On May 28, the first Bio-magnesium Alloy Materials Strategy Summit was held in the form of online meeting. The conference was hosted by National Engineering And Technology Research Center for Magnesium Alloy Materials, International Magnesium Society and Jouranl of Magnesium Alloy. The chairman of the conference was Pan Fusheng and Zhang Xingdong, academicians of the Chinese Academy of Engineering. The joint research and development team of "absorbable magnesium alloy stent" led by them announced at the conference that the domestic absorbable magnesium alloy stent will officially enter the clinical stage this year.

The conference brought together well-known experts in materials science, engineering, clinical medicine and other fields, who shared the latest progress in materials research, material modification, material manufacturing, animal experiments and clinical trials of bio-magnesium alloys in China. Shao Mingli, former director of the China Food and Drug Administration and former vice minister of Health, Cui Yuting, deputy Secretary of the Party Committee of the Ministry of Science and Technology, and Ge Junbo, academician of the Chinese Academy of Sciences, addressed the conference. The participants fully exchanged views on the research and application of bio-magnesium alloy materials, and relevant experts presented the latest developments in this field.

Pan fusheng said That China is a major magnesium resource country, a powerhouse in magnesium alloy material research and a major producer of magnesium products. In the past, to produce absorbable magnesium alloy support in China, most of the pipes were imported. Now, the industrial chain covering the production of absorbable magnesium alloy materials, rough processing of bars, pipe finishing and bracket manufacturing has been opened and implemented. This is an important milestone in the development history of China's stent industry.

Eight years of hone

Breakthrough in magnesium alloy support "neck jam" technology

In terms of material science, stainless steel, titanium and its alloys, shape memory alloys and other common medical metal materials have biological inertia in human body and cannot be degraded. Magnesium is an essential trace element for the human body. Magnesium alloy has excellent biocompatibility and can be degraded in the human body. The degradation products of magnesium are non-toxic and will not cause inflammation and allergic reactions in the body. Therefore, magnesium alloy has become a very ideal medical implant material, thus bringing rich imagination space to the stent industry.

Ge junbo said: "The history of interventional treatment of coronary heart disease has evolved from the earliest balloon expansion to subsequent metal stents, and then to drug-eluting stents. But the fatal drawback of drug-eluting stents is that metal remains in the body for a long time. A decade ago, the world wanted to develop an absorbable stent to replace current metal ones. Unfortunately, after so many years, although we have made some achievements, from the earliest Abbott launched polylactic acid stent, to the modern alloy stent. However, none of the supports we found to be ideal platforms. For now, magnesium is going to be a very good platform. We hope that through the study of magnesium alloy stent, we can have a good tool in clinical treatment of heart disease, myocardial infarction, peripheral vascular disease."

At present, permanent stent implantation is faced with many problems, which has basically become the consensus in the industry.

Firstly, stents are permanently retained in the blood vessels as foreign bodies, which is easy to cause chronic inflammation and lead to late and very late thrombosis and restenosis. Delayed endothelialization or compensatory dilatation of the vessels that lead to stent trabeculae may increase the risk of late thrombosis. Secondly, the natural Angle and curvature of blood vessels, as well as the throbbing and systolic functions of blood vessels, cannot be restored due to the long-term existence of stents.

After implantation, the absorbable magnesium alloy stent can be gradually degraded, and the blood vessels gradually return to their natural state and physiological function, and the vascular risk caused by foreign bodies is significantly reduced. In addition, the mechanical properties of magnesium alloy are similar to those of bone and significantly higher than that of polylactic acid, which can be used to design and manufacture thinner scaffolder and promote endothelialization. Electropolishing process can also be used to treat the surface of magnesium alloy scaffolds to reduce the interference to hemodynamics. In the future, absorbable magnesium alloy scaffolds are expected to be applied in coronary intervention, peripheral intervention, neural intervention and other fields.

