Medical implant assembly comprising a layer of biocompatible-bioactive composite material, method for the preparation thereof and

Abstract

The present disclosure relates to medical implant components comprising a layer of biocompatible-bioactive composite, methods of making and uses thereof; the biocompatible-bioactive composite layer BACL comprises a component (a): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and a component (b): an organic bioactive ingredient.

Description

Technical Field

[0001] The present disclosure relates to a medical implant assembly comprising a biocompatible - bioactive composite layer (BACL), a method for its preparation, and its use; the BACL comprising component (a): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (b): an organic bioactive ingredient. Background Art

[0002] Medical implant assemblies can be used in a variety of clinical and healthcare applications to provide benefits to physicians, surgeons, registered professional nurses, and patients during or after medical treatment. Thanks to the development of materials science and medical science, the prognosis of patients in need of surgery or medical implants has been continuously improved. For example, artificial joints can improve the motor function of individuals or patients suffering from age - related conditions or diseases and can extend the lifespan of the body parts of the individual or patient.

[0003] Microbial or viral infections are common complications during or after surgery and require debridement, extensive use of antibiotics, blood transfusions, and may result in extended hospital stays. This burdens the patient and consumes medical resources. In severe cases, it may lead to sepsis, the need for amputation, or even death. Antibiotics are widely used to reduce the risk of infection during surgery, either by incorporating them into the implant or applying them to the surface. By controlling the release of the drug, bacterial growth can be inhibited and the impact of the antibiotic on tissue repair can be minimized. 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, and bone cement; inorganic substances such as hydroxyapatite, calcium phosphate, and other materials) are used to load antibiotics to meet the above requirements. The layer formed by such an antibiotic carrier and an antibiotic is called an "organic antimicrobial membrane".

[0004] To enhance the performance of medical implants, an organic antimicrobial membrane can be applied as a coating on the surface of the medical implant. However, existing organic antimicrobial membranes may still exhibit certain deficiencies or drawbacks, such as insufficient durability or mechanical strength, or a high risk of contaminating the medical implant. In addition, the cost of existing methods for preparing medical implants coated with an organic antimicrobial membrane may be high, and the applicability of the method may be limited in view of the materials of the organic antimicrobial membrane or the medical implant.

[0005] Therefore, there is still a need to develop novel and cost - effective medical implants and methods for their preparation. Summary of the Invention

[0006] Accordingly, the present disclosure relates to a medical implant assembly comprising:

[0007] (a) A biocompatible substrate (S), and

[0008] (b) A biocompatible - bioactive composite layer (BACL) located above or on the substrate, having a porosity of 0.5% to 40%, preferably a porosity of 30% or less;

[0009] Wherein the biocompatible substrate (S) is made of one or more materials selected from the group consisting of: biocompatible polymers, a first biocompatible metal or alloy, and a first biocompatible ceramic, and

[0010] Wherein the BACL is made of a composite material comprising component (1): a second biocompatible metal or alloy, a second biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive ingredient.

[0011] The present disclosure also relates to a method for preparing the medical implant assembly described herein, which comprises the following steps:

[0012] (i) Providing a biocompatible substrate (S) in a deposition chamber;

[0013] (ii) Reducing the pressure in the deposition chamber to less than 2.5 Torr, such as less than 2.35 Torr, less than 2.2 Torr; and

[0014] (iii) Depositing the composite material of the biocompatible - bioactive composite layer (BACL) by aerosol deposition (AD) to form a BACL above or on the biocompatible substrate, and

[0015] Wherein the composite material comprises component (1): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive ingredient.

[0016] In one aspect, the present disclosure provides a medical implant assembly comprising a biocompatible substrate (S), an auxiliary dense layer (ADL) on the substrate, and a biocompatible - bioactive composite layer (BACL) on the auxiliary dense layer (ADL), i.e., the ADL is located between the biocompatible substrate and the BACL, wherein the ADL is made of a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and

[0017] The ADL has a surface roughness of less than 0.3 μm.

[0018] In one aspect, the present disclosure provides a method for preparing the medical implant assembly described herein, which comprises the following steps:

[0019] (i) Provide a biocompatible substrate (S) in a deposition chamber;

[0020] (ii) Reduce the pressure in the deposition chamber to less than 2.5 Torr, such as less than 2.35 Torr, less than 2.2 Torr; and

[0021] (iii) Deposit a composite material of BACL by aerosol deposition (AD) to form the BACL above or on the biocompatible substrate,

[0022] wherein the composite material comprises component (1): a second biocompatible metal or alloy, a second biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive ingredient.

[0023] In one aspect, the present disclosure provides a method for preparing a medical implant assembly described herein, comprising the following steps:

[0024] (i) Provide a biocompatible substrate (S) in a deposition chamber;

[0025] (ii) Reduce the pressure in the deposition chamber to less than 2.5 Torr, such as less than 2.35 Torr, less than 2.2 Torr;

[0026] (ii') Deposit a material for an auxiliary densification layer (ADL) on the substrate by aerosol deposition (AD), and

[0027] (iii') Deposit a composite material of BACL by aerosol deposition (AD) to form BACL above or on the ADL,

[0028] wherein the material of the ADL comprises a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof.

[0029] In one aspect, the present disclosure provides a medical implant assembly as part or whole 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 anchoring device.

