CN111449830A - Application of implantable metal as accurate and efficient tumor magnetic heat treatment reagent - Google Patents
Application of implantable metal as accurate and efficient tumor magnetic heat treatment reagent Download PDFInfo
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- CN111449830A CN111449830A CN202010269764.6A CN202010269764A CN111449830A CN 111449830 A CN111449830 A CN 111449830A CN 202010269764 A CN202010269764 A CN 202010269764A CN 111449830 A CN111449830 A CN 111449830A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
- A61F2007/009—Heating or cooling appliances for medical or therapeutic treatment of the human body with a varying magnetic field acting upon the human body, e.g. an implant therein
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Abstract
The invention discloses application of implantable metal as a precise and efficient tumor magnetic heat treatment reagent, and belongs to the technical field of biomedical engineering. The implantable metal in the invention generates heat energy under the alternating magnetic field due to the eddy current heat effect, and the temperature can be changed at will by controlling the size and the shape of the implantable metal. Accurate and efficient tumor magnetic thermal treatment can be realized by experimental simulation of an effective killing range of the tumor magnetic thermal treatment device and monitoring the temperature of a tumor part in actual tumor treatment by using an infrared thermal imager. The magnesium alloy has good biocompatibility and biodegradability, and the titanium alloy has good biocompatibility and the like. Therefore, the implantable metal as the accurate and efficient tumor magnetocaloric treatment reagent for tumor magnetocaloric treatment has great potential and clinical conversion value.
Description
Technical Field
The invention relates to application of implantable metal as a precise and efficient tumor magnetic heat treatment reagent, and belongs to the technical field of biomedical engineering.
Background
Magnetocaloric therapy has received much attention since the 80's of the 20 th century as a non-invasive local therapeutic strategy. During the magnetic thermal treatment, the tumor site is usually treated by injecting a magnetic thermal agent, generally magnetic nanoparticles, which can generate heat under the action of a strong alternating magnetic field, resulting in the death of tumor cells. Compared with other types of hyperthermia stimulation methods used clinically, such as laser, radio frequency, microwave or high intensity focused ultrasound, the alternating magnetic field used in the magnetocaloric therapy is not limited by the tissue penetration depth, and does not generate additional thermal side effects at the site without the magnetocaloric agent, thereby being also applicable to the treatment of deeper and larger tumors. Despite the advantages of topical tumor therapy, magnetic hyperthermia is still less clinically useful. One of the main reasons impeding its clinical use is the magnetocaloric agents. On one hand, the more widely used magnetic nanoparticles (such as iron oxide) at present can be effectively heated only under the condition of stronger alternating magnetic field intensity; on the other hand, the safety of the traditional inorganic magnetic nanoparticles in vivo and the like also greatly limit the clinical transformation of the traditional inorganic magnetic nanoparticles.
In recent decades, various medical alloys have been widely used in implantable medical devices due to their high mechanical compatibility, excellent biocompatibility in vivo, etc., and are medical materials with good biocompatibility, especially in the orthopedic field (bone steel plates and screws, porous scaffolds for bone tissues), cardiovascular field (intravascular stents, vascular suture threads), dental implant field, etc. However, no non-magnetic implant alloy has been reported for use in magnetic hyperthermia treatment of tumors.
Disclosure of Invention
In order to solve the problems, the implantable metal is utilized to show excellent eddy thermal performance under an alternating magnetic field with low field intensity due to low resistivity, and the implantable metal is applied as a precise and efficient tumor magnetocaloric treatment reagent.
The first purpose of the invention is to provide the application of the implantable metal as a precise and efficient tumor magnetocaloric treatment reagent.
Further, the implantable metal comprises one or more of magnesium alloy, titanium alloy and aluminum alloy.
Further, the magnesium alloy comprises one or more of Mg-Al, Mg-Zn, Mg-RE, Mg-Mn, Mg-Ca, Mg-Zn, Mg-L i, Mg-Sr and Mg-Sc.
Further, the shape of the implantable metal is rod-shaped, sheet-shaped, ring-shaped or spherical.
Further, the diameter of the implantable metal is 0.1 mm-5 cm.
Further, when the implantable metal is in the shape of a rod, the length of the implantable metal is 0.3mm to 10 cm.
Further, the magnetocaloric therapy is to carry out eddy current heating on the magnesium alloy by a high-frequency induction heating device.