Biotronik has been recognized as the most mature company in the field of absorbable magnesium alloy coronary stents. The company's Magmaris stent product received the international CE certification for the first magnesium alloy stent in 2016 and was launched in Hong Kong, China, in 2018. Based on the company's published 5-year follow-up data of Biosolve-II, the target lesion failure rate (TLF) was 8% and the positive or probable thrombi was 0, indicating that the clinical performance of biosolve-II has the potential to be superior to other absorbable materials.

At present, there is no absorbent magnesium alloy stent on the market in China. From the point of the meeting published results, walk in the forefront of consists of fu-sheng pan, xing-dong zhang two academicians led "absorbable magnesium alloy stents" joint research and development team, the team's technical force mainly comes from the national engineering research center for magnesium alloy materials, national engineering research center for biomedical materials, the double and Beijing medical equipment co., LTD.

The development and manufacturing of absorbable magnesium alloy scaffolds are faced with three major challenges: fast and uncontrollable degradation rate, the balance between effective support time and degradation time of scaffolds, the strength of mechanical properties, and the difficult balance of plasticity. Only by solving these three problems can clinically approved magnesium alloy products be developed.

Everything comes to him who waits. The joint research and development team spent several years on research and development, material modification, processing technology improvement, and broke through a number of technical difficulties.

"The stent is pressed onto the balloon during the process of production and use," Said Dr. Shejia, associate professor at Chongqing University and a member of the joint research team, at the conference. In the process of pressing a support, the deformation of the support is quite large. Therefore, the support should not only have high enough strength, but also have good plasticity, and can not fracture after the stress strain. At present, magnesium alloy materials specially used for cardiovascular stents are very scarce, and the purity of industrial magnesium alloy is low, which cannot meet the medical requirements. The scaffolds need to be carved on microtubes, whose walls are as thin as 200 microns. If the alloy has high levels of impurities, it is likely to break during processing, resulting in a very low yield. In stent development, the strength, plasticity and degradation properties of magnesium alloys are difficult to coordinate. It is also difficult to control the degradation rate and uniformity of magnesium alloy scaffolds after implantation."

In order to solve the purity problem of magnesium alloy, the research team at Chongqing University reduced the Fe content in magnesium alloy to 10ppm through a fluxless self-purification process of magnesium alloy melt with variable temperature. With the increase of purity, the corrosion rate is greatly reduced and the corrosion resistance is significantly improved, which lays an important foundation for the preparation of high-performance medical magnesium alloys. The research team of Chongqing University also developed the continuous forging extrusion technology to obtain continuous cumulative deformation, promote recrystallization, and realize the uniform preparation of magnesium alloy material ingot.

In order to further control the degradation rate of scaffolds in vivo, the RESEARCH and development team developed a composite coating for scaffolds, which can better adjust the degradation time and ensure the effective support of scaffolds within a certain period. In terms of effectively controlling the degradation rate, the Jinshuanghe team effectively dispersed the stress of the scaffold by optimizing the structural design of the scaffold, making it more suitable for the mechanical properties of the magnesium alloy and avoiding the cracking of the protective coating. Due to the poor visibility of magnesium alloy under X-ray, Chindex set up double developing points on the head and tail of the stent to help doctors accurately locate the stent during surgery.

According to Dr. Fugui He, a member of the joint research team and chief scientist of Beijing Chinsus-Shuanghe Medical Device Co., LTD., the domestically developed magnesium alloy used in the stent has surpassed those used by its peers, with tensile strength exceeding 15.9 percent and elongation improved. The trabecula is only 125 microns thick and wide, which is thinner and narrower than the similar products, but the radial support is increased by 16 percent. In vitro simulation experiments showed that the radial support force of the scaffolds was still more than 85% after 2 months, indicating that the comprehensive degradation control method had excellent effect. According to the results of 1, 3, 6 and 10 months in large animal experiments, the vascular endothelialization of stent implantation segment was good, the intima was uniform, and there was no restenosis and no thrombosis.

