesigned and manufactured, only the coils with individual parameters are required to be designed and manufactured, the existing coils are rearranged and combined, the utilization rate of each coil is improved to the greatest extent, and the design and manufacturing cost is reduced.

(8) The ampere-turns of each coil in the coil structure are the same by adjusting the energizing current of each coil, so that the smooth transition of the magnetic field is ensured.

(9) The designed coil has simple and convenient structure, and greatly simplifies the design of the magnetic nanoparticle targeted delivery in-vitro magnetic field coil structure. In the magnetic nanoparticle targeted delivery process, the magnetic field target region position can be accurately focused without moving a coil combination system. The whole equipment is safer, and the targeting accuracy of the magnetic nano particles is improved.

(10) By utilizing the coaxial arrangement of a plurality of narrow coils, only the combination arrangement mode of the thickness of the coil frameworks is reserved between the adjacent coils, so that the magnetic field parameter adjustment is convenient and flexible, the application range is wider, and the magnetic field is safer and more reliable. The power-on current is in a safe range, the power supply can be cut off at any time, and the magnetic is cut off when the power supply is cut off. In addition, more importantly, the magnetic field strength and gradient can be effectively enhanced, so that the magnetic field parameters meet the requirements and meanwhile, the rapid targeted delivery of the magnetic nanoparticles is realized.

(11) The magnetic field strength and gradient can meet the requirement of magnetic nanoparticle targeted delivery by adjusting the axial height, radial width, the heights of other coils, the energizing current and the number of coils of the coil structure. The magnetic field parameter adjusting mode is more diversified and more flexible.

(12) The multi-coil structure is matched with different coil structure forms, and the design modes of different coil heights or the progressive turn-off mode of the coil energizing current are adopted, so that the design of the magnetic field coverage range, the magnetic field intensity, the gradient and the target area size can be effectively considered.

Drawings

FIG. 1 is a schematic diagram of an in vitro magnetic field construction structure in which a plurality of coils are coaxially and closely arranged according to the present invention.

Fig. 2 is a schematic view of a constant-height coil assembly structure of the coil assembly system of the present invention.

Fig. 3 is a schematic view of a highly gradient coil assembly structure of the coil assembly system of the present invention.

Fig. 4 is a schematic diagram of a central symmetrical coil assembly structure of the coil assembly system of the present invention.

Fig. 5 is a schematic diagram of a center-offset coil assembly structure of the coil assembly system of the present invention.

Fig. 6 is a line graph showing the influence of the width of the coil in the radial direction on the magnetic field strength according to the present invention.

Fig. 7 is a flowchart of the determination of the number of remaining coils of the present invention.

Fig. 8 is a line drawing of a magnetic field generated by a coil designed in an embodiment of this invention.

The serial numbers in the figures illustrate: 1 single coil body, 2 coil hollow area, 3 object.

Detailed Description

The specific implementation mode of the invention is to construct a multi-coil combined system by adopting a mode that a plurality of hollow narrow coils are coaxially arranged and only the thickness of a coil framework is reserved between adjacent coils, so as to realize the construction of an external magnetic field of magnetic nanoparticle targeted delivery. The effective magnetic field generated by the coil structure fully covers the detected body, the coil with the minimum height is designed according to the size and the position of the target area, and a proper coil structure form is selected, so that the target area of the coil structure corresponds to the target area of the detected body, and the magnetic field distribution characteristics correspond to the movement track of the magnetic nano particles. And the size of the hollow area of the coil structure is designed according to the size of the detected body. According to the magnetic field intensity and gradient required by magnetic nanoparticle targeted delivery, the axial height, the radial width, the heights of other coils, the energizing current and the number of coils are designed, so that the magnetic field generated by the coil structure meets the magnetic field parameter conditions required by magnetic nanoparticle targeted delivery.

Specific steps of the invention will be described in detail. The design method of the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system comprises the following steps:

step 1, determining the position and the size of a target, performing omnibearing diagnosis on a detected body by adopting proper imaging diagnosis and treatment means such as imaging (CT, DR, nuclear magnetic resonance and the like) or ultrasonic and other diagnosis and treatment means, determining the specific position and the size of a target area, and providing a foundation for the structure form of a coil in a follow-up magnetic nanoparticle targeted delivery system and the height and structure design of a coil with the minimum height.

