Future trends in magnetic source device design for magnetic targeted drug delivery system

Abstract

Magnetic targeted drug delivery systems can improve drug utilization and reduce drug side effects. There are still many difficulties to be overcome in clinical practice. The main problems include providing large enough magnetic capture particles to concentrate drug-loaded magnetic micro-nanoparticles (MNPs) to the lesion site. The existing research focuses on the development of targeted carriers, and the magnet device has not formed a mature research system. Based on the recent development of magnet devices in recent years, this paper proposes the research direction of potential magnet devices. From the dynamic behavior of the particles under the magnetic field, the magnetic system and the mathematical model design direction of the optimized magnet are developed. This article describes the obstacles encountered in drug targeting in the study of magnet devices and summarizes the potential development of future magnet devices.

Keywords

Magnetic targeted drug delivery system magnet device targeted behavior

1. Introduction

The Magnetic Targeted Drug Delivery System (MTDDS) controls the movement of magnetic micro-nanoparticles combined with drugs through an external magnetic field to transport the drug to the lesion site and interact. This technology can concentrate drugs and deliver drugs to the lesion location in an accurate targeted manner. It can reduce the side effects of drugs, increase the concentration of drugs and improve the efficiency of drugs. Targeted magnetic drug therapy can be used to treat various diseases, especially cancer, cardiovascular diseases and other intravascular diseases, such as vascular stenosis, embolism, aneurysm and atherosclerosis. This technology has a wide range of applications and potential huge market demand [1].

In recent years, MTDDS has become a research hotspot in the medical field. However, most of the previous studies were limited to animals, and only a few human clinical trials [2]. Although in vitro experiments are ideal, there are still many difficulties to overcome in the practical application of targeted drugs to the clinic. First, the existing research focuses on the development of magnetic particles, which leads to the inability to form a system for controlling the magnetism of its targeted motion. Second, MTDDS typically consists of a therapeutic agent contained within a biocompatible carrier functionalized or loaded with superparamagnetic iron oxide nanoparticles. Controlling magnetic nanoparticles requires a specific magnetic field. It is necessary to provide sufficient magnetic force to overcome the shear force of blood flow under the safe magnetic field of human body. Concentrate magnetic drugs only at a given target location [3]. For large particles up to 5 μm, a depth of 15 cm can be reached. Unfortunately, intravenously injected particles are usually designed to be smaller than 200 nm to improve circulation time in the body, so that magnetic capture cannot effectively target deep tissues [4]. Due to the rapid attenuation of the magnetic field away from the magnetic source and the magnetic saturation principle, the development of non-contact magnetic targeting technology is limited, and it is difficult to complete deep targeted transportation. Finally, the human body’s acceptance of the magnetic field strength is within a certain range. As the strength of the magnetic field increases, it will affect the cells and metabolic processes, and strengthen the metabolism of the cells [5].

Therefore, it is necessary to achieve a targeted effect by rational design of the magnet device. The key to solving the problem is the application environment carefully considered. Combined with the new superconducting absorbing material, the geometric design of the magnet system is optimized based on the comprehensive principle to improve the permeability. Based on the above problems, this paper focuses on the research progress of magnetic targeting magnet system in recent years. It provides a potential way for the future development of drug magnetic targeting magnet design. A series of difficult problems that hinder the development of MTDDS are also pointed out.

2. Targeting principle

Magnetic particles will magnetize under the action of an external magnetic field. For superparamagnetic nanoparticles, they are more easily aligned with the direction of the external magnetic field after being magnetized by a magnetic field. The relationship between the magnetization M of the magnetic particles and the magnetic field strength H of the magnetic particles is: $\begin{eqnarray}\displaystyle \boldsymbol{M}={\chi}_{m}\boldsymbol{H} & & \displaystyle\end{eqnarray}$ (1) where 𝜒_m is the magnetic susceptibility of the magnetic particles and H is the applied magnetic field.

The magnetic field H acting on the magnetic particles will produce a magnetic induction B , which is known from the relationship between the magnetic flux density and the magnetic field: $\begin{eqnarray}\displaystyle \boldsymbol{B}={\mu}_{0}(\boldsymbol{H}+\boldsymbol{M})={\mu}_{0}(1+{\chi}_{m})\boldsymbol{H}={\mu}_{r}\boldsymbol{H} & & \displaystyle\end{eqnarray}$ (2) μ_r = (1 + 𝜒_m)μ₀, μ_r is the relative magnetic permeability. μ₀ is the vacuum permeability, which is 4π × 10⁻⁷ H/m.

The force of magnetic particles under the action of a magnetic field is: $\begin{eqnarray}\displaystyle \text{} & \text{} & \displaystyle \boldsymbol{F}=(\boldsymbol{m}\cdot {\rm\nabla})\boldsymbol{B}\end{eqnarray}$ (3) $\begin{eqnarray}\displaystyle \text{} & \text{} & \displaystyle \boldsymbol{M}=\frac{\boldsymbol{m}}{\boldsymbol{V }}\end{eqnarray}$ (4) m is the magnetic distance and V is the particle volume.

The magnetization is changed into the relationship between the magnetic field intensity and the measured susceptibility. The above can be translated into: $\begin{eqnarray}\displaystyle \boldsymbol{F}={\mu}_{0}\boldsymbol{V }(\boldsymbol{M}\cdot {\rm\nabla})\boldsymbol{H}={\mu}_{0}\boldsymbol{V }{\chi}_{m}(\boldsymbol{H}\cdot {\rm\nabla})\boldsymbol{H}. & & \displaystyle\end{eqnarray}$ (5)

It can be seen from the above equation that if the targeted control of magnetic particles is to be achieved. The magnetic force can be enhanced by changing the volume size, field strength and magnetic gradient of magnetic particles. Due to the limitation of the nature of the magnet itself, increasing the volume of the particles will lead to the consequences of blocking the blood vessels. It is necessary to reasonably design the magnet device to achieve the purpose of capturing magnetic particles.

