Implants with layered coating implant surfaces and methods thereof

Abstract

The present disclosure relates to an implant (104) having a layered coating implant surface, and a method (300) for manufacturing an implant having an implant surface (1). The implant (104) having an implant surface comprises a micropatterned layer (102) on the implant surface (1) produced by microfabrication, and a main component layer (7, 103) deposited on the micropatterned layer (102) that promotes biointegration of the implant. The micropatterned layer (102) comprises microgrooves (4) arranged in a periodic array with predetermined dimensions.

Description

[Technical field]

[0001] The present invention relates generally to the fields of material science and coating technology. In particular, the present invention relates to layered biocompatible antimicrobial coatings and products made therewith. More particularly, the present invention relates to biocompatible and antimicrobial coatings on implantable surfaces or any other medical products having a bio-bonding surface and the coating process thereof. [Background technology]

[0002] In many surgical interventions, implants are expected to be fixed in the human body and to perform a specific function. Generally, prosthetic implants function as artificial joint elements that allow the movement of the replaced body part. Similarly, various implants perform a desired function that is no longer functioning due to clinical reasons. Implants must be biocompatible, and prosthetic implants are further expected to promote bone union and exhibit desirable material strength.

[0003] Commonly used implant materials include stainless steel, titanium alloys, cobalt-chromium alloys, ceramics, polymers, etc. Some of these materials are susceptible to wear and corrosion, and some induce the risk of causing allergic reactions, inflammation, etc. In addition, implant-associated infections and hospital-acquired infections remain a challenge, with infection rates being quite high, sometimes approaching 30%. Conventional techniques such as thermal spraying (e.g., plasma spraying, flame spraying) can coat the surface of prosthetic implants with biocompatible / bioactive coatings (e.g., hydroxyapatite, titanium or composites), allowing efficient bonding of the implant. However, such conventional thermal spraying methods have the disadvantage that both the substrate and the coating are susceptible to oxidation, phase transformation and induction of residual stress due to the high temperature treatment.

[0004] To address the infection problem, the recommended strategies include incorporating antimicrobial agents (antibiotics or metals) into the coating, which prevent bacterial growth and biofilm formation. One of the conventional methods to achieve an antimicrobial surface on implants is the anodization of the surface of Ti alloy (e.g., Ti-6Al-4V) implants to form cavities / pores. Then, antibiotics or antimicrobial agents such as silver are filled into the cavities / pores formed by the anodization process by electrochemical or dip coating methods. One of the main limiting factors of this method is that the material of the implant is preferably Ti or Ti alloy. Another method to achieve an antimicrobial surface is to coat the surface of the implant with osteoconductive materials loaded with antibiotics (e.g., gentamicin-loaded HA). The disadvantage of this method is the risk of long-term development of antibiotic resistance. Therefore, the release of antibiotics is generally limited to a maximum of 4-6 days or less. However, the sustained activity of suppressing bacterial infection is of high clinical significance in reoperation, immunocompromised patients and tumor patients.

[0005] At the same time, limiting antimicrobial activity, both in quantity and time, to avoid cytotoxic effects and compromising tissue compatibility is a major challenge.

[0006] Another problem has also been noted in the case of joint replacement surgery, that of aseptic loosening, which can lead to revision surgery. Here, efficient implant integration is a key challenge to be addressed. Among the strategies developed, the formation of grooves and ridges on the implant surface is considered an effective way to transfer load / stress onto the cancellous shaft of the implant and prevent the stress shielding effect. However, in such cases, although the grooves / ridges can transfer load to the implant, they are insufficient to ideally promote efficient cell attachment and bone ingrowth, since the size of the grooves and ridges is large in proportion to the cell size. Therefore, the coatings deposited on the implant surface do not show surface properties that effectively promote bone ingrowth.

[0007] Thus, there is a need for layered coatings of biocompatible antimicrobial coatings that may incorporate specifically designed microstructured surface features that enhance biointegrity for efficient implant attachment and simultaneously exhibit sustained antimicrobial activity to inhibit bacterial growth and prevent biofilm formation.

[0008] The information disclosed in the background section of this disclosure is intended to enhance understanding of the general background of the invention and should not be taken as an admission or in any way suggesting that this information forms prior art already known to those skilled in the art. Summary of the Invention

[0009] In a non-limiting embodiment, an implant having an implant surface is disclosed. The implant surface comprises a micropatterned layer on the implant surface and a base component layer. The micropatterned layer comprises microgrooves fabricated by dimensional microfabrication and arranged in a periodic array. Further, the base component layer is deposited on the micropatterned layer of microgrooves. The implant surface promotes biointegration of the implant.

[0010] In another embodiment, the micro-grooves produced by microfabrication have one of the shapes of a semicircle, a quasi-triangle, a cross, a homolateral star, an ellipse, a circle, and a square, and are arranged in at least one of a honeycomb shape or a planar hexagonal close-packed shape. In a non-limiting embodiment, the micro-grooves have dimensions of a width in the range of 10 μm to 50 μm, a depth of 50 μm to 500 μm, and a pattern spacing of 400 μm to 2000 μm.

[0011] In one embodiment, the base component layer includes at least one of titanium, titanium alloy, titanium-tantalum alloy, magnesium alloy, titanium-zirconium alloy, and / or combinations thereof as a base component. The base component layer is deposited using a high pressure cold spray deposition technique. The high pressure cold spray deposition technique allows the synthesis of a porous layer of the main component while preserving the original phase of the sprayed species of the main component. In a non-limiting embodiment, the main component forms a layer having a thickness of 70 μm to 800 μm after being deposited.

