MXPA05013157A - Coated implants and methods of coating - Google Patents

Abstract

A method including forming a first coating layer derived from an alkoxide on a substrate having a dimension suitable for an implant and forming a second coating layer on the first coating layer that promotes osseointegration. An apparatus comprising a substrate having a dimension suitable as a medical or dental implant and a coating on a surface of a first coating layer derived from an alkoxide and a second coating layer that promotes osseointegration.

Description

COATED IMPLANTS AND COVERING METHODS BACKGROUND FIELD Medical / dental implants BACKGROUND Metal implants are widely used in medical and dental applications, such as orthopedic hip and knee surgeries and dental surgery. In the United States more than two million orthopedic procedures and more than ten million dental implant procedures are performed every year. Implants fail due to poor osseointegration between the implant and natural bone. The implants are typically made of metal materials, with titanium (TI) and their alloys being favored due to their biocompatibility and medical properties. In order for the implants to function successfully, a direct chemical bond between the implant and the bone needs to be formed and needs to be retained for many years while the implant is loaded. The metal materials, however, do not form a direct chemical bond with the bone. To promote osseointegration between the metal implant and bone, a layer of osseointegration promoting material is incorporated over the implant. Calcium phosphate ceramic materials are an example of coating materials that promote osseointegration. The most popular coating among the calcium phosphate family is hydroxyapatite (HA) due to its chemical stability and osseoconductivity. Important parameters in the long-term performance of HA-coated implants include a coating-substrate binding strength and biostability (i.e., a low dissolution rate of the coating) at least acceptable. To improve the coating-substrate binding strength (usually a metal) and other properties, a variety of coating techniques have been explored to develop thin coatings (generally less than 10 microns) of HA and other calcium phosphates. U.S. Patent No. 4,908,030 describes a method for forming a thin coating of HA on the implant using bombardment or ion gas. U.S. Patent No. 5,817,326 describes a method in which one or more layers of HA sol-gel are cured to densify on a titanium alloy implant, followed by an ion implantation process without a line of sight, to reinforce the adhesion of the HA coating to the substrate. U.S. Patent No. 5,543,019 discloses a method for forming a thin coating layer on the surface of an implant using a plasma bombardment process. Other methods developed include deposition of the driven laser and electronic magnetron deposition. Another method to improve the binding capacity of an HA coating on a mechanical substrate has been the deposition of a composite coating, where a metal phase is introduced to serve as an intermediate layer or a second phase (continuous or dispersed) in a matrix ha. For example, Dasarathy et al., In "Hydroxyapatite / metal composite coatings formed by electrocodeposition," J. Biomed. Mater. Res., 31, 1-89 (1996) describes electronic co-deposition processes for coating a cobalt / HA composite coating (Co / HA) on a Ti substrate with a bond strength of up to 37 MPa. Using the plasma spray technique, Brossa et al., In "Adhesion properties of plasma sprayed hydroxyapatite coatings for orthopaedic prostheses", Bio-Med. Mater. Eng., 3, 127-136 (1993), and Na ashima et al., In "Hydroxyapatite coating on titanium-sprayed titanium implant," in Bioceramics 6, P. Ducheyne and D. Christiansen (eds.), Butterworth-Heine ann, Oxford, 1993, pp. 449-453, discloses a double layer coating that includes an HA layer on top of a porous Ti precoat on a Ti substrate. This double layer coating proved to form a monolithic HA coating with adhesion properties. The German Patent "Implant Coating", Gruner, Heiko (Plasmainevent A.-G.) Ger. Offen 3,516,411 (Cl.

