Patent Application
20210322653
Long term medical devices of various types that interface with the body can be susceptible to infection. Transcutaneous and internally-positioned medical devices are often susceptible to microbial colonization, which may often originate at the site of transcutaneous access and often progress inwards into nutrient rich environments of the body. However, body cavity infections (where an implant is being held within the body), though less common, can sometimes be even more problematic, even though they statistically occur less frequently. This is because they may be more difficult to access (or even discover) without surgical intervention or investigation, as such infections can occur well beneath the body surface. Also, these body cavities are sparsely perfused by blood and hence immune surveillance is less prevalent and slower. These types of infections can manifest systemic symptoms eventually but the infection is at an advanced stage at this point and difficult to treat. Regardless, both sources of infection, e.g., transcutaneous infection and body cavity infection, are an issue in the field of medical implants, particularly for medical implants that are intended for long term use, e.g., more than a few weeks, months, years, or sometimes a life-time. The challenge with such medical device infections is a combination of factors such as introduction of a microbial load during surgical intervention. In the case of transcutaneous implants, continual existence of the skin breach that may not be effectively closed up by wound healing responses due to the presence of the implant.
One approach to providing antimicrobial properties to an implantable medical device is to coat a surface of the medical device with an anti-infective compound where it may be susceptible to infection, such as bacterial colonization. One of the technical challenges with many antibiotic coatings on medical devices, however, is their lack of long term effectiveness. For example, drug-eluting coatings often deplete quickly in the body due to limited availability of drug reservoir after which they can be ineffective, e.g., a thin coating does not provide a large reservoir, and on the other hand, non-eluting passive coatings tend to bio-foul fairly quickly. This can limit the antimicrobial effect of such technologies to only a few hours, a few days, but typically not in the order of weeks. As long term devices, e.g., 5 days to 5 years, 1 week to 2 years, 2 weeks to 2 year, 4 weeks to 2 years, 1 week to 1 year, 2 weeks to 1 year, 4 weeks to 1 year, 1 week to 6 months, 2 weeks to 6 months, 4 weeks to 6 months, etc., would benefit greatly from a more durable and/or longer lasting form of protection to avoid clinical complications such as mortality and morbidity, implantable medical devices of the present disclosure can provide, in some cases, antimicrobial benefits for either short or long term use.
Thus, the present disclosure is drawn to the application of an antimicrobial metal, which includes elemental metal coatings or metal alloy coatings, provided there is at least one metal present in the metal alloy at a high enough concentration to exhibit antimicrobial properties at a location where the medical device is in contact with body tissue susceptible to infection. In one example, the antimicrobial metal coating can be applied by electroless deposition or other technique, such as sputtering, weaving, dip coating, etc. However, the coating of rubbers, plastics, ceramics, metals, and other materials used for medical devices can be coated effectively using electroless deposition or other electroplating techniques. These coating technologies can be particularly useful in applications where the antimicrobial metal to be applied is intended to include a non-leaching metal, such as the contact killing metal copper. In further detail, though any antimicrobial metal can be used, such as silver, zinc, gold, tin, or alloys thereof, in one specific example, the antimicrobial metal can be or include a contact killing metal, such as copper.
For further clarity, the present disclosure is not directed to coating of the interior of medical devices that do not contact body tissue, e.g., luminal coatings within catheters, for protecting against infection related to blood or other flow of fluid through a medical device, but rather, is directed to protecting medical devices from infections where the medical device contacts body tissue other than luminal fluids on the external surface. The term “tissue” herein excludes blood or urine but rather includes solid body tissue and associated fluid that comes in contact with an exterior surface of a medical device. With this understanding, implementation or use of the medical devices of the present disclosure does not preclude the use of implantable medical device coatings within lumens of the implantable medical device, including even antimicrobial metal layers applied thereto. However, to the extent those types of coatings are used intraluminally, they may or may not be used in conjunction with the exterior antimicrobial metal coatings of the present disclosure without impacting the characteristics of the external antimicrobial metal layers of the present disclosure.
An “implantable medical device” can be defined herein to include a device assembly or merely a single device assembly part that may be coated with the antimicrobial metal coatings of the present disclosure. For example, Ventricular Assist Devices (VADs), often referred to as a “heart pump” or a Left Ventricular Assist Device (LVAD), includes multiple modular parts that are assembled together. One of those parts is known as a driveline, which is a transcutaneous line that electrically connects a controller on the outside of the body to a pump on the inside of the body at a body cavity near the heart. Thus, the VAD as an assembly can be considered to be a medical device as defined herein, but the driveline per se is also considered to be a medical device in and of itself.
