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

Abstract

This disclosure relates to medical implant components comprising a biocompatible-bioactive composite material layer (BACL), methods for preparing such medical implant components, and applications of such medical implant components.

Description

Technical Field

[0001] This disclosure relates to medical implant components comprising a biocompatible-bioactive composite material layer (BACL), and methods for preparing such medical implant components; the BACL comprises component (a): a biocompatible metal or alloy, a biocompatible ceramic, or any mixture thereof, and component (b): an organic bioactive ingredient. This disclosure also relates to methods for preparing such medical implant components and applications of such medical implant components. Prior Technology

[0002] Medical implant components can be used in a variety of clinical and healthcare applications to provide benefits to physicians, surgeons, registered nurses, and patients during or after medical treatment. Thanks to advancements in materials science and medical science, the outcomes for patients requiring surgery or medical implants are continuously improving. For example, artificial joints can improve motor function in individuals or patients with age-related conditions or diseases and can extend the lifespan of body parts.

[0003] Microbial or viral infections are common complications during or after surgery, requiring debridement, extensive antibiotic use, blood transfusions, and potentially prolonged hospitalizations. This burdens patients and consumes medical resources. In severe cases, it can lead to sepsis, amputation, or even death. Antibiotics are widely used to reduce the risk of infection during surgery, either by incorporating them into implants or applying them to the surface. By controlling drug release, bacterial growth can be inhibited and the impact of antibiotics on tissue repair can be minimized. To control drug release and maintain the overall mechanical strength of the implant, antibiotic carriers (organic materials such as polylactic acid, polyethylene glycol, and bone cement; inorganic materials such as hydroxyapatite, calcium phosphate, and other materials) are used to load antibiotics to meet these requirements. The layer formed by such antibiotic carriers and antibiotics is called an "organic antimicrobial membrane."

[0004] To enhance the effectiveness of medical implants, organic antimicrobial films can be applied as coatings to the surface of medical implants. However, existing organic antimicrobial films may still exhibit certain defects or drawbacks, such as insufficient durability or mechanical strength, or a higher risk of contaminating the medical implant. Furthermore, existing methods for preparing medical implants coated with organic antimicrobial films may be costly, and their applicability may be limited given the materials used in the organic antimicrobial film or the medical implant.

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

[0006] Therefore, this disclosure relates to a medical implant component comprising:

[0007] (a) Biocompatible substrate (S), and

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

[0009] 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.

[0010] 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] This disclosure also relates to a method for preparing the medical implant component described herein, comprising the following steps:

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

[0013] (ii) Reduce the pressure in the sedimentation chamber to less than 2.5 Torr, for example, less than 2.35 Torr or less than 2.2 Torr; and

[0014] (iii) A composite material of a biocompatible-bioactive complex material layer (BACL) is deposited via aerosol deposition (AD) to form a BACL on or over the biocompatible substrate, and

[0015] 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 embodiment, this disclosure provides a medical implant component comprising a biocompatible substrate (S), an auxiliary compaction layer (ADL) on the substrate, and a biocompatible-bioactive composite material layer (BACL) on the ADL, wherein 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.

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

[0018] In one embodiment, this disclosure provides a method for preparing the medical implant component described herein, comprising the following steps:

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

[0020] (ii) Reduce the pressure in the sedimentation chamber to less than 2.5 Torr, for example, less than 2.35 Torr or less than 2.2 Torr; and

[0021] (iii) Depositing a composite material of BACL via aerosol deposition (AD) to form the BACL on or above a biocompatible substrate.

[0022] The materials in the ADL include biocompatible metals or alloys, biocompatible ceramics, or any mixture thereof.

[0023] In one embodiment, this disclosure provides a method for preparing the medical implant component described herein, comprising the following steps:

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

[0025] (ii) Reduce the pressure in the sedimentation chamber to less than 2.5 Torr, for example, less than 2.35 Torr or less than 2.2 Torr;

[0026] (ii') A material for depositing an auxiliary dense layer (ADL) on the substrate via aerosol deposition (AD), and

[0027] (iii') Depositing a composite material of BACL via aerosol deposition (AD) to form BACL on or above the ADL.

[0028] The materials in the ADL include biocompatible metals or alloys, biocompatible ceramics, or any mixture thereof.