Further, the high-frequency induction heating equipment is used for providing an alternating magnetic field, and the intensity of the alternating magnetic field is 0.1-10 × 109A·m-1·s-1The action time is 1-120 min.
Further, the application specifically comprises the step of implanting a magnesium alloy rod with the length of 2 mm-5 cm and the diameter of 0.5 mm-2 cm into a tumor part, wherein the strength is 0.5-3.0 × 109A·m-1·s-1Treating for 10-30 min in the alternating magnetic field.
The second purpose of the invention is to provide a tumor magnetic thermal treatment reagent, wherein the tumor magnetic thermal treatment reagent comprises one or more of degradable magnesium alloy, titanium alloy, aluminum alloy and other implantable metals.
The invention utilizes the heat generated by the implantable metal under the alternating magnetic field due to the eddy current effect to increase the temperature, and can reach any temperature by controlling the size and the shape of the implantable metal and the intensity of the alternating magnetic field. The implantable metal with excellent magnetic induction heating is implanted into the tumor of an organism, and can effectively carry out tumor magneto-thermal ablation under the condition of an alternating magnetic field for a plurality of minutes.
The application method of the implantable metal as the accurate and efficient tumor magnetocaloric treatment reagent comprises the following steps:
(1) influence factors of the eddy current thermal effect of the implantable metal (the size (diameter, length and the like), the shape (rod-shaped, sheet-shaped, annular and the like) and the alternating magnetic field intensity and the like of the implantable metal) are fully researched in vitro;
(2) selecting implantable metals with proper sizes and different shapes to perform in-vitro effective killing range experiment simulation calculation;
(3) animal model pre-experiment;
(4) animal model experiments: under the optimal implantation condition, the implantable metal is implanted into the tumor, and the tumor part is exposed in an alternating magnetic field, so that the tumor is subjected to magnetic-thermal ablation;
(5) and evaluating the biocompatibility of the implantable metal and the biodegradability of the magnesium alloy.
The invention has the beneficial effects that:
1. the implantable metal adopted by the invention has very excellent biocompatibility, and the magnesium alloy can be biodegraded in-vivo and in-vitro environments, and does not need to be taken out for the second time after treatment, thereby avoiding the pain of patients caused by the second operation. Simulating the effective killing range of the implantable metal through experiments according to the shape and the size of the tumor, and selecting proper size and quantity and optimal implantation sites; because the implantable metal is uniformly and reasonably distributed and is simulated in an effective killing range, and meanwhile, the normal cells have better heat resistance relative to the tumor cells, the side effect on the surrounding normal tissue cells is greatly reduced, so that the normal functions of the body can not be basically influenced, and the accurate and efficient tumor magnetic-thermal treatment is realized.
2. The invention breaks the traditional magnetic heat treatment mode (mainly uses magnetic nano particles to carry out magnetic heat treatment). Not only widens the application of the implantable metal in the biomedical field, but also provides a new idea for accurate and efficient tumor minimally invasive treatment. Considering the wide clinical application of implantable metals, this strategy has great application prospect in clinical transformation.
Drawings
FIG. 1 is a graph comparing tumor growth curves of different groups of mice in each group using the magnesium alloy rod of example 1 as a magnetocaloric agent for the magnetocaloric ablation treatment of tumors in mice;
FIG. 2 is a sectional view of hematoxylin-eosin (H & E) in a mouse tumor of different treatment modes of the magnesium alloy rod used as a magnetocaloric reagent in the magnetic thermal ablation treatment of the mouse tumor in example 1;
FIG. 3 is a graph comparing the growth curves of different groups of tumors in each group of mice treated by magnetocaloric ablation of tumors in mice using the magnesium alloy rings as the magnetocaloric reagents according to example 2;
FIG. 4 is a graph comparing the growth curves of different groups of tumors in each group of mice treated by magnetocaloric ablation of tumors in mice using the titanium alloy sheet of example 3 as a magnetocaloric reagent;
FIG. 5 is a graph comparing the growth curves of different groups of rabbits in each group treated by magnetocaloric ablation of rabbit tumors using magnesium alloy rods as magnetocaloric reagents according to example 4;
fig. 6 is a comparison graph of rabbit survival curves corresponding to different groups of rabbits in the example 4 magnesium alloy rod as a magnetocaloric reagent for rabbit tumor magnetocaloric ablation treatment.
Detailed Description
The present invention is further described below in conjunction with the following figures and specific examples so that those skilled in the art may better understand the present invention and practice it, but the examples are not intended to limit the present invention.
