技术领域technical field
本发明属于生物医用新材料及其医疗器械产品制造和应用技术领域，尤其涉及一种生物医用可控全降解新材料及其制备方法。The invention belongs to the technical field of manufacturing and application of biomedical new materials and medical device products, and in particular relates to a biomedical controllable full-degradation new material and a preparation method thereof.
背景技术Background technique
随着社会经济的发展和生活水平的提高，人类正空前关注自身的医疗健康事业。生存压力的加大，生活节奏的加快，环境污染的加剧，食品、交通和生产等安全事故以及局部战争、自然灾害等的频繁发生，导致疾病和创伤成为人类永远挥之不去的阴霾。作为现代医学的重要手段——医疗器械的重要基础和组成部分，生物材料用于疾病的诊断和治疗、组织器官的修复、替换或功能增进，使大量挣扎在残、死痛苦边缘的病患得以康复。近年来，全球医疗器械产业高速发展，年均增速是同期国民经济增速的2倍多，被誉为“朝阳产业”，已成为21世纪十分活跃的新经济增长点。以我国为例，我国医疗器械市场2010年增速高达23%，市场规模首次突破1,000亿元大关，成为仅次于美国的世界第二大医疗器械市场，预计到2015年市场规模将接近3,400亿元。正因为生物材料如此巨大的社会和经济价值，其研发工作日益受到世界各国政府、产业界和科技界的高度关注，先后被美、德、日、澳以及我国政府列入高技术关键新材料发展计划。With the development of social economy and the improvement of living standards, human beings are paying unprecedented attention to their own medical and health undertakings. The increasing pressure of survival, the accelerated pace of life, the intensification of environmental pollution, the frequent occurrence of food, transportation and production safety accidents, local wars, and natural disasters have caused diseases and traumas to become the ever-lingering haze of human beings. As an important means of modern medicine—an important basis and component of medical devices, biomaterials are used for the diagnosis and treatment of diseases, the repair, replacement or function enhancement of tissues and organs, so that a large number of patients who are struggling on the verge of disability and death can be treated. recover. In recent years, the global medical device industry has developed rapidly, with an average annual growth rate more than twice that of the national economy during the same period. Known as a "sunrise industry", it has become a very active new economic growth point in the 21st century. Taking my country as an example, the growth rate of my country's medical device market in 2010 was as high as 23%, and the market scale exceeded 100 billion yuan for the first time, becoming the second largest medical device market in the world after the United States. billion. Because of the huge social and economic value of biological materials, its research and development work has increasingly attracted the attention of governments, industries and science and technology circles all over the world, and has been included in the development of high-tech key new materials by the governments of the United States, Germany, Japan, Australia and my country. plan.
生物材料种类繁多，迄今为止，被研究过的已逾千种，广泛医用的也有近百种。其中金属材料因其强度和断裂韧性高、易加工成形等优点，成为目前医学临床尤其是骨科（如脊柱矫形、断骨接合、颅骨修补等）中应用最广的承力植入材料。然而，现有医用金属材料如不锈钢、钴铬合金、镍合金以及钛合金等普遍存在的问题是：除价格昂贵外，力学相容性、生物相容性和生物降解性也不尽如人意。以目前已经在医学临床获得广泛应用的钛合金为例，其主要性能缺陷包括：（1）由于弹性模量不匹配，导致由植入体到相邻骨组织的载荷传递障碍，即产生“应力屏蔽”效应，使其作为内植物的风险（如抑制骨愈合，导致骨疏松、骨吸收或骨萎缩，甚至出现二次骨折等）始终无法规避；（2）纯钛在机体内的降解会导致过敏甚至死亡，典型钛合金Ti6Al4V中的Al和V均有细胞毒性，其中V会引发慢性炎症，Al与无机磷结合，导致缺磷的同时还会诱发老年痴呆症；（3）由于生物降解性差，在受损组织/器官完成功能重建后，植入体须经二次手术取出，因此阻断了患者的康复进程，额外增加了其身心痛苦和经济负担。基于上述原因，在保证安全性的前提下寻找综合性能更佳的新材料、新技术，一直是生物材料研究的重点和热点所在。正是在这种大背景下，镁合金以其诸多优势跃入材料科学家、临床医学专家以及医械高新技术企业的视野。There are many kinds of biological materials. So far, more than a thousand kinds have been studied, and nearly a hundred kinds are widely used in medicine. Among them, metal materials have become the most widely used load-bearing implant materials in medical clinics, especially in orthopedics (such as spinal orthopedics, fractured bone joints, and skull repairs) due to their advantages such as high strength and fracture toughness, and easy processing and forming. However, existing medical metal materials such as stainless steel, cobalt-chromium alloy, nickel alloy, and titanium alloy have common problems: in addition to being expensive, the mechanical compatibility, biocompatibility, and biodegradability are not satisfactory. Taking titanium alloy, which has been widely used in clinical medicine, as an example, its main performance defects include: (1) Due to the mismatch of elastic modulus, the load transfer from the implant to the adjacent bone tissue is hindered, that is, "stress "shielding" effect, making it unavoidable as an implant (such as inhibiting bone healing, leading to osteoporosis, bone resorption or bone atrophy, or even secondary fractures, etc.); (2) The degradation of pure titanium in the body will lead to Allergies and even death, both Al and V in the typical titanium alloy Ti6Al4V are cytotoxic, among which V can cause chronic inflammation, and the combination of Al and inorganic phosphorus can lead to phosphorus deficiency and induce Alzheimer's disease at the same time; (3) due to poor biodegradability , After the functional reconstruction of the damaged tissue/organ is completed, the implant must be taken out by a second operation, thus blocking the patient's recovery process and increasing the patient's physical and mental pain and economic burden. Based on the above reasons, searching for new materials and technologies with better comprehensive performance under the premise of ensuring safety has always been the focus and hotspot of biomaterials research. It is against this background that magnesium alloys have jumped into the field of vision of material scientists, clinical medical experts and high-tech medical equipment companies with their many advantages.
镁合金作为生物医用材料使用具有一系列独特的与生俱来的优势：（一）生物降解性优势。金属镁化学性质活泼，在侵蚀性生理环境（Cl-、有机酸、蛋白质、酶和细胞等）的作用下，镁植入体在服役期间可被逐步生物降解至最后完全消失，克服了金属本体在人体内长期存留所造成的并发症，使患者免受二次手术之苦成为可能，同时意味着在同一病变部位可以多次介入干预。（二）生物相容性优势。镁是人体非异己成分，是人体常量元素之一（Mg2+是人体内仅次于Na+、K+和Ca2+居第4位，细胞内仅次于K+居第2位的阳离子；人体单位体重镁平均含量0.3-0.4g/kg），参与一系列新陈代谢过程，与生命的维持、身体的健康密切相关，在生物磷灰石形成、骨基质转变、骨细胞形成和结合、骨愈合，以及神经、肌肉、心脏等功能的正常发挥方面均扮演着十分重要的角色。因此，镁金属本质上无生物毒性，作为生物材料使用时，只要有效控制镁离子的释放速率，则其降解对宿主有益无害（人体对镁的日常需求量：婴儿40-70mg/d，儿童250mg/d，成人300-700mg/d）。（三）力学相容性优势。镁的Young’s弹性模量与人体骨骼的对应参数（10-40GPa）最为接近，有利于降低甚至消除植入体对人体骨组织潜在的“应力屏蔽”效应，促进骨的生长和愈合。（四）生物活性优势。公开报道的动物试验及临床试验结果表明，镁具有优异的骨诱导性。（五）常规性能优势。镁具有“一低”（密度低）、“两高”（比强度、比刚度高）、“三好”（铸造及切削加工性、尺寸稳定性及可回收循环利用性好）和“四强”（电磁屏蔽能力、减震降噪能力及导热、导电能力强）的特点，因此享有“21世纪绿色工程材料”的美誉，在众多领域尤其是在“轻量化”、“环保化”等具有重大意义或有特殊技术要求的领域，如航空航天、汽车、IT电子、通讯、国防军事等工业部门，镁合金作为结构材料的开发应用已在国际上引起高度关注。（六）资源及价格优势。地球上镁资源十分丰富，地壳金属元素中镁相对含量10.63%，仅次于铝（31.51%）和铁（22.02%）居第三位，是钛含量（2.43%）的4.37倍。其中仅海水中就有“取之不尽，用之不竭”的镁——镁浓度1.1kg/m3，总含量高达2.1×1015吨。丰富的资源及冶炼、成形等技术的迅速发展，导致镁金属及其制品的价格相对钛等而言已显得十分低廉。以原材料为例，国内最新市场报价统计结果表明，目前，99.95%原生镁锭的平均价格（约17.0元/kg）仅为TA0钛锭的（约160.0元/kg）10%左右。基于上述诸多优势，镁合金有望成为理想的生物医用金属新材料，用于包括（1）骨板、骨钉和骨网等骨科内固定器械，（2）人工骨，（3）血管支架以及（4）组织工程支架等在内的诸多高附加值医疗器械产品的制造。The use of magnesium alloy as a biomedical material has a series of unique inherent advantages: (1) The advantage of biodegradability. Magnesium metal is chemically active. Under the action of aggressive physiological environment (Cl- , organic acids, proteins, enzymes and cells, etc.), magnesium implants can be gradually biodegraded to disappear completely during service, overcoming the metal body Complications caused by long-term persistence in the human body make it possible for patients to avoid the suffering of secondary surgery, and at the same time mean that multiple interventions can be performed at the same lesion site. (2) Advantages of biocompatibility. Magnesium is a non-alien component of the human body and one of the constant elements in the human body (Mg2+ is the fourth cation in the human body after Na+ , K+ and Ca2+ , and the second cation in cells after K+ ; the average content of magnesium per unit body weight of the human body is 0.3-0.4g/kg), participates in a series of metabolic processes, and is closely related to the maintenance of life and the health of the body. It plays an important role in healing and the proper functioning of nerves, muscles, heart, etc. Therefore, magnesium metal is essentially non-biologically toxic. When used as a biological material, as long as the release rate of magnesium ions is effectively controlled, its degradation will be beneficial and harmless to the host (the daily demand for magnesium by the human body: 40-70mg/d for infants, children 250mg/d, adult 300-700mg/d). (3) Advantages of mechanical compatibility. The Young's elastic modulus of magnesium is the closest to the corresponding parameters of human bones (10-40GPa), which is beneficial to reduce or even eliminate the potential "stress shielding" effect of implants on human bone tissue, and promote bone growth and healing. (4) Advantages of biological activity. Publicly reported results of animal experiments and clinical trials show that magnesium has excellent osteoinductivity. (5) Conventional performance advantages. Magnesium has "one low" (low density), "two highs" (high specific strength and specific stiffness), "three good" (good casting and machinability, dimensional stability and recyclability) and "four strong" (Electromagnetic shielding ability, shock absorption and noise reduction ability, and strong thermal and electrical conductivity), so it enjoys the reputation of "green engineering materials in the 21st century" and has great significance in many fields, especially in "lightweight" and "environmental protection". Significance or fields with special technical requirements, such as aerospace, automotive, IT electronics, communications, national defense and military industries, the development and application of magnesium alloys as structural materials has attracted great attention internationally. (6) Resource and price advantages. Magnesium resources are very rich on the earth. The relative content of magnesium in the crustal metal elements is 10.63%, second only to aluminum (31.51%) and iron (22.02%), ranking third, which is 4.37 times that of titanium (2.43%). Among them, there is "inexhaustible and inexhaustible" magnesium in seawater alone - the concentration of magnesium is 1.1kg/m3 , and the total content is as high as 2.1×1015 tons. Abundant resources and the rapid development of smelting, forming and other technologies have resulted in the price of magnesium metal and its products being very low compared to titanium. Taking raw materials as an example, the latest domestic market quotation statistics show that at present, the average price of 99.95% primary magnesium ingots (about 17.0 yuan/kg) is only about 10% of that of TA0 titanium ingots (about 160.0 yuan/kg). Based on the above advantages, magnesium alloy is expected to become an ideal biomedical new metal material for orthopedic internal fixation devices including (1) bone plate, bone nail and bone mesh, (2) artificial bone, (3) vascular stent and ( 4) Manufacture of many high value-added medical device products including tissue engineering stents.
