Patent Application
20220125989
Millions of people worldwide have had cardiac devices implanted, including pacemakers and defibrillators, with approximately one million pacemakers and 300,000 cardiac defibrillators implanted each year. The number of individuals with implanted cardiac devices is expected to increase as the average age of the population of many industrialized nations continues to increase. While the majority of individuals with an implanted cardiac device do not experience difficulties associated with the device, in approximately 1.5% of cases the subject develops an infection associated with the implanted device. Under circumstances in which the infected subject requires hospitalization, the mortality rate has a range of 10-15%. Furthermore, infection and mortality rates can be substantially higher for subjects with pre-existing conditions and/or for subjects requiring revisional surgery.
Thus, there is a need in the art for a bactericidal coating that can be used on implanted devices, including but not limited to implanted electrodes. The present disclosure addresses this need.
In some embodiments, the instant specification is directed to the non-limiting exemplary embodiments below. The numbering of the exemplary embodiments is not to be construed as designating levels of importance:
Embodiment 1 provides a composition comprising a substrate at least partially coated with a bactericidal coating, the composition comprising; a substrate having a surface; and a bactericidal layer comprising a bactericidal metal element and a columnar microstructure, wherein the bactericidal layer comprises at least one of the following:
Embodiment 2 provides the composition of Embodiment 1, wherein the bactericidal metal element is at least one selected from the group consisting of Ag, Cu, Zn, Ni, Sn, Au, and Co.
Embodiment 3 provides the composition of any one of Embodiments 1-2, wherein the bactericidal metal element comprises Ag.
Embodiment 4 provides the composition of any one of Embodiments 1-2, wherein the bactericidal metal element comprises Cu. Embodiment 4a provides the composition of any one of Embodiments 1-3, wherein the bactericidal metal element comprises Cu and Ag.
Embodiment 5 provides the composition of any one of Embodiments 1-4, wherein the columnar microstructure comprises a metal nitride or carbon nanotube.
Embodiment 6 provides the composition of Embodiment 5, wherein the metal nitride is at least one selected from the group consisting of titanium nitride (TiN), zirconium nitride (ZrN), tantalum nitride (TaN), and vanadium nitride (VN).
Embodiment 7 provides the composition of Embodiment 6, wherein the metal nitride is TiN.
Embodiment 8 provides the composition of Embodiment 6, wherein the metal nitride is ZrN.
Embodiment 9 provides the composition of any one of Embodiments 1-8, wherein, if the bactericidal metal element is Ag, the columnar microstructure is not titanium nitride (TiN).
Embodiment 10 provides the composition of any one of Embodiments 1-9, wherein the substrate is selected from the group consisting of intramedullary nails, pins, rods, plates, screws, artificial joints, artificial heart components, prosthetic blood vessels, catheters, stents, wound dressings, surgical stitching fibers, and pharmaceutical depots.
Embodiment 11 provides the composition of any one of Embodiments 1-10, wherein the substrate surface comprises titanium or stainless steel. Embodiment 11a provides the composition of any one of Embodiments 1-10, wherein the substrate surface comprises platinum, gold, a platinum-containing alloy, a gold containing alloy, or combinations thereof.
Embodiment 12 provides the composition of any one of Embodiments 1-11, wherein the first layer comprising the bactericidal metal element has a thickness of 0.75 μm.
Embodiment 13 provides the composition of any one of Embodiments 1-12, wherein the second layer comprising the columnar microstructure has a thickness of about 0.50 μm to about 2.00 μm.
Embodiment 14 provides the composition of any one of Embodiments 1-13, wherein the second layer comprising the columnar microstructure has a thickness selected from the group consisting of about 0.50 μm, about 0.75 μm, about 0.800 μm, about 1.00 μm, about 1.20 μm, about 1.60 μm, and about 2.00 μm.
Embodiment 15 provides the composition of any one of Embodiments 1-14, wherein the multilayer is synthesized by a method comprising DC magnetron sputtering the bactericidal metal element onto at least a portion of the substrate's surface and DC reactive magnetron sputtering the columnar microstructure layer onto a portion of the substrate's surface that is coated by the bactericidal metal element.
Embodiment 16 provides the composition of any one of Embodiments 1-15, wherein the bactericidal metal element comprises a percentage of the composite bactericidal layer which is selected from the group consisting of about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%.
Embodiment 17 provides the composition of any one of Embodiments 1-16, wherein the bactericidal metal element comprises a percentage of the composite bactericidal layer which is selected from the group consisting of 9%, 13%, 20%, 22%, and 24%.
Embodiment 18 provides the composition of any one of Embodiments 1-17, wherein the bactericidal metal element comprises 13% of the composite bactericidal layer and the bactericidal metal element is Ag.
Embodiment 19 provides the composition of any one of Embodiments 1-18, wherein the bactericidal metal element comprises a percentage of the composite bactericidal layer which is selected from the group consisting of about 5%, about 6%, about 16%, about 17%, and about 18%.
