System and method for forming antimicrobial orthopedic implants

Abstract

Provides a manufacturing method for antimicrobial orthopedic implants. [Solution] The manufacturing method includes adsorbing vaporized antimicrobial agent onto the outer surface of an orthopedic implant so that heating and cooling of the container results in the formation of an antimicrobial coated orthopedic implant having a surface area concentration of antimicrobial agent on the outer surface of the orthopedic implant that is sufficient to generate an effective barrier of at least 0.5 mm from the periphery of the outer surface.

Description

[Technical Field]

[0001] This disclosure relates to a system, manufacturing method, and packaging configuration for an antimicrobial orthopedic implant having an antimicrobial coating on the outer surface of the implant containing an antimicrobial agent that can be vaporized at a surface area concentration sufficient to prevent bacterial growth on the orthopedic implant, and can further provide a clinically effective barrier around the orthopedic implant. [Background technology]

[0002] Many individuals receive orthopedic surgical implants annually as a result of orthopedic trauma or joint replacement procedures. In the United States, according to the American Academy of Orthopedic Surgeons, more than 600,000 knee prostheses and more than 300,000 hip prostheses are implanted each year. More than one million patients receive metal implants each year to treat fractures. Implant-associated infection is one of the most serious potential complications associated with orthopedic implants, with infection rates exceeding 10% in some high-risk procedures and patient groups. The cost of treating implant-associated infections is significant because treatment often requires surgical removal of the infected implant and long-term antibiotic treatment.

[0003] Implant-associated infections occur when bacteria contaminate the surgical wound site, attach to the surgical implant, and begin to proliferate. Bacteria growing on the implant surface often form a biofilm, which secretes a protective extracellular matrix and exhibits significantly reduced metabolic activity. This biofilm phenotype protects the bacteria from the patient's immune system and systemic antibiotics, making the treatment of implant-associated infections extremely difficult and expensive.

[0004] One solution to prevent implant-associated infections is to treat the surface of surgical implants in a way that prevents bacterial growth and adhesion. Surgical implants have been developed that are coated with antibiotics or antimicrobial compounds to kill bacteria on the surgical wound site or implant surface before they can adhere to and multiply on the implant. Examples include antimicrobial coated pacemaker pouches (TYRX® Absorbable Antimicrobial Envelope), orthopedic implants (ETN PROtect), surgical graft materials (XenMatrix® AB Surgical Graft), and sutures (VICRYL® Plus Antimicrobial Suture).

[0005] A method for vaporizing antimicrobial agents to medical devices such as sutures is disclosed, by placing a device in an inner package having a source of antimicrobial agents, covering the inner packaging with an outer packaging, and providing the packaging with sufficient time, temperature, and pressure conditions to vaporize the antimicrobial agent from the antimicrobial agent source to the device (e.g., U.S. Patents 7,513,093, 8,112,973, 8,133,437, 8,156,718, 8,668,867, 8,960,422, 9,044,531, 9,149,273, 9,474,524, 9,597,067, and 9,597,072). This vapor transfer process has been demonstrated to successfully transfer antimicrobial agents to polymer or paper materials (such as surgical sutures or packaging materials). [Overview of the project] [Means for solving the problem]

[0006] The inventors have surprisingly found that the processes described above in the art for the deposition of antimicrobial agents (typically materials and conditions relating to standard ethylene oxide sterilization parameters) do not provide a clinically effective coating for all orthopedic implant materials. For example, orthopedic implants with metal substrate surfaces do not retain sufficient amounts of antimicrobial agent to inhibit bacterial growth. Furthermore, the distribution of antimicrobial agent along the surface of orthopedic implants can be non-uniform. This may be a result of ethylene oxide sterilization parameters that utilize packaging configurations with vents that allow vapor transfer from the environment into the packaging to enable the penetration of ethylene oxide gas, but also allow leakage of large amounts of volatile antimicrobial agent into the external environment. Moreover, ethylene oxide sterilization typically includes a vacuum phase that draws additional vaporized antimicrobial agent from the packaging. Finally, certain packaging materials used in ethylene oxide sterilization can have a greater ability to absorb vaporized antimicrobial agent than metal substrates, such as certain biocompatible polymers used in packaging and implantable medical devices (e.g., sutures) and certain medical-grade papers.

[0007] Accordingly, this disclosure relates to a system and method for providing an antimicrobial coating on the outer surface of an orthopedic implant (preferably an implant having at least a partially metallic or metallic alloy outer surface), wherein the antimicrobial coating comprises a vaporizable antimicrobial agent at a surface area concentration sufficient to sufficiently inhibit bacterial growth on the implant surface, and further, in certain embodiments, provides a clinically effective inhibitory zone around the implant.

[0008] According to this disclosure, a method for forming an antimicrobial orthopedic implant is disclosed, and the method is To provide a container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface defines a container cavity, the first end defines an opening extending into the container cavity, and the inner surface contains a non-absorbent material. A reservoir of vaporizable antibacterial agent is placed inside the container cavity. Placing an orthopedic implant into the cavity of the container through the first end, wherein the orthopedic implant defines an outer surface, and the placing Sealing the first end of the container so as to seal the cavity of the container Heating the container in a sealed state to vaporize the antibacterial agent by heating the outer surface of the orthopedic implant and the reservoir of the vaporizable antibacterial agent, and Cooling the container in a sealed state, wherein the heating and cooling of the container cause the vaporized antibacterial agent to adsorb onto the outer surface of the orthopedic implant to form an antibacterial-coated orthopedic implant having a surface area concentration of the antibacterial agent on the outer surface of the orthopedic implant sufficient to produce a clinically effective barrier zone of at least 0.5 mm around the outer surface. In a preferred embodiment, the surface area concentration is sufficient to prevent bacterial colony formation on the outer surface of the orthopedic implant. In certain other embodiments, the surface area concentration of the orthopedic implant is greater than or equal to the surface area concentration of the antibacterial agent on the inner surface of the container.

[0009] According to a further embodiment, the method can include depositing a solution of the vaporizable antibacterial agent and a solvent into the cavity, evaporating the solvent from the cavity, and discharging it from the container. In an alternative embodiment, the method can include coating the inner surface of the container with a solution of the vaporizable antibacterial agent and a solvent, evaporating the solvent from the inner surface, and discharging it from the container.

[0010] In an additional embodiment, the heating step includes heating in a temperature range of about 60°C to about 200°C, such as in a range of about 80°C to about 180°C, about 100°C to 170°C, or about 120°C to about 160°C. In a further additional embodiment, the heating step is in a range of about 10 minutes to about 8 hours, such as in a range of about 3 hours to about 6 hours.

[0011] According to a particular embodiment, the container is substantially rigid such that the cavity defines a fixed volume.

[0012] According to certain embodiments, the first end of the container includes a threaded region that extends around the outer surface of the container, the threaded region being configured to engage with a lid having a corresponding threaded region on its inner surface, and the step of sealing the first end of the container includes engaging the first end threaded region and the lid threaded region. Embodiments can further include a sealing member disposed between and configured to contact the lid threaded region and the first end threaded region during the sealing step.

[0013] According to alternative embodiments, the container is substantially deformable, and the cavity defines a first shape having a first volume when the first end is open and takes on a second shape having a second volume that is smaller than the first volume upon deformation. In certain other embodiments, the first end is substantially deformable, and the sealing step includes bringing the opposing walls of the inner surface at the first end into contact with each other and applying pressure to the first end to seal the first end. In additional embodiments, at least a portion of the inner surface of the first end includes a quantity of a sealant that, upon contact, binds the opposing walls to each other to seal the first end. In additional alternative embodiments, the sealing step can include applying a mechanical fastener configured to hold the opposing walls in contact with each other to the sealed first end.

[0014] In still further embodiments of the container, the second end is open, and the step of sealing the container further includes sealing the second end. In certain embodiments, the second end is substantially deformable, such that the sealing step further includes bringing the opposing walls of the inner surface at the second end into contact with each other and applying pressure to the second end to seal the second end.

[0015] According to the present disclosure, an orthopedic implant having an antibacterial coating includes the antibacterial coating on an outer surface, and the surface area concentration of the antibacterial agent on the outer surface of the orthopedic implant is in the range of about 5 μg / cm 2 to about 1000 μg / cm 2 for example, about 10 μg / cm 2 to about 1000 μg / cm 2This is within the range. In additional embodiments, the antimicrobial agent in the reservoir has a total weight, and by vapor deposition, at least 1% to about 95% of the total weight, for example, about 1% to 10%, or about 10% to about 20%, of the antimicrobial agent forms an antimicrobial coating on the outer surface of the orthopedic implant.

[0016] According to this disclosure, the system for forming antimicrobial orthopedic implants described in the above process is: A reservoir for vaporizable antimicrobial agents. Orthopedic implants that define the outer surface, and A container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface defines a cavity containing a non-absorbable material and configured to receive an orthopedic implant, and the first end defines a sealable opening extending into the cavity, The container, orthopedic implant, and vaporizable antimicrobial agent are configured to remain thermally stable in a temperature range of up to 200°C. The reservoir for the vaporizable antimicrobial agent is placed inside the container. Orthopedic implants are placed within a cavity, and their outer surface is substantially free of vaporizable antimicrobial agents.

[0017] According to a particular embodiment, at least a portion of the inner surface of the first end contains an amount of sealant configured to bond the opposing walls together in order to seal the first end, the sealant including, for example, an adhesive material or a thermal bonding material.

[0018] According to this disclosure, a packaging configuration for sterile antimicrobial orthopedic implants is described, and this packaging configuration is: A sterilization container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface contains a non-absorbent material and defines a cavity, and the first end defines a sealable opening extending into the cavity, A sterile orthopedic implant placed within a cavity, comprising a sterile orthopedic implant defining the outer surface, Orthopedic implants have an antimicrobial coating on their outer surface, and the antimicrobial coating contains a surface area concentration of a vaporizable antimicrobial agent on the outer surface of the orthopedic implant. The outer surface has a density of approximately 5 μg / cm³. 2 ~Approx. 1000μg / cm 2 It has a surface area concentration of vaporizable antimicrobial agents within the range of [specify range].

[0019] According to a particular embodiment, the vaporizable antimicrobial agent has a total weight, and at least 1% to about 20% of the total weight of the vaporizable antimicrobial agent is contained in the antimicrobial coating on the orthopedic implant.

[0020] According to this disclosure, an antimicrobial coated implant is described, and this antimicrobial coated implant is Orthopedic implants, wherein the orthopedic implant defines an outer surface that is essentially made of metal or a metal alloy, a polyalkene or its copolymer, or a polyaryletherketone or its copolymer, or a combination thereof, and An antimicrobial coating placed on the outer surface of an orthopedic implant, wherein the antimicrobial implant comprises an antimicrobial coating that essentially consists of a vaporizable antimicrobial agent. Antimicrobial coated implants contain approximately 5 μg / cm³ 2 ~Approx. 1000μg / cm 2 The orthopedic implant has a surface area concentration of antimicrobial agents within a certain range. In preferred embodiments, the surface area concentration is effective in preventing microbial colonization of the orthopedic implant. In certain additional embodiments, the surface area concentration is effective in creating an inhibition zone against microbial colonization units, at least 0.5 mm from the outer surface of the orthopedic implant.

[0021] According to certain embodiments, the vaporizable antimicrobial agent includes halogenated hydroxyl ethers, acyloxydiphenyl ethers, or combinations thereof. In preferred embodiments, the vaporizable antimicrobial agent includes 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan).

