Devices with improved antimicrobial surfaces

Abstract

The medical device includes a base structure having a surface that is laser treated to define at least one projection and / or at least one void extending relative to the surface, and a coating having antibacterial, antimicrobial and / or drug eluting properties is applied to the base structure to engage within or along a surface portion of one or more of the projections and / or voids.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Application No. 63 / 254,752, filed October 12, 2021, the contents of which are incorporated herein by reference. [Background technology]

[0002] [Technical field of the present disclosure] The present disclosure relates to electrodes and biomedical, implantable or diagnostic medical devices that support (or that support) a coating that imparts antibacterial, antimicrobial or drug eluting properties and that have an improved surface topography.

[0003] [background] Due to the aging population and the many neurological and cardiovascular diseases that cannot be alleviated by drug therapy alone, the number of patients requiring implantable neurostimulation devices is increasing significantly. These range from sensors, gastric and cardiac pacemakers, defibrillators, deep brain, nerve, and bone stimulators. Resorbable electronics do not require surgical removal and may offer excellent short-term performance. However, most electronic materials have poor bio- and cytocompatibility, leading to immune responses and infections.

[0004] Infection is a serious complication of devices implanted (or implanted) in the human body. Deep infections are difficult to treat and eradicating the infection often requires removal of the infected implant, which remains a serious complication in many medical procedures. Treatment of deep infections is difficult due to the difficulty in delivering antibiotics to the infected site, and treatment times can vary between 3 and 14 months and may require secondary surgery.

[0005] The antimicrobial properties of metals and metal oxides, especially in the form of microparticles and nanoparticles, have long been recognized and are well documented in the literature. A common drawback of known metal-containing coatings is that efforts to improve the adhesion of such coatings (e.g., to provide durability or scratch resistance) may adversely affect their antimicrobial properties. Conversely, attempts to improve the antimicrobial efficacy of such coatings may adversely affect their ability to stably adhere to implant surfaces. Summary of the Invention

[0006] Hierarchical surface restructuring (HSR™) technology can create hierarchically structured surfaces (HSS) on microelectrodes (or microelectrodes) for ultrahigh surface area and enhanced electrochemically-active surface area. However, electrode materials (e.g., Pt10Ir) or common surface coatings (e.g., TiN or IrO2) deposited on electrode materials may not be antimicrobial. On the other hand, e.g., Cu x Highly effective broad-spectrum antimicrobial materials, such as O, are insulators with poor electrochemical properties and cannot be used as electrodes. Coating a hierarchically restructured electrode or microelectrode array with an atomically thin, ultra-conformal antimicrobial material can confer antimicrobial properties to the electrode or microelectrode array.

[0007] Here, atomically thin thickness is essential to minimize the impact on the nanoscale morphology and function of HSS (e.g., ultra-high surface area, charge storage capacity, impedance, specific capacitance, etc.). Also, ultra-conformality is essential for complete antimicrobial coverage for HSS with complex nanostructures. Here, the two essential features, ultra-conformality and atomically thin thickness, are extremely difficult to achieve with conventional coating techniques (e.g., sputtering, PVD, CVD) due to (1) line-of-sight effect and (2) difficulty in atomic-level thickness control in nanocoatings below 100 nm. In contrast, atomic layer deposition (ALD) coating technology is the ideal (only) technology to achieve the two essential features and ultra-high reproducibility due to its inherently self-limiting coating mechanism. Moreover, ALD technology is being used for modern applications with automated high parallel processing throughput.

[0008] In at least one embodiment, the present disclosure provides a medical device including a base structure having a surface. The surface is laser treated to define at least one protrusion and / or at least one void extending relative to the surface. A coating having antibacterial, antimicrobial and / or drug eluting properties is applied to the base structure such that it engages within or along a surface portion of the one or more protrusions and / or voids.