[0029] In one embodiment, this disclosure provides medical implant components as part or integral of an artificial joint, an insert associated with an artificial joint, a brace, an intervertebral plate, 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, 1.5 μm to 25 μm, about 10 μm, about 20 μm, about 30 μm, about 40 μm, or any reasonable range of values ​​constituted by the values ​​mentioned above as endpoints or single points.

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

[0032] In any of the foregoing embodiments, the surface roughness of 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.

[0033] In any of the foregoing embodiments, the BACL is formed from primary particles with 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, component (1) of BACL is selected from the group consisting of: one or more oxides of aluminum, silicon, titanium and zirconium; one or more nitrides of aluminum, silicon, titanium and zirconium; one or more carbides of aluminum, silicon, titanium and zirconium; one or more oxide-nitrides of aluminum, silicon, titanium and zirconium; one or more oxide-carbides of aluminum, silicon, titanium and zirconium; one or more nitride-carbides of aluminum, silicon, titanium and zirconium; one or more oxide-nitride-carbides of aluminum, silicon, titanium and zirconium; calcium phosphate; hydroxyapatite; halogenated hydroxyapatite; carbonated hydroxyapatite; halocarbonated hydroxyapatite; and any mixture of the foregoing substances.

[0035] In any of the foregoing embodiments, component (2) of 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 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%, for example less than 8%, less than 5%, etc.

[0038] In any of the foregoing embodiments, if an ADL is present, it 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, as measured according to ASTM D3359, is greater than 3B. If the ADL is present, then (i) the adhesion strength between the ADL and the substrate, as measured according to ASTM D3359, is at least 4B; (ii) the adhesion strength between the ADL and the BACL, as measured according to ASTM D3359, is at least 4B; or (iii) both (i) and (ii) are satisfied. In any of the foregoing embodiments, the adhesion strength between the film stack (i.e., ADL+BACL) and the substrate, as measured according to ASTM D3359, is greater than 3B, preferably greater than 4B.

[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 10000X under FE-SEM.

[0042] In any of the foregoing embodiments, if an ADL is present, the surface roughness of 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.

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

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

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

[0046] In any of the foregoing embodiments, the biocompatible polymeric material 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, 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 biocompatible polymeric material has a hardness of at least 400 HV (Vickers hardness), preferably up to 600 HV, and more preferably up to 1000 HV; or its Shore D (Shore hardness) is at least 50, preferably at least 55, more preferably at least 60, and most preferably at least 65.

[0049] In any of the foregoing embodiments, the biocompatible metal or alloy system used for the substrate (S) is selected from the group consisting of: titanium (Ti) or alloys thereof, zirconium (Zr) or alloys thereof, tantalum (Ta) or alloys thereof, niobium (Nb) or alloys thereof, stainless steel, cobalt-chromium-molybdenum (Co-Cr-Mo) alloys and Ti-6Al-4V alloys.

[0050] In any of the foregoing embodiments, the biocompatible ceramic system used for the substrate (S) is selected from the group consisting of oxides, carbides, nitrides, or nitrocarburites 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 performed at a carrier gas flow rate of 300 to 1500 l / h.

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

[0054] In any of the foregoing embodiments, the polished substrate (S) exhibits a surface roughness of at least 0.2 μm. Simple Explanation of the Diagram

[0055] Figures 1 and 2 illustrate an illustrative scheme of the method for preparing the medical implant of the present invention. Implementation

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

[0057] In the context of the specification and the claims, unless otherwise specifically stated, the singular forms "a," "an," and "the" include multiple references. Unless otherwise stated, any and all instances or illustrative language (such as "like") provided herein are for the purpose of better illustrating the invention and not for limiting the scope of the invention.

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

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

[0060] In this disclosure, the term "biocompatibility" or "biocompatibility" means 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 living organisms, etc.

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

[0062] [Medical Implant Components] []

[0063] Inorganic or organic antimicrobial membranes can be applied as coatings to the surface of medical implants to prevent infection, improve prognosis, and / or provide long-term treatment after surgery. Existing inorganic or organic antimicrobial membranes include those 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 the antimicrobial substance can be loaded by impregnation or co-precipitation from solution. However, the thickness of inorganic or organic antimicrobial membranes may be limited by manufacturing processes or (mechanical) strength requirements; thickness is also difficult to control. One possible improvement is the use of 3D transition ceramic structures, but this may lead to increased cost or manufacturing complexity, or the risk of material contamination.