[0022] In certain embodiments, the outer surface of the orthopedic implant comprises at least polyaryletherketone (PAEK) or polyalkene or a copolymer thereof, or a metal or metal alloy, or a combination thereof. In preferred embodiments, the outer surface is titanium or stainless steel, or an alloy thereof, or polyethylene or polyetheretherketone (PEEK) or a copolymer thereof.

[0023] In other embodiments, the inner surface of the container comprises a non-absorbent material such as a metal or metal alloy, such as aluminum or an alloy thereof. In certain embodiments, the metal or metal alloy is in the form of particulate or submicron metal particles applied to the inner surface of the container.

[0024] According to certain embodiments, the outer surface consists essentially of a metal or metal alloy, and a polyalkene or a copolymer thereof, such as titanium or stainless steel or an alloy thereof, and polyethylene or a copolymer thereof. According to certain embodiments, the outer surface consists essentially of a metal or metal alloy, and a polyaryletherketone or a copolymer thereof, such as titanium or stainless steel or an alloy thereof, and PEEK or a copolymer thereof. According to certain embodiments, the outer surface consists essentially of a polyalkene or a copolymer thereof, and a polyaryletherketone or a copolymer thereof, such as polyethylene or a copolymer thereof, and PEEK or a copolymer thereof.

[0025] According to certain embodiments, the surface area concentration of the antibacterial agent in the antibacterial coating is in the range of about 10 μg / cm 2 ~ about 1000 μg / cm 2 .

[0026] According to certain embodiments, the ZOI is in the range of about 0.5 mm to about 5.0 mm.

Brief Description of the Drawings

[0027] The following aspects are illustrative examples, but not limiting, of the various embodiments considered in this disclosure. The above summary and the following detailed description of preferred embodiments of this application will be better understood in conjunction with the accompanying drawings. [Figure 1A] This is a schematic diagram of a packaging system and process for forming an antimicrobial coating on an orthopedic implant according to an embodiment of the present disclosure. [Figure 1B] This is a schematic diagram of a packaging system and process for forming an antimicrobial coating on an orthopedic implant according to an embodiment of the present disclosure. [Figure 1C] This is a schematic diagram of a packaging system and process for forming an antimicrobial coating on an orthopedic implant according to an embodiment of the present disclosure. [Figure 2] This is a side view of a container and lid according to another embodiment of the present disclosure. [Figure 3A] This is a perspective view of a cross-section of an alternative container according to an embodiment of the present disclosure. [Figure 3B] Figure 3A is a side view of an embodiment of the container. [Figure 4A] This is a cross-sectional side view of the alternative container according to this disclosure. [Figure 4B] This is a cross-sectional side view of the alternative container according to this disclosure. [Figure 5A] This is a cross-sectional side view of another container embodiment according to the present disclosure. [Figure 5B] This is a cross-sectional side view of another container embodiment according to the present disclosure. [Modes for carrying out the invention]

[0028] In this text, the words “a” or “an” are used to include one or more, and the word “or” is used to mean a non-restrictive “or” unless otherwise specified. Furthermore, it should be understood that any usage or terminology used herein and not otherwise defined is for illustrative purposes only and not for limitation. Where a range of values ​​is expressed, in other embodiments it includes from a certain value and / or to other specific values. Similarly, where a value is expressed in an approximate form by the preceding “about,” it should be understood that that particular value forms another embodiment. All ranges are inclusive and can be combined. Furthermore, a reference to a value described in a range includes all values ​​within that range. It should also be recognized that certain features of the invention described herein as separate embodiments for clarity may also be shown combined in a single embodiment. Conversely, various features of the invention described as a single embodiment for brevity may also be presented separately or in any subordinate combination.

[0029] As used herein, the phrase “essentially consisting of” is intended to define the claims as including any enumerated materials or steps, and further including any materials and steps that do not substantially affect the essential features of the claimed invention.

[0030] This disclosure relates to a previously undiscovered problem in which, under certain circumstances, the deposition of triclosan under conditions close to standard ethylene oxide (EO) sterilization does not provide a uniform and clinically effective coating on certain implantable medical device surfaces. One particular set of implants is orthopedic implants having a metal or metal alloy substrate surface. These types of implants, when treated under EO sterilization conditions with a triclosan reservoir, do not produce an inhibitory zone sufficient to inhibit bacterial growth. Following the EO sterilization process described in the prior art, only a small portion of the triclosan in the packaging is transferred to the implant surface. A significant portion of the triclosan dose is lost from the packaging container during the vacuum stage of the ethylene oxide sterilization process. Another large portion of the triclosan dose is absorbed by the packaging components, such as the polymer and paper components of the packaging. Due to these losses, the EO triclosan transfer process is inefficient in terms of the yield of triclosan on the final product, and the input of the final product is variable.

[0031] Therefore, this disclosure relates to a system and method for generating an antimicrobial coating on the surface of an orthopedic implant using the deposition of an antimicrobial agent, which can provide a clinically effective barrier at the implant site and simultaneously provide regulatory-approved sterilization to the implant and its associated packaging components. Importantly, the removal of packaging components that have an affinity for triclosan absorption is a desirable outcome. Furthermore, the ability to accurately and uniformly dose the outer surface of the implant is a desired outcome. One advantage of using a metal sterilization container is its higher thermal stability compared to common polymer packaging materials for medical devices. Since triclosan is also thermally stable at temperatures above 160°C, the triclosan vapor transfer conditions may also serve as the conditions for dry heat sterilization of the implant. This makes it possible to achieve triclosan vaporization in the same process and simultaneously as the final sterilization of the implant.

[0032] More specifically, a further advantage of this disclosure is the ability to use antimicrobial vapor transfer processes described among those known as “dry heat” (or “high heat”) sterilization processes, as opposed to current state-of-the-art processes that rely on EO sterilization parameters. Ethylene oxide is toxic, highly flammable, and a known carcinogen. In the United States, the operation of EO sterilization is overseen by the EPA through national emission standards for hazardous air pollutants. One advantage of using sterilization containers with thermally stable, non-absorbent inner surfaces, such as metal inner surfaces, is their higher thermal stability compared to common polymer packaging materials for medical devices. Triclosan is also thermally stable at temperatures above 160°C, so triclosan vapor transfer conditions may also serve as conditions for dry heat sterilization of implants. This makes it possible to achieve the triclosan vapor transfer process in the same process and simultaneously as the final “dry heat” sterilization of implants. Therefore, the ability to provide an alternative to implantable medical device sterilization processes that can replace current EO sterilization processes and still provide clinically effective antimicrobial coatings is desirable and offers beneficial advantages in the orthopedic implant industry.

[0033] As used herein, “zoin” (ZOI) means the distance from the periphery of an implant where there are no measurable microbial colony-forming units (e.g., microbial activity) when the implant is placed in an in vitro environment inoculated with a known amount of colony-forming microorganisms. In certain literature, the ZOI is measured as the total cross-sectional length (e.g., diameter) of the region where measurable microbial activity is absent, and may also include the dimensions of the implant.

[0034] As used herein, “clinically effective inhibition zone” means a ZOI measurement of at least 0.5 mm around an implant where there is no measurable bacterial growth.

[0035] As used herein, “vaporizable” means an antimicrobial compound that can evaporate when exposed to temperatures above 50°C under ambient pressure conditions.

[0036] According to this disclosure, a method for forming an antimicrobial orthopedic implant is disclosed, and the method is To provide a container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface defines a container cavity, the first end defines an opening extending into the container cavity, and the inner surface contains a non-absorbent material. A reservoir of vaporizable antibacterial agent is placed inside the container cavity. The orthopedic implant is positioned within the container cavity through the first end, and the orthopedic implant is positioned to define the outer surface. To seal the first end of the container so as to seal the container cavity, Heating the outer surface of the orthopedic implant and the reservoir of the vaporizable antimicrobial agent, and heating the sealed container to vaporize the antimicrobial agent, and This includes cooling the container while it is sealed. The vaporized antimicrobial agent is adsorbed onto the outer surface of the orthopedic implant so that heating and cooling of the container creates an antimicrobial coated orthopedic implant having a surface area concentration of the antimicrobial agent on the outer surface of the orthopedic implant that is sufficient to generate a clinically effective inhibition zone of at least 0.5 mm from the periphery of the outer surface. In certain embodiments, the surface area concentration of the orthopedic implant is greater than or equal to the surface area concentration of the antimicrobial agent on the inner surface of the container.

[0037] According to this disclosure, the system for forming antimicrobial orthopedic implants described in the above process is: A reservoir for vaporizable antimicrobial agents. Orthopedic implants that define the outer surface, and A container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface defines a cavity containing a non-absorbable material and configured to receive an orthopedic implant, and the first end defines a sealable opening extending into the cavity, The container, orthopedic implant, and vaporizable antimicrobial agent are configured to remain thermally stable in a temperature range of up to 200°C. The reservoir for the vaporizable antimicrobial agent is placed inside the container. Orthopedic implants are placed within a cavity, and their outer surface is substantially free of vaporizable antimicrobial agents.

[0038] According to this disclosure, a packaging configuration for sterile antimicrobial orthopedic implants is described, and this packaging configuration is: A sterilization container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface contains a non-absorbent material and defines a cavity, and the first end defines a sealable opening extending into the cavity, A sterile orthopedic implant placed within a cavity, comprising a sterile orthopedic implant defining the outer surface, Orthopedic implants have an antimicrobial coating on their outer surface, and the antimicrobial coating contains a surface area concentration of a vaporizable antimicrobial agent on the outer surface of the orthopedic implant. The inner surface has a surface area concentration of a vaporizable antibacterial agent. The surface area concentration of the antibacterial coating on orthopedic implants is approximately 5 μg / cm³. 2 ~Approx. 1000μg / cm 2 It is within the range.

[0039] According to this disclosure, an antimicrobial coated implant is described, and this antimicrobial coated implant is Orthopedic implants, wherein the orthopedic implant defines an outer surface that is essentially made of metal or a metal alloy, a polyalkene or its copolymer, or a polyaryletherketone or its copolymer, or a combination thereof, and An antimicrobial coating placed on the outer surface of an orthopedic implant, wherein the antimicrobial implant comprises an antimicrobial coating that essentially consists of a vaporizable antimicrobial agent. Antimicrobial coated implants contain approximately 5 μg / cm³ 2 ~Approx. 1000μg / cm 2The surface area concentration of the antimicrobial agent on the outer surface of the orthopedic implant is within the range of [specify range]. In certain embodiments, the surface area concentration is effective in creating an inhibition zone against microbial colonization units at least 0.5 mm from the outer surface of the orthopedic implant. In certain further embodiments, the surface area concentration is effective in preventing microbial colonization on the outer surface of the orthopedic implant.

[0040] Referring to Figures 1A-C, a method for forming an antimicrobial orthopedic implant is disclosed. The method includes providing a container 100 having a first end 11 and a second end 21, and an inner surface 40 extending between the first end 11 and the second end 21. The inner surface can define a container cavity 50, and the first end 11 can define an opening 70 extending through the container 100 into the cavity 50. According to embodiments of the present invention, the inner surface comprises a non-absorbent material.

[0041] The method further includes the step of placing a reservoir 60 of a vaporizable antimicrobial agent within a container cavity 50. The method further includes the step of placing an orthopedic implant 120 within the cavity 50 through a first end 11, the orthopedic implant 120 defining an outer surface 123.