[0009] [Brief description of the drawings] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate presently preferred embodiments of the invention and, together with the general description given above and the detailed description given below, serve to explain features of the invention. [Brief description of the drawings]

[0010] [Figure 1A] FIG. 1A is an SEM image showing an exemplary substrate structure obtained according to an embodiment of the present invention. [Figure 1B] FIG. 1B is an SEM image showing an exemplary substrate structure obtained according to an embodiment of the present invention. [Figure 1C] FIG. 1C is an SEM image showing an exemplary substrate structure obtained according to an embodiment of the present invention. [Diagram 2] FIG. 2 shows an exemplary surface topography having voids. [Diagram 3] FIG. 3 is a schematic diagram illustrating an exemplary substrate structure having a plurality of protrusions and voids. [Figure 4] FIG. 4 is a schematic diagram illustrating one embodiment of the present disclosure. [Diagram 5] FIG. 5 is a schematic diagram illustrating another embodiment of the present disclosure. [Figure 6] FIG. 6 is a schematic diagram illustrating yet another embodiment of the present disclosure. [Figure 7] FIG. 7 is a schematic diagram illustrating yet another embodiment of the present disclosure. [Figure 8] FIG. 8 is a schematic diagram illustrating yet another embodiment of the present disclosure. [Figure 9A] FIG. 9A is a PEALD CuxO coated Pt10Ir (FIG. 9A) sample. [Figure 9B] FIG. 9B is a PEALD CuxO coated Pt10Ir HSS (FIG. 9B) sample. [Figure 10A] FIG. 10A shows the EDS spectrum and compositional analysis of the PEALD CuO thin film on a silicon substrate (FIG. 10A). [Figure 10B] FIG. 10B shows the EDS spectrum and compositional analysis of the PEALD CuO thin film on the Pt10Ir substrate (FIG. 10B). [Figure 10C]FIG. 10C shows the EDS spectrum and compositional analysis of the PEALD CuO thin film on the Pt10Ir HSR substrate (FIG. 10C). [Figure 11] FIG. 11 shows the XPS results of three PEALD coated samples (silicon, Pt10Ir, and Pt10Ir HSS substrates). [Figure 12A] FIG. 12A shows an SEM image of the CuO on coated Si (FIG. 12A) sample. [Figure 12B] FIG. 12B shows an SEM image of CuO on the coated Pt10Ir (FIG. 12B) sample. [Figure 12C] FIG. 12C shows an SEM image of CuO on the coated Pt10Ir HSS (FIG. 12C) sample. [Figure 12D] FIG. 12D shows an SEM image of CuO on the coated Pt10Ir HSS (FIG. 12D) sample. [Figure 13] FIG. 13 shows the XPS results of three PEALD coated samples (silicon, Pt10Ir, and Pt10Ir HSS substrates). [Figure 14A] FIG. 14 shows AFM scans at the interface of an O3-ALD coated, masked Si sample, where FIG. 14A is an AFM scan showing the tip-mask interface. [Figure 14B] FIG. 14 shows an AFM scan at the interface of an O3-ALD coated masked Si sample, and FIG. 14B is a three-dimensional (3D) view. [Figure 14C] FIG. 14 shows an AFM scan at the interface of an O3-ALD coated masked Si sample, and FIG. 14C is a two-dimensional (2D) top view. [Figure 14D] FIG. 14 shows an AFM scan at the interface of an O3-ALD coated masked Si sample, and FIG. 14D is a two-dimensional (2D) profile at the interface. [Figure 15A]FIG. 15A is an optical image of a mask-coated HSS sample, clearly showing the boundary between the coated and uncoated / masked regions. [Figure 15B] FIG. 15B is an optical image of the mask-coated HSS sample, clearly showing the boundary between the coated and uncoated / masked areas. [Figure 15C] FIG. 15C is an optical image of the mask-coated HSS sample, clearly showing the boundary between the coated and uncoated / masked regions, and FIG. 15C shows the coated region. [Figure 15D] FIG. 15D is an optical image of the mask-coated HSS sample, clearly showing the boundary between the coated and uncoated / masked areas. [Figure 16A] FIG. 16 shows SEM images of a CuO coated HSS sample, with FIG. 16A showing the boundary between the coated and uncoated regions. [Figure 16B] FIG. 16 is an SEM image of a CuO coated HSS sample, and FIG. 16B shows the boundary between the coated and uncoated regions. [Figure 16C] FIG. 16 is an SEM image