Iodine-injected ultra-high molecular weight polyethylene

Abstract

The various embodiments disclosed relate to implants comprising crosslinked iodine-impregnated polyethylene. [Solution] In various embodiments, the implant can be fabricated by exposing polyethylene to an iodine source so that iodine is injected into the polyethylene. In various embodiments, a method for preventing microbial formation on or near the implant includes implanting a crosslinked iodine-injected implant containing polyethylene, where the iodine is gradually released from the implant after implantation.

Description

Technical Field

[0001] 〔Claiming Priority〕 This application claims the benefit of U.S. Provisional Patent Application No. 62 / 885,530, filed Aug. 12, 2019, the benefit of whose priority is hereby claimed and which is hereby incorporated by reference in its entirety.

Background Art

[0002] Ultra-high molecular weight polyethylene (UHMWPE) is the most widely used material for orthopedic implants that join joints, such as hip, knee, ankle, elbow, and shoulder joint replacements due to osteoarthritis. In particular, highly cross-linked UHMWPE is widely used, which is cross-linked using high-energy radiation such as gamma (γ)-rays or electron beams. Cross-linking significantly reduces the wear rate of UHMWPE and reduces the burden of polyethylene particles that can lead to osteolysis. In some implants, antioxidants are added to highly cross-linked UHMWPE to counter the burden of free radicals.

[0003] In UHMWPE implants, infections are one of the main causes of revision of joint replacements. As bacterial antibiotic resistance increases, it has become more difficult to deal with infections in the context of joint replacements.

Summary of the Invention

[0004] In various embodiments, the present invention provides an implant comprising polyethylene infused with iodine.

[0005] In various embodiments, the present invention provides a method of making an implant by exposing polyethylene to an iodine source such that iodine is infused into the polyethylene.

[0006] In various embodiments, the present invention provides a method for preventing microbial formation on or near an implant, including the implantation of a cross-linked iodine-impregnated implant containing polyethylene, wherein iodine is gradually released from the implant after implantation.

[0007] In some embodiments, the cross-linked iodine-impregnated polyethylene implant can reduce microbial formation on and near the implant due to the antibacterial effect of iodine.

[0008] In some embodiments, iodine directly injected into the polyethylene implant is not affected by fitting (meshing), in contrast to other antibacterial agents such as surface coatings.

[0009] In some embodiments, the injected iodine is released from the polyethylene by diffusion over time and can destroy microorganisms on and near the implant.

Brief Description of the Drawings

[0010] The drawings generally show, by way of illustration and not limitation, various embodiments discussed in the text.

[0011] [Figure 1] Figure 1 is a chart showing the oxidative index of the samples of Example 3 according to various embodiments.

[0012] [Figure 2] Figure 2 is a graph showing the wear characteristics of the samples of Example 4 according to various embodiments.

[0013] [Figure 3] Figures 3A - 3D are graphs showing the mechanical properties of the samples of Example 4 according to various embodiments.

[0014] [Figure 4] Figure 4 is a graph showing the impact strength of the samples of Example 4.

[0015] [Figure 5] Figure 5 is a graph showing the amount of iodine in the sample of Example 5. [Disclosure of the Invention]

[0016] Specific embodiments of the subject matter of the invention disclosed below will be referenced in detail. Some examples are partially shown in the accompanying drawings. The subject matter of the invention disclosed will be described in conjunction with the enumerated claims, but it will be understood that the illustrated subject matter is not intended to limit the claims to the subject matter of the invention disclosed.

[0017] Values ​​expressed in range format should be interpreted flexibly, including not only the numerical limits explicitly indicated as the range boundaries, but also all individual numerical values ​​or subranges within that range, as if each numerical value and subrange were explicitly indicated. For example, the range "approximately 0.1% to approximately 5%" or "approximately 0.1% to approximately 5%" should be interpreted to include not only the range from approximately 0.1% to approximately 5%, but also individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges within the specified range (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). The expression "approximately X to Y" is synonymous with "approximately X to approximately Y" unless otherwise specified. Similarly, the statement "approximately X, Y, or approximately Z" is synonymous with "approximately X, approximately Y, or approximately Z" unless otherwise specified.

[0018] In this specification, the terms “a,” “an,” or “the” are used to include one or more unless the context explicitly indicates otherwise. The term “or” is used to mean “or” in a non-exclusive sense unless otherwise specified. The expression “at least one of A and B” is synonymous with “A, B, or A and B.” Furthermore, it should be understood that any other expressions or usages used herein that are not otherwise defined are for illustrative purposes only and not for limitation. The use of section headings is intended to aid the understanding of this specification and should not be construed as a limitation. Information related to a section heading may occur both within and outside of that particular section. Furthermore, all publications, patents, and patent documents referenced herein are incorporated herein in whole by reference as if they were incorporated individually by reference. In the event of any conflicting usage between this specification and a document thus incorporated by reference, the usage in the incorporated reference shall be deemed to complement the usage herein. In the event of an irreconcilable conflict (inconsistency), the usage herein prevails.

[0019] In the manufacturing methods described herein, the steps may be performed in any order without departing from the principles of the invention, unless the temporal or operational order is explicitly stated. Furthermore, the specified steps may be performed simultaneously unless explicitly stated in the language of the claims to be performed separately. For example, the step described in the claim to perform X and the step described in the claim to perform Y may be performed simultaneously in a single operation, and the resulting method falls within the literal scope of the method described in the claims.

[0020] As used herein, the term “about” encompasses the precisely stated value or range, taking into account some degree of variability in a given value or range, such as within 10%, 5%, or 1% of the stated limit for the stated value or range.

[0021] As used herein, the term “substantially” means the majority or most, for example, at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%.

[0022] As used herein, the term “organic group” refers to any functional group containing carbon. Examples include oxygen-containing groups such as alkoxy groups, aryloxy groups, aralkyloxy groups, and oxo(carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylate salts, and carboxylic acid esters; sulfur-containing groups such as alkyl and aryl sulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, O(O)R, C(O)N(R)2, O(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R, (CH2) 0-2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N( R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1~C 100 ) contains hydrocarbyl, where R can be hydrogen (in examples containing other carbon atoms) or a carbon-based part, in which case the carbon-based part may be substituted or unsubstituted.

[0023] As used herein in relation to molecules or organic groups, the term “substitution” refers to a state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. As used herein, the terms “functional group” or “substitution” refer to a group that is substituteable to or substituted in a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I), oxygen atoms in carboxyl groups including hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxylic acid esters, sulfur atoms in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in a variety of other groups. Non-limiting examples of substituents that can bond to substituted carbon (or other) atoms include F, Cl, Br, I, OR, OCO(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OCO(O)R, C(O)N(R)2, OCO(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R, (CH2) 0-2 Examples include N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R. Here, R can be a hydrogen or carbon-based part. For example, R can be hydrogen, (C1~C 100These may be hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl. Alternatively, two R groups bonded to a nitrogen atom or adjacent nitrogen atoms can form a heterocyclyl with the nitrogen atom or multiple atoms.

[0024] As used herein, the term “alkyl” refers to linear and branched alkyl and cycloalkyl groups having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbon atoms, or, in some embodiments, 1 to 8 carbon atoms. Examples of linear alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched alkyl forms. Typical substituted alkyl groups can be substituted once or multiple times with any of the groups described herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0025] As used herein, the term “solvent” refers to a liquid capable of dissolving solids, liquids, or gases. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0026] As used herein, the term “air” generally refers to a mixture of gases at ground level having a composition nearly identical to the innate composition of gases emitted from the atmosphere. In some cases, air is taken in from the surrounding environment. Air has a composition of approximately 78% nitrogen, 21% oxygen, 1% argon, 0.04% carbon dioxide, and small amounts of other gases.

[0027] As used herein, the term "room temperature" refers to a temperature between approximately 15°C and 28°C.

