CN112386745A - Artificial joint material, artificial joint prosthesis containing same and application thereof - Google Patents
Artificial joint material, artificial joint prosthesis containing same and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/3094—Designing or manufacturing processes
- A61F2/30942—Designing or manufacturing processes for designing or making customized prostheses, e.g. using templates, CT or NMR scans, finite-element analysis or CAD-CAM techniques
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/04—Metals or alloys
- A61L27/045—Cobalt or cobalt alloys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/04—Metals or alloys
- A61L27/047—Other specific metals or alloys not covered by A61L27/042 - A61L27/045 or A61L27/06
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/04—Metals or alloys
- A61L27/06—Titanium or titanium alloys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/3094—Designing or manufacturing processes
- A61F2002/30985—Designing or manufacturing processes using three dimensional printing [3DP]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
- A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
The invention discloses an artificial joint material, an artificial joint prosthesis containing the material and application thereof. The artificial joint material comprises metal elements and a base material, wherein the metal elements are selected from at least one of Cu, La, Sr and Mg; the mass percentage of the metal elements is 0.5-6%; the base material is cobalt-chromium alloy, titanium alloy, stainless steel or ceramic. The artificial joint prosthesis is prepared by adopting the raw materials containing the artificial joint material and utilizing a 3D printing, casting or powder alloy process. In the wear particles loaded with copper element, copper ions with proper concentration are generated by utilizing self-sustained release of the copper ions, so that osteoclast activation and proliferation are inhibited to a certain extent, a durable non-drug regulation and control effect is realized, the difficulties of side effects caused by drug therapy and uncontrollable local effective drug concentration are avoided, the generation and development of aseptic loosening of the prosthesis are prolonged, the service life of the prosthesis is prolonged, and the morbidity of joint replacement surgery is reduced.
Description
Technical Field
The invention relates to the field of material preparation, in particular to an artificial joint material, an artificial joint prosthesis containing the material and application of the artificial joint prosthesis.
Background
The artificial joint replacement has the functions of effectively relieving joint pain and reconstructing joint movement, and is the most effective method for clinically treating various middle and late stage severe osteoarticular diseases. About 10% of patients eventually experience aseptic loosening due to periprosthetic bone dissolution within 15 years after the initial artificial joint replacement. Osteoclast activation by wear particles is considered to be a major biological cause of aseptic loosening of the prosthesis.
At present, the exact mechanism by which aseptic loosening of prostheses progresses is not fully understood, although long-term studies have found that the activation of wear particle-induced inflammatory osteoclasts plays a crucial role. When macrophages engulf abraded particles, the macrophages secrete a plurality of inflammatory factors related to bone resorption, and the inflammatory factors act on a nuclear factor kB receptor activator/nuclear factor kB receptor activator ligand/osteoprotegerin signal transduction pathway to activate fibroblasts and osteoblasts to secrete a large amount of RANKL. When RANKL binds to RANK on the membrane of osteoclast precursor cells, it activates nuclear factor- κ (NF- κ B) signaling pathway and a series of osteoclast downstream thereof activates key transcription factors, such as nuclear factor c1(NFATc1) of T cells, inducing osteoclast over-activation, eventually leading to osteolysis around the prosthesis.
Although the artificial joint revision surgery is the main method for treating the prosthesis loosening at present, the defects of large trauma, high cost, uncertain long-term curative effect and the like still exist. Aiming at the pathogenesis of aseptic loosening of the prosthesis, measures such as reducing the generation of wear particles, medicament treatment, gene treatment and the like are tried, and the aim of preventing and treating is achieved by reducing the generation of the wear particles, promoting the synthesis of bones, reducing inflammatory factors or inhibiting the activation of osteoclasts and bone resorption. By modifying the material, it is impossible to improve the wear resistance of the material and completely avoid the generation of wear particles. The current difficulties of drug therapy are how to reduce the side effects caused by the drug and how to control the local effective drug concentration. Although the gene therapy is highly targeted, many key technologies are not solved yet and are still in the experimental stage.
