CN111449830A - Application of Implantable Metals as Precise and Efficient Magnetothermal Therapy Reagents for Tumors - Google Patents
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Abstract
本发明公开了一种可植入金属作为肿瘤精准高效磁热治疗试剂的应用,属于生物医学工程技术领域。本发明中的可植入金属在交变磁场下由于涡流热效应而产生热能,通过控制其尺寸及其形状可以使温度任意变化。通过对其有效杀伤范围的实验模拟及其使用红外热成像仪监测实际肿瘤治疗中肿瘤部位的温度可以实现精准高效的肿瘤磁热治疗。其中镁合金具有良好的生物相容性和生物可降解性,钛合金具有良好的生物相容性等。因此,将可植入金属作为肿瘤精准高效磁热治疗试剂用于肿瘤磁热治疗展现了巨大的潜力和临床转换价值。
The invention discloses the application of an implantable metal as a precise and high-efficiency magnetothermal therapy reagent for tumors, and belongs to the technical field of biomedical engineering. The implantable metal in the present invention generates thermal energy under the alternating magnetic field due to the eddy current thermal effect, and the temperature can be changed arbitrarily by controlling its size and shape. Through the experimental simulation of its effective killing range and the use of infrared thermal imagers to monitor the temperature of the tumor site in actual tumor treatment, accurate and efficient tumor magnetothermal therapy can be achieved. Among them, magnesium alloys have good biocompatibility and biodegradability, and titanium alloys have good biocompatibility. Therefore, the use of implantable metals as precise and efficient magnetothermal therapy reagents for tumor magnetocaloric therapy shows great potential and clinical translation value.
Description
技术领域technical field
本发明涉及一种可植入金属作为肿瘤精准高效磁热治疗试剂的应用,属于生物医学工程技术领域。The invention relates to the application of an implantable metal as a precise and high-efficiency magnetothermal therapy reagent for tumors, and belongs to the technical field of biomedical engineering.
背景技术Background technique
磁热治疗作为一种非侵入性局部治疗策略,自20世纪80年代以来备受关注。在磁热治疗过程中,肿瘤部位通常通过注射磁热试剂,一般是磁性纳米颗粒,磁热试剂在较强的交变磁场作用下可产生热量,导致肿瘤细胞死亡。相比其他类型的临床使用的热疗刺激方式,例如,激光、射频、微波或高强度聚焦超声,磁热治疗中使用的交变磁场不受组织穿透深度的限制,而且在没有磁热试剂的部位不会产生额外的热副作用,从而在治疗深层较大的肿瘤中也同样适用。尽管磁热治疗具有局部肿瘤治疗的优势,但其临床应用仍然较少。阻碍其临床应用的主要原因之一是磁热试剂。一方面目前使用的较为广泛的磁性纳米颗粒(如氧化铁)需要在较强的交变磁场强度下才可以有效加热;另外一方面,传统的无机磁性纳米颗粒在体内的安全性等也大大限制了其临床转化。Magnetothermal therapy as a non-invasive topical treatment strategy has received much attention since the 1980s. In the process of magnetocaloric therapy, a magnetocaloric reagent, usually magnetic nanoparticles, is usually injected into the tumor site. The magnetocaloric reagent can generate heat under the action of a strong alternating magnetic field, resulting in the death of tumor cells. In contrast to other types of clinically used hyperthermic stimulation modalities, such as laser, radiofrequency, microwave or high-intensity focused ultrasound, the alternating magnetic field used in magnetocaloric therapy is not limited by the depth of tissue penetration and can be used without magnetocaloric agents. The site does not produce additional thermal side effects, so it is also suitable for the treatment of deeper and larger tumors. Although magnetothermal therapy has the advantages of local tumor treatment, its clinical application is still rare. One of the main reasons hindering its clinical application is magnetocaloric reagents. On the one hand, the widely used magnetic nanoparticles (such as iron oxide) need to be heated effectively under strong alternating magnetic field strength; on the other hand, the safety of traditional inorganic magnetic nanoparticles in vivo is also greatly limited. its clinical translation.