[0042] Inside of the container As described above, the inner surface 40 comprises a non-absorbent material. As used herein, the non-absorbent material is defined with respect to the described vaporizable antimicrobial agent such that the material comprising the inner surface 40 is resistant to the absorption of the antimicrobial agent. However, the vaporizable antimicrobial agent may be adsorbed onto the inner surface 40. Preferred non-absorbent materials include most metals and metal alloys. Preferred non-absorbent materials include aluminum and its alloys, as well as stainless steel. Furthermore, a material that is otherwise absorbent to the vaporizable antimicrobial agent can be non-absorbent at least along the inner surface 40 of the container 100. For example, referring to Figures 4A-4B, an inner surface 40 having a sealant 35 in the form of a thermally bonded layer is shown at the first end 11. As shown, the layer 35 is metallized in the inner surface 40 having submicrometer-sized metal particles 32. The particles 32 make the inner surface 40 non-absorbent but do not substantially hinder the function of the thermally bonded layer 35 in sealing the first end 11.

[0043] Vaporizable antibacterial agent Suitable antimicrobial agents may be selected from, but are not limited to, halogenated hydroxy ethers, acyloxydiphenyl ethers, or combinations thereof. In particular, the antimicrobial agent may be halogenated 2-hydroxydiphenyl ether and / or halogenated 2-acyloxydiphenyl ether, for example, as represented by the following formula.

[0044] [ka]

[0045] In the above formula, each Hal represents the same or different halogen atom, Z represents hydrogen or an acyl group, and w represents a positive natural number in the range of 1 to 5. Each of the benzene rings is preferably ring A, but may also contain one or more halogenable lower alkyl groups, lower alkoxy groups, allyl groups, cyano groups, amino groups, or lower alkanoyl groups. Preferably, useful lower alkyl groups and lower alkoxy groups as substituents on the benzene ring are methyl groups or methoxy groups, respectively. Halogenated lower alkyl groups and trifluoromethyl groups are preferred.

[0046] Furthermore, antimicrobial activity similar to that of the halogen-o-hydroxy-diphenyl ethers in the above formula can be obtained using O-acyl derivatives that undergo partial or complete hydrolysis under actual usage conditions. Ethers of acetic acid, chloroacetic acid, methyl or dimethylcarbamic acid, benzoic acid, chlorobenzoic acid, methylsulfonic acid, and chloromethylsulfonic acid are particularly preferred.

[0047] One particularly preferred antimicrobial agent within the range of the above formula is 2,4,4'-trichloro-2'-hydroxydiphenyl ether, commonly known as triclosan. Triclosan is a broad-spectrum antimicrobial agent used in a variety of products and is generally effective against a large number of organisms associated with SSI. Such microorganisms include, but are not limited to, Staphylococcus species, Staphylococcus epidermidis, Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus, and combinations thereof.

[0048] In a further embodiment, the method may include depositing a solution of a vaporizable antimicrobial agent and solvent in a cavity 50, evaporating the solvent from the cavity 50 and discharging it from the container 100 to form a reservoir 60 of the vaporizable antimicrobial agent in the cavity 50. In an alternative embodiment, the method may include coating the inner surface 40 of the container 100 with a solution of the vaporizable antimicrobial agent and solvent, evaporating the solvent from the inner surface 40 and discharging it from the container 100 to form a reservoir 60 of the vaporizable antimicrobial agent.

[0049] Orthopedic implants Orthopedic implants are understood to be implantable medical devices that are either prosthetics used to help repair damaged bone or to replace bone. An exemplary and non-limiting list of preferred orthopedic implants provided herein includes bone plates, intramedullary nails, bone screws, pins, spinal rods, K-wires, intervertebral disc replacements, metal compression staples (e.g., Nitinol), metal meshes used in craniofacial applications, external fixation screws or pins (e.g., Schantz screws and Steinmann pins), as well as joint replacement components used in hip, knee, and shoulder replacement procedures, such as acetabular cups, femoral stems, tibial trays, patellar prostheses, and femoral condyle components.

[0050] As described above, the orthopedic implant defines the outer surface 123. The outer surface according to a particular preferred embodiment may include a metal or metal alloy, polyaryletherketone (PAEK) or its copolymer, or polyalkene or its copolymer, or any combination of the aforementioned materials. Preferred metals include, for example, titanium, stainless steel, nickel, cobalt, chromium, and their metal alloys. Preferred polyalkenes are polyethylene or its copolymer. Preferred examples include high-density polyethylene (HDPE), ultra-high molecular weight polyethylene (UHMWPE), medium-density polyethylene (MDPE), ultra-low molecular weight polyethylene (ULMWPE), high molecular weight polyethylene (HMWPE), high-density crosslinked polyethylene (HDXLPE), crosslinked polyethylene (PEX or XLPE), linear low-density polyethylene (LLDPE), low-density polyethylene (LDPE), or very low-density polyethylene (VLDPE), and blends or copolymers thereof. Under certain high-temperature conditions, such as those described below, above 100°C, without thermal degradation or other undesirable effects, those skilled in the art can determine which polyalkenes or copolymers thereof possess the necessary chemical properties to withstand the conditions requiring high temperatures. Preferred examples of PAEK polymers include, but are not limited to, polyether ether ketone (PEEK) carbon-reinforced PEEK, polyether ketone ketone (PEKK), polyether ketone (PEK), or polyether ketone ether ketone ketone (PEKEKK), or blends or copolymers thereof.

[0051] It should be understood that in certain embodiments, a thin film of absorbable biocompatible polymer material can be applied to the outer surface of an orthopedic implant to further increase the surface area concentration of the vaporizable antimicrobial agent. Preferably, the biocompatible polymer material is reabsorbable and has high thermal stability. For example, under conditions utilizing high temperatures in the range of 100°C to 200°C, most biocompatible absorbable materials undergo thermal degradation and are therefore unsuitable for use in the described systems and processes.

[0052] According to this disclosure, the method includes the step of sealing the first end 11 of the container 100 so as to seal the container cavity 50 from the external environment. In certain embodiments, the container 100 is substantially rigid so that the cavity 50 defines a fixed volume. An exemplary rigid container 100 may be a cylindrical aluminum tube schematically shown in Figures 1A to 1C.

[0053] container According to a particular embodiment, the first end 11 of the container 100 includes a threaded region 13 extending around the outer surface of the container 100, the threaded region 13 being configured to engage with a lid 80 having a threaded region 83 corresponding to an inner or outer surface, and the step of sealing the first end 11 of the container 100 includes engaging the first end threaded region 13 with the lid threaded region 83, as shown, for example, in Figure 1B. The embodiment may further include a sealing member 36 positioned between and in contact with the lid threaded region 83 and the first end threaded region 13 during the sealing step. A particular preferred sealing member 36 may include, for example, a crush washer or an O-ring configured to provide a liquid-tight seal.

[0054] Referring to Figure 2, the substantially rigid container is shown in the general shape of a cigar tube having a tapered first end 11, and the lid 80 having a corresponding taper. In addition to the seal formed from the engagement of the respective threaded regions, the taper of the first end 11 and the lid 80 provides a mechanical friction fitting engagement, thereby improving the seal of the container cavity 50.

[0055] According to an alternative embodiment, referring to Figures 3-4, the container 100 is substantially deformable, and the cavity 50 defines a first shape having a first volume when the first end 11 is open, and a second shape having a second volume smaller than the first volume when deformed. In certain other embodiments, the first end 11 is substantially deformable, and the sealing step includes applying pressure to the first end 11 so as to seal the first end 11 by bringing the opposing walls 43, 45 of the inner surface 40 of the first end 11 into contact with each other. In an additional embodiment, at least a portion of the inner surface of the first end 11 contains a sealant 35, such as an adhesive or thermal binder, in such an amount that the opposing walls 43, 45 contact each other to seal the first end 11 when in contact. In an additional alternative embodiment, the sealing step may include applying a mechanical fastener configured to keep the opposing walls in contact with each other to the sealed first end.

[0056] In a further embodiment, referring to Figures 5A to 5B, the container 100 is in the shape of a pre-formed metal tray (e.g., aluminum or other suitable metal or alloy) having a first end 11 (as shown, in this embodiment, the upper portion of the tray) and a second end 21 (as shown, in this embodiment, the bottom or base of the tray), and an inner surface 40 extending between the first end 11 and the second end 21. The inner surface 40 contains a non-absorbent metal and defines a cavity 50 within the container 100. The first end 11 includes an opening 70 extending into the cavity 50, which further includes an orthopedic implant 120 and a reservoir 60 for a vaporizable antimicrobial agent (located at the base of the container 100 as shown herein). The lid 80 is in the form of a metal foil, such as aluminum. The lid 80 is configured to seal the cavity 50 at the opening 70. The sealing between the container 100 and the lid 80 can be achieved, for example, by ultrasonically welding the lid 80 to the container 100 along the periphery of the first end 11. Furthermore, the lid 80 can be sealed with the container 100 by using a sealant containing an adhesive or a thermal binder. The sealing is sufficient to prevent leakage of the vaporizable antimicrobial agent and to maintain it within the cavity during the process of vapor transfer to the outer surface 124 of the orthopedic implant 120.

[0057] In a further embodiment, referring to Figures 1A to 1C, the container 100 may include a porous spacer (not shown) at its bottom (i.e., the second end 21), which can act as a standoff to prevent the orthopedic implant 120 from contacting the inner surface of the bottom of the container 100 when the orthopedic implant 120 is placed inside the container 100. The spacer allows the reservoir 60 to be placed at the bottom of the container 100 below or within the spacer's holes, preventing contact between the orthopedic implant 120 and the reservoir 60, or otherwise preventing the orthopedic implant 100 from obstructing the vaporization of the antimicrobial agent from the reservoir 60.

[0058] In alternative embodiments, the container 100 may be formed (e.g., molded or extruded) from a relatively heat-stable polymer such as polypropylene or nylon that can withstand the dry heat sterilization temperature. In certain embodiments, the container 100 may be rigid as shown and described in Figures 1-2, or it may be flexible but deformable as shown in Figures 3-4. To prevent the absorption of antimicrobial agents onto or into the polymer container, the inner surface 40 may be coated with a thin non-polymer layer, such as a silica coating produced by chemical vapor deposition. The non-polymer coating on the inner surface 40 of the polymer container 100 may also be aluminum or other suitable metals or alloys that can be coated onto the inner surface 40 by, for example, vapor deposition or a vacuum metallization process.

[0059] As shown in Figures 3 and 4, in further embodiments where the container 100 is flexible (or otherwise deformable), the container 100 may also be formed from a thermally stable polymer such as nylon, and may include a thin film of a nonpolymer material such as aluminum or silica coated on the inner surface 40 by either a lamination process or a vapor deposition process.

[0060] According to a further embodiment of the container 100, which is a flexible or otherwise deformable container 100, the container 100 can be formed as a layered laminated film structure having an outer layer of a heat-stable polymer film such as nylon, and an intermediate layer of aluminum foil (or other suitable metal or metal alloy), the inner surface 40 may include a heat-stable polymer film such as nylon, and the reservoir 60 is compounded into the film in the inner surface 40. When the container 100 is subjected to a dry heat sterilization process, for example at 160°C, for 4 hours, some of the antimicrobial agent in the reservoir 60 vaporizes in the inner surface 40 and subsequently deposits on the outer surface 123 of the orthopedic implant 120, forming an antimicrobial coating. The internal metal layer in this embodiment acts as a barrier against the diffusion of the antimicrobial agent, and as a result, the antimicrobial agent remains contained within the container cavity 50.

[0061] Now, returning to the described formation method, once the container is sealed, referring to Figure 1C, the method proceeds in the following steps: The container 100 is heated in a sealed state to heat the outer surface 123 of the orthopedic implant 120 and the reservoir 60 of the vaporizable antimicrobial agent, thereby vaporizing the antimicrobial agent, and This may further include cooling the container 100 while it is sealed. Heating and cooling the container 100 causes the vaporized antimicrobial agent to adsorb onto the outer surface 123 of the orthopedic implant 120 to the non-absorbent material of the inner surface 40 of the container 100, so that an antimicrobial coated orthopedic implant is formed having a surface area concentration of antimicrobial agent 124 on the outer surface of the orthopedic implant that is sufficient to create a clinically effective inhibition zone of at least 0.5 mm from the periphery of the outer surface.