[0012] In yet another embodiment, the implant having an implant surface further comprises an antimicrobial component layer deposited on the primary component layer using physical vapor deposition (PVD) techniques. The antimicrobial component layer is configured for continuous release of the antimicrobial component from the antimicrobial component layer to inhibit microbial growth and prevent colonization on the implant surface. In a non-limiting embodiment, the antimicrobial component comprises at least one of silver (Ag), gold (Au), zinc (Zn), platinum (Pt), palladium (Pd), iridium (Ir), and copper (Cu), nickel (Ni), or combinations thereof.

[0013] In another embodiment, the antimicrobial component layer has a deposition thickness ranging from 1 nm to 500 nm. The deposition thickness is adjusted by adjusting the duration of deposition based on the deposition rate of the antimicrobial component on the implant surface. The deposition thickness is determined based on the surface area of ​​the implant to prevent cytotoxicity due to the antimicrobial component.

[0014] In a non-limiting embodiment, a method of manufacturing an implant having an implant surface is disclosed. The method includes micromachining to form a micropatterned layer on the implant surface. The micropatterned layer comprises microgrooves arranged in a periodic array with predetermined dimensions. The method further includes depositing a base component layer on the micropatterned layer. The implant surface promotes biointegration of the implant.

[0015] In other embodiments, the method further comprises one or more intermittent steps of ultrasonic cleaning, surface cleaning and drying to remove organic / inorganic and other surface impurities, a further step of surface blasting with blasting media to increase surface roughness and post-treatment with nitrogen / compressed air blowing, sterilization and packaging / storage.

[0016] The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the exemplary aspects, embodiments and features described above, further aspects, embodiments and features will become apparent by reference to the drawings and the following detailed description.

[0017] (Objective of the Invention) It is an object of the present invention to provide an implant having an implant surface that promotes biointegration of the implant upon implantation.

[0018] Another object of the present invention is to prevent bacterial growth on the implant surface, thereby promoting better biocompatibility and biointegration of the implant. [Brief description of the drawings]

[0019] The accompanying drawings, which are incorporated in and constitute a part of this disclosure, illustrate exemplary embodiments and, together with the description, explain the disclosed embodiments. In the drawings, the leftmost digit or digits of a reference number identify the figure in which the reference number first appears. The same numbers are used throughout the figures to reference like features and components. Some embodiments of implants and / or methods according to embodiments of the present subject matter are described, by way of example only, with reference to the accompanying drawings.

[0020] [Figure 1] FIG. 1 illustrates an exemplary environment 100 of an implant having an implant surface according to an embodiment of the present invention. [Figure 2a] FIG. 2 shows a longitudinal cross section of an implant surface having microgrooves according to one embodiment of the present invention. [Figure 2b] FIG. 2 shows a longitudinal cross section of an implant surface having microgrooves according to one embodiment of the present invention. [Figure 2c] FIG. 2 shows a longitudinal cross-section of an implant surface having a main component layer deposited on a micropatterned layer according to one embodiment of the present invention. [Figure 2d]FIG. 2 shows a top-view scanning electron microscope (SEM) image of an implant surface when a main component layer is deposited on a micropatterned layer in accordance with one embodiment of the present invention. [Figure 2e] FIG. 2 shows a longitudinal cross-section of an implant surface upon deposition of an antimicrobial layer onto the main component layer and the micropatterned layer forming an antimicrobial microstructured coating according to one embodiment of the present invention. [Diagram 3] 1 is a flow chart illustrating a method for manufacturing an implant having an implant surface according to an embodiment of the present invention. [Figure 4] 1 is a flow chart illustrating a method for manufacturing an implant having an implant surface with an antimicrobial component layer according to one embodiment of the present invention. [Diagram 5] 1A-1D illustrate an embodiment of a method for manufacturing an implant having an implant surface along with intermediate steps used in the sequential layer deposition according to the present disclosure. [Figure 6a] 1 is a graphical representation showing a significant increase in mineralization on implants having an antimicrobial micropatterned layer flank compared to a reference titanium-VPS layer on the implant surface according to one embodiment of the present invention. [Figure 6b] 1 is a graphical representation showing a significant reduction in bacterial activity on an implant having an antibacterial micropatterned layer flank compared to a reference titanium-VPS layer on an implant according to an embodiment of the present invention. [Figure 7] FIG. 1 shows histopathological sections of bone samples showing evidence of clear bone formation at the bone-implant interface in (a) a group receiving an implant with an antibacterial micropatterned layer according to one embodiment of the present invention and (b) a group receiving a reference titanium vacuum plasma sprayed layer. [Figure 8] FIG. 1 shows micro-computed tomography of excised bone samples showing bone growth on the implant surface having an antibacterial micro-patterned layer exhibiting biobonding according to one embodiment of the present invention.

[0021] Those skilled in the art will appreciate that the block diagrams herein are conceptual diagrams of exemplary systems embodying the principles of the present subject matter. Similarly, any flow charts, flow diagrams, state transition diagrams, pseudocode, or the like will be understood to represent various processes that may be substantially represented on a computer-readable medium and executed by a computer or processor, whether or not such a computer or processor is explicitly shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment or implementation of the subject matter described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.