近几十年来,各种医用合金由于其高机械兼容性,体内优异的生物相容性等性能,已被广泛应用于植入式医疗设备,特别是在骨科领域(骨钢板和螺钉,骨组织的多孔支架)、心血管领域(血管内支架,血管缝合丝线)以及牙种植体等领域,是一类具有良好生物相容性的医用材料。但是目前还没有报道能够将非磁性植入合金应用于肿瘤磁热治疗中。In recent decades, various medical alloys have been widely used in implantable medical devices due to their high mechanical compatibility, excellent in vivo biocompatibility and other properties, especially in the field of orthopedics (bone plates and screws, bone tissue It is a kind of medical material with good biocompatibility. However, there is no report on the application of non-magnetic implantable alloys in tumor magnetocaloric therapy.
发明内容SUMMARY OF THE INVENTION
为解决上述问题,本发明利用可植入金属由于其较低的电阻率,在低场强的交变磁场下展现出非常优异的涡流热性能,提供一种可植入金属作为肿瘤精准高效磁热治疗试剂的应用。In order to solve the above problems, the present invention utilizes the implantable metal to exhibit very excellent eddy current thermal performance under the alternating magnetic field of low field strength due to its low resistivity, and provides an implantable metal as a precise and efficient magnetic field for tumors. Application of thermal therapeutic agents.
本发明的第一个目的是提供一种可植入金属作为肿瘤精准高效磁热治疗试剂的应用。The first objective of the present invention is to provide the application of an implantable metal as a precise and efficient magnetothermal therapy agent for tumors.
进一步地,所述的可植入金属包括镁合金、钛合金、铝合金中的一种或多种。Further, the implantable metal includes one or more of magnesium alloy, titanium alloy, and aluminum alloy.
进一步地,所述的镁合金包括Mg-Al、Mg-Zn、Mg-RE、Mg-Mn、Mg-Ca、Mg-Zn、Mg-Li、Mg-Sr、Mg-Sc中的一种或多种。Further, the magnesium alloy includes one or more of Mg-Al, Mg-Zn, Mg-RE, Mg-Mn, Mg-Ca, Mg-Zn, Mg-Li, Mg-Sr, Mg-Sc kind.
进一步地,所述的可植入金属的形状为棒状、片状、环状或球状。Further, the shape of the implantable metal is rod-like, sheet-like, annular or spherical.
进一步地,所述的可植入金属的直径为0.1mm~5cm。Further, the diameter of the implantable metal is 0.1 mm˜5 cm.
进一步地,所述的可植入金属的形状为棒状时,可植入金属的长度为0.3mm~10cm。Further, when the shape of the implantable metal is rod-like, the length of the implantable metal is 0.3 mm˜10 cm.
进一步地,所述的磁热治疗是通过高频感应加热设备对镁合金进行涡流加热。Further, the magnetothermal treatment is to perform eddy current heating on the magnesium alloy through a high-frequency induction heating device.
进一步地,所述高频感应加热设备用于提供交变磁场,其交变磁场强度为0.1~10×109A·m-1·s-1,作用时间为1~120min。Further, the high-frequency induction heating device is used to provide an alternating magnetic field, the intensity of the alternating magnetic field is 0.1-10×10 9 A·m -1 ·s -1 , and the action time is 1-120 min.
进一步地,所述的应用具体包括将长度为2mm~5cm,直径为0.5mm~2cm的镁合金棒植入肿瘤部位,在强度为0.5~3.0×109A·m-1·s-1的交变磁场中处理10~30min。Further, the application specifically includes implanting a magnesium alloy rod with a length of 2 mm to 5 cm and a diameter of 0.5 mm to 2 cm into the tumor site. Treat in alternating magnetic field for 10-30min.
本发明的第二个目的是提供一种肿瘤磁热治疗试剂,所述的肿瘤磁热治疗试剂包括可降解镁合金、钛合金、铝合金等可植入金属中的一种或多种。The second object of the present invention is to provide a tumor magnetocaloric therapy agent, which includes one or more of degradable magnesium alloys, titanium alloys, aluminum alloys and other implantable metals.
