1.Overview
Biomedical material is an important branch of material science.It is a new carrier material with high technical content and high economic value,which is used to diagnose,treat or replace human tissues and organs or improve their functions.It is a new developing field of material science and technology.Biomedical materials make greater contributions to exploring the mysteries of human life and ensuring human health and longevity.
Over the past 10 years,the market growth rate of biomedical materials and products has been maintained at about 20%-25%.It is expected that in the next 10-15 years,the medical device industry including biomedical materials will reach the market scale of pharmaceutical products and become the pillar industry of the world economy in the 21st century.
Among biomedical metal materials,titanium and its alloys have become the preferred materials for medical implant products such as artificial joints(hip,knee,shoulder,ankle,elbow,wrist,finger joint,etc.),bone trauma products(intramedullary nails,plates,screws,etc.),spinal orthopedic internal fixation system,dental implants,dental brackets,dental orthopedic wires,artificial heart valves,interventional cardiovascular stents,etc.At present,there is no better metal material than titanium alloy for clinical application.Developed countries and world-renowned implant product suppliers attach great importance to the research and development of titanium alloy,and have launched a series of new medical titanium alloy materials,including bioactive titanium alloy bionic materials.They have also made many patented design and development in the surface treatment of medical titanium alloy materials,giving medical titanium alloy materials better bioactivity to meet the physiological needs of human body,So as to achieve the purpose of early recovery of patients.
The world's population is nearly 6.5 billion.According to incomplete statistics,there are nearly 400 million disabled people,60 million physically disabled people and 2 billion dental patients.At present,there are only 35 million people implanted with biomaterial devices,and the annual amount of joint replacement is about 1.5 million,which is far from the number of people who actually need replacement.Therefore,the market demand potential of biomedical materials is huge.As the first choice of Biomedical Metal materials,the demand for titanium and its alloys will also increase greatly.Therefore,it is imperative to strengthen the research and development of medical titanium alloy materials[1].
2.Development history,latest progress and market situation of biomedical titanium and its alloy materials
The development and application of biomedical titanium and its alloys have experienced four landmark stages.
2.1 initial application
In the early 1950s,first in Britain and the United States,commercial pure titanium was used to make bone plates,screws,intramedullary nails and hip joints.Because the bone plate needs to be shaped during surgery in order to apply the physiological and anatomical shape of the broken bone,until now,commercial pure titanium(is05832-2)after special processing is still used to manufacture bone plate and supporting screws,such as the full series of AO plates and screws produced by Mathys Medical Ltd.,Switzerland,the designated manufacturer of AO internal fixation implants,which cannot be replaced by high-strength titanium alloy.It is found that there are obvious problems of insufficient strength and stiffness in the manufacture of intramedullary nail and hip joint with commercial pure titanium.In order to avoid the fracture failure of internal fixation implants and improve the strength of implants,high-strength Ti-6A1-4V(is05832-2)alloy has been used to replace pure titanium materials in Britain,the United States,Russia,Japan and other countries.
2.2 development stage
Ti-6A1-4V alloy itself is also developing.Ti-6a1-4veli high damage tolerance titanium alloy with high fracture toughness,low crack growth rate and low gap element has emerged.Up to now,it still accounts for more than 80%of titanium alloy implant products.
Although Ti-6A1-4V alloy has excellent properties,because V element can cause malignant tissue reaction and may have toxic and side effects on human body,material scientists are prompted to study new titanium alloy materials without v.Since the 1980s,biomaterialists in Germany and Switzerland have successively developed ti-5a1-2.5fe and ti-6a1-7nb alloys.Among the two alloys,the clinical application of ti-6a1-7nb(is05832?11)alloy is more successful.In 1985,ruisulzer Medical Technology Co.,Ltd.first used forged ti-6a1-7nb-protasu1100 material to manufacture hip joint handle,and obtained quasi production registration[2],which is used in clinic,with good market response.At present,this kind of product has been introduced into China.Swiss Mathys also uses ti-6ai-7nb alloy to manufacture non reamed interlocking intramedullary nail system(including tibia,humerus and femur)and hollow screws for the treatment of femoral neck fractures.
2.3 improvement stage
Since the 1990s,in terms of titanium alloy implant materials,there have been reports about the potential harm of aⅡto human body,and it is believed that A1 will cause osteoporosis,mental disorder and other diseases.Therefore,biomaterialists began to explore and study new biological titanium alloys without V and A1.Among them,ti-13nb-13zr alloy(ASTM f1713-1996)and Ti alloy have been successfully developed and clinically approved.12mo-6zr-2fe alloy(ASTM f1813-1997).