[0062] The heating step may include heating the container to a temperature in the range of about 60°C to 200°C. In a preferred embodiment, the temperature is at least greater than 80°C, for example, about 80°C to 180°C, or 100°C to 170°C, or 120°C to 160°C, or any combination or partial combination of the endpoints of the temperature ranges enumerated herein. Furthermore, the heating step may be carried out in the range of about 10 minutes to about 8 hours, for example, about 30 minutes to about 7 hours, 1 hour to 6 hours, 1 hour to 4 hours, or 2 hours to 4 hours, or any combination or partial combination of the endpoints of the disclosed ranges enumerated herein. According to certain other embodiments, the heating range can be extended from a maximum of about 80 hours, for example, 70 hours, 60 hours, 50 hours, 40 hours, 30 hours, 20 hours, or 10 hours, or any combination or partial combination of the endpoints of the ranges enumerated herein.

[0063] While not bound by any particular theory, the use of non-absorbent material along the inner surface of the container is thought to allow for a greater amount of vaporizable antimicrobial agent to be available on the outer surface of the orthopedic implant, because the inner surface does not act as an absorption sink for the deposition of vaporizable antimicrobial agent. Furthermore, sealing the container results in a greater total mass of vaporizable antimicrobial agent available for deposition on the outer surface of the orthopedic implant. Finally, higher temperatures can also accommodate a greater increase in the amount of vaporization in the reservoir than can be achieved in lower temperature ranges. Therefore, any combination of non-absorbent inner surfaces, sealed container systems, and high temperatures provided in accordance with this disclosure is an improvement over the aforementioned process utilizing standard EO sterilization parameters and enables a wider selection of orthopedic implants formed using antimicrobial deposition so that clinically effective ZOIs can be provided.

[0064] Therefore, according to a particular embodiment, an antimicrobially coated orthopedic implant includes an antimicrobial coating on its outer surface, and the surface area concentration of the antimicrobial agent on the outer surface of the orthopedic implant is approximately 5 μg / cm³. 2 ~Approx. 1000μg / cm 2 A range, for example, 10 μg / cm³ 2 ~Approx. 1000μg / cm 2 , or approximately 5 μg / cm³ 2 ~about 10μg / cm 2 , or approximately 5 μg / cm³ 2 ~Approx. 100μg / cm 2 , or any combination or partial combination of the endpoints of the ranges enumerated herein.

[0065] In additional embodiments, the antimicrobial agent in the reservoir has a total weight, and by vapor deposition, at least 1% to about 95% of the total weight of the antimicrobial agent forms an antimicrobial coating on the outer surface of the orthopedic implant. If the outer surface of the orthopedic implant contains metal or a metal alloy, or substantially or mostly metal or a metal alloy, the weight percentage of the antimicrobial agent contained in the antimicrobial coating may be at the lower end of the listed weight percentage ranges. Suitable weight percentage ranges for substantially or almost entirely metal or metal alloy outer surfaces may further include, for example, 1% to about 20%, or 1% to about 10%, or about 1% to about 5%, or about 5% to about 10%, or about 5% to about 20%, and any combination or partial combination of the endpoints of the ranges listed herein. If the outer surface of the implant contains at least partially or almost entirely a polymer or copolymer, the weight percentage range may include endpoints of over 30% to about 95%, for example, 40%, 50%, 60%, 70%, 80%, or 90%.

[0066] Although the above method is described in the context of performing sterilization on orthopedic implants using the high-temperature process described above, it should be understood that the method can be applied to perioperative and intraoperative situations, and the above method steps can be performed in the operating room or near the operating site during or close to the time frame of surgery. The above components can be provided to the surgeon or surgical team member as a prepared system (i.e., an already sealed container containing an orthopedic implant and reservoir in a cavity, requiring only heating and cooling to vaporize an antimicrobial agent onto the outer surface of the implant). Alternatively, separate components can be provided for perioperative assembly, in which case the heating and cooling steps can be performed after the assembly of the components and sealing of the container are completed according to the above steps.

[0067] According to this disclosure, referring to Figures 1A-B, the system for forming the antimicrobial orthopedic implant described in the above process is: Reservoir 60 of vaporizable antibacterial agent, An orthopedic implant 120 defining the outer surface 123, and A container 100 having a first end 11 and a second end 21, and an inner surface 40 extending between the first end 11 and the second end 21, wherein the inner surface 40 defines a cavity 50 made of a non-absorbable material and configured to receive an orthopedic implant 120, and the first end 11 defines a sealable opening 70 extending into the cavity 50, The container 100, the orthopedic implant 120, and the vaporizable antimicrobial agent are configured to remain thermally stable in a temperature range of up to 200°C. A reservoir 60 containing a vaporizable antimicrobial agent is placed inside container 100. The orthopedic implant 120 is placed within the cavity 50, and its outer surface 123 is substantially free of vaporizable antimicrobial agents.

[0068] The systems described herein can be considered embodiments of this disclosure relating to the arrangement of the enumerated elements prior to the aforementioned heating and cooling steps (for example, as shown in Figures 1A-B). It should be understood that the features and components described above, and their respective properties, when describing a method for forming an antimicrobially coated implant, are equally applicable herein when describing the individual components of the system. For example, the description provided above for a vaporizable antimicrobial agent is considered equally applicable when describing the various elements and features of the system. Furthermore, the features or sub-features or elements described above for the container 100, the orthopedic implant 120, or any other elements, and arising therefrom, are also applicable herein.

[0069] Therefore, the system comprises a reservoir 60 of a vaporizable antimicrobial agent, the vaporizable antimicrobial agent comprising halogenated hydroxyl ethers, acyloxydiphenyl ethers, or combinations thereof. In certain embodiments, the vaporizable antimicrobial agent comprises 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan).

[0070] According to additional embodiments, the outer surface 123 of the orthopedic implant 120 comprises at least polyaryletherketone (PAEK) or its copolymer, polyalkene or its copolymer, or metal or metal alloy, or a combination thereof. In certain embodiments, the outer surface comprises metal or metal alloy. Preferably, the metal is titanium, stainless steel, or an alloy containing titanium or steel. In certain embodiments, the outer surface comprises PAEK or its copolymer. Preferably, PAEK is polyetheretherketone (PEEK) or its copolymer. In certain embodiments, the outer surface comprises polyalkene or its copolymer. Preferably, the polyalkene is polyethylene or its copolymer.

[0071] In certain embodiments of the system, the container 100 is substantially rigid so that the cavity 50 defines a fixed volume. In certain further embodiments, the first end 11 includes a threaded region 13 extending around the outer surface of the container 100, and the system further includes a lid 80 having a threaded region 83 configured to engage with the first end threaded region 13, the engagement between the first end threaded region 13 and the lid threaded region 83 sealing the first end 11. In additional embodiments, the system may further include a sealing member 36 positioned between the lid threaded region 83 and the first end threaded region 13 and configured to contact them.

[0072] In an alternative embodiment, the container 100 is substantially deformable, and the cavity 50 defines a first shape having a first volume when the opening 70 is open at the first end 11, and the container 100 is configured to deform when pressure is applied to take a second shape in which the cavity 50 has a second volume smaller than the first volume. In an additional embodiment, the first end 11 is substantially deformable such that the opposing walls 43, 45 of the inner surface 40 at the first end 11 are configured to come into contact with each other when force is applied to close the opening 70 and seal the first end 11. In an additional embodiment, at least a portion of the inner surface at the first end 11 contains a sealant 35, such as an adhesive or thermal binder, in an amount such that the opposing walls 43, 45 come into contact with each other to seal the first end 11 when in contact. In an additional alternative embodiment, the system includes mechanical fasteners configured to keep the opposing walls 43, 45 in contact with each other.

[0073] In further embodiments, the second end 21 defines a sealable opening extending into the cavity 50. In some embodiments, the second end 21 is substantially deformable such that opposing walls 43, 45 of the inner surface 40 at the second end are configured to contact each other and seal the second end when force is applied.

[0074] According to this disclosure, with reference to Figure 1C, a packaging configuration for a sterile antimicrobial orthopedic implant is described, and this packaging configuration is, A sealed sterile container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface contains a non-absorbent material and defines a cavity, and the first end defines a sealable opening extending into the cavity, A sterile orthopedic implant placed within a cavity, comprising a sterile orthopedic implant defining the outer surface, Orthopedic implants have an antimicrobial coating on their outer surface, and the antimicrobial coating contains a surface area concentration of a vaporizable antimicrobial agent on the outer surface of the orthopedic implant. The inner surface has a density of approximately 5 μg / cm³. 2~Approx. 1000μg / cm 2 It has a surface area concentration of vaporizable antimicrobial agents within the range of [specify range].

[0075] The packaging configurations described herein can be considered embodiments relating to the arrangement and features of the enumerated elements after the dry heat sterilization and vapor deposition processes have been completed and the antimicrobial coating has been formed on the outer surface of the orthopedic implant.

[0076] According to certain embodiments, the vaporizable antimicrobial agent of the antimicrobial coating includes halogenated hydroxyl ethers, acyloxydiphenyl ethers, or combinations thereof. In preferred embodiments, the vaporizable antimicrobial agent includes 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan).

[0077] According to additional embodiments, the outer surface 123 of the orthopedic implant 120 comprises at least polyaryletherketone (PAEK) or its copolymer, polyalkene or its copolymer, or metal or metal alloy, or a combination thereof. In certain embodiments, the outer surface comprises metal or metal alloy. Preferably, the metal is titanium, stainless steel, or an alloy containing titanium or steel. In certain embodiments, the outer surface comprises PAEK or its copolymer. Preferably, PAEK is polyetheretherketone (PEEK) or its copolymer. In certain embodiments, the outer surface comprises polyalkene or its copolymer. Preferably, the polyalkene is polyethylene or its copolymer.

[0078] According to a particular embodiment, the first end 11 includes a threaded region 13 extending around the outer surface of the container 100, and the packaging configuration further includes a lid 80 having a threaded region 83 engaged with the first end threaded region 13 so as to seal the first end 11. In an additional embodiment, the system may further include a sealing member 36, such as a crush washer or O-ring, positioned and in contact between the lid threaded region 83 and the first end threaded region 13.

[0079] In further embodiments, for example, as shown in Figures 4A to 4B, at least a portion of the inner surface 40 at the first end 11 contains a sealant 35 in an amount that connects the opposing walls 43, 45 to each other in order to seal the first end 11. Examples of the sealant 35 include adhesive materials or thermal bonding materials. In additional embodiments, the packaging configuration may include mechanical fasteners applied to the opposing walls 43, 45 to bring the opposing walls 43, 45 into contact with each other and seal the container 100.

[0080] According to a particular embodiment, an antimicrobially coated orthopedic implant includes an antimicrobial coating on its outer surface, and the surface area concentration of the antimicrobial agent on the outer surface of the orthopedic implant is approximately 5 μg / cm³. 2 ~Approx. 1000μg / cm 2 This is within the range. In additional embodiments, the vaporizable antimicrobial agent in the container has a total weight, and at least 1% of the total weight of the vaporizable antimicrobial agent is contained in an antimicrobial coating on an orthopedic implant.