In further detail, “implantable medical devices” as described herein exclude medical devices that routinely access the lumen of a subject by a non-surgical procedure, such as by access through a natural body lumen, e.g. urethral access, vaginal access, oral access, e.g., oral or nasal tracheal tube, or routine needle or catheter port access through the skin and into a luminal vessel. Overall, a vascular access catheter (needle or catheter port access), such as a peripherally inserted central catheter (PICC), a central venous catheter (CVC), a hemodialysis catheter (HD), an arterial catheter, etc., an intrauterine device (IUD) (vaginal access), a urinary catheter (urethral access), an endotracheal tube, an endoscope (colon, nasal, oral access) are not considered to be an implantable medical device as defined herein, even if they remain in the body for an extended period of time. These types of medical devices that are excluded from the “implantable medical device” definition herein can be referred to herein collectively as “luminal medical devices,” as they are either inserted luminally into the body, or the lumen of the body is accessed routinely without surgical incision, e.g., needle or catheter port. In further detail, simple surgical fasteners, such as pins, wires, staples, screws, nails, including those used in orthopedics and other surgeries are also not considered to be implantable medical devices herein due to their simplicity. However, to the extent that they may be used in the context of a larger implantable medical device, they may be likewise coated along with the larger/bulkier and more complex medical device such as an orthopedic prosthetic, e.g., joint replacement prosthetic, bone replacement prosthetic, prosthetic plates specialized for specific anatomical structures, prosthetic support rods other than fasteners, prosthetic devices that have an internal and an external component, etc.
On the other hand, the implantable medical devices described herein are directed toward medical devices that are often extraluminal within the body, but in cases where they do access a body lumen, e.g., tympanostomy tubes (accessing the tympanic membrane through the external auditory canal), they do so in connection with surgical access and implantation. Thus, the implantable medical devices often include other overlapping features, such as not dwelling in the vasculature or urinary tract, and these devices often encounter low fluid (liquid) flow rates around the device (lower than blood flow or urine flow rates).
A few example “implantable medical devices” that may include an added risk of infection due to surgical or implantation complications that can be coated with antimicrobial metal as disclosed herein include, but are not limited to, shunts such as cerebral shunts; ventricular drainage (EVD) devices; ventricular assist devices (VADs) including the transcutaneous drivelines and internally implanted pumps; tympanostomy tubes (ear tubes); sensory or neurological implants such as neurotransmitters; orthopedic implants; surgically implanted feeding tubes provided they surgically cross tissue, e.g. gastric feeding tubes (G-tubes), gastrojejunal feeding tubes, or jejunal feeding tubes; transcutaneous tracheal tubes; surgical meshes, e.g., hernia mesh; transcutaneous sensors, e.g., glucose sensor; implantable sinus drainage devices (that are at least partially implanted within tissue); etc.; to name a few.
As another point of distinction regarding the antimicrobial implantable medical devices, methods, and systems in accordance with the present disclosure, unlike catheters, many of these devices are not attached or used with infusion or aspiration ports that introduce intraluminal pressure (positive or negative) when in operation. Shunts, tympanostomy tubes, electrical power or control lines, implants, etc., are often implanted surgically across tissue or within the body of a subject to operate based on natural fluid flow, electrical control, structural support, etc., without the use of a pump, aspirator, syringe, etc., when in use. These devices are intended to sit within tissue without potential or possible disruptive pressure being applied when in use, for example. Thus, in one example, the implantable medical device in operation includes a lumen that is not subjected to externally applied positive or negative pressure while in use after implantation.
In accordance with this, the present disclosure is drawn to an antimicrobial implantable medical device that can include an implantable medical device, and an antimicrobial metal applied to an exterior surface of at least a portion of the implantable medical device that is positionable within the body tissue or traverses the body tissue when surgically placed for implantation, e.g., by a procedure including a tissue incision, at least partially within the body of a subject. The antimicrobial metal applied to the exterior surface can be positioned at a location in contact with a location of surgical tissue incision or can be implanted beneath or adjacent to the location of surgical incision, for example. The antimicrobial metal can be an antimicrobial metal coating applied by any of a number of coating technologies, such as electroless deposition, or can be applied to a surface by other methodologies, such as by application of a metal filament or fiber to a surface, such as by weaving. The implantable medical device can be at a location where the antimicrobial implantable medical device is within or traverses the body of the subject, in one example, and the antimicrobial metal can be at least 0.5 cm on one side of the body tissue (when within the tissue or traversing the tissue), or at least 0.5 cm on both sides of the body tissue (when traversing the tissue). In other examples, the antimicrobial metal can be independently at least 1 cm, at least 2.5 cm, at least 5 cm, or at least 10 cm on one or both sides of the body tissue. The term “traverses” herein refers to the crossing of a single body tissue from one side to the other, such as skin, an organ wall, the tympanic membrane, etc. Traversing the tissue includes crossing the tissue at the site of an incision and not through a natural body lumen or via needle or catheter port entry, e.g., incisions occurring across the skin, muscle, intestines, tympanic membrane, etc. The term “tissue” is not used so specifically that it refers to a single tissue type or another tissue type, but rather a tissue structure as may define an organ, e.g., stomach, heart, skin, intestines, etc., or the structural components of the musculoskeletal system, e.g., bone, muscles, ligaments, etc.