of a CuO coated HSS sample, and FIG. 16C shows the boundary between the coated and uncoated regions. [Figure 16D] FIG. 16 is an SEM image of a CuO coated HSS sample, and FIG. 16D is of the masked area. [Figure 16E] FIG. 16 is an SEM image of a CuO coated HSS sample, and FIG. 16E depicts the surface structure of the coated area. [Figure 17A] FIG. 17A shows EDS mapping of the area around the interface between the masked and unmasked regions of the HSS sample. [Figure 17B] FIG. 17B shows EDS mapping of the area around the interface between the masked and unmasked regions of the HSS sample. [Figure 17C] FIG. 17C shows EDS mapping of the area around the interface between the masked and unmasked regions of the HSS sample. [Figure 17D] FIG. 17D shows EDS mapping of the area around the interface between the masked and unmasked regions of the HSS sample. [Figure 17E] FIG. 17E shows EDS mapping of the area around the interface between the masked and unmasked regions of the HSS sample. [Figure 17F] FIG. 17F shows EDS mapping of the area around the interface between the masked and unmasked regions of the HSS sample. [Figure 18] Figure 18 shows the ICP-MS analysis of the uncoated Si substrate and the culture medium (water). The Y-axis represents the cumulative release of Cu ions detected by ICP-MS. [Figure 19] Figure 19 shows the ICP-MS analysis of the uncoated Si substrate and the culture medium (sterile LB growth medium). The Y-axis represents the cumulative release of Cu ions detected by ICP-MS. [Figure 20] Figure 20 shows the ICP-MS analysis of CuO coated "flat" and HSS substrates versus uncoated substrates in distilled water. The Y-axis represents the cumulative release of Cu ions detected by ICP-MS. [Figure 21] Figure 21 shows ICP-MS analysis of CuO coated "flat" and HSS Pt substrates versus uncoated substrates in sterile LB medium. The Y-axis represents the cumulative release of Cu ions detected by ICP-MS. [Figure 22] Figure 22 shows agar plates after wiping and inoculating CuO-coated Si substrates with (A) Staphylococcus aureus and (B) Escherichia coli. Images are representative of duplicates. [Diagram 23]Figure 23 shows OD600 measurements of liquid cultures inoculated from Si substrates + / - CuO coating. These cultures were incubated for 18 hours from the initial inoculation. PBS (phosphate buffered saline) was included as a negative control. [Figure 24] Figure 24 shows agar plates after wiping and inoculating an uncoated "flat" Pt substrate with (A) S. aureus and (B) E. coli. Images are representative of duplicates. [Diagram 25] Figure 25 shows agar plates after wiping and inoculating uncoated Pt HSS substrates with (A) Staphylococcus aureus and (B) Escherichia coli. Images are representative of duplicates. [Figure 26] Figure 26 shows agar plates after wiping and inoculating a CuO-coated "flat" Pt substrate with (A) S. aureus and (B) E. coli. Images are representative of duplicates. [Figure 27] Figure 27 shows agar plates after wiping and inoculating CuO-coated Pt HSS substrates with (A) Staphylococcus aureus and (B) Escherichia coli. Images are representative of duplicates. [Figure 28] Figure 28 shows OD600 measurements of liquid cultures inoculated from uncoated Pt substrates, either "flat" or "HSS" surfaces. These cultures were incubated for 18 hours from the initial inoculation. PBS (phosphate buffered saline) was included as a negative control. [Figure 29] Figure 29 shows OD600 measurements of liquid cultures inoculated from CuO coated Pt substrates, either "flat" or "HSS" surfaces. These cultures were incubated for 18 hours from the initial inoculation. PBS (phosphate buffered saline) was included as a negative control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] [Detailed Description] In the drawings, like numerals refer to like elements throughout. Certain terms are used herein for convenience only and are not intended to limit the present invention. Preferred embodiments of the present invention will now be described. However, based on this disclosure, it should be understood that the present invention is not limited by the preferred embodiments described herein.