但令人遗憾的是，镁自身热力学稳定性差（E0=-2.37V NHE），表面自氧化膜薄（~10nm）而疏松（因PBR=0.80）且无“自愈”能力，不能对基体提供有效的保护。据报道，纯镁经HBSS（Hank’s平衡盐溶液）225h的侵蚀，质量损失高达99%。因此，镁合金的生物医用不但没有受益于其独特的生物降解特性，相反，却一直受困于降解过快带来的系列问题，如：a）材料制品服役性能尤其是机械完整性的过早衰减甚至失效，b）危害生物相容性，c）大剂量具有潜在生物毒性的合金元素的迅速释放，d）增加宿主镁代谢压力，甚至引发高血镁症，e）导致局部pH值急剧攀升，以及f）局部组织积气，等。基于上述原因，发展新材料尤其是基于镁或镁合金的新型复合材料，增强材料生物降解可控性（不仅可生物降解，而且降解速率能够根据需要进行调节）的同时，改善材料的生物相容性甚至赋予其生物活性，以满足医学临床对材料综合性能的苛刻要求，具有十分重要的意义，成为生物医用新材料及医疗器械领域的重要课题。Unfortunately, the thermodynamic stability of magnesium itself is poor (E0 =-2.37V NHE), the self-oxidized film on the surface is thin (~10nm) and loose (because of PBR=0.80) and has no "self-healing" ability, so it cannot repair the substrate. provide effective protection. It is reported that the mass loss of pure magnesium is as high as 99% after being eroded by HBSS (Hank's balanced salt solution) for 225 hours. Therefore, the biomedical application of magnesium alloys not only does not benefit from its unique biodegradation characteristics, but has been suffering from a series of problems caused by too fast degradation, such as: a) The service performance of the material product, especially the premature mechanical integrity Attenuation or even failure, b) endangering biocompatibility, c) rapid release of large doses of potentially biotoxic alloying elements, d) increasing the stress on host magnesium metabolism, and even triggering hypermagnesemia, e) causing a sharp rise in local pH , and f) local tissue gas accumulation, etc. Based on the above reasons, the development of new materials, especially new composite materials based on magnesium or magnesium alloys, can enhance the controllability of biodegradation of materials (not only biodegradable, but also the degradation rate can be adjusted according to needs), while improving the biocompatibility of materials It is of great significance to meet the stringent requirements of clinical medicine for the comprehensive performance of materials, and it has become an important topic in the field of biomedical new materials and medical devices.
迄今为止，以生物医学为应用背景，基于表面改性的镁和镁合金基复合材料制备技术的开发已取得累累硕果。涉及主要表面改性技术包括：（1）常规微弧氧化（MAO）技术（指以非降解性或几乎无降解能力的MAO陶瓷膜为制备对象的MAO技术，下同），（2）基于常规MAO的复合技术，如MAO/有机涂覆、MAO/化学沉积等，（3）有机涂覆，（4）化学转化，（5）仿生钝化，（6）阴极沉积，（7）阳极沉积，（8）IBAD（离子束辅助沉积），（9）溶胶-凝胶法，（10）硅烷改性，（11）离子注入，（12）离子镀，（13）电化学聚合，以及（14）水热法，等。上述技术及其制得的复合材料虽然各具优势，但也存在严重缺陷：或专注于对基体生物降解性的抑制和生物相容性的改善，不但没有考虑表面改性层在受损组织/器官完成功能重建后的“功成身退”——生物降解问题，相反，为提高改性效果，却按常规思路在合成/施加致密性、非降解性改性层上下功夫；或虽然顾及到改性层的生物降解性，但综合使役性能却并不理想。就前者而言，以利用对基体的MAO处理实现复合材料的制备为例，由于采用常规电解液（如硅酸盐、磷酸盐和氟化物基电解液），因此所得MAO膜主要成分为几乎不可降解或降解性很差的硅酸盐、磷酸盐或氟化物。这对于非医用镁合金而言无疑是无可挑剔的，但却与镁合金生物医用的最大亮点——生物降解性的利用构成严重矛盾。换言之，当作为“免二次手术”植入器械或管状/腔状组织/器官支架材料如血管支架等使用时，即使在服役环境下基体能够按照预期逐步降解、吸收，非降解性壳体（MAO膜等表面改性膜层）或其剥离碎片的长期存在，也将使免除机体永久性外源体反应的一切努力前功尽弃，甚至带来灾难性后果（如堵塞血管）。就后者而言，以利用在基体表面涂覆可降解高分子材料实现复合材料的制备为例，存在以下主要问题：（1）未考虑高分子材料酸性降解产物的潜在危害，如a.导致局部生理环境的酸化继而引发无菌性炎症，b.加速镁合金基体的降解，因此未见提出针对性的应对/防患措施；（2）高分子材料孤立使用或仅与非降解性HA（羟基磷灰石）复合使用，限制了其改性效果和应用范畴；（3）涂层/基体结合力不理想，等。So far, with biomedicine as the application background, the development of surface-modified magnesium and magnesium alloy matrix composite materials has achieved fruitful results. The main surface modification technologies involved include: (1) Conventional Micro-arc Oxidation (MAO) technology (referring to the MAO technology that uses non-degradable or almost non-degradable MAO ceramic membranes as the preparation object, the same below), (2) based on conventional MAO composite technology, such as MAO/organic coating, MAO/chemical deposition, etc., (3) organic coating, (4) chemical conversion, (5) biomimetic passivation, (6) cathode deposition, (7) anode deposition, (8) IBAD (Ion Beam Assisted Deposition), (9) Sol-Gel Method, (10) Silane Modification, (11) Ion Implantation, (12) Ion Plating, (13) Electrochemical Polymerization, and (14) Hydrothermal method, etc. Although the above-mentioned technologies and the composite materials produced have their own advantages, they also have serious defects: or focus on the inhibition of matrix biodegradability and the improvement of biocompatibility, not only do not consider the surface modification layer in damaged tissue/ After the completion of the functional reconstruction of the organ, the issue of biodegradation is "retire after success". On the contrary, in order to improve the modification effect, efforts have been made to synthesize/apply a dense and non-degradable modification layer according to the conventional thinking; or although taking into account the The biodegradability of the modified layer, but the comprehensive service performance is not ideal. As far as the former is concerned, taking the use of MAO treatment on the substrate to realize the preparation of composite materials as an example, since conventional electrolytes (such as silicate, phosphate, and fluoride-based electrolytes) are used, the main components of the obtained MAO film are almost impossible. Silicates, phosphates or fluorides that degrade or are poorly degradable. This is undoubtedly impeccable for non-medical magnesium alloys, but it constitutes a serious contradiction with the biggest bright spot of magnesium alloys in biomedicine—the utilization of biodegradability. In other words, when it is used as a "secondary operation-free" implant device or tubular/luminal tissue/organ scaffold material such as vascular stent, even in the service environment, the matrix can be gradually degraded and absorbed as expected, and the non-degradable shell ( The long-term existence of surface modified film layers such as MAO film) or its peeled off fragments will also make all efforts to avoid permanent foreign body reactions in the body useless, and even bring catastrophic consequences (such as blockage of blood vessels). As far as the latter is concerned, taking the preparation of composite materials by coating degradable polymer materials on the surface of the substrate as an example, there are the following main problems: (1) The potential hazards of acidic degradation products of polymer materials are not considered, such as a. The acidification of the local physiological environment then triggers aseptic inflammation, b. Accelerates the degradation of the magnesium alloy matrix, so no specific countermeasures/prevention measures have been proposed; (2) Polymer materials are used in isolation or only in combination with non-degradable HA ( Hydroxyapatite) used in combination, which limits its modification effect and application range; (3) Coating/substrate bonding force is not ideal, etc.
发明内容Contents of the invention
本发明的目的在于针对现有生物医用材料及其应用技术中存在的主要问题，提供一种生物医用可控全降解新材料及其制备方法。The purpose of the present invention is to provide a new biomedical controllable fully degradable material and a preparation method thereof for the main problems existing in the existing biomedical materials and their application technologies.
本发明通过以下技术方案予以实现：The present invention is achieved through the following technical solutions:
一种生物医用可控全降解材料的制备方法，其包括以下主要步骤：A preparation method of a biomedical controllable fully degradable material, which comprises the following main steps:
a）熔炼和成形：熔炼纯镁或镁合金，并进行成形制造，获得制品基体；a) Smelting and forming: smelting pure magnesium or magnesium alloy, and performing forming to obtain the product matrix;
b）阳极极化：将步骤a）所得制品基体经表面整理后浸入浓度为20.0mg/L-100.0g/L的氯化钠的水基溶液中，以等面积的相同材料的制品为对电极，通电进行处理；b) Anodic polarization: immerse the product matrix obtained in step a) into a water-based solution of sodium chloride with a concentration of 20.0mg/L-100.0g/L after surface treatment, and use an equal-area product of the same material as the counter electrode , power on for processing;
c）涂覆：包括以下主要步骤：c) Coating: including the following main steps:
c-1）溶液的配制：c-1) Preparation of solution:
1#溶液：为PLLA、PLGA或其混合物的有机溶剂基溶液，其浓度为0.2-75.0g/L；1# solution: an organic solvent-based solution of PLLA, PLGA or their mixture, with a concentration of 0.2-75.0g/L;
2#溶液：为以氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其中两种以上混合物为固体分散相，以水、丙酮、乙醇、正丁醇或其中两种以上混合物为液体的悬浮液，其中所述固体分散相的浓度为0.5-45.0g/L；2# solution: use magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP, CPP or two or more of them as the solid dispersed phase, and use water, acetone, ethanol, n-butanol or two or more of them The mixture is a liquid suspension, wherein the concentration of the solid dispersed phase is 0.5-45.0 g/L;
3#溶液：为以氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其中两种以上混合物为固体分散相，以PLLA、PLGA或其混合物的有机溶剂基溶液为液体的悬浮液，其中所述PLLA、PLGA或其混合物的浓度为0.2-75.0g/L，所述固体分散相的质量占固体分散相与PLLA、PLGA或PLLA与PLGA混合物总质量的0.5%-40%；3# solution: it uses magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP, CPP or two or more of them as the solid dispersed phase, and PLLA, PLGA or the organic solvent-based solution of their mixture as the liquid Suspension, wherein the concentration of the PLLA, PLGA or mixture thereof is 0.2-75.0g/L, and the mass of the solid dispersed phase accounts for 0.5%-40% of the total mass of the solid dispersed phase and PLLA, PLGA or the mixture of PLLA and PLGA ;
c-2）涂层的涂覆：对经步骤b）处理过的制品基体进行涂覆处理，获得兼具降解防护和自降解特性的功能膜，所述涂覆处理采用如下三种方案中的一种以上进行：c-2) Coating of coating: Coating the product substrate treated in step b) to obtain a functional film with both degradation protection and self-degradation properties, the coating treatment adopts the following three schemes Do more than one:
方案一：联合使用c-1）步骤所配1#溶液和2#溶液，遵循先用1#溶液后用2#溶液再用1#溶液的顺序，进行一轮以上涂覆；Option 1: Use the 1# solution and 2# solution prepared in step c-1) in combination, follow the order of using 1# solution first, then 2# solution, and then 1# solution, and carry out more than one round of coating;
方案二：独立使用c-1）步骤所配3#溶液进行一轮以上涂覆。Scheme 2: Independently use the 3# solution prepared in step c-1) for more than one round of coating.