[0081] According to this disclosure, an antimicrobial coated implant is described, and this antimicrobial coated implant is Orthopedic implants, wherein the orthopedic implant defines an outer surface that is essentially made of metal or a metal alloy, a polyalkene or its copolymer, or a polyaryletherketone or its copolymer, or a combination thereof, and An antimicrobial coating placed on the outer surface of an orthopedic implant, wherein the antimicrobial implant comprises an antimicrobial coating that essentially consists of a vaporizable antimicrobial agent. Antimicrobial coated implants contain approximately 5 μg / cm³ 2 ~Approx. 1000μg / cm 2 Having a surface area concentration of antibacterial agents on the outer surface of orthopedic implants within the range, Surface area concentration creates a clinically effective inhibition zone against microbial-forming units at least 0.5 mm from the outer surface of orthopedic implants.

[0082] According to a particular embodiment, the outer surface is a metal or a metal alloy. In a preferred embodiment, the metal or metal alloy is titanium or stainless steel or an alloy thereof. According to a particular embodiment, the outer surface is a polyalkene or a copolymer thereof. In a preferred embodiment, the polyalkene is polyethylene or a copolymer thereof. According to a particular embodiment, the outer surface is PAEK or a copolymer thereof. In a preferred embodiment, PAEK is polyetheretherketone (PEEK).

[0083] According to certain embodiments, the outer surface includes a combination of the aforementioned materials. For example, in certain embodiments, the outer surface essentially consists of a metal or metal alloy and a polyalkene or its copolymer. Preferably, the outer surface essentially consists of titanium or stainless steel or their alloys and polyethylene or its copolymer. In certain alternative embodiments, the outer surface essentially consists of a metal or metal alloy and a polyaryletherketone or its copolymer. Preferably, the outer surface essentially consists of titanium or stainless steel or their alloy, and PEEK or its copolymer. In certain further alternative embodiments, the outer surface essentially consists of a polyalkene or its copolymer and a polyaryletherketone or its copolymer. Preferably, the outer surface essentially consists of polyethylene or its copolymer and PEEK or its copolymer.

[0084] According to certain embodiments, the vaporizable antimicrobial agent includes halogenated hydroxyl ethers, acyloxydiphenyl ethers, or combinations thereof. Preferably, the vaporizable antimicrobial agent includes 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan).

[0085] According to an additional embodiment, the antimicrobial coating is applied to the outer surface of an orthopedic implant at a density of 10 μg / cm². 2 ~Approx. 1000μg / cm 2 This results in a surface area concentration within a certain range.

[0086] In further embodiments, the effective ZOI of an antimicrobially coated implant is in the range of approximately 0.5 mm to approximately 5.0 mm. [Examples]

[0087] In the following embodiments, unless otherwise specified, ethylene oxide (EO) sterilization conditions (or “process” or “parameters,” etc.) refer to exposing the implant to 55°C at ambient pressure for 15 minutes, followed by further exposure to 55°C under vacuum for 3 hours and 45 minutes.

[0088] (Example 1) We attempted to vapor transfer triclosan to a metal orthopedic implant according to the process described in U.S. Patent No. 8,668,867 to investigate whether the described process can effectively adhere triclosan to the metal surface.

[0089] 1) Titanium alloy (Ti-6Al-7Nb(TAN)), 2) 316L stainless steel, and 3) approximately 0.55 mg / cm³ 2 A series of metal pins (approximately 4 mm x 30 mm) including TAN pins with poly(D,L-lactide) (PLA) coating were tested.

[0090] Triclosan (IRGACARE MP Triclosan Lot No. 0013227542) was incorporated into a high-density polyethylene (HDPE) sheet at a concentration of 2.56% by weight (approximately 16 mg of triclosan).

[0091] The pins were co-packaged with a triclosan-impregnated HDPE sheet in a four-layer packaging material suitable for EO sterilization, which had an outer PET layer, a polyethylene layer, a foil moisture-proof layer, and an inner polyethylene heat-sealing layer, with the foil layer (moisture-proof layer) positioned between two other layers. The packaging was sterilized and heat-treated at 55°C for 4 hours.

[0092] After the EO sterilization process was completed, the antimicrobial activity of the pins was measured. 3.03 × 10⁻⁶ 9CFU / mL of Staphylococcus aureus (S. aureus) was spread onto a pre-formed plate using a sterile cotton swab, and pins were gently pressed into the surface of the spread plate, but they did not penetrate the agar. The plate was incubated for 24 hours, and then the ZOI was measured for each pin.

[0093] The total band was measured across the width of the implant (short axis), and the results are as follows: Stainless steel: Minimal observed growth reduction zone (without ZOI), TAN: The observed growth reduction zone is smallest (including ZOI), The TAN-PLA material was 12.4mm ZOI.

[0094] Considering the width of the implant (approximately 4.0 mm), and dividing by 2 to account for the ZOI on each side of the implant, the ZOI around each implant type is as follows: Stainless steel: None, TAN: None, The TAN-PLA was approximately 4.2 mm thick.

[0095] Therefore, the results showed that only polymer-coated pins (TAN-PLA) could provide clinically effective ZOI, while pins with only a metal substrate surface were unable to retain a clinically significant amount of triclosan.

[0096] (Example 2) The following tests were conducted from the perspective of Experiment 1 to identify methods for increasing triclosan retention on metal substrate surfaces. Metal implants were subjected to alkaline surface treatment and a dry heat transfer process in packaging having a substantially metallic inner surface. Triclosan content was measured by UV assay, and ZOI was measured using the pour plate method. The results were compared with those of Example 1.

[0097] The implants used in this test were 12 titanium anodized screws (4.0 mm x 24 mm inner diameter) and 26 TAN anodized pins (4.0 mm x 30 mm). The alkali treatment composition was potassium hydroxide (KOH) for 4 hours, 8 hours, or 24 hours. Subsequently, the implants were subjected to triclosan deposition under high temperature conditions in a container with an aluminum inner surface.

[0098] Alkaline treatment The sample was washed with 1% Alconox, scrubbed thoroughly with a brush, and then washed with DI water.

[0099] Next, the samples were placed together in a beaker, 300 mL of DI water was added, and the mixture was heated and boiled for 15 minutes. Then, the beaker was cooled, the samples were removed, and they were air-dried on crumpled aluminum foil.

[0100] A 6M KOH solution was prepared. Using five separate Nalgene plastic bottles with lids, the samples were separated as follows: six screws treated with KOH for 8 hours, six screws treated with KOH for 24 hours, seven pins treated with KOH for 8 hours, seven pins treated with KOH for 24 hours, and twelve pins treated with KOH for 4 hours. All bottles were left at 60°C for the desired time. The bottle lids were left slightly loose to prevent gas buildup.

[0101] After the processing time for each bottle was complete, the KOH solution was removed from the bottles, leaving the samples. The bottles were rinsed three times with DI water, and then the samples were immersed in PBS for approximately 5 minutes. The PBS was removed, and each bottle was washed again three times with DI water. The samples were then removed from each bottle and placed on crumpled aluminum foil until dry.

[0102] Triclosan vapor deposition Aluminum bottle with aluminum foil seal A triclosan / ethyl acetate mixture was prepared by weighing 60 mg of triclosan and placing it in an aluminum bottle with 0.5 mL of ethyl acetate, then rotating the bottle. The lid was removed from the bottle and it was air-dried overnight.

[0103] Next, the sample was placed in a bottle and suspended in place using a steel wire frame.

[0104] Once the sample was in place, multiple layers of aluminum foil were placed over the bottle opening and tightly wrinkled to form a seal. The seal was reinforced by wrapping steel wire around the foil lid.

[0105] The sample bottle was placed in a 160°C oven for approximately 4 hours.

[0106] To compare the results, several additional samples were subjected to triclosan deposition in Example 1 according to the process described above. Table 1 below shows the decomposition of the samples and the respective processing conditions.

[0107] [Table 1] ** For reasons unknown, the bacteria used for testing with the pour plate method were not viable, and therefore no data regarding ZOI was generated.

[0108] Table 2 below provides SEM images of the surface of TAN pins after KOH treatment, showing the increase in surface area with increasing duration of potassium hydroxide alkali treatment of anodized TAN pins.

[0109] [Table 2]

[0110] [Table 3]

[0111] [Table 4]

[0112] Triclosan extraction and UV measurement In this process, extraction times of 2 hours, 4 hours, and 24 hours were investigated to determine whether a quantity of triclosan had deposited on the sample implant. A triclosan standard was prepared by weighing the initial mass of triclosan into a volumetric flask and dissolving it in 10 mL of solvent (100% acetonitrile). Using this stock solution of triclosan, a standard was prepared in a 10 mL volumetric flask and covered with foil to protect it from light. Then, 1 mL of the sample was transferred to a plastic cuvette and analyzed under UV light at 280 nm using a NanoDrop2000c spectrophotometer. After creating a standard curve by plotting the absorbance at 280 nm against the triclosan concentration, the implant samples described above were analyzed.

[0113] Sample preparation 1. Pins or screws treated with triclosan in a bottle or pouch were placed in a sterile 15 mL centrifuge tube. 2.5 mL of acetonitrile was added to each tube placed on a shaking incubator. The tubes were shaken at 250 rpm for 2 hours, 4 hours, or 24 hours. 3. The pins and screws were then transferred to separate sterile tubes. The sample solution was stored at 4°C until analysis. 4. For analysis, a 15 mL centrifuge tube containing the sample was vortexed for a short time. Next, 5.1 mL of the sample was analyzed at a wavelength of 280 nm using a UV Nanodrop instrument, and the concentration of each sample was determined from the constructed standard curve. Samples showing very high initial absorbance were diluted 1:10 with acetonitrile.

[0114] [Table 5]

[0115] [Table 6]

[0116] A 4mm x 30mm anodized TAN pin treated with alkali for 4 hours had 1.50 mg of triclosan on its surface when triclosan transfer was performed in a metal container at 160°C for 4 hours. In contrast, the same sample subjected to triclosan transfer from a sleeve in a foil pouch at 55°C showed only 0.027 mg of triclosan. Therefore, comparing the same metal substrate and alkalization conditions, dry-heat sealed metal containers resulted in a more than 55-fold increase in triclosan on the implant surface compared to EO sterilization conditions.

[0117] [Table 7]

[0118] The duration of the alkaline treatment is positively correlated with the amount of triclosan recovered from the pin surface in a dry heat process within an all-metal container.

[0119] Example 3: Cooling rate for high heat transfer processes This experiment was conducted to determine whether the cooling rate after a dry heat transfer process in an aluminum container, as described in Example 2, affects the deposition of triclosan onto TAN pins. In this experiment, the difference in deposition was measured between cases where the pins were left to cool in a hot oven and cases where they were immediately placed on a cold countertop to cool.

[0120] The aluminum bottle containers were first washed with IPA and ethyl acetate and then dried. Next, 2 mg of triclosan was placed in each bottle. A porous stainless steel metal mesh was placed at the bottom of each container to act as a standoff to prevent the pins from directly contacting the triclosan reservoir.

[0121] TAN pins were placed in the containers, one pin per container. The aluminum containers were sealed with lids, and each included an aluminum crush washer.

[0122] The bottle was placed in the oven and heated at 160°C for 4 hours.

[0123] After the heat cycle was complete, I turned off the oven. I immediately removed half of the bottle from the oven and placed it on a cool countertop, leaving the other half inside the oven.

[0124] Table 8 below shows the reservoir weight of triclosan before heating began, the initial mass of the system, and the final mass of the system after cooling was complete. System mass loss is recorded as the difference between the initial and final masses of the sample and can only be attributed to the loss of vaporized triclosan from the container during either heating or cooling.

[0125] [Table 8]

[0126] The surface triclosan content of the sample pins was further measured by UV analysis using the same method as described in Example 2. The UV data is shown in Table 9 below.