3. Magnetic source device

In view of recent advances in magnetic targeting research in recent years, the text provides a basis for the future development of magnetic targeting magnets.

3.1. Magnet system

The main direction of research in recent decades is mainly to study permanent magnets and electromagnets as magnetic source generating devices [6–8]. Permanent magnets are easier to obtain and less expensive, maintaining the magnetic field without a power source. However, permanent magnets are not easy to achieve random adjustment of the magnetic field in the spatial and temporal dimensions. The magnetic field generated by the electromagnet can control the form and intensity of the magnetic field by changing the current. Nonetheless, this method requires high power consumption to obtain the required magnetic field [9]. Compared with the above two methods, the superconducting magnetic material has high carrying current capacity and low power dissipation. And this way can produce magnetic field intensity and magnetic field gradient stronger magnetic field, stronger application. However, superconductor materials are expensive to manufacture as new materials, and the design of the magnet system is hardly considered. Consider the prospect of medical applications, and integrate the characteristics of the above magnetic source devices. The development status of new magnetic materials should be concerned and the existing magnets should be optimized. In order to accelerate the realization of medical magnetic targeting in clinical application.

3.2. Dynamic behavior between particles under magnetic field

In order to improve the magnetic targeting efficiency and optimize the distribution of the magnetic field to improve the performance of the system, Cao et al. set up an external magnet system to study the dynamic behavior of MNP interactions when magnetic particles are exposed to an external magnetic field. They used permanent magnets, as shown in Fig. 1, to generate gradient magnetic fields in both horizontal and vertical ways to observe the transport status of MNP in these two modes [10]. The experimental results show that the interaction between magnetic particles is directly related to the magnetic field generated by different settings of the same permanent magnet. Adjacent magnetic particles are easy to form chain clusters. The vertical gradient magnetic field is generated to set the permanent magnet, and more magnetic particles can be concentrated in the selected area. This phenomenon can be used to enhance the concentration of particles in the process of magnetic targeting. It also promotes the effective combination of targeted particles and cells in the lesion area.

Since a single set of experimental backgrounds will be significantly different from actual verification [11], consider the existence of vacancies in the study of enhanced particle-particle interactions to improve the targeted behavior of high-concentration drugs, and the dynamic behavior of particles. The research focuses on the particles and the particles themselves and ignores the magnetic source itself that manipulates the particles [12–14]. The interaction between the particles in the process of capturing particles should be considered in consideration of the direction of the magnetic field, the frequency of the magnetic field, etc., possibly the magnet of the magnetic source device. The breakthrough of design, for the high efficiency of the targeted concentration of a large number of magnetic particles needs to be paid attention to in future research.

Fig. 1.

Dynamic behavior of particles under two magnetic field gradients.

3.3. Magnet device

3.3.1. Permanent magnet

First, the realization of magnetic induction requires a large attraction field to attract drug particles far away from the lesion. Second, local focusing is necessary to ensure that the drug is only delivered to the target lesion. On the one hand, permanent magnets are more attractive for continuous processing because they can continuously generate strong magnetic fields without consuming energy. On the other hand, in magnetic targeted drug delivery, it is important to concentrate the drug around the target lesion. This cannot only improve the therapeutic effect, but also minimize the side effects on the surrounding normal cells.

Sarwar, A. et al. shows an optimal dual-magnet system [15], as shown in Fig. 2. After magnetization, the MNPs can be pushed within a distance of 3 to 5 cm. The system uses a semi-definite quadratic programming design to ensure the global optimal magnet configuration, manufacturing, detailed characterization, comparison with the theory, and then testing in a rat experiment. However, the working distance of human beings is now 4 cm, this is what adult patients need. The system is designed using a previously developed semi-deterministic optimization technique that guarantees the global best (optimal) magnetization direction and characterizes its magnetic field in detail through a 3-D magnetic field measurement system.

Fig. 2.

Dual magnet system device [15].

Sergey et al. proposed an improved Halbach array design with a simple structure, as shown in Fig. 3, which can achieve efficient focused magnetic drug targeting [16]. First, by optimizing the size of the magnetic force, the shape and size of the permanent magnet composed of the proposed Halbach array are determined. Next, the local focus with wide attraction is optimized. To determine the gap between the central cylindrical and transverse cuboid magnets of the proposed Halbach array. Based on the optimized parameters, a new Halbach array was fabricated, which was then used to verify the design through multiple simulations and experiments.

Fig. 3.

Permanent magnet array diagram [16].

Sergey Erokhin pointed out that it would be more convenient for the magnetic system to consist of hexagonal magnet bars [17]. The hexagonal rod has discrete possible moment direction sets of rods, and its design, manufacture and assembly are relatively simple. The discretization of the magnetization direction has almost no effect on the achievable gradient projection, providing almost the same magnetic field gradient.

In the field of non-drug magnetic targeting, according to GIAMAG patent design, as shown in Fig. 4, in order to generate high magnetic field strength and magnetic field gradients, Skjeltorp AT et al. have designed the most powerful magnetic separator on the market.

Fig. 4.

GIAMAG magnet design.