[0028] As used herein, the term “coating” refers to a continuous or discontinuous layer of material on a coated surface, the material layer may penetrate the surface and fill areas such as pores, and the material layer may have any three-dimensional shape, including planar or curved surfaces. In one example, a coating can be formed on one or more surfaces, which may be porous or non-porous, by immersion in a bath of coating material.

[0029] As used herein, the term “surface” refers to the boundary or side of an object, which may have any three-dimensional shape, such as a plane, curve, or angle, and which may be continuous or discontinuous. The term “surface” generally refers to the outermost boundary of an object that has no depth, but when the term “pore” is used in relation to a surface, the term surface refers to both the openings of the surface and the depth to which the pores extend below the surface into the substrate.

[0030] Summary of the Invention Microorganisms are commonly found on and near joint implants. Revisions to joint replacement surgery are frequently performed due to infections. However, currently, microorganisms do not have resistance to iodine, unlike, for example, antibiotics. Iodine has a long history in the medical field as a preservative and is already present in the human body for thyroid function.

[0031] Iodine has a high antibacterial effect. When iodine is injected into polymer implants such as polyethylene implants, the iodine diffuses into the human body over time, making it possible to combat microbial accumulation, biofilm formation, and infection. For example, iodine is released into the joint cavity where the polyethylene implant is located, killing the microorganisms that cause infection. Therefore, iodine-injected polyethylene implants can be used both preventively and for the treatment of infections.

[0032] In various embodiments, iodine-impregnated polyethylene implants and methods for producing them are disclosed herein. The implants may be, for example, ultra-high molecular weight polyethylene (UHMWPE), or highly crosslinked polyethylene (HXPE) into which an iodine solution such as an iodophore (e.g., povidone-iodine) has been impregnated via a diffusion mechanism, or other aqueous iodine solutions such as solvent-containing solutions. In one example, Lugol's solution may be used.

[0033] After injection, iodine can be retained in the amorphous regions of the polyethylene implant. Once the implant enters the body, the iodine can escape from the polyethylene within the body and diffuse into the surrounding area of ​​the implant. This enables antimicrobial protection by killing microorganisms in the joint cavity and within the implant. Iodine can act antimicrobially, for example, by attacking proteins in microorganisms.

[0034] Iodine-injected polyethylene implants In various embodiments, the implant may include uncrosslinked or crosslinked iodine-impregnated polyethylene. The iodine may be present, for example, in polyethylene at a concentration of about 5 to about 3000 μg / cm³. 3 (For example, approximately 200 to 1000 μg / cm³) 3 It is possible to have a concentration of ) . In some embodiments, iodine is uniformly distributed throughout the polyethylene. In some embodiments, the polyethylene is saturated with iodine. In some embodiments, a portion of the polyethylene is selectively treated with iodine, while other portions are not treated with iodine.

[0035] Polyethylene implant materials may include, for example, ultra-high molecular weight polyethylene (UHMWPE), ultra-low molecular weight polyethylene, high-density polyethylene, high molecular weight polyethylene, high-density crosslinked polyethylene, medium-density polyethylene, low-density polyethylene, linear low-density polyethylene, ultra-low-density polyethylene, branched polyethylene, or combinations thereof.

[0036] For example, UHMWPE is a unique form of ultra-high molecular weight polyethylene, with commercial-grade materials typically having molecular weights in the range of 2 million to 7 million. Commercial polyethylene typically has molecular weights in the range of 50,000 to 100,000 (50,000 to 100,000), which is less than 1 / 25th of that value. UHMWPE is most widely used in orthopedic implants that join joints, such as replacements for hip, knee, ankle, elbow, and shoulder joints affected by osteoarthritis.

[0037] The implant material may contain UHMWPE. Any suitable ratio of the implant material may be approximately 1% to 100% by weight, approximately 90% to 100% by weight, or less than approximately 1% by weight, or approximately 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or more by weight of UHMWPE. UHMWPE may form a homogeneous or heterogeneous mixture with the other components of the implant material.

[0038] The implant material may have any appropriate amount of voids within it, which are portions of the implant material occupied by porous regions (e.g., not occupied by solids or liquids). The implant material may have voids of about 0.001 to about 80 vol%, about 1 to about 50 vol%, about 1 to about 20 vol%, about 5 to about 15 vol%, or less than about 0.001 vol%, or about 0.005 to about 15 vol%, or voids of 0.005 to about 15 vol%, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, or about 50 vol%. The voids in the implant material may have any appropriate distribution within the implant material. In some embodiments, the voids in the implant material can be distributed substantially uniformly.

[0039] UHMWPE is a semicrystalline linear homopolymer of ethylene, and in some embodiments, it can be produced by stereospecific polymerization using a Zieglar-Natta catalyst at low pressure (6–8 bar) and low temperature (66–80°C). The synthesis of UHMWPE yields a fine granular powder. Its molecular weight and distribution can be controlled by processing parameters such as temperature, time, and pressure. The molecular weight of UHMWPE is generally at least about 2,000,000 g / mol. Suitable UHMWPE materials for use as raw materials can be in the form of powder or powder mixture. Examples of suitable UHMWPE materials include GUR® 1020 and GUR® 1050, available from Ticona Engineering Polymers.

[0040] In addition to UHMWPE, the implant material may include other suitable components. In certain embodiments, UHMWPE can be combined with another crosslinkable polymer. The crosslinkable polymer may be any polymer that can be crosslinked using radiation, chemical crosslinking agents, or physically crosslinked under suitable conditions.In some examples, polymers include, for instance, acrylonitrile butadiene styrene (ABS) polymer, acrylic polymer, celluloid polymer, cellulose acetate polymer, cycloolefin copolymer (COC), ethylene vinyl acetate (EVA) polymer, ethylene vinyl alcohol (EVOH) polymer, fluororesin, ionomer, acrylic / PVC alloy, liquid crystal polymer (LCP), polyacetal polymer (POM or acetal), polyacrylate polymer, polyacrylonitrile polymer (PAN or acrylonitrile), polyamide polymer (PA or nylon), polyamide-imide polymer (PAI), polyaryl ether ketone polymer (PAEK or ketone), polybutadiene polymer (PBD), polybutylene polymer (PB), polybutylene terephthalate polymer (PBT), polycaprolactone polymer (PCL), polychlorotrifluoroethylene polymer (PCTFE), polyethylene terephthalate polymer (PET), polycyclohexylene dimethylene terephthalate polymer (PCT), and These can be thermoplastic polymers such as recarbonate polymers, polyhydroxyalkanoate polymers (PHA), polyketone polymers (PK), polyester polymers, polyethylene polymers (PE), polyetheretherketone polymers (PEEK), polyetherketoneketone polymers (PEKK), polyetherimide polymers (PEI), polyethersulfone polymers (PES), chlorinated polyethylene polymers (PEC), polyimide polymers (PI), polylactic acid polymers (PLA), polymethylpentene polymers (PMP), polyphenylene oxide polymers (PPO), polyphenylene sulfide polymers (PPS), polyphthalamide polymers (PPA), polypropylene polymers, polystyrene polymers (PS), polysulfone polymers (PSU), polytrimethylene terephthalate polymers (PTT), polyurethane polymers (PU), polyvinyl acetate polymers (PVA), polyvinyl chloride polymers (PVC), polyvinylidene chloride polymers (PVDC), and styrene-acrylonitrile polymers (SAN).In addition to UHMWPE, exemplary types of polyethylene include, for example, ultra-low molecular weight polyethylene (ULMWPE), high molecular weight polyethylene (HMWPE), high-density polyethylene (HDPE), high-density cross-linked polyethylene (HDXLPE), cross-linked polyethylene (PEX or XLPE), medium-density polyethylene (MDPE), low-density polyethylene (LDPE), linear low-density polyethylene (LLDPE), and very low-density polyethylene (VLDPE).