方案三：联合使用c-1）步骤所配1#溶液、2#溶液和3#溶液，遵循先用1#溶液后用2#溶液再用3#溶液的顺序，进行一轮以上涂覆。Scheme 3: Combined use of 1# solution, 2# solution and 3# solution prepared in step c-1), follow the order of using 1# solution first, then 2# solution, and then 3# solution, and carry out more than one round of coating.
步骤b）中所述氯化钠用硝酸钠、硫酸钠、氯化锂、硝酸锂、硫酸锂、氯化钾、硝酸钾、硫酸钾、氯化铵、硝酸铵、硫酸铵、氯化镁、硝酸镁、硫酸镁或其中两种以上混合物部分或全部代替。The sodium chloride described in step b) uses sodium nitrate, sodium sulfate, lithium chloride, lithium nitrate, lithium sulfate, potassium chloride, potassium nitrate, potassium sulfate, ammonium chloride, ammonium nitrate, ammonium sulfate, magnesium chloride, magnesium nitrate , magnesium sulfate or a mixture of two or more of them can be partially or completely replaced.
步骤c-1）中所述1#溶液和3#溶液的有机溶剂为A溶剂和B溶剂中的一种，其中A溶剂为环氧氯丙烷、二氯甲烷或氯仿中的一种以上，B溶剂为A溶剂与丙酮、乙醇或正丁醇中一种以上均匀混合后得到的混合物；步骤c-1）中所述2#溶液和3#溶液中的纯镁和镁合金为粉末状、颗粒状、片状、丝状、带状、管状或晶须状，且其在任何相同环境介质中的开路电位不高于制品基体中纯镁或镁合金的开路电位。The organic solvent of 1# solution and 3# solution described in step c-1) is one of A solvent and B solvent, wherein A solvent is more than one of epichlorohydrin, dichloromethane or chloroform, B The solvent is a mixture obtained by uniformly mixing solvent A with more than one of acetone, ethanol or n-butanol; the pure magnesium and magnesium alloy in the 2# solution and 3# solution described in step c-1) are powdery, granular shape, flake, filament, ribbon, tube or whisker, and its open circuit potential in any same environmental medium is not higher than that of pure magnesium or magnesium alloy in the product matrix.
步骤c-1）中所述1#溶液用熔融态PLLA、熔融态PLGA或熔融态PLLA与熔融态PLGA的混合物代替；步骤c-1）中所述3#溶液用以氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其中两种以上混合物为固体分散相，以熔融态PLLA、熔融态PLGA或熔融态PLLA与熔融态PLGA的混合物为液体的悬浮液代替，其中所述固体分散相的质量占固体分散相与PLLA、PLGA或PLLA与PLGA混合物总质量的0.5%-40%。The 1# solution described in step c-1) is replaced with molten PLLA, molten PLGA or a mixture of molten PLLA and molten PLGA; the 3# solution described in step c-1) is used for magnesium oxide, magnesium hydroxide , pure magnesium, magnesium alloy, β-TCP, CPP or a mixture of two or more of them is a solid dispersed phase, replaced by a liquid suspension of molten PLLA, molten PLGA, or a mixture of molten PLLA and molten PLGA, wherein The mass of the solid dispersed phase accounts for 0.5%-40% of the total mass of the solid dispersed phase and PLLA, PLGA or the mixture of PLLA and PLGA.
步骤c-2）中方案一所述1#溶液和2#溶液之一种用3#溶液代替；步骤c-2）中所述涂覆方法包括浸涂、刷涂、旋涂或喷涂。One of the 1# solution and 2# solution described in Scheme 1 in step c-2) is replaced by 3# solution; the coating method described in step c-2) includes dip coating, brush coating, spin coating or spray coating.
当涂覆含PLLA或PLGA的涂层后，进行自然固化或人工固化处理，待该涂层部分或完全固化后，再进行后续涂层的涂覆；当涂覆氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其中两种以上混合物后，进行干燥处理。After coating the coating containing PLLA or PLGA, carry out natural curing or artificial curing treatment, and after the coating is partially or completely cured, the subsequent coating is carried out; when coating magnesium oxide, magnesium hydroxide, pure After magnesium, magnesium alloy, β-TCP, CPP or a mixture of two or more thereof, drying treatment is carried out.
一种由上述制备方法制得的生物医用可控全降解材料，其包括纯镁或镁合金基体以及覆盖基体表面的兼具降解防护和自降解特性的功能膜；所述功能膜包括No.1涂层和No.2涂层中至少一种；所述No.1涂层为以氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其中两种以上混合物为夹心层的可降解高分子材料层；所述No.2涂层为以氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其中两种以上混合物为增强相的可降解高分子材料基复合材料层，其中所述增强相的质量占复合材料质量的0.5%-40%；所述No.1涂层和No.2涂层中的可降解高分子材料为PLLA、PLGA或其混合物。A biomedical controllable fully degradable material prepared by the above preparation method, which includes a pure magnesium or magnesium alloy substrate and a functional film covering the surface of the substrate with both degradation protection and self-degradation properties; the functional film includes No.1 At least one of coating and No.2 coating; the No.1 coating is a sandwich layer with magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP, CPP or a mixture of two or more thereof Degradable polymer material layer; the No.2 coating is a degradable polymer material base with magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP, CPP or a mixture of two or more of them as the reinforcing phase. Composite material layer, wherein the mass of the reinforcing phase accounts for 0.5%-40% of the mass of the composite material; the degradable polymer material in the No.1 coating and No.2 coating is PLLA, PLGA or a mixture thereof.
所述No.1涂层和No.2涂层分别为一层以上，且不同层的成分、结构和厚度相同或不同；所述No.1涂层中夹心层两侧的可降解高分子材料层的成分、结构和厚度相同或不同；所述No.1涂层中的夹心层用No.2涂层代替；所述No.1涂层中夹心层两侧的可降解高分子材料层的至少一层用No.2涂层代替。The No.1 coating and the No.2 coating have more than one layer respectively, and the composition, structure and thickness of different layers are the same or different; the degradable polymer materials on both sides of the sandwich layer in the No.1 coating The composition, structure and thickness of the layers are the same or different; the sandwich layer in the No.1 coating is replaced by the No.2 coating; the degradable polymer material layer on both sides of the sandwich layer in the No.1 coating At least one layer shall be replaced with No.2 coating.
所述No.1涂层和No.2涂层中的纯镁和镁合金为粉末状、颗粒状、片状、丝状、带状、管状或晶须状，且其在任何相同环境介质中的开路电位不高于基体纯镁或镁合金的开路电位。The pure magnesium and magnesium alloys in the No.1 coating and No.2 coating are in the form of powder, granule, flake, wire, ribbon, tube or whisker, and they are in any same environmental medium The open circuit potential is not higher than the open circuit potential of the base pure magnesium or magnesium alloy.
本发明材料制备方法步骤a）之熔炼和成形可以任何公知的或商业上可获得的技术进行，如：保护性气氛下的熔炼，铸造、锻压、挤压或切削成形，等等。熔炼的作用在于获得化学成分及夹杂物（如氧化物夹杂）、含气量（如氢气）等控制水平满足要求的高质量的熔体（金属或合金液）；成形包括利用上述熔体直接成形（如铸造）或间接成形（即先以上述熔体制得坯料如铸锭，再对坯料进行处理，如锻造、挤压和切削等）。The smelting and forming of step a) of the material preparation method of the present invention can be carried out by any known or commercially available techniques, such as melting under protective atmosphere, casting, forging, extrusion or cutting, etc. The role of smelting is to obtain a high-quality melt (metal or alloy liquid) with chemical composition, inclusions (such as oxide inclusions), gas content (such as hydrogen) and other control levels that meet the requirements; forming includes direct forming using the above melt ( Such as casting) or indirect forming (that is, the billet is first obtained from the above melt, such as ingot, and then the billet is processed, such as forging, extrusion and cutting, etc.).
本发明材料制备方法步骤b）中表面整理的目的在于去除制品在加工、储运期间表面残留或产生的毛刺、污垢、氧化皮等，以获得满足后续处理要求的表面质量。表面整理可以任何公知的或商业上可获得的物理和/或化学技术进行，如：砂纸/砂轮打磨，抛光布抛光，有机溶剂包括无水乙醇、丙酮等直接或在超声波等外场作用下脱脂，碱洗，酸洗，水洗，等等。The purpose of surface finishing in step b) of the material preparation method of the present invention is to remove burrs, dirt, scale, etc. remaining or generated on the surface of the product during processing, storage and transportation, so as to obtain a surface quality that meets the requirements of subsequent treatment. Surface finishing can be carried out by any known or commercially available physical and/or chemical techniques, such as: sandpaper/grinding wheel grinding, polishing cloth polishing, organic solvents including absolute ethanol, acetone, etc., directly or under the action of external fields such as ultrasonic waves, degreasing, Alkaline washing, pickling, water washing, etc.
本发明材料制备方法步骤b）中阳极极化的主要目的，在于实现对基体材料进行“去活”和表面糙化双重处理，在改善材料耐蚀性的同时，为涂层/基体之间的紧密结合奠定坚实的结构基础。所谓“去活”，是指利用阳极极化的选择性溶解作用将基体表层电化学活性更高的微阳极溶解“挖除”，留下电化学惰性更强的微阴极。阳极极化处理时，电源可在直流、交流或脉冲电源中进行选择。虽然也可以按照常规做法，使用不锈钢、石墨或铂片等惰性材料作为对电极，而采取“以等面积的相同材料的制品为对电极”即“对等双极”的策略，则既可避免异质对电极对电解液潜在的污染危害，又可在对称交流或脉冲电源的作用下，确保两极工件同步获得近乎一致的处理效果，成倍提高阳极极化处理的效率，从而最大程度地实现节能、增效的目的。作为对电极的制品，其几何形状可以与工件相同或不同。当然，以与工件相同的材料作为对电极材料使用时，对电极的面积也可以与工件面积不同。阳极极化时电压/电流幅值、频率及其占空比、处理时间等具体工艺参数，则可根据对处理效果的不同要求进行灵活控制。阳极极化电解液中氯化钠浓度过低，即使使用高电流密度/高电压作用较长时间，也无法获得令人满意的处理效果；浓度过高，原料成本增加的同时对处理效果的改善并无明显益处，因此，宜将氯化钠的浓度控制在20.0mg/L-100.0g/L的范围。阳极极化时，溶液温度可控制在1-85℃；处理时间则可根据施加电参数的大小，电解质浓度的高低，以及表面糙化程度的具体要求等进行灵活控制。The main purpose of anodic polarization in step b) of the material preparation method of the present invention is to realize the dual treatment of "deactivation" and surface roughening of the substrate material, while improving the corrosion resistance of the material, it is the coating/substrate. Tight integration lays a solid structural foundation. The so-called "deactivation" refers to the use of the selective dissolution of anodic polarization to dissolve and "dig out" the micro-anode with higher electrochemical activity on the surface of the substrate, leaving a micro-cathode with stronger electrochemical inertness. When anodizing, the power supply can be selected from DC, AC or pulse power supply. Although it is also possible to use inert materials such as stainless steel, graphite or platinum sheets as counter electrodes according to conventional practices, the strategy of "using products of the same material of equal area as counter electrodes", that is, "peer bipolar", can avoid The potential pollution hazard of the heterogeneous counter electrode to the electrolyte, and under the action of a symmetrical AC or pulse power supply, can ensure that the workpieces of the two poles can be synchronously obtained almost the same treatment effect, and the efficiency of anodic polarization treatment can be doubled, so as to realize the maximum The purpose of saving energy and increasing efficiency. The article used as the counter electrode may have the same or different geometry as the workpiece. Of course, when the same material as that of the workpiece is used as the counter electrode material, the area of the counter electrode may be different from the area of the workpiece. Specific process parameters such as voltage/current amplitude, frequency and its duty cycle, and processing time during anodic polarization can be flexibly controlled according to different requirements for processing effects. The concentration of sodium chloride in the anodic polarization electrolyte is too low, even if high current density/high voltage is used for a long time, satisfactory treatment effect cannot be obtained; if the concentration is too high, the cost of raw materials will increase and the treatment effect will be improved at the same time There is no obvious benefit, therefore, it is advisable to control the concentration of sodium chloride in the range of 20.0mg/L-100.0g/L. During anodic polarization, the temperature of the solution can be controlled at 1-85°C; the processing time can be flexibly controlled according to the magnitude of the applied electric parameters, the concentration of the electrolyte, and the specific requirements of the degree of surface roughness.