[0023] In the following detailed description of the embodiments of the present disclosure, reference is made to the accompanying drawings, which form a part of this specification, and in which are shown by way of illustration specific embodiments in which the present disclosure may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present disclosure, it being understood that other embodiments may be utilized and changes may be made without departing from the scope of the present disclosure. Thus, the following description is not to be taken in a limiting sense.

[0024] Disclosed herein is an implant having an implant surface. The implant surface comprises a micro-patterned layer on the implant surface and a base component layer. The micro-patterned layer comprises micro-grooves fabricated by micromachining of a predetermined dimension and arranged in a periodic array. Further, the base component layer is deposited on the micro-patterned layer of micro-grooves. The implant surface promotes bio-integration of the implant. The material of said implant surface may be selected from the group consisting of stainless steel, cobalt chromium alloy, cobalt-chromium-molybdenum alloy, zirconium alloy, titanium alloy, ceramic, polymer, and other materials requiring a coating on the surface, or other combinations thereof.

[0025] In one aspect, the implant surface comprises a micropattern layer of microfabricated microgrooves in the shape of a semicircle, a quasi-triangle, a cross, a homolateral star, an ellipse, a circle, or a square, and is arranged in at least one of a honeycomb pattern or a planar hexagonal close-packed pattern. In a non-limiting embodiment, the microgrooves have a width in the range of 10 μm to 50 μm, a depth of 50 μm to 500 μm, and a pattern spacing of 400 μm to 2000 μm.

[0026] In one embodiment, the main component layer comprises at least one of titanium and titanium alloys, titanium-tantalum alloys, magnesium alloys, titanium-zirconium alloys and / or combinations thereof as main components. The main component layer is deposited by high pressure cold spray deposition technique. The high pressure cold spray deposition technique allows for the synthesis of a main component layer with porosity while preserving the original phase of the sprayed species of the main component. In a non-limiting embodiment, the main component forms a layer thickness of 70 μm to 800 μm after being deposited.

[0027] In one embodiment, the main component layer is deposited using a high pressure cold spray technique that allows to synthesize a coating with porosity while preserving the original phase of the sprayed species. The coating is carried out in high pressure mode with pressures up to 35 bar to 50 bar, standoff distances between 15 mm and 20 mm, with argon, nitrogen and / or compressed air as carrier gases, and preheated between 400 ° C and 800 ° C, allowing the deposition of the coating species by forming a condensed layer on the substrate surface.

[0028] In another aspect, the implant having an implant surface further comprises an antimicrobial component layer deposited on the primary component layer using physical vapor deposition (PVD) techniques. The antimicrobial component layer is configured to continuously release the antimicrobial component from the antimicrobial component layer to inhibit bacterial growth and prevent colonization on the implant surface. In a non-limiting embodiment, the antimicrobial component comprises at least one of silver (Ag), gold (Au), zinc (Zn), platinum (Pt), palladium (Pd), iridium (Ir), and copper (Cu), nickel (Ni), or a combination thereof.

[0029] In another embodiment, the antimicrobial component layer has a deposition thickness ranging from 1 nm to 500 nm. The deposition thickness is controlled by adjusting the duration of deposition based on the rate of deposition of the antimicrobial component on the implant surface. The deposition thickness is determined based on the surface area of ​​the implant to prevent cytotoxicity due to the antimicrobial component.

[0030] In one embodiment, the antimicrobial component layer can be synthesized by physical vapor deposition in an argon atmosphere at a partial pressure of 1-30 mbar and sputtering at ambient temperature conditions with a DC / RF power of 10 W-300 W to form a layer with a thickness of 1-500 nm.

[0031] In a non-limiting embodiment, a method of manufacturing an implant having an implant surface is disclosed. The method includes microfabrication to form a micropatterned layer on the implant surface. The micropatterned layer comprises microgrooves arranged in a periodic array with predetermined dimensions. The method further includes depositing a base component layer on the micropatterned layer. The implant surface promotes biointegration of the implant.

[0032] In other embodiments, the method further comprises one or more intermittent steps of ultrasonic cleaning, surface cleaning and drying to remove organic / inorganic and other surface impurities, a further step of surface blasting with a blasting media to increase surface roughness, and post-treatment steps with nitrogen / compressed air blowing, sterilization, and packaging / storage.

[0033] FIG. 1 illustrates an exemplary environment 100 of an implant having an implant surface according to an embodiment of the present invention.

[0034] The present disclosure discloses an implant 104 having a layered coating implant surface that promotes biointegration of the implant upon implantation. The environment 100 for an implant having an implant surface comprises a manufactured implant 101 having a layered coating to form an implant 104 having an implant surface. The layered coating further comprises a micro-patterned layer 102 on the implant surface and a main component layer 103 deposited on the micro-patterned layer. In one embodiment, the implant may be used in a body, e.g., a human body, to provide support to or replace, partially or completely, a structure or function of the body. For example, the manufactured implant may be an orthopedic implant, a dental implant, a spinal implant, a bionic, etc. In one aspect of the present invention, the manufactured implant 101 may be shaped according to the purpose / structure of the implant. For example, in the case of an orthopedic implant, the manufactured implant 101 may be shaped like a femur.

[0035] In one embodiment, the implant material 2 is selected from the group consisting of biocompatible materials, bioabsorbable materials, or stainless steels, cobalt-chromium alloys, cobalt-chromium-molybdenum alloys, zirconium alloys, titanium alloys, ceramics, polymers, and other materials requiring a coating on the surface, or other combinations thereof, further constituting the implant surface 1. In other embodiments, there are partial implants where only a portion or parts of the implant need to be embedded.