[0127] [Table 9]

[0128] Example 4: Alkali-to-non-alkali dry heat treatment The objective of this experiment was to evaluate the effect of alkali treatment on TAN pins as described in Example 2. Untreated electropolished stainless steel pins were added to this study to refer to the observed effect of alkali treatment on TAN pins. This study used the same parameters as in Example 2, administering 2 / 3 mg, 2 mg, or 6 mg of triclosan to alkali-treated and untreated TAN pins. The results were measured using UV analysis as described in Example 2. In this example, the dose of triclosan was varied to observe whether the implant could still adsorb an effective amount of triclosan in a relatively low mass reservoir within the container system.

[0129] Alkali-treated sample The alkaline-treated pins underwent the same process as described in Example 2 for an 8-hour alkaline treatment.

[0130] Preparation of triclosan reservoir The aluminum bottle containers were washed and cleaned with IPA and ethyl acetate.

[0131] A triclosan solution was prepared by adding 48 mg of triclosan to 800 μL of ethyl acetate (60 mg / ml).

[0132] 10 μL of solution was added to the bottle containing the 2 / 3 mg dose, 30 μL to the bottle containing the 2 mg dose, and 90 μL to the bottle containing the 6 mg dose. Then, ethyl acetate was added to each bottle to bring the total volume of each container to 100 μL.

[0133] The containers were left unsealed and allowed to dry overnight.

[0134] As described in the example, each container had a metal mesh offset positioned at the bottom of the container. Pins were then added to the containers, one pin per bottle. The bottles were then sealed with lids, including aluminum crush washers.

[0135] Next, the sample was placed in an oven at 160°C for 4 hours.

[0136] Table 10 (and Figure 6) below shows the theoretical dose applied to each container, the amount of triclosan in each container measured by mass difference, the amount of triclosan on each implant after the dry heat transfer process measured by the UV method described above, and the calculated amount of triclosan on each pin as a weight percentage of the measured original amount of triclosan in the reservoir.

[0137] [Table 10]

[0138] TIFF2026083201000013.tif87133

[0139] These results indicate that alkali treatment improved triclosan adsorption to TAN pins, but this was not statistically significant. The tests further showed that TAN as a metal substrate surface appeared to have a higher affinity for triclosan than electropolished stainless steel. These tests further confirmed that, regardless of the metal substrate surface, increasing the dose at the lower limit correspondingly increased the amount of triclosan that migrated onto the outer surface of the implant.

[0140] Example 5: Comparison of high-temperature triclosan migration versus implant surface This experiment was conducted to further investigate triclosan vapor transfer under dry heat versus EO sterilization process conditions, as previously performed in Example 2. Furthermore, in this test, PEEK was added as the implant surface substrate. As previously mentioned, under EO sterilization conditions, it is presumed that the polymer substrate surface has a sufficiently high affinity for triclosan, offsetting the loss of reservoir mass and still absorbing a sufficient amount. This test directly compares the ability of the dry heat transfer process to deposit triclosan on the PEEK surface with the transfer process under EO sterilization conditions. Furthermore, in both Example 1 and Example 2, implants with metal substrate surfaces were unable to achieve a significant amount of triclosan on the surface under the EO sterilization transfer process.

[0141] In this experiment, for each implant material and transfer condition, samples will be tested for triclosan content by both UV analysis and ZOI measurement using a pour plate protocol with Staphylococcus aureus (S. Aureus) in agar plates. Furthermore, the robustness of the antimicrobial coating on the surface of each sample will be measured by testing the samples immediately after the vapor transfer process is complete, and after immersion in PBS solution for 1 hour and 24 hours.

[0142] Table 11 below shows the samples used in this test, identified by implant material type (e.g., steel, TAN, or PEEK), migration conditions (EO pouch method or high-temperature bottle method), and elution time. The table is broken down into sample IDs based on UV analysis and ZOI analysis.

[0143] [Table 11]

[0144] Triclosan content - ZOI

[0145] [Table 12]

[0146] Table 12 below shows a relative comparison of triclosan dose, packaging material, temperature and time parameters, sample surface substrate, post-treatment test conditions, and measurement parameters for both UV and ZOI analysis.

[0147] [Table 13]

[0148] [Table 14]

[0149] [Table 15]

[0150] [Table 16]

[0151] As can be seen in the table, for all materials, the initial triclosan transferred to the target device was more than 10 times higher in the non-absorbent packaging at 160°C compared to the EO pouch. This is despite the fact that the EO pouch packaging contained 13.6 mg of triclosan compared to 1.86 mg in the metal bottle container. For metal samples, this resulted in effective ZOI ranging from over 2 mm initially and after 1 hour, whereas the ZOI generated by samples in the EO pouch container was less than 1 mm for TAN pins and indistinguishable for electropolished stainless steel. PEEK samples had more than 10 times the amount of triclosan at all time points, demonstrating sustained retention of triclosan after implantation, although the ZOI was similar to when either sample was immediately placed on a pour plate or when the sample was pre-eluted for 1 hour. The observation of ZOIs (0.7 mm) in the high-temperature PEEK sample at 24 hours, compared to the absence of zones in conventionally processed PEEK samples, may be due to the continued retention of triclosan remaining after 24 hours of pre-elution (0.12 mg vs. 0.004 mg).

[0152] [Implementation Method] (1) A method for forming an antimicrobial implant, To provide a container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface contains a non-absorbent material, defines a container cavity, and the first end defines an opening extending into the container cavity. A reservoir of vaporizable antibacterial agent is placed inside the container cavity, The orthopedic implant is positioned within the container cavity through the first end, wherein the orthopedic implant defines the outer surface, To seal the first end of the container so as to seal the container cavity, The outer surface of the orthopedic implant and the reservoir of the vaporizable antibacterial agent are heated, and the sealed container is heated to vaporize the antibacterial agent. This includes cooling the container while it is sealed, A method for adsorbing vaporized antimicrobial agent onto the outer surface of an orthopedic implant such that heating and cooling of the container results in the formation of an antimicrobial coated orthopedic implant having a surface area concentration of the antimicrobial agent on the outer surface of the orthopedic implant that is sufficient to generate an effective barrier of at least 0.5 mm around the outer surface. (2) The method according to Embodiment 1, wherein the arrangement of the reservoir for the vaporizable antimicrobial agent includes depositing a solution of the vaporizable antimicrobial agent and solvent in the cavity and evaporating the solvent from the cavity to the outside of the container. (3) The method according to Embodiment 1, wherein the arrangement of the reservoir of the vaporizable antimicrobial agent includes coating the inner surface of the container with a solution of the vaporizable antimicrobial agent and solvent, and evaporating the solvent from the inner surface to the outside of the container. (4) The method according to any one of Embodiments 1 to 3, wherein the vaporizable antimicrobial agent comprises a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof. (5) The method according to Embodiment 4, wherein the vaporizable antimicrobial agent comprises 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan).

[0153] (6) The method according to any one of embodiments 1 to 5, wherein the outer surface of the orthopedic implant comprises at least polyaryletherketone (PAEK) or polyalken or copolymer thereof, or metal or metal alloy, or a combination thereof. (7) The method according to embodiment 6, wherein the outer surface includes a metal or a metal alloy. (8) The method according to Embodiment 7, wherein the metal is titanium, stainless steel, or an alloy containing titanium or steel. (9) The method according to Embodiment 6, wherein the PAEK is polyether ether ketone (PEEK) or a copolymer thereof. (10) The method according to Embodiment 6, wherein the polyalkene is polyethylene or a copolymer thereof.

[0154] (11) The method according to any one of embodiments 1 to 10, wherein the heating step includes heating to a temperature range of about 60°C to about 200°C. (12) The method according to Embodiment 11, wherein the heating step includes heating to a temperature range of about 80°C to about 180°C. (13) The method according to Embodiment 11, wherein the heating step includes heating to a temperature range of about 120°C to about 160°C. (14) The method according to any one of embodiments 1 to 13, wherein the heating step is in the range of about 10 minutes to about 8 hours. (15) The method according to Embodiment 14, wherein the heating step is in the range of about 3 to 6 hours.

[0155] (16) The method according to any one of embodiments 1 to 15, wherein the inner surface includes a metal or a metal alloy. (17) The method according to embodiment 16, wherein the inner surface comprises aluminum or an alloy thereof. (18) The surface area concentration of the antibacterial agent on the outer surface of the orthopedic implant is approximately 5 μg / cm² 2 ~Approx. 1000μg / cm 2 The method according to any one of embodiments 1 to 17, which falls within the range of [the specified range]. (19) The method according to any one of embodiments 1 to 18, wherein the antimicrobial agent in the reservoir has a total weight, and at least 1% to about 20% of the total weight of the antimicrobial agent is vapor-transferred onto the outer surface of the antimicrobial-coated orthopedic implant. (20) The method according to any one of embodiments 1 to 19, wherein the container is substantially rigid such that the cavity defines a fixed volume.

[0156] (21) The method according to any one of embodiments 1 to 20, wherein the first end includes a threaded region extending around the outer surface of the container, the threaded region being configured to engage with a lid having a corresponding threaded region on the inner surface, and the step of sealing the first end of the container includes engaging the first end threaded region and the lid threaded region. (22) The method according to embodiment 21, further comprising a sealing member positioned between the lid thread region and the first end thread region and configured to contact them during the sealing step. (23) The method according to any one of embodiments 1 to 19, wherein the container is substantially deformable, and the cavity defines a first shape having a first volume when the first end is open, and when deformed, the cavity takes on a second shape having a second volume smaller than the first volume. (24) The method according to Embodiment 23, wherein the first end is substantially deformable, and the sealing step includes applying pressure to the first end to seal the first end by bringing the opposing inner walls of the first end into contact with each other. (25) The method according to Embodiment 24, wherein at least a portion of the inner surface of the first end contains an amount of sealant such that the opposing walls bond to each other when in contact, in order to seal the first end.

[0157] (26) The method according to embodiment 24, further comprising applying a mechanical fastener configured to keep the opposing walls in contact with each other to the sealed first end. (27) The method according to any one of embodiments 1 to 26, wherein the second end is open, and the sealing step further comprises sealing the second end. (28) The method according to Embodiment 27, wherein the second end is substantially deformable, and as a result the sealing step further includes applying pressure to the second end so that the opposing inner walls of the second end come into contact with each other and the second end is sealed. (29) A system for forming an antimicrobial implant, A reservoir for vaporizable antimicrobial agents, Orthopedic implants that define the external surface, A container comprising a first end and a second end, and an inner surface made of a non-absorbable material extending between the first end and the second end, wherein the inner surface defines a cavity configured to receive the orthopedic implant, and the first end defines a sealable opening extending into the cavity, The container, the orthopedic implant, and the vaporizable antimicrobial agent are configured to remain thermally stable in a temperature range of up to 200°C. A system in which a reservoir of the vaporizable antimicrobial agent is placed inside the container, the orthopedic implant is placed inside the cavity, and the outer surface is substantially free of the vaporizable antimicrobial agent. (30) The system according to Embodiment 29, wherein the vaporizable antimicrobial agent comprises a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof.

[0158] (31) The system according to Embodiment 30, wherein the vaporizable antimicrobial agent comprises 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan). (32) The system according to any one of embodiments 1 to 31, wherein the outer surface of the orthopedic implant comprises at least polyaryletherketone (PAEK), polyalkene, or metal or metal alloy, or a combination thereof. (33) The system according to embodiment 32, wherein the outer surface includes a metal or a metal alloy. (34) The system according to embodiment 33, wherein the metal is titanium, stainless steel, or an alloy containing titanium or steel. (35) The system according to embodiment 32, wherein the PAEK is polyetheretherketone (PEEK) or a copolymer thereof.