阳极极化结束后，材料最好分别进行清洗、干燥等处理，包括自来水和/或蒸馏水、去离子水漂洗，热风或压缩空气吹干或加热炉烘干，或易挥发性有机溶剂如乙醇、丙酮等漂洗后晾干等。清洗、干燥的目的在于去除吸附在工件表面的非目标产物，包括阳极极化副产物、阳极极化电解液等，避免溶液交叉污染及影响后续处理效果。After the anodic polarization is completed, it is best to clean and dry the materials separately, including rinsing with tap water and/or distilled water, deionized water, drying with hot air or compressed air or drying in a heating furnace, or volatile organic solvents such as ethanol, After rinsing with acetone, etc., dry it. The purpose of cleaning and drying is to remove non-target products adsorbed on the surface of the workpiece, including anodic polarization by-products, anodic polarization electrolyte, etc., to avoid cross-contamination of the solution and affect the subsequent treatment effect.
本发明材料制备方法步骤c）中将各种涂层材料液化（配制成溶液或熔化使用）的主要目的，在于方便涂覆并确保获得均一的涂覆效果。所述PLLA、PLGA的有机溶剂可根据溶解速率、固化方式和速率以及涂层孔隙率等具体要求，在A溶剂、B溶剂以及其它任何公知的或商业上可获得的溶剂中择优选择。当配制成有机溶剂基溶液使用时，可降解高分子材料的浓度过低，则单次涂覆获得的涂层厚度过薄，涂覆效率过低；浓度过高，则溶液粘度过大，不利于涂覆且涂层均匀性差。可降解高分子材料的具体浓度，则可根据涂覆速率、涂层质量（如均匀性、孔隙率等）要求进行控制。当氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其混合物作为可降解高分子材料基复合材料的增强相使用时，用量过低，则改性效果不明显；用量过高，则导致复合材料涂层整体性能包括内聚力、与基体结合力以及降解防护性能等明显恶化。当氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其混合物作为1）以PLLA、PLGA或其混合物的有机溶剂基溶液为液体的悬浮液，或2）以熔融态PLLA、熔融态PLGA或熔融态PLLA与熔融态PLGA的混合物为液体的悬浮液的固体分散相使用时，将其质量控制在占固体分散相与PLLA、PLGA或PLLA与PLGA混合物总质量的0.5%-40%，则是为了确保获得满足要求的复合材料涂层。配制2#溶液时，控制其中固体分散相的浓度为0.5-45.0g/L，原因有二：其一，浓度过低，则单次涂覆获得的膜层厚度过薄，涂覆效率过低；其二，浓度过高，则固体分散相均匀分散的难度加大且溶液稳定性变差，不利于涂覆且膜层质量差。为获得高质量的悬浮液，所述氧化镁、氢氧化镁、纯镁、镁合金、β-TCP和CPP的分散可在机械、超声或压缩空气等搅拌条件下进行。涂覆操作时，每种涂层材料的具体涂覆次数则根据涂层结构、厚度等需要进行控制。当使用相同涂层材料进行多次涂覆时，每次涂覆使用的溶液可以相同，也可以不同。对于相同的涂覆溶液，获得的涂层厚度与涂覆次数正相关。The main purpose of liquefying (preparing into a solution or melting for use) various coating materials in step c) of the material preparation method of the present invention is to facilitate coating and ensure a uniform coating effect. The organic solvents of the PLLA and PLGA can be preferably selected from A solvent, B solvent and any other known or commercially available solvents according to specific requirements such as dissolution rate, curing mode and rate, and coating porosity. When used as an organic solvent-based solution, if the concentration of the degradable polymer material is too low, the thickness of the coating obtained in a single coating is too thin, and the coating efficiency is too low; Conducive to coating and poor coating uniformity. The specific concentration of degradable polymer materials can be controlled according to the requirements of coating rate and coating quality (such as uniformity, porosity, etc.). When magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP, CPP or their mixtures are used as the reinforcing phase of the degradable polymer matrix composite material, the modification effect will not be obvious if the dosage is too low; If the coating is high, the overall performance of the composite coating, including cohesion, bonding with the matrix, and degradation protection performance, will be significantly deteriorated. When magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloys, β-TCP, CPP, or mixtures thereof are used as 1) a suspension in an organic solvent-based solution of PLLA, PLGA, or a mixture thereof, or 2) PLLA in a molten state , When the solid dispersed phase of molten PLGA or the mixture of molten PLLA and molten PLGA is a liquid suspension, its quality is controlled at 0.5% of the total mass of the solid dispersed phase and PLLA, PLGA or PLLA and PLGA mixture- 40%, it is to ensure that the required composite coating is obtained. When preparing the 2# solution, control the concentration of the solid dispersed phase to 0.5-45.0g/L, for two reasons: first, if the concentration is too low, the thickness of the film layer obtained by a single coating is too thin, and the coating efficiency is too low ; Second, if the concentration is too high, the difficulty of uniform dispersion of the solid dispersed phase increases and the stability of the solution becomes poor, which is not conducive to coating and poor film quality. In order to obtain a high-quality suspension, the dispersion of the magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP and CPP can be carried out under stirring conditions such as mechanical, ultrasonic or compressed air. During the coating operation, the specific coating times of each coating material are controlled according to the needs of the coating structure and thickness. When using the same coating material for multiple coats, the solution used for each coat can be the same or different. For the same coating solution, the obtained coating thickness is positively correlated with the number of coatings.
本发明所述氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其混合物的涂覆方式可以电泳沉积、磁控溅射或离子束辅助沉积等技术代替。The coating method of magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP, CPP or their mixtures described in the present invention can be replaced by techniques such as electrophoretic deposition, magnetron sputtering or ion beam assisted deposition.
值得注意的是，本发明材料中功能膜与基体之间可能存在自氧化薄膜，即基体与周围环境（包括大气，清洗溶液如水、无水乙醇、碱洗液或酸洗液等，阳极极化溶液等）接触时其表层被自然氧化所生成的主要由基体的氧化物、氢氧化物（如氧化镁、氢氧化镁）或其混合物组成的膜层。这种“自氧化薄膜”是大多数金属及其合金在常规制造环境（与之相对应的是真空等特殊制造环境）下的必然产物，不过因为其厚度通常很薄（纳米级），对材料一般使役性能的影响基本可以忽略不计。It is worth noting that there may be an autoxidized film between the functional film and the substrate in the material of the present invention, that is, the substrate and the surrounding environment (including the atmosphere, cleaning solutions such as water, absolute ethanol, alkali or pickling solution, etc., anodic polarization solution, etc.) when its surface is naturally oxidized to form a film layer mainly composed of substrate oxides, hydroxides (such as magnesium oxide, magnesium hydroxide) or a mixture thereof. This "self-oxidation film" is the inevitable product of most metals and their alloys in conventional manufacturing environments (corresponding to special manufacturing environments such as vacuum). The impact on general service performance is basically negligible.
本发明材料及其制备方法中所用氧化镁、氢氧化镁、纯镁、镁合金、β-TCP和CPP可以是商业上可获得的或自制的任何形状、尺寸和结晶度的产品。其中纯镁和镁合金尤以粉末状、颗粒状、片状、丝状、带状、管状或晶须状产品为宜。为增强涂层中纯镁和镁合金的稳定性，使用前可按公知的或商业上可获得的技术对其进行表面改性处理。控制制备方法及制得的涂层中纯镁或镁合金的开路电位不高于基体中纯镁或镁合金的开路电位，目的在于获得所需的涂层并确保服役状态下涂层组分不是作为阴极性组分加速基体的降解，而是最好优先于基体（如作为牺牲阳极）发生降解。The magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP and CPP used in the material of the present invention and its preparation method can be commercially available or self-made products of any shape, size and crystallinity. Among them, pure magnesium and magnesium alloys are preferably powdery, granular, flake, filamentary, ribbon, tubular or whisker-like. In order to enhance the stability of pure magnesium and magnesium alloy in the coating, it can be surface modified according to known or commercially available techniques before use. Control the preparation method and the open circuit potential of pure magnesium or magnesium alloy in the prepared coating is not higher than the open circuit potential of pure magnesium or magnesium alloy in the matrix, the purpose is to obtain the required coating and ensure that the coating components in service state are not As a cathodic component accelerates the degradation of the matrix, it is better to degrade preferentially over the matrix (eg as a sacrificial anode).
本发明材料中No.1涂层和No.2涂层设计为一层以上，且不同层（这里的“不同层”是指以No.1涂层或No.2涂层为结构单位而言的）的成分（如：氧化镁、氢氧化镁、纯镁、镁合金、β-TCP或CPP的用量；高分子材料的种类及其分子量等）、结构（如致密度、孔隙率、表面粗糙度等）和厚度相同或不同，另外，No.1涂层中夹心层两侧的高分子材料层的成分（种类及其分子量等）、结构和厚度相同或不同，其目的均在于充分利用不同材料组成单元的特性以实现对材料整体综合性能尤其是生物降解性、生物相容性以及涂层/基体结合力、涂层内聚力等的成功控制。No.2涂层以及No.1涂层中夹心层及其两侧高分子材料层的具体厚度，可根据实际使用需要灵活控制。在进行No.1涂层的制备时，为增强夹心层与其两侧的高分子材料层的结合力，夹心层的涂覆宜选在首层高分子材料层完全固化前进行，或适当控制夹心层两侧的高分子材料层的孔隙率，或在涂层涂覆过程结束后以适当规范进行热处理。No.1 coating and No.2 coating are designed to be more than one layer in the material of the present invention, and different layers (here " different layers " refer to No.1 coating or No.2 coating as structural unit composition (such as: magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP or CPP dosage; type of polymer material and its molecular weight, etc.), structure (such as density, porosity, surface roughness Degree, etc.) and thickness are the same or different. In addition, the composition (type and molecular weight, etc.), structure and thickness of the polymer material layers on both sides of the sandwich layer in the No.1 coating are the same or different. The purpose is to make full use of the different The characteristics of the material constituent units are used to achieve the successful control of the overall comprehensive performance of the material, especially the biodegradability, biocompatibility, coating/matrix binding force, coating cohesion, etc. The specific thickness of the No.2 coating and the sandwich layer in the No.1 coating and the polymer material layers on both sides can be flexibly controlled according to actual use needs. In the preparation of No.1 coating, in order to enhance the bonding force between the sandwich layer and the polymer material layers on both sides, the coating of the sandwich layer should be carried out before the first layer of polymer material layer is completely cured, or the sandwich layer should be properly controlled. The porosity of the polymer material layer on both sides of the layer, or heat treatment with appropriate specifications after the coating application process.