Ti-13nb-13zr alloy is a biological titanium alloy with good comprehensive properties such as low elastic modulus,high strength,high toughness,high fatigue strength and good biocompatibility,which was developed by American scientists in the early 1990s.Compared with Ti-6A1-4V,its elastic modulus is 30%lower and its plane fracture toughness is 20%(65mpa.M1/2);The bending and shear modulus are 30%-40%lower,and the corrosion rate in the same human simulated body fluid is 40%.After cold and hot processing,while maintaining high strength,the modulus can be reduced to 50MPa,which is closer to human cortical bone[3].At present,this material is used to make dental implants by internationally renowned dental material manufacturers.
Ti-12mo-6zr-2fe alloy is also a biomedical titanium alloy respected by international well-known metal implant manufacturers in recent years.This alloy has low elastic modulus,high strength,high fracture toughness(90Mpa.M1/2),good wear resistance and excellent corrosion resistance.It is a metastable p-type biomedical titanium alloy with good comprehensive properties.Compared with Ti-6A1-4V,the elastic modulus is 25%lower,the flexibility of the material is better,the fracture toughness is about 80%(90:52),and it also has excellent mechanical properties:the tensile strength is 20%higher than that of Ti-6A1-4V,and the fatigue strength is 47%.One of the largest orthopedic professional group companies in the world??Stryker howmedia osteonics(Stryker joint branch),a subsidiary of Stryker group,uses ti-12mo-6zr-2fe alloy(tmzfr beta)to manufacture meridiantmzf femoral stems in howmedia partnership system(hip prosthesis system).This system has reached the highest standard of orthopaedic clinical requirements in terms of quality,function and clinical effect??Top class.Stryker spine(Stryker spine branch)also uses timozrfe alloy to manufacture the cervical anterior plate system(reflex anterior ceramic hate).The above two products have been introduced into the Chinese market.
2.4 innovation stage
Without innovation,there will be no progress.In recent years,there are many innovative achievements in medical titanium alloy.
(1)Development and application of Ni Ti shape memory alloy(ntsma)
In the early 1980s,Ni Ti shape memory alloy successfully dried orthopedic clinic,attracted the attention of orthopaedic experts and clinicians,and called it"magic metal".This functional material has peculiar shape memory effect,super elasticity,fatigue resistance,wear resistance,corrosion resistance and good biocompatibility.It is composed of 56%(mass%)Ni and 44%(mass%)titanium.The deformation temperature of ntsma used in orthopedic clinic is 0℃-5℃,and the recovery temperature is about 37℃.After fixing the fracture with ntsma material,the shape recovery is produced by heating up under the wet compress of body temperature or hot saline,but the bone limits the material recovery,so as to produce a dynamic and continuous pressure or clamping force at the fracture end to fix the fracture.The basic research of ntsma material in China is later than that in foreign countries,but it is in the international leading position in clinical application research.In 2000,in terms of orthopaedic implants,Lanzhou Ximai Memory Alloy Co.,Ltd.obtained the product quasi production registration of the State Drug Administration,which promoted the clinical application of ntsma orthopaedic implants.At present,three enterprises in China have registered and produced ntsma internal fixation devices,mainly including cross stitch nail,patellar concentrator,embracing steel plate,Ni Ti arch memory compression connector,intramedullary nail and other products[4].
Ntsma is also used in interventional therapy.Interventional therapy is an advanced non-surgical clinical technology developed rapidly in recent 10 years.Under the monitoring of X-ray image,this technology usually uses the puncture intubation technology to transport the special wire,catheter,balloon or support bracket to the lesions in the body along the blood vessel or other lumens in the body for local treatment.It has the characteristics of light trauma,less pain,less risk,time-saving,reliable and fast recovery.Interventional therapy materials include stent materials and delivery system materials,among which ntsmao is the first choice.Interventional therapy in China has developed rapidly in recent years,with an annual growth rate of 20%-30%.In 2002,nearly 150000 patients received interventional therapy.At present,the materials required for interventional therapy mainly rely on imports,and more than 20 enterprises have obtained FDA certification and entered the Chinese market.Its product quality and performance are better than domestic products,and the after-sales service is in place,but the price is expensive,about 12000 yuan/piece-16000 yuan/piece.The main suppliers include Johnson&Johnson Company cordis Co.,medtro nig,Inc,and numed Canada Inc;There are also some production companies in China,such as Beijing Sitai new technology development company,Beijing Xinquan company,Beijing Longzhou Feidu Memory Alloy Application Research Institute,etc.