Step 2, calculating magnetic field parameters required by targeted delivery of the magnetic nanoparticles according to the selected magnetic nanoparticle parameters and the attribute of the detected body, wherein the process comprises the following 2 steps:

because the magnetic nano particles are delivered in a targeted mode in the detected body, the magnetic nano particles are only subjected to the effects of magnetic field force and fluid viscous resistance. Therefore, when the magnetic field force is equal to the fluid viscous resistance, the magnetic nano particles do uniform motion. According to the magnetic nanoparticle targeting delivery efficiency required during actual targeting delivery, the movement speed of the magnetic nanoparticles is brought into a fluid viscous resistance equation, so that the magnetic field force required during magnetic nanoparticle targeting delivery can be obtained, and further the magnetic field strength and gradient required during magnetic nanoparticle targeting delivery can be obtained.

F _s = 3πηd _H v _p

wherein,F _s is fluid viscous resistance;ηis the viscosity of the fluid in the subject;d _H hydrodynamic diameter of the magnetic nanoparticles;v _p is the movement speed of the magnetic nanoparticles.

Step 22, bringing the fluid viscous resistance into a magnetic field force calculation formula to obtain a magnetic field gradient required by magnetic nanoparticle targeted delivery, wherein the magnetic field force formula is as follows:

F _s =F _m =V _p M·▽B

wherein,F _m is magnetic field force;V _p is the volume of the magnetic nano particles;Mmagnetization in units of volume of magnetic nanoparticles; (V)BIs a magnetic field gradient.

M=χ _p H

And 3, designing the height and the structure of the minimum-height coil according to the target size determined in the step 1.

The minimum height coil is used for generating an in-vitro targeting magnetic field target area, is placed opposite to the target area, and can enable the magnetic drugs to be precisely targeted and gathered in the target area. The structure form of the coil with the minimum height and the height of the coil can be designed according to the target size determined by the imaging diagnosis and treatment means in the step 1, and the structure of the coil can be a single coil or a plurality of coils with equal heights.

When the dimension of the target region in the axial direction of the coil structure is smaller than 8.5mm, a single coil may be used as the minimum height coil, at which time the number of the minimum height coilsn ₁ =1. When the dimension of the target area in the coil axial direction is greater than 8.5mm, a plurality of equal-height coils may be used instead of a single coil as the minimum-height coil of the entire coil assembly system, and at this time, the overall height of the plurality of equal-height coils is still the height of the minimum-height coil in the coil assembly system.

Height of minimum height coilhThe method comprises the following steps:

h=（c+1.58）/0.67

wherein,cis the dimension of the target area in mm in the axial direction of the coil structure.

。

and 4, designing the structural form of the coil combination system according to the target position determined in the step 1.

The coil structure forms of the coil assembly system can be divided into various types including, but not limited to, a constant-height coil structure, a height gradient coil structure, a center-symmetrical coil structure, and a center-offset coil structure, as shown in fig. 2, 3, 4, and 5, respectively.

When a plurality of target areas exist in the object and/or the size of the target areas is larger than 20mm, the structural form of the coil combination system is designed into a coil combination structure with equal height, and the height of each coil in the coil combination system is the minimum height coil height h. Because the length of the uniform magnetic field (the size of the target area) in the axial direction of the coil structure is similar to the whole height of the coil structure, the target area size is gradually reduced in a later stage by matching with a mode of gradually cutting off the coil, and the step 8 is shown in detail; the movement and aggregation of the magnetic nano particles towards target areas at different positions can be flexibly realized; the uniform magnetic field generated by the constant-height coil combination structure in the axial direction of the coil structure is beneficial to the aggregation of magnetic nano particles in a large-size target area;

when the target area is positioned at the upper/lower edge of the detected body, the structural form of the coil combination system is designed into a height gradual change type coil combination structure, the coil with the minimum height is placed over against the target area, and the heights of the other coils are gradually increased in sequence, and the step 63 is shown in detail; the height of each coil from top to bottom of the coil structure is gradually increased or gradually decreased.