From a material development perspective, increasing the wear resistance of materials, reducing or eliminating wear particle generation remains the direction of effort of most biomaterials scientists. Among the metallic materials for orthopedic implants, cobalt-chromium alloys have been used for more than 30 years due to their advantages of high strength, excellent corrosion resistance, bio-safety and low cost, which has the advantage that a large diameter femoral head can be used during operation to reduce friction and wear, and cannot be replaced at present. Although years of clinical application show that the cobalt-chromium metal joint prosthesis has satisfactory short-term and medium-term clinical effects, the problems of 1) prosthesis abrasion and a series of biological reactions brought by the prosthesis abrasion, 2) poor biocompatibility and the like still exist. These problems restrict the therapeutic effect of artificial joint replacement, and therefore, the development of modification studies of cobalt-chromium alloys is urgently needed. In recent years, many researchers have improved the wear resistance of materials from the viewpoints of component design, microstructure micro-control, surface modification, and the like. Although these studies have played an important role in promoting the development of joint materials, it is difficult to completely eliminate the generation of wear particles in the prior art, which means that a series of adverse biological reactions such as osteolysis caused by wear particles always exist. This shows that in the present stage that the development of materials can not completely eliminate the generation of wear particles of the joint prosthesis, the development of materials of the joint prosthesis can not simply consider the problem of wear resistance, and the biocompatibility is also important. Therefore, the design and development of materials cannot be limited to the concept of bone disease repair, and the characteristics of the disease must be considered sufficiently.
Disclosure of Invention
The invention provides an artificial joint material, which comprises a metal element and a base material, wherein the metal element is selected from at least one of Cu, La, Sr and Mg; the mass percentage of the metal element is 0.5-6%, for example, 1-5%, 1.5-4.5%, 2.0-4.0%, 2.5-3.5%, and exemplarily, the mass percentage of the metal element is 3%, 6%.
According to an embodiment of the present invention, the metallic element is preferably Cu, La or Sr, more preferably Cu.
According to an embodiment of the present invention, the base material may be a material known in the art, such as cobalt-chromium alloy, titanium alloy, stainless steel, or ceramic. Preferably, the base material is a cobalt-chromium alloy or a titanium alloy. For example, the cobalt-chromium alloy and the titanium alloy do not contain nickel, gallium and beryllium. Preferably, the cobalt-chromium alloy contains, by mass, 25-28.0% of Cr, 5-9.0% of W, 0.8-2.5% of Si, not more than 0.008% of Mn, not more than 0.001% of N, not more than 0.02% of Fe, and the balance of Co. For example, the titanium alloy contains, in mass%, 3.0 to 9.0 wt% of Al, 2.0 to 6.0 wt% of V, and the balance Ti.
According to an embodiment of the invention, the artificial joint material is a cobalt chromium alloy containing copper. For example, the cobalt-chromium alloy containing copper element contains 25-28.0 wt% of Cr, 5-9.0 wt% of W, 0.8-2.5 wt% of Si, 0.5-6 wt% of Cu, less than or equal to 0.008 wt% of Mn, less than or equal to 0.001 wt% of N, less than or equal to 0.02 wt% of Fe and the balance of Co by mass percent. Preferably, the cobalt-chromium alloy containing copper elements contains 26-27.5 wt% of Cr, 6-8.0 wt% of W, 1-2 wt% of Si, 1-4 wt% of Cu, less than or equal to 0.008 wt% of Mn, less than or equal to 0.001 wt% of N, less than or equal to 0.02 wt% of Fe and the balance of Co by mass percentage. Illustratively, the cobalt-chromium alloy containing copper elements contains, by mass percent, Cr28.0 wt%, W8.0 wt%, Si 2 wt%, Cu 3 wt%, Mn less than or equal to 0.008 wt%, N less than or equal to 0.001 wt%, Fe less than or equal to 0.02 wt%, and the balance of Co.
According to an embodiment of the invention, the artificial joint material is a titanium alloy containing copper. For example, the copper-containing titanium alloy contains, by mass, 3.0 to 9.0 wt% of Al, 2.0 to 6.0 wt% of V, 0.5 to 6 wt% of Cu, and the balance Ti. Preferably, the titanium alloy containing copper elements contains, by mass, 4.0-7.0 wt% of Al, 3.0-5.0 wt% of V, 3-6 wt% of Cu, and the balance of Ti. Illustratively, the titanium alloy containing copper elements comprises 6.0 wt% of Al, 4.0 wt% of V, 6 wt% of Cu and the balance of Ti in percentage by mass.