C23C4 / 04) Nov. 12, 1986, describes a multilayer coating comprising a precoating of Ti, a layer composed of Ti / HA and an upper layer of HA formed by plasma deposition. Multilayer coated implants show fast and stable fusion between the coated implant and the bone. On the substrate Ti-6A1-4V Ferraris et al., In "Vacuum plasma spray deposition of titanium particle / glass-ceramic matrix biocomposites", J. Am. Ceram. Soc, 79, 1515-11520 coated with plasma a coating composed of bioactive glass reinforced with Ti particles which exhibited a bond strength greater than that of the monolithic bioactive glass coating. Pure titanium implants have become a preferred choice in place of calcium phosphate coated implants in recent years due to the critical disadvantages of the above calcium phosphate coatings. Plasma spraying and electronic deposition coating are two main techniques that were widely used for HA coatings. These methods tend to have problems with the dissolution of calcium phosphate, a percentage of 50% through high-temperature processing. The different phases of calcium phosphate not sprayed on implants are easy to dissolve in body solutions. The calcium phosphate-coated implant by these methods also fails in its long-term stability frequently due to the fracture at the titanium-coating interface that appears to be caused by the poor adhesion of the HA film to the metal substrate. In addition, the electron deposition plasma and the coating have to produce a non-uniform coating when applied to an irregular or porous surface. Accordingly, there is a need for an implant with improved binding strength and biostability, as well as a method for forming that implant for use in orthopedic and dental applications. In addition, a majority of commercially available titanium implant systems utilize some degree of macroporous surface photography based on preclinical and clinical data that a rugged surface topography appears to improve the rate at which functional implant-tissue integration was effected. Consequently, a coating on a rough implant surface is needed.

SUMMARY A method is described. In one embodiment, the method is suitable for coating biocompatible, biostable and bony conductive material on metal implant surfaces. The exemplary method includes forming a first coating layer on a portion of a substrate (e.g., a metal material) having a suitable dimensions for an implant (e.g., a medical or dental implant), and forming a second layer of coating on the first coating layer, the second coating layer including a material having a properties that promotes osseointegration. For coating multiple layers as described, the first coating layer can be a simple molecular weight layer that can be red by a metal implant surface to promote or achieve chemical bonding or other adhesion. In another embodiment, the first coating layer is made from trifunctional alkoxide silanes (such as alkoxysilanes) that have to form a chemical bond between the metal implant. The rive derivatives may include a ligand positively charged onto a surface of the formed layer or film. The second coating layer can be a layer of calcium phosphate material, such as nanomaterial hydroxyapatite particles, which can be measured (eg, ionically bound) or otherwise adhered to the first positively charged coating layer. In one embodiment, the second coating layer is made of a negatively charged hydroxyapatite (HA) nanoparticle, colloidal solution. The negatively charged crystalline hydroxyapatite nanoparticles have to form a relatively strong bond with the first coating layer positively charged through ionic bonding forces. The attraction to the first positively charged coating layer can also produce a negative charge on the surface of the second coating layer. Methods to immobilize bone by inducing growth factors on the conductive bone hydroxpartite that accelerates the fixation of the implant to bone is also described. An apparatus is also described. In a modality, an apparatus includes a substrate having the invention suitable as an implant for use in a medical or dental application. The substrate can be a metal material such as titanium, tantalum, cobalt, chromium and their respective alloys. Since it may be desirable, in one application to insert or include (implant) the substrate in bone material, the substrate includes a surface coating on a portion thereof.; representatively, at least one portion that is intended to serve or is designed to be in contact with bone or other tissue. In one embodiment, the surface coating includes at least two coating layers: a first coating layer having a property so as to bind or otherwise adhere to the substrate, particularly a metal substrate; and a second coating layer on the first coating layer having a property that promotes osseointegration between the apparatus and the bone or other tissue. Growth factors that induce bone, possibly the second layer of coating, can also be added. The additional features, modalities and benefits will be evident in view of the Figures and the detailed description presented here.

BRIEF DESCRIPTION OF THE DRAWINGS The characteristics, aspects and advantages of the modalities will become perfectly evident from the following detailed description, the appended claims and the accompanying drawings in which: Figure 1 schematically illustrates a cross-sectional side view of a portion of a substrate having multiple coating layers on a surface. Figure 2 shows an evaluation by RT-PCR of steady-state mRNA levels of type I collagen, osteopontin, osteocalcin, TO1, T02, and T03 in rat bone marrow stromal cells cultured on Ti disks with turned surfaces , with HA turned over, etched with acid, etched with HA-acid. A control gene, GAPDH, was used as an internal control. Figure 3 shows a test - implant placement on day 14 of osseointegration in vivo in the rat femur (n = 6).