When the target area is located at the middle part of the object, the structural form of the coil combination system is designed into a central symmetry type coil combination structure, the coil with the minimum height is arranged in the middle of the coil combination system, and the heights of the other coils at the upper side and the lower side are symmetrically distributed and are larger than those of the coil with the minimum height, and the specific details are shown in the step 63.

By adopting the design method of the coil structure form with the magnetic field distribution characteristics more consistent with the magnetic nanoparticle movement track, the targeted delivery of the magnetic nanoparticles can be realized without moving a coil combination system, so that the focusing of the target point position of the coil combination system is more accurate, the whole equipment is safer, and the targeting efficiency and the targeting accuracy are improved.

And 5, designing the size of the hollow area of the coil structure according to the body surface size of the target area of the detected body and the maximum body surface size of a path required by the coil structure from outside the detected body to reach the target area.

The hollow area of the coil structure is used for accommodating and placing the target area of the object, the size of the hollow area is the minimum size capable of accommodating the target area of the object, and the coil structure can be ensured to smoothly reach the target area of the object from the outside of the object without being destroyed.

Measuring body surface diameter of target region of subject aAnd maximum diameter of body surface of the subject on the necessary path from outside of the subject to reach the target regionbThe dimensions of the hollow region of the coil structure are calculated taking the following formula.

For example, the target area is located at the upper middle position of the detected body, the size of the hollow area of the coil structure can ensure that the coil structure moves from the upper end of the detected body without being damaged, and the coil structure can smoothly move to the minimum height so that the axial center of the coil is aligned with the axial center of the target area.

Step 6, designing the axial height, the radial width, the heights of other coils, the energizing current and the number of coils of the coil structure according to the magnetic field parameters determined in the step 2, so that the magnetic field intensity and gradient generated by the coil structure meet the requirement of magnetic nanoparticle targeted delivery, wherein the process comprises the following 5 steps:

step 61, designing the axial height of the coil structure; the axial height of the coil combination system should ensure that the effective magnetic field generated by the coil combination system covers the whole object, and the magnetic field intensity and gradient generated by the coil structure meet the requirement of step 2.

Axial height of coil assemblyLExpressed as:L≥p/1.18

wherein,Lthe axial height of the coil combination system is in mm;pthe length of the object in the axial direction of the coil structure is in mm.

When (when)L=pWhen 1.18, the requirement of the effective magnetic field to cover the whole detected body is met, and if the magnetic field strength and gradient do not meet the requirement of the step 2, the axial height of the coil combination system can be increased to ensure thatL>p1.18, until the magnetic field meets the requirements; specific axial height of coil structureHThe value determination is detailed in step 65.

Step 62, designing the radial width of the coil structure; the width of the radial direction of the coil structure influences the intensity of the magnetic field generated by the coil, and the intensity of the magnetic field is basically unchanged after being increased along with the increase of the width of the radial direction of the coil, if the width of the coil is continuously increased, the resistance and the heating condition of the coil are only increased, and the contribution to the magnetic field is not great; therefore, according to the required magnetic field intensity, the radial width of the coil structure is designed, and the radial width of each coil in the coil structure is consistent; as can be seen from the relationship curve of the influence of the radial width of the coil structure on the magnetic field intensity in fig. 6, the radial width of the coil should be less than 200mm for a conventional subject.

Step 63, designing the heights of the rest coils; the coil combination system is characterized in that other coils except the coil with the minimum height are all the rest coils.

For a coil combination structure with equal height, the heights of the rest coils are equal to the height of the coil with the minimum heighthI.e. in coil-combined systemsThe heights of all coils areh。

For the height gradient type coil combination structure, the heights of the other coils are distributed in an equal-difference array, the height difference of the coils between the adjacent coils is constant, and the range of the difference value is 5-30 mm.

For the central symmetry type coil combination structure, when the heights of the other coils on the upper side and the lower side of the coil with the minimum height are equal, the heights of the other coils are 5mm higher than those of the coil with the minimum height. When the heights of the other coils on the upper side and the lower side of the coil with the minimum height are changed, the heights of the other coils on the single side are distributed in an equal-difference array, the difference value range is 5 mm-30 mm, and the heights of the coils on the outer side are large.

For the center offset type coil combination structure, the heights of the other coils on the upper side and the lower side of the coil with the minimum height are consistent with the arrangement mode of the heights of the other coils in the center symmetry type coil combination structure, and the outside of the center offset side is less than the outside of the center offset side by a few coils.