According to the embodiment of the present invention, the form of the artificial joint material is not limited, and may be, for example, powder.
The invention also provides application of the artificial joint material in preparation of artificial joint prostheses.
The invention also provides an artificial joint prosthesis containing the artificial joint material.
The invention also provides a preparation method of the artificial joint prosthesis, which comprises the following steps: the artificial joint prosthesis is prepared by adopting the raw materials containing the artificial joint material and utilizing a 3D printing, casting or powder alloy process.
Preferably, the preparation method comprises the following steps:
1) preparing an artificial joint material containing 0.5-6% of copper element by mass percent; the artificial joint material is preferably cobalt-chromium alloy containing copper or titanium alloy containing copper;
2) preparing the artificial joint prosthesis by using a 3D printing, casting or powder metallurgy process; the artificial joint prosthesis is preferably a copper-containing cobalt chromium joint prosthesis or a copper-containing titanium joint prosthesis.
Wherein the chromium-cobalt alloy and the copper-containing cobalt-chromium alloy have the meanings as described above.
Wherein the titanium alloy and the copper element-containing titanium alloy have the meanings as described above.
Wherein the 3D printing, casting and powder metallurgy processes are processes known in the art, preferably a 3D printing process, more preferably a laser 3D printing process. The laser 3D printing process comprises the following steps:
(1) placing the artificial joint material in a powder cylinder of a selective laser forming system, and filling nitrogen into equipment to reduce the oxygen content to be below 0.5%;
(2) and (3) importing the three-dimensional slice data of the sample into a selective laser forming system, adjusting the position of a forming plate to enable the laser spot to be in the best exposure position, importing printing process parameters, and starting a laser to perform laser 3D printing forming.
Wherein the printing process parameters include: the laser power is 80-95W, the scanning speed is 650-900 mm/s, the scanning interval is 0.009-0.012 mm, the powder layer thickness is 0.025-0.035 mm, and the laser spot is 20-50 microns.
The invention also provides application of the artificial joint material or the artificial joint prosthesis in inhibiting macrophage from secreting inflammatory factors and inhibiting osteoclast from activating. Furthermore, the artificial joint material or the artificial joint prosthesis can reduce the expression of NF-kB protein and inhibit an NF-kB signal channel; can also reduce the expression level of osteoclast differentiation genes such as transcription factors TRAP, NFATc1 and Cath-K and the like at the downstream of an NF-kB signal channel. Furthermore, the artificial joint material or the artificial joint prosthesis can relieve periprosthetic osteolysis and delay aseptic loosening.
The inventor finds that the biological functionalization of the medical metal material is considered to be one of the best choices for solving the problems of poor biocompatibility and single function of the traditional metal material. The method has the advantages that the biomedical function of a specific metal element is exerted by utilizing the slow release of the specific metal element, and the biological safety and the excellent mechanical property of the material are kept, so that the method has important application value for the redevelopment of the traditional medical metal material.
Copper, lanthanum, strontium, magnesium and other elements are essential elements in human body, particularly copper is one of important trace elements essential in human body, participates in the metabolism of normal cells in human body and the synthesis of more than 30 coenzymes, and plays an active role in bone metabolism. The concentration of copper in serum is 0.17-0.027mmol/L, and the world health organization recommends that healthy adults should absorb 2-3mg of copper per day. The copper element deficiency can reduce the activity of copper-containing enzymes related to bone metabolism, further influence the maturation of ossein and elastin, and finally lead to the occurrence of abnormal mineralization of bone tissues and osteoporosis. The compendium of materia Medica (1 st, 4 th, 345) states that "red copper filings mainly cause fracture and can be welded into bone and six animals with damage". Copper plays an important role in fracture healing and prevention and treatment of osteoporosis, and the osteoporosis can be caused by the deficiency of copper. The inventor researches and discovers that from the aspect of cell biology, trace copper ions dissolved from copper-containing medical metal not only have the effect of promoting osteogenesis, but also can inhibit osteoclast proliferation and inhibit bone resorption by using copper ions with proper concentration. The application surprisingly discovers that the artificial joint prosthesis containing the proper copper element content cannot avoid the generation of wear particles of joint materials, but the wear particles loaded with the copper element generate copper ions with proper concentration by utilizing the self-sustained release of the copper ions, so that the proliferation of osteoclasts is inhibited, and the potential medical prevention and treatment efficacy of the artificial joint material on the aseptic loosening complication of the prosthesis caused by the activation of the osteoclasts induced by the wear particles is well reflected.