[0030] In one embodiment, the thickness of the BACL is from 0.1 μm to 80 μm, preferably from 0.5 to 50 μm, more preferably from 1 to 6 μm, such as 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 by the values mentioned above as endpoints or single points.

[0031] In any of the foregoing embodiments, the medical implant assembly has a surface roughness of 0.3 μm or higher.

[0032] In any of the foregoing embodiments, the surface roughness of the BACL is from 0.05 μm to 4 μm, such as from 0.1 μm to 3.5 μm, from 0.15 μm to 3 μm, from 0.075 μm to 3.75 μm, from 0.2 μm to 2.5 μm, and the like.

[0033] In any of the foregoing embodiments, the BACL is formed of primary particles having a D50 in the range of 0.1 μm to 10 μm, preferably in the range of 0.5 μm to 3 μm.

[0034] In any of the foregoing embodiments, the component (1) of the BACL is 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; oxide-nitrides of one or more of aluminum, silicon, titanium, and zirconium; oxide-carbides of one or more of aluminum, silicon, titanium, and zirconium; nitride-carbides of one or more of aluminum, silicon, titanium, and zirconium; oxide-nitride-carbides of one or more of aluminum, silicon, titanium, and zirconium; phosphates of calcium; hydroxyapatite; halogenated hydroxyapatite; carbonated hydroxyapatite; halogenated carbonated hydroxyapatite; and any mixture of the foregoing substances.

[0035] In any of the foregoing embodiments, the component (2) of the BACL is selected from the group consisting of: antibiotics, platelet-rich plasma (PRP), collagen, steroids, nucleic acids, antibodies, functional fragments of antibodies, and any mixture of the foregoing substances.

[0036] In any of the foregoing embodiments, the component (2) of the 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.

[0037] In any of the foregoing embodiments, the thickness variation of the BACL is less than 10%, such as less than 8%, less than 5%, and the like.

[0038] In any of the foregoing embodiments, if present, the ADL has a thickness of 0.5 μm to 10 μm, preferably 1 μm to 3 μm.

[0039] In any of the foregoing embodiments, the adhesion strength between the substrate and the BACL is greater than 3B as measured according to ASTM D3359. If the ADL is present, then (i) the adhesion strength between the ADL and the substrate is at least 4B as measured according to ASTM D3359, (ii) the adhesion strength between the ADL and the BACL is at least 4B as measured according to ASTM D3359, or (iii) both (i) and (ii) are satisfied simultaneously. In any of the foregoing embodiments, the adhesion strength between the film stack (i.e., ADL + BACL) and the substrate is greater than 3B, preferably greater than 4B, as measured according to ASTM D3359.

[0040] In any of the foregoing embodiments, if an ADL is present, the thickness variation of the ADL is less than 10%.

[0041] In any of the foregoing embodiments, if an ADL is present, the ADL has a porosity of less than 1%, preferably measured at a magnification of 10,000X under FE-SEM.

[0042] In any of the foregoing embodiments, if an ADL is present, the surface roughness of the BACL is from 0.05 μm to 4 μm, such as from 0.1 μm to 3.5 μm, from 0.15 μm to 3 μm, from 0.075 μm to 3.75 μm, from 0.2 μm to 2.5 μm, etc.

[0043] In any of the foregoing embodiments, if an ADL is present, the component (1) of the composite material of the biocompatible metal or alloy, biocompatible ceramic or any mixture thereof with the BACL is different.

[0044] In any of the foregoing embodiments, if an ADL is present, the component (1) of the composite material of the biocompatible metal or alloy, biocompatible ceramic or any mixture thereof with the BACL is the same.

[0045] In any of the foregoing embodiments, the medical implant assembly comprises at least two biocompatible - bioactive composite layers (BACL).

[0046] In any of the foregoing embodiments, the biocompatible polymer is selected from the group consisting of: polytetrafluoroethylene (PTFE), polyetheretherketone (PEEK), polyethylene (PE), polyurethane (PU), and polyvinyl chloride (PVC).

[0047] In any of the foregoing embodiments, the PE is low density polyethylene (LDPE), high density polyethylene (HDPE), or ultra-high molecular weight polyethylene (UHMWPE).

[0048] In any of the foregoing embodiments, the hardness of the biocompatible polymer is at least 400 HV (Vickers hardness), preferably up to 600 HV, more preferably up to 1000 HV; or its Shore D (Shore hardness) is at least 50, preferably the Shore D is at least 55, more preferably the Shore D is at least 60, and most preferably the Shore D is at least 65.

[0049] In any of the foregoing embodiments, the biocompatible metal or alloy for the substrate (S) is selected from the group consisting of: 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) alloy, and Ti-6Al-4V alloy.

[0050] In any of the foregoing 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), and aluminum (Al).

[0051] In any of the foregoing 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.

[0052] In any of the foregoing embodiments, AD is carried out at a carrier gas flow rate of 300 to 1500 l / h.

[0053] In any of the foregoing embodiments, the temperature of the substrate during the deposition of the ADL and / or BACL ranges from 5°C to 50°C, for example at least 15°C, preferably not higher than 35°C.

[0054] In any of the foregoing embodiments, the substrate (S) is polished to exhibit a surface roughness of at least 0.2 μm. Description of the Drawings

[0055] Figure 1 and 2 Shows an illustrative scheme of a method for preparing a medical implant of the present invention. Detailed Description

[0056] To facilitate understanding of the disclosure herein, the terms used herein are hereby defined as follows.