[0041] In some cases, implant materials can include polypropylene. Polypropylene would be particularly desirable if the final product is a mesh, stent, breast augmentation material, suture material, or other medical device. In one alternative, polypropylene (or other polymers) can be used as one layer in a multilayer medical device. Exemplary polypropylenes include homopolymer polypropylene, block copolymer polypropylene, and random copolymer polypropylene.

[0042] In some embodiments, the implant material may include one or more suitable additives that impart desired physical or chemical properties. Exemplary suitable additives include radiopaque materials, antimicrobial materials such as silver ions, antibiotics, and microparticles and / or nanoparticles that perform various functions. Preservatives, colorants, and other conventional additives may also be used.

[0043] In various embodiments, iodine-injected polyethylene implants may contain antioxidants. The antioxidant may be present in an amount of about 0.01% to about 5.0% by weight of the polyethylene implant (for example, about 0.05% to about 0.50% by weight of the polyethylene implant). In some embodiments, the antioxidant can be uniformly distributed within the polyethylene.

[0044] Iodine-injected polyethylene implants can retain properties related to mechanical strength despite the iodine injection. For example, in pin-on-plate abrasion analysis, polyethylene can have an average cumulative mass loss of approximately 0.001 g to 0.005 g over abrasion analyses spanning approximately 10,000 to 1,300,000 cycles (e.g., an average cumulative mass loss of approximately 0.001 g to 0.003 g over abrasion analyses spanning approximately 20,000 to 1,200,000 cycles).

[0045] Similarly, iodine-impregnated polyethylene implants can maintain an elastic modulus of approximately 250 MPa to approximately 400 MPa (e.g., approximately 300 MPa to approximately 350 MPa) and an elongation at break of approximately 475% to approximately 515%.

[0046] In some embodiments, the medical implant may be an orthopedic implant. In various embodiments, the medical implant may constitute or be part of a bearing (bearing portion) of an artificial hip joint, hip liner, knee joint, knee liner, intervertebral disc replacement, shoulder, elbow, foot, ankle, finger, mandible, or artificial heart.

[0047] Implant compression Disclosed herein are methods for injecting iodine into polyethylene implants in various embodiments. These methods may involve exposing polyethylene to an iodine source, such as an iodine solution, so that iodine is injected into the polyethylene. The solution may include, for example, an iodine solution such as an iodophor (e.g., povidone-iodine), or other aqueous iodine solutions such as solvent-containing solutions. In one example, Lugol's solution can be used. The polyethylene may be, for example, in resin form, partially compacted form, or fully compacted form.

[0048] Before injection, polyethylene implants can be prepared and consolidated. Before consolidation, polyethylene can be mixed with various materials. For example, in some embodiments, the implant material (including, for example, UHMWPE) can be prepared by a method that includes blending polyethylene powder with other suitable materials, such as a blend with another polymer or a blend with an antioxidant. Such processes may include physical mixing, solvent-assisted mixing, solvent-assisted mixing (e.g., CO2) under supercritical temperature and pressure conditions, and ultrasonic mixing.

[0049] Consolidation can be performed after materials have been blended or prepared. Consolidation shapes and forms the material for implants, determining the shape, size, density, mechanical properties, and other attributes of the implant material. Consolidation can include, for example, cold sintering, molten consolidation, or a combination thereof, in addition to other consolidation techniques known in the art. Cold sintering is a method that does not use melting, while molten consolidation involves melting and shaping polyethylene material.

[0050] In some embodiments, polyethylene powder can be sintered at low temperatures to provide an implant material. In this case, the implant material undergoes virtually no melting. The implant material may be a solid formed before a compaction step that involves melting, for example. For example, the implant material may be a solid formed from UHMWPE powder, in which virtually no melting occurs during the formation of the implant material.

[0051] In some embodiments, the implant material may be a low-temperature sintered material. This method may include low-temperature sintered polyethylene powder and any additional components to form the implant material. Low-temperature sintering generally involves applying sufficient pressure under low-shear conditions to fuse the boundaries of spherical powder polyethylene particles together. Low-temperature sintering may include any suitable sub-melting compaction technique such as compression molding, direct compression molding, ram extrusion, hot isostatic pressing, ram extrusion, high-pressure crystallization, injection molding, and combinations thereof.

[0052] Cold sintering is a method that does not dissolve polyethylene. Cold sintering can bring polyethylene to any suitable maximum temperature, e.g., about 30°C, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or about 150°C, as long as substantially no dissolution of the polyethylene occurs.

[0053] If low-temperature sintering can be carried out in air, the initial compression of the polyethylene powder can reduce the air content, and more importantly, the oxygen content, thereby reducing the oxidation of polyethylene during compaction and during the later stages of the method. In some embodiments, low-temperature sintering can be carried out under near-inert conditions, where the air is replaced by an unreactive gas such as nitrogen or argon, or under vacuum and reduced pressure.

[0054] In some embodiments, the implant material can be melt-consolidated. Melt consolidation can include any suitable melt consolidation procedure. Melt consolidation can include consolidation techniques above any suitable melting point, such as compression molding, direct compression molding, ram extrusion, hot isostatic pressing, ram extrusion, high-pressure crystallization, injection molding, and combinations thereof. Molten consolidation can include any appropriate pressure, such as approximately 20 psi to 250,000 psi, approximately 100 psi to approximately 100,000 psi, approximately 2,000 to approximately 10,000 psi, or approximately 100 psi or less, or approximately 200 psi, 300, 500, 750, 1,000, 1,500, 2,000, 2,500, 5,000, 7,500, 10,000, 15,000, 20,000, 25,000, 50,000, 75,000, 100,000, 150,000, 200,000, or approximately 250,000 psi or more.

[0055] Generate enough heat to melt polyethylene. For example, by melt consolidation, the minimum temperature of polyethylene can be about 60°C, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 250, 275, or about 300°C or higher, as long as the polyethylene melts.

[0056] Molten consolidation can be carried out in air, or under near-inert conditions where the air is replaced by an inert gas such as nitrogen or argon, or under vacuum or reduced pressure.

[0057] additives In various embodiments, the present invention provides a method for adding one or more antioxidants, such as vitamin E, to polyethylene before injecting iodine. Suitable antioxidants are described in detail above.

[0058] As shown in the following sequence, the oxidation of polyethylene can occur via the free radical pathway, making antioxidants useful for implants. RH + IN → R · Start R· + O2 → ROO· ROO· + RH → ROOH + R· propagation ROOH → RO· + HO· RO· + RH → ROH + R· Chain branching HO· + RH → HOH + R· ROO· (RO· etc.) → Inert product Termination ROO· + AH → ROOH + A· RO· + AH → ROH + A· Inhibition (Stabilization) HO· + AH → HOH + A·

[0059] In the sequence described above, RH is a polymer (e.g., polyethylene such as UHMWPE), IN is an initiator (e.g., irradiation), and AH is an inhibitor (e.g., an antioxidant that scavenges free radicals).

[0060] Antioxidants include, for example, tocopherol, tocopherol phosphite, tocotrienol, vitamin E, vitamin E acetate, vitamin E phosphite, rosemary oil, pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), dimethyl butanediate / 4-hydroxy-2,2,6,6-tetramethyl-1-piperidineethanol copolymer, tannic acid, bilberry extract, vitamin C, carotene, flavonoids, isoflavonoids, neoflavonoids, lignin, kinin, ubiquinone, vitamin K1, metals, glutathione, propyl gallate, octyl gallate, lauryl gallate, resveratrol, rosmarinic acid, rutin, 5-aminosalicylic acid, butylated hydroxyanisole, butylated hydroxytoluene, phenolic compounds, and monomeric or polymeric hindered amine stabilizers.