本发明利用可植入金属在交变磁场下由于涡流效应产热升温,并且可以通过控制可植入金属的尺寸、形状以及交变磁场强度从而达到任意温度。将这种具有优异磁感应加热的可植入金属植入到生物体的肿瘤内部,在交变磁场条件下作用数分钟可以有效的进行肿瘤磁热消融。The invention utilizes the implantable metal to generate heat due to the eddy current effect under the alternating magnetic field, and can achieve any temperature by controlling the size, shape and the strength of the alternating magnetic field of the implantable metal. The implantable metal with excellent magnetic induction heating can be implanted into the tumor of the living body, and it can effectively perform magnetic thermal ablation of the tumor under the condition of alternating magnetic field for several minutes.
本发明中可植入金属作为肿瘤精准高效磁热治疗试剂的应用中的使用方法,包括如下步骤:In the present invention, an implantable metal is used as a precise and high-efficiency magnetothermal therapy reagent for tumors, and the use method includes the following steps:
(1)体外充分探究可植入金属涡流热效应的影响因素(可植入金属的尺寸(直径、长度等)、形状(棒状、片状、环状等)以及交变磁场强度等);(1) Fully explore the influencing factors of the eddy current thermal effect of the implantable metal in vitro (the size (diameter, length, etc.), shape (rod, sheet, ring, etc.) of the implantable metal, and the strength of the alternating magnetic field, etc.);
(2)选取合适尺寸的不同形状的可植入金属进行体外有效杀伤范围实验模拟计算;(2) Selecting implantable metals of different shapes and suitable sizes to carry out the experimental simulation calculation of the effective killing range in vitro;
(3)动物模型预实验;(3) Animal model pre-experiment;
(4)动物模型实验:在最佳植入条件下,将可植入金属植入到肿瘤内部,将肿瘤部位暴露于交变磁场中,从而实现肿瘤的磁热消融;(4) Animal model experiment: Under optimal implantation conditions, implantable metal is implanted into the tumor, and the tumor site is exposed to an alternating magnetic field, so as to realize the magnetothermal ablation of the tumor;
(5)可植入金属生物相容性及镁合金生物降解性评价。(5) Evaluation of implantable metal biocompatibility and magnesium alloy biodegradability.
本发明的有益效果:Beneficial effects of the present invention:
1、本发明所采用的可植入金属具有非常优异的生物相容性,且其中镁合金在体内外环境中均可生物降解,治疗后不需要二次取出,避免了二次手术给病人带来的痛苦。根据肿瘤的形状和大小,通过实验模拟可植入金属的有效杀伤范围,选择合适的尺寸和数量及其最佳植入位点;由于可植入金属分布均匀合理且进行了有效杀伤范围的模拟,同时正常细胞相对于肿瘤细胞有更好的耐热性,从而大大降低了对周围正常组织细胞的副作用,以至于基本上不会对机体的正常功能产生影响,从而实现精准高效肿瘤磁热治疗。1. The implantable metal used in the present invention has very excellent biocompatibility, and the magnesium alloy can be biodegraded in the environment inside and outside the body, and it does not need to be taken out twice after treatment, which avoids the need for secondary surgery to bring the patient. pain to come. According to the shape and size of the tumor, the effective killing range of the implantable metal was simulated experimentally, and the appropriate size and quantity and its optimal implantation site were selected; because the distribution of the implantable metal was uniform and reasonable, and the effective killing range was simulated At the same time, normal cells have better heat resistance than tumor cells, which greatly reduces the side effects on surrounding normal tissue cells, so that it basically does not affect the normal function of the body, so as to achieve precise and efficient tumor magnetothermal therapy. .
2、本发明打破了传统的磁热治疗方式(主要使用磁性纳米颗粒来进行磁热治疗)。不仅拓宽了可植入金属在生物医学领域的应用,而且为精确高效的肿瘤微创治疗提供了新的思路。考虑到可植入金属在临床的广泛应用,这种策略在临床转化中有很大的应用前景。2. The present invention breaks the traditional way of magnetothermal therapy (mainly using magnetic nanoparticles for magnetothermal therapy). It not only broadens the application of implantable metals in the field of biomedicine, but also provides new ideas for precise and efficient minimally invasive tumor treatment. Considering the wide range of clinical applications of implantable metals, this strategy holds great promise for clinical translation.