The invention has the beneficial effects that:
the invention provides an artificial joint material containing copper element and an artificial joint prosthesis containing the material. Although the generation of the joint material wear particles cannot be avoided, copper ions with proper concentration are generated in the wear particles loaded by the copper element by means of self-sustained release of the copper ions, osteoclast activation and proliferation are inhibited to a certain extent, a lasting non-drug regulation and control effect is realized, the difficulties of side effects and uncontrollable local effective drug concentration caused by drug treatment are avoided, the generation and development of aseptic loosening of the prosthesis are prolonged, the service life of the prosthesis is prolonged, and the incidence of joint replacement is reduced.
Drawings
FIG. 1 shows the expression level of NF- κ B protein (a) and its corresponding electrophoretogram (B).
FIG. 2 shows NF-. kappa.B protein immunofluorescence staining (X320) of Co29Cr9W and Co29Cr9W3Cu powders, respectively, after culturing osteoclasts for 5 days.
Fig. 3 shows the gene expression level of osteoclast activation: (a) NF-kB and its downstream transcription factor, (B) NFATc1, (c) TRAP and (d) Cath-K.
FIG. 4 is Micro-CT analysis of bone dissolution: (a) control, (b) Co29Cr9W, and (c) Co29Cr9W3 Cu.
FIG. 5 shows the osteoclast morphology on the surface of Ti6Al4V and Ti6Al4V-6 Cu:
(a-f) staining of cytoskeleton of osteoclast RAW264.7 after culturing on the surface of Ti6Al4V (a-c) and Ti6Al4V-Cu (d-f) for 1 d;
(g-l) cytoskeletal staining of osteoclasts after 3d incubation on the surface of Ti6Al4V (g-i) and Ti6Al4V-Cu (j-l).
FIG. 6 shows the expression of inflammatory factor genes after 3 and 7 days of co-culture of Ti6Al4V and Ti6Al4V-6Cu alloy with macrophages: (a) CCK8, (b, h) IL-1 β, (c, i) IL-6, (d, j) IL-10, (e, k) TNF- α, (f) INOS, (g) ARG.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
In the following examples:
the mouse monocyte macrophage cell line (RAW264.7) used herein was purchased from the china academy of sciences type culture collection cell bank. DMEM culture solution containing 10% FBS is used as cell culture solution, and cells are placed in 5% CO2The culture was carried out at 37 ℃ in a saturated humidity incubator, and the medium was changed 1 time every 2 days. During the culture period, the morphology and fusion of the cells were observed by an inverted microscope. When the cell density is 80-90%, digesting with 0.25% pancreatin and 0.1% EDTA, blowing, beating, mixing, and subculturing or inoculating according to the ratio of 1: 4. Macrophages and osteoblastsThe relevant experiments are all performed at 5X 104The density of cells/well was seeded on the sample. RAW264.7 mouse macrophage cell line is also osteoclast precursor, and RAW264.7 cell line is 5 × 104One cell/well was inoculated on the sample, the fluid was changed every other day, and RANKL inducing fluid containing 50ng/mL was added to induce osteoclastogenesis. The sample size for cell culture is
Co29Cr9W and Co29Cr9W3Cu powder with the granularity less than 10 mu m are adopted to simulate wear particles generated by friction of the joint prosthesis, and the wear particles and cells are cultured together to study the cell biological reaction. Before the experiment, acetone is adopted to carry out ultrasonic treatment on the powder for 1 hour, oil is removed, and then alcohol is adopted to carry out ultrasonic treatment for 30 minutes; then, centrifuging at 3000r/min for 10 minutes by using a centrifuge to filter impurities; sterilizing at 121 deg.C for 20 min; drying at 60 deg.C, and placing in 4 deg.C humidity refrigerator for use. Cell biology experiments are divided into two groups: group A was a Co29Cr9W (CCW) powder group containing no copper, group B was a Co29Cr9W3Cu (CCWC) powder group containing copper, and the powders were mixed with a PBS solution to prepare a suspension at a concentration of 4g/L for Co-culture with cells.