[0057] In the context of the specification and claims, unless specifically stated otherwise, the singular forms "a", "an", and "the" include plural references. Any and all examples or exemplary language (e.g., "such as") provided herein are for illustrative purposes only to better explain the invention and do not limit the scope of the invention unless otherwise stated.

[0058] It should be understood that any numerical range described in this specification includes all sub-ranges subsumed therein. For example, the range "50 to 70 °C" includes all sub-ranges and specific values between the minimum value of 50 °C and the maximum value of 70 °C, including, for example, 58 °C to 67 °C, and 53 °C to 62 °C, 60 °C, or 68 °C. Since the disclosed numerical ranges are continuous, they contain every value between the minimum and maximum values. Unless otherwise stated, the various numerical ranges indicated in this specification are approximate.

[0059] In the present invention, the term "about" refers to an acceptable deviation of a given value as measured by a person skilled in the art, which depends in part on how the value is measured or determined.

[0060] In the present disclosure, the term "biocompatible" or "biocompatibility" means having the ability to come into contact with a living system without producing adverse effects, such as (severe) allergic reactions, damage to cells, tissues, or organs in vivo, and the like.

[0061] In the present disclosure, the term "porosity" refers to the level of pore space in a material.

[0062] Medical implant component

[0063] Inorganic or organic antimicrobial membranes can be applied as coatings 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 antimicrobial membranes using organic gelling or polymeric materials (such as gelatin, poly(lactic acid) (PLA, including poly-D,L-lactic acid (PDLLA)), poly(glycolic acid) (PGA), etc.) or hydroxyapatite, and antimicrobial substances can be loaded by impregnating the membrane or co-precipitating from a solution. However, the thickness of inorganic or organic antimicrobial membranes may be limited due to the requirements of the preparation process or (mechanical) strength; the thickness is also difficult to control. One possible improvement is to use a 3D transition ceramic structure, but this may lead to an increase in cost or production complexity, or to a risk of contaminating the material.

[0064] Accordingly, in the present disclosure, there is provided a medical implant component comprising a biocompatible substrate (S) and a biocompatible - bioactive composite layer (BACL) having a porosity of 0.5% to 40% located above or on the substrate, wherein the BACL is made of a composite material comprising component (1): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive ingredient. In one aspect, the medical implant component comprises a biocompatible substrate (S), an auxiliary dense layer (ADL) on the substrate, and a biocompatible - bioactive composite layer (BACL) on the auxiliary dense layer (ADL), i.e., the ADL is located between the biocompatible substrate and the BACL, and the ADL is made of a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof.

[0065] Details of the components or layers of the medical implant component are described below.

[0066] Biocompatible substrate

[0067] In the present disclosure, once biocompatible substrates known in the art have desired properties such as sufficient mechanical strength (hardness, robustness, etc.), chemical inertness, biocompatibility, etc., they can be used. For example, the material used to prepare the biocompatible substrate can have a hardness (Vickers hardness) of at least 400 HV or a Shore D (Shore hardness) of at least 50. In various embodiments, the biocompatible substrate can be made of one or more materials selected from the group consisting of biocompatible polymers, biocompatible metals or alloys, and biocompatible ceramics.

[0068] Examples of biocompatible polymers include (but are not limited to) polyketones such as polyetheretherketone (PEEK); (halogenated) polyolefins such as polyethylene (PE), poly(ethylene - propylene), polytetrafluoroethylene (PTFE), and polyvinyl chloride (PVC); polyurethanes, etc. In various embodiments, the PE is low - density polyethylene (LDPE), high - density polyethylene (HDPE), or ultra - high - molecular - weight polyethylene (UHMWPE).

[0069] 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) alloy, and Ti - 6Al - 4V alloy.

[0070] Examples of biocompatible ceramics include, but are not limited to, 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), and aluminum (Al).

[0071] In one embodiment, the surface roughness (Ra) of the biocompatible substrate is less than 0.3 μm; or greater than 0.01 μm. In one embodiment, the biocompatible substrate has a linear thermal expansion coefficient in the range of 6×10 -6 to 18×10 -5 .

[0072] Biocompatible - bioactive composite layer (BACL)

[0073] In the present disclosure, the biocompatible-bioactive composite layer (BACL) is used to achieve the above advantages, for example, presenting high structural stability, providing extended / sustained / long-term release of one or more bioactive components, and the like.

[0074] The BACL is made of a composite material, which comprises component (1): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive ingredient. The composite material can be in solid form, such as a mixture, an admixture, a powder, etc., and is substantially homogeneous. In one embodiment, the composite material is a solid dispersion comprising components (1) and (2). In one embodiment, the composite material is a solid dispersion composed of components (1) and (2).

[0075] The materials of component (1), namely the biocompatible metal or alloy, the biocompatible ceramic, or any mixture thereof, are 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; oxide-nitrides of one or more of aluminum, silicon, titanium, and zirconium; oxide-carbides of one or more of aluminum, silicon, titanium, and zirconium; nitride-carbides of one or more of aluminum, silicon, titanium, and zirconium; oxide-nitride-carbides of one or more of aluminum, silicon, titanium, and zirconium; calcium phosphates; hydroxyapatite; halogenated hydroxyapatite; carbonated hydroxyapatite; halogenated carbonated hydroxyapatite; and any mixture of the foregoing substances.