DETAILED DESCRIPTION A coated apparatus and a method for coating an apparatus are described. In one embodiment, the appropriate apparatus is a medical / dental implant. The implant in this context means a device that is intended to be placed within a human body, to connect skeletal structures (for example, a hip implant) or to serve as an attachment for a part of the body (for example, an attachment for a artificial tooth). Figure 1 shows a medical / dental apparatus that includes a substrate 10 of a metal material. A suitable metal material for a medical / dental implant includes, but is not limited to, titanium, tantalum, cobalt or chromium, or their respective alloys. A suitable titanium alloy is the titanium (Ti) -aluminium (Al) -vanadium (V) alloy (for example, Ti-6% Al-4% V). The substrate 10 includes the surface 15 (upper surface as observed) which may not have a regular topography or may be porous (eg, macroporous). Referring to Figure 1, on top of a portion of the surface 15 of the substrate 10 is the first coating layer 20, of, for example, a material having such a property that it will bind or otherwise associate or adhere to the substrate 10. Suitable materials for the first coating layer include, but are not limited to, alkoxide-derived materials. Representatively, the first coating layer 20 is derived from an alkoxide having the general formula: YR2M (OR_) x-_ where M is one of silicon (Si), titanium (Ti), boron (B), aluminum ( Al), zirconium or other types of ceramics metals; where R_ is an alkyl portion such as methyl or ethyl; where R2 is an organic portion such as an alkyl (for example, methyl, ethyl), pyridinbenzene, benzene; where Y is a positively charged portion, such as a portion of amine (NH2) or metal (e.g. Fe, Ca, Mg); and where x is the valence state of M. A material suitable for use in the formation of the first coating layer 20 is a multifunctional silane. Representatively, a suitable multifunctional alkoxysilane is a trifunctional silane, aminopropyltrimethoxysilane (APS). The APS tends to bind to a metal substrate through the alkoxy groups and provide a positively charged surface through the ligand attached to the amine. (substrate-0-Si-R-NH +). Another example of positively charged ligand (YR) that may be suitable is pyridine-Fe. In one embodiment, the first coating layer is a single molecular layer (a monolayer) having, in this illustration, positive ligands positively bonded to one surface of the coating (the substrate opposite the surface 10). The first coating layer 20 can be formed on a portion of a substrate surface, including the entire surface. Suitable methods for forming the first coating layer 20 include wet coating techniques such as dipping and spraying. For dip coating, a portion of the surface of the substrate 10, including the entire surface, is immersed in an alkoxide solution in the presence of a catalyst and alcohol. The alkoxide can then be subjected to hydrolysis and condensation reactions to form a network (e.g., a polymer network) of the first control layer 20 on the non-submerged surface. Referring to Figure 1, on the first coating layer 20 (upper surface as seen) is the second coating layer 30. In one embodiment, the second coating layer 30 is a material that promotes osseointegration between the substrate 10 and the bone material (for example, human bone material). A suitable material is a calcium phosphate material such as hydroxyapatite (HA). In one embodiment, the second coating layer 30 is a layer that includes crystalline HA nanoparticles (e.g., having an average particle size of the order of an average particle size of 10 to 100 nanometers). One source of HA nanoparticles is Berkeley Advanced Biomaterials, Inc. of San Leandro, California. Representatively, the BABI-HAP-N20MR has a particle size of the order of 20 nanometers. The HA nanoparticles can be introduced onto a substrate surface 10 (on the first coating layer 20) in the form of a colloid. To form a colloid, the HA nanoparticles can be combined (dispersed) in solution with a solvent and mixed at a pH of the order of 7 to 10. A representative amount of HA in a colloid is of the order of 0.15 weight percent. The HA nanoparticles of the second coating layer 30 have a property tending to ionically bind to the first coating layer 20, particularly to positively charged ligands of the first coating layer 20. The ionic bond creates an "automatically assembled" coating (a combination of a first coating layer 20 and a second coating layer 30). A static charge attraction can be created on a surface of the second coating layer 30 between the positively charged ligands and the appositively charged nanoparticles. Using HA nanoparticles as the material of the second coating layer 30, a thin layer (eg, a monolayer) has strong adhesion properties that promote osseointegration.