Embodiment 20 provides the composition of any one of Embodiments 1-19, wherein the bactericidal metal element comprises about 5% of the composite bactericidal layer and the bactericidal metal element is Cu.
Embodiment 21 provides the composition of any one of Embodiments 1-20, wherein the composite coating has a thickness in the range of about 0.5 μm to about 30 μm, such as but not limited to about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1.0 μm, about 1.2 μm, about 1.4 μm, about 1.6 μm, about 1.8 μm, about 2.0 μm, about 2.5 μm, about 3.0 μm, about 4 μm, about 5 μm, about 6 μm, about 8 μm, about 10 μm, about 12 μm, about 14 μm, about 16 μm, about 18 μm, about 20 μm, about 22 μm, about 25 μm, or about 30 μm.
Embodiment 22 provides the composition of any one of Embodiments 1-21, wherein the composite bactericidal layer is synthesized by co-deposition of the bactericidal metal element and Ti or Zr onto at least a portion of the substrate's surface with a partial pressure of Na. Embodiment 22a provides the composition of any one of Embodiments 1-21, wherein the composite is synthesized by co-deposition of one or more bactericidal metal elements and one or more transitions metals (such as Ti and Zr) onto at least a portion of the substrate's surface with a partial pressure of N2
Embodiment 23 provides the composition of any one of Embodiments 1-22, wherein the composition is in contact with an electrolyte solution.
Embodiment 24 provides the composition of any one of Embodiments 1-23, wherein the electrolyte solution contains at least one bacterial species.
Embodiment 25 provides the composition of Embodiment 24, wherein the bacterial species is at least one of S. aureus and P. aeruginosa.
Embodiment 26 provides the composition of any one of Embodiments 24-25, wherein proximal and distal bacterial growth within the electrolyte solution is reduced or eliminated.
Embodiment 27 provides an electrode article that is implantable in a subject, the article comprising: an electrode substrate having a surface; and a bactericidal layer comprising a bactericidal metal element and a columnar microstructure, wherein the bactericidal layer comprises at least one of the following:
Embodiment 28 provides the article of Embodiment 27, wherein the bactericidal metal element is at least one selected from the group consisting of Ag, Cu, Zn, Ni, Sn, Au, and Co.
Embodiment 29 provides the article of any one of Embodiments 27-28, wherein the bactericidal metal element comprises Ag.
Embodiment 30 provides the article of any one of Embodiments 27-28, wherein the bactericidal metal element comprises Cu. Embodiment 30a provides the article of any one of Embodiments 27-29, wherein the bactericidal metal element comprises Cu and Ag.
Embodiment 31 provides the article of any one of Embodiments 27-30, wherein the columnar microstructure layer comprises a metal nitride or carbon nanotube.
Embodiment 32 provides the article of any one of Embodiments 27-31, wherein the metal nitride is at least one selected from the group consisting of titanium nitride (TiN), zirconium nitride (ZrN), tantalum nitride (TaN), and vanadium nitride (VN).
Embodiment 33 provides the article of Embodiment 32, wherein the metal nitride is TiN.
Embodiment 34 provides the article of Embodiment 32, wherein the metal nitride is ZrN.
Embodiment 35 provides the article of any one of Embodiments 27-34, wherein the substrate surface comprises titanium or stainless steel. Embodiment 35a provides the article of any one of Embodiments 27-34, wherein the substrate surface comprises platinum, gold, a platinum-containing alloy, a gold containing alloy, or combinations thereof.
Embodiment 36 provides the article of any one of Embodiments 27-35, wherein the electrode comprises an implantable medical device selected from the group consisting of a pacemaker, cardioverter defibrillator, retinal implant, phrenic nerve stimulator, glucose biosensor, cochlear implant, and an electrical stimulator for pain relief management, Parkinson's disease, and/or epilepsy.
Embodiment 37 provides the article of any one of Embodiments 27-36, wherein the first layer comprising the bactericidal metal element has a thickness of 0.75 μm.
Embodiment 38 provides the article of any one of Embodiments 27-37, wherein the second layer comprising the columnar microstructure has a thickness of about 0.50 μm to about 2.00 μm.
Embodiment 39 provides the article of any one of Embodiments 27-38, wherein the second layer comprising the columnar microstructure has a thickness selected from the group consisting of 0.50 μm, 0.75 μm, 0.800 μm, 1.00 μm, 1.20 μm, 1.60 μm, and 2.00 μm.
Embodiment 40 provides the article of any one of Embodiments 27-39, wherein the mutilayer is synthesized by DC magnetron sputtering the bactericidal metal element onto at least a portion of the substrate's surface and DC reactive magnetron sputtering the columnar microstructure layer onto a portion of the substrate's surface that is coated by the bactericidal metal element.