[0076] Component (2), i.e., the material of the organic bioactive ingredient, is selected from the group consisting of: antibiotics, platelet-rich plasma (PRP), collagen, steroids, nucleic acids, antibodies, functional fragments of antibodies, and any mixture of the foregoing substances. In one embodiment, component (2) may be an antibiotic, such as β-lactam, glycopeptide, lipopeptide, rifamycin, macrolide, aminoglycoside, fluoroquinolone, lincosamide (e.g., lincomycin, clindamycin, pirilimycin), tetracycline, fusidic acid, etc. In one embodiment, component (2) may be a substance beneficial to or capable of enhancing cell or tissue repair, such as platelet-rich plasma (PRP), steroids, DNA / RNA, antibodies. In one embodiment, the organic bioactive ingredient is insoluble or almost insoluble in water or an aqueous medium, such as a physiological medium (e.g., PBS, saline, etc.).

[0077] In one embodiment, the medical implant assembly comprises a biocompatible substrate (S) and two or more biocompatible-bioactive composite layers (BACL). In one embodiment, the medical implant assembly consists of a biocompatible substrate (S) and one or more biocompatible-bioactive composite layers (BACL). In one embodiment, the medical implant assembly consists of a biocompatible substrate (S) and one or more biocompatible-bioactive composite layers (BACL), wherein the one or more BACL consist of: hydroxyapatite, halogenated hydroxyapatite, carbonated hydroxyapatite, halogenated carbonated hydroxyapatite, or any mixture of the foregoing substances.

[0078] In one embodiment, one or more biocompatible-bioactive composite layers (BACL) are located on or above the substrate (e.g., when there is an auxiliary dense layer (ADL) described below). Each of the one or more BACL should independently have a porosity of 0.5% to 40%, preferably 0.8% to 35%, such as at least 1%, at least 5%, at least 7.5%, at least 10%, at most 37.5%, at most 30%, at most 25%, at most 20%, at most 15%, or within any reasonable numerical range formed by the values mentioned above as endpoints, so that the medical implant can exhibit excellent effects, such as good durability, encapsulation and release profiles of bioactive ingredients, etc. The appropriate porosity of the layer can be achieved by, for example, the method of preparing the medical implant described herein.

[0079] In one embodiment, the thickness of each BACL is independently from 0.5 μm to 80 μm, such as at least 0.1 μm, at least 0.5 μm, at least 1 μm, at least 2 μm, at least 3 μm, at least 4 μm, at least 5 μm, at least 6 μm, at least 7 μm, at least 8 μm, at least 9 μm, at least 10 μm, at least 11 μm, at least 12 μm, at least 13 μm, at least 14 μm, at least 15 μm, at least 20 μm, at least 25 μm, at least 30 μm, at least 35 μm; or at most 80 μm, at most 70 μm, at most 65 μm, at most 60 μm, at most 55 μm, at most 50 μm, at most 45 μm, at most 40 μm; any reasonable numerical range formed by the values mentioned above as endpoints, such as 0.5 μm to 30 μm, 40 μm to 55 μm, 5 μm to 8 μm, etc.

[0080] In one embodiment, the adhesion strength between the substrate and the BACL, measured according to ASTM D3359, is at least or greater than 3B, preferably at least or greater than 4B, more preferably at least 5B.

[0081] In one embodiment, the surface roughness of each BACL is independently between 0.05 μm and 4.0 μm, such as 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 by any of the above endpoint values.

[0082] In one embodiment, each BACL is independently formed from primary particles having the following D50: in the range of 0.1 μm to 10 μm, such as 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; in any reasonable numerical range formed by the values mentioned above as endpoints, such as 0.5 μm to 3 μm, 0.8 μm to 5 μm, etc.

[0083] Without being bound by theory, the BACL is (almost) uniform and continuous layer because it is prepared by the AD technique as disclosed herein. Specifically, based on the observation results of FE-SEM (e.g., 5000X) after ion milling, the BACL may not have obvious single crystals. In addition, through X-ray diffraction analysis, the crystallinity of the BACL can be reduced by at least 15%, preferably at least 20%, compared to the pure powder of its (composite) material.

[0084] Auxiliary dense layer (ADL)

[0085] In one aspect, the medical implant component further includes an auxiliary dense layer (ADL) that is located on the biocompatible substrate (S) and between the biocompatible substrate (S) and the BACL. The ADL is made 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 can contribute to the adhesion between the biocompatible substrate and the BACL.

[0086] In one embodiment, the thickness of the ADL is from 0.3 μm to 1.5 μm, such as 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; any reasonable numerical range formed by the values mentioned above as endpoints, such as 0.5 μm to 1 μm, 0.4 μm to 1.2 μm, 0.6 μm to 0.95 μm, etc.

[0087] In one embodiment, the adhesion strength between the ADL and the biocompatible substrate, measured according to ASTM D3359, is at least or greater than 3B, preferably at least or greater than 4B, more preferably at least 5B. In one embodiment, the adhesion strength between the film stack (i.e., the combination of the ADL and the BACL) and the biocompatible substrate, measured according to ASTM D3359, is at least or greater than 4B, more preferably at least 5B.