Step 64, designing a coil structure electrifying current; the determination of the energizing current needs to consider not only the magnetic nanoparticle targeting delivery magnetic field parameter, but also the wire diameter, the power of a power supply, the resistance of the coil, the heating and other conditions used in coil winding manufacture; the energizing current cannot exceed the upper limit of the current that can be borne by the wire diameter and is less than the maximum current that can be provided by the power supply. In addition, under the condition of no cooling system, the temperature of the coil does not exceed the upper limit of safety regulation in the whole process of targeted delivery of the magnetic nano particles, so that the normal use and safety of the equipment are ensured.

In general, the energizing current is the maximum safe current allowed to pass by the wire diameter used in winding the coil structure, so as to ensure the magnetic field intensity and improve the targeting efficiency of the magnetic nano particles; in addition, care should be taken to ensure that the ampere-turns of each coil in the coil structure are the same, resulting in a smooth transition of the magnetic field from coil to coil.

Step 65, designing the number of coils; number of coilsNFor the number of all coils in the coil combination system, including the minimum height coil numbern ₁ And the number of the other coilsn ₂ The method comprises the steps of carrying out a first treatment on the surface of the The number of coils should be combined with the coilsThe axial height, the minimum height coil height, the coil structure form and the rest coil heights of the combined system are designed, and meanwhile, the requirements of the step 2 on the magnetic field intensity and the gradient are met.

N=n ₁ +n ₂

Minimum height coil countn ₁ See step 3 for details.

Number of remaining coilsn ₂ Is determined by:

(1) if the axial height of the coil assembly systemLSubtracting the minimum height coil heighthThe number of the other coils is less than or equal to 0n ₂ Is 0.

(2) Otherwise, subtracting the coil former thickness delta from the difference, and subtracting the remaining coil height adjacent to the coil with the minimum height determined according to the coil structurea _i If the difference is less than or equal to 0, the number of the other coils n ₂ =n ₂ +1, finally obtaining the number of the other coils asn ₂ The method comprises the steps of carrying out a first treatment on the surface of the If the difference is greater than 0, the number of the other coilsn ₂ =n ₂ +1, and continuing to repeat the operation judgment of (2) until the difference is less than or equal to 0; the whole judging flow is shown in fig. 7.

If the magnetic field generated by the coil combination system does not meet the requirement, the number of the other coils is continuously increased until the magnetic field generated by the coil combination system meets the requirement.

for the case of constant axial height of the coil combination system, the larger the number of coils, the larger the magnetic field intensity, the faster the magnetic nanoparticle targeted delivery speed and the higher the targeting efficiency.

Step 7, assembling a coil structure, placing a subject in a hollow region of a coil combination system, aligning a target region of the coil combination system with the target region determined in the step 1, and injecting magnetic nano particles into the subject, wherein the process comprises the following 3 steps:

and 71, coaxially arranging all the coils according to the coil structure, only keeping the thickness of a coil framework between adjacent coils, and wiring according to the winding direction of each coil so that the magnetic field directions generated by each coil are the same.

And 72, placing the object in a hollow area of the coil combination system, and aligning the axial center position of the coil with the minimum height to the center of the target area determined by the imaging diagnosis and treatment means in the step 1.

Step 73, injecting magnetic nanoparticles into the subject.

Step 8, energizing the coil combination system to generate an in-vitro targeting delivery magnetic field of the magnetic nanoparticles, so that the magnetic nanoparticles generate directional movement under the action of the in-vitro targeting delivery magnetic field; when the equal-height coil combined structure is adopted, the coil is matched with a step-by-step turn-off mode, so that the magnetic nano particles are precisely gathered at the micro target area in the most efficient targeted delivery mode.

Energizing all coils of the coil combination system according to the energizing current of each coil, so that the coils generate an in-vitro magnetic field required by targeted delivery of magnetic nanoparticles; however, when the structural form of the coil combination system adopts a constant-height coil combination structure, after all coils are electrified to effectively gather magnetic nano particles in the current target area, the coil electrifying current is turned off one by one from the position far away from the target area by adopting a mode of gradually turning off the coils until only the smallest-height coil electrifying at the target area is reserved at last (from outside to inside or from left to right or from right to left), so that the size of the target area of the magnetic targeting coil structure is gradually reduced, and the magnetic nano particles are precisely gathered in the position of the tiny target area in the most efficient targeting delivery mode, thereby realizing the dynamic change of the target area range of the coil structure and the rapid and precise gathering of the magnetic nano particles in the tiny target area.