In another example, a method of ameliorating implantable medical device-related infections can include surgically placing an antimicrobial implantable medical device of the present disclosure at least partially within the body of a subject. The antimicrobial metal of the antimicrobial implantable medical device can be positioned for implantation at a location within a body tissue or traversing the body tissue. In one specific example, the method can include applying an electrical potential to the antimicrobial metal while the metal layer is positioned at the location. In another specific example, the antimicrobial implantable medical device can be a transcutaneous device, and the method can further include leaving a margin of at least 0.5 cm, at least 1 cm, at least 2.5 cm, at least 5 cm, or at least 10 cm outside of the body beyond the location of insertion through the cutaneous tissue.
In another example, a method of manufacturing an antimicrobial implantable medical device can include electroplating/electroless deposition on an implantable medical device as described and defined herein at least at a location where the implantable medical device is to be positioned within a body tissue or traversing the body tissue for implantation. In one specific example, the electroless deposition can be carried out using a divalent copper salt source material which in solution is reduced to metallic copper in the presence of a reducing agent which in turn gets oxidized and the metallic copper atoms are deposited on any surface in the bath including the medical device surfaces thus generating a antimicrobial metal layer. Other metal sources can be used for other metals or metal alloys. In one example, the medical device can have a polymer surface and the method can further include the preliminary step of introducing surface roughness to the polymer surface. Introducing surface roughness, for example, can include chemical etching, mechanical abrasion, physical etching, plasma treatment, etc.
When discussing the medical devices or methods herein, relative details from a discussion of either is considered applicable to the other, whether or not they are explicitly discussed in the context of that example. Thus, for example, in discussing tympanostomy tubes in the context of the medical devices herein, such disclosure is also related to any methods and/or systems also included herein, and vice versa, etc.
Turning now to the antimicrobial metal that is applied to or coated on the medical devices as described herein, examples of metals that can be used include copper, silver, zinc, gold, or alloys thereof. The term “alloys” includes various combinations of two or more of copper, silver, zinc, or gold, but can also include alloys of one or more of these metals with any other metal(s) or non-metal(s) that may provide a therapeutic or other practical property. For example, as copper oxidizes, copper can be alloyed with another metal, such as silver, zinc, and/or gold, but may also be alloyed with metals that may not be necessarily antimicrobial in nature. Examples of other metals that can be alloyed with copper include iron, nickel, aluminum, etc., for the purpose of slowing or preventing oxidation, or for some other therapeutic or practical purpose, e.g., enhanced metal adherence to the medical device surface material, modification of metallurgic properties such as flexibility and/or resilience, etc. As copper is a good metal for providing anti-infective properties due to its ability to contact kill without ion diffusion into or around neighboring tissue, if copper is used, it can be included in the alloy as a substantial portion, e.g., greater than 50 wt %, and a lesser proportion of other metals (or non-metals) may be included to contribute to reduction in copper oxidation, to contribute to antimicrobial effect, e.g., silver, zinc, and/or gold, to contribute to another therapeutic effect, to address a manufacturing concern, to enhance or improve a metal alloy physical property, e.g., flexibility, resilience, malleability, medical device adhesion, etc. Thus, if a copper alloy is used, in one example, the copper can be present in the alloy at from 50 wt % to 99 wt %, from 50 wt % to 95 wt %, from 50 wt % to 90 wt %, from 50 wt % to 80 wt %, 55 wt % to 99 wt %, from 55 wt % to 95 wt %, from 55 wt % to 90 wt %, from 55 wt % to 80 wt %, 60 wt % to 99 wt %, from 60 wt % to 95 wt %, from 60 wt % to 90 wt %, from 60 wt % to 80 wt %, or from 55 wt % to 70 wt %.
In accordance with the present disclosure, a metal based electroplating/electroless deposition technology can be used to address the persistent problem of infections associated with medical devices. The design of this active technology will have long-term, broad spectrum efficacy without relying on release/elution of an active agent. This technology can potentially be applied to the external surface of a wide range of transcutaneous and implantable medical devices.