In FIGS. 1 to 3, CCW represents the Co29Cr9W group, and CCWC represents the Co29Cr9W3Cu group.
Example 1
1. Preparing copper-cobalt-chromium alloy powder: the alloy comprises 28.0 wt% of Cr, 8.0 wt% of W, 2 wt% of Si, 3 wt% of Cu, less than or equal to 0.008 wt% of Mn, less than or equal to 0.001 wt% of N, less than or equal to 0.02 wt% of Fe and the balance of Co; it was denoted as Co29Cr9W3Cu powder;
2. the artificial joint prosthesis is prepared by adopting a 3D printing technology, and Co29Cr9W3Cu powder is printed into the artificial joint prosthesis, and the steps are as follows:
starting the equipment, placing the powder in a powder cylinder of a selective laser forming system, and filling nitrogen into the equipment to reduce the oxygen content to be less than 0.5%; three-dimensional slice data of the sample are led into a selective laser forming system, and the position of a forming plate is adjusted to enable laser spots to be in the optimal exposure position; and introducing printing process parameters, wherein the laser power is 895W, the scanning speed is 650/s, the scanning interval is 0.011mm, and the powder layer thickness is 0.025 mm. The laser spot is 50 microns; and starting a laser to perform laser 3D printing and forming.
The artificial joint prosthesis is used as a material, particles are prepared in vitro, and abrasion particles generated in the in-vivo use process of the prosthesis are simulated; osteoclasts were Co-cultured for 5 days with 3D-printed wear particles of cobalt chromium copper alloy and copper-containing cobalt chromium alloy (Co29Cr9W3Cu) and copper-free wear particles (prosthetic material was Co29Cr9W powder), respectively. The operating conditions for the co-cultivation were as follows:
the slow release effect of copper ions in the wear particles is utilized, the targeting effect and inflammatory tissues are utilized, the secretion of inflammatory factors by macrophages and the activation of osteoclasts are inhibited, and the periprosthetic osteolysis is further inhibited;
the expression level of nuclear factor-kappa B (NF-kappa B) protein of the activated cell nucleus is detected and compared by using western blot after the Co29Cr9W powder and the Co29Cr9W3Cu powder are cultured with the osteoclast for 5 days. 2X 10 Using RAW264.7 cells5Inoculating each well into 6-well plate, inducing osteoclast generation by using RANKL, and culturing for 7 days together with the sample; the medium was removed and washed 3 times with PBS. Extracting protein by RIPA lysate (Beyotime, China), and detecting the concentration of NF-kB protein by BCA method by taking 5 mu l of protein; loading the rest proteins onto polyacrylamide gel for electrophoresis; after electrophoresis, the cells were transferred to a polyvinylidene fluoride (PVDF) membrane (Millipore, Billerica, MA, USA) at 300 mA; then, it was kept in an immunoblotting apparatus (Bio-Rad, Hercules, Calif., USA) for 1.5 hours. The membranes were blocked with 5% skim milk in PBS containing Tween-20(PBS-T) at room temperature and shaken overnight. Primary antibody incubation, i.e., deblock, was performed using NF-. kappa.B (1:1000, Abcam, USA) and GAPDH (1:1000, Boster, China) antibodies, 1ml of diluted primary antibody was aspirated, and incubated with the membrane in a hybridization bag overnight at 4 ℃. The membrane was removed, washed 3 times with TBST for 10 minutes each, diluted 1:1000 with goat anti-rabbit secondary antibody, and incubated with the membrane in a hybridization bag on a side-swing shaker for 1-2 hours. After the membranes were removed and washed, an appropriate amount of ECL developing solution (solution a: solution B ═ 1:1) was added to each membrane, and color development by the enhanced chemiluminescence method was performed in a dark room, and the gray values of the lanes were analyzed and compared by Imgae J software.
(1) Exempt fromFluorescence staining: experiment samples were placed in 24-well plates and seeded with cells at a cell density of 5X 104One per ml. After the cells were cultured in the sample to the set time point, 300. mu.L of 4% paraformaldehyde was added to each well and fixed at room temperature for 20 minutes. mu.L of 0.1% Triton X-100 was added for 5 minutes of permeation, and the mixture was gently washed 2 times with PBS, and 500. mu.L of 1% Bovine Serum Albumin (BSA) in PBS blocking solution was added to each well and blocked at room temperature for 30 minutes. mu.L of primary anti-NF-. kappa.B dilution (1:300) was added to each well and incubated at room temperature for 2 hours. Then washed 3 times with PBS for 5 minutes each. And taking a picture by using a Nikon fluorescence microscope, wherein blue light is taken at an excitation wavelength of 400-440 nm, and red light is taken at an excitation wavelength of 510-550 nm.