本发明材料及其制备方法中PLLA和PLGA可以任何其它公知的或商业上可获得的具有生物降解特性的高分子材料部分或全部代替，如胶原蛋白、明胶和壳聚糖等天然可降解高分子材料，以及其它人工合成可降解高分子材料。β-TCP和CPP也可以任何其它公知的或商业上可获得的可降解无机生物材料部分或全部代替。In the material of the present invention and its preparation method, PLLA and PLGA can be partially or completely replaced by any other known or commercially available polymer materials with biodegradable properties, such as natural degradable polymers such as collagen, gelatin and chitosan materials, and other synthetic degradable polymer materials. β-TCP and CPP can also be partially or completely replaced by any other known or commercially available degradable inorganic biomaterials.
需要指出的是，本发明中所指纯镁包括：1）不同纯度水平的镁金属，2）纯镁制品，和3）含纯镁部件（组元）的制品。本发明中所指镁合金包括：1）不同合金组元及合金化水平的镁基合金，2）镁基复合材料，以及3）镁合金制品，和4）含镁合金部件（组元）的制品。It should be pointed out that the pure magnesium referred to in the present invention includes: 1) magnesium metal with different purity levels, 2) pure magnesium products, and 3) products containing pure magnesium parts (components). The magnesium alloy referred to in the present invention includes: 1) magnesium-based alloys with different alloy components and alloying levels, 2) magnesium-based composite materials, and 3) magnesium alloy products, and 4) magnesium-containing alloy parts (components) products.
与现有技术相比，本发明的优点是多方面的，突出表现在以下两个方面：Compared with prior art, advantage of the present invention is many-sided, and outstanding performance is in following two aspects:
（1）材料集理想特性于一身 就本发明材料的功能膜部分而言，其中可降解高分子材料由于生物相容性优良且具有流体→固体转化及疏水特性，不仅是氧化镁、氢氧化镁、纯镁、镁合金、β-TCP和CPP等非块体材料理想的“粘结剂”，而且同时具备冷/热成形性好，厚度、致密度及降解性等灵活可控的特点；其中氧化镁、氢氧化镁、纯镁、镁合金、β-TCP和CPP不仅具备生物降解能力，而且降解产物是人体所需的营养素。另一方面，氧化镁、氢氧化镁、纯镁和镁合金同时还具有与可降解高分子材料的酸性降解产物（如PLLA降解的中间产物乳酸和最终产物二氧化碳和水）发生中和反应，缓冲/消除其潜在危害（如无菌性炎症等）的突出作用。此外，作为高分子材料基复合材料的增强相，氧化镁、氢氧化镁、纯镁、镁合金、β-TCP和CPP不仅可以在一定程度上改善基体的力学性能，而且可以在较大程度上改善涂层/基体结合力以及涂层的降解防护性能并调节涂层的降解速率。基于上述分析，本发明材料中的功能膜不仅兼具优异的生物相容性和降解防护性（对基体），而且自身具有可控生物降解性——既能在特定阶段如植入初期有效阻断环境中侵蚀性介质的作用通道，对基体形成严密保护（降解防护），又能随着受损组织/器官的功能重建而自身逐渐降解（自降解），最终暴露基体以利其自然降解、吸收，且其降解防护能力及自降解速率均可以通过膜层成分、结构和厚度进行调控。如在其它参数相同的前提下，功能膜厚度越厚，则其降解防护能力越强；功能膜结构越疏松，则其降解防护能力越弱；功能膜自身组成成分越难降解，则其自降解速率越慢。而本发明材料的基体部分——纯镁或镁合金兼具生物相容性、力学相容性、生物降解性和生物活性，且其降解速率可通过成分、微观结构优化如合金化、晶粒细化等技术进行调控。因此，本发明材料整体具有明显的优势——有望彻底消除现有材料普遍存在的或因片面强调生物降解性而损害生物相容性或机械完整性，或因片面强调降解防护性而损害生物降解性等弊端，从而为可降解生物材料生物降解特性利用和降解速率控制之间的矛盾提供理想的解决方案。(1) The material integrates ideal characteristics. As far as the functional film part of the material of the present invention is concerned, the degradable polymer material is not only magnesium oxide, magnesium hydroxide, , pure magnesium, magnesium alloy, β-TCP and CPP and other non-bulk materials are ideal "binders", and at the same time have the characteristics of good cold/hot formability, flexible and controllable thickness, density and degradation; among them Magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloys, β-TCP and CPP not only have biodegradability, but also the degradation products are nutrients needed by the human body. On the other hand, magnesium oxide, magnesium hydroxide, pure magnesium and magnesium alloys also have the ability to neutralize the acidic degradation products of degradable polymer materials (such as the intermediate product of PLLA degradation, lactic acid, and the final products of carbon dioxide and water). / Eliminate its prominent role in potential hazards (such as sterile inflammation, etc.). In addition, as the reinforcing phase of polymer matrix composites, magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloys, β-TCP and CPP can not only improve the mechanical properties of the matrix to a certain extent, but also can Improve the coating/substrate bonding force and the degradation protection performance of the coating and adjust the degradation rate of the coating. Based on the above analysis, the functional film in the material of the present invention not only has excellent biocompatibility and degradation resistance (to the matrix), but also has controllable biodegradability—it can effectively prevent Break the action channel of the erosive medium in the environment, form a tight protection for the matrix (degradation protection), and gradually degrade itself (self-degradation) with the functional reconstruction of the damaged tissue/organ, and finally expose the matrix to facilitate its natural degradation. Absorption, and its degradation protection ability and self-degradation rate can be regulated by the composition, structure and thickness of the film layer. For example, under the same premise of other parameters, the thicker the functional film is, the stronger its degradation protection ability is; the looser the functional film structure is, the weaker its degradation protection ability is; The slower the rate. And the matrix part of the material of the present invention—pure magnesium or magnesium alloy has biocompatibility, mechanical compatibility, biodegradability and bioactivity, and its degradation rate can be optimized through composition, microstructure such as alloying, crystal grain fine-tuning and other techniques. Therefore, the material of the present invention has obvious advantages as a whole - it is expected to completely eliminate the common existing materials or damage biocompatibility or mechanical integrity due to one-sided emphasis on biodegradability, or damage biodegradation due to one-sided emphasis on degradation protection. Therefore, it provides an ideal solution for the contradiction between the utilization of biodegradable properties of degradable biomaterials and the control of degradation rate.
（2）技术协同实现材料的优化制备 本发明材料制备方法基于对不同材料、不同技术的优势及其协同效应的充分认识，将成形技术与表面改性技术有机复合，尤其是联合利用阳极极化与有机/无机涂覆技术，在基体表面构筑涂层/基体、涂层/涂层间结合紧密，成分、结构和厚度等可调因此降解防护和自降解特性可控，同时具有优异生物相容性和生物活性的多重防御体系，为生物医用可控全降解材料的制备提供了新的思路。具体而言，在含侵蚀性离子如氯离子、硝酸根离子或硫酸根离子的电解液中进行阳极极化处理，纯镁或镁合金的表层金属原子将离子化，即发生阳极溶解。由于成分、微观结构等的不均匀性，基体微区溶解过程不均匀进行，阳极溶解作用表现出选择性，即微阳极区优先溶解，因此，客观上，阳极极化对基体不仅具有“去活”作用，而且具有显著的糙化作用，可形成大量显微“锚点”，从而为涂层/基体间的紧密结合创造条件。当氧化镁、氢氧化镁、纯镁、镁合金、β-TCP和CPP作为涂层材料独立使用时，存在涂覆困难、结合力差等突出问题，而将其作为有机涂层的夹心层或高分子材料基复合材料的弥散相（增强相）使用时，上述问题则迎刃而解。因此，利用本发明提供的技术，可实现可控全降解材料的优化制备。(2) Technology synergy realizes the optimized preparation of materials With organic/inorganic coating technology, the coating/matrix and coating/coating are closely combined on the surface of the substrate, and the composition, structure and thickness can be adjusted, so the degradation protection and self-degradation characteristics are controllable, and at the same time it has excellent biocompatibility The multiple defense system of sex and biological activity provides a new idea for the preparation of biomedical controllable fully degradable materials. Specifically, anodic polarization treatment is performed in an electrolyte solution containing corrosive ions such as chloride ions, nitrate ions or sulfate ions, and the surface metal atoms of pure magnesium or magnesium alloys will be ionized, that is, anodic dissolution will occur. Due to the inhomogeneity of composition, microstructure, etc., the dissolution process of the matrix micro-area is not uniform, and the anodic dissolution shows selectivity, that is, the micro-anode area is preferentially dissolved. Therefore, objectively, anodic polarization has not only "deactivation" effect on the matrix "Effect, and has a significant roughening effect, which can form a large number of microscopic "anchor points", thereby creating conditions for a tight bond between the coating/substrate. When magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP and CPP are used independently as coating materials, there are outstanding problems such as difficult coating and poor bonding force, and they are used as a sandwich layer of an organic coating or When the dispersed phase (reinforcing phase) of the polymer-based composite material is used, the above problems can be easily solved. Therefore, using the technology provided by the invention, the optimized preparation of controllable fully degradable materials can be realized.
附图说明Description of drawings
图1是实施方式中材料制备方法工艺流程图；Fig. 1 is a process flow chart of the material preparation method in the embodiment;
图2是实施方式中材料断面结构示意图；Fig. 2 is a schematic diagram of a cross-sectional structure of a material in an embodiment;
图3是实施方式中材料功能膜断面结构示意图；3 is a schematic diagram of a cross-sectional structure of a material functional film in an embodiment;
图中：1-基体，2-功能膜，a-可降解高分子材料层，b-氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其中两种以上混合物层，c-可降解高分子材料层，d-以氧化镁、氢氧化镁、纯镁、镁合金、β-TCP、CPP或其中两种以上混合物为增强相的可降解高分子材料基复合材料层。In the figure: 1-substrate, 2-functional film, a-degradable polymer material layer, b-magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP, CPP or a mixture of two or more thereof, c - Degradable polymer material layer, d - Degradable polymer material-based composite material layer with magnesium oxide, magnesium hydroxide, pure magnesium, magnesium alloy, β-TCP, CPP or a mixture of two or more of them as the reinforcing phase.
具体实施方式Detailed ways
以下结合附图和实例对本发明的具体实施作进一步说明，但本发明的实施和保护范围不限于此。The specific implementation of the present invention will be further described below in conjunction with the accompanying drawings and examples, but the implementation and protection scope of the present invention are not limited thereto.
如图1所示，为本发明生物医用可控全降解材料制备方法工艺流程图。本发明材料的制备方法由熔炼、成形→阳极极化→涂覆三大主要步骤构成。其中熔炼、成形的目的在于获得材料（化学及相组成、微观结构、晶粒大小等）、形状和尺寸等满足要求的制品基体；阳极极化的主要作用在于实现对制品基体表面的“去活”和“糙化”双重处理；涂覆的作用在于在基体表面构筑功能膜。As shown in Figure 1, it is a process flow chart of the preparation method of the biomedical controllable fully degradable material of the present invention. The preparation method of the material of the invention consists of three main steps of smelting, forming→anodic polarization→coating. Among them, the purpose of smelting and forming is to obtain the product matrix that meets the requirements of material (chemical and phase composition, microstructure, grain size, etc.), shape and size; the main function of anodic polarization is to realize the "deactivation" of the surface of the product matrix " and "roughening" double treatment; the function of coating is to build a functional film on the surface of the substrate.
如图2所示，为本发明材料断面结构示意图。本发明生物医用可降解材料由纯镁或镁合金基体1及覆盖在基体1表面的功能膜2整体构筑而成。As shown in Fig. 2, it is a schematic diagram of the cross-sectional structure of the material of the present invention. The biomedical degradable material of the present invention is integrally constructed by a pure magnesium or magnesium alloy substrate 1 and a functional film 2 covering the surface of the substrate 1 .
