Medical implant components with biocompatible-bioactive composite material layer, method of making the same and applications of the same

Abstract

To provide a cost-effective medical implants and processes for preparing the same.SOLUTION: There is provided a medical implant component, comprising: (a) a biocompatible substrate (S); and (b) at least one biocompatible-bioactive composite material layer (BACL), having porosity of 0.5% to 40%, arranged above or on the substrate, wherein the biocompatible substrate (S) is made from a material or materials selected from the group consisting of a biocompatible polymeric material, a first biocompatible metal or alloy and a first biocompatible ceramic, and wherein the BACL is made of a composite material comprising component (1): a second biocompatible metal or alloy, a second biocompatible ceramic or any mixtures thereof, and component (2): an organic bioactive ingredient.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to a medical implant member including a biocompatible-bioactive composite material layer (BACL), and a method for manufacturing the same. The BACL includes component (a): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (b): an organic bioactive component. The present disclosure also relates to a method for manufacturing a medical implant member and uses of the medical implant member.

Summary of the Invention

Problems to be Solved by the Invention

[0002] Medical implant members can be used in various clinical and medical applications to benefit physicians, surgeons, nurses, and patients during or after medical treatment. With the development of materials science and medicine, the prognosis of patients who require surgery or medical implants has been continuously improved. For example, artificial joints can improve the motor function of subjects and patients suffering from age-related diseases and symptoms, and may extend the lifespan of the body parts of the subjects and patients.

[0003] It is common for infectious diseases caused by microorganisms or viruses to occur during or after surgery. In such cases, drainage, extensive use of antibiotics, blood transfusion may be required, and the length of hospitalization may also be prolonged. This not only places a burden on the patient but also leads to a waste of medical resources. In severe cases, it may lead to sepsis, amputation, and even death. To reduce the risk of infection during surgery, antibiotics are widely used by incorporating them into implants or coating their surfaces. The growth of bacteria can be suppressed, and the impact of antibiotics on tissue repair can be minimized by controlling the release of the drug. To control the release of the drug and maintain the overall mechanical strength of the implant, antibiotic carriers (organic substances such as polylactic acid, polyethylene glycol, bone cement, and inorganic substances such as hydroxyapatite, calcium phosphate, and other materials) are used, and antibiotics are loaded onto the carrier to meet the above requirements. The layer formed by such an antibiotic carrier and an antibiotic is called an "organic antibacterial film."

[0004] To enhance the performance of medical implants, it is conceivable to use an organic antibacterial film as a coating on the surface of medical implants. However, existing organic antibacterial films may still have certain defects and drawbacks, such as insufficient durability and mechanical strength. Also, the risk of contaminating medical implants is high. In addition, the existing manufacturing process of medical implants coated with an organic antibacterial film may be costly, and depending on the materials of the organic antibacterial film and medical implants, the applicability of the process may be limited.

[0005] Therefore, the development of new and cost-effective medical implants and their manufacturing methods is still needed.

Means for Solving the Problem

[0006] The present disclosure relates to a medical implant member and includes the following.

[0007] (a) A biocompatible substrate (S), (b) At least one biocompatible-bioactive composite material layer (BACL) provided above or on the substrate, having a porosity of 0.5% to 40%, and The biocompatible substrate (S) is made of one or more materials selected from the group consisting of a biocompatible polymer material, a first biocompatible metal or alloy, and a first biocompatible ceramic. The BACL is made of a composite material containing component (1): a second biocompatible metal or alloy, a second biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive component.

[0008] The present disclosure also relates to a method for manufacturing a medical implant member described herein, including the steps described below.

[0009] (i) A step of supplying a biocompatible substrate (S) into a film-forming chamber; (ii) A step of reducing the pressure in the film-forming chamber to less than 2.5 Torr; and (iii) A step of forming a biocompatible-bioactive composite material layer (BACL) above or on the biocompatible substrate by aerosol deposition (AD); including The composite material is component (1): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive component.

[0010] In one aspect of the present disclosure, a medical implant member is provided that includes a biocompatible substrate (S), an auxiliary adhesion layer (ADL) on the substrate, and a biocompatible-bioactive composite material layer (BACL) on the auxiliary adhesion layer (ADL), that is, the ADL is located between the biocompatible substrate and the BACL, and the ADL is composed of a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof. The surface roughness of the ADL is less than 0.3 μm.

[0011] In one aspect of the present disclosure, a method for manufacturing a medical implant member described herein is provided, including the steps shown below.

[0012] (i) Supplying a biocompatible substrate (S) into a film-forming chamber; (ii) Reducing the pressure in the film-forming chamber to less than 2.5 Torr, for example less than 2.35 Torr, less than 2.2 Torr; and (iii) Forming a biocompatible-bioactive composite material layer (BACL) above or on the biocompatible substrate by aerosol deposition (AD); including wherein the material of the ADL includes a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof.

[0013] In one aspect of the present disclosure, there is provided a method for manufacturing a medical implant member as described herein, including the steps shown below.

[0014] (i) Supplying a biocompatible substrate (S) into a film-forming chamber; (ii) Reducing the pressure in the film-forming chamber to less than 2.5 Torr, for example less than 2.35 Torr, less than 2.2 Torr; (ii’) Forming a material of an auxiliary adhesion layer (ADL) on the substrate by aerosol deposition (AD); and (iii’) Forming the composite material of BACL by aerosol deposition (AD) and forming BACL above or on the ADL; including the material of the ADL includes a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof.

[0015] In one aspect of the present disclosure, a medical implant member is provided as part or all of an artificial joint, an insert related to an artificial joint, a stent, an intervertebral disc, a screw, an artificial bone plate, an intervertebral spacer, or a permanent or temporary fixing device.