Example 1: magnesium alloy rod (MgA) as magnetic heating reagent for mouse tumor magnetic heating ablation
The tumor volume of the mouse to be treated in the subcutaneous breast cancer model is 100mm3On the left and right sides, magnesium alloy rods (D is 0.7mm, L is 4.0mm) which are subjected to the experimental simulation calculation of the effective tumor killing range are implanted into the tumor of the mouse at the optimal implantation position, the tumor part of the mouse is exposed in an alternating magnetic field for 10 minutes after the mouse is anesthetized, and the tumor volume is monitored every two days after the treatment of different means is finished for 14 days.
After the treatment is finished, monitoring the tumor volume of the mice by using a vernier caliper, as shown in fig. 1, when the magnesium alloy rod magnetic heat therapeutic agent is used for mouse tumor magnetic heat ablation treatment, comparing the tumor growth curve of tumor-bearing mice, randomly dividing the mice into 4 groups (5 mice in each group), wherein the first group is a Control group (Control); the second group is a material group (MgA); the third group is an alternating magnetic field group (AMF, H)appl×fappl＝2.0×109A·m-1·s -110 min); the fourth group is a material combined alternating magnetic field group (MgA + AMF, H)appl×fappl＝2.0×109A·m-1·s -110 min). Implantation of only magnesium alloy or exposure of only mouse tumors to alternating magnetic fields did not affect normal growth of tumors relative to the control group, whereas implantation of magnesium alloy at the tumor site and exposure to alternating magnetic fields resulted in complete magnetothermal ablation of mouse tumors with no recurrence in the treated group within 14 days.
After the mice were treated for 12H, their tumors were subjected to hematoxylin-eosin (H)&E) Dyeing, as shown in fig. 2, the evaluation chart of the magnesium alloy rod magnetic heat therapeutic agent for mouse tumor magnetic heat ablation treatment on tumor treatment slices of tumor-bearing mice is shown, the mice are randomly divided into 4 groups (5 mice in each group), and the first group is a Control group (Control); the second group is a material group (MgA); the third group is an alternating magnetic field group (AMF, H)appl×fappl＝2.0×109A·m-1·s -110 min); the fourth group is a material combined alternating magnetic field group (MgA + AMF, H)appl×fappl＝2.0×109A·m-1·s-110 min). Compared with the control group, the state of tumor cells is not influenced by only implanting magnesium alloy or only exposing the mouse tumor to an alternating magnetic field, and the cell nucleus of the mouse tumor in the treatment group is obviously solidified and shrunk, which indicates that all the tumor cells are apoptotic.
Example 2: magnesium alloy ring (MgR) as magnetic heat reagent for mouse tumor magnetic heat ablation
The tumor volume of the mouse to be treated in the subcutaneous breast cancer model is 100mm3And when the treatment is finished, monitoring the tumor volume once every two days for 14 days.
After the treatment is finished, monitoring the tumor volume of the mice by using a vernier caliper, as shown in fig. 3, when the magnesium alloy ring magnetic-thermal therapeutic agent is used for mouse tumor magnetic-thermal ablation treatment, comparing the tumor growth curve of tumor-bearing mice, randomly dividing the mice into 2 groups (5 mice in each group), wherein the first group is a Control group (Control); the second group is a material combined alternating magnetic field group (MgR + AMF, H)appl×fappl＝2.0×109A·m-1·s-110 min). When the magnesium loop was implanted at the tumor site and exposed to an alternating magnetic field, the mouse tumor was completely ablated by magnetothermal ablation and no recurrence occurred in the treated group within 14 days, relative to the control group.
Example 3: titanium alloy sheet (TiS) as magnetocaloric reagent for mouse tumor magnetocaloric ablation
The tumor volume of the mouse to be treated in the subcutaneous breast cancer model is 100mm3And when the treatment is finished, monitoring the tumor volume once every two days for 14 days.
After the treatment is finished, monitoring the tumor volume of the mice by using a vernier caliper, as shown in fig. 4, when the titanium alloy sheet magnetic thermal therapeutic agent is used for mouse tumor magnetic thermal ablation treatment, comparing the tumor growth curve of tumor-bearing mice, randomly dividing the mice into 2 groups (5 mice in each group), wherein the first group is a Control group (Control); the second group is a material combined alternating magnetic field group (TiS + AMF, H)appl×fappl＝1.5×109A·m-1·s-110 min). When the titanium alloy sheet was implanted into the tumor site and exposed to an alternating magnetic field, the tumor was completely ablated by magnetocaloric heat in the mice, and no recurrence occurred in the treatment group within 14 days, relative to the control group.