[0088] In one embodiment, the thickness variation of the ADL is less than 10%, preferably less than 8%, more preferably less than 5%.

[0089] In one embodiment, the porosity of the ADL is less than 1%, preferably less than 0.8%, more preferably less than 0.5%.

[0090] Application of the medical implant component

[0091] Medical implant components can be used in a variety of applications due to their excellent properties (including, but not limited to, good durability, good biocompatibility, adjustable drug release rate, etc.). Examples of such applications include, but are not limited to, artificial joints (e.g., knee replacements, hip replacements, shoulder replacements, radiocarpal joint replacements; cups, heads, stems, etc.), inserts related to artificial joints, stents, intervertebral discs, screws, artificial bone plates, intervertebral spacers, or parts or all of permanent or temporary anchoring devices (e.g., for orthodontics, surgery, etc.).

[0092] In one embodiment, the surface of the medical implant component has a checkerboard pattern. In one embodiment, the surface roughness of the medical implant component is 0.3 μm or higher, preferably 0.8 μm or higher, such as 0.9 μm or higher, 1 μm or higher, etc. In any of the foregoing embodiments, the thickness variation of the BACL (excluding surface structural features) is less than 10%.

[0093] Method for preparing a medical implant component

[0094] Conventional methods for preparing coatings or layers on the substrate of a medical implant component include plasma spraying, physical vapor deposition (PVD), chemical vapor deposition (CVD), spraying processes (thermal spraying or cold spraying), sintering processes, etc. The inventors of the present case have found that it would be advantageous to use aerosol deposition (AD) to deposit materials to form the BACL (and optionally the ADL).

[0095] Briefly, the AD process can exhibit the following advantages in preparing the medical implant components described herein: (1) The deposition rate is higher than that of the PVD / CVD process, which has the benefit of improving production efficiency; (2) The temperature for the process of depositing the BACL (and optionally the ADL) (e.g., close to room temperature) can be significantly lower than that for the PVD / CVD (e.g., higher than 300 °C and even up to 800 °C), thermal spraying or cold spraying (about 300 °C) processes; (3) The required vacuum level is less restricted compared to performing the PVD / CVD process; (4) The AD process is easier to scale up compared to the PVD / CVD process; (5) The thickness of the layer is easy to adjust and can be larger; (6) The adhesion strength of one or more deposited layers is significantly higher than that obtained by the PVD / CVD, thermal spraying or cold spraying processes; (7) The density and conformability of one or more deposited layers can be higher than those obtained by the thermal spraying or cold spraying processes; (8) One or more deposited layers or coatings can be near net shape, which may be difficult to achieve when using the PVD / CVD, thermal spraying or cold spraying processes; and (9) The cost can be significantly lower than that of the PVD / CVD, thermal spraying or cold spraying processes.

[0096] Compared with solution-based technologies, the AD process has various advantages over other surface treatment technologies. For example, there is no need for pre-treatment of the substrate by anodization as in other technologies (oxidation, corrosion, etc.) used to form porous 3D structures, such as impregnation with a polymer dispersion (optionally also containing a bioactive agent, such as an antibiotic), solution spraying, solution dripping processes, etc. In addition, the layers formed by the AD process can exhibit (minor) surface irregularities, such as a checkerboard pattern, and such (minor) surface irregularities may be beneficial for desired applications such as cell or tissue regeneration in vivo. In one embodiment, the surface irregularities can have obtuse angles instead of the acute angles exhibited in needle-like or flake-like morphologies formed by other surface processing technologies, and can reduce the likelihood of requiring repair caused by mechanical stresses generated during transportation, packaging, and installation during clinical use. Without being bound by theory, horizontal (pressed) strips of the composite material can be observed in a cross-sectional view, which define the space (and porosity) that can be used to introduce one or more bioactive components, and thus the distribution of the one or more bioactive components can be more uniform than in conventional loading methods.

[0097] Therefore, one or more layers of a medical implant component exhibit high stability and enhanced mechanical strength; the three-dimensional (micro) structure of the layer with porosity can play an important role in providing mechanical strength, load-bearing, and protecting bioactive components. In addition, there is no need to transfer semi-finished products or products during the process of depositing the layer, so the risk of contaminating semi-finished products or products due to transfer (required in other types of deposition processes) can be eliminated or avoided.

[0098] The inventors of the present case surprisingly found that the AD process is advantageous in preparing medical implant components, particularly BACL.

[0099] Therefore, the present disclosure also relates to a method for preparing the medical implant component described herein, which comprises the following steps:

[0100] (i) Providing a biocompatible substrate (S) in a deposition chamber;

[0101] (ii) Reducing the pressure in the deposition chamber to less than 2.5 Torr, such as less than 2.35 Torr, less than 2.2 Torr; and

[0102] (iii) Depositing a composite material of a biocompatible-bioactive composite layer (BACL) by aerosol deposition (AD) to form a BACL above or on the biocompatible substrate, and

[0103] wherein the composite material comprises component (1): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (2): an organic bioactive component.