For magnetite nanoparticles, the saturation magnetization is as follows: $\begin{eqnarray}\displaystyle \boldsymbol{M}_{S}\approx {\rm\Delta}{\chi}\frac{\boldsymbol{B}}{{\mu}_{0}}\approx 4\times 10^{5}∼\text{A}/\text{m}. & & \displaystyle\end{eqnarray}$ (6)

Based on the magnetization saturation of the magnet, a field strength of approximately 1 T can be obtained [8]. For targeted operations of particles of size r = 50 nm, a magnetic field gradient is required as shown below: $\begin{eqnarray}\displaystyle |{\rm\nabla}\boldsymbol{B}|\approx 400∼\text{T}/\text{m}. & & \displaystyle\end{eqnarray}$ (7)

At present, there is no other permanent magnet device on the market that can achieve the same effect on magnetic separation and capture of magnetic nanoparticles. Permanent magnets on the market can generate high magnetic fields, but the increase in magnetic field gradients is limited. GIAMAG magnets can reach B ∇ B ≈ 900 T²/m and can be fabricated in different geometries in radial and axial directions to accommodate magnetic field requirements for different lesion locations. This design involves the neighborhood of the magnet design, which produces a background magnetic field on the magnetic target of the drug to achieve non-contact targeted behavior.

Improving the targeting function of permanent magnets can be achieved by changing the shape and structure of permanent magnets and their permutations and combinations. Firstly, the magnetic field intensity of magnetized permanent magnet is obtained by digital simulation. Then, the finite element multi-physics simulation software is used to build the hydrodynamic model. Finally, the effect of setting permanent magnet is verified.

3.3.2. Electromagnet direction

Compared with permanent magnets, in order to realize the adjustment of the magnetic field in space, the electromagnetic system can be realized by changing the current and the coil structure.

In order to enable the micro-robot to adapt to any blood vessel, Jang. D et al. specially set up an electromagnetic system to regulate the movement of the micro-robot [18], as shown in Fig. 5. The electromagnetic system consists of a pair of Helmholtz and Maxwell electric coils. The Helmholtz coils that make up inside the electrical coil create a uniform magnetic field that magnetizes the micro-robot and aligns it in the desired direction.

Fig. 5.

Targeted drug delivery technology for micro robots under magnet system.

To improve the problem of insufficient contact of the drug with the target cells, the drug Brownian diffusion is overcome and the drug is evenly dispersed in the lesion site. The Pei N team uses magnetic nanoparticles to enhance the drug delivery system that faces the cell surface with a two-pair coil system of Helmholtz and Maxwell coils. Maxwell coils are used to generate gradient magnetic fields in the target area. The uniform background magnetic field generated by the gradient magnetic field superimposed on the Helmholtz coil generates a magnetic field in a specific direction. With the proposed magnetic targeting system, almost uniform unidirectional magnetic force can be generated in a certain area. G protein-coupled receptor activation efficiency can be increased by about 6 times. The total dose required for the same activation performance was reduced to 15.3% of the original case. The magnetic targeting system can be further optimized to increase the magnetic field strength and gradient, and the current in the coil reaches 16 A, taking care to reduce coil heating and power consumption [19].

To achieve deep magnetic capture, Pei et al. proposed a new electromagnet structure that changes the magnetic field distribution based on the magnetic edge effect [20], as shown in Fig. 6. The existing research on the use of special magnets only focuses on the motion behavior of particles in cylindrical space located in the center of the electromagnet. However, the particle distribution in large areas around the magnet has not been reported. In order to further fully understand the dynamic characteristics of MNP under special gradient magnetic field, a similar electromagnetic device was designed and fabricated. Wei Zhong et al. pointed out that the finite element numerical simulation in 2D geometry is used to calculate the magnetic force on magnetic nanoparticles under a special electromagnet [21]. Unlike existing research, they found that MNP eventually did not accumulate in the center of a given container, but was attracted to the outer ring of the magnet hole. This phenomenon can be considered when the lesion area is a region.

At the same time, it has been found that numerical procedures can approximate the shape and position of the MNP capture without flow. Under the same conditions, the particle distribution is consistent with the simulation experiment, and the moving speed of MNP in the simulation is much faster than in the experiment. The actual MNP aggregation effect should be estimated and considered to accurately predict MNP motion using the flow in the experiment in future studies. The results of the analysis may contribute to the design of magnetic particles and the motion analysis of magnetic particles for the transport of magnetic materials in biomedical applications.

Fig. 6.

Simplified 2D model of experimental electromagnet.

To explore the effect of magnetic field on capsule priority positioning in the bifurcation area of vascular system. And explore the retention of the capsule in this part once the external magnet closed [22]. Use a sharp steel link used as a magnetic concentrator to connect to the magnet to locate the magnetic field area. A self-made electromagnetic device made of two electromagnets is used for magnetic capture in the body, as shown in Fig. 7. The magnet is assembled by a copper wire wound on a reel and a steel core. There is a sharp tip on one side of the magnetic core, which can effectively concentrate the magnetic field on the target area. Each electromagnet has a separate power source that allows us to turn on them with different polarities, so that the tips form the north and south poles respectively. In addition, the magnetic core is connected to the steel chain from the other side to increase the mutual influence of the magnets.

Fig. 7.

Schematic diagram of the electromagnetic device [22].

Hajiaghajani, A. et al. first proposed a method for calculating the required magnetic force for the design method of muscle and blood vessel electromagnets, as shown in Fig. 8 [23]. Secondly, by explaining the mutual influence of coil specifications on the generated magnetic force, a design algorithm for the force is proposed. This can be used to adjust the coil size to fit and optimize for the corresponding container. Optimization means that the most effective magnetic force is generated with a lower H intensity, so that the maximum allowable magnetic exposure of the human body can pass. The coil size and wire diameter show the mutual influence on the generated magnetic field in question. There is a trade-off between the low ampere turns of the coil and the low terminal resistance to achieve the best power consumption coil. In addition, this method simplifies the use of magnetic drug delivery in local clinics due to the easy availability of low-voltage power supplies.