In addition,ntsma is also used in dental orthodontic treatment.Ntsma dental arch wire produced by Xigui Institute of Beijing General Institute of nonferrous metals(now Beijing Youyan Yijin Co.,Ltd.)is not only sold and applied in China,but also exported overseas.
(2)Manufacture of cervical and lumbar interbody fusion cage(cage)with porous Ni Ti(pnt)alloy bioactive material
Biorthex company of Canada has developed a cervical and lumbar interbody fusion cage made of porous Ni Ti alloy patented material actiporetm,which is used for the treatment of orthopaedic spinal injury.This material has a porosity of about 65%and an average pore size of 215μm-230μm.It has biological activity and promotes the rapid growth of new bone through micropores and scaffolds.The micropores in multiple directions are connected internally to produce capillary penetration,which promotes the blood,basic nutrients and bone marrow to enter the interbody fusion cage.The elastic modulus of this metal implant material is close to that of cancellous bone,so as to avoid the stress shielding effect,promote bone reconstruction and provide good environmental support for the growth of bone cells.Bone growth cells and nutrients penetrate into interconnected micropores to accelerate bone integration.The biggest feature of this interbody fusion cage is that it does not need bone grafting(interbody fusion cage with other materials needs bone transplantation and its own iliac bone).After 3.1 years of transplantation,the bone reconstruction is completed inside the fusion cage and matched with the surrounding bone density.Through animal experiments,pnt alloy has good biocompatibility[5,6].In 2000,the product obtained CE certification and began to be sold in Europe and some Asian markets.At present,more rigorous clinical verification is being stepped up to apply for FDA certification.The product is also expected to be introduced into the Chinese market in the near future.
(3)Artificial hip prosthesis made of porous titanium alloy
Biological fixed(non cemented)artificial joint is a kind of artificial joint prosthesis highly praised by experts and clinicians in the field of orthopedics.It requires that the material or surface of the hip joint handle has biological activity,which can induce the growth of bone cells and produce bone integration at the interface between the joint handle and the femoral medullary cavity,so as to avoid the disadvantages of bone cement fixation,that is,loosening,sinking and dislocation after long-term use.Therefore,the use of porous titanium alloy in some stages of the joint handle will give the prosthesis bioactivity and contribute to the bony physiological combination between the handle and the medullary cavity.In the late 90s,scientists in Germany and Japan successfully made use of directional solidification technology to prepare directional solidification porous metal materials(foam metals)using hydrogen,oxygen and nitrogen as foaming gases.Krupp(GB implantat technologie GmbH)of Germany used this technology to produce porous titanium alloy femoral stem prosthesis.
(4)Application of porous titanium alloy coating technology in the manufacture of artificial joint prosthesis
Another method of manufacturing biological fixed artificial joint is to produce pores on the surface of titanium alloy joint handle.Micro titanium beads(microsphere powder)can be sintered or plasma sprayed on part of the surface of the joint handle to make the surface porous,reduce the difference between the elastic modulus of the implant and bone,and be conducive to the growth of bone cells and the delivery of nutrition,so as to obtain physiological bone integration.For example,the proximal end of the American exactech acumatchtm-a series hip joint handle adopts titanium beads with a diameter of 0.28mm,which are three-dimensional arranged.After sintering,the sum of the three rows of beads is 0.84mm,and the average pore size is 152μm.The average void ratio was 35%,indicating that 35%of the bone grew into the space on the surface of the sintered titanium beads in the handle.
Biological fixed joint prostheses(hip and knee joints)are mostly coated with porous spray(titanium microsphere powder),such as Zimmer company,exactech company,Taiwan United Company,etc.In addition to plasma spraying of titanium alloy beads(microspheres),Encore Medical Corporation of the United States has invented 3dmatrix TM porous spraying technology in recent years.Instead of using spherical particles,this technology uses a random three-dimensional shaped particle with a particle size of 180μm-850μm.Surface aperture size after spraying 250μm-450μm.The porosity can reach 61%.Clinical research shows that:100μm-500μThe pore size of M is the most suitable for bone growth.This advanced porous spraying technology makes the surface of the prosthesis stem have better biological activity and provide a better bone growth interface.