The stent is expected to enter clinical trials this year.

In terms of market data, although PCI operations in China have reached the level of one million, the number of operations per one million population is 729 in China and 2951 in the United States, according to frost Sullivan's data. China's percutaneous coronary intervention device market still has great potential. The use of absorbable stents has been growing, and the Market for absorbable stents in China is expected to maintain high growth.

Absorbable magnesium alloy

It has a promising future in the medical field

In addition to stent development, magnesium-based products have attracted extensive attention in other fields due to their good biocompatibility. At the conference site, experts from many places in China shared the progress of medical application of magnesium alloy materials. In addition to absorbable scaffolds, the development of bone implants for magnesium alloys is a major research area in China.

Yu Kun, professor at the School of Materials Science and Engineering, Central South University, said, "Magnesium alloys are being used more and more widely in degradable metal materials, but the main problem with magnesium is that the degradation rate is too fast, so how to control the degradation of magnesium is very important. "We did magnesium composite and we found that it was very effective for bone defects. It was very quick to repair and complete bone defects."

Chen Liang, Director of the Department of Bone and Soft Tissue Oncology, Affiliated Cancer Hospital of Chongqing University, shared the current situation and prospect of the application of magnesium alloy in the treatment of bone tumor. "Magnesium alloy materials are widely used in bone tissue engineering, but there are only a few basic studies on bone tumor therapy, and there are few clinical studies and large animal trials," he said. Because magnesium base material has good biocompatibility, bone conduction and bone integration, if the future in combination with other core material, magnesium based materials in mechanical strength, corrosion resistance, and in such aspects as particle release rate control to a breakthrough, in the future, the magnesium alloy materials in bone tumor treatment will be very promising."

Shengfeng Guo, a professor from Southwest University, shared the study on the effect of absorbable magnesium alloy on bone repair. Compared with traditional bone repair materials, the absorbability of magnesium alloy avoids the need for a second operation, and the good biomechanical compatibility of magnesium alloy and its mechanical properties are similar to bone tissue can effectively avoid the stress shielding effect, he said. Magnesium alloys are also bone inducible because magnesium ions induce new bone formation.

In the field of ophthalmology, Li Xiangji, M.D., deputy chief ophthalmologist at the Third Affiliated Hospital of Chongqing Medical University, shared a study on the application of coated magnesium absorbable materials in glaucoma drainage surgery. In this study, we found that coated magnesium-based materials have better biocompatibility, less toxicity to human Tenon cystic fibroblasts (HTCFs), and can inhibit the proliferation of HTCFs.

In addition, researches on magnesium alloy in oral and intestinal staplers, orbital diseases, ureteral stents and other fields are also being carried out in China and some progress has been made, which is expected to bring revolutionary products like absorbable magnesium alloy stents in the future.

Shao Mingli said at the meeting, "China's medical device industry has grown from scratch and from small to large in decades of development, forming a relatively complete system that can basically meet the health and medical needs of the Chinese people. But frankly speaking, the development of China's medical device industry is still in the stage of breakthrough and transformation. Due to technical barriers, development basis, research and development system, the development of basic disciplines and other factors, we are still facing a lot of 'neck' problems. In a sense, materials are the basis of medical device innovation. Magnesium alloy, a green material for the 21st century, has a huge market in various fields.

"In China's 14th Five-year Plan for scientific and technological innovation, high-end medical equipment products such as fully degradable vascular stents, high-end alloy composites, and new energy polymerization products such as hydrogen energy storage have been listed as key research and development priorities. It is suggested that relevant enterprises and research institutes integrate the forces of all parties to establish and improve the magnesium alloy industry chain and innovation chain. "We need to make original innovations and technological breakthroughs in emerging and interdisciplinary areas related to magnesium alloys."

Fortunately, at the first Bio-magnesium Alloy Materials Strategy Summit, we have seen the spark of material innovation and breakthrough.