Embodiment 41 provides the article of any one of Embodiments 27-40, wherein the bactericidal metal element comprises a percentage of the composite bactericidal layer which is selected from the group consisting of about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%.
Embodiment 42 provides the article of any one of Embodiments 27-41, wherein the bactericidal metal element comprises a percentage of the composite bactericidal layer which is selected from the group consisting of 9%, 13%, 20%, 22%, and 24%.
Embodiment 43 provides the article of any one of Embodiments 27-42, wherein the bactericidal metal element comprises 13% of the composite bactericidal layer and the bactericidal metal element is Ag.
Embodiment 44 provides the article of any one of Embodiments 27-43, wherein the bactericidal metal element comprises a percentage of the composite bactericidal layer which is selected from the group consisting of about 5%, about 6%, about 16%, about 17%, and about 18%.
Embodiment 45 provides the article of any one of Embodiments 27-44, wherein the bactericidal metal element comprises about 5% of the composite bactericidal layer and the bactericidal metal element is Cu.
Embodiment 46 provides the article of any one of Embodiments 27-45, wherein the composite coating has a thickness in the range of about 0.5 μm to about 30 μm, such as but not limited to about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1.0 μm, about 1.2 μm, about 1.4 μm, about 1.6 μm, about 1.8 μm, about 2.0 μm, about 2.5 μm, about 3.0 μm, about 4 μm, about 5 μm, about 6 μm, about 8 μm, about 10 μm, about 12 μm, about 14 μm, about 16 μm, about 18 μm, about 20 μm, about 22 μm, about 25 μm, or about 30 μm.
Embodiment 47 provides the article of any one of Embodiments 27-46, wherein the composite is synthesized by co-deposition of the bactericidal metal element and Ti or Zr onto at least a portion of the substrate's surface with a partial pressure of N2. Embodiment 47a provides the article of any one of Embodiments 27-46, wherein the composite is synthesized by co-deposition of one or more bactericidal metal elements and one or more transitions metals (such as Ti and Zr) onto at least a portion of the substrate's surface with a partial pressure of N2.
Embodiment 48 provides the article of any one of Embodiments 27-47, wherein the composition is in contact with an electrolyte solution.
Embodiment 49 provides the article of any one of Embodiments 27-48, wherein the electrolyte solution contains at least one bacterial species.
Embodiment 50 provides the article of Embodiment 49, wherein the bacterial species is at least one of S. aureus and P. aeruginosa.
Embodiment 51 provides the article of any one of Embodiments 49-50, wherein proximal and distal bacterial growth within the electrolyte solution is reduced or eliminated.
Embodiment 52 provides the article of any one of Embodiments 27-51, wherein an electrical potential is applied to the electrode.
Embodiment 53 provides the article of Embodiment 52, wherein the electrical potential applied to the electrode ranges from about +0.1 V to about +0.8 V.
Embodiment 54 provides the article of any one of Embodiments 52-53, wherein ions of the bactericidal metal element are released in the electrolyte solution.
Embodiment 55 provides the article of any one of Embodiments 52-54, wherein proximal and distal bacterial growth within the electrolyte solution is reduced or eliminated.
Embodiment 56 provides the article of any one of Embodiments 27-55, wherein the bactericidal layer does not decrease the efficiency of underlying electrode.
Embodiment 57 provides the article of any one of Embodiments 27-56, wherein the subject is a mammal.
Embodiment 58 provides the article of Embodiment 57, wherein the mammal is a human.
Embodiment 59 provides the composition of any one of Embodiments 1-26, wherein the bactericidal layer comprises the composite, and wherein an amount of the bactericidal metal element is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% (mol/mol) based on a total moles of metal elements for forming the bactericidal layer.
Embodiment 60 provides the composition of any one of Embodiments 1-26 and 59, wherein the bactericidal layer comprises the composite, and a deposition pressure of the bactericidal metal element and a deposition pressure of a metal element for forming the columnar microstructure are each independently about 1 mTorr, about 2 mTorr, about 3 mTorr, about 4 mTorr, about 5 mTorr, about 10 mTorr, about 15 mTorr, about 20 mTorr, about 25 mTorr, about 30 mTorr, about 40 mTorr, about 50 mTorr, about 60 mTorr, about 70 mTorr, about 80 mTorr, about 90 mTorr, or about 100 mTorr.
Embodiment 61 provides the article of any one of Embodiments 27-58, wherein the bactericidal layer comprises the composite, and wherein an amount of the bactericidal metal element is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% (mol/mol) based on a total moles of metal elements for forming the bactericidal layer.
Embodiment 62 provides the article of any one of Embodiments 27-58 and 61, wherein the bactericidal layer comprises the composite, and a deposition pressure of the bactericidal metal element and a deposition pressure of a metal element for forming the columnar microstructure are each independently about 1 mTorr, about 2 mTorr, about 3 mTorr, about 4 mTorr, about 5 mTorr, about 10 mTorr, about 15 mTorr, about 20 mTorr, about 25 mTorr, about 30 mTorr, about 40 mTorr, about 50 mTorr, about 60 mTorr, about 70 mTorr, about 80 mTorr, about 90 mTorr, or about 100 mTorr.