[0016] In one embodiment, the BACL is from 0.1 μm to 80 μm, preferably from 0.5 μm to 50 μm, more preferably from 1 μm to 6 μm, for example, from 0.75 μm to 15 μm, from 1.5 μm to 25 μm, about 10 μm, about 20 μm, about 30 μm, about 40 μm, or any reasonable numerical range formed with the above numerical values as endpoints or single points.

[0017] In any of the above embodiments, the medical implant member has a surface roughness of 0.3 μm or more.

[0018] In any of the above embodiments, the BACL has a surface roughness of 0.05 μm to 4 μm, for example, 0.1 μm to 3.5 μm, 0.15 μm to 3 μm, 0.075 μm to 3.75 μm, 0.2 μm to 2.5 μm, etc.

[0019] In any of the above embodiments, the BACL is formed from primary particles having a D50 in the range of 0.1 μm to 10 μm, preferably 0.5 μm to 3 μm.

[0020] In any of the above embodiments, the component (1) in the BACL includes one or more selected from the group consisting of oxides of one or more of aluminum, silicon, titanium, and zirconium; nitrides of one or more of aluminum, silicon, titanium, and zirconium; carbides of one or more of aluminum, silicon, titanium, and zirconium; oxynitrides of one or more of aluminum, silicon, titanium, and zirconium; oxycarbides of one or more of aluminum, silicon, titanium, and zirconium; carbonitrides of one or more of aluminum, silicon, titanium, and zirconium; oxynitridocarbonates of one or more of aluminum, silicon, titanium, and zirconium; calcium phosphate salts; hydroxyapatite; halogenated hydroxyapatite; carbonated hydroxyapatite; halogenated carbonated hydroxyapatite, and mixtures thereof.

[0021] In any of the above embodiments, component (2) in BACL is selected from the group consisting of antibiotics, platelet-rich plasma (PRP), collagen, steroids, nucleic acids, antibodies, functional fragments of antibodies; and any mixtures thereof.

[0022] In any of the above embodiments, component (2) in BACL is present in an amount of 0.3 wt% to 25 wt%, preferably 0.5 wt% to 20 wt%, based on the total weight of the composite material.

[0023] In any of the above embodiments, the thickness variation of BACL is less than 10%, such as less than 8%, less than 5%, etc.

[0024] In any of the above embodiments, when ADL is present, its thickness is 0.5 μm to 10 μm, preferably 1 μm to 3 μm.

[0025] In any of the above embodiments, when measured by ASTM D3359, the adhesion strength between the substrate and BACL is greater than 3B. When ADL is present, (i) the adhesion strength between ADL and the substrate is at least 4B as measured by ASTM D3359, (ii) the adhesion strength between ADL and BACL is at least 4B as measured by ASTM D3359, or (iii) both (i) and (ii) are satisfied.

[0026] In any of the above embodiments, the adhesiveness between the film stack (i.e., ADL + BACL) and the substrate is greater than 3B, preferably greater than 4B, when measured by ASTM D3359.

[0027] In any of the above embodiments, when ADL is present, the thickness variation of ADL is less than 10%.

[0028] In any of the above embodiments, when ADL is present, the porosity of ADL is less than 1%, preferably determined by measuring at a magnification of 10,000 times with FE-SEM.

[0029] In any of the above embodiments, when the ADL is present, the BACL is 0.05 μm to 4 μm, for example, 0.1 μm to 3.5 μm, 0.15 μm to 3 μm, 0.075 μm to 3.75 μm, 0.2 μm to 2.5 μm, etc.

[0030] In any of the above embodiments, when the ADL is present, the biocompatible metal or alloy, biocompatible ceramic, or any mixture thereof is different from the component (1) of the composite material of the BACL.

[0031] In any of the above embodiments, when the ADL is present, the biocompatible metal or alloy, biocompatible ceramic, or any mixture thereof is the same as the component (1) of the composite material of the BACL.

[0032] In any of the above embodiments, the medical implant member includes at least two biocompatible - bioactive composite material layers (BACL).

[0033] In any of the above embodiments, the biocompatible polymer material is selected from the group consisting of polytetrafluoroethylene (PTFE), polyetheretherketone (PEEK), polyethylene (PE), polyurethane (PU), and polyvinyl chloride (PVC).

[0034] In any of the above embodiments, the PE is low - density polyethylene (LDPE), high - density polyethylene (HDPE), or ultra - high - molecular - weight polyethylene (UHMWPE).

[0035] In any of the above embodiments, the biocompatible polymer material has a hardness of at least 400 HV (Vickers hardness), preferably at most 600 HV, more preferably at most 1000 HV. Or, at least Shore D hardness (Shore hardness) 50, preferably at least Shore D hardness 55, more preferably at least Shore D hardness 60, most preferably at least Shore D hardness 65.

[0036] In any of the above embodiments, the biocompatible metal or alloy for the substrate (S) is selected from the group consisting of titanium (Ti) or its alloy, zirconium (Zr) or its alloy, tantalum (Ta) or its alloy, niobium (Nb) or its alloy, stainless steel, cobalt-chromium-molybdenum (Co-Cr-Mo) alloy, and Ti-6Al-4V alloy.

[0037] In any of the above embodiments, the biocompatible ceramic for the substrate (S) is selected from the group consisting of oxides, carbides, nitrides, or carbonitrides of any of the following elements: silicon (Si), titanium (Ti), tantalum (Ta), tungsten (W), zirconium (Zr), niobium (Nb), chromium (Cr), aluminum (Al).

[0038] In any of the above embodiments, AD is carried out using a carrier gas selected from the group consisting of N2, O2, Ar, He, clean dry air (CDA), and any combination thereof.

[0039] In any of the above embodiments, AD is carried out at a flow rate of the carrier gas of 300 to 1500 L / hour.

[0040] In any of the above embodiments, the temperature of the substrate during the film formation of ADL and / or BACL is in the range of 5°C to 50°C, for example at least 15°C and preferably not exceeding 35°C.