To form a coated substrate as illustrated in Figure 1, the surface of the substrate is initially cleaned perfectly and charged (eg, negatively charged) through chemical processing. The first coating layer 20 is then applied to a portion of the surface of the substrate 10 by immersion or other wet coating process. The curing of the first coating layer 20 can be carried out at room temperature in a matter of minutes. In the embodiment where the first coating layer 20 is derived from (APS), a monolayer can provide a uniform one-dimensional distribution of cations formed on the outermost surface of the first coating layer 20. The substrate 10 that includes the first layer of coating 20 is then immersed in a solution that includes, in one embodiment, an HA colloid, to form the second coating layer 30 (eg, an anionic layer of HA). Representatively, the substrate 10 can be immersed in an HA colloid solution for several minutes (eg, 10 minutes) then rinsed and cured. The second coating layer 30 can be cured at a temperature from room temperature to about 100 ° C to form additional layers of the second layer material. coating (for example, multiple HA layers) can repeat the process. The representative thickness for the second coating layer 30 of one or more HA layers is of the order of 10 nanometers (eg, one layer) at 100 nanometers. The multilayer coating (e.g., the first coating layer 20 and the second coating layer 30) thus formed may have a negatively charged surface. This automatically mounted multi-layer ionic coating or film can also be synthesized on an implant of virtually any shape and can provide a conformational coating on a rough metal (e.g., titanium) surface that can be maintained with the coating layer. In one embodiment, the method applies sol-gel processing in an automatically assembled method to produce an ultra-thin coating of calcium phosphate (eg, HA), at a nanometer scale of ambient temperature at 200 ° C. A coating of crystalline HA as It was described as having high bioactivity and biocompatibility. The electrostatic nature of the coating improves the adhesion of an HA film to implant surfaces. It is believed that the adhesion is due to a first or primary coating layer chemically bonded to the metal implant and a second layer ionically bound to the first layer. In one embodiment, a process produces a multilayer coating in the order of 10 nm to 200 nm in thickness. Using a surface coating of calcium phosphate (eg HA) and accelerating osteoblastic adhesion can therefore be generated by reducing the heating time during implantation, and will be beneficial for patients with inadequate bones or implant designs that support a significant load, for which definitive treatments are not currently available. The described coating can also be non-toxic based on in vitro and in vivo assays. The results of a coating with APS (first coating layer) and HA (second coating layer) indicate that the genes associated with bone formation (coll, OPN, OCN) were also expressed between the tested condition, while the specific genes of the implant were up-regulated in disc coated with HA up to 50 percent.

EXAMPLES Example 1 Sol Preparation of Hydroxyapatite (HA): Nano-powder of HA (-20 nm) was used for the formulation. Preparation of sol de HA: Materials: BABI-HAP-20MR (net weight of 100 g in ammonium hydroxide), ether, 2-methoxyethanol and dH20. Add 1M NaOH and adjust the pH to 9-10. Move the transparent solution over the top. Take HA powder by adding 2-methoxyethanol (3 percent). Stir ultrasonically for 30 minutes at room temperature (RT) to produce a 3 percent HA colloid.

Example 2: Preparation of automatically assembled coating Cleaning of Ti substrate: Preparation of Piranha solution: Add 45 ml of H202 at 30 percent and then 105 ml of 100% H2S04 (3: 7) in a 200 ml glass beaker. The resulting solution is divided into 3 parts and added to three 60 ml glass bottles. Commercial implants are introduced into the solutions, respectively. The bottles are then placed in an oven at 80 ° C for 1 hour. Rinse exhaustively with H20 Milli-Q. Rinse again with absolute ethanol. Dry in the oven. Modification with APS of the surface of Ti: Preparation of 5 percent PSA solution: Add 3-aminopropyltriethoxysilane in pure Toluene. Immerse the implant in 15 percent APS solution for 15 hours at RT. Stir ultrasonically for 30 minutes each time in toluene, methanol / toluene (1: 1) and methanol. Thoroughly rinse with Milli-Q water to remove residual APS.