In more detail with respect to copper, in addition to the cationic nature of copper ions (Cu2+) that cause them to bind or become attracted to negatively charged protective cell wall components and obliterate or otherwise disrupt or damage the cell membrane or wall, e.g., bacteria or other microbes, as mentioned briefly, copper can also kill microbes by contact with the elemental metal or with an alloy of the elemental metal (rather than by ions that slowly diffuse into solution over time). Thus, copper in particular can be a good material for use in the coating on the medical device exterior surface because it can kill pathogens continuously upon surface contact where the medical device is directly interfacing with the body tissue to actively reduce microbial colonization at the interface, regardless of ion diffusion. This can occur by virtue of the charge density where the microbe contacts the copper or copper alloy, which may cause membrane damage, nucleic acid damage, and/or generation of a reactive oxygen species that may be detrimental to the microbe. Thus, copper ions do not necessarily need to diffuse or leach out from the surface of the implantable medical device and into the fluid to kill microbes in order to have a good anti-infective effect, though some diffusion around the medical device can provide an added area of protection over time (the time it takes to diffuse outward). Instead, the native elemental or alloyed copper surface can possess active antimicrobial properties that can prevent colonization, and furthermore, the diffusion of ions out into the tissue via any fluid therebetween can enhance further the antimicrobial effect. Because of the contact killing nature of copper in particular, this allows elemental or alloyed copper coatings to last long-term without depletion or consumption of the killing effectiveness. In still further detail, an additional benefit of using a metal with contact killing properties, e.g., copper, is that it may not expose the subject to undesired high dosages of copper, as may be the case if treating tissue with a more eluting-type coating.
The use of a thin coating of copper for use on implantable medical devices may not have been considered previously, particularly for implantable medical devices as defined herein, as an antimicrobial candidate for coating because with some implantable medical devices, there may be a desired degree of flexibility that has been thought to be desirable. A substantially thick copper coating, or even polymeric materials compounded with high concentrations of copper salts in the resin, can become quite rigid. On the other hand, a thin copper-eluting coating may not cause the medical device to be overly rigid, but as a conventional eluting coating, the same issues with respect to antimicrobial agent depletion due to elution from the thin coating may not be more effective than antibiotic coatings, as the minimum effective concentration (MEC) of the copper in such a coating may not be maintainable over a longer period of time to be effective for even a week, for example.
Thus, in accordance with examples of the present disclosure, an antimicrobial metal can be coated as a thin layer, e.g., from 0.0001 μm to 50 μm, from 0.0005 μm to 1 μm, or from 0.001 μm to 0.1 μm, on a medical device to provide an antimicrobial layer thereon. The metal can be as described previously, and can include copper, silver, zinc, gold, or an alloy thereof. In one example, the metal can include copper, which is a contact killer. In still further detail, the metal coating can be a copper or copper alloy layer on a surface of the implantable medical device surface, that can be effectively non-leaching (particularly with copper), and which can retain its contact killing properties over a long period of time, e.g., 1 year or longer. By referring to some antimicrobial metals (typically electroless deposition layers) as “non-leaching” or “non-eluting,” this does not infer that no copper ions or other metal ions that may be present, such as in a copper alloy, elute out into the immediately surrounding tissue at all, but rather, the term non-leaching or non-eluting is defined herein as eluting less than 10 (parts per million) ppm, less than 5 ppm, less than 1 ppm, or less than 100 parts per billion (ppb) of a respective elemental metal, by weight, out from the coating into the surrounding tissue. There can be coatings, for example, where one metal may be non-leaching and the other metal may exceed these limits, but that may be acceptable as determined on a case by case basis based on the total metal content of the specific metal and the impact that metal may have on surrounding body tissue.
The antimicrobial metal can be applied as a layer by any of a number of methods, such as sputter coating, spray coating, or dip coating. However, in one specific example, the antimicrobial metal layer can be applied by electroless deposition. With this process, continuous layers of atomic metal, such as copper or copper alloy, can be electrically applied on an implantable medical device at or along a transcutaneous portion, at or along another portion susceptible to infection within the body, or over the entire implantable medical device. The thin layer can be applied so that the implantable medical device, where desired, can retain some of its flexibility. In other examples, the thickness can be such that the medical device becomes more rigid. There may be occasions to select thicker, more rigid coatings, and other occasions to select thinner coatings, depending on the application.