Example 4: magnesium alloy rod used as magnetocaloric reagent for rabbit tumor magnetocaloric ablation
To demonstrate the unlimited advantages of magnetic hyperthermia in tissue penetration, we further used this strategy to treat larger size subcutaneous hepatoma tumors grown in rabbits. In the experiment, rabbits carrying liver cancer tumors are randomly divided into two groups (3 rabbits in each group), wherein one group is implanted with the magnesium alloy rod, and the other group is not implanted with the magnesium alloy rod as a control, because the tumor volume before treatment is large (800 mm to 800 mm)3) The experimental method adopts 3 MgA rods (D is 1.0mm, L is 8.0mm) with larger diameter and longer length to carry out rabbit experiment, the magnesium alloy rods simulated in vitro effective range are implanted into the tumor of New Zealand white rabbit at the optimal implantation position, after the tumor is anesthetized, the tumor part is exposed in an alternating magnetic fieldMonitoring the tumor volume every four days after different treatment methods are finished for 15 minutes under the condition, and when the volume exceeds 10000mm3Rabbits were considered dead.
After the treatment is finished, monitoring the tumor volume of the rabbits by using a vernier caliper, as shown in fig. 5, when the magnesium alloy magnetocaloric therapeutic agent is used for the rabbit tumor magnetocaloric ablation treatment, comparing the tumor growth curve of the rabbits with tumor, wherein the rabbits are randomly divided into 2 groups (3 rabbits in each group), and the first group is a Control group (Control); the second group is a material combined alternating magnetic field group (MgA + AMF, H)appl×fappl＝1.5×109A·m-1·s-110 min). Compared with a control group, after the magnesium alloy is implanted and exposed to an alternating magnetic field, the rabbit tumors are completely thermally ablated after 4 days, and the magnesium alloy shows excellent tumor inhibiting effect in the magnetothermal treatment of larger tumors.
Comparing the survival curves of rabbits, as shown in fig. 6, the magnesium alloy rod used as a magnetocaloric reagent for the survival curve of rabbits with tumor in the magnetocaloric ablation treatment is randomly divided into 2 groups (3 rabbits in each group), and the first group is a Control group (Control); the second group is a material combined alternating magnetic field group (MgA + AMF, H)appl×fappl＝1.5×109A·m-1·s-110 min). Compared with the control group, after the magnesium alloy is implanted and exposed to the alternating magnetic field, the tumor of the rabbit is completely thermally ablated, and two rabbits of the three treated rabbits have no tumor recurrence and completely eliminate the tumor, and the two rabbits survive for more than 90 days after the treatment.
Example 5: evaluation of biocompatibility and magnesium alloy degradation performance of implantable metal as magnetocaloric reagent
Magnesium alloy rods were subcutaneously implanted into healthy female mice for various periods of time (3 days, 10 days, 20 days, 40 days, 90 days), respectively, with mice that were not implanted with magnesium alloy as a control group. After the local implantation, the mice were first observed for abnormalities such as adverse inflammatory reactions. The mice are randomly killed in 3 days, 10 days, 20 days, 40 days and 90 days after implantation, the magnesium alloy rod in the body is taken out, a large number of corrosion cracks appear on the surface of the magnesium alloy rod along with the increase of time, the degradation of the magnesium alloy rod in the body is gradually realized, and the weight loss of the magnesium alloy rod is about 20% in 3 months. XRD analysis shows that the degradation products are mainly magnesium hydroxide and calcium phosphate, which shows that the magnesium alloy rod shows good biodegradability. After the implantation, the mice were randomly sacrificed at 3 days, 10 days, 20 days, 40 days, and 90 days, and brain tissue, liver tissue, spleen tissue, heart tissue, lung tissue, kidney tissue, and subcutaneous tissue were dissected and removed and cut into two halves. Half of the organs were fixed in 4% formalin, paraffin was embedded, and further H & E staining was performed according to a conventional procedure to assess the safety of the magnesium alloy after implantation. Dissolving the other half part of each organ and tissue in aqua regia, and measuring the content of magnesium element in each organ. Blood samples are collected simultaneously for blood biochemical and hematological detection. By measuring the content of magnesium in different organs of a mouse, compared with the mouse without the magnesium alloy rod, the content has no significant difference, and the ion release generated by the degradation of the magnesium alloy can not interfere with the physiological behavior of the normal organ. Meanwhile, histological examination of major organs further proves that the magnesium alloy rod has no obvious side effect on mice after being implanted. Compared with a control group, the blood biochemical index and the hematology detection data of the magnesium alloy bar implanted into the mouse are normal. The above results all demonstrate the excellent biosafety and biodegradability of magnesium alloys.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.