附图说明Description of drawings
图1是实施例1镁合金棒作为磁热试剂用于小鼠肿瘤磁热消融治疗每组小鼠不同组肿瘤生长曲线对比图;Fig. 1 is a comparison diagram of tumor growth curves of different groups of mice in each group of mice in the magnetothermal ablation therapy of a magnesium alloy rod in Example 1 as a magnetocaloric reagent;
图2是实施例1镁合金棒作为磁热试剂用于小鼠肿瘤磁热消融治疗不同治疗处理方式的小鼠肿瘤苏木精-伊红(H&E)切片图;Fig. 2 is the hematoxylin-eosin (H&E) slice diagram of the mouse tumor of Example 1 where magnesium alloy rods are used as a magnetocaloric reagent for the magnetocaloric ablation of mouse tumors with different treatment methods;
图3是实施例2镁合金环作为磁热试剂用于小鼠肿瘤磁热消融治疗每组小鼠不同组肿瘤生长曲线对比图;Fig. 3 is a comparison diagram of tumor growth curves in different groups of mice in each group of mice in the magnetothermal ablation treatment of each group of mice using magnesium alloy rings as a magnetocaloric reagent in Example 2;
图4是实施例3钛合金片作为磁热试剂用于小鼠肿瘤磁热消融治疗每组小鼠不同组肿瘤生长曲线对比图;Fig. 4 is the comparison diagram of the tumor growth curves of different groups of mice in each group of mice in the magnetothermal ablation therapy of the titanium alloy sheet of Example 3 as a magnetocaloric reagent;
图5是实施例4镁合金棒作为磁热试剂用于兔子肿瘤磁热消融治疗每组兔子不同组肿瘤生长曲线对比图;Fig. 5 is the comparison chart of the tumor growth curves of different groups of rabbits in each group of rabbits in magnetothermal ablation treatment of each group of rabbits by using magnesium alloy rods as magneto-caloric reagents in Example 4;
图6是实施例4镁合金棒作为磁热试剂用于兔子肿瘤磁热消融治疗每组兔子不同组对应的兔子生存曲线对比图。Figure 6 is a comparison diagram of the survival curves of rabbits corresponding to different groups of rabbits in each group of rabbits in the magnetothermal ablation treatment of rabbit tumors using magnesium alloy rods as magnetocaloric reagents in Example 4.
具体实施方式Detailed ways
下面结合附图和具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.
实施例1:镁合金棒(MgA)作为磁热试剂用于小鼠肿瘤磁热消融Example 1: Magnesium alloy rod (MgA) as a magnetocaloric reagent for magnetocaloric ablation of tumor in mice
待皮下乳腺癌模型的小鼠肿瘤体积长到100mm3左右时,将经过肿瘤有效杀伤范围实验模拟计算的镁合金棒(D=0.7mm,L=4.0mm)以最优的植入位置植入到小鼠肿瘤内部,将小鼠麻醉后,使其肿瘤部位暴露于交变磁场中10分钟,不同手段治疗结束后,每两天监测一次肿瘤体积,共监测14天。When the tumor volume of the mice in the subcutaneous breast cancer model grows to about 100mm 3 , the magnesium alloy rod (D=0.7mm, L=4.0mm), which has been simulated and calculated by the effective tumor killing range, is implanted at the optimal implantation position. Inside the tumor of the mouse, after the mice were anesthetized, the tumor site was exposed to an alternating magnetic field for 10 minutes. After the treatment with different methods, the tumor volume was monitored every two days for a total of 14 days.