[0104] In one aspect, the present disclosure relates to a method for preparing a medical implant component described herein, the method comprising the steps of:

[0105] (i) providing a biocompatible substrate (S) in a deposition chamber;

[0106] (ii) reducing the pressure in the deposition chamber to less than 2.5 Torr, such as less than 2.35 Torr, less than 2.2 Torr;

[0107] (ii') depositing a material for an auxiliary dense layer (ADL) on the substrate by aerosol deposition (AD), and

[0108] (iii') depositing a composite material for BACL by aerosol deposition (AD) to form BACL over or on the ADL, and

[0109] wherein the material of the ADL comprises a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof.

[0110] In various embodiments, steps (ii') and (iii') can be performed at least twice to form multiple biocompatible-bioactive composite layers (BACL).

[0111] The biocompatible substrate can be the biocompatible substrate described herein. In one embodiment, the biocompatible substrate is made of one or more materials selected from the group consisting of: biocompatible polymeric materials, biocompatible metals or alloys, and biocompatible ceramics. In one embodiment, the biocompatible polymeric materials are 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).

[0112] The AD process can be carried out by known means and equipment. The equipment for carrying out the AD process can include an aerosol generation unit (comprising, for example, one or more carrier gas sources, mass flow controllers (MFC), an aerosol generation chamber), a deposition chamber (equipped with, for example, a nozzle / atomizer, a support plate or platform, etc.), and a vacuum system (such as a pump).

[0113] Various parameters of the AD process can be adjusted. Examples of the parameters include (but are not limited to) the type of one or more carrier gases; the flow rate; the distance between the nozzle and the substrate support; the angle of incidence of the aerosol flow towards the substrate; the vacuum in the deposition chamber; the concentration, particle size, type of one or more materials of the biocompatible protective coating in the aerosol flow; the temperature in the chamber; the temperature of the substrate; etc.

[0114] Examples of the one or more carrier gases include, but are not limited to, nitrogen (N2), oxygen (O2), argon (Ar), helium (He), clean dry air (CDA), and any combination and fraction thereof. The flow rate of the carrier gas can be from 300 to 1500 l / hr, such as about 300 l / h, about 350 l / h, about 400 l / h, about 450 l / h, about 500 l / h, about 550 l / h, about 600 l / h, about 650 l / h, about 700 l / h, about 750 l / h, about 800 l / h, about 850 l / h, about 900 l / h, about 950 l / h, about 1000 l / h, about 1100 l / h, about 1200 l / h, about 1300 l / h, about 1400 l / h, about 1500 l / h; or any reasonable numerical range formed by the values mentioned above as endpoints, such as 500 l / h to 650 l / h, 350 to 1300 l / h, etc.

[0115] During the AD process, the temperature (of the biocompatible substrate) can be controlled in the range of 5°C to 50°C, such as 15°C to 45°C, preferably not higher than 35°C.

[0116] The D50 of the material powder can be in the range of 0.1 μm to 10 μm, such as 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 in any reasonable numerical range formed by the values mentioned above as endpoints, such as 0.5 μm to 3 μm, 0.8 μm to 5 μm, etc. One or more pre-treatments, such as grinding, sieving, etc., can be performed on the raw materials to provide one or more materials for deposition by the AD process.

[0117] Once the deposition of one or more biocompatible-bioactive composite layers (BACL) (and optionally an auxiliary dense layer (ADL)) is completed, the product can be post-treated, such as cleaning, shaping, etc.

[0118] Examples

[0119] The following examples are provided to make those skilled in the art of the present invention better understand the present invention, but are not intended to limit the scope of the present invention.

[0120] Materials, methods, and test models

[0121] The materials of the biocompatible-bioactive composite material layer include Si3N4, Al2O3, TiN (4N purity), and hydroxyapatite, which are available from Sigma-Aldrich.

[0122] If needed, the materials can be further processed by UPE-Celanese GUR@1020-E.

[0123] The porosity of the layer can be measured by Hitachi S-4300FE-SEM. The thickness and roughness can be measured by KLA-D500. The adhesion strength can be evaluated according to ASTM D3359.

[0124] The antibacterial activity can be evaluated by JIS Z 2801. Specifically, the samples or composite material layers (e.g., 5 cm × 5 cm) are cleaned and disinfected, and then inoculated with a test suspension containing one or more target microorganisms. The inoculated samples / composite material layers are covered with plastic film and incubated at a selected temperature and time, e.g., incubated at 35 °C for 24 hours. After incubation, the samples / composite material layers are washed to calculate the microorganism concentration.

[0125] Example 1

[0126] Silicon nitride (D50 is about 1.8 μm, about 25 mL) and vancomycin powder (about 2 g) are used as the composite materials; they are introduced into a nylon jar of a grinder and uniformly mixed at 60 rpm under ambient conditions for 3 hours. The mixed powder is put into an aerosol generator for subsequent procedures.

[0127] The Ti substrate is washed in an ultrasonic cleaner with acetone, alcohol, and deionized water (10 minutes each), dried and then placed in the chamber of an aerosol deposition (AD) device; the chamber is evacuated to 2.2 Torr or lower. Then, a processing gas (e.g., He) is introduced into the aerosol generator at an appropriate flow rate (e.g., 10 to 15 liters per minute) to generate a uniform aerosol of the mixed powder, which is introduced into the chamber and uniformly sprayed on the substrate to form a BACL. After the AD process is completed, the deposited substrate is recovered and washed with clean dry air (CDA) to remove the residual powder on its surface, and placed in a drying oven for storage and subsequent tests.