Electroless deposition works well on metal or conductive substrates. However, it can be useful to electroplate plastics, rubbers, ceramics, and/or other non-conductive, semi-conductive, or insulating materials. For example, electroless deposition chemistry allows electrically inert substrates such as plastics, rubbers, thermoplastics, and/or polymers to be plated with conductive metals facilitated by in-solution electrochemistry. Using copper electroplating as an example, Formula I shows an example chemical equation for electroplating a non-conductive material, as follows:
CuY2−+2CH2O+4OH−→Cu0+H2+2HCOO−+Y4−+2H2O Formula 1
where Y represents a copper anion, such as sulfate, chloride, or phosphate; and Cu0 represents elemental copper electroplated on the surface of the substrate being plated, e.g., the implantable medical device.
In further detail, polymeric substrates can be employed in electroless deposition applications by treating the surface to make it adherent, e.g., cleaning, etching, and/or roughing, etc., and then the polymeric substrate can be dipped in a bath of a divalent metal, such as copper or nickel, for example, to give it a very thin coating of electrically conducting metal (typically less than 1 μm). There are other dipping, sputtering, and/or spraying methodologies that can be used to establish thicker layers, such as by multiple dip coatings or multi-coat spraying layers so that the antimicrobial metal “layer” is actually multiple layers of metal. Thus, the term “layer” includes any arrangement of metals as a single layer or as multiple adjacent layers that function as a “layer” of metal.
If electroplating the thin metal coating applied previously, the thin layer of metal can be electroplated similar to more conventional methods where a metal base is electroplated, e.g., with a metal ion source and a charge carrier while applying electrical potential to the charge carrier bath. Depending on the physical properties of the antimicrobial metal layer desired, the electroplating can occur to leave a layer that is from wear and tear that the plated part has to withstand, the coating can be anything from 0.0001 μm to 50 μm, though thinner layers may provide more implantable medical device flexibility when that is a consideration.
By using electroplating/electroless deposition to apply an antimicrobial metal to an implantable medical device, there can be several advantages achieved. For example, the electroplating can be carried out so that most or essentially all of the elemental metal from the metal source can be made available to the surface of the substrate to impart a higher degree of killing power, and in the case of copper, a higher degree of contact killing potential. This can also help bind the metal tightly to the substrate, even to a polymeric substrate or other non-conductive substrate with negligible leaching, e.g., “effectively non-leaching” levels as defined previously. Electroplating/electroless deposition can also provide for the application of a more precisely controlled application of the thin metal layer, which enables surface modification without compromising device features, e.g. flexibility, comfort, etc. The nature of electroless chemistry incorporates layers of the metal on an atom-by-atom level with areas exposed getting coated, including deformities, cracks, crevices, etc. This can prevent bacterial colonization at the surface, rather than permit colonization followed by killing through ion diffusion. These types of metal layers can also provide a consistent cover of substrate surfaces that may be inherently non-uniform, e.g., silicone.
The antimicrobial metal can be applied to the exterior surface of the medical device using methodologies other than forming a metal layer, as described above. For example, the antimicrobial metal can be provided in the form of an antimicrobial metal fiber or filament positioned at least partially at the exterior surface. The fiber or filament can be a fiber or filament coated with the antimicrobial metal, or the fiber or filament can be formed from, e.g., core to surface, of the antimicrobial metal. In one example, the antimicrobial metal fiber or filament includes copper. In another example, the antimicrobial metal fiber or filament is woven with a structural fiber or filament of the antimicrobial implantable medical device, e.g., polyester (or other polymer) fibers found on some drivelines used for various medical devices. The antimicrobial implantable medical device can thus be, or include, a driveline for an internal device that is powered externally.
As the surface of the implantable medical device is coated to include an antimicrobial metal, the metal can be activated by passing a small electrical potential across the surface to enhance, in some instances, the efficacy and strength of the antimicrobial performance.
In another example, a protective coating may be applied on top of the antimicrobial metal layer, such as a wax, a hydrophilic polymer, a hydrophobic polymer, etc., to prevent corrosion, for storage purposes, or even for therapeutic purposes. Likewise, the metal can be alloyed, as described previously, for any of a number of purposes, including preventing metal corrosion.
Referring now to
Ear tubes 110 are inserted surgically to alleviate or prevent ear infections. However, ear tubes are also sometimes the cause of secondary infection, in the form of postoperative otorrhea where pus formation or fluid accumulation occurs at the implantation site. This can lead to ear tube malfunction and recurrent infection symptoms. By coating the ear tube with an antimicrobial metal layer 120, these infections can be reduced.