Fig. 8.

Design of electromagnet for magnetic drug targeting of human muscles and arteries [23].

In the past two decades, there have been few reports on the application of pulsed magnetic fields in the rapid development of biological research, but the targeted pulsed magnetic field magnetic source devices designed specifically for targeted therapy. According to experiments, they show that bipolar pulsed magnetic fields are more suitable for magnetic drug focusing and targeted therapy than static, sinusoidal, unipolar pulsed magnetic fields [24]. Compared with other magnetic fields. Alternating magnetic field is more conducive to the release of drugs in the targeting process, so that drugs can fully act on the lesion area. Xiong H et al. proposed a multifunctional energy-saving magnetic field generator. It produces alternating magnetic fields and bipolar pulsed magnetic fields with high energy savings and energy re-use. The generated bipolar pulsed magnetic field has a peak current of 130 A and an intensity of 70.3 mT. The resulting alternating magnetic field has an intensity of 11.0 mT and a RMS current of 20 A [25].

As a magnetic targeting magnetic source device, electromagnet has great potential. However, it can be further optimized to improve the magnetic field intensity and gradient, while reducing coil heating and power consumption. In addition, due to the cumbersome structure of the components; it is not suitable for hospital installation. Power supplies have too much navigational magnetic field capacity and should be smaller and more efficient in future designs.

3.3.3. Superconducting magnet

As we all know, high-temperature body superconductors (HTS bodies) can capture 17.6 Tesla at 29 K [26], which is much larger than permanent magnet arrays. In addition, the HTS block exhibits an ultra-high magnetic field gradient, which is almost 75 times the magnetic field gradient obtained using a permanent magnet at a distance of 20 mm [27].

According to the surface current density and volume current density model [28]. At the magnetic field source, for PM and HTS blocks, the magnetic gradient distribution is calculated at 1 mm above the surface. The maximum value of PM is 0.35 Tesla, and the maximum value of HTS is 0.28 Tesla. When the permanent magnet is used as the magnetic field source, 12% of the MNPs are concentrated at the edge of the target area, while at other positions, the concentration is still 8%. When using a superconductor operating at 65 K, due to its stronger magnetic capture ability, the particles are obviously concentrated in the center (23%), and there are no magnetic particles outside the range of 2.5 mm from the center. The HTS block exhibits a better concentration ability on the target (iron particles) under similar magnetic field strength, and also has a higher magnetic field when the working temperature is lowered. If the target area is very small (diameter < 5 mm), it is strongly recommended that the HTS block is more suitable for MTDDS than the PM block.

Li et al. used REBCO coated conductors to combine Maxwell coils that traditionally generate uniform and gradient magnetic fields with bed coils that produce uniform and gradient magnetic fields [9]. A Maxwell coil with high gradient magnetic field and uniform magnetic field along X, Y, Z-axis and a Maxwell coil with gradient magnetic field are designed. Each coil can be charged independently by power supply. The maximum magnetic field gradient produced by the gradient Maxwell coil along the Z axis is approximately 70 T/m. The maximum magnetic field gradient of the gradient bed coil of the superconducting magnet is approximately 20 T/m along the X and Y and Z axes. And the combination of these coils is capable of producing a 3D magnetic field and magnetic force distribution, greatly improving the operability of magnetic particles in complex blood vessels.

REBCO coated HTS superconducting magnets are being designed for magnetic nanoparticle drug delivery systems. There is a big breakthrough in the design of MTDDS magnets using superconductors. Seungyong Hahn et al. proposed a high temperature superconductor coil that uses a REBCO coated conductor strip on a 30-micron thick substrate [29]. The coil produces a 14.4 Tesla magnetic field inside a 31.1 Tesla resistive background magnet, resulting in a DC magnetic field of 45.5 Tesla, which is the highest known magnetic field. Jianhua Liu et al. recently used self-made all-superconducting magnets to successfully achieve the world record of 32.35 T DC magnetic field [30].

Superconducting materials with low power and high load capacity can generate high-intensity and high-gradient magnetic fields, which can be compared with permanent magnets and resistive electromagnets in MTDDS applications. Due to the difficulty in mastering superconducting technology, large-scale commercial production has not yet been realized. The promotion of medical use needs to be weighed between its production cost and performance.

3.3.4. Hybrid magnet system

Magnetic fields are used to control magnetic carriers in a fluid environment. There are three main types of magnet systems to generate magnetic fields. The first is an external magnet system based on macroscopic form [31]; the second is an integrated internal magnetic system [32,33]; the last is a hybrid magnet system consisting of an outer magnet and an inner magnet [34,35]. Due to the combination of hybrid systems, the magnetic field strength and gradient can be controlled by magnets inside and outside the microsystem, respectively. It produces a more flexible magnetic field, more efficient manipulation of magnetic particles, and has potential in future applications.

Han X team designed a hybrid system. Two rectangular microconductors are used to change the gradient magnetic field of the magnetic field by changing the direction and size of the current in the microfilament [36]. A permanent magnet is placed outside to generate a relatively large uniform magnetic field and act on the selected observation area, as shown in Fig. 9. It is verified by experiments that the external uniform magnetic field and the current flowing in the microwire have a significant influence on the control of the magnetic carrier. The Cao Q team then combined two types of magnetic sources: a uniform magnetic field between the two coils of the Helmholtz coil as the background field; and a pair of parallel microconductors used as the gradient magnetic source to carry the current in the opposite direction. It is more efficient to capture particles by means of a superimposed uniform background magnetic field. And changing the current of the Helmholtz coil system without changing the micromagnetic source; the magnetic fluid nanoparticles can be transported in different movement trajectories in the microfluidic channel.