[0036] FIG. 2(a) shows a cross-section of an implant surface having microgrooves according to one embodiment of the present invention.

[0037] In another embodiment of the present invention, a micro-patterned layer 102 is formed on the implant surface by microfabrication tools and techniques. The micro-patterned layer 102 according to the present application comprises micro-grooves 4 arranged in a periodic array with predetermined dimensions. The micro-patterning on the implant surface improves the surface morphology of the implant, allows better adhesion of subsequent layers, and also serves as a scaffold for cell attachment and proliferation for better bio-integration. However, the dimensions of the micro-grooves 4, such as their shape, depth, width, and inter-pattern distance, play an important role in improving these aspects. The geometric aspects such as width, depth, and inter-pattern distance are denoted by "d", "t" and "s" respectively (FIG. 2(a)). The micro-grooves 4 according to the present disclosure are in the shape of at least one of a semicircle, a quasi-triangle, a cross, an isosceles star, an ellipse, a circle, and a square, and in the arrangement of at least one of a honeycomb or a planar hexagonal close-packed arrangement. Furthermore, the microgrooves 4 are in a dimensional range consisting of one or more of a width of 10 μm to 50 μm, a depth of 50 μm to 500 μm, and a pattern distance of 400 μm to 2000 μm. The shape and dimensions of the microgrooves 4 in one embodiment can be predefined in a manner based on the type of implant, the surface area of ​​the implant that requires biointegration, the site of the implant on the body, and the cell size ratio. For example, a micropattern of semicircular shape in a planar hexagonal close-packed array can be used in an orthopedic implant to promote bone integration (see FIG. 2(b)).

[0038] FIG. 2(c) is a cross-sectional view of an implant surface with a main component layer deposited on a micropatterned layer according to an embodiment of the present invention.

[0039] In one embodiment of the present invention, an implant having an implant surface 1 has a main component layer 103 on top of a micropatterned layer 102. Commonly used implant materials include stainless steel, titanium alloys, cobalt-chromium alloys, ceramics, and polymers. Some of these materials are susceptible to wear and corrosion, and may pose a risk of causing allergic reactions, inflammation, and the like. In addition, implant-associated infections and hospital-acquired infections remain a challenge, with a significant infection rate, sometimes approaching 30%. Conventional techniques such as thermal spraying (plasma spraying, flame spraying, etc.) for depositing the main component layer 103 can coat the prosthetic implant surface 1 with a biocompatible / bioactive coating (e.g., hydroxyapatite, titanium, or composites) that allows for efficient bonding of the implant. However, such conventional thermal spraying methods have the disadvantage that both the implant surface 1 and the coating layer are susceptible to oxidation, phase transformation, and induction of residual stresses by high-temperature treatment.

[0040] Therefore, according to one embodiment of the present disclosure, it is disclosed that the main component layer 103 on the implant surface 1 is deposited by cold spraying, which allows the synthesis of a coating with porosity while preserving the original phase of the sprayed species. The porosity of the deposited main component layer 103 further promotes cell attachment and proliferation on the implant surface 1, achieving better bio-bonding. Figure 2(d) shows a top-view scanning electron microscope (SEM) image of the implant surface 1 upon deposition of the main component layer 103 on the micropatterned layer 102, according to one embodiment of the present invention.

[0041] In this case, the coated layered implant surface 1 essentially serves two functions. Releases effective amounts of silver ions, inhibiting bacterial / fungal growth and preventing colonization. Over time, the silver content in the membrane is continuously depleted, thereby sustaining the antibacterial effect. · At the same time, the micropatterned layer in addition to the rough morphology of the main component layer 103 allows cell attachment and rapid cell proliferation, which significantly improves the quality of the biobonding and at the same time reduces the risk of infection and bacterial colonization. Furthermore, the titanium coating is biocompatible and does not corrode in body fluids, such as synovial fluid in the case of knee joint implants.

[0042] FIG. 2(e) shows a cross-sectional view of an implant surface upon deposition of an antimicrobial layer forming an antimicrobial microstructured coating on the main component layer and the micropatterned layer according to one embodiment of the present invention.

[0043] In addition to the micropattern layer 102 and the main component layer 103 layers, the biobonding of the implant with the implant surface 1 may be enhanced by an antimicrobial layer according to an embodiment. The deposition of the antimicrobial layer prevents the formation of a bacterial film that may lead to infection at the interface between the implant site and the body fluids in the body. FIG. 2(e) shows an embodiment in which an antimicrobial component, such as silver, is deposited on the main component layer 103. This layer gradually releases ions upon embedding the implant in the implant site in the body, preventing or significantly reducing bacterial activity at the implant site. Thus, the antimicrobial component layer is configured to continuously release the antimicrobial component from the antimicrobial component layer, inhibiting bacterial growth and preventing colonization at the implant surface l. The antimicrobial component is comprised of at least one of silver (Ag), gold (Au), zinc (Zn), platinum (Pt), palladium (Pd), iridium (Ir) and copper (Cu), nickel (Ni), or a combination thereof, and has a deposition thickness in the range of 1 nm to 500 nm. It has been observed that antimicrobial components may cause cytotoxicity above a corresponding threshold. To avoid this, the thickness of the deposition may be adjusted by adjusting the duration of the deposition based on the deposition rate of the antimicrobial component on the implant surface 1, and the thickness of the deposition is determined based on the surface area of ​​the implant to prevent cytotoxicity due to the antimicrobial component. For example, the thickness of the antimicrobial component layer on an implant with a large surface area may be smaller compared to the thickness of the antimicrobial component layer on an implant with a small surface area. Physical vapor deposition (PVD) is a process used to produce a metal vapor that can be deposited as a thin, highly adherent pure metal or alloy coating on a conductive material. The use of PVD technology for the deposition of the antimicrobial layer allows for unique control over the nanoscale thickness of the deposition layer, calculated based on the deposition rate.