[0012] 1A-3, an exemplary medical device substrate structure 10 according to an embodiment of the present disclosure is described. Potential medical devices include, but are not limited to, electrodes, microelectrode arrays, stents, orthopedic and dental implants, and the like. The substrate structure 10 and coating 32 of the medical device 30 may be selected to provide a combination of desired structural and antimicrobial properties. The substrate structure 10 shown has a topography of a surface 12 defined by a plurality of macroprojections 14, microprojections 16, and nanoprojections 18. The surface 12 may also include a plurality of voids 20. Although described as an exemplary structure, the substrate structure 10 of the medical device 30 may have more or fewer projections and may or may not include voids.

[0013] In the illustrated embodiment, the outer circumferential surface has a topography defined by a plurality of discrete macroprotrusions 14 distributed about and extending outwardly from the outer circumferential surface 12 (see FIG. 1A). In one embodiment, the macroprotrusions 14 are substantially uniformly distributed across the entire outer circumferential surface of the solid monolithic substrate. In one embodiment, the macroprotrusions have a width between about 0.15 μm and about 50 μm. In another embodiment, the macroprotrusions have a width between about 0.2 μm and about 30 μm. In yet another embodiment, the macroprotrusions have a width between about 1 μm and about 20 μm.

[0014] A plurality of discrete microprotrusions 16 are distributed on and extend outwardly from the macroprotrusions 14 (see FIG. 1B). In one embodiment, the width of the microprotrusions 16 is from about 0.15 μm to about 5 μm. In another embodiment, the width of the microprotrusions 16 is from about 0.2 μm to about 2 μm. In yet another embodiment, the width of the microprotrusions 16 is from about 0.4 μm to about 1.5 μm. In one embodiment, the microprotrusions 16 are distributed across the macroprotrusions 14 in the form of a periodic undulation of the microprotrusion height. The periodic undulation is believed to be generated and controlled by the wavelength of the laser irradiation.

[0015] A plurality of discrete nanoprojections 18 are distributed on and extend outward from the microprojections 16 (see FIG. 1C). In one embodiment, the nanoprojections 18 have a width of about 0.01 μm to about 1 μm. In another embodiment, the nanoprojections 18 have a width of about 0.02 μm to about 1 μm. In yet another embodiment, the nanoprojections 18 have a width of about 0.075 μm to about 0.8 μm. In one embodiment, the nanoprojections 18 are distributed across the microprojections 16 in tubular and / or spherical morphologies. The nanoprojections 18 are believed to be generated and controlled by the number of pulses and pulse duration. Without being bound to a particular theory, it is believed that the macro-, micro-, and nanoprojections are formed by the laser drilling voids in the substrate surface, followed by redepositing material from the voids (void material) onto the substrate surface as these projections. It is therefore important that the laser irradiation be performed without purging the substrate with gas or applying substantial gas pressure, as this would tend to cause material from the voids to be blown away rather than redeposited on the substrate. The atmosphere in which the laser irradiation is performed is generally not considered important, so long as the removed void material is not blown away and can be redeposited on the substrate. For example, for materials such as Ti, nitrogen is required to react with Ti to form electrochemically active high surface area TiN. The drilling effect is strongest at the center of the laser spot, so the laser spot traversing the substrate surface creates spot overlap, resulting in a Gaussian distribution of the applied laser radiation.

[0016] In another embodiment of the invention, in addition to these discrete macro-, micro-, and nano-protrusions extending outward from the substrate surface, the surface structure 12 may have an array of laser-induced voids 20 (see FIG. 2) whose length and depth depend on the laser parameters used. Thus, in this embodiment, the peripheral surface further has a topography with a plurality of voids 20 distributed on the peripheral surface, extending to a depth through the substrate. The voids have a depth through the substrate of about 50 nm to about 500 nm, preferably about 100 nm to about 250 nm. The width of the voids is about 50 nm to about 500 nm, preferably about 100 nm to about 250 nm. The voids are spaced apart from adjacent voids by a distance of about 50 nm to about 250 nm.