[0061] In various embodiments, the antioxidant may be a suitable free radical scavenger, such that the antioxidant can neutralize free radicals before they react with oxygen to form oxidized species. The antioxidant may be any suitable antioxidant that enables the formation of implants containing UHMWPE that are resistant to oxidation, such as melt-stabilized materials containing UHMWPE that have little or no oxide layer when melt-stabilized in an oxygen-containing environment. Antioxidants or a combination of antioxidants may be included in any suitable weight percent of the liquid composition, for example, about 0.01% to about 100% by weight, about 1% to about 100% by weight, about 5% to about 100% by weight, about 0.01% or less by weight of the liquid composition, or about 0.1% by weight, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9, 99.99, or about 99.999% or more by weight of the composition. One or more antioxidants may include any suitable weight % of a UHMWPE-containing material, such as a solid material injected with an antioxidant containing UHMWPE, a melt-consolidated material containing UHMWPE, a preheating material containing UHMWPE, or an irradiated material containing UHMWPE in an amount of about 0.01% to about 20% by weight, about 0.1% to about 5% by weight, about 0.01% or less by weight, or about 0.05% by weight, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, or about 20% or more by weight of UHMWPE-containing melt-stabilized material.

[0062] In various embodiments, antioxidants include tocopherol, tocopherol phosphite (tocopherol containing a phosphite protecting group), tocotrienol, vitamin E, vitamin E acetate, Irganox® 1010 [pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate)], Tinuvin® 622LD [dimethyl butanediate / 4-hydroxy-2,2,6,6-tetramethyl-1-piperidineethanol copolymer], tannic acid, bilberry extract, vitamin C (e.g., ascorbyl palmitate or other lipid-soluble forms), carotene (e.g., vitamin A, lycopene), flavonoids (e.g., flavonoids). These may include labonol, isoflavonoids, neoflavonoids, lignin (e.g., enterodiol), quinine, ubiquinone (e.g., coenzyme Q10), vitamin K1, metals (e.g., selenium), glutathione, propyl gallate, octyl gallate, lauryl gallate, resveratrol, rosmarinic acid, rutin, 5-aminosalicylic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), phenolic compounds (e.g., t-butylhydroquinone), and monomeric or polymeric hindered amine stabilizers [e.g., derivatives of 2,2,6,6-tetramethylpiperidine-1-yl, e.g., 2,2,6,6-tetramethylpiperidine-1-yl]oxidanil or TEMPO]. In some embodiments, the antioxidant may be one of the following: vitamin E, vitamin E acetate, vitamin E phosphite (vitamin E containing a phosphite-type protecting group), pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), dimethyl butanediate / 4-hydroxy-2,2,6,6-tetramethyl-1-piperidineethanol copolymer, tannic acid, rosemary oil, and bilberry extract.In various embodiments, vitamin E phosphite or tocopherol phosphite can be used, which can provide vitamin E or tocopherol, respectively, by deprotection using suitable deprotection means such as hydrolysis (e.g., exposure to water containing any acid or base).

[0063] For example, the antioxidant can be a compound of formula (I) or (Ib)

Chemical formula

Chemical formula

Chemical formula

[0064] As used herein, "vitamin E" (for example, alone or as a derivative such as vitamin E acetate) means racemic α-tocopherol, RRR-α-tocopherol, SRR-α-tocopherol, SSR-α-tocopherol, SRS-α-tocopherol, SSS-α-tocopherol, RSR-α-tocopherol, RRS-α-tocopherol, RSS-α-tocopherol, racemic β-tocopherol, RRR-β-tocopherol, SRR-β-tocopherol, SSR-β-tocopherol, SRS-β-tocopherol, SSS-β-tocopherol, RSR-β-tocopherol, RRS- It may be β-tocopherol, RSS-β-tocopherol, racemic γ-tocopherol, RRR-γ-tocopherol, SRR-γ-tocopherol, SSR-γ-tocopherol, SRS-γ-tocopherol, SSS-γ-tocopherol, RSR-γ-tocopherol, RRS-γ-tocopherol, RSS-γ-tocopherol, racemic δ-tocopherol, RRR-δ-tocopherol, SRR-δ-tocopherol, SSR-δ-tocopherol, SRS-δ-tocopherol, SSS-δ-tocopherol, RSR-δ-tocopherol, RRS-δ-tocopherol, and RSS-δ-tocopherol.

[0065] Tocopherols can have the following structures: [ka] Variable R 1 , R 2 , and R 3 Each of these can be independently hydrogen, substituted, or unsubstituted (C1~C 10 ) alkyl, and substituted or unsubstituted (C1~C 10 ) Selected from alkenyls. The stereochemistry of tocopherol can be a racemic mixture or at least one of RRR, SRR, SSR, SRS, RSR, RRS, RSS and SSS isomers. In some embodiments, R 1 , R 2 , and R 3 These are each methyl and other (C1~C) 10) is alkyl (e.g., α-tocopherol). In some embodiments, R 1 and R 3 These are each methyl and other (C1~C) 10 ) is alkyl, and R 2 R is hydrogen (β-tocopherol). In some embodiments, R 2 and R 3 These are each methyl and other (C1~C) 10 ) is alkyl, and R 1 R is hydrogen (γ-tocopherol). In some embodiments, R 1 and R 2 Each of them is hydrogen, and R 3 (C1~C) 10 It is alkyl (δ-tocopherol).

[0066] Tocotrienols can have the following structures. [ka] Variable R 1 , R 2 , and R 3 Each of these can be independently hydrogen, substituted, or unsubstituted (C1~C 10 ) alkyl, and substituted or unsubstituted (C1~C 10 ) Selected from alkenyls. The stereochemistry of the tocotrienol can be a racemate or at least one of the R and S isomers. In some embodiments, R 1 , R 2 and R 3 These are each methyl and other (C1~C) 10 ) is alkyl (e.g., α-tocotrienol). In some embodiments, R 1 and R 3 These are each methyl and other (C1~C) 10 ) is alkyl, and R 2 R is hydrogen (β-tocotrienol). In some embodiments, R 2 and R 3 These are each methyl and other (C1~C) 10 ) is alkyl, and R1 R is hydrogen (γ-tocotrienol). In some embodiments, R 1 and R 2 Each of them is hydrogen, and R 3 (C1~C) 10 (δ-tocotrienol) is alkyl. Tocopherols or tocotrienols can be natural or synthetic.

[0067] Methods for adding antioxidants include obtaining or providing implant materials containing polyethylene. These methods may include coating the implant material with a liquid composition or embedding it instead. These methods may also include melt-compacting a solid material injected with antioxidants to provide a melt-compacted material.

[0068] Methods for adding antioxidants to polyethylene may include any appropriate physical operations (e.g., cold sintering, coating, melt compaction, preheating, irradiation, or melt stabilization) before, during, or after any appropriate step of the method, such as molding, compression, compaction, material removal, or other processing, to provide the desired shape, part size, or other physical attributes, and to make the part suitable for its intended use.

[0069] In some embodiments, one or more agents, such as bioactive agents, can be added to the material. Such additions can be achieved at any stage of preparation, but may be preferable after any heat treatment to reduce the possibility of deactivation of the bioactive agents. Exemplary agents include antibiotics, steroids, drugs (e.g., analgesics), growth factors such as osteogenic proteins, osteocytes, osteoclasts or other cells, vitamins, chondroitin, glucosamine, glycosaminoglycans, phosphoenolpyruvic acid, ATP, high-energy phosphate compounds such as 5'-AMP, and other small molecule biological agents or other chemical or biological agents. In some examples, stem cells can be loaded onto polyethylene-containing materials, and such materials can function as scaffolds that allow for the growth and differentiation of bone or cartilage within a polymer framework. The presence of antioxidants in polyethylene-containing materials (e.g., via at least one of mixing with UHMWPE powder and coating the implant material) can also act to prevent the disintegration of the polymer scaffold in its environment of use and provide oxidative protection to the bioactive agents or stem cells loaded onto the scaffold.