Embodiment 63 provides the article of any one of Embodiments 27-58, 61 and 62, wherein the article further comprises a power source, such as a battery or a power supply.
The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application.
Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.
Throughout this document, values expressed in a range format should be interpreted in a flexible manner 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. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise.
Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.
In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.
In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.
Pacemaker electrodes are often coated with titanium nitride (TiN) to enhance the performance of the implanted electrode for pacing and recording applications. The TiN coatings have columnar microstructure formed by TiN (
One feature of such coatings is the pore formed by the voids between the columnar microstructure (
Many implantable devices have bactericidal coatings to decrease the risk of infection, with such coatings often comprising small organic molecules, such as antibiotics, which are embedded in the surface of the implant and are gradually released. However, bactericidal coatings including small organic compounds can be problematic as the use of such compounds tends to lead to resistances, such as antibiotic resistance. Additionally, antibiotic coatings often reduce the overall surface area of the electrode by blocking pores, thereby decreasing the charge transfer efficiency of the electrode.
It was conceived that the pores between the columnar microstructures would also allow for bactericidal elements (such as bactericidal metal elements) beneath, around, or within the columnar microstructures to be accessible such that the bactericidal elements are able to kill bacteria adhered or in close proximity to the coatings and therefore suppresses biofilm formation. The pores add to the effective surface area of the electrode, allowing the overall geometric electrode size to be reduced while retaining desirable charge exchange performance. The pores would also allow for the diffusion of ions of bactericidal elements to the bacteria in the biological solutions not immediately adjacent to the columnar microstructures.
Accordingly, in some aspects, the present invention is directed to a bactericidal coating (also referred to as “bactericidal layer” or “coating”) having resistance to bacteria, such as resistance to the formation of microfilm by bacteria thereon. In some embodiments, the bactericidal layer includes a columnar microstructure, as well as a bactericidal element beneath, around, and/or within the columnar microstructure. In some embodiments, when the bactericidal coating is exposed to a solution, such as blood plasma or other body fluids, ions of the bactericidal element are released and enriched in proximity to the bactericidal coating, such as in the voids between multiple columnar microstructures. In some embodiments, ions of the bactericidal element are released in response to an application of electrical potential to the bactericidal layer.
In some aspects, the present invention is directed to a composition having resistance to bacteria, such as resistance to the formation of microfilm by bacteria thereon. In some embodiments, the composition includes a substrate having a surface, and a bactericidal layer. In some embodiments, the bactericidal layer includes a columnar microstructure, as well as a bactericidal element beneath, around, and/or within the columnar microstructure. In some embodiments, when the composition is exposed to a solution, such as blood plasma or other body fluids, ions of the bactericidal element are released and enriched in proximity to the composition, such as in the voids between multiple columnar microstructures. In some embodiments, ions of the bactericidal element are released in response to an application of electrical potential to the bactericidal layer.
In some aspects, the present invention is directed to an electrode article having resistance to bacteria, such as resistance to the formation of microfilm by bacteria thereon. In some embodiments, the electrode article includes an electrode substrate having a surface, and a bactericidal layer. In some embodiments, the bactericidal layer includes a columnar microstructure, as well as a bactericidal element beneath, around, and/or within the columnar microstructure. In some embodiments, when the electrode article is exposed to a solution, such as blood plasma or other body fluids, ions of the bactericidal element are released and enriched in proximity to the electrode article, such as in the voids between multiple columnar microstructures. In some embodiments, ions of the bactericidal element are released in response to an application of electrical potential to the bactericidal layer.
It is worth noting that, although the instant specification sometimes uses artificial pacemaker as a non-limiting illustrative example, the composition and the electrode article as described herein are not limited thereto. One of ordinary skill in the art would understand that the desirable features of the instant composition and electrode article make the composition and electrode article suitable for all implantable devices, such as pacemakers, cardioverter defibrillators, retinal implants, phrenic nerve stimulators, glucose biosensors, cochlear implants, or electrical stimulators for pain relief management/Parkinson's disease/epilepsy, as well as other non-implantable articles where bactericidal effects and/or biofilm resistance are desired.
Certain abbreviations used herein follow: CFU, colony forming units; CV, cyclic voltammetry; DC, direct current; EDS, energy dispersive spectroscopy; ICP-MS, inductively coupled plasma mass spectrometry; OD, optical density; PVD, physical vapor deposition; SEM, scanning electron microscopy; SS, stainless steel; TaN, tantalum nitride; TiN, titanium nitride; VN, vanadium nitride; XRD, x-ray diffraction; ZrN, zirconium nitride.
The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.