For example, when a combined structure of equal-height coils with 3 coils is adopted, the coils are numbered from top to bottom, namely 1# coil, 2# coil and 3# coil, and the minimum-height coil aligned with the target area is 2# coil. At the beginning, all 3 coils are electrified, so that magnetic nano particles are rapidly gathered in the current target area. Then, the 1# and 3# coils are turned off, leaving only the 2# coil above the target area energized (including but not limited to this coil turn-off approach, it is also possible to turn off the 1# coil first, then turn off the 3# coil, or vice versa, etc.), causing the magnetic nanoparticles to move further toward the target area and eventually aggregate and reside at the target area.

The invention adopts a mode that a plurality of hollow coils are coaxially arranged, and only the thickness of a coil framework is reserved between adjacent coils to construct an external targeting magnetic field, as shown in figure 1. The hollow region is used for accommodating a target region where a subject is placed. The coils are coaxially arranged, only the thickness of a coil skeleton is reserved between the adjacent coils, the coil skeleton is used for constructing a high-field strength and high-gradient magnetic field which enable the coil structure to have a uniform magnetic field with a certain length in the axial direction, the magnetic field is slightly attenuated in the radial direction of the coil structure, and the larger magnetic field strength is reserved at the center of the coil, so that the targeted delivery of magnetic nanoparticles is carried out on the deep target area of the detected body. The flexible control of the magnetic field intensity, the magnetic field range and the target area size can be realized by controlling the axial height, the radial width, the number of coils, the energizing current and the minimum height of the coil structure.

Examples

The magnetic nanoparticle targeted delivery diagnosis and treatment system provided by the invention is used for targeted delivery of the magnetic nanoparticles in the urinary bladder of the mouse.

Step 1: the position and size of the target in the mouse bladder were diagnosed by CT, and as a result, the target region was found to be located at the uppermost end of the mouse body in the longitudinal direction of the bladder, and the length was about 5mm.

Step 2: magnetic nanoparticles with an inner diameter of 3.5um, a hydrodynamic diameter of 4.3um, a magnetic susceptibility of 3.1 and a saturation magnetization of 126A/m were targeted for delivery in aqueous solution at a speed of 2 mm/s. The viscous drag of water was 1.002×10 ^-3 Ns/m ² Bringing the above parameters into the fluid viscous drag equationF _s = 3πηd _H v _p The fluid viscous resistance of the obtained magnetic nano particles in the aqueous solution at the speed of 2mm/s is 81.17N. When the magnetic nano particles do uniform motion, the magnetic nano particles are magneticThe field force is equal to the fluid viscous drag, and therefore, the magnetic field force is 81.17N. Bringing the magnetic field force and the related parameters of the magnetic nano particles into a formulaF _s =F _m =V _p M·▽BThe magnetic field gradient required to obtain targeted delivery of magnetic nanoparticles should be 3.6T/m or more. Bringing the saturation magnetization and magnetic susceptibility of the magnetic nanoparticles into the formulaM= χ _p HThe magnetic field strength required by the targeted delivery of the magnetic nano particles is more than or equal to 40.6mT. And (5) designing a coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system according to the parameters.

Step 3: the size of the target area is 5mm, and the height calculation formula of the coil is calculated according to the minimum heighth=（c+1.58)/0.67, the minimum height coil height is 10mm. The dimension of the target area in the axial direction of the coil structure is smaller than 8.5mm, so that the minimum-height coil adopts a single-coil structure form, and the number of the minimum-height coils is reducedn ₁ =1。

Step 4: and (3) designing the structural form of the coil combination system according to the target position determined in the step (1). Consider that the target area is located at the uppermost bladder. Therefore, a coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system is built by selecting a height gradient coil structure or a constant-height coil structure. In this embodiment, a coil structure with equal height is selected for illustration, and the coil power-on mode is shown in step 8.