[0041] In any of the above embodiments, the substrate (S) is polished to exhibit a surface roughness of at least 0.2 μm.

Brief Description of the Drawings

[0042]

Figure 1

Figure 2

Best Mode for Carrying Out the Invention

[0043] To facilitate understanding of the present disclosure, the terms used in this specification are defined as follows.

[0044] In the context of this specification and the claims, the singular forms "a," "an," and "the" are to be construed as including plural referents unless the context clearly dictates otherwise. Unless otherwise specified, all examples or exemplary expressions (such as "such as") described in this specification are for the sole purpose of making the description of the invention according to this specification easier to understand and do not limit the scope of the invention according to this specification.

[0045] The numerical ranges described in this specification are to be understood as being intended to include all sub-ranges subsumed therein. For example, a range of "50 to 70 °C" includes all sub-ranges and specific values between the stated minimum value of 50 °C and the stated maximum value of 70 °C, such as, for example, 58 °C to 67 °C, 53 °C to 62 °C, 60 °C, or 68 °C. Since the disclosed numerical ranges are continuous, each numerical value between the minimum and maximum values is included. Unless otherwise specified, the various numerical ranges shown in this specification are approximate.

[0046] In the present invention, the term "about" refers to the acceptable error of a given value as measured by a person skilled in the art and depends in part on the method of measuring or determining that value.

[0047] In the present disclosure, the term "biocompatible" or "biocompatibility" means having the ability to come into contact with a biological system without causing harmful effects, such as, for example, (severe) allergic reactions, damage to cells, tissues, or organs within the body.

[0048] In the present disclosure, the term "porosity" refers to the degree of pore space within a material.

[0049] [Medical implant member] Inorganic or organic antimicrobial membranes can be applied as a coating on the surface of medical implants to avoid infection, improve prognosis, and / or provide long-term treatment after surgery. Existing inorganic or organic antimicrobial membranes include those using organic gelling agents or polymer materials such as gelatin, polylactic acid (including PLA, poly-D,L-lactic acid (PDLLA)), polyglycolic acid (PGA), or hydroxyapatite, and the antimicrobial substances can be carried by membrane immersion or coprecipitation from a solution. However, the thickness of the inorganic or organic antimicrobial membrane may be limited by the preparation process and requirements for mechanical strength. Also, it is difficult to adjust the thickness. As an improvement measure, using a 3D transitional ceramic structure may be considered, but it may lead to increased costs and complexity of the manufacturing process, and there is also a risk of raw material contamination.

[0050] Therefore, the present disclosure provides a medical implant member including a biocompatible substrate (S) and a biocompatible-bioactive composite material layer (BACL), with a porosity of 0.5% to 40% above or on the substrate. Here, BACL is composed of a composite material including component (1): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive component. In one aspect, the medical implant member includes a biocompatible substrate (S), an auxiliary adhesion layer (ADL) on the substrate, and a biocompatible-bioactive composite material layer (BACL) on the auxiliary adhesion layer (ADL). That is, ADL is located between the biocompatible substrate and BACL, and ADL is composed of a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof.

[0051] Details of the components or layer configurations of the medical implant member are described below.

[0052] [Biocompatible substrate] In the present disclosure, when having desired properties, such as sufficient mechanical strength (hardness, toughness, etc.), chemical inertness, biocompatibility, etc., biocompatible substrates known in the art can be used. For example, the manufacturing material of the biocompatible substrate may have a hardness of at least 400 HV (Vickers hardness) or a Shore D hardness (Shore hardness) of at least 50. In some embodiments, the biocompatible substrate can be manufactured from one or more materials selected from the group consisting of biocompatible polymer materials, biocompatible metals or alloys, and biocompatible ceramics.

[0053] Examples of biocompatible polymer materials include, but are not limited to, polyketones such as polyetheretherketone (PEEK), (halogenated) polyalkylenes such as polyethylene (PE), poly(ethylene-propylene), polytetrafluoroethylene (PTFE), polyvinyl chloride (PVC), polyurethane, etc. In some embodiments, the PE is low-density polyethylene (LDPE), high-density polyethylene (HDPE), or ultra-high molecular weight polyethylene (UHMWPE).

[0054] Examples of biocompatible metals or alloys include, but are not limited to, titanium (Ti) or its alloys, zirconium (Zr) or its alloys, tantalum (Ta) or its alloys, niobium (Nb) or its alloys, stainless steel, cobalt-chromium-molybdenum (Co-Cr-Mo) alloys, and Ti-6Al-4V alloys.

[0055] Examples of biocompatible ceramics include, but are not limited to, oxides, carbides, nitrides, or nitrocarbides of any of the following elements: silicon (Si), titanium (Ti), tantalum (Ta), tungsten (W), zirconium (Zr), niobium (Nb), chromium (Cr), aluminum (Al).

[0056] In one embodiment, the biocompatible substrate has a surface roughness (Ra) of less than 0.3 μm; or more than 0.01 μm. In one embodiment, the biocompatible substrate has a linear coefficient of thermal expansion in the range of 6×10 -6 to 18×10 -5 .

[0057] (Biocompatible - Bioactive Composite Layer (BACL)) In the present disclosure, the biocompatible - bioactive composite layer (BACL) is used to achieve the above - mentioned advantages such as, for example, exhibiting high structural stability or providing extended / sustained / long - term release of bioactive components.

[0058] The BACL is composed of a composite material including component (1): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive component. The composite material is in a solid form such as admixtures, blends, powders, etc., and is substantially homogeneous. In one embodiment, the composite material is a solid dispersion including components (1) and (2). In one embodiment, the composite material is a solid dispersion consisting only of components (1) and (2).