治疗结束后,用游标卡尺监测小鼠的肿瘤体积,如图1所示,镁合金棒磁热治疗剂用于小鼠肿瘤磁热消融治疗对荷瘤小鼠的肿瘤生长曲线对比图,小鼠随机分成4组(每组5只),第一组为对照组(Control);第二组为材料组(MgA);第三组为交变磁场组(AMF,Happl×fappl=2.0×109A·m-1·s-1,10min);第四组为材料联合交变磁场组(MgA+AMF,Happl×fappl=2.0×109A·m-1·s-1,10min)。相对于对照组,只植入镁合金或者仅将小鼠肿瘤暴露于交变磁场中不会影响肿瘤的正常生长,而将镁合金植入肿瘤部位并将其暴露于交变磁场下,小鼠肿瘤完全被磁热消融,且14天内治疗组均没有复发。After the treatment, the tumor volume of the mice was monitored with a vernier caliper. As shown in Figure 1, the magnesium alloy rod magnetocaloric therapeutic agent was used to compare the tumor growth curve of the tumor-bearing mice with the magnesium alloy rod magnetocaloric ablation therapy. The mice were randomly selected. Divided into 4 groups (5 in each group), the first group is the control group (Control); the second group is the material group (MgA); the third group is the alternating magnetic field group (AMF, H appl × f appl = 2.0 × 10 9 A·m -1 ·s -1 , 10min); the fourth group is the material combined alternating magnetic field group (MgA+AMF, H appl ×f appl =2.0×10 9 A·m -1 ·s -1 , 10min ). Relative to the control group, implantation of magnesium alloys alone or exposure of mouse tumors to alternating magnetic fields alone did not affect normal tumor growth, whereas implantation of magnesium alloys at tumor sites and exposure to alternating magnetic fields did not affect tumor growth in mice. Tumors were completely ablated by magnetothermal, and none of the treatment groups recurred within 14 days.
在小鼠治疗12h后,对其肿瘤进行苏木精-伊红(H&E)染色,如图2所示,镁合金棒磁热治疗剂用于小鼠肿瘤磁热消融治疗对荷瘤小鼠的肿瘤治疗切片评价图,小鼠随机分成4组(每组5只),第一组为对照组(Control);第二组为材料组(MgA);第三组为交变磁场组(AMF,Happl×fappl=2.0×109A·m-1·s-1,10min);第四组为材料联合交变磁场组(MgA+AMF,Happl×fappl=2.0×109A·m-1·s-1,10min)。相对于对照组,只植入镁合金或者仅将小鼠肿瘤暴露于交变磁场中不会影响肿瘤细胞的状态,而治疗组的小鼠肿瘤细胞核固缩非常明显,表明肿瘤细胞全部凋亡。After the mice were treated for 12 hours, their tumors were stained with hematoxylin-eosin (H&E), as shown in Figure 2. Magnesium alloy rod magnetocaloric therapeutic agent was used for tumor magnetocaloric ablation in mice on tumor-bearing mice. Tumor treatment slice evaluation chart, mice were randomly divided into 4 groups (5 mice in each group), the first group was the control group (Control); the second group was the material group (MgA); the third group was the alternating magnetic field group (AMF, H appl ×f appl =2.0×10 9 A·m -1 ·s -1 , 10min); the fourth group is the material combined alternating magnetic field group (MgA+AMF, H appl ×f appl =2.0×10 9 A· m -1 ·s -1 , 10 min). Compared with the control group, only implanting magnesium alloys or exposing mouse tumors to alternating magnetic fields did not affect the state of tumor cells, while the tumor cells in the treatment group had very obvious pyknosis, indicating that all tumor cells were apoptotic.
实施例2:镁合金环(MgR)作为磁热试剂用于小鼠肿瘤磁热消融Example 2: Magnesium alloy ring (MgR) as a magnetocaloric reagent for magnetocaloric ablation of tumor in mice
待皮下乳腺癌模型的小鼠肿瘤体积长到100mm3左右时,将经过肿瘤有效杀伤范围实验模拟计算的镁合金环植入到小鼠肿瘤内部,将小鼠麻醉后,使其肿瘤部位暴露于交变磁场中10分钟,治疗结束后,每两天监测一次肿瘤体积,共监测14天。When the tumor volume of the mice in the subcutaneous breast cancer model grew to about 100 mm 3 , the magnesium alloy ring calculated by the experimental simulation of the effective tumor killing range was implanted into the tumor of the mouse. After the mice were anesthetized, the tumor site was exposed to In the alternating magnetic field for 10 minutes, after the end of treatment, the tumor volume was monitored every two days for a total of 14 days.