[0159] (36) The system according to embodiment 32, wherein the polyalkene is polyethylene or a copolymer thereof. (37) The system according to any one of embodiments 29 to 36, wherein the container is substantially rigid such that the cavity defines a fixed volume. (38) The system according to any one of embodiments 29 to 37, wherein the first end includes a threaded region extending around the outer surface of the container, and the system further includes a lid having a threaded region configured to engage with the first end threaded region, the engagement between the first end threaded region and the lid threaded region seals the first end. (39) The system according to embodiment 38, further comprising a sealing member positioned between the lid thread region and the first end thread region and configured to contact them. (40) The system according to any one of embodiments 29 to 36, wherein the container is substantially deformable, and the cavity defines a first shape having a first volume when the first end is open, and the container is configured to deform when pressure is applied to take a second shape having a second volume less than the first volume of the cavity.

[0160] (41) The system according to any one of embodiments 29 to 36, wherein the first end is substantially deformable such that the opposing inner walls at the first end are configured to come into contact with each other and seal the first end when force is applied. (42) The system according to embodiment 41, wherein at least a portion of the inner surface at the first end contains an amount of sealant configured to bond the opposing walls together in order to seal the first end. (43) The system according to Embodiment 42, wherein the sealing agent includes an adhesive material or a thermal bonding material. (44) The system according to embodiment 41, further comprising a mechanical fastener configured to keep the opposing walls in contact with each other in order to seal the container. (45) The system according to any one of embodiments 29 to 44, wherein the second end defines a sealable opening extending into the cavity.

[0161] (46) The system according to embodiment 45, wherein the second end is substantially deformable such that the opposing inner walls at the second end are configured to come into contact with each other and seal the second end when force is applied. (47) Packaging configuration for sterile antimicrobial orthopedic implants, A sealed sterilization container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface contains a non-absorbent material and defines a cavity, and the first end defines a sealable opening extending into the cavity, A sterile orthopedic implant disposed within the cavity, wherein the orthopedic implant includes a sterile orthopedic implant that defines the outer surface, The orthopedic implant has an antimicrobial coating on its outer surface, and the antimicrobial coating comprises a surface area concentration of a vaporizable antimicrobial agent on the outer surface of the orthopedic implant. The surface area concentration of the antibacterial coating on the orthopedic implant is approximately 5 μg / cm². 2 ~Approx. 1000μg / cm 2 Packaging configurations within the range of. (48) The packaging configuration according to Embodiment 47, wherein the vaporizable antimicrobial agent comprises a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof. (49) The packaging configuration according to Embodiment 48, wherein the vaporizable antimicrobial agent comprises 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan). (50) The packaging configuration according to any one of embodiments 47 to 49, wherein the outer surface of the orthopedic implant comprises at least polyaryletherketone (PAEK), polyalkene, or metal or metal alloy, or a combination thereof.

[0162] (51) The packaging configuration according to Embodiment 50, wherein the outer surface includes metal or a metal alloy. (52) The packaging configuration according to Embodiment 50, wherein the metal is titanium, stainless steel, or an alloy containing titanium or steel. (53) The packaging configuration according to Embodiment 50, wherein the PAEK is polyetheretherketone (PEEK) or a copolymer thereof. (54) The packaging configuration according to Embodiment 51, wherein the polyalkene is polyethylene or a copolymer thereof. (55) The packaging configuration according to any one of embodiments 47 to 54, wherein the container is substantially rigid such that the cavity defines a fixed volume.

[0163] (56) The packaging configuration according to any one of embodiments 47 to 55, wherein the first end includes a threaded region extending around the outer surface of the container, and the system further includes a lid having a threaded region engaged with the first end threaded region so that the first end is sealed. (57) The packaging configuration according to embodiment 56, further comprising a sealing member positioned between the lid screw region and the first end screw region and in contact with them. (58) The packaging configuration according to any one of embodiments 47 to 54, wherein the container is substantially deformable, and the cavity defines a first shape having a first volume when the first end is open, and the container is configured to deform when pressure is applied to take a second shape having a second volume smaller than the first volume. (59) The packaging configuration according to any one of embodiments 47 to 54, wherein the first end is substantially deformable such that the opposing inner walls at the first end are configured to come into contact with each other and seal the first end when force is applied. (60) The packaging configuration according to Embodiment 59, wherein at least a portion of the inner surface at the first end contains an amount of sealant that connects the opposing walls to each other in order to seal the first end.

[0164] (61) The packaging configuration according to Embodiment 60, wherein the sealing agent includes an adhesive material or a thermal bonding material. (62) The packaging configuration according to embodiment 59, further comprising a mechanical fastener configured to keep the opposing walls in contact with each other in order to seal the container. (63) The packaging configuration according to any one of embodiments 47 to 62, wherein the second end defines a sealable opening extending into the cavity. (64) The packaging configuration according to embodiment 63, wherein the second end is substantially deformable such that the opposing inner walls at the first end are configured to come into contact with each other and seal the second end when force is applied. (65) The surface area concentration of the antibacterial coating is approximately 10 μg / cm² 2 ~Approx. 1000μg / cm 2 A packaging configuration according to any of embodiments 47 to 64, which falls within the range of the specified dimensions.

[0165] (66) The packaging configuration according to any one of embodiments 47 to 64, wherein the vaporizable antimicrobial agent has a total weight, and at least 1% to a maximum of about 20% of the total weight of the vaporizable antimicrobial agent is contained in the antimicrobial coating on the orthopedic implant. (67) An antimicrobially coated orthopedic implant, An orthopedic implant, wherein the orthopedic implant defines an outer surface that is essentially made of metal or a metal alloy, polyalkene or its copolymer, or polyaryletherketone or its copolymer, or a combination thereof. An antimicrobial coating disposed on the outer surface of the orthopedic implant, wherein the antimicrobial implant comprises an antimicrobial coating essentially made of a vaporizable antimicrobial agent, The aforementioned antibacterial coated implant contains approximately 5 μg / cm³ 2 ~Approx. 1000μg / cm 2 An antimicrobially coated orthopedic implant having a surface area concentration of the antimicrobial agent on the outer surface of the orthopedic implant within the range of [specify range]. (68) The implant according to embodiment 67, wherein the outer surface is made of metal or a metal alloy. (69) The implant according to embodiment 68, wherein the metal or metal alloy is titanium, stainless steel, or an alloy thereof. (70) The implant according to embodiment 67, wherein the outer surface is a polyalkene or a copolymer thereof.

[0166] (71) The implant according to embodiment 70, wherein the polyalken is polyethylene or a copolymer thereof. (72) The implant according to embodiment 67, wherein the outer surface is a polyarylether ketone or a copolymer thereof. (73) The implant according to embodiment 72, wherein the polyaryletherketone is polyetheretherketone (PEEK). (74) The implant according to embodiment 67, wherein the outer surface is essentially made of a metal or metal alloy and a polyalkene or copolymer thereof. (75) The implant according to embodiment 74, wherein the outer surface is essentially made of titanium or stainless steel or an alloy thereof, and polyethylene or a copolymer thereof.

[0167] (76) The implant according to embodiment 67, wherein the outer surface is essentially made of a metal or metal alloy and a polyarylether ketone or copolymer thereof. (77) The implant according to embodiment 76, wherein the outer surface is essentially made of titanium or stainless steel or an alloy thereof, and PEEK or a copolymer thereof. (78) The implant according to Embodiment 67, wherein the outer surface is essentially made of a polyalkene or copolymer thereof and a polyaryletherketone or copolymer thereof. (79) The implant according to embodiment 78, wherein the outer surface is essentially made of polyethylene or a copolymer thereof and PEEK or a copolymer thereof. (80) The implant according to any one of embodiments 67 to 79, wherein the vaporizable antimicrobial agent comprises a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof.

[0168] (81) The implant according to Embodiment 80, wherein the vaporizable antimicrobial agent comprises 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan). (82) The surface area concentration is 10 μg / cm² 2 ~Approx. 1000μg / cm 2 An implant according to any one of embodiments 67 to 81, which falls within the range of [the specified range]. (83) The implant according to any one of embodiments 67 to 82, wherein the surface area concentration generates an effective inhibition zone (ZOI) for microbial colony-forming units extending at least 0.5 mm from the outer surface of the orthopedic implant. (84) The implant according to any one of embodiments 67 to 83, wherein the effective ZOI is in the range of about 0.5 mm to about 5.0 mm. (85) The method according to any one of embodiments 1 to 28, wherein the surface area concentration on the outer surface of the orthopedic implant is equal to or greater than the surface area concentration of the antibacterial agent on the inner surface of the container.

[0169] (86) The method according to Embodiment 1, wherein arranging the reservoir of the vaporizable antimicrobial agent includes melting a solid mass of the vaporizable antimicrobial agent and depositing the molten material in the cavity of the container. (87) The method according to Embodiment 1, wherein the arrangement of the reservoir of the vaporizable antimicrobial agent includes coating the outer surface of the orthopedic implant with the vaporizable antimicrobial agent and placing the orthopedic implant in the cavity.

Claims

1. A method for forming an antibacterial implant, To provide a container having a first end and a second end, and an inner surface extending between the first end and the second end, wherein the inner surface contains a non-absorbent material and defines a container cavity, the non-absorbent material contains a metal or a metal alloy, and the first end defines an opening extending into the container cavity. The method involves placing a reservoir of a vaporizable antimicrobial agent within the container cavity, wherein the vaporizable antimicrobial agent includes a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof. The orthopedic implant is positioned within the container cavity through the first end, wherein the orthopedic implant defines the outer surface, To seal the first end of the container so as to seal the container cavity, The outer surface of the orthopedic implant and the reservoir containing the vaporizable antibacterial agent are heated, and the sealed container is heated to vaporize the antibacterial agent. This includes cooling the container while it is sealed, The heating and cooling of the container adsorbs the vaporized antimicrobial agent onto the outer surface of the orthopedic implant so that the antimicrobial coating of the orthopedic implant is formed having a surface area concentration of the antimicrobial agent on the outer surface of the orthopedic implant that is sufficient to generate an effective barrier of at least 0.5 mm around the periphery of the outer surface. The aforementioned heating includes heating to a temperature range of approximately 60°C to approximately 200°C. The outer surface of the orthopedic implant contains titanium or a titanium alloy, stainless steel or an alloy thereof, or polyaryletherketone (PAEK) or polyalkene or a copolymer thereof. The method wherein the non-absorbent material is resistant to the absorption of the antimicrobial agent.

2. The method according to claim 1, wherein the arrangement of the reservoir for the vaporizable antimicrobial agent includes depositing a solution of the vaporizable antimicrobial agent and solvent within the container cavity and evaporating the solvent from the container cavity to the outside of the container.

3. The method according to claim 1, wherein the arrangement of the reservoir of the vaporizable antimicrobial agent includes coating the inner surface of the container with a solution of the vaporizable antimicrobial agent and solvent, and evaporating the solvent from the inner surface to the outside of the container.

4. The method according to claim 1, wherein the vaporizable antimicrobial agent comprises 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan).

5. The method according to any one of claims 1 to 4, wherein the outer surface of the orthopedic implant is titanium or a titanium alloy, stainless steel or an alloy thereof, or polyaryletherketone (PAEK) or polyalkene or a copolymer thereof.

6. The method according to any one of claims 1 to 5, wherein the outer surface of the orthopedic implant is titanium or a titanium alloy.

7. The method according to any one of claims 1 to 5, wherein the outer surface of the orthopedic implant is made of stainless steel or an alloy thereof.

8. The method according to any one of claims 1 to 5, wherein the outer surface of the orthopedic implant is a polyaryletherketone (PAEK), a polyalken, or a copolymer thereof.