[0059] The above-mentioned component (1), that is, the component which is a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, is selected from the group consisting of one or more oxides of aluminum, silicon, titanium, zirconium; one or more nitrides of aluminum, silicon, titanium, zirconium; one or more carbides of aluminum, silicon, titanium, zirconium; one or more oxynitrides of aluminum, silicon, titanium, zirconium; one or more oxycarbides of aluminum, silicon, titanium, zirconium; one or more carbonitrides of aluminum, silicon, titanium, zirconium; one or more oxynitride carbides of aluminum, silicon, titanium, zirconium; calcium phosphate salts; hydroxyapatite; halogenated hydroxyapatite; carbonated hydroxyapatite; halogenated carbonated hydroxyapatite, and mixtures thereof.

[0060] The above-mentioned component (2), that is, the component which is an organic bioactive component, is selected from the group consisting of antibiotics, platelet-rich plasma (PRP), collagen, steroids, nucleic acids, antibodies, functional fragments of antibodies; and any mixtures thereof. In one embodiment, component (2) may be an antibiotic such as β-lactam, glycopeptide, lipopeptide, rifamycin, macrolide, aminoglycoside, fluoroquinolone, lincosamide (e.g., lincomycin, clindamycin, pirlimycin), tetracycline, fusidic acid, etc. In one embodiment, component (2) may also be a substance that is beneficial to cells or tissues or can enhance their repair, such as platelet-rich plasma (PRP), steroids, DNA / RNA, antibodies. In one embodiment, the organic active component is insoluble or hardly soluble in water or an aqueous medium such as a physiological medium (e.g., PBS, saline, etc.).

[0061] In one embodiment, the medical implant member includes a biocompatible substrate (S) and two or more biocompatible-bioactive composite material layers (BACLs). In one embodiment, the medical implant member is composed only of a biocompatible substrate (S) and a biocompatible-bioactive composite material layer (BACL(s)), where the BACL(s) consists of hydroxyapatite; halogenated hydroxyapatite; carbonated hydroxyapatite; halogenated carbonated hydroxyapatite, or a mixture thereof.

[0062] In one embodiment, the biocompatible-bioactive composite material layer (BACL(s)) is located on or above the substrate (for example, when an auxiliary adhesion layer (ADL) described below is present). Each BACL(s) is independently in the range of 0.5% to 40%, preferably 0.8% to 35%, for example, at least 1% or more, at least 5% or more, at least 7.5% or more, at least 10% or more, 37.5% or less, 30% or less, 25% or less, 20% or less, 15% or less, or any reasonable numerical range configured with the above values as endpoints so that the medical implant exhibits excellent effects, such as good durability of bioactive components, encapsulation, release profile, etc. The appropriate porosity of this layer can be achieved, for example, by the manufacturing method of the medical implant described herein.

[0063] In one embodiment, each BACL(s) independently has a thickness in the range of 0.5 μm to 80 μm, for example, 0.1 μm or more, 0.5 μm or more, 1 μm or more, 2 μm or more, 3 μm or more, 4 μm or more, 5 μm or more, 6 μm or more, 7 μm or more, 8 μm or more, 9 μm or more, 10 μm or more, 11 μm or more, 12 μm or more, 13 μm or more, 14 μm or more, 15 μm or more, 20 μm or more, 25 μm or more, 30 μm or more, 35 μm or more, or 80 μm or less, 70 μm or less, 65 μm or less, 60 μm or less, 55 μm or less, 50 μm or less, 45 μm or less, 40 μm or less, or any reasonable numerical range with the above values as endpoints, such as 0.5 μm to 30 μm, 40 μm to 55 μm, 5 μm to 8 μm, etc.

[0064] In one embodiment, when measured by ASTM D3359, the adhesion strength between the substrate and BACL is at least 3B or more, preferably at least 4B or more, more preferably at least 5B or more.

[0065] In one embodiment, each BACL(s) is independently in the range of 0.05 μm to 4.0 μm, for example, 0.1 μm to 3.75 μm, 0.2 μm to 3.5 μm, 0.3 μm to 3.25 μm, 0.4 μm to 3 μm, 0.5 μm to 2.5 μm, or any reasonable numerical range formed with the above numerical values as endpoints.

[0066] In one embodiment, each BACL(s) is independently formed from primary particles with a D50 in the range of 0.1 μm to 10 μm, for example, about 0.2 μm, about 0.3 μm, about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1 μm, about 1.5 μm, about 2 μm, about 2.5 μm, about 3 μm, about 3.5 μm, about 4 μm, about 4.5 μm, about 5 μm, about 5.5 μm, about 6 μm, about 6.5 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm; or a reasonable numerical range with the above numerical values as endpoints, such as 0.5 μm to 3 μm, 0.8 μm to 5 μm, etc.

[0067] Without being bound by theory, since BACL is prepared by the AD technology disclosed herein, it is a (substantially) homogeneous and continuous layer. In particular, BACL may not have an obvious single crystal when observed by FE-SEM (e.g., 5000 times) during ion milling. Furthermore, the crystallinity of BACL may be reduced by at least 15%, preferably at least 20% as compared with the pure powder of the (composite) material by X-ray diffraction analysis.

[0068] (Auxiliary Adhesion Layer (ADL)) In one aspect, the medical implant member further includes an auxiliary adhesion layer (ADL), which is located on the biocompatible substrate (S) and between the biocompatible substrate (S) and the BACL. The ADL is composed of a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof (which may be the same as or different from the material of component (1) of the BACL). The ADL may assist in the adhesion between the biocompatible substrate and the BACL.