[0044] FIG. 3 is a flow chart illustrating a method for making an implant having an implant surface according to one embodiment of the present invention.

[0045] As shown in FIG. 3, a method for manufacturing an implant having an implant surface 1 is described.

[0046] The order in which the method is described is not intended to be construed as a limitation, as any number of the described method blocks can be combined in any order to implement the method.

[0047] In block 301, the method 300 may include microfabrication to form a micropatterned layer on the implant surface 1. The micropatterned layer 102 includes microgrooves 4 arranged in a periodic array with predetermined dimensions. The shape of the microgrooves 4 may be at least one of a semicircular, semitriangular, cross, isolateral star, elliptical, circular, and rectangular shape, and may be arranged in a honeycomb or planar hexagonal close-packed pattern. In one embodiment, the material of the implant surface 1s may be selected from the group consisting of stainless steel, cobalt-chromium alloy, cobalt-chromium-molybdenum alloy, zirconium alloy, titanium alloy, ceramics, polymers, and other materials that require a coating on the surface to enhance biocompatibility. The microfabrication includes forming the microgrooves 4 with a dimension range of 10 μm to 50 μm in width, 50 μm to 500 μm in depth, and 400 μm to 2000 μm in pattern spacing.

[0048] In block 302, the method 300 may include depositing a base component layer 103 on the micropatterned layer 102. The base component layer 103 is made of at least one of titanium and a titanium alloy. The deposition of the base component layer 103 is performed using a high pressure cold spray deposition technique. The cold spray deposition technique allows the synthesis of a base component layer 103 with porosity while preserving the original phase of the sprayed species of the base component. The deposition of the base component forms a layer thickness of 70 μm to 800 μm. The implant surface 1 promotes biointegration of the implant. In one embodiment, the base component of the coating composition is a metal agent made of either titanium (Ti) or a titanium alloy. In one embodiment, the base component of the coating composition is in the form of a powder (grain size <65-90 μm) deposited by spray deposition and may form a layer thickness in the range of 70 μm to 500 μm.

[0049] The method 300 may further include depositing an antimicrobial component layer on the primary component layer 103 using physical vapor deposition (PVD), the antimicrobial component layer configured for continuous release of the antimicrobial component from the antimicrobial component layer to inhibit bacterial growth and prevent colonization on the implant surface 1. The antimicrobial component may comprise at least one of silver (Ag), gold (Au), zinc (Zn), platinum (Pt), palladium (Pd), iridium (Ir), copper (Cu) and nickel (Ni), or a combination thereof.

[0050] The antibacterial component layer has a deposition thickness in the range of 1 nm to 500 nm. The deposition thickness of the antibacterial component layer is adjusted by adjusting the duration of deposition based on the deposition rate of the antibacterial component on the implant surface 1. The deposition thickness is determined based on the surface area of ​​the implant so as to prevent cytotoxicity caused by the antibacterial component.

[0051] Method 300 may further include one or more intermittent steps of ultrasonic cleaning, surface cleaning and drying to remove organic / inorganic and other surface impurities, a further step of surface blasting with a blasting media to increase surface roughness, and post-treatment steps with nitrogen / compressed air blowing, sterilization and packaging / storage.

[0052] FIG. 4 is a flow chart illustrating a method for manufacturing an implant having an implant surface according to another embodiment of the present invention.

[0053] As shown in FIG. 4, a method for manufacturing an implant having an implant surface 1 is described.

[0054] In block 401, the method 400 may include microfabrication to form a micropatterned layer on an implant surface 1. The micropatterned layer 102 comprises microgrooves 4 arranged in a periodic array with predetermined dimensions.

[0055] At block 402, the method 400 may include depositing a base layer 103 over the micropatterned layer 102, the implant surface 1 promoting biointegration of the implant.

[0056] In block 403, the method 400 may include depositing an antimicrobial component layer on the main component layer 103 using physical vapor deposition (PVD) techniques, the antimicrobial component layer being configured to continuously release antimicrobial components from the antimicrobial component layer to inhibit bacterial growth and prevent colonization on the implant surface 1.

[0057] The method 400 may further include depositing an antimicrobial component layer on the primary component layer 103 using physical vapor deposition (PVD) techniques, the antimicrobial component layer configured for continuous release of antimicrobial components from the antimicrobial component layer to inhibit bacterial growth and prevent colonization on the implant surface 1. The antimicrobial component comprises at least one of silver (Ag), gold (Au), zinc (Zn), platinum (Pt), palladium (Pd), iridium (Ir), copper (Cu) and nickel (Ni), or a combination thereof.