9. The method according to claim 8, wherein the outer surface of the orthopedic implant is polyetheretherketone (PEEK) or a copolymer thereof.

10. The method according to any one of claims 1 to 9, wherein the heating includes heating to a temperature range of about 80°C to about 180°C.

11. The method according to any one of claims 1 to 9, wherein the heating includes heating to a temperature range of about 120°C to about 160°C.

12. The method according to any one of claims 1 to 11, wherein the heating includes heating for a range of about 10 minutes to about 8 hours.

13. The method according to claim 12, wherein the heating includes heating for a range of about 3 to 6 hours.

14. The method according to any one of claims 1 to 13, wherein the inner surface comprises aluminum or an alloy thereof.

15. The surface area concentration of the antibacterial agent on the outer surface of the orthopedic implant is approximately 5 μg / cm². ２ ~Approx. 1000μg / cm ２ The method according to any one of claims 1 to 14, which is within the range of [the specified range].

16. The method according to any one of claims 1 to 15, wherein the antimicrobial agent in the reservoir has a total weight, and at least 1% to about 20% of the total weight of the antimicrobial agent is vapor-transferred onto the outer surface of the antimicrobial-coated orthopedic implant.

17. The method according to any one of claims 1 to 16, wherein the container is substantially rigid such that the container cavity defines a fixed volume.

18. The method according to any one of claims 1 to 17, wherein the first end includes a threaded region extending around the outer surface of the container, the threaded region being configured to engage with a lid having a corresponding threaded region on the inner surface, and the sealing involves engaging the threaded region of the first end with the threaded region of the lid.

19. The method according to claim 18, wherein the container further includes a sealing member, the sealing member being configured to be positioned between and in contact with the threaded region of the lid and the threaded region of the first end in order to seal the container.

20. The method according to any one of claims 1 to 16, wherein the container is substantially deformable, and the container cavity defines a first shape having a first volume when the first end is open, and when deformed, the container cavity takes on a second shape having a second volume smaller than the first volume.

21. The method according to claim 20, wherein the first end is substantially deformable, and the sealing step includes applying pressure to the first end to seal the first end by bringing the opposing inner walls of the first end into contact with each other.

22. The method according to claim 21, wherein at least a portion of the inner surface of the first end contains an amount of sealant such that the opposing walls bond to each other upon contact in order to seal the first end.

23. The method according to claim 21, further comprising applying a mechanical fastener configured to keep the opposing walls in contact with each other to the sealed first end.

24. The method according to any one of claims 1 to 23, wherein the second end is open, and the sealing step further comprises sealing the second end.

25. The method according to claim 24, wherein the second end is substantially deformable, and as a result, the sealing step further includes applying pressure to the second end so as to bring the opposing inner walls of the second end into contact with each other and seal the second end.

26. A system for forming antimicrobial implants, A reservoir for an antimicrobial agent that can be vaporized by heating, wherein the antimicrobial agent comprises a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof. A container comprising a first end and a second end, and an inner surface, wherein the inner surface comprises a non-absorbent material, the inner surface extends between the first end and the second end, the antimicrobial agent in the reservoir is in fluid communication with the container, the non-absorbent material comprises a metal or metal alloy, the inner surface defines a cavity configured to receive an orthopedic implant defining the outer surface, and the first end defines a sealable opening extending into the cavity, The invention includes a heating device capable of heating the antibacterial agent in the reservoir to a temperature range of approximately 60°C to approximately 200°C. The container, the orthopedic implant, and the antibacterial agent are configured to remain thermally stable within the temperature range. The container is configured such that the reservoir for the antimicrobial agent is placed inside the container, and the orthopedic implant is placed inside the cavity. The outer surface of the orthopedic implant is substantially free of the vaporizable antimicrobial agent, The container can be heated within the heating device to the temperature range described above in order to vaporize the antibacterial agent. The antibacterial agent is in fluid communication with the orthopedic implant within the container, but before vaporization by heating, the antibacterial agent is not in direct contact with the outer surface of the orthopedic implant. The outer surface of the orthopedic implant contains titanium or a titanium alloy, stainless steel or an alloy thereof, or polyaryletherketone (PAEK) or polyalkene or a copolymer thereof. The non-absorbent material is resistant to the absorption of the antibacterial agent in the system.

27. The system according to claim 26, wherein the antimicrobial agent comprises 2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan).

28. The system according to claim 27, wherein the outer surface of the orthopedic implant is titanium or a titanium alloy, stainless steel or an alloy thereof, or polyaryletherketone (PAEK) or polyalkene or a copolymer thereof.

29. The system according to claim 28, wherein the outer surface of the orthopedic implant is made of titanium or a titanium alloy.

30. The system according to claim 28, wherein the outer surface of the orthopedic implant is made of stainless steel or an alloy thereof.

31. The system according to claim 28, wherein the outer surface of the orthopedic implant is polyetheretherketone (PEEK) or a copolymer thereof.

32. The system according to claim 28, wherein the outer surface of the orthopedic implant is polyethylene or a copolymer thereof.

33. The system according to any one of claims 26 to 32, wherein the container is substantially rigid such that the cavity defines a fixed volume and is heatable in an oven.

34. A system for forming antimicrobial implants, A reservoir for a vaporizable antimicrobial agent, wherein the vaporizable antimicrobial agent comprises a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof. A container having a first end and a second end, and an inner surface extending between the first end and the second end, comprising a non-absorbable material, wherein the non-absorbable material comprises a metal or a metal alloy, the inner surface defines a cavity configured to receive an orthopedic implant defining an outer surface, and the first end defines a sealable opening extending into the cavity, The container, the orthopedic implant, and the vaporizable antimicrobial agent are configured to remain thermally stable in a temperature range of up to 200°C. The container is configured such that the reservoir of the vaporizable antimicrobial agent is placed inside the container, and the orthopedic implant is placed inside the cavity. The aforementioned outer surface is substantially free of the vaporizable antimicrobial agent, The first end includes a threaded region extending around the outer surface of the container, and the system further includes a lid having a threaded region configured to engage with the threaded region of the first end, the engagement between the threaded region of the first end and the threaded region of the lid sealing the first end, The outer surface of the orthopedic implant contains titanium or a titanium alloy, stainless steel or an alloy thereof, or polyaryletherketone (PAEK) or polyalkene or a copolymer thereof. The non-absorbent material is resistant to the absorption of the antibacterial agent in the system.

35. The system according to claim 34, further comprising a sealing member positioned between the threaded region of the lid and the threaded region of the first end, and configured to contact them.

36. A system for forming antimicrobial implants, A reservoir for a vaporizable antimicrobial agent, wherein the vaporizable antimicrobial agent comprises a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof. A container having a first end and a second end, and an inner surface extending between the first end and the second end, comprising a non-absorbable material, wherein the non-absorbable material comprises a metal or a metal alloy, the inner surface defines a cavity configured to receive an orthopedic implant defining an outer surface, and the first end defines a sealable opening extending into the cavity, The container, the orthopedic implant, and the vaporizable antimicrobial agent are configured to remain thermally stable in a temperature range of up to 200°C. The container is configured such that the reservoir of the vaporizable antimicrobial agent is placed inside the container, and the orthopedic implant is placed inside the cavity. The aforementioned outer surface is substantially free of the vaporizable antimicrobial agent, The container is substantially deformable, and the cavity defines a first shape having a first volume when the first end is open, and the container is configured to deform when pressure is applied to take on a second shape in which the cavity has a second volume smaller than the first volume. The outer surface of the orthopedic implant contains titanium or a titanium alloy, stainless steel or an alloy thereof, or polyaryletherketone (PAEK) or polyalkene or a copolymer thereof. The non-absorbent material is resistant to the absorption of the antibacterial agent in the system.

37. A system for forming antimicrobial implants, A reservoir for a vaporizable antimicrobial agent, wherein the vaporizable antimicrobial agent comprises a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof. A container having a first end and a second end, and an inner surface extending between the first end and the second end, comprising a non-absorbable material, wherein the non-absorbable material comprises a metal or a metal alloy, the inner surface defines a cavity configured to receive an orthopedic implant defining an outer surface, and the first end defines a sealable opening extending into the cavity, The container, the orthopedic implant, and the vaporizable antimicrobial agent are configured to remain thermally stable in a temperature range of up to 200°C. The container is configured such that the reservoir of the vaporizable antimicrobial agent is placed inside the container, and the orthopedic implant is placed inside the cavity. The aforementioned outer surface is substantially free of the vaporizable antimicrobial agent, The first end is substantially deformable such that the opposing inner walls at the first end come into contact with each other and seal the first end when force is applied. The outer surface of the orthopedic implant contains titanium or a titanium alloy, stainless steel or an alloy thereof, or polyaryletherketone (PAEK) or polyalkene or a copolymer thereof. The non-absorbent material is resistant to the absorption of the antibacterial agent in the system.

38. The system according to claim 37, wherein at least a portion of the inner surface at the first end contains an amount of sealant configured to bond the opposing walls together in order to seal the first end.

39. The system according to claim 38, wherein the sealing agent includes an adhesive material or a thermal bonding material.

40. The system according to claim 37, further comprising a mechanical fastener configured to keep the opposing walls in contact with each other in order to seal the container.

41. A system for forming antimicrobial implants, A reservoir for a vaporizable antimicrobial agent, wherein the vaporizable antimicrobial agent comprises a halogenated hydroxyl ether, an acyloxydiphenyl ether, or a combination thereof. A container comprising a first end and a second end, and a non-absorbable material, the container having an inner surface extending between the first end and the second end, wherein the non-absorbable material comprises a metal or a metal alloy, the inner surface defines a cavity configured to receive an orthopedic implant defining an outer surface, and the first end defines a sealable opening extending into the cavity, The container, the orthopedic implant, and the vaporizable antimicrobial agent are configured to remain thermally stable in a temperature range of up to 200°C. The container is configured such that the reservoir of the vaporizable antimicrobial agent is placed inside the container, and the orthopedic implant is placed inside the cavity. The aforementioned outer surface is substantially free of the vaporizable antimicrobial agent, The second end defines a sealable opening that extends into the cavity, The outer surface of the orthopedic implant contains titanium or a titanium alloy, stainless steel or an alloy thereof, or polyaryletherketone (PAEK) or polyalkene or a copolymer thereof. The non-absorbent material is resistant to the absorption of the antibacterial agent in the system.

42. The system according to claim 41, wherein the second end is substantially deformable such that the opposing inner walls at the second end are configured to come into contact with each other and seal the second end when force is applied.

43. The method according to any one of claims 1 to 25, wherein the surface area concentration on the outer surface of the orthopedic implant is equal to or greater than the surface area concentration of the antibacterial agent on the inner surface of the container.

44. The method according to claim 1, wherein the arrangement of the reservoir for the vaporizable antimicrobial agent includes melting a solid mass of the vaporizable antimicrobial agent and depositing the molten material in the container cavity of the container.

45. The method according to claim 1, wherein the arrangement of the reservoir of the vaporizable antimicrobial agent includes coating the outer surface of the orthopedic implant with the vaporizable antimicrobial agent and placing the orthopedic implant in the container cavity.

46. A system for use in the method according to any one of claims 1 to 25 and 43 to 45, The reservoir and, The container includes, wherein the opening is a sealable opening. The container, the orthopedic implant, and the vaporizable antimicrobial agent are configured to remain thermally stable in a temperature range of up to 200°C. The reservoir of the vaporizable antimicrobial agent is placed inside the container, and the orthopedic implant is placed inside the cavity of the container. A system wherein the outer surface substantially does not contain the vaporizable antimicrobial agent.

Images