[0064] Therefore, this disclosure provides a medical implant assembly comprising a biocompatible substrate (S) and a biocompatible-bioactive composite material 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 embodiment, the medical implant assembly comprises a biocompatible substrate (S), an auxiliary densifying layer (ADL) on the substrate, and a biocompatible-bioactive composite material layer (BACL) on the auxiliary densifying 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. [, , ]

[0065] The following describes the components or layers of a medical implant assembly in detail. [, , ]

[0066] [Biocompatible substrate] []

[0067] In this disclosure, biocompatible substrates known in the art can be used once they possess the desired properties, such as sufficient mechanical strength (hardness, robustness, etc.), chemical inertness, and biocompatibility. For example, the material used to prepare the biocompatible substrate may have a hardness of at least 400 HV (Vickers hardness) or at least 50 Shore D (Shore hardness). In various embodiments, the biocompatible substrate may 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 polymeric materials include (but are not limited to) polyketides, such as polyetheretherketone (PEEK); (halogenated) polyolefins, such as polyethylene (PE), poly(ethylene-propylene), polytetrafluoroethylene (PTFE), and polyvinyl chloride (PVC); polyurethanes, etc. In various embodiments, 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 alloys thereof, zirconium (Zr) or alloys thereof, tantalum (Ta) or alloys thereof, niobium (Nb) or alloys thereof, stainless steel, cobalt-chromium-molybdenum (Co-Cr-Mo) alloys and Ti-6Al-4V alloys. [, , ]

[0070] Examples of biocompatible ceramics include (but are not limited to) oxides, carbides, nitrides, or nitrides 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 another embodiment, the biocompatible substrate has a linear coefficient of thermal expansion ranging from 6 × 10⁻⁶ to 18 × 10⁻⁵. [, , ]

[0072] [Biocompatible] [-] [Bioactive Composite Material Layer] [(BACL)]

[0073] In this disclosure, a biocompatible-bioactive complex material layer (BACL) is used to achieve the above advantages, such as exhibiting high structural stability and providing prolonged / sustained / long-term release of one or more bioactive components. [, , ]

[0074] 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. The composite material may be in solid form, such as a mixture, blend, powder, etc., and is substantially homogeneous. In one embodiment, the composite material is a solid dispersion comprising components (1) and (2). In another embodiment, the composite material is a solid dispersion composed of components (1) and (2). [, , ]

[0075] Component (1), namely, the material of biocompatible metal or alloy, biocompatible ceramic or any mixture thereof, is selected from the group consisting of: one or more oxides of aluminum, silicon, titanium and zirconium; one or more nitrides of aluminum, silicon, titanium and zirconium; one or more carbides of aluminum, silicon, titanium and zirconium; one or more oxide-nitrides of aluminum, silicon, titanium and zirconium; one or more oxide-carbides of aluminum, silicon, titanium and zirconium; one or more nitride-carbides of aluminum, silicon, titanium and zirconium; one or more oxide-nitride-carbides of aluminum, silicon, titanium and zirconium; calcium phosphate; hydroxyapatite; hydroxyapatite halide; hydroxyapatite carbonate; hydroxyapatite halide carbonate; and any mixture of the foregoing. [, , ]

[0076] Component (2), i.e., 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. In one embodiment, component (2) may be an antibiotic, such as β-lactamase, glycopeptide, lipopeptide, rifamycin, macrolides, aminoglycosides, fluoroquinolones, lincomycin (e.g., lincomycin, clindamycin, pirilimycin), tetracycline, fusidic acid, and analogues. In one embodiment, component (2) may be a substance that is beneficial to or can enhance cell or tissue repair, such as platelet-rich plasma (PRP), steroids, DNA / RNA, and antibodies. In one embodiment, the organic bioactive ingredient is insoluble or almost insoluble in water or aqueous media, such as physiological media (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 material layers (BACLs). In another embodiment, the medical implant assembly comprises a biocompatible substrate (S) and one or more biocompatible-bioactive composite material layers (BACLs). In one embodiment, the medical implant assembly comprises a biocompatible substrate (S) and one or more biocompatible-bioactive composite material layers (BACLs), wherein the one or more BACLs are composed of hydroxyapatite, hydroxyapatite halide, hydroxyapatite carbonate, hydroxyapatite halide carbonate, or any mixture thereof. [, , ]