Fig. 9.

Schematic diagram of the designed hybrid magnet system.

Therefore, it is conceivable to use an electromagnet to generate a background magnetic field in a small area (generating a multi-type driving magnetic field), and a stent close to the lesion portion is subjected to deep targeting using a permanent magnet or a magnetized superconducting magnet.

For invasive treatments in the background field, due to their inherent high magnetic properties, magnetic nanoparticles can be directly used as drug delivery systems in high magnetic fields. Or the micro-robot driven by the external magnetic field carries the magnetic drug particles by the micro-robot and releases and promotes the penetration of the drug to the target position.

3.4. Optimizing the mathematical model design of the magnet

The Shipo team proposes the overall design of the magnetic carrier, including shape, size, and coating. If the most suitable magnetic carrier cannot be achieved through animal experiments, it is necessary to establish predictive and more effective mathematical models for animal experiments. The design of magnets for clinical conditions provides a theoretical basis [2].

Shashi Sharma team developed a mathematical model. The trajectory of magnetic nanoparticle clusters in blood vessels is described by the local magnetic field applied by cylindrical magnets in vitro, as shown in Fig. 10 [37]. MTDDS is one of the effective targeting and delivery methods for delivering drugs to specific targets with local magnetic fields [38,39]. Magnetic nanoparticles flow along the vessel axis and apply a magnetic field perpendicular to the direction of blood flow, using the classical fourth-order Runge–Kutta method to solve the mathematical equations used in the model to predict magnetic particle trajectories within the blood vessel. The magnet is within 4.5 cm of the region of interest and predicts forces that have a significant effect on the transport of the magnetic carrier in the fluid, including magnetic force, drag and buoyancy. This mathematical model can predict the feasibility of promoting deep targeting behavior by predicting the behavior of magnetic carriers in blood vessels. It also provides a simpler verification method for the target efficiency of the magnet device.

Fig. 10.

Schematic diagram of magnetic nanoparticles transported in blood vessels.

Barnsley team proposed an optimized magnet array design. The magnet is divided into three-dimensional arrangement of uniformly distributed point torque. The field emitted by an array composed of arbitrary magnetic elements is calculated. The normalized magnetic force of the magnet array on the superparamagnetic particles at the position of interest is calculated. The initial array is constructed to occupy the volume to be optimized, including magnetized and unmagnetized elements, where the magnetized element occupies the position closest to the interested position. A set of parameters can be designed according to the region of the lesion area to maximize the magnetic force of any magnetized element arrangement. The relevant parameters of magnetic force can be set, including the depth of positioning, the required force and direction. However, the maximum depth up to now is 5 cm [40]. For the same volume of magnetic materials, the obtained array can generate almost twice to three times the magnetic force. This is an array constructed by cubic elements, which depends on the optimization distance. The versatility of the optimization program is presented in the form of a Halbach array design. The array is specifically designed to drive and retain magnetic particles at different tissue depths inside the brain to prevent flow.

The magnetic properties of the MNPs required for various diseases vary, and the design of the optimized magnet array is very flexible in generating magnetic forces. In the long run, the magnet array has a great role in the application and promotion of magnetic targeting technology in medical treatment.

4. Obstacles and prospects of magnetic source device research

4.1. Experimental problems of magnetic source devices

(1) The Owen J team studied the effect of using blood instead of saline on targeting efficiency and found that the targeting efficiency was greatly reduced. This was due to the low shear rate in the environment under ideal experiments, neglecting the shear force effect, and very in vitro. Less consideration is given to the difference in experimental fluids compared to blood characteristics [41,42]. Even if the human body is complex, there are many complex influencing factors. Attention should be paid to the importance of using appropriate models in developing targeting efficiency. Otherwise, the developed magnet system needs to be continuously modified and optimized to delay the research progress.

(2) The shape of the magnetic carrier is considered. In the current magnetic targeting study, the basic default MNP is a sphere. In the long run, rod-like particles are a favorable factor for infiltration into human tissue [43]. Cao Q found that the magnetic field direction was adjusted without changing the magnetic field intensity. It is helpful for achieving faster lateral migration of elliptical magnetic particles in a non-rotating manner. The reason is that the direction of the magnetic field has a significant impact on the configuration of the relative strength of the magnetic field [44]. However, the application of magnetic field strength in magnetic targeting systems will be limited, and the control of rod-shaped particles is still a difficult problem for drug targeting systems today.

(3) When using the magnet array, the manufacturing problem of the magnet. Due to different treatment sites, the generated magnet arrays are different, and the manufacturing process is complicated, and the manufacturing cost is expensive. The Halbach array for focused magnetic drug targeting proposed by Hyeonwoo Kee et al. can be easily manufactured using a simple 3D printed housing and several commercial permanent magnets [16]. Other magnet array manufacturing solutions can also refer to such solutions.

(4) Although the simulation results provide more information about the magnetic intensity effects in MTDDS, their accuracy is difficult to prove. Lester et al. Leicester et al. tried to use many particles of the same size to show the trajectory and support his calculation model. However, the particles would interfere with each other and affect the observation results.