(5)Application of hydroxyapatite(HA)coating technology in the manufacture of titanium alloy artificial joints
Using plasma spraying technology to spray a part of the joint prosthesis stem with hydroxyapatite(HA)coating is also one of the methods to manufacture biological artificial joints.Structurally speaking,human bone itself is a natural composite material composed of osteogenic fibers and hydroxyapatite.Hydroxyapatite(Ca5(0h)(P04)3)contains hydroxyl groups that can bond with human tissue.Its chemical composition and crystal structure are very similar to the hydroxyapatite crystals that constitute human tissue.After implantation into human hard tissue,it can bond well with bone,and can induce bone tissue to grow into micropores,with slight tissue reaction.After several months of implantation,bone bonding can generally be achieved at the closely matched interface,which has become the preferred coating material in bioactive ceramics.
The bonding strength between HA coating and titanium alloy matrix is the key to the clinical application effect of titanium alloy implant.As long as there is a macro interface between coating and matrix,the bonding strength between them is not satisfactory.Generally,the bonding strength between the coating and titanium alloy matrix shall not be less than 40MPa,and the coating thickness shall be 150μm-200μm。The coating is too thick,the bonding strength decreases,and the coating is easy to break.Therefore,the whole plasma spraying process is operated by robot to ensure the uniformity of coating thickness.The coating contains micropores and larger pores,which are porous and random.The pore size of micropores is 3μm-5μm.The size of the larger hole is 50μm-100μm。The pore size can be detected under scanning electron microscope.At the same time,ha must maintain continuous purity(generally more than 99.9%)and stable crystal structure.
Most joint manufacturers at home and abroad have biological titanium alloy artificial prosthesis stems made by this technology.
(6)Application of Al2O3 ceramic coating technology in the manufacture of titanium alloy artificial joint
The purity of 99.8%was reduced by plasma spraying technologyα?Al2O3 micro powder is sprayed on the hip prosthesis stem(stem material Ti6A14V),and then cooled in liquid C02 to form at its interfaceγ-Al2O3,at the same time,the crystallization strength of matrix and A1203 shall not be less than 20MPa,which is also one of the methods to manufacture biological(non bone cement)artificial joints.Al2O3 ceramic materials are also used to make the ball joint of hip joint and the lining of hip joint acetabulum.The autopsy of the dead using the prosthesis made of the above materials and other clinical tests show that the debris of A1203 ceramic material will not cause the inflammatory reaction of synovial tissue in the joint capsule,and there is no synovial hyperplasia and necrosis.This prosthesis is most suitable for patients with younger age and greater postoperative activity.It can be seen that Al2O3 ceramic material has excellent biocompatibility with human tissue.Al2O3 ceramic material also has high physical stability,no biodegradation,excellent hydrophilicity on the material surface,and can effectively form water molecular film to reduce friction,hardness and fatigue.High labor strength and wear resistance are 30-40 times higher than CoCrMo alloy.The products are manufactured by serma and Italian orthopedics company.This technology is also used in the joint products of Baimu aviation materials company of Beijing Aviation Materials Research Institute.
(7)Hydroxyapatite(HA)-glass titanium composite used in artificial joint manufacturing
In the late 1990s,Japanese materials scientist Takeo maruno and others developed a new biomedical titanium alloy composite material for manufacturing artificial joints.This material is based on Ti-6A1-4V alloy.Glass powder(alumina borosilicate glass,i.e.al2o3-b2o5-sio2,volume percentage is about 85%,and the rest are glass modified oxides Na2O,K2O,Li2O,ZrO2 and TiO2)with good adhesion to the matrix material,stable biochemical performance and safety performance,no reaction with HA,and excellent adhesion with HA powder is selected.The average diameter of glass powder is 17μm)High purity HA powder was mixed and coated on the surface of titanium alloy matrix to form glass titanium composite containing ha.Another key to the research of this material is that the thermal expansion coefficient of the sintered composite layer is lower than that of the titanium alloy matrix.Only in this way,the contact interface between the composite layer and the titanium alloy matrix can produce a compact,stable and closely combined composite layer with the matrix material due to thermal diffusion reaction.
The artificial hip prosthesis stem made of HA-G-Ti composite material is proved to be a cheap artificial hip prosthesis with strong durability and excellent initial fixation.The HA-G thickness of the composite layer can be adjusted arbitrarily,with excellent biocompatibility.The HA-G composite layer has good adhesion with the matrix,and peeling and spalling have not been found.The long-term clinical effect needs to be further observed,so this material is also a biomedical titanium alloy material with great market development potential[7].