[0078] In one embodiment, one or more biocompatible-bioactive composite material layers (BACLs) are located on or above a substrate (e.g., when an auxiliary compacting layer (ADL) as described below is present). Each or more BACLs should independently have a porosity of 0.5% to 40%, preferably 0.8% to 35%, for example, at least 1%, at least 5%, at least 7.5%, at least 10%, up to 37.5%, up to 30%, up to 25%, up to 20%, up to 15%, or any reasonable range of values ​​constituting the endpoints mentioned above, such that the medical implant exhibits excellent effects, such as good durability, encapsulation of bioactive components, and release profiles. The appropriate porosity of this layer can be achieved by methods for preparing medical implants, such as those described herein. [, , ]

[0079] In one embodiment, the thickness of each BACL is independently from 0.5 μm to 80 μm, for example 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 consisting of 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 adhesive strength between the substrate and the BACL, as measured according to ASTM D3359, is at least or greater than 3B, preferably at least or greater than 4B, and 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, 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 range of values ​​consisting of any of the aforementioned 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, 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; in any reasonable range of values ​​constituting the endpoints mentioned above, for example, 0.5 μm to 3 μm, 0.8 μm to 5 μm, etc.

[0083] Unbound by theory, BACL is a (nearly) homogeneous and continuous layer because it is prepared using the AD technique as disclosed herein. Specifically, based on observations by FE-SEM (e.g., 5000X) after ion milling, BACL may not exhibit obvious single crystals. Furthermore, X-ray diffraction analysis shows that the crystallinity of BACL is reduced by at least 15%, preferably at least 20%, compared to pure powder of its (composite) material.

[0084] [Auxiliary dense layer] (ADL)

[0085] In one embodiment, the medical implant component further includes an auxiliary densifying layer (ADL) situated on 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 facilitates 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, 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; any reasonable range of values ​​constituting the endpoints mentioned above, 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, as measured according to ASTM D3359, is at least or greater than 3B, preferably at least or greater than 4B, and more preferably at least 5B. In another embodiment, the adhesion strength between the film stack (i.e., the combination of ADL and BACL) and the biocompatible substrate, as measured according to ASTM D3359, is at least or greater than 4B, and more preferably at least 5B.

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

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

[0090] [Applications of Medical Implant Components] []

[0091] Medical implant components are suitable for a wide range of applications due to their excellent properties, including (but not limited to) good durability, good biocompatibility, and adjustable drug release rates. Examples of such applications include (but are not limited to) parts or all of artificial joints (e.g., knee replacements, hip replacements, shoulder replacements, radiocarpal replacements; cups, heads, rods, etc.), inserts associated with artificial joints, braces, intervertebral plates, screws, artificial bone plates, intervertebral spacers, or 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] [Methods for Preparing Medical Implant Components]

[0094] Conventional methods for preparing coatings or layers on substrates of medical implant components include plasma spraying, physical vapor deposition (PVD), chemical vapor deposition (CVD), spraying processes (thermal spraying or cold spraying), sintering processes, etc. The inventors of this invention have found that using aerosol deposition (AD) to deposit materials to form BACL (and, where applicable, ADL) would be advantageous.

[0095] In short, the AD process offers 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 benefits production efficiency; and (2) the temperature (e.g., close to room temperature) used for the deposition of BACL (and, where applicable, ADL) can be significantly lower than that used for PVD / CVD. (e.g., temperatures above 300°C and even up to 800°C), thermal spraying or cold spraying (around 300°C) processes; (3) fewer restrictions on the required vacuum level compared to PVD / CVD processes; (4) easier to scale up compared to PVD / CVD processes; (5) layer thickness is easily adjustable and can be greater; (6) the adhesion strength of one or more deposited layers is significantly higher than that obtained by 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 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 PVD / CVD, thermal spraying or cold spraying processes; and (9) the cost can be significantly lower than that of PVD / CVD, thermal spraying or cold spraying processes.