Though the ear tube 110 shown in
In another example, as shown in
In one example, the shunt 210 can be a cerebral shunt, which is a transcutaneous device that can be subject to infection where the shunt exits the brain and head 202 and enters 204 again to be ported beneath a body surface to a drainage location where the cerebral shunt may exit 206 and enter 208 the body at or near a drainage location. In other examples not shown, cerebral shunts can exit the brain one time and re-enter the drainage location one time, or can exit and re-enter at or near the head, and then be passed beneath the body surface to enter the drainage location. Example cerebral shunts that can be used to drain cerebral spinal fluid (CSF) from any of the ventricles to elsewhere in the body include ventriculoperitoneal (VP) shunts (draining to the peritoneal cavity), ventriculoatrial (VA) shunts (draining to the right atrium of the heart), ventriculopleural (VPL) shunts (draining to the pleural cavity), ventriculocisternal (VC) shunts (draining to the cisternal magna), ventriculosubgaleal (SG) shunts (draining to the subgaleal space), lumboperitoneal (LP) shunts (draining to the peritoneal cavity), etc.
Similar to cerebral shunts, external ventricular drains (EVDs) can also be used to drain cerebral spinal fluid (CSF) from any ventricle of the brain, but the fluid is drained outside of the body rather than within the body. Thus, EVDs are also considered to be implantable medical devices in accordance with the present disclosure, as they are implanted surgically and are not considered to be luminal medical devices as described herein.
Cerebral shunts of various types, as well as EVDs, can be used to manage conditions such as hydrocephalus. These types of devices fail in the first year about 40% of the time, with an overall failure rate of about 50%. Infection is one of the major reasons for failure. For example, the region of the device the shunt exits and enters the head (at the brain) or other body location is susceptible to microbial ingress. Commercially available antimicrobial systems include the Medtronic ARES, which is an antibiotic coated EVD. Other antimicrobial protection systems include the J&J Codman system and the Cook Spectrum system, both of which are not very effective for longer term use. Furthermore, many antibiotics used in these types of cerebral shunts and/or EVDs use antibiotics such as Minocycline/Clindamycin and Rifampin that are known to be ineffective against some bacterial strains (gram negative and yeast). Even with these antibiotic coatings, mortality and morbidity rates still remain high, e.g., Pediatric Cerebral Shunts have a 6-25% morbidity and about a 2.7% mortality rate with over a $35,000 treatment cost per instance. The antimicrobial metal layers applied to shunts, surgically implanted drainage tubes such as EVDs, or the like can provide an alternative to antimicrobial colonization intervention, and may work well against antibiotic resistance bacterial strains.
In another example, and as shown in
Thus, in accordance with the present disclosure, the ventricular assist device (VAD) 310, or component thereof (driveline 312, pump tubing 308, fluidic fittings 314, or the like), can be coated with a thin antimicrobial metal layer 320, such as copper, silver, zinc, gold, or an alloy thereof to reduce the impact or chances that a subject will get an infection at the transcutaneous site, or at other sites where the device crosses or intimately contacts body tissues or organs. In one example, the thin metal layer can be copper or a copper alloy. The thin metal layer can be as described previously with respect to material, layer thickness, application process, etc. The thin metal layer, as shown likewise in previous examples, can be present at least at one location, and sometimes multiple locations, where the medical device is inserted within or traverses a body tissue, such as the skin 302 or heart muscle 304, as shown by example and not limitation.
There are also other implantable medical devices that can be coated with the antimicrobial metal layers of the present disclosure, but which are not specifically shown in the FIGS. However, these implantable medical devices, or components thereof (which are also defined to be “implantable medical devices”) can likewise be coated with a thin antimicrobial metal layer, such as copper, silver, zinc, gold, or an alloy thereof to reduce the impact or chances that a subject will get an infection at the transcutaneous site, or at other sites where the device crosses or intimately contacts body tissues or organs. As mentioned, the thin metal layer can be copper or a copper alloy, for example. The thin metal layer can be as described previously with respect to material, layer thickness, application process, etc.
Examples of such devices include orthopedic implants, which can be used to treat bone fractures, osteoarthritis, scoliosis, spinal stenosis, chronic pain, joint replacement, etc. As mentioned, simple surgical fasteners, such as pins, wires, staples, screws, nails, etc. are not considered to be implantable medical devices in accordance with the present disclosure. The orthopedic implants that can be coated with an antimicrobial metal layer in accordance with the present disclosure may otherwise be susceptible to bacterial colonization as a result of the surgery, or even bacterial colonization introduced after surgery. Staphylococci, particularly Staphylococcus aureus or Staphylococcus epidermidis, are particularly prevalent with orthopedic implants. Bacterial infection can lead to, for example, bone tissue infections such as osteomyelitis, septic arthritis, or prosthetic joint infections (PJI). Pathways for infection can be septic arthritis, hematogenous (bacteria introduced in blood then introduced to local tissue at the site of the implant), and bone infiltration (from surgery, injury, etc.). As orthopedic implants are of many different types of materials, bacterial adhesion can be problematic with some materials for certain types of bacteria. With adhesion at the implant site, bacterial colonization can occur at the surface, and some bacteria can secrete a layer of slime or form a biofilm that is self-protecting. By applying the antimicrobial thin metal layers to implantable devices as described herein, the surfaces that may be susceptible to adhesion can be reduced due to particularly contact killing that can occur with copper layers.