[0058] The antimicrobial component layer has a deposition thickness ranging from 1 nm to 500 nm. The deposition thickness is adjusted by adjusting the duration of deposition based on the deposition rate of the antimicrobial component on the implant surface 1. The deposition thickness is determined based on the surface area of ​​the implant so as to prevent cytotoxicity caused by the antimicrobial component.

[0059] Method 400 may further include one or more intermittent steps of ultrasonic cleaning, surface cleaning and drying to remove organic / inorganic and other surface impurities, further steps of surface blasting with blasting media to increase surface roughness, post-treatment with nitrogen / compressed air blowing, sterilization and packaging / storage.

[0060] FIG. 5 shows an embodiment of a method for manufacturing an implant having an implant surface 1 along with intermediate steps used in the layer-by-layer deposition according to the present disclosure.

[0061] The method of manufacturing an implant having an implant surface 1 with intermediate steps used for sequential layer deposition includes one or more intermittent steps of ultrasonic cleaning, surface cleaning and drying to remove organic / inorganic and other surface impurities, further steps of surface blasting with blasting media to increase surface roughness, and post-treatment steps of nitrogen / compressed air blowing, sterilization and packaging / storage. The order in which the method is described is not intended to be construed as limiting, and the method can be performed combining any number of the described method steps in any order. EXAMPLES

[0062] Example 1: Preparation of microgrooves on implant surface 1: Ultrasonic cleaning and drying: First, the implant material is subjected to ultrasonic cleaning and drying of the implant surface 1 to remove organic / inorganic and other surface impurities. The material of the implant surface may be selected from the group consisting of stainless steel, cobalt-chromium alloy, cobalt-chromium-molybdenum alloy, zirconium alloy, titanium alloy, ceramics, polymers, and other materials that require a coating on the surface, or combinations thereof.

[0063] Micromachining: The cleaned surface is subjected to micromachining on the surface to form periodic microgrooves 4. A micropattern layer 102 on the implant surface 1 is created using a micromachining tool 2 to form the microgrooves 4. The coating process includes pre-patterning of the substrate surface to obtain identical periodic microgrooves 4, and the processing techniques of micromachining include, but are not limited to, laser patterning, photolithography, microimprinting, selective laser melting / additive manufacturing, microstamping, etching, or others and combinations thereof. The microgrooves 4 are fabricated to have defined shapes and dimensions. The geometric aspects such as width, depth, and pattern-to-pattern distance are indicated using "d", "t", and "s" (Figure 2(a)). The microgrooves 4 are arranged in a periodic arrangement such as a planar hexagonal close-packed array 4 (Figure 2b) or a honeycomb-like array. The shape of the microgrooves 4 consists of at least one of the following: semicircle, quasi-triangle, cross, homolateral star, ellipse, circle, and square. The micro-grooves 4 created by micro-machining have dimensions of width in the range of 10 μm to 50 μm, depth in the range of 50 μm to 500 μm, and pattern distance in the range of 400 μm to 2000 μm. This step further includes ultrasonic cleaning, rinsing and drying of the implantable surface during micro-machining to remove surface impurities.

[0064] Surface blasting: Further, a blasting device 5 is used to perform surface blasting with blasting media on the implant surface 1 to increase the surface roughness, and silicon carbide (SiC), alumina (Al 2 O 3 ), silicon dioxide (SiO 2 ) powder, or other combinations thereof. The blasting process is followed by a step of ultrasonically cleaning and drying the implant surface 1 during surface blasting to remove organic / inorganic and other surface impurities.

[0065] Example 2: Deposition of a layer of the main component on an implant surface 1 with microgrooves 4 The method may include a step of depositing the main component on the implant surface 1. The deposition of the main component coating on the substrate surface is carried out by the coating technique of high pressure cold spray 6. The coating is carried out in high pressure mode at a pressure of 35 bar to 50 bar, with a stand-off distance between 15 mm to 20 mm, preheated to between 400 ° C to 800 ° C, with argon, nitrogen and / or compressed air as carrier gas, allowing the deposition of the coating species by forming a condensed layer on the substrate surface. This high pressure cold spray 6 allows the synthesis of a porous coating, preserving the original phase of the sprayed species. The implant surface coated with the main component layer 7, 103 is further subjected to surface cleaning and drying of the implant surface 1 in order to remove surface impurities.

[0066] The deposition of the main component layer 7, 103 on the micropatterned surface 3 can also be performed by a coating technique selected from the group consisting of thermal spraying, vacuum plasma spraying, atmospheric plasma spraying, detonation spraying, or a combination thereof. By using a technique such as high pressure cold spray deposition for the deposition of the main component layer, the need for a binder between the implant surface and the main component is overcome, thereby significantly reducing the comparative cost of manufacture.

[0067] Example 3: Deposition of antimicrobial component layer The method of depositing an antimicrobial component layer 9 on an implantable surface includes depositing an antimicrobial Ag layer. The antimicrobial agent coated on the implantable surface has an Ag concentration ranging from 0.1 atomic % to 45 atomic %. Silver (Ag), a precious metal (E0 = +0.80 V), does not corrode in water and is easily absorbed by silver ions (Ag) either by direct contact or by release of free ions. + Ag metal is known to exert antibacterial functions because it gradually releases ions from the bacteria. These metal ions react with various structures of bacteria and damage the cell walls, cell membranes, and metabolic activities within the cells. This prevents or inhibits the growth of bacteria and prevents colony formation.