[0096] Compared to solution-based techniques, the anodizing process offers several advantages over other surface treatment technologies. For example, unlike other techniques for forming porous 3D structures (oxidation, etching, etc.), which require substrate pretreatment via anodizing (e.g., impregnation with polymer dispersions, which may further contain bioactive agents such as antibiotics), solution spraying, or solution drop processing, the AD process eliminates the need for substrate pretreatment. Furthermore, layers formed by the AD process can exhibit (less) surface irregularities, such as checkerboard patterns, which may be beneficial for applications such as the regeneration of living cells or tissues. In one embodiment, the surface irregularities may have obtuse angles, rather than the acute angles exhibited in needle-like or sheet-like morphologies formed by other surface processing techniques, reducing the likelihood of repairs required due to mechanical stresses generated during transport, packaging, and installation during clinical use. Unconstrained by theory, horizontal (pressed) bands of the composite material can be observed in cross-sectional views, 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 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 porous layers plays an important role in providing mechanical strength, load-bearing capacity, and protection of bioactive components. Furthermore, there is no need to transfer semi-finished or finished products during the deposition process, thus eliminating or avoiding the risk of contamination of semi-finished or finished products due to transfer (required in other types of deposition processes).

[0098] The inventors of this case were surprised to find that the AD process is advantageous in the fabrication of medical implant components, particularly BACL.

[0099] Therefore, this disclosure also relates to a method for preparing the medical implant component described herein, comprising the following steps: (i) Providing a biocompatible substrate (S) in the deposition chamber; (ii) Reduce the pressure in the sedimentation chamber to less than 2.5 Torr, for example, less than 2.35 Torr or less than 2.2 Torr; and (iii) A composite material of a biocompatible-bioactive complex material layer (BACL) is deposited via aerosol deposition (AD) to form a BACL on or over the biocompatible substrate, and

[0100] 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.

[0101] In one embodiment, this disclosure relates to a method for preparing the medical implant component described herein, comprising the following steps: (i) Providing a biocompatible substrate (S) in the deposition chamber; (ii) Reduce the pressure in the sedimentation chamber to less than 2.5 Torr, for example, less than 2.35 Torr or less than 2.2 Torr; (ii') A material for depositing an auxiliary dense layer (ADL) on the substrate via aerosol deposition (AD), and (iii') A composite material of BACL is deposited via aerosol deposition (AD) to form BACL above or on the ADL, and

[0102] The materials in the ADL include biocompatible metals or alloys, biocompatible ceramics, or any mixture thereof.

[0103] In various embodiments, steps (ii') and (iii') may be performed at least twice to form multiple biocompatible-bioactive composite material layers (BACL).

[0104] The biocompatible substrate may 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 polymers, biocompatible metals or alloys, and biocompatible ceramics. In one embodiment, the biocompatible polymer is selected from the group consisting of: polyetheretherketone (PEEK), polyethylene (PE), and polyvinyl chloride (PVC). In one embodiment, PE is low-density polyethylene (LDPE), high-density polyethylene (HDPE), or ultra-high molecular weight polyethylene (UHMWPE).

[0105] AD processes can be performed using known means and equipment. Equipment used for AD processes may include an aerosol generation unit (including, for example, one or more carrier gas sources, a mass flow controller (MFC), and an aerosol generation chamber), a deposition chamber (equipped with, for example, nozzles / atomizers, support plates, or platforms), and a vacuum system (e.g., a pump).

[0106] Various parameters of the AD process can be adjusted. Examples of such parameters include (but are not limited to) one or more types of carrier gases; flow rate; distance between the nozzle and the substrate support; angle of incidence of the aerosol flow towards the substrate; vacuum level in the deposition chamber; concentration, particle size, and type of one or more materials of the biocompatible protective coating in the aerosol flow; temperature in the chamber; temperature of the substrate; etc.

[0107] Examples of 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 portion thereof. The carrier gas flow rate can be from 300 to 1500 l / hr, for example, 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 range of values ​​consisting of the values ​​mentioned above as endpoints, such as 500 l / h to 650 l / h, 350 to 1300 l / h, etc.

[0108] The temperature during the AD process (for biocompatible substrates) can be controlled within the range of 5°C to 50°C, for example, 15°C to 45°C, preferably not exceeding 35°C.