Example implantable medical devices (along with where they are implanted) that can be coated with an antimicrobial thin metal layer include, but are not limited to: Austim-Moore prostheses (neck of femur), Baksi's prostheses (elbow), Charnley prostheses (hip), Harrington rods (spine), Hartshill rectangles (spine), Insall Burstein prostheses (knee), Richard N. W. Wohns interspinous implant and implantation instrument (between adjacent dorsal vertebrae), Luque rod (spine), Neer's prostheses (shoulder), McLaughlin's plate (inter-trochanteric fracture), Souter's prosthesis (elbo), Steffee plate (spine), Swanson prostheses (finger joint), Thompson prosthesis (neck of femur), etc. There are many other prosthetic devices that can be coated with copper or another antimicrobial metal in accordance with the present disclosure to prevent bacterial adhesion and colonization.
Other implantable medical devices that can be coated with an antimicrobial metal layer include sensory or neurological implants, such as those for treating disorders of the brain or other neurological systems. Surgically implantable medical devices for the treatment of hearing loss, such as otosclerosis, can be coated with an antimicrobial metal layer, including devices at common infection locations of hearing restoration implant devices, e.g., cochlear implants. Otitis media can be treated with ear tubes, as previously described. Electrical devices, such as neurostimulators, can likewise be implanted to stimulate the brain or other neurological systems to treat any of a number of neurological diseases, such as epilepsy, Parkinson's disease, treatment-resistant depression, etc. In these instances, for example, the lead wires and/or other transcutaneous or trans-tissue structures can likewise be coated with copper or other antimicrobial metal as described herein at locations susceptible to infection.
Cardiovascular implantable medical devices (excluding vascular catheters as defined herein, for example) are another category of devices that can benefit from the antimicrobial metal layers described herein. These types of devices can be used to treat heart failure, cardiac arrhythmia, ventricular tachycardia, valvular heart disease, angina pectoris, atherosclerosis, etc. Example implantable medical devices considered to be cardiovascular include the artificial heart, the artificial heart valve, (implantable) cardioverter-defibrillator, cardiac pacemaker, sensors such as glucose sensors, etc.
It is to be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
As used herein, the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. The degree of flexibility of this term can be dictated by the particular variable and would be within the knowledge of those skilled in the art to determine based on experience and the description herein.
Sizes, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 1.0 to 2.0 percent” should be interpreted to include not only the explicitly recited values of about 1.0 percent to about 2.0 percent, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 1.1, 1.3, and 1.5, and sub-ranges such as from 1.3 to 1.7, 1.0 to 1.5, and from 1.4 to 1.9, etc. This same principle applies to ranges reciting only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
It is also noted that any of the device features described herein and/or shown in the FIGS. can be combined together in any manner that is not specifically shown or described. For example, it is not the purpose of the present disclosure to put together every possible combination of features in the drawings or description, but rather to describe fully the combination of concepts to be combined with various types.
The following illustrates several examples of the present disclosure. However, it is to be understood that the following examples are only illustrative of the application of the principles of the present disclosure. Numerous modifications and alternative structures, compositions, methods, and systems may be devised without departing from the present disclosure. The appended claims are intended to cover such modifications and arrangements.