Step 5: the body surface size of the bladder part after the mice are stretched out and the maximum body surface size reaching the bladder part from outside the body (the bellies and buttocks of the mice are fat and positioned near the bladder) was measured.

As is clear from the measurement results, the maximum body surface size of the bladder part, the bellyband and the buttocks is 60mm or less. The calculation formula of the dimension of the hollow area is carried into the formula, and the hollow area of the coil structure system is designed to be phi 70mm.

Step 6: (1) because the magnetic nano particles are injected into the object by adopting a perfusion mode, the axial distance of the object after perfusion is about 30mm, and the value is brought into the axial height of the coil combination system LCan be obtained by the calculation formula of (2)L≥25.5mm。

(2) As is clear from the change law of the width of the coil in the radial direction and the magnetic field intensity, since the inflection point exists in the vicinity of 200mm, the width of the coil in the radial direction is set to 200mm.

(3) The coil structure with equal height is adopted, so that the heights of the other coils are also 10mm of the height of the coil with the minimum height.

(4) The coil is made by winding enameled wires with phi of 1mm, the power supply power is 1200W, the maximum output current is 8A when the coil is supplied with power, and the temperature of the coil does not exceed the prescribed upper limit when the coil continuously works for 1min, so that the energizing current is 7A.

(5) The minimum height coil number can be known from the step 3n ₁ 1. According to the flow shown in fig. 7, the number of the remaining coils was calculated, and the calculation result was 2.

At this time, the number of coils of the coil combination system is 3, the magnetic field strength generated by the coil combination system is 335mT, and the magnetic field gradient is 3.7T/m, as shown in FIG. 8. The magnetic field intensity and the gradient are larger than the required magnetic field parameters, so that the number of coils is not required to be increased. The number and the height of the coils with the minimum height, the number and the height of the other coils and the thickness of the coil frame are brought into the axial height of the coil combination systemLThe final coil combination system axial height was found to be 40mm.

Step 7: because of the structure of the coils with equal height, all the coils are coaxially arranged, only the thickness of a coil framework is reserved between adjacent coils, and wiring is carried out according to the winding direction of each coil, so that the directions of magnetic fields generated by each coil are the same, and a magnetic nanoparticle targeting delivery magnetic field is formed.

And placing the urinary bladder part of the mouse in a hollow area of a coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system, and aligning the axial center position of the uppermost coil in the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system to the center of a target area of the urinary bladder of the mouse.

The magnetic nanoparticles were infused into the mouse bladder by perfusion.

Step 8: firstly, each coil is electrified, after magnetic nano particles are effectively gathered in a current target area, the current of the coil at the lowest position far away from a mouse bladder target area is turned off, so that the magnetic nano particles are further close to the mouse bladder target area, when the magnetic nano particles are gathered in the current target area, the current of the coil adjacent to the coil with the smallest height is turned off, and therefore the magnetic nano particles are finally gathered in the mouse bladder target area, dynamic change of the target area range of a coil structure and rapid and accurate gathering of the magnetic nano particles in a tiny target area are realized. Under the action of the targeted delivery magnetic field, the magnetic nano particles generate directional movement and continuously gather and stay towards the target area.

Claims

1. The design method of the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system is characterized by comprising the following steps of:

step 1, determining the position and the size of a target in advance;

2. The method for designing the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system according to claim 1, which is characterized in that: and step 1, diagnosing a detected body by adopting an imaging diagnosis and treatment means, and determining the specific position and the specific size of a target.

3. The method for designing the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system according to claim 1, which is characterized in that: the step 2 is specifically implemented as follows:

step 21, according to the required magnetic nanoparticle targeting delivery efficiency, bringing the movement speed of the magnetic nanoparticles into a fluid viscous resistance equation, and calculating fluid viscous resistance, wherein the fluid viscous resistance equation is as follows:

F _s = 3πηd _H v _p

Step 22, when the magnetic nano particles do uniform motion, the magnetic field force is equal to the fluid viscous resistance, and the magnetic field strength and gradient required by the magnetic nano particles during targeted delivery can be obtained by a magnetic field force formula, wherein the magnetic field force equation is as follows:

F _s = F _m = V _p M·▽B

M=χ _p H

4. The method for designing the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system according to claim 1, which is characterized in that: the step 3 is that the minimum height coil is placed opposite to the target area, when the size of the target area in the axial direction of the coil structure is smaller than 8.5mm, a single coil is adopted as the minimum height coil, and the number of the minimum height coils is the same at the momentn ₁ When the size of the target area in the coil axial direction is greater than 8.5mm, a plurality of equal-height coils are adopted to replace a single coil as the minimum-height coil of the whole coil combination system, and at this time, the overall height of the plurality of equal-height coils is still the height of the minimum-height coil in the coil combination system;

Height of minimum height coilhThe method comprises the following steps:

h=（c+1.58）/0.67

。

5. the method for designing the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system according to claim 1, which is characterized in that: step 4, when a plurality of target areas exist in the object and/or the size of the target areas is larger than 20mm, the structural form of the coil combination system is designed into a coil combination structure with equal height, and the height of each coil in the coil combination system is the minimum height coil heighth；

When the target area is positioned at the upper edge and the lower edge of the detected body, the structural form of the coil combination system is designed into a height gradual change type coil combination structure, the coil with the minimum height is placed over against the target area, and the heights of the other coils are gradually increased in sequence; the height of each coil from top to bottom of the coil structure is gradually increased or gradually reduced;

when the target area is positioned at the middle part of the detected body, the structural form of the coil combination system is designed into a central symmetrical coil combination structure, the coil with the minimum height is arranged in the middle of the coil combination system, and the heights of the other coils at the upper side and the lower side are symmetrically distributed and are larger than the height of the coil with the minimum height;

6. The method for designing the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system according to claim 1, which is characterized in that: step 5 of measuring the body surface diameter of the target region of the subjectaAnd maximum diameter of body surface of the subject on the necessary path from outside of the subject to reach the target regionbTaking the following formula, and calculating to obtain the size of the hollow area of the coil structure;

7. The method for designing the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system according to claim 1, which is characterized in that: the step 6 is specifically implemented as follows:

step 61, designing the axial height of the coil structure; the axial height of the coil combination system should ensure that the effective magnetic field generated by the coil combination system covers the whole object;

Axial height of coil assemblyLExpressed as:L ≥ p/1.18；

when (when)L = pWhen 1.18, the requirement of the effective magnetic field to cover the whole detected body is met, and if the magnetic field strength and gradient do not meet the requirement of the step 2, the axial height of the coil combination system can be increased to ensure thatL > p1.18, until the magnetic field meets the requirements;

step 65, designing the number of coils; number of coilsNFor the number of all coils in the coil combination system, including the minimum height coil numbern ₁ And the number of the other coilsn ₂ The method comprises the steps of carrying out a first treatment on the surface of the The number of coils is designed by combining the axial height, the minimum height coil height, the coil structure form and the rest coil heights of the coil combination system;

N= n ₁ + n ₂

minimum height coil countn ₁ Is determined as in step 3;

number of remaining coilsn ₂ Is determined by:

(2) otherwise, subtracting the coil former thickness delta from the difference, and subtracting the remaining coil height adjacent to the coil with the minimum height determined according to the coil structure a _i If the difference is less than or equal to 0, the number of the other coilsn ₂ = n ₂ +1, finally obtaining the number of the other coils asn ₂ The method comprises the steps of carrying out a first treatment on the surface of the If the difference is greater than 0, the number of the other coilsn ₂ = n ₂ +1, and continuing to repeat the operation judgment of (2) until the difference is less than or equal to 0;

。

8. the method for designing the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system according to claim 1, which is characterized in that: the step 7 is specifically implemented as follows:

step 73, injecting magnetic nanoparticles into the subject.

9. The method for designing the coil structure of the magnetic nanoparticle targeted delivery diagnosis and treatment system according to claim 1, which is characterized in that: step 8, all coils of the coil combination system are electrified to generate an in-vitro magnetic field required by targeted delivery of the magnetic nanoparticles; when the structural form of the coil combination system adopts a constant-height coil combination structure, after all coils are electrified to effectively gather magnetic nano particles in the current target area, the coil is turned off step by step, the coil electrifying current is turned off one by one from the position far away from the target area until the coil electrifying at the minimum height at the target area is reserved finally, and the magnetic nano particles are precisely gathered in the micro target area in the most efficient targeted delivery mode.