[0070] Irradiation of implants Compacted polyethylene implants can be irradiated before or after injection. Irradiation may include irradiation to induce crosslinking in the polyethylene implant after compaction. Alternatively or additionally, the implant may be irradiated after injection. Irradiation can be carried out, for example, by electron beam or gamma ray irradiation. Generally, irradiation can be carried out at temperatures, for example, about 60°C to about 300°C, which results in the induction of crosslinking. In some cases, irradiation to induce crosslinking can be carried out at temperatures that do not melt the polyethylene. Irradiation can be carried out with a total irradiation dose, for example, about 1 kGy to about 100,000 kGy.

[0071] In some embodiments, this method may include preheating the molten-consolidated material before irradiation for crosslinking. In other embodiments, preheating does not occur before irradiation for crosslinking (e.g., the consolidated material is at approximately ambient or room temperature when irradiation begins). In some embodiments, the irradiation step to induce crosslinking may be performed immediately after consolidation, for example, while the consolidated material has not yet completely cooled, so that the material can be effectively preheated at the time of irradiation to induce crosslinking.

[0072] In some embodiments, preheating may involve heating the material to a temperature higher than room temperature and below or above the melting point of polyethylene or a mixture of polyethylene and other components, for example, about 50°C to about 110°C, or below about 50°C, or about 55°C, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 140, 145, or above about 150°C, so that the material has a preheated temperature at the start of irradiation.

[0073] The crosslinking irradiation can be any suitable irradiation. This irradiation can be visible light, infrared, ultraviolet, electron beam, gamma ray, or X-ray radiation. When ionizing radiation is used to carry out the crosslinking reaction, the radiation sources include atomic piles, resonant transformer accelerators, van de Graaff electron accelerators, linac electron accelerators, betatrons, synchrotrons, cyclotrons, etc. The radiation from these sources generates ionizing radiation such as electrons, protons, neutrons, deuterium, gamma rays, X-rays, alpha particles, and beta particles. When ionizing radiation is used, sufficient dose rates and / or absorbed doses can be used to induce and / or control the degree of crosslinking. In some embodiments, during irradiation, the temperature of the polyethylene or a mixture of polyethylene and other components can be maintained below its melting point.

[0074] In some embodiments, the temperature of polyethylene or a mixture of polyethylene and other components can be raised above its melting point during irradiation to induce crosslinking. In various embodiments, the temperature can be raised during irradiation, or the temperature can be maintained at about 60°C, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 250, 275, or about 300°C or higher.

[0075] In some embodiments, polyethylene or a mixture of polyethylene and other components may be preheated to a temperature, for example, above room temperature and below or above its melting point, before irradiation. In various embodiments, polyethylene or a mixture of polyethylene and other components may be preheated to a temperature below its melting point, and then irradiated while maintaining the temperature of the preheated polyethylene or the mixture of polyethylene and other components below its melting point.

[0076] In various embodiments, the crosslinking-inducing irradiation, such as electron beam irradiation or gamma ray irradiation, is approximately 1 kGy to approximately 100,000 kGy, 10 kGy to approximately 1,000 kGy, approximately 50 kGy to approximately 500 kGy, 50 kGy to approximately 300 kGy, or approximately 1 Use a total dose of kGy or less, or approximately 5, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 750, 1,000, 1,250, 1,500, 1,750, 2,000, 2,500, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 20,000, 25,000, 50,000, 75,000, or approximately 100,000 kGy or more. In various embodiments, irradiation includes using dose rates of approximately 0.001 mGy / h to approximately 500 MGy (megagray) / h, approximately 1 mGy / h to approximately 50 MGy / h, or less than or equal to approximately 0.001 mGy / h, or approximately 0.005 mGy / h, 0.01, 0.05, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, or more than approximately 500 MGy / h.

[0077] In some embodiments, irradiation to induce crosslinking can be carried out, for example, in the presence of a crosslinking polymer. The crosslinking polymer may induce crosslinking within polyethylene. The crosslinking polymer may be, for example, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, or a combination thereof. Alternatively, the degree of crosslinking can be reduced by the presence of other reagents that can scavenge free radicals.

[0078] Additional polymers can be blended with the polyethylene-containing material before, during, or after any suitable step of the method (e.g., compaction, preheating, irradiation, and injection). In one embodiment, tribological components such as metal and / or ceramic joint components, and / or pre-assembled bipolar components can be bonded to the polyethylene-containing material. In other embodiments, metal backing (e.g., plates or shields) can be added. In further embodiments, prismatic metals, fiber metals, and Surmesh can be used. TM Surface components such as (trademark) coatings, meshes, spongy titanium, and / or metal or polymer coatings can be added to or bonded to polyethylene-containing materials. Radioactive markers or radioactive pacifiers such as balls, wires, bolts, or pegs (plugs) made of tantalum, steel, and / or titanium can be added. Locking features such as rings, bolts, pegs, snaps, and / or cement / adhesives can be added. These additional components can be used to design sandwich-type implants, radioactively marked implants, metal-backed implants to prevent direct contact with bone, and implants with functional growth surfaces and / or locking features.

[0079] In some embodiments, the implant can be irradiated additionally or alternatively after injection. Compared to irradiation that induces crosslinking, this step can be performed after iodine has been injected into the implant and does not necessarily induce crosslinking in the implant material. In this case, irradiation can be performed, for example, by electron beam or gamma ray irradiation. Generally, irradiation can be performed at temperatures, for example, from about 60°C to about 300°C.

[0080] Implant injection It is possible to inject iodine into polyethylene implants (or, alternatively, to mix iodine into polyethylene before molding). In some embodiments, polyethylene can be saturated with iodine. Free iodine is attractive for promoting the antimicrobial release of iodine in vivo. Povidone-iodine is an iodine-containing polyvinyl polymer that can make iodine water-soluble. Povidone-iodine is a chemical complex of povidone (PVP), hydrogen iodide, and elemental iodine, and its chemical structure is as follows: [ka] Povidone-iodine is soluble in water, ethyl alcohol, isopropyl alcohol, polyethylene glycerol, and glycerol, among other solvents. Povidone-iodine gradually releases free iodine into solution, as shown in the following formula.

number

[0081] Free iodine kills eukaryotic or prokaryotic cells through lipid iodation and oxidation of cytoplasmic and membrane compounds. Specifically, free iodine can act as an antimicrobial agent against bacteria, fungi, protists, and viruses. Microorganisms do not currently develop resistance to free iodine.

[0082] Generally, providing anti-infective activity to medical devices or instruments (or other auxiliary materials) that use iodine can be achieved by exposing the medical device to iodine and transferring (delivering) the iodine to a polymer-type medical device. For example, polymers such as the polyethylene implant material discussed herein can be treated in any form, such as resin, powder, or solidified form.

[0083] In some embodiments, povidone-iodine can be directly mixed into the powdered polyethylene material before molding. However, blending iodine into the resin or polyethylene powder may affect the solidification of the resin. Therefore, it is preferable to inject iodine into the implant material in a compacted form (e.g., compacted sheet, bar, extruded, or net).

[0084] The minimum iodine concentration required to achieve antimicrobial activity is approximately 2 ppm of povidone-iodine. Therefore, the concentration of the povidone-iodine solution used herein for injecting polyethylene implants can be, for example, greater than 0.002 mg / mL.

[0085] In some embodiments, the source of iodine may be an iodine-containing solution, such as a povidone-iodine solution, which makes the iodine water-soluble. In the case of a povidone-iodine solution, the concentration may be, for example, about 0.1% to about 10.0% by weight of povidone-iodine (for example, about 1.0% to about 3.0% by weight of povidone-iodine).