In vitro antimicrobial performance of copper-plated silicone ear tubes was compared to uncoated untreated silicone ear tubes, where the copper-plated silicone antimicrobial ear tubes were characterized for performance based on a log-scale reduction scale (Log R). Thus, the higher the Log R value, the lower level of bacterial colonization because the high value indicates a higher level of improvement against the untreated silicone ear tubes. In this study, both types of ear tubes were exposed to Staphylococcus aureus. At the same time for comparison, the performance of commercially available antimicrobial ear tubes, namely silver oxide impregnated Activent® ear tubes was also similarly studied and characterized in terms of Log R. Furthermore, a second set of Activent® ear tubes was also obtained and coated with the copper-plating antimicrobial layer similar to that described above. All three ear tube groups in the study were exposed to daily saline change outs for 7 days prior to microbial challenge. The data collected was based on a bacterial challenge where a concentration ˜1×104 CFU/mL of bacteria was exposed to the ear tubes, and the colonies were allowed to incubate at 37° C. in in the presence of saline-based nutrient broth for 24 hours. Both biofilm (adherent bacteria) and planktonic (free floating bacteria) recoveries from the respective devices and surrounding media is shown in
As can be seen in
The same study of Example 1 was conducted, except that instead of silicone ear tubes, fluoropolymer (FLP) based ear tubes were used instead. Both biofilm (adherent bacteria) and planktonic (free floating bacteria) recoveries from the respective devices and surrounding media is shown in
As can be seen in
In vitro antimicrobial performance of a copper-plated silicone EVD was compared to an uncoated untreated silicone EVD, where the copper-plated EVD was characterized for performance based on a log-scale reduction (Log R). Thus, the higher the Log R value, the lower the level of bacterial colonization because the high value indicates a higher level of improvement against the untreated silicone EVD. In this study, both types of EVD tubing were exposed to Staphylococcus epidermidis. At the same time for comparison, the performance of two commercially available antimicrobial coating systems were also evaluated, namely the Cook Spectrum coating on EVD available from Cook Medical (USA) and the ARES® antibiotic-impregnated coating system from Medtronic (USA). The data collected was based on a bacterial challenge where a concentration ˜1×106 CFU/mL of bacteria was exposed to the devices, and the colonies were allowed to incubate at 37° C. in in the presence of saline-based nutrient broth. Only biofilm (bacterial adherent) recoveries were collected, but were collected after Day 0 (initial) and Day 7 (1 week later) exposure to daily saline changeouts. Both time points were exposed to 24 h of microbial challenge described above. The data collected is shown by way of example in
As can be seen, the copper coating technology of the present disclosure showed at least equivalent antimicrobial efficacy to both of the antibiotic catheters at Day 0, but the copper coating also effectively retained antimicrobial efficacy after 7 days of simulated conditioning, while both antibiotic catheters had a significantly reduced efficacy.
The same study of Example 3 was conducted, except that instead of challenging the medical devices with Staphylococcus epidermidis, the devices were challenged with Staphylococcus aureus. The data collected is shown by way of example in
In vitro antimicrobial performance of a copper-plated polyurethane EVD was compared to an uncoated and untreated polyurethane EVD, where the copper-plated silicone antimicrobial EVD was characterized for performance based on a log-scale reduction (Log R). Thus, the higher the Log R value, the lower the level of bacterial colonization because the high value indicates a higher level of improvement against the untreated silicone EVD. In this study, both types of EVDs were exposed to Staphylococcus aureus. At the same time for comparison, the performance of a commercially available antimicrobial coating system was evaluated, namely the Cook Spectrum coating from Cook Medical (USA). All medical devices in the study were exposed to daily saline change outs for 7 days prior to microbial challenge. The data collected was based on a bacterial challenge where a concentration ˜1×104 CFU/mL of bacteria was exposed to the ear tubes, and the colonies were allowed to incubate at 37° C. in the presence of saline-based nutrient broth fluid for 24 hours. Both biofilm (adherent bacteria) and planktonic (free floating bacteria) recoveries from the respective devices and surrounding media is shown in
A pilot rabbit study was conducted to determine the tolerance of the animal to exposure to the copper plating, e.g., to determine if there would be a biological reaction to the copper to identify if there would be tolerance at a site of a surgically generated incision site or as an implanted device. For this study, copper-plated shunt devices as well as devices coated with the ARES® antibiotic-impregnated coating system, from Medtronic (USA), were implanted subcutaneously into pockets of the skin of a rabbit. The shunt material that was evaluated for this study was silicone. For comparison, uncoated shunts were also implanted in the same rabbit. The shunts were left in the rabbit for 10 days to understand the biological reaction to the new material, and then extracted from the animals to evaluate the antimicrobial effect of the copper plating vs. the ARES® antibiotic-impregnated coating system vs. uncoated devices under in vitro conditions. To evaluate solely the outside of the medical devices for the antimicrobial study, the inside of the shunts were sealed off with epoxy so that the evaluation was solely related to the exterior of the implanted device.
The shunt devices extracted from the animals were inoculated with bacterial cultures and incubated under in vitro conditions, e.g., on a rotary shaker at 37° C. The copper-plated shunts exhibited almost a Log 3 reduction in growth of Staphylococcus aureus compared to the uncoated device, whereas the ARES® antibiotic-impregnated coating system was only slightly better, e.g., less than a Log 1 reduction, compared to the uncoated device. The raw data for the study is shown in
While the forgoing examples and descriptions are illustrative of the principles of the present technology in one or more particular applications, it will be apparent to those of ordinary skill in the art that numerous modifications in form, usage and details of implementation can be made without the exercise of inventive faculty, and without departing from the principles and concepts of this technology. Accordingly, it is not intended that the technology be unduly limited.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2019/065474 | 12/10/2019 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62777486 | Dec 2018 | US |