The results of the experiment are shown in FIG. 1. From the experimental results, the expression level of NF- κ B protein in the Co29Cr9W3Cu group was significantly reduced compared to the Co29Cr9W powder, and the difference was statistically significant (p < 0.05). FIG. 2 shows immunofluorescence staining of NF-. kappa.B protein after osteoclasts were Co-cultured with Co29Cr9W and Co29Cr9W3Cu powders for 5 days, respectively. Green fluorescence (second panel 2) was Alexa Fluor 488-labeled goat anti-rabbit IgG and blue fluorescence (first panel 2 and third panel 2) was DAPI staining. As can be seen from FIG. 2, the fluorescence intensity expression of NF- κ B protein in the Co29Cr9W group is significantly higher than that in the Co29Cr9W3Cu group, indicating that the Co29Cr9W3Cu group can significantly down-regulate the expression of NF- κ B protein.
(2) The expression levels of osteoclast differentiation marker genes such as activated cell nuclear factor-kB (NF-kB) and downstream transcription factor anti-tartaric acid phosphatase (TRAP), activated T cell nuclear factor c1(NFATcl) and cathepsin K (Cath-K) are detected by RT-PCR, and the expression condition of the specific gene related to osteoclast differentiation by Co29Cr9W3Cu powder is observed, as shown in FIG. 3. Co29Cr9W and Co29Cr9W3Cu powders were Co-cultured with osteoclasts for 3 and 7 days, respectively, and as can be seen from FIG. 3a, the expression level of NF- κ B gene in the Co29Cr9W3Cu group was lower than that in the Co29Cr9W group at each time point, and the differences were statistically significant. This result is consistent with immunoblot NF- κ B protein expression. Co29Cr9W3Cu powder also down-regulated the gene expression levels of osteoclast differentiation transcription factors NFATc1, TRAP and Cath-K downstream of NF- κ B, and the differences have statistical significance (FIG. 3B-c). The experimental result shows that the Co29Cr9W3Cu powder not only inhibits NF-kB signal channels, but also participates in down-regulating the expression levels of osteoclast differentiation genes such as transcription factors TRAP, NFATc1 and Cath-K at the downstream of the NF-kB signal channels.
Example 2
The artificial joint prosthesis obtained in example 1 generates wear particles during in vivo use; respectively implanting wear particles of cobalt-chromium-copper alloy (Co29Cr9W) and wear particles of copper-containing cobalt-chromium alloy (Co29Cr9W3Cu) into skull bone seams of mice for Co-culture to establish a skull bone dissolution model, and specifically comprising the following steps:
(1) and (4) feeding the animals. Experimental animals healthy C57 male mice were purchased from the university of army medical and military animal laboratories (n ═ 30, 6-8 weeks old). Raising in a clean animal house, and molding after one week. All animal experiments were approved by the animal administration at the army-military medical university.
(2) Co29Cr9W and Co29Cr9W3Cu powder suspensions were prepared. The powder particle size is less than 10 μm, and the average particle size is 5 μm. And drying the powder subjected to ultrasonic cleaning by using acetone and alcohol, placing the powder in a constant-temperature oven, and baking the powder for 8 hours at 180 ℃ to remove endotoxin of the powder, so that the influence on an experimental result is avoided. Cooling the powder to room temperature, placing the powder in a jar containing alcohol, ultrasonic cleaning for 3 times, replacing fresh alcohol, and standing for 5 days. Removing alcohol, and washing the powder with sterile PBS solution for 3 times; after centrifugation, the cells were subjected to UV sterilization in a sterile operating table and air-dried. Weighing 4g of powder, adding 1L of sterile PBS to prepare powder suspension, and placing the powder suspension in a refrigerator with 4 ℃ humidity for later use.