[0068] It has been identified that antimicrobial components may cause cytotoxicity above their corresponding threshold. To avoid this situation, the deposition thickness may be adjusted by adjusting the duration of deposition based on the deposition rate of the antimicrobial component on the implant surface 1, and the deposition thickness is determined based on the surface area of ​​the implant in such a way as to prevent cytotoxicity due to the antimicrobial component. For example, the thickness of the antimicrobial component layer on an implant with a large surface area may be smaller compared to the thickness of the antimicrobial component layer on an implant with a small surface area. Physical vapor deposition (PVD) is a process used to generate metal vapor that can be deposited as a thin, highly adherent pure metal or alloy coating on a conductive material, thereby eliminating the need for a bonding material between the main component layer 103 and the antimicrobial component layer 9, significantly reducing the comparative cost of manufacturing. The use of PVD techniques for the deposition of the antimicrobial layer allows unique control of the thickness of the deposited layer at the nanoscale, calculated based on the deposition rate. The antimicrobial Ag layer is synthesized by a process of physical vapor deposition at a partial pressure of 1-30 mbar in an argon atmosphere and sputtering at DC power / RF power of 10 W-300 W under ambient temperature conditions to obtain a layer thickness of 1-500 nm.

[0069] The deposition of the antimicrobial component layer 9 onto the implantable surface is further followed by steps of cleaning and sterilization of the coated implant surface 1 .

[0070] Example 4: Post-processing Post-processing steps during deposition of the various layers may include one or more post-processing steps, such as, for example, nitrogen / compressed air blowing to clean the implant surface 1, sterilization and packaging / storage of the implant having the implant surface 1.

[0071] Example 5: The ability of the implant surface 1 to inhibit bacterial growth was evaluated by setting up an antibacterial activity assay in which bacterial inocula were cultured on the surface of the coupon disc. After 24 hours of incubation, the bacterial inocula were harvested and plated in a Petri dish for colony counting. The implant surface 1 with the micropatterned layer 102 and the main component layer 7,103, which may consist of antibacterial components consisting of titanium and Ag9 resulting in an antibacterial micropatterned layer, was then prepared by plating a 10 mm diameter and 3 mm thick Ti 6 Al 4 A TiV coupon disk of similar shape and dimensions was synthesized on the disk and, as a reference, a ... 6 Al 4 V coupon discs were used. Figure 6(a) is a graphical representation showing a significant increase in mineralization in implants having an antimicrobial component layer 9 and a micropatterned layer flank on the implant surface 1 according to an embodiment of the present invention. Mineralization activity at two different time points for the antimicrobial microstructured coating and the reference Ti-VPS coating is shown (* indicates significant difference at p<0.5).

[0072] Antibacterial activity against gram-negative Escherichia coli and gram-positive Staphylococcus aureus was examined. The antibacterial microstructured layer showed a 4 log reduction and a 2 log reduction, respectively, for Escherichia coli and Staphylococcus aureus, compared to the reference titanium vacuum plasma sprayed layer (VPS). (FIG. 6(b) shows a graphical representation demonstrating a significant reduction in bacterial activity on an implant having an antibacterial component layer 9 on the implant surface 1 and a micropatterned layer flank, according to one embodiment of the present invention.)

[0073] Example 6 In order to verify the safety of implants with an implant surface 1 with an antibacterial microstructured layer and to evaluate the biological response, an in vivo implant study was performed. As a test system, New Zealand white rabbits were selected as a suitable species for a 13-week implant study. The study design consisted of two groups receiving cylindrical implants with an antibacterial microstructured layer and cylindrical implants with a reference titanium vacuum plasma sprayed layer. Under sterile conditions, the implants were inserted into the tibia of New Zealand white rabbits after incision and the wound was sutured. 13 weeks after implant placement, the rabbits were humanely sacrificed and bone specimens containing the implants were extracted. After demineralization, histopathological sections of the bone specimens were prepared. The implants did not cause any side effects, including irritation or inflammatory reactions. Gross and histopathological observations of the bone samples revealed that the microscopic tissue composition was comparable in both groups. Histopathological sections showed clear evidence of bone formation at the bone-implant interface in the group that received implants with the antibacterial microstructured layer and the group that received the reference titanium vacuum plasma sprayed layer (see FIG. 7 which shows histopathological sections of bone samples showing clear evidence of bone formation at the bone-implant interface in (a) the group that received implants with the antibacterial micropatterned layer and (b) the group that received the reference titanium vacuum plasma sprayed layer according to one embodiment of the present invention).

[0074] Example 7: The biointegration of the implant was evaluated by performing micro-computed tomography of excised bone samples that received implants with antibacterial microstructured layers from the in vivo test described above. Bone growth was observed (white arrow) on the implant surface 1 with the antibacterial microstructured layer, resulting in osseointegration of the implant (see FIG. 8, which shows a micro-computed tomography of an excised bone sample with bone growth observed on the implant surface 1 with the antibacterial micropatterned layer showing biointegration according to an embodiment of the present invention). The description of an embodiment having multiple elements that are associated with each other does not imply that all such elements are required. On the contrary, various optional elements are described to illustrate the wide variety of possible embodiments of the present invention.