[0128] Example 2

[0129] Hydroxyapatite (HA) (D50 is about 2.1 μm, about 25 ml) and vancomycin powder (about 2 g) are used as the composite materials; they are introduced into a nylon jar of a grinder and uniformly mixed at 60 rpm under ambient conditions for 3 hours. The mixed powder is put into a drying oven for storage and subsequent procedures.

[0130] Pure HA powder is introduced into the container of the aerosol generator. Subsequently, the Ti substrate is washed (for 10 minutes each) with acetone, alcohol, and deionized water in an ultrasonic cleaner, dried and then placed into the chamber of the aerosol deposition (AD) device; the chamber is evacuated to 2.2 Torr or lower. Then a processing gas (e.g., He) is introduced into the aerosol generator at an appropriate flow rate (e.g., 10 to 15 liters per minute) to generate a uniform aerosol of HA powder, which is introduced into the chamber and evenly sprayed onto the substrate to form an ADL. After the deposition of the ADL is completed, the deposited substrate is retrieved and cleaned with clean dry air (CDA) to remove the residual HA powder on its surface. The substrate is placed again into the chamber of the aerosol deposition (AD) device; the chamber is evacuated to 2.2 Torr or lower. The HA powder is removed from the container of the aerosol generator, and a mixed powder of HA and an antibiotic is introduced into the container. Then a processing gas (e.g., He) is introduced into the aerosol generator at an appropriate flow rate (e.g., 10 to 15 liters per minute) to generate a uniform aerosol of the mixed powder of HA and an antibiotic, which is introduced into the chamber and evenly sprayed onto the substrate to form a BACL (on the ADL). After the deposition of the BACL is completed, the deposited substrate is retrieved and cleaned with clean dry air (CDA) to remove the residual powder on its surface, and placed in a drying oven for storage and subsequent testing.

[0131] Example 3 (Comparative)

[0132] An implant sample with a polymeric surface coating impregnated with an antibiotic is provided as a comparative example herein. The Ti-6Al-4V substrate is subsequently polished with sandpaper having grit numbers of 400, 600, ……, 1,500, and then immersed in a solution of HF:H2SO4 (1M:4M) for 5 minutes; the substrate is cleaned with deionized water in an ultrasonic cleaner for 20 minutes to remove the acid remaining on the surface.

[0133] Then, the clean substrate is anionized by immersing it in a 0.2M Ca(H2PO2)2 solution (Alfa Aesar, Germany) at 300V, 100 mA / cm 2 (from a DC power supply) for 5 minutes. After treatment, the substrate is rinsed with deionized water for 5 minutes to remove the residual anion solution and dried for subsequent use.

[0134] The treated substrate is immersed in a dichloromethane solution of 5% poly D,L-lactide-co-glycolide (PLGA) and 2 g vancomycin, and withdrawn from the solution at a rate of 2 cm / min. The sample thus obtained is dried at ambient temperature for 30 minutes for subsequent testing.

[0135] Example 4

[0136] The samples obtained in Examples 1 to 3 were respectively immersed in 50 mL of phosphate buffer physiological solution (1X PBS, Gibco, thermo fisher scientific, Waltham, USA) at 37 °C and shaken on an oscillator at 30 rpm for 20 minutes. Then, the substrates were respectively placed in 200 mL of fresh phosphate buffer physiological solution, and 5 mL of samples were taken every 12 hours for measuring the antibiotic concentration. The antibacterial ability was also evaluated.

[0137] The characteristics and test results of the medical implant components described in Examples 1 to 3 are listed in Table 1:

[0138] Table 1

[0139]

[0140] The maximum drug release time of the present invention is expected to be up to 15 to 23 days or even longer. The drug release amount within the first 12 hours is expected to be at most 2 mg (e.g., at most 1.7 mg, or at least 1 to 1.2 mg), at most 1.4 mg (e.g., at most 1.2 mg, or at least 0.7 mg) within the subsequent 36 hours (i.e., from the 12th hour to the 48th hour), and at most 0.8 mg (e.g., at most 0.7 mg, or at least 0.2 mg) after 48 hours.

[0141] The present invention significantly shows better effects than existing medical implant components. Specifically, the membrane structures of the samples obtained in Examples 1 and 2 remained stable and intact after 10 days of testing. After 10 days of testing, the FTIR spectra of BACL in the samples of Examples 1 and 2 still showed the signal of vancomycin, indicating that vancomycin could still be released from the membrane after 10 days. In contrast, the antibiotic-loaded membrane layers obtained by conventional polymer coating and direct impregnation methods (Example 3) tended to deteriorate and even peel off from the substrate under simulated human physiological conditions, and almost no vancomycin signal was observed in the FTIR spectra of the polymer membranes for the samples obtained in the tests after 5 or 6 days. In addition, the samples of Examples 1 and 2 passed the antibacterial ability test, but the samples of Comparative Example 3 did not pass the antibacterial ability test, as shown in Table 1 above.

[0142] In addition, compared with the conventional polymer impregnation process, the AD process can be carried out with a simpler procedure because the powder of the composite material can be conveniently prepared by mixing and no liquid-based cleaning is required. However, the conventional polymer impregnation process will require complex procedural steps, including multiple transfers of the substrate, liquid-based cleaning, and drying.