[0069] In one embodiment, the ADL has a thickness of 0.3 μm to 1.5 μm, for example, at least 0.4 μm, at least 0.5 μm, at least 0.6 μm, at least 0.65 μm, at least 0.7 μm, at least 0.75 μm, at least 0.8 μm, at least 0.85 μm, at least 0.95 μm, or at most 1.45 μm, at most 1.4 μm, at most 1.35 μm, at most 1.3 μm, at most 1.25 μm, at most 1.2 μm, at most 1.15 μm, at most 1.1 μm, at most 1.05 μm, at most 1 μm, or a reasonable numerical range with the above values as endpoints, for example, 0.5 μm to 1 μm, 0.4 μm to 1.2 μm, 0.6 μm to 0.95 μm, etc.

[0070] In one embodiment, when measured by ASTM D3359, the adhesion strength between the ADL and the biocompatible substrate is at least 3B or more, preferably at least 4B or more, more preferably at least 5B or more. In one embodiment, when measured by ASTM D3359, the adhesion strength between the film stack (i.e., the combination of the ADL and the BACL) and the biocompatible substrate is at least 4B or more, more preferably at least 5B or more.

[0071] In one embodiment, the thickness variation of the ADL is less than 10%, preferably less than 8%, more preferably less than 5%.

[0072] In one embodiment, the ADL has a porosity of less than 1%, preferably less than 0.8%, more preferably less than 0.5%.

[0073] (Use of Medical Implant Members) Due to excellent properties (such as durability, biocompatibility, and the ability to adjust drug release rate), medical implant members can be used in various applications. Examples of such applications include part or all of an artificial joint (e.g., knee joint replacement, hip joint replacement, shoulder joint replacement, wrist joint replacement; cup, head, stem, etc.), inserts related to artificial joints, stents, intervertebral discs, screws, artificial bone plates, vertebral body spacers, or permanent or temporary fixation devices (used in orthodontics, surgery, etc.).

[0074] In one embodiment, the surface of the medical implant member has a checkerboard pattern. In one embodiment, the surface of the medical implant member has a roughness of 0.3 μm or more, preferably 0.8 μm or more, for example 0.9 μm or more, 1 μm or more, etc. In any of the above embodiments, the variation in the thickness of the BACL (excluding surface structural features) is less than 10%.

[0075] [Manufacturing Method of Medical Implant Members] Conventional methods for forming a coating or layer on a substrate of a medical implant member include plasma spraying, physical vapor deposition (PVD), chemical vapor deposition (CVD), spray processes (thermal or cold spray), sintering processes, etc. The inventors have found that it is advantageous to form a film of the material to form the BACL (and optionally the ADL) using aerosol deposition (AD).

[0076] As briefly described below, in the manufacture of the medical implant members described in this specification, AD may have the following advantages. (1) The film formation rate is faster than that of the PVD / CVD method, which has the advantage of increasing production efficiency. (2) The temperature during the film formation process of the BACL (and optionally the ADL) can be significantly lower (e.g., near room temperature) than that of the PVD / CVD method (e.g., 300 °C or more, up to 800 °C in some cases), thermal spraying or low-temperature thermal spraying (about 300 °C). (3) The required degree of vacuum has fewer constraints compared to the PVD / CVD method. (4) There is a possibility that it is easier to scale up compared to the PVD / CVD method. (5) The thickness of the layer can be easily adjusted and may be made thicker. (6) The adhesion of the film-forming layer is significantly higher than that obtained by the PVD / CVD method, thermal spraying, or low-temperature thermal spraying process. (7) The density and compatibility of the film-forming layer may be higher than those obtained by thermal spraying or low-temperature thermal spraying. (8) The film-forming layer or coating may be in a near-net shape (almost the final shape) that is difficult with the PVD / CVD method, thermal spraying, or low-temperature thermal spraying. (9) There is a possibility of significantly reducing costs compared to the PVD / CVD method, thermal spraying, and low-temperature thermal spraying.

[0077] When compared with the method using a solution, the AD process has various advantages over other surface treatment methods. For example, in other methods, in order to form a film on a porous 3D structure (such as oxidation, corrosion, etc.), impregnation into a polymer dispersion (optionally containing a bioactive agent such as an antibiotic), solution spraying, a solution dropping process, etc. are required, and pretreatment of the substrate is necessary. Furthermore, the layer formed by such an AD process may show (slight) surface irregularities, such as a checkerboard pattern, and such (slight) surface irregularities may be beneficial for desired applications such as the regeneration of living cells and tissues. In one embodiment, the surface irregularities form obtuse angles rather than acute angles as occur when forming a film in a needle-like or sheet-like shape by other surface treatment methods, and the possibility of repair due to mechanical stress during transportation, packaging, and installation during clinical use can be reduced. Without being bound by theory, horizontal (compressive) stripes of the composite material may be observed in a cross-sectional view, which defines the space (and porosity) into which bioactive components can be introduced, and thereby the distribution of bioactive components may be more uniform than in conventional filling processes.

[0078] Thus, the layer of the medical implant member exhibits high stability and enhanced mechanical strength. The three-dimensional (microscopic) structure of the porous layer may play an important role in providing mechanical strength and filling and protecting bioactive components. Furthermore, since there is no need to move the semi-finished product or product during the film-forming process, it is possible to eliminate or avoid the risk of contamination of the semi-finished product or product due to movement as required in other film-forming processes.

[0079] The inventors surprisingly discovered that the AD process is advantageous for the production of medical implant members, particularly BACL.

[0080] The present disclosure also relates to a method for manufacturing a medical implant member described herein, including the following steps. (i) Supplying a biocompatible substrate (S) into a film-forming chamber; (ii) Reducing the pressure in the film-forming chamber to less than 2.5 Torr, for example, less than 2.35 Torr, less than 2.2 Torr; and (iii) Forming a biocompatible-bioactive composite material layer (BACL) above or on the biocompatible substrate by aerosol deposition (AD), including the step of forming the BACL; The composite material includes component (1): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive component.