治疗结束后,用游标卡尺监测小鼠的肿瘤体积,如图3所示,镁合金环磁热治疗剂用于小鼠肿瘤磁热消融治疗对荷瘤小鼠的肿瘤生长曲线对比图,小鼠随机分成2组(每组5只),第一组为对照组(Control);第二组为材料联合交变磁场组(MgR+AMF,Happl×fappl=2.0×109A·m-1·s-1,10min)。相对于对照组,将镁合环植入肿瘤部位并将其暴露于交变磁场下,小鼠肿瘤完全被磁热消融,且14天内治疗组均没有复发。After the treatment, the tumor volume of the mice was monitored with a vernier caliper. As shown in Figure 3, the magnesium alloy ring magnetocaloric therapeutic agent was used to compare the tumor growth curve of the tumor-bearing mice with the magnesium alloy ring magnetocaloric ablation therapy. The mice were randomly selected. Divided into 2 groups (5 in each group), the first group is the control group (Control); the second group is the material combined alternating magnetic field group (MgR+AMF, H appl ×f appl =2.0×10 9 A·m -1 · s -1 , 10 min). Compared with the control group, the tumor was completely ablated by magnetothermal ablation in mice with magnesium rings implanted at the tumor site and exposed to an alternating magnetic field, and there was no recurrence in the treatment group within 14 days.
实施例3:钛合金片(TiS)作为磁热试剂用于小鼠肿瘤磁热消融Example 3: Titanium alloy sheet (TiS) as a magnetocaloric reagent for magnetocaloric ablation of mouse tumors
待皮下乳腺癌模型的小鼠肿瘤体积长到100mm3左右时,将经过肿瘤有效杀伤范围实验模拟计算的钛合金片植入到小鼠肿瘤内部,将小鼠麻醉后,使其肿瘤部位暴露于交变磁场中10分钟,治疗结束后,每两天监测一次肿瘤体积,共监测14天。When the tumor volume of the subcutaneous breast cancer model mice grows to about 100mm 3 , the titanium alloy sheet calculated by the experimental simulation of the effective killing range of the tumor is implanted into the mouse tumor, and the mouse is anesthetized, and the tumor site is exposed to In the alternating magnetic field for 10 minutes, after the end of treatment, the tumor volume was monitored every two days for a total of 14 days.
治疗结束后,用游标卡尺监测小鼠的肿瘤体积,如图4所示,钛合金片磁热治疗剂用于小鼠肿瘤磁热消融治疗对荷瘤小鼠的肿瘤生长曲线对比图,小鼠随机分成2组(每组5只),第一组为对照组(Control);第二组为材料联合交变磁场组(TiS+AMF,Happl×fappl=1.5×109A·m-1·s-1,10min)。相对于对照组,将钛合金片植入肿瘤部位并将其暴露于交变磁场下,小鼠肿瘤完全被磁热消融,且14天内治疗组均没有复发。After the treatment, the tumor volume of the mice was monitored with a vernier caliper. As shown in Figure 4, the titanium alloy sheet magnetocaloric therapeutic agent was used for the comparison of tumor growth curves of tumor-bearing mice for magnetothermal ablation therapy of tumors in mice. The mice were randomly selected. Divided into 2 groups (5 in each group), the first group was the control group (Control); the second group was the material combined with alternating magnetic field group (TiS+AMF, H appl ×f appl =1.5×10 9 A·m -1 · s -1 , 10 min). Compared with the control group, when the titanium alloy sheet was implanted into the tumor site and exposed to an alternating magnetic field, the tumor of the mice was completely ablated by magnetothermal, and there was no recurrence in the treatment group within 14 days.