[0143] Briefly, the present disclosure provides methods and medical implant components having various advantages over the prior art, particularly simpler procedures, extended release times of bioactive components from the medical implant components, and higher component structural stability.

[0144] Those of ordinary skill in the art to which this invention pertains should understand that changes and modifications can be made to the teachings and disclosures of this invention without departing from the spirit and scope of this application. Based on the foregoing, this application intends to cover any changes and modifications thereto, provided that such changes and modifications or their equivalents fall within the scope as defined by the appended claims.

Claims

1. A medical implant assembly comprising: (a) a biocompatible substrate S, and (b) at least one biocompatible-bioactive composite material layer BACL located above or on said substrate, having a porosity of 0.5% to 40%; wherein the biocompatible substrate S is made of one or more materials selected from the group consisting of: a biocompatible polymeric material, a first biocompatible metal or alloy, and a first biocompatible ceramic, and The BACL is made of a composite material, wherein the composite material comprises component (1): a second biocompatible metal or alloy, a second biocompatible ceramic or any mixture thereof, and component (2): an organic bioactive component.

2. The medical implant component of claim 1, wherein the component (1) of the BACL is 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; oxide-nitrides of one or more of aluminum, silicon, titanium and zirconium; oxide-carbides of one or more of aluminum, silicon, titanium and zirconium; nitride-carbides of one or more of aluminum, silicon, titanium and zirconium; oxide-nitride-carbides of one or more of aluminum, silicon, titanium and zirconium; calcium phosphates; hydroxyapatite; halogenated hydroxyapatite; carbonated hydroxyapatite; halogenated carbonated hydroxyapatite; and any mixtures of the foregoing.

3. The medical implant component of any preceding claim, wherein the BACL has a thickness of 0.1 μm to 80 μm, 0.5 μm to 50 μm, or 1 μm to 6 μm.

4. The medical implant component according to any preceding claim, wherein the adhesion strength between the substrate and BACL is greater than 3B as measured according to ASTM D3359.

5. A medical implant component according to any preceding claim, having a surface roughness of 0.3 μm or more.

6. A medical implant component according to any preceding claim, wherein the BACL is formed from primary particles of the composite material having a D50 in the range of 0.1 μm to 10 μm.

7. The medical implant assembly according to any preceding claim, wherein the component (2) of 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 mixtures of the foregoing.

8. The medical implant component according to any preceding claim, wherein component (2) of the BACL is present in an amount of 0.3 wt% to 25 wt%, based on the total weight of the composite material.

9. The medical implant component according to any preceding claim, further comprising an auxiliary dense layer ADL, wherein: 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 any mixture thereof, The third biocompatible metal or alloy, biocompatible ceramic or any mixture thereof is selected from the biocompatible metal or alloy, biocompatible ceramic or any mixture thereof as defined in claim 2, and the ADL has a surface roughness of less than 0.3 μm.

10. The medical implant component of claim 9, wherein the ADL has a thickness of 0.5 μm to 10 μm.

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

12. The medical implant component of any one of claims 9 to 11, wherein the thickness of the ADL varies by less than 10%.

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

14. The medical implant component according to any one of claims 9 to 13, wherein 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.

15. A medical implant assembly according to any preceding claim, which is part or all of an artificial joint, an insert associated with an artificial joint, a stent, an intervertebral disc, a screw, an artificial bone plate, an intervertebral spacer or a permanent or temporary anchoring device.

16. The medical implant component of any preceding claim, wherein the substrate has a surface roughness of at least 0.2 μm.

17. A method of preparing a medical implant component according to any preceding claim, comprising the steps of: (i) providing a biocompatible substrate S in a deposition chamber; (ii) reducing the pressure in the deposition chamber to less than 2.5 Torr; and (iii) depositing a composite material of a biocompatible-bioactive composite layer BACL by aerosol deposition AD to form a BACL over or on the biocompatible substrate, and wherein the composite material comprises component (1): a biocompatible metal or alloy, a biocompatible ceramic or any mixture thereof, and component (2): an organic bioactive component.

18. The method according to claim 18, further comprising a step (ii') after the step (ii): (ii') depositing the material of the auxiliary dense layer ADL on the substrate by aerosol deposition AD, and wherein said step (iii) is step (iii'): (iii') depositing the composite material of the BACL by aerosol deposition AD to form the BACL above or on the ADL, and The material of the ADL comprises a biocompatible metal or alloy, a biocompatible ceramic or any mixture thereof.

19. The method of claim 17 or 18, wherein the AD is performed with a carrier gas selected from the group consisting of: N2, O2, Ar, He, clean dry air (CDA), and any combination thereof.

20. The method according to any one of claims 17 to 19, wherein the AD is performed with a carrier gas flow rate of 300 to 1500 l / h.

21. The method of any one of claims 17 to 20, wherein during the depositing, the temperature of the substrate is in the range of 5°C to 50°C.

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

23. The method according to any one of claims 17 to 22, wherein the biocompatible substrate S is made of one or more materials selected from the group consisting of: a biocompatible polymeric material, a biocompatible metal or an alloy.

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

25. The method according to any one of claims 17 to 24, wherein the substrate S is polished to exhibit a surface roughness of at least 0.2 μm.

26. The method according to any one of claims 17 to 25, wherein step (iii) or step (iii') is performed at least twice to form a plurality of BACLs.

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