[0081] One aspect of the present disclosure relates to a method for manufacturing a medical implant member described herein, including the following steps. (i) Supplying a biocompatible substrate (S) into a film-forming chamber, (ii) Reducing the pressure in the film-forming chamber to less than 2.5 Torr, for example, less than 2.35 Torr, less than 2.2 Torr; (ii’) Forming a material of an auxiliary high-density layer (ADL) on the substrate by aerosol deposition (AD); and (iii’) Forming the composite material of BACL by aerosol deposition (AD), including the step of forming the BACL above or on the ADL; The material of the ADL includes a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof.

[0082] In some embodiments, steps (ii') and (iii') can be performed at least twice to form a plurality of biocompatible-bioactive composite material layers (BACL).

[0083] Biocompatible substrates can employ those disclosed herein. In one embodiment, the biocompatible substrate is made of a material or materials selected from the group consisting of a biocompatible polymer material, a biocompatible metal or alloy, and a biocompatible ceramic. In one embodiment, the biocompatible polymer material is selected from the group consisting of polyetheretherketone (PEEK), polyethylene (PE), and polyvinyl chloride (PVC). In one embodiment, the PE is low-density polyethylene (LDPE), high-density polyethylene (HDPE), or ultra-high molecular weight polyethylene (UHMWPE).

[0084] The AD process can be carried out using known means and devices. The devices for carrying out the AD process can include an aerosol generation unit (e.g., including a carrier gas source, a mass flow controller (MFC), an aerosol generation chamber), a film-forming chamber (e.g., equipped with a nozzle / nebulizer, a support plate or stage, etc.), a vacuum system (e.g., a pump), and the like.

[0085] Various parameters of the AD process can be adjusted. Examples of parameters include, but are not limited to, the type and flow rate of the carrier gas, the distance between the nozzle and the substrate support, the incident angle of the aerosol flow to the substrate, the degree of vacuum in the film-forming chamber, the concentration, particle size, type of the material of the biocompatible protective coating layer in the aerosol flow, the temperature in the chamber, the temperature of the substrate, and the like.

[0086] Examples of the carrier gas include, but are not limited to, nitrogen (N2), oxygen (O2), argon (Ar), helium (He), clean dry air (CDA), and any combination and ratio thereof. The flow rate of the carrier gas is in the range of 300 to 1500 L / hour, for example, about 300 L / hour, about 350 L / hour, about 400 L / hour, about 450 L / hour, about 500 L / hour, about 550 L / hour, about 600 L / hour, about 650 L / hour, about 700 L / hour, about 750 L / hour, about 800 L / hour, about 850 L / hour, about 900 L / hour, about 950 L / hour, about 1000 L / hour, about 1100 L / hour, about 1200 L / hour, about 1300 L / hour, about 1400 L / hour, about 1500 L / hour; or a reasonable numerical range with the above values as endpoints, for example, 500 L / hour to 650 L / hour, 350 L / hour to 1300 L / hour, etc.

[0087] The temperature (of the biocompatible substrate) during the AD process can be controlled in the range of 5°C to 50°C, for example, in the range of 15°C to 45°C, and preferably is 35°C or less.

[0088] The material powder can have a D50 in the range of 0.1 μm to 10 μm. For example, about 0.2 μm, about 0.3 μm, about 0.4 μm, about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1 μm, about 1.5 μm, about 2 μm, about 2.5 μm, about 3 μm, about 3.5 μm, about 4 μm, about 4.5 μm, about 5 μm, about 5.5 μm, about 6 μm, about 6.5 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm; or a reasonable numerical range with the above values as endpoints, for example, 0.5 μm to 3 μm, 0.8 μm to 5 μm, etc. The raw material may be subjected to pretreatment such as pulverization and sieving to supply the material for film formation by the AD process.

[0089] When the film formation of the biocompatible - bioactive composite material layer (BACL) (and any optional adhesion assisting layer (ADL)) is completed, the product may be subject to post - treatments such as cleaning and shaping.

Example

[0090] Examples are given below to make the present invention easier to understand for those with ordinary skills in the technical field to which the present invention pertains, but are not intended to limit the scope of the invention.

[0091] [Materials, Methods, Experimental Models] The materials for the biocompatible-bioactive composite material layer include Si3N4, Al2O3, TiN (purity 4N), and hydroxyapatite, which are available for purchase from Sigma-Aldrich.

[0092] If necessary, the materials can be further processed with UPE-Celanese GUR@1020-E.

[0093] The porosity of the layer is measured by Hitachi S-4300 FE-SEM. The thickness and roughness are measured by KLA-D500. The adhesion is evaluated by ASTM D3359.

[0094] The antibacterial property can be evaluated by JIS Z 2801. Specifically, the test piece or composite material layer (e.g., 5 cm × 5 cm) is washed and disinfected, and inoculated with a test suspension containing the target microorganism. The inoculated test piece / composite material layer is covered with a plastic film and cultured at a selected temperature and time (e.g., 35°C for 24 hours). After culturing, the test piece / composite material layer is washed and the microorganism concentration is calculated.

[0095] (Test Example 1) Silicon nitride (D50 about 1.8 μm, about 25 ml) and vancomycin powder (about 2 g) were used as the composite material. They were introduced into a nylon container of a milling machine and uniformly mixed at room temperature at 60 rpm for 3 hours. The mixed powder was put into an aerosol generator and the following procedure was carried out.

[0096] The titanium substrate was washed with acetone, alcohol, and deionized water in an ultrasonic cleaner for 10 minutes each, dried, and then placed in the chamber of an aerosol deposition (AD) apparatus. The inside of the chamber was evacuated to 2.2 Torr or less. Thereafter, a processing gas (e.g., helium) was introduced into the aerosol generator at an appropriate flow rate (e.g., 10 - 15 L / min) to generate a uniform aerosol of the mixed powder, which was introduced into the chamber and sprayed uniformly onto the substrate to form a BACL film. After the AD process was completed, the film - formed substrate was taken out, the residual powder on the surface was removed with clean dry air (CDA), and it was stored in a drying cabinet in preparation for subsequent tests.