实施例4:镁合金棒作为磁热试剂用于兔子肿瘤磁热消融Example 4: Magnesium alloy rods used as magnetocaloric reagents for magnetocaloric ablation of rabbit tumors
为了证明磁热治疗在组织穿透方面不受限制的优势,我们进一步使用这一策略来治疗在兔子身上生长的更大尺寸的皮下肝癌肿瘤。本实验将携带肝癌肿瘤的兔子随机分为两组(每组3只),其中一组植入镁合金棒,另一组未植入镁合金棒作为对照,由于治疗前肿瘤体积较大(~800mm3),本实验采用3根直径较大、长度较长的MgA棒(D=1.0mm,L=8.0mm)进行兔实验。将经过体外有效范围模拟的镁合金棒以最优的植入位置植入到新西兰大白兔肿瘤内部,将其麻醉后,使其肿瘤部位暴露在交变磁场条件下15分钟,不同手段治疗结束后,每四天监测肿瘤体积,当体积超过10000mm3时认为兔子死亡。To demonstrate the unrestricted advantage of magnetothermal therapy in terms of tissue penetration, we further used this strategy to treat larger sized subcutaneous hepatocellular carcinoma tumors grown in rabbits. In this experiment, the rabbits carrying liver cancer tumors were randomly divided into two groups (3 in each group), one of which was implanted with magnesium alloy rods, and the other group was not implanted with magnesium alloy rods as a control. Due to the large tumor volume before treatment (~ 800mm 3 ), in this experiment, three MgA rods (D=1.0mm, L=8.0mm) with larger diameter and longer length were used for the rabbit experiment. The magnesium alloy rods simulated by the effective range in vitro were implanted into the tumor of New Zealand white rabbits at the optimal implantation position. After anesthesia, the tumor site was exposed to alternating magnetic field conditions for 15 minutes. After treatment with different methods , the tumor volume was monitored every four days, and the rabbit was considered dead when the volume exceeded 10,000 mm3 .
治疗结束后,用游标卡尺监测兔子的肿瘤体积,如图5所示,镁合金磁热治疗剂用于兔子肿瘤磁热消融治疗对荷瘤兔子的肿瘤生长曲线对比图,兔子随机分成2组(每组3只),第一组为对照组(Control);第二组为材料联合交变磁场组(MgA+AMF,Happl×fappl=1.5×109A·m-1·s-1,10min)。相对于对照组,将镁合金植入后,再将其暴露于交变磁场下,兔子肿瘤4天后完全热消融,镁合金在针对较大的肿瘤磁热治疗中表现出优异的抑制肿瘤的效果。After the treatment, the vernier caliper was used to monitor the tumor volume of the rabbit. As shown in Figure 5, the magnesium alloy magnetocaloric therapeutic agent was used for the comparison of the tumor growth curve of the tumor-bearing rabbits in the magnetocaloric ablation of the rabbit tumor. The rabbits were randomly divided into 2 groups (each group). Group 3), the first group was the control group (Control); the second group was the material combined alternating magnetic field group (MgA+AMF, H appl ×f appl =1.5×10 9 A·m -1 ·s -1 , 10min). Compared with the control group, after implanting the magnesium alloy and then exposing it to an alternating magnetic field, the rabbit tumor was completely thermally ablated 4 days later, and the magnesium alloy showed excellent tumor-inhibiting effect in magnetothermal therapy for larger tumors .
对比兔子生存曲线,如图6所示,镁合金棒作为磁热试剂用于兔子肿瘤磁热消融治疗对荷瘤兔子的生存曲线图,兔子随机分成2组(每组3只),第一组为对照组(Control);第二组为材料联合交变磁场组(MgA+AMF,Happl×fappl=1.5×109A·m-1·s-1,10min)。相对于对照组,将镁合金植入后,再将其暴露于交变磁场下,兔子肿瘤完全热消融,而且,三只治疗的兔子中有两只没有发生肿瘤复发,肿瘤完全消除,而且这两只兔子治疗后存活超过了90天。The survival curve of rabbits was compared, as shown in Figure 6. Magnesium alloy rods were used as magnetocaloric reagents for tumor-bearing rabbits. The rabbits were randomly divided into 2 groups (3 in each group), the first group The second group was the material combined with alternating magnetic field group (MgA+AMF, H appl ×f appl =1.5×10 9 A·m -1 ·s -1 , 10min). Compared with the control group, after implantation of magnesium alloy and exposure to alternating magnetic field, the rabbit tumor was completely thermally ablated. Moreover, two of the three treated rabbits did not experience tumor recurrence, the tumor was completely eliminated, and the tumor was completely eliminated. Two rabbits survived more than 90 days after treatment.