4.2. Future prospects for the development of MTDDS magnetic source devices

(1) Focus on the magnet system that generates high magnetic field and high gradient magnet design in magnet design. The magnetic array design optimized by Shahi Sharma’s team produces almost two to three times the magnetic force of the same magnetic material. The magnetic field gradient is increased by changing the shape of the magnet or forming a magnet array. Some magnets are large in size and used to generate background magnetic fields, and some magnets have sharp tips and are used for local targeting control. The game and aggregation of the two types of magnetic fields require digital simulation to find the optimal solution based on the location of the target’s lesion.

(2) Magnetic field has obvious advantages as an external field energy source for micro-robots. First, the micro-robots made of magnetically sensitive materials have the characteristics of high driving efficiency and rapid response. Secondly, the magnetic materials are easy to obtain, and the magnetic field does not excite the parts other than the magnetically sensitive materials. In the field of biomedicine, low-frequency magnetic fields and lower-strength magnetic fields are also safer for active living organisms. This also makes the application of magnetic fields as external field driving energy for micro-robots more diverse. This paper reviews the development status of magnet equipment in recent years, and puts forward constructive suggestions for optimizing the magnetic field system.

(3) Encourage the development of new magnetic configurations to achieve specific magnetic field distribution and unique manipulation functions that traditional magnets cannot achieve. Research on magnetic nanoparticles includes driving methods such as gradient magnetic field drive and rotating magnetic field drive. The corresponding dynamic behavior of nanoparticles includes translational motion and spiral motion. If a magnetic drive system is compatible with multiple drive modes at the same time, the positioning function can be expanded. How to achieve multi-degree-of-freedom targeted control of MNP is also the key to the study of magnetically driven magnetic nanoparticles.

(4) The magnetic field generated by the electromagnet can control the form and intensity of the magnetic field by changing the current. The bipolar pulsed magnetic field is more suitable for magnetic drug focusing and targeted therapy [29]; the rotation mode of magnet motion is the most suitable for drug navigation compared with other control modes [45]; The pulse width of the magnetic field has a potential for magnetic drug targeting in the future [46]. Optimization of the electromagnet system requires not only the increase of the magnetic field strength and gradient, but also the clinical application. The heating and power consumption of electromagnetic coils should be concerned, and the overall structure of the equipment should also be simplified. The power unit should be smaller and more efficient in future design. A coil that generates a strong magnetic field will consume high current and generate additional heat, which may eventually destroy the coil wire shield and cause damage to the patient’s external tissues. Therefore, by considering the limitation of coil current, the coil design must be changed to achieve the lowest conductivity loss while producing the highest available magnetic force. It is also necessary to consider eliminating the demand for magnetically targeted high ampere power supply in MNP.

(5) At present the superconducting system modeling software is not perfect enough. The expected effect cannot be achieved through simulation test. However, compared with permanent magnet and electromagnetic body, superconducting system is easier to obtain larger magnetic field intensity and magnetic field gradient [9]. For selecting permanent magnets as the magnet device. To generate high magnetic field strength and gradient. Try to replace them with superconducting magnetic materials.

(6) For the combination design of various types of magnet systems, it is better to verify the drug targeting effect [25,36], and it can be explored in the combination design of internal and external magnet systems and the use of different magnetic source combinations.

(7) The establishment of a dynamic mathematical model of magnetic carriers needs to be able to meet the needs of complex targeting behaviors. But it can’t carry too much calculation. In order to realize the real-time target control of magnetic particles by the magnetic source device. The algorithm needs to be optimized. Regarding the magnetic field generated by the magnet device combined with the dynamic behavior of the particles.

(8) The magnetic force decreases sharply as the distance increases. Therefore, the maximum magnetic targeting force is achieved when the magnet is as close to the particles as possible. For the magnet array, the magnetic field generated by magnetizing the permanent magnet array is as close as possible to the magnetic field measured around the built-in device. To this end, the magnetization angle in each sub-block is detected, so that the collective magnetic field generated by these sub-blocks best matches the measured magnetic field. Select to minimize the sum of all measurement points, only select the data as suitable as possible. To get the least used array and the optimal solution.

(9) In addition, MTDDS can be improved by combining ultrasound, laser, and other physical forces.

5. Conclusions

MTDDS is now a research hotspot in the medical field, but there are still many difficulties to overcome in the practical application of targeted drug delivery to the clinic. The main problems in clinical practice are providing sufficient magnetic capture particles to the lesion site. This paper reviews the development status of magnet equipment in recent years, and puts forward constructive suggestions for optimizing the magnetic field system. This article analyzes four types of magnet systems: permanent magnets, electromagnets, superconducting magnets, and hybrid magnets. It mainly focuses on the advantages and disadvantages of various types of magnets and their potential for future use. Start from the mathematical model of optimizing the magnet. Aiming at the effect that the existing mathematical model can achieve, the optimization that needs to be carried out in the future is proposed. The problem that MNPs targeting is neglected under the experimental conditions of studying magnet devices is proposed. Summarize the potential development of magnet devices in the future, and put forward the research direction of potential magnet devices.

Footnotes

Acknowledgement

This work was supported by the National Natural Science Foundation of China (No. 51707104), the State Scholarship Fund of China (No. 201908420196) and in part by Research Fund for Excellent Dissertation of China Three Gorges University (2020SSPY054).

References

Liu

, Kinetic Study of Targeted Delivery of Magnetic Drugs, Shanghai Jiao Tong University, China, 2008.

Shapiro

Kulkarni

Nacev

Muro

Stepanov

P.Y.

and Weinberg

I.N.

, Open challenges in magnetic drug targeting, Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 7(3) (2014), 446–457, doi:10.1002/wnan.1311.