[0097] (Test Example 2) As the composite material, hydroxyapatite (HA) (D50 of about 2.1 μm, about 25 ml) and vancomycin powder (about 2 g) were used. They were introduced into a nylon container of a milling machine and uniformly mixed at room temperature at 60 rpm for 3 hours. The mixed powder was placed in dried carbonite for storage and subsequent procedures.

[0098] Pure HA powder was introduced into the container of the aerosol generator. Next, the Ti substrate was washed with acetone, alcohol, and deionized water in an ultrasonic cleaner for 10 minutes each, dried, and then placed in the chamber of the aerosol deposition (AD) device. The inside of the chamber was evacuated to 2.2 Torr or less. Next, a processing gas (e.g., helium) was introduced into the aerosol generator at an appropriate flow rate (e.g., 10 - 15 L / min) to generate a uniform aerosol of HA powder. This aerosol was introduced into the chamber and sprayed uniformly onto the substrate to form an ADL film. After the formation of the ADL film was completed, the formed substrate was taken out, washed with clean dry air (CDA), and the HA powder remaining on its surface was removed. The substrate was placed again in the chamber of the aerosol deposition (AD) device, and the inside of the chamber was evacuated to 2.2 Torr or less. The HA powder was taken out from the container of the aerosol generator, and a mixed powder of HA and an antibiotic was introduced into the same container. Then, a processing gas (e.g., helium) was introduced into the aerosol generator at an appropriate flow rate (e.g., 10 - 15 L / min) to generate a uniform aerosol of the mixed powder of HA and the antibiotic, which was introduced into the chamber and sprayed uniformly onto the substrate to form a BACL (on the ADL). After the formation of the BACL film was completed, the formed substrate was recovered, the residual powder on the surface was removed with clean dry air (CDA), and it was stored in a drying cabinet in preparation for subsequent tests.

[0099] (Test Example 3 (Comparative Example)) In this specification, a test example of an implant having a surface coating of a polymer material impregnated with an antibiotic was provided as a comparative example. Then, the Ti - 6Al - 4V substrate was polished with sandpapers of grit numbers 400, 600, ··· up to 1,500, and immersed in an HF:H2SO4 (1M:4M) solution for 5 minutes. The substrate was washed with deionized water in an ultrasonic cleaner for 20 minutes to remove the residual acid on the surface.

[0100] After that, the washed substrate was placed in a solution of 0.2M Ca(H2PO2)2 (Alfa Aesar, Germany) at 300V, 100mA / cm 2The substrate was anionized by immersion in (from a DC power supply) for 5 minutes. After this treatment, the substrate was washed with deionized water for 5 minutes to remove the remaining anion solution, dried, and then used.

[0101] The treated substrate was immersed in a dichloromethane solution of 5% PLGA (poly D,L-lactide-glycolide copolymer) and 2 g of vancomycin and pulled out of the solution at a rate of 2 cm / min. The sample thus obtained was dried at room temperature for 30 minutes for subsequent tests.

[0102] (Test Example 4) The samples obtained from Test Examples 1 to 3 were each immersed in 50 mL of phosphate-buffered saline (1×PBS, Gibco, thermo fisher scientific, Waltham, USA) at 37 °C and shaken on a shaker at 30 rpm for 20 minutes. Thereafter, each petri dish was placed in 200 mL of a new phosphate-buffered saline aqueous solution, and 5 mL of the sample was collected every 12 hours to measure the concentration of the antibiotic. Also, the antibacterial ability was evaluated.

[0103] Table 1 shows the characteristics and test results of the medical implant members shown in Test Examples 1 to 3.

[0104]

Table 1

[0105] The maximum time for drug release of the present invention is expected to be 15 to 23 days, or more. The amount of drug released in the first 12 hours is expected to be a maximum of 2 mg (for example, a maximum of 1.7 mg, or at least 1 to 1.2 mg), 1.4 mg (for example, a maximum of 1.2 mg, or at least 0.7 mg) in the subsequent 36 hours (i.e., from 12 hours to 48 hours), and 0.8 mg (for example, a maximum of 0.7 mg, or at least 0.2 mg) after 48 hours.

[0106] The present invention exhibits an effect that is clearly superior to existing medical implant members. In particular, the film structures of the samples obtained in Test Examples 1 and 2 maintained a stable and complete state even after 10 days of testing. The FTIR spectra of the BACL of the samples in Test Examples 1 and 2 after 10 days of testing still showed the signal of vancomycin, indicating that vancomycin can be released from the film even after 10 days. In contrast, the film layer containing antibiotics obtained by the conventional polymer coating and direct immersion process (Test Example 3) is prone to degradation and tends to peel off from the substrate under conditions simulating human physiological conditions, and almost no signal of vancomycin was observed in the FTIR spectra of the polymer films of the samples obtained in the test on the 5th or 6th day. Also, the samples in Test Examples 1 and 2 passed the antibacterial test, but the samples in Test Example 3 failed (see Table 1).

[0107] Furthermore, since the powder of the composite material can be easily prepared by mixing and does not require washing in liquid, the AD process can be carried out in a simpler manner compared to the conventional polymer immersion process. However, the conventional polymer immersion process requires complex steps such as multiple transfers of the substrate, washing in liquid, and drying.

[0108] In short, the present disclosure provides a method and a medical implant member that have various advantages over existing technologies, particularly a simpler method, an extended release time of bioactive components from the medical implant member, and an improved structural stability of the member.

[0109] Those skilled in the art should understand that they can make modifications and variations to the teachings and disclosures of the present invention without departing from the essence and spirit of the present application. Based on the above content, the present application intends to include such modifications and variations on the condition that the modifications or variations or their equivalents are within the scope defined in the appended claims.