[0109] The D50 of the material powder can range from 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 within any reasonable range of values ​​formed by the endpoints mentioned above, such as 0.5 μm to 3 μm, 0.8 μm to 5 μm, etc. The raw material can be pretreated with one or more processes, such as grinding, sieving, etc., to provide materials for deposition of one or more materials via the AD process.

[0110] Once the deposition of one or more biocompatible-bioactive composite material layers (BACL) (and, if applicable, auxiliary dense layers (ADL)) is completed, the product can be post-processed, such as by cleaning or shaping. [Example] []

[0111] The following examples are provided to enable those skilled in the art to better understand the invention, but are not intended to limit the scope of the invention. [Materials, Methods, and Test Models] []

[0112] The materials of the biocompatible-bioactive composite material layer include Si3N4, Al2O3, TiN (4N purity), and hydroxyapatite, which are available from Sigma-Aldrich. []

[0113] If necessary, the material can be further processed using UPE-Celanese GUR@1020-E.

[0114] The porosity of the layer can be measured using a Hitachi S-4300 FE-SEM. Thickness and roughness can be measured using a KLA-D500. Adhesion strength can be evaluated according to ASTM D3359.

[0115] Antimicrobial activity can be assessed using JIS Z 2801. Specifically, the sample or complex material layer (e.g., 5 cm × 5 cm) is washed and sterilized, then inoculated with a test suspension containing one or more target microorganisms. The inoculated sample / complex material layer is covered with a plastic film and incubated at a selected temperature and time, for example, at 35°C for 24 hours. After incubation, the sample / complex material layer is washed to calculate the microbial concentration. [Example] [1]

[0116] Silicon nitride (D50 approximately 1.8 μm, approximately 25 ml) and vancomycin powder (approximately 2 g) were used as composite materials; they were introduced into the nylon jar of a mill and uniformly mixed at 60 rpm for 3 hours under ambient conditions. The mixed powder was then placed in an aerosol generator for subsequent processes.

[0117] The Ti substrate was 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) apparatus; the chamber was evacuated to 2.2 Torr or lower. Next, a process gas (e.g., He) was introduced into an aerosol generator at an appropriate flow rate (e.g., 10 to 15 L / min) to generate a homogeneous aerosol of mixed powders, which was introduced into the chamber and uniformly sprayed onto the substrate to form a BACL. After the AD process was completed, the deposited substrate was recovered and cleaned with clean dry air (CDA) to remove residual powder from its surface, and then placed in a drying oven for storage and subsequent testing. [Example] [2]

[0118] Hydroxyapatite (HA) (D50 approximately 2.1 μm, approximately 25 ml) and vancomycin powder (approximately 2 g) were used as composite materials; they were introduced into the nylon canister of a grinder and uniformly mixed at 60 rpm for 3 hours under ambient conditions. The mixed powder was placed in a drying oven for storage and subsequent processes.

[0119] Pure HA powder is introduced into the container of the aerosol generator. Next, 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 the aerosol deposition (AD) apparatus; the chamber is evacuated to 2.2 Torr or lower. A process gas (e.g., He) is then introduced into the aerosol generator at an appropriate flow rate (e.g., 10 to 15 L / min) to generate a uniform aerosol of HA powder, which is introduced into the chamber and uniformly sprayed onto the substrate to form the ADL. After the ADL deposition is complete, the deposited substrate is recovered and cleaned with clean, dry air (CDA) to remove residual HA powder from its surface. The substrate is placed back into the chamber of the aerosol deposition (AD) apparatus; the chamber is evacuated to 2.2 Torr or lower. The HA powder is removed from the container of the aerosol generator, and a mixture of HA and antibiotic powder is introduced into the container. Next, a processing gas (e.g., He) is introduced into the aerosol generator at an appropriate flow rate (e.g., 10 to 15 liters / minute) to produce a homogeneous aerosol of the mixed powder of HA and antibiotics. This aerosol is then introduced into the chamber and uniformly sprayed onto the substrate to form BACL (on the ADL). After the BACL deposition is complete, the deposited substrate is recovered and washed with clean dry air (CDA) to remove residual powder from its surface, and then placed in a drying oven for storage and subsequent testing. [Example] [3 (] [Comparative] [)]

[0120] An implant sample with a polymeric material surface coating impregnated with antibiotics is provided as a comparative example in this paper. The Ti-6Al-4V substrate was then polished with sandpaper with grit numbers of 400, 600, ..., 1,500, and then immersed in a solution of HF:H₂SO₄ (1M:4M) for 5 minutes; the substrate was then cleaned with deionized water in an ultrasonic cleaner for 20 minutes to remove residual acid from the surface.