Claims (10)
1. An implantable metal is applied as a precise and efficient magnetic-thermal treatment reagent for tumors.
2. The use according to claim 1, wherein the implantable metal comprises one or more of a magnesium alloy, a titanium alloy, an aluminum alloy, a cobalt-chromium alloy, a medical grade stainless steel.
3. Use according to claim 2, wherein the magnesium alloy comprises one or more of Mg-Al, Mg-Zn, Mg-RE, Mg-Mn, Mg-Ca, Mg-Zn, Mg-L i, Mg-Sr, Mg-Sc.
4. The use according to claim 1, wherein the implantable metal is in the shape of a rod, a sheet, a ring or a sphere.
5. The use according to claim 4, wherein the implantable metal has a diameter of 0.1mm to 5 cm.
6. The use according to claim 4, wherein the implantable metal has a length of 0.3mm to 10cm when the implantable metal is in the form of a rod.
7. Use according to claim 1, characterized in that the magnetocaloric treatment consists in heating the implantable metal by eddy currents with a high-frequency induction heating device.
8. The use according to claim 7, wherein the high-frequency induction heating apparatus is used for providing an alternating magnetic field with an alternating magnetic field strength of 0.1-10 × 109A·m-1·s-1The action time is 1-120 min.
9. The application of claim 1, wherein the application specifically comprises implanting a magnesium alloy rod with a length of 2 mm-5 cm and a diameter of 0.5 mm-2 cm at a tumor site with a strength of 0.5-3.0 × 109A·m-1·s-1Treating for 10-30 min in the alternating magnetic field.
10. The tumor magnetic thermal treatment reagent is characterized by comprising implantable metal.
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| CN202010269764.6A CN111449830A (en) | 2020-04-08 | 2020-04-08 | Application of implantable metal as accurate and efficient tumor magnetic heat treatment reagent |
| PCT/CN2020/103303 WO2021203577A1 (en) | 2020-04-08 | 2020-07-21 | Use of implantable metal as accurate and efficient magnetocaloric tumor treatment reagent |
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| US20050234532A1 (en) * | 2002-01-18 | 2005-10-20 | Eggers Philip E | System method and apparatus for localized heating of tissue |
| CN106806014A (en) * | 2015-11-30 | 2017-06-09 | 财团法人金属工业研究发展中心 | Implanted magnetic seed |
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| CN101477867A (en) * | 2008-10-07 | 2009-07-08 | 同济大学 | Magnetic material having high magnetic heating performance and preparation thereof |
| CN101601607A (en) * | 2009-05-22 | 2009-12-16 | 东南大学 | A kind of tumor cell is carried out magnetic induction heating, imaging and thermometric method simultaneously |
| US9681979B2 (en) * | 2013-12-01 | 2017-06-20 | Massachusetts Institute Of Technology | Independent magnetically-multiplexed heating of portions of a target |
| CN108525128B (en) * | 2018-03-26 | 2021-02-12 | 清华大学 | Application of liquid metal as tumor magnetic thermal therapy medium |
| CN110468303B (en) * | 2019-07-30 | 2020-05-22 | 华南理工大学 | Medical magnetic heat treatment copper-nickel alloy and preparation method thereof |
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- 2020-07-21 WO PCT/CN2020/103303 patent/WO2021203577A1/en active Application Filing
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| US20050234532A1 (en) * | 2002-01-18 | 2005-10-20 | Eggers Philip E | System method and apparatus for localized heating of tissue |
| CN106806014A (en) * | 2015-11-30 | 2017-06-09 | 财团法人金属工业研究发展中心 | Implanted magnetic seed |
| CN109431657A (en) * | 2018-10-25 | 2019-03-08 | 京东方科技集团股份有限公司 | Device, biodegrading process, the artificial bone of external control artificial bone degradation speed |
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| DONGHEE SON: "Bioresorbable Electronic Stent Integrated with Therapeutic Nanoparticles for Endovascular Diseases", 《ACS NANO》 * |
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