Dry at room temperature (RT) for 1 to 2 minutes and store until use. Alkaloid water: Add NaOH in Milli-Q water and adjust the pH to 10.

Example 3 Synthesis of the ultra-thin film of Hi droxi apatite: Immerse the modified titanium implants with APS in 3 percent HA solution for 10 minutes at RT. Rinse with dH20 alkaloid. Cure at 100 ° C for 30 minutes.

Example 4 Cross-sectional Tap Test for the tensile strength (adhesion) of the ultra-thin HA film on titanium: The adhesion of the ultra-thin HA film on metallic titanium was carried out by means of a cross-sectional equipment (Precision Gage &Tool Co., Ohio). Briefly, the specimens were placed on a firm base, at room temperature. An area free of scratches and minor surface imperfections was selected, using the crosscut tool to make parallel cuts.

To make a second cut at 90 degrees centered on the original cuts to create a grid in the film. Place the center of the test tape on the grid and smooth it in place. To make good contact with the film, carve the tape firmly with a pencil rubber. Wait approximately 90 seconds and then remove the tape. Grab the free end and pull quickly back on itself as close as possible to a 180 degree angle. Use the illuminated amplifier of the equipment, examine the area of the grid by the removed coating. The adhesion of the coating was evaluated according to the following scale: 5B - no coating on the grid frames was detached; 4B - no more than about the area was detached; 3B - about 5 to 15 percent of the area was peeled off; 2B: approximately 15 to 35 percent of the area was detached. IB: about 35 to 65 percent of the area was shed. 0B: Flanging is better than Grade IB. A degree of 5B was obtained for the coating formed as described in Examples 1-3 on the metallic titanium and showed a very strong adhesion of the coating.

Example 5 Test for cellular toxicity of the nano-HA coating in vitro: A disc including a coating formed as described with reference to Examples 1-3 was used for cell culture studies in vi tro. Male, adult Sprague-Dawley rats (approximately 100-150 g body weight) were used to isolate bone marrow stromal cells (BMSC). The BMSC were divided into 4 groups and grown on top of a turned disc, disc etched with acid, disc coated with HA turned, and disc coated with HA etched with acid. The BMSCs were maintained in a conventional osteoblastic differentiation medium. The BMSC proliferated uniformly on the HA surfaces and no significant differences were noticed between the groups during the experimental period, suggesting that the coating formed as described did not exhibit any cellular toxicity. The culture was finished at 14 days and the BMSC were harvested for the preparation of total RNA. Steady-state expression in the RNAs encoding the extracellular bone matrix protein and the genes associated with the implant were evaluated by RT-PCR. Figure 2 shows an evaluation by RT-PCR of steady state mRNA levels of type I collagen (coll), osteopontin (OPN), osteocalcin (OCN), T01, T02 and T03 in rat bone marrow stromal cells . The expression levels of these mRNA species were similar in those groups. Figure 2 also shows a control gene, GAPDH that was used as an internal control. The results indicate that the genes associated with bone formation (coll, OPN, OCN) were equally expressed between the tested condition, while the implant-specific genes were up-regulated in discs coated with HA up to 50 percent.

Example 6 Cell Adhesion - in vivo osseointegration: Miniature Ti rods with or without HA coating were UV sterilized and implanted in the femur of adult male Sprague-Dawley rats according to the method described above. On day 14, the femurs were harvested and subjected to the implant push test. The titanium implant coated with HA showed an increase of more than 200 percent of the thrust values compared to the uncoated group. The results are illustrated in Figure 3. This coating suggests that the HA-coated structure, coated as described in Examples 1-3, can positively stimulate osseointegration. The roughness of the surface coated with HA was similar to that of the uncoated titanium implant surface (Table 1).