[0086] If the iodine source is an iodine solution, the iodine can be present in a solvent that is an aprotic solvent, such as water, ethanol, isopropanol, or other suitable solvents. When water is used as the solvent, the iodine concentration can be, for example, 0.1% to 10% w / w. A polar solvent can be used to constitute the desired concentration of the oxidizing agent (e.g., water, ethyl alcohol, isopropyl alcohol, polyethylene glycerol, glycerol), or iodine (I2) or iodide (I2). - Another complex containing ) can be used.

[0087] The weight ratio of iodine-containing agent, such as povidone-iodine (or other suitable iodine-containing oxidizing agent), to polyethylene can be, for example, approximately 1:1 to over 50:1, and the resulting solution of povidone-iodine to polyethylene can be any ratio greater than zero. Ratios of 50:1 or higher are effective and allow for faster injection rates. Higher ratios can create an iodine reservoir.

[0088] The injection of polyethylene implants can be carried out, for example, by immersing or soaking the polyethylene implants in an iodine solution after compaction of the implants. For example, polyethylene implants can be placed in a bath of iodine solution.

[0089] In some embodiments, the bath can be heated to allow iodine to be efficiently incorporated into the polyethylene. The bath can be heated, for example, from near room temperature (e.g., about 25°C) to about 100°C (e.g., about 80°C to about 95°C). Heating can be performed during polyethylene injection. While it is possible to heat the bath to allow iodine to be injected at a faster rate, it should not be heated to such an extent that it affects the integrity of the compacted polyethylene. Temperatures above 100°C may impair the mechanical properties of the polyethylene and may affect the long-term use of the implant. In some embodiments, the iodine-injected polyethylene can also be post-heated to improve the homogeneity and depth of the povidone-iodine.

[0090] Immersion can be carried out for, for example, about 1 hour to about 16 days, or up to about 30 days, or until the compacted polyethylene is saturated.

[0091] Iodine can be injected into the entire polyethylene implant morphology, or into specific functions, such as the rim of the acetabular cup. Certain parts of the implant can be masked or left unimmersed during injection, for example. Iodine concentration can also be varied throughout the entire molded object by masking or selective exposure of the structure.

[0092] By impregnating UHMWPE or other polymers containing antioxidants such as vitamin E with iodine, the oxidation of the material due to the oxidative activity of iodine can be reduced. [Examples]

[0093] Various embodiments of the present invention can be better understood by referring to the following examples provided herein. The present invention is not limited to the examples given herein.

[0094] Example 1. Preparation of iodine-injected polyethylene samples Iodine-impregnated polyethylene samples were prepared using the materials summarized in Table 1 below.

[0095] [Table 1]

[0096] The iodine solution used was povidone-iodine #10730575 from Acros Organics (Haele, Belgium). The various polyethylenes used included ultra-high molecular weight polyethylene (UHMWPE), vitamin E UHMWPE, and vitamin E highly cross-linked polyethylene.

[0097] First, polyethylene was molded into an implant shape and compacted. The polyethylene powder was then cold-sintered at ambient temperature for 30 minutes under a force of 21 tons in a 2-inch (5.08 cm) diameter cylindrical compression mold.

[0098] In samples B and C, a 17% by weight vitamin E solution dissolved in isopropyl alcohol was uniformly applied to the outer surface of a low-temperature sintered cylindrical form using a cotton swab. The total amount of vitamin E applied was approximately 4-5 grams. The low-temperature sintered form readily absorbed all of the applied solution. This form was dried at ambient temperature for 12 hours under nitrogen purging. Next, in all samples, this form was returned to a compression mold and compacted under pressure exceeding the melting point of polyethylene.

[0099] Next, sample C was subjected to irradiation treatment to induce crosslinking. For samples A, B, and C, gamma ray irradiation was used at doses of approximately 25 kGy to 45 kGy (sterilization level) and temperatures of approximately 60°C to 300°C.

[0100] After irradiation to induce compaction and any crosslinking (in the case of sample C), povidone-iodine was injected into the sample. The povidone-iodine solution was prepared to a concentration of 10% (w / w) (by weight) in deionized (DI) water using approximately 10 g of povidone-iodine per 90 g of deionized (DI) water. Three 150 mL baths of 10% povidone-iodine solution were used. Three polyethylene samples A, B, and C were each immersed in one bath. The containers of each bath were placed in a water bath with an average temperature of approximately 60°C. The temperature of approximately 60°C allowed for iodine uptake at a moderate rate without decomposing the compacted polyethylene. The samples were left immersed for 14 days. The resulting samples gradually changed color as iodine was injected into the polyethylene samples.

[0101] UHMWPE+ iodine samples A-C were tested for iodine concentration at two locations on polyethylene implants after injection, sterilization, and aging. Samples were tested using X-ray fluorescence (XRF) with a 10 mm diameter aperture. Analysis of the samples revealed the following povidone-iodine densities.

[0102] [Table 2]

[0103] XRF measurements analyzed the concentration of povidone-iodine in the samples. Depending on the test location, the sample concentration ranged from approximately 70 to 90 μg / cm³. 3 It showed povidone-iodine.

[0104] Example 2. Elution from iodine-injected polyethylene samples. Samples from Example 1 were maintained at 50°C, and the release of iodine over time was tested. The release experiments were conducted under conditions exaggerated compared to those in the human body. The samples were placed in a water bath at approximately 50°C. The sample conditions are summarized in Table 3 below.

[0105] [Table 3]

[0106] All samples D through F were gamma-sterilized at approximately 25 kGy to 27 kGy before aging. Iodine release was observed over 21 days. Coloration of sample D (iodine-injected UHMWPE), F (iodine-injected HXPE containing vitamin E), and control UHMWPE was observed at 1, 14, and 21 days. Under these conditions, the majority of iodine was released after approximately 21 days. It is expected that it will take much longer for iodine to be released under physiological conditions.

[0107] Example 3. Oxidation index of iodine-implanted polyethylene samples. The samples were also tested for oxidative degradation, wear analysis, and mechanical properties. The samples were aged using high temperature and high oxygen pressure according to ASTM F2003-02(2015). The aged samples were compared to UHMWPE (as obtained), aged UHMWPE, and other aged polymer samples. The tested samples are summarized in Table 4 below.

[0108] [Table 4]

[0109] Figure 1 shows the oxidation index of each sample (UHMWPE, iodine UHMWPE, VE UHMWPE, VE iodine UHMWPE, HXLPE VE, and HXLPE VE iodine) as described in more detail in Table 4 above. The oxidation index of the iodine-treated samples was generally low, with the exception of the "iodine UHMWPE" sample which did not contain vitamin E.

[0110] The oxidation index of the samples injected with the antioxidant vitamin E was less than 1. Overall, no oxidation was observed for any of the vitamin E-injected polymers (e.g., oxidation index less than 1 in the graph). Oxidation was observed only in the case of iodine-injected UHMWPE (e.g., oxidation index greater than 1).

[0111] Example 4. Mechanical properties of iodine-impregnated polyethylene samples. Iodine-impregnated polyethylene samples were also tested for abrasion analysis using pin-on-plate analysis, as shown in Figure 2. The weight of the samples was measured to indicate the average cumulative mass loss per number of pin-on-plate abrasion analyses. As shown in Figure 2, iodine-impregnated but unaged UHMWPE samples were compared to unused UHMWPE. Here, the unused (virgin) UHMWPE showed an average cumulative mass loss of up to 0.0072 g over 1,000,000 tests. In contrast, the iodine-impregnated samples showed an average cumulative mass loss of approximately 0.0028 g over 1,000,000 tests.