如图3所示，为本发明材料的功能膜断面结构示意图。其中a涂层、b涂层和c涂层叠加在一起，属于本发明所述No.1涂层，b涂层属于No.1涂层的夹心层。其中d涂层属于本发明所述No.2涂层。As shown in FIG. 3 , it is a schematic diagram of the cross-sectional structure of the functional film of the material of the present invention. Wherein a coating, b coating and c coating are superimposed together and belong to No.1 coating in the present invention, and b coating belongs to the sandwich layer of No.1 coating. Wherein the d coating belongs to the No.2 coating of the present invention.
以下结合本发明的优选实施例，对本发明的上述特征作进一步详细说明。The above-mentioned features of the present invention will be further described in detail below in conjunction with preferred embodiments of the present invention.
实施例中所用材料包括高纯镁（纯度99.9%），镁合金AZ31、AZ91、WE43和ZK60。按照材料成分分别进行熔炼，成形，获得试件。其中熔炼条件：温度750-760℃，0.3vol%SF6+50vol%CO2与空气的混合气体保护，熔体保温时间30min。成形技术包括金属型铸造（高纯镁和上述全部镁合金）、压铸（镁合金AZ31和AZ91）、锻造（镁合金WE43）和热挤压（镁合金AZ31和ZK60），其中金属型铸造条件：710-720℃；压铸条件：浇注温度660℃，型温220℃，压射比压50MPa，压射速率40m/s；锻造条件：以圆柱形铸锭为坯料，自由锻，始锻温度400℃，终锻温度320℃，锻造比1.87，每次锻造前420℃保温2h；热挤压条件：以圆柱形铸锭为坯料，挤压温度350℃，挤压比20，挤压速率1.5m/min。线切割上述试件获得尺寸为20mm×15mm×2.5mm的测试试样。按如下规范对试样进行表面整理：碱洗→水洗→酸洗→水洗→水磨砂纸由粗到细依次打磨→水洗→无水乙醇超声清洗→热风吹干→备用，其中碱洗条件：40.0g/L氢氧化钠、10.0g/L磷酸钠和0.2g/L十二烷基苯磺酸钠的复配溶液，95℃，15min；酸洗条件：20.0g/L硝酸、50.0g/L硝酸镁与50.0g/L无水乙醇的复配溶液，25℃，15sec；水洗条件：自来水和蒸馏水依次漂洗。Materials used in the examples include high-purity magnesium (purity 99.9%), magnesium alloys AZ31, AZ91, WE43 and ZK60. Smelting and shaping are carried out according to the material composition to obtain test pieces. Among them, melting conditions: temperature 750-760 ℃, 0.3vol%SF6 +50vol%CO2 mixed gas protection with air, melt holding time 30min. Forming techniques include metal mold casting (high purity magnesium and all the above magnesium alloys), die casting (magnesium alloys AZ31 and AZ91), forging (magnesium alloy WE43) and hot extrusion (magnesium alloys AZ31 and ZK60), in which metal mold casting conditions: 710- 720°C; die-casting conditions: pouring temperature 660°C, mold temperature 220°C, injection specific pressure 50MPa, injection speed 40m/s; forging conditions: cylindrical ingot as blank, free forging, initial forging temperature 400°C, final The forging temperature is 320°C, the forging ratio is 1.87, and the temperature is kept at 420°C for 2 hours before each forging; the hot extrusion conditions: the cylindrical ingot is used as the billet, the extrusion temperature is 350°C, the extrusion ratio is 20, and the extrusion speed is 1.5m/min. The above test piece was cut by wire to obtain a test sample with a size of 20mm×15mm×2.5mm. Finish the surface of the sample according to the following specifications: alkali washing→water washing→acid washing→water washing→water abrasive paper grinding from coarse to fine→water washing→ultrasonic cleaning with absolute ethanol→hot air drying→reserve, among which the alkali cleaning condition: 40.0g Compound solution of /L sodium hydroxide, 10.0g/L sodium phosphate and 0.2g/L sodium dodecylbenzenesulfonate, 95°C, 15min; pickling conditions: 20.0g/L nitric acid, 50.0g/L nitric acid Composite solution of magnesium and 50.0g/L absolute ethanol, 25°C, 15sec; washing conditions: rinse with tap water and distilled water in sequence.
实施例1Example 1
以金属型铸造态高纯镁试样为研究对象。以蒸馏水为溶剂，配制20.0g/L氯化钠溶液作为阳极极化电解液。将同一材质的等面积试样与导线连接后分别接正弦AC电源的两个输出端口，并浸入控温25℃的上述电解液中，保持试样间距3cm，50Hz恒流1.0mA/cm2处理30min。水洗、干燥后，发现试样表面均匀分布肉眼可见的尺寸和深度一致的细碎坑点。以二氯甲烷为溶剂，配制40.0g/LPLLA溶液，标记为S01；以正丁醇为分散剂（液体），添加10.0g/L氧化镁（固体分散相），搅拌均匀获得悬浮液，标记为S02；以环氧氯丙烷与丙酮的均匀混合物（混合体积比2:1）为溶剂，首先配制25.0g/LPLLA溶液（液体）共5份，之后分别加入5.0g/L氧化镁、氢氧化镁、纯镁粉（球形，中位粒径d50=47μm）、β-TCP和CPP（固体分散相），搅拌均匀获得悬浮液，分别标记为溶液S03-1、S03-2、S03-3、S03-4和S03-5。按如下规范对阳极极化试样进行浸涂处理：将试样浸入溶液S01，7sec后取出，待涂层固化后将试样浸入悬浮液S02，15sec后取出，以冷风吹干涂层后将试样浸入溶液S01，3sec后取出，待涂层固化将试样浸入溶液S03-1，10sec后取出，待涂层固化后将试样浸入溶液S01，3sec后取出，待涂层固化将试样浸入溶液S03-2，10sec后取出，待涂层固化后将试样浸入溶液S01，3sec后取出，待涂层固化将试样浸入溶液S03-3，10sec后取出，待涂层固化后将试样浸入溶液S01，3sec后取出，待涂层固化将试样浸入溶液S03-4，10sec后取出，待涂层固化后将试样浸入溶液S01，3sec后取出，待涂层固化将试样浸入溶液S03-5，10sec后取出，待涂层固化后将试样浸入溶液S01，3sec后取出，待涂层固化。结果在阳极极化试样表面获得均匀的复合涂层（功能膜），该涂层由1）以氧化镁为夹心层的PLLA涂层，和2）分别以氧化镁、氢氧化镁、纯镁、β-TCP或CPP为增强相的PLLA基复合材料为夹心层的PLLA涂层依次叠加而成。The sample of high-purity magnesium as cast metal was taken as the research object. Using distilled water as solvent, prepare 20.0g/L sodium chloride solution as anodic polarization electrolyte. Connect the equal-area samples of the same material to the wires, then connect them to the two output ports of the sinusoidal AC power supply, and immerse them in the above-mentioned electrolyte with a temperature control of 25°C, keep the distance between the samples at 3cm, and treat with a constant current of 1.0mA/cm2at 50Hz 30min. After washing and drying, it was found that the surface of the sample was uniformly distributed with finely divided pits of the same size and depth visible to the naked eye. Use dichloromethane as solvent, prepare 40.0g/LPLLA solution, marked as S01 ; use n-butanol as dispersant (liquid), add 10.0g/L magnesium oxide (solid dispersed phase), stir evenly to obtain suspension, marked is S02 ; using a homogeneous mixture of epichlorohydrin and acetone (mixing volume ratio 2:1) as solvent, first prepare 5 parts of 25.0g/LPLLA solution (liquid), then add 5.0g/L magnesium oxide, hydrogen Magnesium oxide, pure magnesium powder (spherical, median particle size d50 =47μm), β-TCP and CPP (solid dispersed phase), stirred evenly to obtain a suspension, respectively marked as solution S03 -1, S03 -2, S03 -3, S03 -4 and S03 -5. Dip-coat the anodized sample according to the following specifications: immerse the sample in the solution S01 and take it out after 7 seconds. After the coating is cured, immerse the sample in the suspension S02 and take it out after 15 seconds. Dry the coating with cold air Finally, immerse the sample in solution S01 and take it out after 3 sec. After the coating is cured, immerse the sample in solution S03 -1 and take it out after 10 sec. After the coating is cured, immerse the sample in solution S01 and take it out after 3 sec. After the layer is cured, immerse the sample in solution S03 -2 and take it out after 10 sec. After the coating is cured, immerse the sample in solution S01 and take it out after 3 sec. After the coating is cured, immerse the sample in solution S03 -3 and take it out after 10 sec. , after the coating is cured, immerse the sample in the solution S01 , take it out after3 sec; After the coating is cured, immerse the sample in solution S03 -5 and take it out after 10 sec. After the coating is cured, immerse the sample in solution S01 and take it out after 3 sec until the coating is cured. Results A uniform composite coating (functional film) was obtained on the surface of the anodized sample, which was composed of 1) PLLA coating with magnesium oxide as the sandwich layer, and 2) magnesium oxide, magnesium hydroxide, pure magnesium , β-TCP or CPP as the reinforcing phase of the PLLA-based composite material as the sandwich layer of PLLA coating layered in sequence.
以SBF（模拟体液）为测试介质（其成分与人体血浆化学成分对比情况见表1），控制容面比（即溶液体积与试样表面积之比）24ml/cm2，溶液更新间隔期24h，测试温度37℃条件下，对上述试样分别进行体外生物降解性能测试。结果表明：试样在约21d后基体才开始出现肉眼可见的蚀痕，相比空白试样（即仅表面整理而未进行阳极极化及涂覆处理的试样）浸入后即开始腐蚀的结果，其初期抗降解能力明显增强，表明功能膜对基体具有良好的生物降解防护能力；功能膜在约37d后基本完全消失，表明其具有良好的自降解特性；试样在约195d后完全降解，表明材料整体具有全降解特性。Take SBF (simulated body fluid) as the test medium (see Table 1 for the comparison of its composition and the chemical composition of human plasma), control the volume-to-surface ratio (that is, the ratio of the solution volume to the surface area of the sample) to 24ml/cm2 , and the solution renewal interval is 24h. Under the test temperature of 37°C, the in vitro biodegradation performance tests were carried out on the above samples respectively. The results show that the substrate of the sample begins to show visible corrosion marks after about 21 days, compared with the blank sample (that is, the sample with only surface finishing but no anodic polarization and coating treatment) that begins to corrode after immersion , its initial anti-degradation ability is obviously enhanced, indicating that the functional film has good biodegradation protection ability to the substrate; the functional film basically disappears after about 37d, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 195d, It shows that the material as a whole has full degradation characteristics.