Table 1 Turned Lathe-HA Rp-p 0.252 0.315 Rms 0.050 0.047 Ra 0.041 0.040 In the paragraphs, specific modalities were described. However, it will be evident that modifications and changes can be made to this without departing from the spirit and scope of the claims. The specifications and drawings can therefore be considered as illustrative rather than restrictive. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (31)

1. CLAIMS Having described the invention as above, the content of the following claims is declared as property. A method characterized in that it comprises: forming a first coating layer derived from an alkoxide on a substrate having a dimension suitable for the implant; and forming a second coating layer on the first coating layer, the second coating layer comprising a material having a property that promotes osseointegration. A method according to claim 1, characterized in that the substrate is a metal material and the metal material is selected from the group consisting of tantalum, cobalt, chromium, titanium, a cobalt alloy, a chromium alloy, or a titanium alloy. 3. The method according to claim 2, characterized in that the substrate is a metal material and the metal material comprises titanium. 4. The method according to claim 3, characterized in that the metal material is a titanium alloy comprising six percent by weight of vanadium. 5. The method according to claim 1, characterized in that the formation of the first coating layer comprises contacting the substrate with an alkoxide having a ligand comprising a positively charged portion. 6. The method according to claim 5, characterized in that the positively charged portion comprises an amine portion. The method according to claim 1, characterized in that the formation of a first coating layer comprises contacting the substrate with an aminopropyltrimethoxysilane. The method according to claim 1, characterized in that the first coating layer comprises a positively charged surface. The method according to claim 1, characterized in that the formation of the second coating layer comprises contacting the substrate with a coating solution comprising nano-sized hydroxyapatite particles. The method according to claim 9, characterized in that the coating solution comprises a mixed solvent comprising alcohol, dH20, ether and a base. 11. The method according to claim 10, characterized in that the coating solution has a pH of 7 to 10. The method according to claim 1, characterized in that before forming the second coating layer the method comprises drying the first coating layer. The method according to claim 12, characterized in that the drying comprises drying for one minute at room temperature. The method according to claim 1, characterized in that it further comprises drying the second coating layer at a temperature from room temperature to 100 ° C. 15. The method of compliance with the claim 1, characterized in that the first coating layer comprises a single molecular layer. The method according to claim 1, characterized in that the second coating layer comprises a single layer of nano hydroxyapatite particles. The method according to claim 1, characterized in that the second coating layer comprises a plurality of layers of nanodix-sized hodrixiapatite particles. 18. The method according to claim 17, characterized in that the second coating layer has a thickness of order of 10 to 100 nm. 19. The method according to claim 18, characterized in that the second coating layer has a thickness of 20 nm. 20. The method according to claim 1, characterized in that a surface of the second coating layer is negatively charged. 21. An apparatus, characterized in that it comprises: a substrate having a suitable dimension as a medical or dental implant; and a coating on the surface, the coating comprising a first coating layer derived from an alkoxy and a second coating layer having a property that promotes osseointegration. The apparatus according to claim 21, characterized in that the substrate contains a metal material selected from the group consisting of tantalum, cobalt, chromium, titanium, a tantalum alloy, a cobalt alloy, a chromium alloy and a titanium alloy. 23. The apparatus according to claim 21, characterized in that the substrate comprises a metal material and the metal material comprises titanium. 24. The apparatus according to claim 23, characterized in that the metal material is a titanium alloy comprising six percent by weight of aluminum and four percent of vanadium. 25. The apparatus in accordance with the claim 21, characterized in that the first coating layer is derived from an alkoxide having a ligand with a portion that produces a positive surface charge. 26. The apparatus according to claim 25, characterized in that the portion comprises an amine. 27. The apparatus according to claim 21, characterized in that the first coating layer has a property that is bonded to the substrate. 28. The apparatus according to claim 21, characterized in that the second coating layer comprises nano-sized hydroxyapatite particles. 29. The apparatus according to claim 21, characterized in that the second coating layer comprises at least three percent by weight of hydroxyapatite. 30. The apparatus in accordance with the claim 21, characterized in that the coating comprises a negative surface charge. 31. The apparatus in accordance with the claim 21, characterized in that the alkoxide has the general formula: YR2M (OR?) X_lf where M is selected from one of silicon, titanium, boron, aluminum and zirconium; where R_ is an alkyl portion; where R2 is an organic portion; where Y is a portion of ligand positively charged; and where x is the valence state of M.