The term “bactericidal” as used herein refers to a substance or structure which kills bacteria including, but not limited to metals, disinfectants, antiseptics, or antibiotics.
The term “multilayer coating” as used herein refers to a substance which is stably adhered to at least a portion of the surface of an object, which is referred to as the substrate, wherein the substance comprises two or more discrete layers of differing composition which are stably adhered to each other. The term “bilayer coating” as used herein refers to a substance which is stably adhered to the surface of an object, which is referred to as the substrate, wherein the substance comprises two discrete layers of differing composition which are stably adhered to one another.
The term “columnar microstructure” as used herein refers to the morphological features of a material observable at the micrometer (μm)) scale, wherein the structure comprises a low density or porous network and an array of parallel uniform-sized rods of higher density which are perpendicularly arranged with respect to the basal plane of the substrate upon which the material is deposited. The pillars normally have an average width ranging from about 50 μm to about 750 μm, such as about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, about 100 μm, about 120 μm, about 140 μm, about 160 μm, about 180 μm, about 200 μm, about 250 μm, about 300 μm, about 400 μm, about 500 μm, or about 750 μm. The pores formed by the voids between the pillars normally have an average diameter ranging from 20 nm to 300 nm, such as about 50 nm, about 60 nm, about 70 nm, about 80 nm, about 90 nm, about 100 nm, about 120 nm, about 140 nm, about 160 nm, about 180 nm, about 200 nm, about 250 nm, about 300 nm.
The term “composite coating” as used herein refers to a substance which is stably adhered to the surface of an object, referred to as the substrate, wherein the substance comprises at least two constituent materials that are not discretely divided into two layers.
The term “distal growth” as used herein refers to the growth of bacteria in the electrolyte solution which are located at a distance sufficiently far from the coating-electrolyte solution interface as to avoid direct contact with the coating composition.
The term “electrode” as used herein refers to any electrically conductive element used to contact a non-metallic component of a circuit and may refer to an anode and/or cathode.
The term “electrolyte solution” as used herein refers to an electrically conductive liquid comprising a solvent, non-limiting examples including water, and an ionizable substance, referred to as the electrolyte. In certain embodiments, the term may refer to blood, growth media, and/or other liquid biological samples.
The term “magnetron sputtering” as used herein refers to a method of physical vapor deposition (PVD), wherein a thin film is deposited onto the surface of a substrate. The process involves ion bombardment of a source material, the target, resulting in sputtering of the target material which is deposited on the surface of the substrate. Magnetron sputtering employs a magnetron source in which positive ions present in the plasma of a magnetically enhanced glow discharge bombard the target, which can be powered by direct current (DC), but the present invention is not limited thereto. One of ordinary skill in the art would understand that the PVD and sputtering as described herein can also be carried out with radio frequency (RF), pulsed DC, evaporation, and the like, and these PVD/sputtering methods are within the scope of the present invention. In certain embodiments the present invention relates to compositions prepared by reactive sputtering, such as a reactive sputtering process in which the magnetron sputtering process is coupled with a chemical reaction, thereby depositing material other than the target source upon the substrate.
The term “proximal growth” as used herein refers to the growth of bacteria in the electrolyte solution which are located sufficiently close to the coating-electrolyte solution interface as to directly contact the coating composition.
The term “stably adhered” as used herein refers to two substances united by a molecular force acting in the area of contact which is of sufficient strength to avoid dissociation under the anticipated conditions.
The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of” as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt % to about 5 wt % of the material, or about 0 wt % to about 1 wt %, or about 5 wt % or less, or less than, equal to, or greater than about 4.5 wt %, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt % or less. The term “substantially free of” can mean having a trivial amount of, such that a composition is about 0 wt % to about 5 wt % of the material, or about 0 wt % to about 1 wt %, or about 5 wt % or less, or less than, equal to, or greater than about 4.5 wt %, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt % or less, or about 0 wt %.
The term “solvent” as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.
The term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X1, X2, and X3 are independently selected from noble gases” would include the scenario where, for example, X1, X2, and X3 are all the same, where X1, X2, and X3 are all different, where X1 and X2 are the same but X3 is different, and other analogous permutations.
Bactericidal Coating/Composition/Electrode Article
In certain embodiments, the coatings disclosed herein take advantage of the columnar microstructure to provide a mechanism to release bactericidal elements. The current disclosure provides a coating composition comprising a bactericidal element, non-limiting examples including Ag, Cu, Zn, Sn, Au, Ni, and/or Co, wherein the incorporation of the bactericidal element does not disrupt the columnar microstructure and/or does not reduce the efficiency of the underlying electrode, thereby retaining performance while adding bactericidal functionality. Bactericidal ions of the bactericidal element, generated either via passive dissolution or upon application of a potential, are enriched within and near the columnar microstructure. The voids between adjacent columnar microstructures act as a reservoir for bactericidal ions, which is replenished from bactericidal element adjacent to the pores. Ion containing biological solutions, having access to these pores, are susceptible to the activity of the bactericidal ions, whether proximal or distal in solution (
In one aspect, the coatings described herein are superior to conventional bactericidal coatings comprising small molecule antibiotics. In certain embodiments, loading antibiotic compounds in the correlated pores of such compositions decreases the effectiveness of the coatings for charge exchange. In certain embodiments, the presently described bactericidal ions are selectively released upon application of an electrical potential, whereas no such control is available for the release of antibiotic compounds. In certain embodiments, bactericidal elements are less likely to lead to the development of antibiotic resistance.