[0112] As shown in Figures 3A and 3B, each sample was further tested for mechanical properties, including modulus of elasticity and elongation at fracture. Samples tested for mechanical properties included iodine-implanted UHMWPE ("H-iodine UHMWPE" and "V-iodine UHMWPE") as well as UHMWPE ("HUHMWPE" and "VUHMWPE"). The test samples included both samples machined perpendicular to the molding direction ("H") and thin fragment samples perpendicular to the molding direction ("V"). Mechanical properties were tested using an Instron 5985 calibrated with a 50 kN load cell. The test procedure used was the standard ASTM D638-10 procedure at a speed of 5.0 mm / min.

[0113] As shown in Figures 3A to 3D, the iodine-injected UHMWPE exhibited an elastic modulus of approximately 300 MPa to 350 MPa, compared to the uninjected UHMWPE with an elastic modulus of approximately 350 MPa to 400 MPa. The samples showed an elongation at fracture of approximately 475% to 515% for the iodine-injected UHMWPE, compared to the uninjected UHMWPE with an elongation at fracture of approximately 415% to 450%.

[0114] The yield point tensile strengths of both the iodine-impregnated and unimpregnated samples were approximately 20 MPa to 22 MPa. However, the fracture point tensile strength was approximately 25 MPa to 27 MPa for the iodine-impregnated samples, compared to approximately 24 MPa to 25 MPa for the unimpregnated samples. Overall, when the mechanical properties of the samples were tested, they were more ductile. In general, the addition of iodine to UHMWPE did not adversely affect the mechanical properties of the samples.

[0115] Figure 4 shows the impact strength (kJ / m²) of the sample. 2 This shows that the average impact strength of unused UHMWPE samples is approximately 100 kJ / m². 2 However, the average impact strength of the iodine-injected UHMWPE samples was approximately 120 kJ / m 2 That was the case.

[0116] Example 5 A second set of iodine-impregnated polyethylene samples was prepared using the materials summarized in Table 5 below.

[0117] [Table 5]

[0118] The povidone-iodine used was a polyvinylpyrrolidone-iodine complex from Acros Organics (Hale, Belgium). The Lugol solution used was 15% Lugol iodine from APC Pure (Cheshire, UK). The various polyethylenes used included ultra-high molecular weight polyethylene (UHMWPE).

[0119] First, polyethylene was molded into an implant shape and compacted. The polyethylene powder was then cold-sintered at ambient temperature for 30 minutes under a force of 21 tons in a cylindrical compression mold with a diameter of 2 inches (5.08 cm).

[0120] After compaction, iodine in either povidone-iodine solution or Lugol's solution was injected into the samples. Povidone-iodine solution was prepared at 0.1–10% w / w (by weight) in deionized (DI) water. Lugol's solution was used as is. Each polyethylene sample was immersed in a bath of approximately 150 mL to 1 L of each solution. The containers in each bath were submerged in a warm bath with an average temperature of approximately 60°C to a maximum of approximately 95°C. Depending on the temperature used, iodine could be released at a reasonable rate without decomposing the compacted polyethylene. The samples were immersed for 1–14 days. When iodine was injected into the polyethylene samples, the color of the resulting samples changed.

[0121] Iodine-implanted UHMWPE samples were tested for iodine concentration at various locations after implantation. Samples were tested by X-ray fluorescence (XRF) using a 3 mm diameter aperture. For example, in the analysis of UHMWPE samples D-F implanted with 1% w / w (weight ratio) iodine, the following iodine concentrations were detected after 6 days.

[0122] [Table 6]

[0123] XRF measurements were used to determine the iodine concentration in the sample. The sample concentration ranged from approximately 250 to 930 μg / cm³ depending on the injection time. 3 The iodine concentration was shown.

[0124] Additional embodiments. The following exemplary embodiments are provided, but their numbering should not be construed as indicating importance.

[0125] Embodiment 1 includes an implant containing crosslinked iodine-impregnated polyethylene.

[0126] Embodiment 2 has an average iodine concentration of approximately 5 to approximately 3000 μg / cm³ in the polyethylene implant. 3 This includes Embodiment 1.

[0127] Embodiment 3 has an average iodine concentration of approximately 200 to 1000 μg / cm³ in the polyethylene implant. 3 This includes any one of Embodiments 1 to 2.

[0128] Embodiment 4 includes any of Embodiments 1 to 3, wherein iodine is uniformly distributed in polyethylene.

[0129] Embodiment 5 includes any of Embodiments 1 to 4, wherein the polyethylene is saturated with iodine.

[0130] Embodiment 6 includes any of Embodiments 1 to 5, wherein the polyethylene is ultra-high molecular weight polyethylene, ultra-low molecular weight polyethylene, high-density polyethylene, high molecular weight polyethylene, high-density crosslinked polyethylene, medium-density polyethylene, low-density polyethylene, linear low-density polyethylene, ultra-low-density polyethylene, branched polyethylene, or a combination thereof.

[0131] Embodiment 7 includes any of Embodiments 1 to 6, wherein the polyethylene contains an antioxidant.

[0132] Embodiment 8 includes any of Embodiments 1 to 7, wherein the antioxidant is at least one of tocopherol, tocopherol phosphite, tocotrienol, vitamin E, vitamin E acetate, vitamin E phosphite, rosemary oil, pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), dimethyl butanediate / 4-hydroxy-2,2,6,6-tetramethyl-1-piperidineethanol copolymer, tannic acid, bilberry extract, vitamin C, carotene, flavonoids, isoflavonoids, neoflavonoids, lignin, kinin, ubiquinone, vitamin K1, metals, glutathione, propyl gallate, octyl gallate, lauryl gallate, resveratrol, rosmarinic acid, rutin, 5-aminosalicylic acid, butylated hydroxyanisole, butylated hydroxytoluene, phenol compounds, and a monomeric or polymeric hindered amine stabilizer.

[0133] Embodiment 9 includes any of Embodiments 1 to 8, wherein the antioxidant is uniformly distributed in the polyethylene.

[0134] Embodiment 10 includes any of Embodiments 1 to 9, wherein the antioxidant is approximately 0.01% to approximately 5.0% by weight of polyethylene.

[0135] Embodiment 11 includes any of Embodiments 1 to 10, wherein the antioxidant is approximately 0.05% to approximately 0.50% by weight of polyethylene.

[0136] Embodiment 12 includes embodiments 1 to 11, wherein the implant is a hip, knee, shoulder, back, elbow, chest, manubrium, foot, ankle, or dental implant.

[0137] Embodiment 13 includes any of Embodiments 1 to 12, wherein the polyethylene has an average cumulative mass loss of about 0.001 g to about 0.005 g over about 10,000 to about 1,300,000 abrasion analyses in pin-on-plate analysis.

[0138] Embodiment 14 includes any of Embodiments 1 to 13, wherein the polyethylene has an average cumulative mass loss of about 0.001 g to about 0.003 g over about 20,000 to about 1,200,000 abrasion analyses in pin-on-plate analysis.

[0139] Embodiment 15 includes any of Embodiments 1 to 14, wherein the polyethylene has an elastic modulus of about 250 MPa to about 400 MPa.

[0140] Embodiment 16 includes any of Embodiments 1 to 15, wherein the polyethylene has an elastic modulus of about 300 MPa to about 350 MPa.

[0141] Embodiment 17 includes any of Embodiments 1 to 16, wherein the polyethylene has an elongation at break of approximately 475% to approximately 515%.

[0142] Embodiment 18 includes any of Embodiments 1 to 17, wherein the polyethylene has an elongation at break of approximately 490% to approximately 505%.

[0143] Embodiment 19 includes any of Embodiments 1 to 18, wherein the polyethylene has an oxidation index of about 0 to about 8.

[0144] Embodiment 20 includes any of Embodiments 1 to 19, wherein the polyethylene has an oxidation index of about 0 to about 1.

[0145] Embodiment 21 is a method for manufacturing a polyethylene implant, the method comprising exposing polyethylene to an iodine source so that iodine is injected into the polyethylene.

[0146] Embodiment 22 includes Embodiment 21, in which the iodine-impregnated polyethylene is saturated with iodine.