(3) Osteolysis model surgery. Mice were randomized into 3 groups: PBS group, Co29Cr9W group, and Co29Cr9W3Cu group (n is 10 groups/group). Before surgery, the mice were weighed and recorded, and then anesthetized with 40mg/kg intraperitoneal injection with 40g/L chloral hydrate. After anesthesia, the head and four limbs of the mouse are fixed on an operating table, the hair of the mouse is uniformly shaved off by a hair shaver from the middle point of the connecting line between the two ears of the mouse and the point between the sagittal suture point of the skull and the two eyes, and the hair is disinfected by the anidine. Then, an incision of about 1cm in length was made with a scalpel along the body surface projection of the midsagittal suture of the skull, exposing 1.0cm by 1.0cm of periosteum. Prepared 20 μ l of prepared PBS containing powder was uniformly applied to the surface of the skull centered on the junction of the sagittal suture and the coronal suture of the mouse skull. Then, the incision was closed with 4-0 sutures to ensure that the suspension did not leak. After operation, mice are injected with penicillin to prevent postoperative infection death; after the mice are anesthetized and revived, the mice are sent back to an animal room for feeding and observation.
(4) Mice were sacrificed 14 days post-surgery. After anesthetizing the mouse, dissecting the thoracic cavity of the mouse, collecting the apical blood of the mouse, placing the blood in a centrifuge tube, centrifuging the blood for 10 minutes at 4000r/min, taking another centrifuge tube for storing the supernatant, and placing the supernatant in a refrigerator at the temperature of-20 ℃ for later use. The neck of a mouse is killed, the scalp of the mouse is cut off by scissors, the skull of the mouse is peeled off by a scalpel, and the mouse is quickly placed in 4 percent paraformaldehyde and fixed for 48 hours; then, 5 mouse skulls were randomly taken out for Micro-CT scanning to analyze the skull seam bone dissolution degree
FIG. 4 is a Micro-CT analysis of the skull bone suture bone dissolution degree of the mouse skull. FIG. 4a is a blank group, and the osteolytic zone and depth of the crater of the skull sutures of the mice in the Co29Cr9W group are more evident than in the blank group by comparative analysis (FIG. 4 b); osteolysis also occurred in the skull sutures of mice in the Co29Cr9W3Cu group, but the osteolysis zone, depth of the crater was slightly less than in the Co29Cr9W group (FIG. 4 c).
Example 3
1. Preparing copper-containing titanium alloy powder: the alloy comprises 6.0 wt% of Al, 4.0 wt% of V, 6.0 wt% of Cu and the balance of Ti in percentage by mass; it was designated as Tl6Al4V-6Cu powder;
2. the artificial joint prosthesis is prepared by adopting a 3D printing technology, and Tl6Al4V-6Cu powder is printed into the artificial joint prosthesis, and the steps are as follows:
starting the equipment, placing the powder in a powder cylinder of a selective laser forming system, and filling nitrogen into the equipment to reduce the oxygen content to be less than 0.5%; and (3) importing the three-dimensional slice data of the sample into a selective laser forming system, and adjusting the position of a forming plate to enable laser spots to be in the optimal exposure position. And introducing printing process parameters, wherein the laser power is 95W, the scanning speed is 900mm/s, the scanning interval is 0.011mm, and the powder layer thickness is 0.025 mm. The laser spot is 50 microns; and starting a laser to perform laser 3D printing and forming.
The joint prosthesis generates wear particles during in vivo use; osteoclasts were co-cultured with 3D-printed wear particles of titanium alloy (Tl6Al4V) and copper-containing titanium alloy (Tl6Al4V-6Cu) for 1 and 3 days, and the cell culture experimental procedure is detailed in example 1.
RAW264.7 cells were co-cultured with the sample after osteoclast induction for 1 and 3 days, and subjected to skeletal staining observation, wherein red fluorescence of (a), (d), (g) and (j) in FIG. 5 was stained with phalloidin, and blue fluorescence of (b), (e), (h) and (k) was stained with DAPI. The results show that the Ti6Al4V-6Cu surface formed fewer multinucleated giant cells than the Ti6Al4V control (see FIGS. 5 d-f).