实施例2Example 2
以金属型铸造态AZ31镁合金试样为研究对象。除将电解液改为以去离子水配制的20.0mg/L的氯化钠溶液外，阳极极化其它条件控制同实施例1，结果发现：除凹坑密度及深度降低外，处理效果同实施例1。除将溶剂改为氯仿，溶质PLLA改为PLGA外，溶液S01配制的其它条件控制同实施例1。除将氧化镁分别改为氢氧化镁、纯镁粉（球形，中位粒径d50=47μm）、β-TCP或CPP外，溶液S02配制的其它条件控制同实施例1，对应溶液分别标记为S02-1、S02-2、S02-3和S02-4。按如下规范对水洗、干燥后的阳极极化试样进行浸涂处理：将试样浸入溶液S01，7sec后取出，待涂层固化后将试样浸入溶液S02-1，15sec后取出，以冷风吹干涂层后将试样浸入溶液S01，3sec后取出，待涂层固化后将试样浸入溶液S02-2，10sec后取出，以冷风吹干涂层后将试样浸入溶液S01，3sec后取出，待涂层固化后将试样浸入溶液S02-3，10sec后取出，以冷风吹干涂层后将试样浸入溶液S01，待涂层固化后将试样浸入溶液S02-4，10sec后取出，以冷风吹干涂层后将试样浸入溶液S01，待涂层固化。结果在试样表面获得均匀的涂层（功能膜），该涂层由分别以氢氧化镁、纯镁、β-TCP和CPP为夹心层的PLGA涂层依次叠加而成。同实施例1进行材料体外生物降解性能测试，结果表明：试样在约14d后基体才开始出现肉眼可见的蚀痕，表明功能膜对基体具有一定的生物降解防护能力；功能膜在约30d后基本完全消失，表明其具有良好的自降解特性；试样在约90d后完全降解，表明材料整体具有全降解特性。The sample of AZ31 magnesium alloy in mold casting state was taken as the research object. Except that the electrolyte was changed to 20.0 mg/L sodium chloride solution prepared with deionized water, other conditions of anodic polarization were controlled the same as in Example 1. It was found that the treatment effect was the same as that of the implementation except that the density and depth of pits were reduced. example 1. Except that the solvent was changed to chloroform, and the solute PLLA was changed to PLGA, the other conditions for the preparation of the solutionS01 were controlled as in Example 1. Except changing magnesium oxide to magnesium hydroxide, pure magnesium powder (spherical, median particle size d50 =47μm), β-TCP or CPP, the other conditions of solution S02 preparation are the same as in Example 1, and the corresponding solutions are respectively Marked as S02 -1, S02 -2, S02 -3 and S02 -4. Dip-coat the anodized sample after washing and drying according to the following specifications: immerse the sample in solution S01 and take it out after 7 seconds; after the coating is cured, immerse the sample in solution S02 -1 and take it out after 15 seconds. After drying the coating with cold wind, immerse the sample in solution S01 and take it out after 3 sec. After the coating is cured, immerse the sample in solution S02 -2 and take it out after 10 sec. After drying the coating with cold wind, immerse the sample in the solution S01 , take it out after 3 sec, immerse the sample in the solution S02 -3 after 10 sec, after the coating is cured, take it out after 10 sec, dry the coating with cold air, then immerse the sample in the solution S01 , and immerse the sample in the solution after the coating is cured The solution S02 -4 was taken out after 10 sec, and the coating was dried with cold wind, and then the sample was immersed in the solution S01 until the coating was cured. As a result, a uniform coating (functional film) was obtained on the surface of the sample. The coating was sequentially stacked by PLGA coatings with magnesium hydroxide, pure magnesium, β-TCP and CPP as sandwich layers. The in vitro biodegradability test of the material was carried out the same as in Example 1, and the results showed that the substrate of the sample began to have visible corrosion marks after about 14 days, indicating that the functional film had a certain biodegradation protection ability for the substrate; Almost completely disappeared, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 90 days, indicating that the material as a whole has full degradation characteristics.
实施例3Example 3
以金属型铸造态AZ91镁合金试样为研究对象。除将电解液改为以蒸馏水配制的100.0g/L氯化钠溶液外，阳极极化其它条件控制同实施例1，结果发现：除单个凹坑面积增大，凹坑密度及其分布均匀性降低外，其它同实施例1。同实施例1进行溶液S03-1的配制。以该溶液对经水洗、干燥后的阳极极化试样分别进行刷涂、旋涂和喷涂处理，获得面密度为1.75mg/cm2的均匀的氧化镁/PLLA复合材料涂层（功能膜）。同实施例1进行材料体外生物降解性能测试，结果表明：试样在约42d后基体才开始出现肉眼可见的蚀痕，表明功能膜对基体具有良好的生物降解防护能力；功能膜在约75d后基本完全消失，表明其具有良好的自降解特性；试样在约170d后完全降解，表明材料整体具有全降解特性。The sample of AZ91 magnesium alloy in mold casting state was taken as the research object. Except that the electrolyte was changed to 100.0g/L sodium chloride solution prepared with distilled water, the other conditions of anodic polarization were controlled the same as in Example 1. It was found that, except for the increase in the area of a single pit, the density of pits and the uniformity of their distribution Except reducing, other is with embodiment 1. The preparation of solution S03 -1 was carried out as in Example 1. Use this solution to brush, spin and spray the washed and dried anodized sample respectively to obtain a uniform magnesium oxide/PLLA composite coating (functional film) with an area density of 1.75mg/cm2 . The in vitro biodegradability test of the material was carried out the same as in Example 1, and the results showed that: the substrate of the sample began to have visible corrosion marks after about 42 days, indicating that the functional film had good biodegradation protection ability for the substrate; Almost completely disappeared, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 170d, indicating that the material as a whole has full degradation characteristics.
实施例4Example 4
以金属型铸造态WE43镁合金试样为研究对象。除将电解液中的氯化钠分别改为硝酸钠、硫酸钠、氯化锂、硝酸锂、硫酸锂、氯化钾、硝酸钾、硫酸钾、氯化铵、硝酸铵、硫酸铵、氯化镁、硝酸镁或硫酸镁外，阳极极化其它条件控制及结果同实施例1。以氯仿与无水乙醇的均匀混合物（混合体积比4:1）为溶剂，首先分别配制5.0、10.0、15.0和20.0g/LPLLA溶液，然后边机械搅拌边加入10.0g/L氢氧化镁，混合均匀后获得悬浮液，标记为溶液S04-1、S04-2、S04-3和S04-4。按如下规范对水洗、干燥后的阳极极化试样进行浸涂处理：将试样浸入溶液S04-1，45sec后取出，待涂层固化后将试样浸入溶液S04-2，30sec后取出，待涂层固化后将试样浸入溶液S04-3，45sec后取出，待涂层固化后将试样浸入溶液S04-4，30sec后取出，待涂层固化。结果在试样表面获得均匀的由不同含量的氢氧化镁为增强相的PLLA基复合材料涂层叠加而成的复合涂层（功能膜）。同实施例1进行材料体外生物降解性能测试，结果表明：试样在约20d后基体才开始出现肉眼可见的蚀痕，表明功能膜对基体具有良好的生物降解防护能力；功能膜在约45d后基本完全消失，表明其具有良好的自降解特性；试样在约120d后完全降解，表明材料整体具有全降解特性。The sample of WE43 magnesium alloy in mold casting state was taken as the research object. In addition to changing the sodium chloride in the electrolyte into sodium nitrate, sodium sulfate, lithium chloride, lithium nitrate, lithium sulfate, potassium chloride, potassium nitrate, potassium sulfate, ammonium chloride, ammonium nitrate, ammonium sulfate, magnesium chloride, Except for magnesium nitrate or magnesium sulfate, the control and results of other conditions of anodic polarization are the same as in Example 1. Using a homogeneous mixture of chloroform and absolute ethanol (mixing volume ratio 4:1) as a solvent, first prepare 5.0, 10.0, 15.0 and 20.0 g/L PLLA solutions respectively, then add 10.0 g/L magnesium hydroxide while stirring mechanically, and mix Suspensions were obtained after homogenization, labeled solutions S04 -1 , S04 -2 , S04 -3 and S04 -4. Dip-coat the washed and dried anodized sample according to the following specifications: immerse the sample in solution S04 -1, take it out after 45 sec, and immerse the sample in solution S04 -2 after 30 sec after the coating is cured Take it out, after the coating is cured, immerse the sample in the solution S04 -3, take it out after 45 sec, after the coating is cured, immerse the sample in the solution S04 -4, take it out after 30 sec, and wait for the coating to be cured. Results A uniform composite coating (functional film) was obtained on the surface of the sample, which was superimposed by PLLA-based composite coatings with different contents of magnesium hydroxide as the reinforcing phase. The in vitro biodegradability test of the material was carried out the same as in Example 1, and the results showed that the substrate began to show visible corrosion marks after about 20 days, indicating that the functional film had good biodegradation protection ability for the substrate; Almost completely disappeared, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 120d, indicating that the material as a whole has full degradation characteristics.
实施例5Example 5
以金属型铸造态ZK60镁合金试样为研究对象。阳极极化工艺条件控制及结果同实施例1。以环氧氯丙烷与丙酮的均匀混合物（混合体积比3:1）为溶剂，配制75.0g/LPLLA溶液，标记为S05；以乙醇为分散剂（液体），添加45.0g/L氢氧化镁（固体分散相），搅拌均匀获得悬浮液，标记为S06；以氯仿为溶剂，首先配制75.0g/LPLLA溶液，然后加入0.377g/L的氢氧化镁，搅拌均匀获得悬浮液，标记为S07。按如下规范对水洗、干燥后的阳极极化试样进行7轮浸涂处理：将试样浸入溶液S05中，20sec后取出，待涂层固化后将试样浸入溶液S06中，10sec后取出，待涂层干燥后将试样浸入溶液S05中，45sec后取出，待涂层固化后将试样浸入溶液S07，30sec后取出，待涂层固化后将试样浸入溶液S05中，45sec后取出，待涂层固化。结果在试样表面获得均匀的复合涂层（功能膜），该涂层由1）以氢氧化镁为夹心层的PLLA涂层，2）以氢氧化镁/PLLA复合材料为夹心层的PLLA涂层依次叠加而成。同实施例1进行材料体外生物降解性能测试，结果表明：试样在约37d后基体才开始出现肉眼可见的蚀痕，表明功能膜对基体具有一定的生物降解防护能力；功能膜在约85d后基本完全消失，表明其具有良好的自降解特性；试样在约130d后完全降解，表明材料整体具有全降解特性。The ZK60 magnesium alloy sample in metal mold casting state was taken as the research object. The anodic polarization process condition control and results are the same as in Example 1. Use the homogeneous mixture of epichlorohydrin and acetone (mixing volume ratio 3:1) as solvent to prepare 75.0g/LPLLA solution, marked as S05 ; use ethanol as dispersant (liquid), add 45.0g/L magnesium hydroxide (solid dispersed phase), stir evenly to obtain a suspension, marked as S06 ; use chloroform as a solvent, first prepare a 75.0g/LPLLA solution, then add 0.377g/L magnesium hydroxide, stir evenly to obtain a suspension, marked as S07 . The washed and dried anodized samples were subjected to 7 rounds of dip-coating treatment according to the following specifications: immerse the sample in the solutionS05 , take it out after 20sec, and immerse the sample in the solutionS06 after 10sec after the coating is cured Take it out, immerse the sample in the solutionS05 after the coating is dry, take it out after 45sec, immerse the sample in the solutionS07 after the coating is cured, take it out after 30sec, and immerse the sample in the solutionS05 after the coating is cured , Take it out after 45sec, and wait until the coating is cured. As a result, a uniform composite coating (functional film) was obtained on the surface of the sample, which was composed of 1) PLLA coating with magnesium hydroxide as the sandwich layer, and 2) PLLA coating with magnesium hydroxide/PLLA composite material as the sandwich layer. Layers are superimposed sequentially. The in vitro biodegradability test of the material was carried out the same as in Example 1, and the results showed that the substrate of the sample began to have visible corrosion marks after about 37 days, indicating that the functional film had a certain biodegradation protection ability for the substrate; Almost completely disappeared, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 130d, indicating that the material as a whole has full degradation characteristics.