Claims

1. (a)A biocompatible substrate (S), (b)At least one biocompatible-bioactive composite material layer (BACL) provided above or on the substrate and having a porosity of 0.5% to 40%, The biocompatible substrate (S) is made of one or more materials selected from the group consisting of a biocompatible polymer material, a first biocompatible metal or alloy, and a first biocompatible ceramic, The BACL is a medical implant member made of a composite material containing component (1): a second biocompatible metal or alloy, a second biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive component.

2. Component (1) within the BACL is one or more selected from the group consisting of oxides of one or more of aluminum, silicon, titanium, zirconium; nitrides of one or more of aluminum, silicon, titanium, zirconium; carbides of one or more of aluminum, silicon, titanium, zirconium; oxynitrides of one or more of aluminum, silicon, titanium, zirconium; oxycarbides of one or more of aluminum, silicon, titanium, zirconium; carbonitrides of one or more of aluminum, silicon, titanium, zirconium; oxynitride carbides of one or more of aluminum, silicon, titanium, zirconium; calcium phosphate salts; hydroxyapatite; halogenated hydroxyapatite; carbonated hydroxyapatite; halogenated carbonated hydroxyapatite, and mixtures thereof. The medical implant member according to claim 1.

3. The thickness of the BACL is 0.1 μm to 80 μm, 0.5 μm to 50 μm, or 1 μm to 6 μm. The medical implant member according to claim 1 or 2.

4. The adhesive strength between the substrate and the BACL is greater than 3B as measured by ASTM D3359. The medical implant member according to any one of claims 1 to 3.

5. The surface roughness is 0.3 μm or more. The medical implant member according to any one of claims 1 to 4.

6. The BACL is formed from primary particles of a composite material having a D50 in the range of 0.1 μm to 10 μm. The medical implant member according to any one of claims 1 to 5.

7. The component (2) in the BACL is selected from the group consisting of antibiotics, platelet-rich plasma (PRP), collagen, steroids, DNA, RNA, antibodies, functional fragments of antibodies; and any mixture thereof, the medical implant member according to any one of claims 1 to 6.

8. The component (2) in the BACL is present in an amount of 0.3% to 25% by weight based on the total weight of the composite material, the medical implant member according to any one of claims 1 to 7.

9. Furthermore, it includes an auxiliary adhesion layer (ADL), The ADL is located between the biocompatible substrate and the BACL, The ADL is made of a third biocompatible metal or alloy, a biocompatible ceramic, or a mixture thereof, The third biocompatible metal or alloy, biocompatible ceramic, or any mixture thereof is selected from those defined in claim 2, The ADL has a surface roughness of less than 0.3 μm, the medical implant member according to any one of claims 1 to 8.

10. The thickness of the ADL is 0.5 μm to 10 μm, the medical implant member according to claim 9.

11. (i) The adhesion strength between the ADL and the substrate is at least 4B as measured by ASTM D3359, (ii) The adhesion strength between the ADL and the BACL is at least 4B as measured by ASTM D3359, or (iii) Both (i) and (ii) are satisfied, The medical implant member according to claim 9 or 10.

12. The variation in the thickness of the ADL is less than 10%, the medical implant member according to any one of claims 9 to 11.

13. The ADL has a porosity of less than 1%, the medical implant member according to any one of claims 9 to 12.

14. The third biocompatible metal or alloy, biocompatible ceramic, or any mixture thereof is different from the component (1) of the composite material of the BACL, the medical implant member according to any one of claims 9 to 13.

15. Part or all of an artificial joint, an insert related to an artificial joint, a stent, an intervertebral disc, a screw, an artificial bone plate, an intervertebral spacer, or a permanent or temporary fixing device, the medical implant member according to any one of claims 1 to 14.

16. The medical implant member according to any one of claims 1 to 15, wherein the substrate has a surface roughness of at least 0.2 μm.

17. A method for manufacturing a medical implant member according to any one of claims 1 to 16, comprising: (i) a step of supplying a biocompatible substrate (S) into a film-forming chamber; (ii) a step of reducing the pressure in the film-forming chamber to less than 2.5 Torr; and (iii) a step of forming a biocompatible-bioactive composite material layer (BACL) above or on the biocompatible substrate by aerosol deposition (AD); The composite material is component (1): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive component. A method for manufacturing a medical implant member.

18. Further comprising step (ii') following step (i), (ii') a step of forming a material of an auxiliary adhesion layer (ADL) on the substrate by aerosol deposition (AD); Step (iii) is step (iii'), (iii') a step of forming the composite material of BACL by aerosol deposition (AD) and forming BACL above or on ADL; The material of the ADL is a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof. The method according to claim 18.

19. The AD is N ２ , O ２ , Ar, He, clean dry air (CDA), and the method according to claim 17 or 18, which is carried out using a carrier gas selected from the group consisting of any combination thereof.

20. The AD is carried out at a carrier gas flow rate of 300 to 1500 L / h. The method according to any one of claims 17 to 19.

21. The temperature of the substrate during film formation is in the range of 5°C to 50°C. The method according to any one of claims 17 to 20.

22. The primary particles of the powder of the composite material of BACL, the powder of the material of ADL, or both powders have a D50 in the range of 0.1 μm to 10 μm. The method according to any one of claims 17 to 21.

23. The biocompatible substrate (S) is made of one or more materials selected from the group consisting of biocompatible polymer materials, biocompatible metals or alloys. The method according to any one of claims 17 to 22.

24. The material of the ADL is different from component (1) of the composite material of BACL. The method according to any one of claims 17 to 23.

25. The method according to any one of claims 17 to 24, wherein the substrate (S) is polished so as to exhibit a surface roughness of at least 0.2 µm. **Claim 26** The method according to any one of claims 17 to 25, wherein the step (iii) or the step (iii') is carried out at least twice to form a plurality of BACL films.

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