In certain embodiments, the present disclosure is readily applicable to implantable cardiac electrodes, including pacemaker leads (
It should be noted that the electrode coating described herein are not limited to implantable devices, but can be applied to any situation wherein proximal and distal bactericidal activity is desired, including, but not limited to, electrolysis cells and aquaria. Furthermore, the present disclosure may be applied to implantable devices that do not require an applied potential in their ordinary function, but rather may tolerate application of a potential.
The present disclosure relates in one aspect to coating compositions comprising a bactericidal layer further comprising a bactericidal element and a columnar microstructure. In certain embodiments the bactericidal layer is a multilayer, such as a bilayer, a tri-layer, and so on. It should be noted that, although the instant specification mainly uses bilayer coatings as illustrative non-limiting examples of the multilayer coatings, the instant specification is not limited thereto. Structures such as tri-layer coatings, tetra-layer coatings, and so on are specifically included. For example, an SEM image of an exemplary tri-layer coating is shown in
The present disclosure relates in another aspect to a coating composition comprising a bactericidal layer further comprising a bactericidal element and columnar microstructure, which is stably adhered to the surface of an electrode. In certain embodiments, the bactericidal layer is a multilayer, such as a bilayer, a tri-layer, and so on. In other embodiments, the bactericidal layer is a composite of the bactericidal element and the columnar microstructure. In certain embodiments, the electrode comprises at least one implantable medical device selected from the group consisting of a pacemaker, cardioverter defibrillator, retinal implant, phrenic nerve stimulator, glucose biosensor, cochlear implant, and an electrical stimulator for pain relief management, Parkinson's disease, and/or epilepsy. In certain embodiments, application of an electric potential to the coating composition releases bactericidal ions. In certain embodiments, the bactericidal ions effectively reduce or eliminate proximal and distal bacterial growth or adhesion.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.
The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.
The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.
In Examples 1-1 and 1-2, bilayer coatings that are formed by sequentially coating substrates with a bactericidal layer and a columnar microstructure layer. (It should be noted that, although the instant specification mainly uses bilayer coatings as illustrative non-limiting examples of the multilayer coatings, the instant specification is not limited thereto. Structures such as tri-layer coatings, tetra-layer coatings, and so on are specifically included. For example, an SEM image of an exemplary tri-layer coating is shown in
Bilayer coatings of Ag and TiN have been synthesized using DC magnetron sputtering for the Ag layer and DC magnetron reactive sputtering for the TiN layer to arrive at sequentially sputtered coatings (
Scanning electron microscopy (SEM) was performed on representative deposition samples demonstrating the “cube-corner” microstructure characteristic of columnar growth at the coating surface (
X-ray diffraction (XRD) was used to confirm the discrete nature of the Ag and TiN layers (
The Ag/TiN bilayer coating compositions were fractured after cooling in liquid N2 to further confirm the discrete nature of the Ag and TiN layers. The columnar microstructure of the TiN, and the columnar fragments of TiN resulting from the fracture, are clearly observed by SEM (
aRectangle numbers refer to sections of Ag/TiN coating demarcated in FIG. 8.
Electrochemical measurements were performed on Ag/TiN bilayer coatings utilizing an electrochemical cell comprising a working electrode (Ag/TiN coating), a counter electrode (platinum coil), and an Ag/AgCl reference electrode. Cyclic voltammetry (CV) was performed with an applied electrical potential difference between the counter and working electrodes, wherein the resulting electrical current was measured (
The Ag/TiN coatings with 0.50 μm and 0.75 μm TiN layer thicknesses resulted in the highest oxidation potentials, indicating a greater extent of Ag oxidation. A higher observed Ag ion concentration in the electrolyte after an applied potential is indicative of more facile access of the Ag layer by the electrolyte solution. Additionally, the SEM cross-section of the Ag/TiN coating shows a dense layer near the bottom surface of the coating. Thus, without wishing to be bound by theory, the higher measured Ag-ion concentration observed in the electrolyte solution of the Ag/TiN coating (0.75 μm thick TiN layer), as compared to the 0.50 μm thick TiN layer sample, indicates that the electrolyte has easier access to the Ag layer, and accordingly, the dense interfacial layer of the 0.75 μm thick TiN layer sample has more defects. This result was unexpected, as both layer thicknesses are less than the estimated 1 μm thick dense layer observed in thicker coated samples.