[0075] It will be apparent that where a single device or article is described herein, multiple devices / articles (whether they cooperate or not) may be used in place of the single device / article. Similarly, where two or more devices or articles (whether they cooperate or not) are described herein, it will be apparent that a single device / article may be used in place of the two or more devices or articles, or that a different number of devices / articles may be used in place of the number of devices or programs shown. The functionality and / or features of a device may alternatively be embodied by one or more other devices not explicitly described as having such functionality / features. Thus, other embodiments of the invention need not include a device itself. Finally, the language used herein has been primarily selected for ease of reading and explanation, and not to define or limit the inventive subject matter. It is therefore intended that the scope of the invention be limited not by this detailed description, but by the claims set forth in the application based hereon. It is therefore intended that the embodiments of the invention are illustrative, but not limiting, of the scope of the invention, as defined in the following claims.

[0076] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those of skill in the art. The various aspects and embodiments disclosed in the examples herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated in the following claims.

Claims

1. An implant (104) having an implant surface (1), a micropatterned layer (102) formed on the implant surface (1) by microfabrication, the micropatterned layer (102) comprising microgrooves (4) arranged in a periodic array with predetermined dimensions; a main component layer (7, 103) deposited on the fine pattern layer (102); the main component layer (7, 103) comprises as main components at least one of titanium and titanium alloys, titanium-tantalum alloys, magnesium alloys, titanium-zirconium alloys and / or combinations thereof, the main component layer (7, 103) is deposited using a high pressure cold spray deposition technique (6, 402), the cold spray deposition technique (6, 402) allows the synthesis of the main component layer (7, 103) with porosity while preserving the original phase of the sprayed species of the main component, the main component forming a layer with a thickness of 70 μm to 800 μm after deposition, An implant (104), wherein the implant surface (1) promotes biointegration of the implant (104).

2. 2. The implant (104) of claim 1, wherein the microgrooves (4) have a shape consisting of at least one of a semicircle, a quasi-triangle, a cross, a homolateral star, an ellipse, a circle, and a square, and an arrangement consisting of at least one of a honeycomb pattern or a planar hexagonal close-packed arrangement, and the microgrooves have a dimension range consisting of at least one of a width of 10 μm to 50 μm, a depth of 50 μm to 500 μm, and a pattern spacing of 400 μm to 2000 μm.

3. an antimicrobial component layer (9) deposited on said main component layer (7, 103) using physical vapor deposition (PVD) techniques (403), said antimicrobial component layer (9) configured to continuously release an antimicrobial component from said antimicrobial component layer (9) to inhibit bacterial growth and prevent colonization on said implant surface (1); 10. The implant (104) of claim 1, wherein the antimicrobial component comprises at least one of silver (Ag), gold (Au), zinc (Zn), platinum (Pt), palladium (Pd), iridium (Ir), and copper (Cu), nickel (Ni), or combinations thereof.

4. 4. The implant (104) of claim 3, wherein the antimicrobial component layer (9) has a deposition thickness in the range of 1 nm to 500 nm, the deposition thickness being adjusted by adjusting the duration of the deposition based on the rate of the deposition of the antimicrobial component on the implant surface, and the deposition thickness being determined based on the surface area of ​​the implant so as to prevent cytotoxicity by the antimicrobial component.

5. 1. A method for producing an implant having an implant surface (300), comprising: A microfabrication step (301) of forming a micropatterned layer on the surface of the implant, the micropatterned layer comprising microgrooves arranged in a periodic array of predetermined dimensions; depositing (302) a main component layer (103) on the micropattern layer; the main component layer (103) comprises as main components at least one of titanium and titanium alloys, titanium-tantalum alloys, magnesium alloys, titanium-zirconium alloys and / or combinations thereof, the deposition of the main component layer (103) is carried out using a high pressure cold spray deposition technique (6,402), which allows the synthesis of the main component layer (103) with porosity while preserving the original phases of the sprayed species of the main component, the deposition of the main component forming a layer with a thickness of 70 μm to 800 μm, A method wherein the implant surface promotes biointegration of the implant.

6. 6. The method of claim 5, further comprising one or more intermittent steps of ultrasonic cleaning, surface cleaning and drying to remove organic / inorganic and other surface impurities, a further step (502) of surface blasting with a blasting media to increase surface roughness, and post-processing steps of nitrogen / compressed air blowing, sterilization and packaging / storage.

7. The fine grooves (4) have at least one of a semicircular shape, a quasi-triangular shape, a cross shape, a star shape with sides equal to one another, an ellipse shape, a circular shape, and a square shape, and are arranged in a honeycomb shape or a planar hexagonal close-packed shape; 6. The method of claim 5, wherein the microfabrication step includes forming the microgrooves (4) in a dimension range consisting of one or more of: width 10 μm to 50 μm, depth 50 μm to 500 μm, and pattern spacing 400 μm to 2000 μm.

8. depositing an antimicrobial component layer (9) on said main component layer (7, 103) using physical vapor deposition (PVD) techniques (403), said antimicrobial component layer configured to continuously release antimicrobial components from said antimicrobial component layer to inhibit bacterial growth and prevent colonization on said implant surface; 6. The method of claim 5, wherein the antimicrobial component comprises at least one of silver (Ag), gold (Au), zinc (Zn), platinum (Pt), palladium (Pd), iridium (Ir), copper (Cu) and nickel (Ni), or a combination thereof.

9. the antimicrobial component layer (9) has a deposition thickness in the range of 1 nm to 500 nm, the deposition thickness being adjusted by adjusting the duration of deposition based on the deposition rate of the antimicrobial component on the implant surface; The method of claim 8 , wherein the deposition thickness is determined based on a surface area of ​​the implant to prevent cytotoxicity from the antimicrobial component.

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