[0147] Embodiment 23 includes any of Embodiments 21 to 22, wherein the iodine source includes an iodine-containing solution.

[0148] Embodiment 24 includes any of Embodiments 21 to 23, wherein the iodine source includes an iodophore selected from the group consisting of povidone-iodine and aqueous iodine solutions.

[0149] Embodiment 25 includes any of Embodiments 21 to 24, wherein the iodine-containing solution includes a solvent in which the solvent is aprotic.

[0150] Embodiment 26 includes any of Embodiments 21 to 25, wherein the aprotic solvent is water, ethanol, or isopropanol.

[0151] Embodiment 27 includes any of Embodiments 21 to 26, wherein the implant further contains an antioxidant.

[0152] Embodiment 28 includes any of Embodiments 21 to 27, further comprising adding an antioxidant to the implant.

[0153] Embodiment 29 includes any of Embodiments 21 to 28, wherein the addition of the antioxidant includes mixing or injection.

[0154] Embodiment 30 includes any of Embodiments 21 to 29, wherein the iodine-containing solution is approximately 0.1% to approximately 10.0% by weight of povidone-iodine.

[0155] Embodiment 31 includes any of Embodiments 21 to 30, wherein the iodine-containing solution is approximately 1.0% to approximately 3.0% by weight of povidone-iodine.

[0156] Embodiment 32 includes any of Embodiments 21 to 31, wherein the injection involves immersing polyethylene in an iodine solution.

[0157] Embodiment 33 includes any of Embodiments 21 to 32, wherein the polyethylene is immersed for up to approximately 30 days.

[0158] Embodiment 34 includes any of Embodiments 21 to 33, wherein the polyethylene is immersed for approximately 1 hour to approximately 16 days.

[0159] Embodiment 35 includes any of Embodiments 21 to 34, wherein the polyethylene is immersed at a temperature of approximately 20 degrees Celsius to approximately 100 degrees Celsius.

[0160] Embodiment 36 includes any of Embodiments 21 to 35, wherein the polyethylene is immersed at a temperature of approximately 60 to 95 degrees Celsius.

[0161] Embodiment 37 includes any of Embodiments 21 to 36, wherein the weight ratio of the iodine-containing solution to polyethylene is approximately 1:1 to approximately 50:1.

[0162] Embodiment 38 includes any of Embodiments 21 to 37, further comprising compacting the polyethylene before injection.

[0163] Embodiment 39 includes any of Embodiments 21 to 38, further comprising irradiating polyethylene after injection.

[0164] Embodiment 40 includes any of Embodiments 21 to 39, wherein the irradiation includes at least one of electron beam irradiation and gamma ray irradiation.

[0165] Embodiment 41 includes any of Embodiments 21 to 40, wherein the irradiation is performed at a temperature of approximately 60°C to approximately 300°C.

[0166] Embodiment 42 includes any of Embodiments 21 to 41, wherein the irradiation includes a total irradiation dose of approximately 1 kGy to approximately 100,000 kGy (kilogray).

[0167] Embodiment 43 includes any of Embodiments 21 to 42, further comprising preheating the polyethylene before irradiation.

[0168] Embodiment 44 includes any of Embodiments 21 to 43, wherein irradiation induces crosslinking of polyethylene.

[0169] Embodiment 45 includes any of Embodiments 21 to 44, wherein the irradiation is performed in the presence of a crosslinked polymer.

[0170] Embodiment 46 includes any of Embodiments 21 to 45, wherein the crosslinking polymer is at least one of trimethylolpropane, acrylate, trimethylolpropane trimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, and combinations thereof.

[0171] Embodiment 47 is a method for preventing microbial formation on or near an implant, comprising implanting a cross-linked iodine-injected implant containing polyethylene, wherein iodine is gradually released from the implant after implantation.

[0172] Embodiment 48 includes Embodiment 47, wherein the iodine release is a gradual release of iodine over a period of about 15 days to about 10 years.

[0173] Embodiment 49 includes any of Embodiments 47 to 48, wherein the iodine release is a gradual release of iodine over a period of about 15 to 30 days.

[0174] Embodiment 50 includes any of Embodiments 47 to 49, wherein the method substantially prevents the growth of bacteria on the surface of the implant.

[0175] Embodiment 51 includes any of Embodiments 47 to 50, wherein the method substantially prevents biofilm formation on the surface of the implant.

Claims

1. An implant containing iodine-injected polyethylene, wherein the average concentration of iodine in the polyethylene implant is approximately 5 to approximately 3000 μg / cm³. 3 That is an implant.

2. The aforementioned iodine is present in polyethylene implants at a concentration of approximately 200 to 1000 μg / cm³. 3 The implant according to claim 1, having an average concentration.

3. The implant according to claim 1, wherein the polyethylene is ultra-high molecular weight polyethylene, ultra-low molecular weight polyethylene, high-density polyethylene, high molecular weight polyethylene, high-density crosslinked polyethylene, medium-density polyethylene, low-density polyethylene, linear low-density polyethylene, ultra-low-density polyethylene, branched polyethylene, or a combination thereof.

4. The implant according to claim 1, wherein the polyethylene comprises an antioxidant comprising at least one of tocopherol, tocopherol phosphite, tocotrienol, vitamin E, vitamin E acetate, vitamin E phosphite, rosemary oil, pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), dimethyl butanediate / 4-hydroxy-2,2,6,6-tetramethyl-1-piperidineethanol copolymer, tannic acid, bilberry extract, vitamin C, carotene, flavonoids, isoflavonoids, neoflavonoids, lignin, kinin, ubiquinone, vitamin K1, metals, glutathione, propyl gallate, octyl gallate, lauryl gallate, resveratrol, rosmarinic acid, rutin, 5-aminosalicylic acid, butylated hydroxyanisole, butylated hydroxytoluene, phenolic compounds, and monomeric or polymeric hindered amine stabilizers.

5. The implant according to claim 4, wherein the antioxidant is in an amount of about 0.01% to about 5.0% by weight of polyethylene.

6. The implant according to claim 1, wherein the implant comprises crosslinked iodine-impregnated polyethylene.

7. The implant according to claim 1, wherein the polyethylene has an average cumulative mass loss of about 0.001 g to about 0.005 g over about 10,000 to about 1,300,000 abrasion analyses in pin-on-plate analysis.

8. The implant according to claim 1, wherein the polyethylene has an elastic modulus of about 250 MPa to about 400 MPa.

9. The implant according to claim 1, wherein the polyethylene has an elongation at break of approximately 475% to approximately 515%.

10. A method for manufacturing an implant containing polyethylene, comprising exposing the polyethylene to an iodine source such that iodine is injected into the polyethylene.

11. The method according to claim 10, wherein the iodine source comprises an iodine phore selected from povidone-iodine, aqueous iodine solution, and Lugol's solution.

12. The method according to claim 11, wherein the iodine-containing solution is about 0.1% by weight to about 10.0% by weight of povidone-iodine.

13. The method according to claim 10, further comprising adding an antioxidant to the implant.

14. The method according to claim 10, wherein the injection comprises immersing the polyethylene in an iodine solution for up to approximately 30 days.

15. The method according to claim 14, wherein the immersion of the polyethylene is carried out at a temperature of approximately 20 to approximately 100°C.

16. The method according to claim 10, wherein the weight ratio of the iodine-containing solution to polyethylene is about 1:1 to about 50:

1.

17. The method according to claim 10, further comprising compacting the polyethylene before injection.

18. The method according to claim 10, further comprising irradiating the polyethylene.

19. A method for preventing microbial formation on or near an implant, comprising implanting a cross-linked iodine-injected implant containing polyethylene, wherein iodine is gradually released from the implant after implantation.

20. The method according to claim 19, wherein the gradual release of iodine includes releasing iodine over a period of about 15 days to about 10 years.

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