实施例5:可植入金属作为磁热试剂的生物相容性及镁合金降解性能评价Example 5: Biocompatibility of implantable metals as magnetocaloric reagents and evaluation of degradation performance of magnesium alloys
将镁合金棒皮下植入到健康雌性小鼠体内,分别经历不同的时间(3天,10天,20天,40天,90天),没有植入镁合金的小鼠作为对照组。局部植入后首先观察小鼠是否有不良炎症反应等异常情况。植入后分别于3天,10天,20天,40天,90天随机取小鼠处死,将体内的镁合金棒取出,随着时间的增加,镁合金棒表面出现大量的腐蚀裂纹,说明其在体内逐渐降解,且3个月的时间其失重约20%。XRD分析显示其降解产物主要是氢氧化镁和磷酸钙,表明镁合金棒表现出良好的生物降解性。植入后分别于3天,10天,20天,40天,90天随机取小鼠处死,将其解剖取出脑组织、肝脏组织、脾脏组织、心脏组织、肺组织、肾脏组织和皮下组织并将其切成两半。将一半的器官固定在4%福尔马林中,嵌入石蜡,按常规程序进行进一步H&E染色,评定镁合金植入后的安全性。将各器官和组织的另一半部分,在王水中溶解,然后测定各器官镁元素的含量。同时采集血样进行血液生化及血液学检测。通过测量镁元素在小鼠不同器官中的含量,相比未植入镁合金棒的小鼠没有显著性差异,表明镁合金的降解产生的离子释放不会干扰正常的器官的生理行为。同时,对主要器官的组织学检查进一步证实,镁合金棒的植入对小鼠无明显副作用。与对照组相比,镁合金棒植入小鼠的血生化指标和血液学检测数据均为正常。以上结果均证明了镁合金优异的生物安全性和生物可降解性。The magnesium alloy rods were subcutaneously implanted into healthy female mice for different time periods (3 days, 10 days, 20 days, 40 days, 90 days), and the mice without magnesium alloys were used as a control group. After local implantation, the mice were first observed for abnormal conditions such as adverse inflammatory reactions. Mice were randomly selected and sacrificed at 3 days, 10 days, 20 days, 40 days, and 90 days after implantation, and the magnesium alloy rods in the body were taken out. It is gradually degraded in the body and about 20% of its weight is lost over 3 months. XRD analysis showed that its degradation products were mainly magnesium hydroxide and calcium phosphate, indicating that the magnesium alloy rods exhibited good biodegradability. Mice were randomly sacrificed at 3 days, 10 days, 20 days, 40 days, and 90 days after implantation, and the brain tissue, liver tissue, spleen tissue, heart tissue, lung tissue, kidney tissue and subcutaneous tissue were dissected and removed. Cut it in half. Half of the organs were fixed in 4% formalin, embedded in paraffin, and further H&E staining was performed according to routine procedures to assess the safety of magnesium alloy implantation. The other half of each organ and tissue was dissolved in aqua regia, and then the magnesium content of each organ was determined. At the same time, blood samples were collected for blood biochemical and hematological tests. By measuring the content of magnesium in different organs of mice, there was no significant difference compared with mice without magnesium alloy rods, indicating that the ion release generated by the degradation of magnesium alloys does not interfere with the normal physiological behavior of organs. At the same time, histological examination of major organs further confirmed that the implantation of magnesium alloy rods had no obvious side effects on mice. Compared with the control group, the blood biochemical indexes and hematological test data of the magnesium alloy rod-implanted mice were normal. The above results all demonstrate the excellent biosafety and biodegradability of magnesium alloys.
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例,本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换,均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。The above-mentioned embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or transformations made by those skilled in the art on the basis of the present invention are all within the protection scope of the present invention. The protection scope of the present invention is subject to the claims.
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