The results of the ICP-MS analysis of the electrolyte solutions indicated that a positive potential does yield silver ions in solution in all but one case. In instances in which the potential is reversed, such that re-deposition of the Ag ions onto the coating can occur, thicker coatings do not yield any measurable ion content in the solution. Without wishing to be limited by any theory, this phenomenon is likely a consequence of the natural diffusion lengths of the ion in solution within the voids between columns. On the basis of this rationale, the diffusion speed of the ions is less than 0.125 μm/s, as the ions do not emerge after a thickness of 1 μm is reached.
Re-deposition of Ag ions from the electrolyte solution to the columnar TiN surface was observed in a SEM image of a fractured Ag/TiN sample after electrochemical cycling (
aRectangle numbers refer to sections of Ag/TiN coating demarcated in FIG. 12.
In a manner analogous to the preparation of Ag/TiN bilayer coatings, Cu/TiN bilayer coatings have been synthesized using DC magnetron sputtering for the Cu layer and DC reactive magnetron sputtering for the TiN layer to arrive at sequentially sputtered coatings. The thickness of coatings was measured by stylus profilometry on an Ambios XP-2. In certain embodiments, a thickness of 0.75 μm was obtained for the Cu layer. In certain embodiments, a thickness of 0.50 μm, 0.80 μm, 1.20 μm, and 1.60 μm was obtained for the TiN layer.
Scanning electron microscopy (SEM) was performed on representative deposited samples, which similarly demonstrate characteristic columnar growth at the coating surface (
The Cu/TiN bilayer coating was subjected to XRD analysis (
Electrochemical measurements were performed on Cu/TiN bilayer coatings utilizing an electrochemical cell as otherwise previously described (
In Example 2 several single layered composite coatings, which were formed by co-depositing a bactericide metal element and a nitride columnar microstructure-forming metal in the presence of N2, are described. It should be noted that the composite coatings as described herein are not limited to the single layered composite coatings. As shown in
Composite coatings were synthesized by the co-deposition of either Ti or Zr and either Ag or Cu under partial pressure of N2. A number of coatings were prepared with varied deposition parameters, comprising variations of Ag power, Ti power, and time (Tables 3-5). The composition percentages provided in Tables 3-5 are with respect to the metals only and ignore the nitrogen content. However, the nitrogen atomic content is approximately equal to the titanium content, corroborating that the base material is TiN for each composition.
Selected Ag/TiN composite coatings were subjected to SEM (
Ag particulates began to appear on the surface of the coatings after several days which were clearly observed by SEM (
In contrast to composite Ag/TiN coatings, incorporation of Cu as the bactericidal element in composite TiN coatings does not result in the formation of Cu nanoparticles. The addition of Cu does not influence the pillar structure. Without wishing to be bound by theory, this phenomenon, or lack thereof, is likely the result of a combination of possible copper nitride (CuN) formation, and the relatively small size of the Cu atom as compared to Ag. However, nanoparticle formation is not a requisite characteristic of bactericidal activity.
The migration of Ag to the periphery of the columnar microstructures was examined with Ag/ZrN composite coatings. The SEM images of a several Ag/ZrN composite coatings prepared with varied deposition parameters were obtained (
Bactericidal activity of coated metal discs on static biofilm formation of S. aureus and P. aeruginosa was evaluated using the crystal violet staining method. Bactericidal metal discs were added to wells of 96-well microplate before static incubation at 37° C. After incubation, plates were rinsed to remove planktonic cells and adherent cells were quantified by staining with crystal violet and subsequently measuring absorbance at 570 nm. The resultant absorbance values using Ag/TiN coatings were plotted for S. aureus (
Each bactericidal coated metal disc was placed in a sterile test tube with 2 mL of Luria-Bertani (LB) media, and the mixture was inoculated with 1 mL of either S. aureus or P. aeruginosa which were grown to an OD600 of approximately 0.200. The samples were incubated at 37° C. for 4 hours and the absorbance (600 nm) of each sample was measured at every 20 minutes. After an incubation period of 4 hours, a 1 μL aliquot was removed from each sample and spotted onto a Luria-Bertani agar plate which was further incubated and monitored for colony growth.