Cao

Han

and Li

, Enhancement of the efficiency of magnetic targeting for drug delivery: Development and evaluation of magnet system, Journal of Magnetism and Magnetic Materials 323(15) (2011), 1919–1924, doi:10.1016/j.jmmm.2010.11.058.

Bertrand

and Leroux

J.-C.

, The journey of a drug-carrier in the body: An anatomo-physiological perspective, J. Control Release 161 (2012), 152–163.

Tian

and Wu

, The influence of magnetic field on healthy human blood cells (Doctoral dissertation), 1994.

Odenbach

, Microstructure and rheology of magnetic hybrid materials, Archive of Applied Mechanics 86(1–2) (2016), 269–279, doi:10.1007/s00419-015-1092-6.

Erb

R.M.

Martin

J.J.

Soheilian

Pan

and Barber

J.R.

, Actuating soft matter with magnetic torque, Advanced Functional Materials 26(22) (2016), 3859–3880, doi:10.1002/adfm.201504699.

Skjeltorp

A.T.

Dommersnes

and Høyer

, New forceful magnetic bioseparation using GIAMAG magnet systems, MRS Advances 2(24) (2017), 1297–1301, doi:10.1557/adv.2017.113.

and Ren

, High-gradient magnetic field for magnetic nanoparticles drug delivery system, IEEE Transactions on Applied Superconductivity 28(6) (2018), 1–7, doi:10.1109/tasc.2018.2836999.

10.

Cao

Wang

Zhang

Feng

Zhang

Han

, Targeting behavior of magnetic particles under gradient magnetic fields produced by two types of permanent magnets, IEEE Transactions on Applied Superconductivity 26(4) (2016), 1–5, doi:10.1109/tasc.2016.2514716.

11.

Wittbracht

Weddemann

Eickenberg

and Hütten

, On the direct employment of dipolar particle interaction in microfluidic systems, Microfluidics and Nanofluidics 13(4) (2012), 543–554, doi:10.1007/s10404-012-0995-6.

12.

Gao

van Reenen

Hulsen

M.A.

de Jong

A.M.

Prins

M.W.J.

and den Toonder

J.M.J.

, Chaotic fluid mixing by alternating microparticle topologies to enhance biochemical reactions, Microfluidics and Nanofluidics 16(1–2) (2013), 265–274, doi:10.1007/s10404-013-1209-6.

13.

Lin

H.-C.

Y.-H.

and Chen

C.-Y.

, Structural instability of an oscillating superparamagnetic micro-bead chain, Microfluidics and Nanofluidics 17(1) (2013), 73–84, doi:10.1007/s10404-013-1286-6.

14.

Odenbach

, Microstructure and rheology of magnetic hybrid materials, Archive of Applied Mechanics 86(1–2) (2016), 269–279, doi:10.1007/s00419-015-1092-6.

15.

Sarwar

Lee

Depireux

D.A.

and Shapiro

, Magnetic injection of nanoparticles into rat inner ears at a human head working distance, IEEE Transactions on Magnetics 49(1) (2013), 440–452, doi:10.1109/tmag.2012.2221456.

16.

Kee

Lee

and Park

, Optimized Halbach array for focused magnetic drug targeting, Journal of Magnetism and Magnetic Materials 514 (2020), 167180, doi:10.1016/j.jmmm.2020.167180.

17.

Erokhin

and Berkov

, Magnetic targeted drug delivery to the human eye retina: An optimization methodology, IEEE Journal of Electromagnetics, RF and Microwaves in Medicine and Biology (2018), 1, doi:10.1109/jerm.2018.2873943.

18.

Jeong

Jang

and Chung

S.K.

, Target drug delivery technology (Carrying, releasing, penetrating) using acoustic bubbles embedded in an electromagnetically driven microrobot, in: 2018 IEEE Micro Electro Mechanical Systems (MEMS), 2018, doi:10.1109/memsys.2018.8346481.

19.

Cao

Han

Chun

Liu

and Li

, Note: Magnetic targeting for enhancement of the activation efficiency of G protein-coupled receptor with a two-pair coil system, Review of Scientific Instruments 87(1) (2016), 016103, doi:10.1063/1.4939732.

20.

Pei

Huang

and Zheng

, In vitro study of deep capture of paramagnetic particle for targeting therapeutics, Journal of Magnetism and Magnetic Materials 321(18) (2009), 2911–2915, doi:10.1016/j.jmmm.2009.04.041.

21.

Wei

and Wang

, Investigation of magnetic nanoparticle motion under a gradient magnetic field by an electromagnet, Journal of Nanomaterials 2018 (2018), 1–5, doi:10.1155/2018/6246917.

22.

Voronin

D.V.

Sindeeva

O.A.

Kurochkin

M.A.

Mayorova

Fedosov

I.V.

Semyachkina-Glushkovskaya

, In vitro and in vivo visualization and trapping of fluorescent magnetic microcapsules in a bloodstream, ACS Applied Materials & Interfaces 9(8) (2017), 6885–6893, doi:10.1021/acsami.6b15811.

23.

Hajiaghajani

Hashemi

and Abdolali

, Adaptable setups for magnetic drug targeting in human muscular arteries: Design and implementation, Journal of Magnetism and Magnetic Materials 438 (2017), 173–180, doi:10.1016/j.jmmm.2017.04.058.

24.

Zhao

and Luo

, Research on targeting oscillating magnetic field generator, in: 2008 World Automation Congress, IEEE, 2008, pp. 1–3.

25.

Xiong

Sun

Liu

and Shi

, A multifunctional energy-saving magnetic field generator, Review of Scientific Instruments 89(3) (2018), 034704, doi:10.1063/1.4990629.