[0121] Next, the cleaned substrate was anionized by immersing it in a 0.2 M Ca(H₂PO₂)₂ solution (Alfa Aesar, Germany) for 5 minutes at 300 V and 100 mA / cm² (from a DC power supply). After treatment, the substrate was rinsed with deionized water for 5 minutes to remove residual anion solution and dried for subsequent use.

[0122] The treated substrate was immersed in a 5% dichloromethane solution of poly(D,L-lactide-co-glycolic acid) (PLGA) and 2 g vancomycin, and then extracted from the solution at a rate of 2 cm / min. The resulting sample was dried at ambient temperature for 30 minutes for subsequent testing. [Example] [4]

[0123] The samples obtained in Examples 1 to 3 were immersed in 50 mL of phosphate-buffered saline (PBS, 1X PBS, Gibco, Thermo Fisher Scientific, Waltham, USA) at 37°C and shaken at 30 rpm for 20 minutes. Next, the substrates were placed in 200 mL of fresh phosphate-buffered saline, and 5 mL samples were taken every 12 hours to measure antibiotic concentration. Antibacterial activity was also evaluated.

[0124] The characteristics and test results of the medical implant components in Examples 1 to 3 are listed in Table 1: Table 1 [feature] [Example 1] [Example 2] [Example 3] [(] [Comparative] Porosity of BACL 13% 17% - BACL thickness 11 μm 14 μm 23 μm Surface roughness 0.9 μm 1.02 μm 1.7 Adhesion strength to substrate 5B 5B 3B Drug release time (days) >10 >10 5~6 Staphylococcus aureus concentration (log CFU / ml) after 24 hours < 1 < 1 > 5×10 2 Time used for sample preparation Approximately 5 hours Approximately 6 hours Approximately 12 hours

[0125] The maximum drug release time of this invention is expected to be 15 to 23 days or even longer. The expected drug release is up to 2 mg (e.g., up to 1.7 mg, or at least 1 to 1.2 mg) in the first 12 hours, up to 1.4 mg (e.g., up to 1.2 mg, or at least 0.7 mg) in the following 36 hours (i.e., from the 12th to the 48th hour), and up to 0.8 mg (e.g., up to 0.7 mg, or at least 0.2 mg) after 48 hours.

[0126] This invention demonstrates significantly superior performance compared to 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, the FTIR spectra of the BACL of the samples in Examples 1 and 2 still showed vancomycin signals, indicating that vancomycin could still be released from the membrane after 10 days. In contrast, the antibiotic-loaded membranes obtained by the conventional polymer coating and direct impregnation method (Example 3) tended to deteriorate and even detach from the substrate under simulated human physiological conditions, and almost no vancomycin signals were observed in the FTIR spectra of the polymer membranes for samples obtained after 5 or 6 days of testing. Furthermore, the samples in Examples 1 and 2 passed the antibacterial activity test, but the sample in Comparative Example 3 failed the antibacterial activity test, as shown in Table 1 above.

[0127] Furthermore, compared to conventional polymer impregnation processes, the AD process can be performed using a simpler procedure because the powder of the composite material can be conveniently prepared by mixing without the need for liquid-based cleaning. However, conventional polymer impregnation processes require complex steps, including multiple transfers of the substrate, liquid-based cleaning, and drying.

[0128] In short, this disclosure provides methods and medical implant components that have various advantages over prior art, particularly simpler procedures, extended release time of bioactive components from the medical implant component, and greater component structural stability.

[0129] Those skilled in the art will 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 above, this application is intended to cover any such changes and modifications, provided that the changes or modifications or their equivalents fall within the scope defined by the appended claims.

Claims

1. A medical implant component comprising: (a) a biocompatible substrate (S), and (b) at least one biocompatible-bioactive composite material layer (BACL) located above or on the 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: biocompatible polymeric materials, 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 mixture thereof, and component (2): an organic bioactive ingredient, wherein component (2) in the BACL is present in an amount of 0.5 wt.% to 25 wt.% based on the total weight of the composite material.