The bactericidal activity of coated discs was quantitatively examined. The results indicate that Ag/TiN coatings with low a low Ag composition do not possess bactericidal activity against distal S. aureus, however Ag/TiN coatings with a high Ag composition possess some bactericidal activity against distal bacteria even in the absence of an applied potential (FIGS. 25A-25E). Similar results were observed with P. aeruginosa, wherein some bactericidal activity against distal bacteria was observed in the absence of an applied potential (
Similar experiments were performed Cu/TiN coated materials (
Overnight cultures of P. aeruginosa were diluted 1:200 in LB and grown to an OD600 between 0.200 and 0.600 to prepare a stock solution. Utilizing an OD600 to CFU conversion factor, the stock solution was diluted to 1×10−4 CFU/mL in pH 7 PBS buffer, which was used directly in CV experiments (either 20 mL or 1 mL of stock solution total volume). The electrochemical cell used in the CV experiments comprised a Ag/TiN coated stainless steel working electrode (Ag/TiN Sample 20, Table 4), a platinum counter electrode, and a reference electrode. The potential was cycled from 0 V to 0.8 V to 0 V 20 times and the current was measured. Immediately following electrochemical cycling, a 200 μL aliquot was removed and plated on a LB agar plate. Similarly, an aliquot was removed and diluted 1:10 and 200 μL of the diluted sample was plated on a LB agar plate. The remaining solution was incubated at 37° C. and allowed to shake for 30 to 60 minutes, before an aliquot was removed and plated on a LB agar plate. LB agar plates were allowed to incubate at 37° C. with shaking for 12-18 hours. After the incubation period colonies grown on agar plates were counted and compared to the control (
aAg/TiN Sample 20 (Table 4) was used in these experiments (13% Ag and 87% Ti)
bAn accurate CFU/ml value could not be determined due to excessive colony formation
The results of the CV experiments employing bactericidal coatings demonstrate significant distal bactericidal activity against P. aeruginosa, wherein a reduction of 98.53% and 100% were achieved after 30 and 60 minutes, respectively. However, immediately after the electrochemical cycling no significant reduction was observed. These results indicate that the diffusion of eluted ions is slow and that time is required for substantial bactericidal activity when the volume is significant. In experiments in which the total volume was 1 mL, as opposed to 20 mL, a reduction of 94.78% was observed after electrochemical cycling. Thus, longer waiting times or reduced volume lead to substantial, or complete, reduction of the bacterial population.
Similar CV experiments were performed using Cu/TiN coatings under an applied potential to evaluate bactericidal activity against P. aeruginosa with a total volume of 1 mL in all cases. In all cases, even immediately after electrochemical cycling, substantial bactericidal activity was observed, with >50% of reduction of the bacterial population (Table 7). Thus, Cu/TiN coatings also demonstrate significant bactericidal activity under applied potential.
aCu/TiN Sample 1 (Table 5) was used in these experiments (4.89% Cu and 95.11% Ti);
bCu/TiN Sample 2 (Table 5) was used in these experiments (5..87% Cu and 94.13% Ti)
In non-limiting embodiments, impurities, bactericidal or not, added to the columnar microstructures could reduce the size of or completely block the pores between the columnar microstructures.
Since the bactericidal elements sometimes have small solubilities in aqueous solutions, efficacy of the coatings sometimes requires a potential to be added to the coatings (as would be applied in normal operation of some implantable articles) to oxidize the bactericidal elements, thereby releasing bactericidal ions.
The present study therefore provides results of measurements of the range of impurity (bactericidal) element additions that retain the important columnar microstructure.
Coatings were synthesized using reactive dc-magnetron sputtering. Bactericidal elements were added to the TiN by co-sputtering from an elemental source. The amount of bactericidal element was controlled in the coating by adjusting the power to the source (increased power results in increased deposition rate), or by variation of the distance from the source to the substrate. In the latter case, many different concentrations of bactericidal element could be investigated in a single deposition.
After deposition, the microstructure of the bactericidal element containing coatings was characterized using scanning electron microscopy (SEM). The composition of the coatings was measured using energy dispersive spectroscopy (EDS). X-ray diffractometry was used to investigate the role of the bactericidal element on the crystal texturing in the coating which is strongly correlated with the columnar microstructure.
In certain embodiments, different bactericidal atoms can have differing impact on the TiN microstructure due to the mass of the element and how they sputter among other potential parameters. In what follows, representative data that was used in this analysis will be introduced.
Measurement of the crystal structure by x-ray diffractometry (XRD) is shown in
In general, the addition of a bactericidal or impurity element to the TiN eventually impacts the microstructure and the electrochemical performance of the coatings as the concentration increases.
A flow cell apparatus was configured which allowed the application of a potential to the coatings under liquid flow conditions. As the phosphate buffered saline (PBS) solution passed through the cell, when oxidation occurred, ions were released. The output of the cell was passed through a tube into an inductively-coupled plasma mass spectrometer to measure the ion concentration. Since the tube coupling the cell to the spectrometer had a small diameter, there was a delay in the detection of the released ions. To compensate for this effect, the potential was increased in steps of 0.1V per 5-minute time interval.
This data suggest that release rates can be tailored for the application by adjusting the potential and the initial concentration of the antimicrobial element in the coating. In addition, voltage pulse height and duration will play important roles.
The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application.
The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.
While the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.
The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/104,241, filed Oct. 22, 2020, which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63104241 | Oct 2020 | US |