ELISA and PCR detection results show that Ti6Al4V-6Cu can down-regulate the expression of inflammatory factors (IL-1 beta, IL-6 and TNF-alpha) of RAW264.7 cells and up-regulate the expression level of anti-inflammatory factors (IL-10) (shown in figure 6). This result suggests that Cu2+The ions are effective in inhibiting osteoclast and macrophage activities.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An artificial joint material, characterized in that the artificial joint material comprises a metal element and a base material, wherein the metal element is at least one selected from Cu, La, Sr and Mg; the mass percentage of the metal elements is 0.5-6%; the base material is cobalt-chromium alloy, titanium alloy, stainless steel or ceramic.
2. The artificial joint material according to claim 1, wherein the base material is a cobalt-chromium alloy or a titanium alloy, and the metal element is Cu;
preferably, the cobalt-chromium alloy and the titanium alloy do not contain nickel, gallium and beryllium;
preferably, the cobalt-chromium alloy contains, by mass, 25-28.0% of Cr, 5-9.0% of W, 0.8-2.5% of Si, not more than 0.008% of Mn, not more than 0.001% of N, not more than 0.02% of Fe, and the balance of Co;
preferably, the titanium alloy contains, by mass, 3.0 to 9.0 wt% of Al, 2.0 to 6.0 wt% of V, and the balance of Ti.
3. An artificial joint material according to claim 1 or 2, wherein the artificial joint material is a cobalt chromium alloy containing copper;
preferably, the cobalt-chromium alloy containing copper elements contains 25-28.0 wt% of Cr, 5-9.0 wt% of W, 0.8-2.5 wt% of Si, 0.5-6 wt% of Cu, less than or equal to 0.008 wt% of Mn, less than or equal to 0.001 wt% of N, less than or equal to 0.02 wt% of Fe and the balance of Co by mass percentage.
4. The artificial joint material according to claim 1 or 2, wherein the artificial joint material is a titanium alloy containing copper;
preferably, the titanium alloy containing copper element contains Al 3.0-9.0 wt%, V2.0-6.0 wt%, Cu 0.5-6 wt% and Ti in balance.
5. The artificial joint material according to any one of claims 1 to 4, wherein the artificial joint material is a powder.
6. Use of the artificial joint material according to any one of claims 1 to 5 for the preparation of an artificial joint prosthesis.
7. An artificial joint prosthesis comprising the artificial joint material according to any one of claims 1 to 5.
8. A method of manufacturing an artificial joint prosthesis according to claim 7, characterized in that the method comprises the steps of: preparing the artificial joint prosthesis by using a raw material comprising the artificial joint material according to any one of claims 1 to 5, using a 3D printing, casting or powder alloy process;
preferably, the preparation method comprises the following steps:
1) preparing an artificial joint material containing 0.5-6% of copper element by mass percent; the artificial joint material is preferably cobalt-chromium alloy containing copper or titanium alloy containing copper;
2) preparing the artificial joint prosthesis by using a 3D printing, casting or powder metallurgy process; the artificial joint prosthesis is preferably a copper-containing cobalt chromium joint prosthesis or a copper-containing titanium joint prosthesis.
9. The method of manufacturing an artificial joint prosthesis according to claim 8, wherein the 3D printing is a laser 3D printing process, the laser 3D printing process comprising the steps of:
(1) placing the artificial joint material in a powder cylinder of a selective laser forming system, and filling nitrogen into equipment to reduce the oxygen content to be below 0.5%;
(2) the three-dimensional slice data of the sample is led into a selective laser forming system, the position of a forming plate is adjusted to enable laser spots to be located at the optimal exposure position, printing process parameters are led in, and a laser is started to carry out laser 3D printing forming;
wherein the printing process parameters include: the laser power is 80-95W, the scanning speed is 650-900 mm/s, the scanning interval is 0.009-0.012 mm, the powder layer thickness is 0.025-0.035 mm, and the laser spot is 20-50 microns.
10. Use of the artificial joint material according to any one of claims 1 to 5 or the artificial joint prosthesis according to claim 7 for inhibiting secretion of inflammatory factors by macrophages and for inhibiting activation of osteoclasts;
preferably, the artificial joint material or the artificial joint prosthesis can down-regulate NF-kB protein expression and inhibit NF-kB signal channels; can also down regulate the expression level of transcription factors TRAP, NFATc1 and Cath-K osteoclast differentiation genes at the downstream of an NF-kB signal channel;
preferably, the artificial joint material or the artificial joint prosthesis can relieve periprosthetic osteolysis and delay aseptic loosening.
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