2. The medical implant component of claim 1, wherein component (1) of the BACL is selected from the group consisting of: one or more oxides of aluminum, silicon, titanium and zirconium; one or more nitrides of aluminum, silicon, titanium and zirconium; one or more carbides of aluminum, silicon, titanium and zirconium; one or more oxide-nitrides of aluminum, silicon, titanium and zirconium; one or more oxide-carbides of aluminum, silicon, titanium and zirconium; one or more nitride-carbides of aluminum, silicon, titanium and zirconium; one or more oxide-nitride-carbides of aluminum, silicon, titanium and zirconium; calcium phosphate; hydroxyapatite; hydroxyapatite halide; hydroxyapatite carbonate; hydroxyapatite halide carbonate; and any mixture of the foregoing substances.

3. The medical implant component of claim 1, 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 assembly of claim 1, wherein the adhesive strength between the substrate and BACL is greater than 3B, as measured according to ASTM D3359.

5. The medical implant component of claim 1 has a surface roughness of 0.3 μm or higher.

6. The medical implant component of claim 1, wherein the BACL is formed from primary particles of the composite material with a D50 in the range of 0.1 μm to 10 μm.

7. The medical implant component of claim 1, wherein 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 mixture of the foregoing.

8. The medical implant component of claim 1, wherein component (2) in the BACL is present in an amount of 0.5 wt.% to 20 wt.% based on the total weight of the composite material.

9. A medical implant component as described in any of claims 1 to 8, further comprising an auxiliary compaction 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, which is selected from the biocompatible metals or alloys, biocompatible ceramics 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, wherein (i) the adhesive strength between the ADL and the substrate is at least 4B as measured by ASTM D3359, (ii) the adhesive strength between the ADL and the BACL is at least 4B as measured by ASTM D3359, or (iii) both (i) and (ii) are satisfied.

12. The medical implant component as claimed in claim 9, wherein the thickness variation of the ADL is less than 10%.

13. The medical implant component of claim 9, wherein the ADL has a porosity of less than 1%.

14. The medical implant component of claim 9, wherein the third biocompatible metal or alloy, biocompatible ceramic or any mixture thereof is different from the composition (1) of the composite material of the BACL.

15. The medical implant components described in claims 1 to 8 are part or all of an artificial joint, an insert related to an artificial joint, a brace, an intervertebral plate, a screw, an artificial bone plate, an intervertebral spacer, or a permanent or temporary anchoring device.

16. The medical implant assembly of claims 1 to 8, wherein the substrate has a surface roughness of at least 0.2 μm.

17. A method for preparing a medical implant component as claimed in any one of claims 1 to 16, 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 material layer (BACL) by aerosol deposition (AD) to form a BACL over or on the biocompatible substrate, 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.

18. The method of claim 17, further comprising a step (ii') following step (ii): (ii') depositing a material of an auxiliary dense layer (ADL) on the substrate via aerosol deposition (AD), wherein step (iii) is step (iii'): (iii') depositing a composite material of the BACL via aerosol deposition (AD) to form the BACL over or on the ADL, wherein 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 carried out using a carrier gas selected from the group consisting of: N2, O2, Ar, He, clean dry air (CDA) and any combination thereof.

20. The method of claim 17 or 18, wherein the AD is performed at a carrier gas flow rate of 300 to 1500 l / hr.

21. The method of claim 17 or 18, wherein the temperature of the substrate is in the range of 5°C to 50°C during the deposition.

22. The method of claim 17 or 18, wherein the primary particles of the powder of the BACL composite material, the primary particles of the powder of the ADL material, or both have a D50 in the range of 0.1 μm to 10 μm.

23. The method of claim 17 or 18, wherein the biocompatible substrate (S) is made of one or more materials selected from the group consisting of: biocompatible polymeric materials, biocompatible metals or alloys.

24. The method of claim 17 or 18, wherein the material of the ADL is different from the composition (1) of the composite material of the BACL.

25. The method of claim 17 or 18, wherein the substrate (S) is polished to exhibit a surface roughness of at least 0.2 μm.

26. The method of request item 17 or 18, wherein step (iii) or step (iii') is performed at least twice to form a plurality of BACLs.

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