(8)Anodizing and coloring treatment of titanium and its alloys are used in orthopedic equipment,plastic surgery and dentistry.
Anodizing and coloring the surface of titanium and its alloy.In terms of its functionality,coating oxide film on the surface improves the wear resistance,corrosion resistance and cyclic fatigue resistance of titanium alloy matrix in human environment.In addition,the oxide film on the surface also solves the problem of metal ion dissolution to a great extent,reduces cytotoxicity and greatly improves the biocompatibility of the implant.For its aesthetics,with the gradual increase of the types and specifications of titanium alloy implants,it also brings trouble to clinical identification.As a unique property of titanium alloy,the hair color of surface oxide film can be used to identify implants of different specifications and categories in surgery,which is convenient for surgical operation.In addition,due to the biocompatibility,good corrosion resistance,light weight and comfortable wearing of titanium,the clinical application of titanium as denture(implant)and orthopaedic restoration is gradually increasing.People's restoration of dentures not only emphasizes the restoration of functions such as chewing,pronunciation and service life,but also has increasing requirements for the beauty of dentures.The color beauty of dentures can give people visual aesthetic enjoyment[8].This advantage is even more obvious in plastic surgery.
The reason why the titanium surface shows different colors after oxidation is that the main component of the oxide film formed on the metal titanium surface is titanium oxide.The thin film material composed of this component is transparent and can strongly reflect and refract light.When titanium is heated in an oxygen atmosphere or anodized,a titanium oxide film with a thickness of hundreds of a is coated on the titanium surface.If the light shines on the titanium coated with oxide film,the reflected light on the oxide film surface will interfere with the light reflected on the metal interface through the transparent oxide film,showing various beautiful interference colors[9].With the different thickness of oxide film,the surface of titanium can show various colors such as yellow,green,gold and pink.
The oxidation coloring of titanium mainly includes anodic oxidation,atmospheric oxidation and chemical treatment.In addition,there are plasma nitriding,nitrogen ion implantation,physicochemical vapor deposition and other methods.
Compared with the other two oxidation coloring methods of titanium,the anodic oxidation method has the advantages of simple process,rich color tone of surface coloring,and easy control of color tone.Therefore,this oxidation method is the most promising oxidation coloring technology.
The surface coloring treatment of bone fixation implants and instruments usually adopts anodizing method,and its colors include:golden yellow,bronze,sapphire blue,bright brown,rose red and elegant green.
3.Research,development,sale,market application status and existing problems of biomedical titanium and its alloys in China
3.1 research,development and market application status of biomedical titanium and its alloys
Since the mid-1980s,the clinical and Application Research of NiTi shape memory alloy in medical implants in China has reached the international advanced level.Shanghai Iron and Steel Research Institute,Tianjin Metallurgical Materials Research Institute and Rare Metals Research Institute of Beijing Nonferrous Metals Research Institute have jointly developed many medical implant products with local medical experts and professors.Such as:embracing steel plate,patellar claw,cross stitch nail,intramedullary nail,artificial joint,dental arch wire and other products.However,it was not until 2000 that the first nickel titanium shape memory alloy product(from Lanzhou Ximai Shape Memory Alloy Co.,Ltd.)was approved and registered by the State Pharmaceutical Administration.
Although China is rich in titanium reserves,it lags behind in medical titanium.It can not be compared with Europe and the United States in scientific research,equipment,technology,process and application.In 1998,the second orthopedic device factory of Tianjin medical device industry company was the first to obtain the trial production registration of"titanium bone plate"and"titanium bone screw"issued by the state medical administration,and became the first titanium implant manufacturer in China.The enterprise achieved good economic benefits that year.In the next few years,titanium implants have sprung up by domestic medical device manufacturers.At present,enterprises with good application in China include Changzhou Wujin No.3 medical device factory,Changzhou Kanghui medical device Co.,Ltd.However,many problems have also occurred in the specific use process,such as implant fatigue and fracture,difficulty in shaping during surgery,and even many medical disputes,which of course has a lot to do with the choice of materials.
In 1992,China formulated the standard of titanium and its alloy processing materials for surgical implants(gbl3810-1992),but there are few kinds of alloys.In 1997,the above standard was revised,namely GB/t13810?1997。However,in actual use,the manufacturer of surgical implants has not fully understood the performance of this material,and the material manufacturer has no internal control standard for surgical implant materials.For example,the ti-6al-4veli high damage tolerance alloy standard commonly used by foreign surgical implant manufacturers has not been popularized and applied in China.