26.

Durrell

J.H.

Dennis

A.R.

Jaroszynski

Ainslie

M.D.

Palmer

K.G.B.

Shi

Y.-H.

, A trapped field of 17.6 T in melt-processed, bulk Gd-Ba-Cu-O reinforced with shrink-fit steel, Superconductor Science and Technology 27(8) (2014), 082001, doi:10.1088/0953-2048/27/8/082001.

27.

Takeda

Mishima

Fujimoto

Izumi

and Nishijima

, Development of magnetically targeted drug delivery system using superconducting magnet, Journal of Magnetism and Magnetic Materials 311(1) (2007), 367–371, doi:10.1016/j.jmmm.2006.10.1195.

28.

Chen

and Yan

, Simulation and observation of magnetic mineral particles aggregating into chains in a uniform magnetic field, Minerals Engineering 79 (2015), 10–16, doi:10.1016/j.mineng.2015.05.002.

29.

Hahn

Kim

Painter

Dixon

, 45.5-tesla direct-current magnetic field generated with a high-temperature superconducting magnet, Nature 570(7762) (2019), 496–499, doi:10.1038/s41586-019-1293-1.

30.

Liu

Wang

Qin

Zhou

Wang

, World record 32.35-tesla direct-current magnetic field generated with whole superconductor magnet, Superconductor Science and Technology 33(3) (2020), doi:10.1088/1361-6668/ab714e.

31.

Takeda

Mishima

Fujimoto

Izumi

and Nishijima

, Development of magnetically targeted drug delivery system using superconducting magnet, Journal of Magnetism and Magnetic Materials 311(1) (2007), 367–371, doi:10.1016/j.jmmm.2006.10.1195.

32.

Ramadan

Samper

and Poenar

D.P.

, Microcoils for transport of magnetic beads, Applied Physics Letters 88(3) (2006), 032501, doi:10.1063/1.2149150.

33.

Smistrup

Tang

P.T.

Hansen

and Hansen

M.F.

, Microelectromagnet for magnetic manipulation in lab-on-a-chip systems, Journal of Magnetism and Magnetic Materials 300(2) (2006), 418–426, doi:10.1016/j.jmmm.2005.05.031.

34.

Assadsangabi

Mohamed Ali

M.S.

and Takahata

, Planar variable inductor controlled by ferrofluid actuation, IEEE Transactions on Magnetics 49(4) (2013), 1402–1406, doi:10.1109/tmag.2012.2228212.

35.

Basore

J.R.

Lavrik

N.V.

and Baker

L.A.

, Single-pore membranes gated by microelectromagnetic traps, Advanced Materials 22(25) (2010), 2759–2763, doi:10.1002/adma.201000566.

36.

Han

Wang

Cao

Feng

Zhang

and Li

, Numerical and experimental investigations on the manipulation of magnetic particles in a microsystem using a hybrid magnet system, IEEE Transactions on Applied Superconductivity 26(4) (2016), 1–4, doi:10.1109/tasc.2016.2514713.

37.

Sharma

Katiyar

V.K.

and Singh

, Mathematical modelling for trajectories of magnetic nanoparticles in a blood vessel under magnetic field, Journal of Magnetism and Magnetic Materials 379 (2015), 102–107, doi:10.1016/j.jmmm.2014.12.012.

38.

Alexiou

Arnold

Klein

R.J.

Parak

F.G.

Hulin

Bergemann

, Locoregional cancer treatment with magnetic drug targeting, Cancer Research 60(23) (2000), 6641–6648.

39.

Alexiou

Schmidt

Klein

Hulin

Bergemann

and Arnold

, Magnetic drug targeting: biodistribution and dependency on magnetic field strength, Journal of Magnetism and Magnetic Materials 252 (2002), 363–366, doi:10.1016/s0304-8853(02)00605-4.

40.

Barnsley

L.C.

Carugo

and Stride

, Optimized shapes of magnetic arrays for drug targeting applications, Journal of Physics D: Applied Physics 49(22) (2016), 225501, doi:10.1088/0022-3727/49/22/225501.

41.

Owen

Grove

Rademeyer

and Stride

, The influence of blood on targeted microbubbles, Journal of The Royal Society Interface 11(100) (2014), 20140622, doi:10.1098/rsif.2014.0622.

42.

Takalkar

A.M.

Klibanov

A.L.

Rychak

J.J.

Lindner

J.R.

and Ley

, Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow, Journal of Controlled Release 96(3) (2004), 473–482, doi:10.1016/j.jconrel.2004.03.002.

43.

Fernandes

Smyth

N.R.

Muskens

O.L.

Nitti

Heuer-Jungemann

Ardern-Jones

M.R.

, Interactions of skin with gold nanoparticles of different surface charge, shape, and functionality, Small 11(6) (2014), 713–721, doi:10.1002/smll.201401913.

44.

Cao

Wang

and Han

, Rotational motion and lateral migration of an elliptical magnetic particle in a microchannel under a uniform magnetic field, Microfluidics and Nanofluidics 22(1) (2018), 3.

45.

Shapiro

, Towards dynamic control of magnetic fields to focus magnetic carriers to targets deep inside the body, Journal of Magnetism and Magnetic Materials 321(10) (2009), 1594–1599, doi:10.1016/j.jmmm.2009.02.094.

46.

Xiong

Tang

Wang

Huang

Qiu

, Design and implementation of tube bulging by an attractive electromagnetic force, Journal of Materials Processing Technology 273 (2019), 116240, doi:10.1016/j.jmatprotec.2019.05.021.