实施例6Example 6
以压铸AZ91镁合金试样为研究对象。阳极极化工艺条件控制及结果同实施例1。除将PLLA浓度改为0.2g/L，氢氧化镁浓度改为0.5g/L外，溶液S05和S06配制的其它条件控制同实施例5。除将PLLA浓度改为0.2g/L，氢氧化镁浓度改为0.133g/L外，溶液S07配制的其它条件控制同实施例5。同实施例5对水洗、干燥后的阳极极化试样进行涂覆，结果同实施例5。同实施例1进行材料体外生物降解性能测试，结果表明：试样在约12d后基体才开始出现肉眼可见的蚀痕，表明功能膜对基体具有一定的生物降解防护能力；功能膜在约25d后基本完全消失，表明其具有良好的自降解特性；试样在约147d后完全降解，表明材料整体具有全降解特性。The die-casting AZ91 magnesium alloy sample was taken as the research object. The anodic polarization process condition control and results are the same as in Example 1. Except that the concentration of PLLA was changed to 0.2g/L, and the concentration of magnesium hydroxide was changed to 0.5g/L, the other conditions for the preparation of solutionsS05 andS06 were controlled the same as in Example 5. Except that the concentration of PLLA was changed to 0.2g/L and the concentration of magnesium hydroxide was changed to 0.133g/L, the other conditions for the preparation of solutionS07 were controlled as in Example 5. The washed and dried anodized sample was coated in the same way as in Example 5, and the results were the same as in Example 5. The in vitro biodegradability test of the material was carried out the same as in Example 1, and the results showed that the substrate of the sample began to have visible corrosion marks after about 12 days, indicating that the functional film had a certain biodegradation protection ability for the substrate; Almost completely disappeared, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 147d, indicating that the material as a whole has full degradation characteristics.
实施例7Example 7
以锻造WE43镁合金试样为研究对象。阳极极化工艺条件控制及结果同实施例1。同实施例1进行溶液S02的配制。将PLLA固体颗粒加热至完全熔融状态并210℃保温，标记为溶液S08。按如下规范对水洗、干燥后的阳极极化试样进行浸涂处理：将试样浸入溶液S08，30sec后取出，待涂层固化后将试样浸入溶液S02，15sec后取出，待涂层干燥后将试样浸入溶液S08，2sec后取出，待涂层固化。结果在试样表面获得均匀的以氧化镁为夹心层的PLLA涂层。同实施例1进行材料体外生物降解性能测试，结果表明：试样在约5d后基体才开始出现肉眼可见的蚀痕，表明功能膜对基体具有一定的生物降解防护能力；功能膜在约12d后基本完全消失，表明其具有良好的自降解特性；试样在约100d后完全降解，表明材料整体具有全降解特性。The forged WE43 magnesium alloy sample was taken as the research object. The anodic polarization process condition control and results are the same as in Example 1. Carry out the preparation of solutionS02 with embodiment 1. The solid particles of PLLA are heated to a completely molten state and kept at 210°C, which is marked as solution S08 . Dip-coat the anodized sample after washing and drying according to the following specifications: immerse the sample in solution S08 and take it out after 30 sec. After the coating is cured, immerse the sample in solution S02 and take it out after 15 sec. After the layer is dry, immerse the sample in the solution S08 , take it out after 2 sec, and wait for the coating to solidify. Results A uniform PLLA coating with magnesium oxide as the sandwich layer was obtained on the surface of the sample. The in vitro biodegradability test of the material was carried out the same as in Example 1, and the results showed that the substrate of the sample began to have visible corrosion marks after about 5 days, indicating that the functional film had a certain biodegradation protection ability for the substrate; Almost completely disappeared, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 100d, indicating that the material as a whole has full degradation characteristics.
实施例8Example 8
以挤压态AZ31镁合金试样为研究对象。阳极极化工艺条件控制及结果同实施例1。将190.0gPLLA固体颗粒加热至完全熔融状态并210℃保温，加入5.0g氧化镁与5.0g氢氧化镁的混合物，搅拌均匀获得悬浮液，标记为溶液S09。按如下规范对水洗、干燥后的阳极极化试样进行浸涂处理：将试样浸入溶液S09，45sec后取出，待涂层固化后将试样浸入溶液S09，3sec后取出，待涂层固化。结果在试样表面获得均匀的以氧化镁和氢氧化镁为增强相的PLLA基复合材料涂层。同实施例1进行材料体外生物降解性能测试，结果表明：试样在约10d后基体才开始出现肉眼可见的蚀痕，表明功能膜对基体具有一定的生物降解防护能力；功能膜在约23d后基本完全消失，表明其具有良好的自降解特性；试样在约130d后完全降解，表明材料整体具有全降解特性。The extruded AZ31 magnesium alloy sample was taken as the research object. The anodic polarization process condition control and results are the same as in Example 1. Heat 190.0g of PLLA solid particles to a completely molten state and keep it warm at 210°C, add a mixture of 5.0g of magnesium oxide and 5.0g of magnesium hydroxide, stir evenly to obtain a suspension, which is marked as solution S09 . Dip-coat the anodized sample after washing and drying according to the following specifications: immerse the sample in solution S09 , take it out after 45 seconds, immerse the sample in solution S09 after the coating is cured, take it out after 3 seconds, and wait for coating layer solidified. Results A uniform PLLA-based composite coating with magnesium oxide and magnesium hydroxide as reinforcing phases was obtained on the surface of the sample. The in vitro biodegradability test of the material was carried out the same as in Example 1, and the results showed that the substrate of the sample began to have visible corrosion marks after about 10 days, indicating that the functional film had a certain biodegradation protection ability for the substrate; Almost completely disappeared, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 130d, indicating that the material as a whole has full degradation characteristics.
实施例9Example 9
以压铸态AZ31镁合金试样为研究对象。阳极极化工艺条件控制及结果同实施例1。以氯仿为溶剂，配制5.0、10.0、15.0、20.0和25.0g/LPLLA溶液，分别标记为溶液S10-1、S10-2、S10-3、S10-4和S10-5；以乙醇为分散剂（液体），添加10.0g/L氢氧化镁（固体分散相）搅拌均匀获得悬浮液，标记为S11。按如下规范对水洗、干燥后的阳极极化试样进行浸涂处理：将试样浸入溶液S10-1，15sec后取出，待涂层固化后将试样浸入溶液S11，3sec后取出，待涂层固化后将试样浸入溶液S10-2，15sec后取出，待涂层固化后将试样浸入溶液S11，3sec后取出，待涂层固化后将试样浸入溶液S10-3，15sec后取出，待涂层固化后将试样浸入溶液S11，3sec后取出，待涂层固化将试样浸入溶液S10-4，15sec后取出，待涂层固化后将试样浸入溶液S11，3sec后取出，待涂层固化后将试样浸入溶液S10-5，15sec后取出，待涂层固化后将试样浸入溶液S11，3sec后取出，待涂层固化。结果在试样表面获得均匀的以氢氧化镁为夹心层的PLLA涂层，该涂层的特点在于夹心层两侧的PLLA具有不同的厚度。同实施例1进行材料体外生物降解性能测试，结果表明：试样在约17d后基体才开始出现肉眼可见的蚀痕，表明功能膜对基体具有一定的生物降解防护能力；功能膜在约32d后基本完全消失，表明其具有良好的自降解特性；试样在约127d后完全降解，表明材料整体具有全降解特性。The die-cast AZ31 magnesium alloy sample was taken as the research object. The anodic polarization process condition control and results are the same as in Example 1. Using chloroform as solvent, prepare 5.0, 10.0, 15.0, 20.0 and 25.0 g/LPLLA solutions, which are respectively marked as solutions S10 -1, S10 -2, S10 -3, S10 -4 and S10 -5; Ethanol is the dispersant (liquid), add 10.0g/L magnesium hydroxide (solid dispersed phase) and stir evenly to obtain a suspension, marked as S11 . Dip-coat the washed and dried anodized sample according to the following specifications: immerse the sample in solution S10 -1 and take it out after 15 sec. After the coating is cured, immerse the sample in solution S11 and take it out after 3 sec. After the coating is cured, immerse the sample in solution S10 -2 and take it out after 15 sec; after the coating is cured, immerse the sample in solution S11 and take it out after 3 sec; after the coating is cured, immerse the sample in solution S10 -3 , take it out after 15 sec, immerse the sample in solution S11 after the coating is cured, take it out after 3 sec, immerse the sample in solution S10 -4 after the coating is cured, take it out after 15 sec, immerse the sample in the solution after the coating is cured S11 , take it out after 3 sec, immerse the sample in solution S10 -5 after the coating is cured, take it out after 15 sec, immerse the sample in solution S11 after the coating is cured, take it out after 3 sec, and wait for the coating to cure. Results A uniform PLLA coating with magnesium hydroxide as a sandwich layer was obtained on the surface of the sample. The coating is characterized in that the PLLA on both sides of the sandwich layer has different thicknesses. The in vitro biodegradability test of the material was carried out the same as in Example 1, and the results showed that the substrate of the sample began to have visible corrosion marks after about 17 days, indicating that the functional film had a certain biodegradation protection ability for the substrate; Almost completely disappeared, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 127d, indicating that the material as a whole has full degradation characteristics.
实施例10Example 10
以挤压态ZK60镁合金试样为研究对象。阳极极化条件控制及结果同实施例1。同实施例1进行溶液S01、S02和S03-1的配制。按如下规范对水洗、干燥后的阳极极化试样进行浸涂处理：将试样浸入溶液S03-1，60sec后取出，待涂层固化后将试样浸入溶液S02，15sec后取出，待涂层干燥后将试样浸入溶液S03-1，20sec后取出，待涂层固化后将试样浸入溶液S02，15sec后取出，将试样浸入溶液S01，30sec后取出，待涂层固化。结果在试样表面获得复合涂层（功能膜），该涂层由1）以氧化镁为夹心层的氧化镁/PLLA复合材料涂层，和2）以氧化镁为夹心层，两侧分别为氧化镁/PLLA复合材料涂层和PLLA涂层的涂层叠加而成。同实施例1进行材料体外生物降解性能测试，结果表明：试样在约6d后基体才开始出现肉眼可见的蚀痕，表明功能膜对基体具有一定的生物降解防护能力；功能膜在约15d后基本完全消失，表明其具有良好的自降解特性；试样在约100d后完全降解，表明材料整体具有全降解特性。The extruded ZK60 magnesium alloy sample was taken as the research object. The anodic polarization condition control and results are the same as in Example 1. The preparation of solutions S01 , S02 and S03 -1 was carried out as in Example 1. Dip-coat the washed and dried anodized sample according to the following specifications: immerse the sample in solution S03 -1 and take it out after 60 sec. After the coating is cured, immerse the sample in solution S02 and take it out after 15 sec. After the coating is dry, immerse the sample in solution S03 -1 and take it out after 20 sec. After the coating is cured, immerse the sample in solution S02 and take it out after 15 sec. Immerse the sample in solution S01 and take it out after 30 sec. layer solidified. As a result, a composite coating (functional film) was obtained on the surface of the sample, which consisted of 1) MgO/PLLA composite coating with MgO as the sandwich layer, and 2) MgO as the sandwich layer, with two sides respectively Magnesia/PLLA composite coating and PLLA coating are superimposed. The in vitro biodegradability test of the material was carried out the same as in Example 1, and the results showed that the substrate of the sample began to have visible corrosion marks after about 6 days, indicating that the functional film had a certain biodegradation protection ability for the substrate; Almost completely disappeared, indicating that it has good self-degradation characteristics; the sample is completely degraded after about 100d, indicating that the material as a whole has full degradation characteristics.
进一步参照医疗器械生物学评价ISO 10993标准，以医学临床上广泛使用的钛合金Ti6Al4V为阴性对照，对上述实施例中各试样分别进行以溶血率和体外细胞毒性为代表的生物相容性测试，结果表明：各试样均表现出与Ti6Al4V相当的良好的生物相容性。Further referring to the ISO 10993 standard for biological evaluation of medical devices, and taking the titanium alloy Ti6Al4V widely used in medical clinics as a negative control, the biocompatibility tests represented by hemolysis rate and in vitro cytotoxicity were performed on the samples in the above examples. , the results showed that: each sample showed good biocompatibility comparable to Ti6Al4V.
表1：测试介质与人体血浆化学成分对比Table 1: Comparison of test medium and human plasma chemical composition
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