[0017] The substrate surface 10 according to the present disclosure is produced by exposing the outer peripheral surface of a solid monolithic substrate of a biocompatible metal to pulses of laser irradiation. In one embodiment, the laser spot diameter is about 1 μm to about 1000 μm. In another embodiment, the laser spot diameter is about 2 μm to about 250 μm, and in yet another embodiment, the laser spot diameter is about 5 μm to about 200 μm. In one embodiment, the number of pulses of laser irradiation per spot is about 10 to about 1500 pulses. In another embodiment, the number of pulses of laser irradiation per spot is about 20 to about 1000, and in yet another embodiment, the number of pulses of laser irradiation per spot is about 100 to about 500. In one embodiment, the pulse wavelength of the laser is about 200 nm to about 1500 nm. In another embodiment, the pulse wavelength is about 400 to about 1000, and in yet another embodiment, the pulse wavelength is in the range of about 400 to about 800. In one embodiment, the laser pulse width is about 1 femtosecond to about 5 picoseconds. In another embodiment, the laser pulse width is about 1 femtosecond to about 3 picoseconds. In one embodiment, the laser irradiance is about 200 Watts / cm 2 ~ approx. 5000 watts / cm 2The exposure may be carried out by moving a spot of laser radiation (or laser illumination) across the periphery of the solid monolithic substrate at a speed of about 50 mm / min to about 1000 mm / min, although the speed is not critical to the invention and only affects the cost-effectiveness of carrying out the method of the invention.

[0018] Examples of suitable lasers include the Coherent Libra-F Ti:Sapphire Amplifier Laser System, the Rofin Startfemto, and the Coherent AVIA laser. According to the present disclosure, the resulting electrodes have a polarization of about 1000 mV or less, preferably about 500 mV or less, and more preferably about 200 mV or less.

[0019] 4, medical device 30 includes a coating 32 applied over surface 12 of substrate structure 10. Coating 32 may have a variety of properties, for example, antibacterial and / or antimicrobial properties. Coating 32 may also have drug eluting properties, such as, for example, anti-cancer agents, and / or antibacterial or antimicrobial agents.

[0020] Antimicrobial coatings or thin films containing germicidal elements such as zinc, copper and / or silver are known to have germicidal properties when in ionic form. Most of these elements form oxides when exposed to oxygen under certain processing and / or operating conditions, which may also exhibit antimicrobial properties. Examples include zinc oxide, silver oxide, copper oxide, etc.

[0021] The basic coating is known, but laser restructuring or texturing of the substrate structure 10 configures the surface 12 for maximum effectiveness of the coating. For example, in the embodiment shown in FIG. 4, the protrusions 14, 16, 18 and voids 20 define an enlarged surface area that facilitates maximum application of coating.

[0022] Turning to the medical device 30' shown in Figure 5, the coating 32' is applied only within the voids 20. In such a configuration, the exposure of the coating 32' is minimal and can be utilized in applications where slow, sustained release is desired. In the embodiment shown in Figure 6, the coating 32'' of the medical device 30'' is applied along the surface 12 between the macroprojections 14 and within the voids 20. Compared to the previous embodiment, the coating 32'' is exposed along a larger surface area and therefore may be released more quickly, yet is still protected as it is below the outer extensions of the projections 16, 18.

[0023] In the medical device 32''' illustrated in FIG. 7, the coating 32''' is applied along the surface 12 between the microprotrusions 16. In this configuration, the coating 32''' is closer to the outer surface for more rapid release upon contact, yet is protected by the nanoprotrusions 18 extending further outward. Conversely, in the medical device 32 illustrated in FIG. iv So, Coating 32 iv is applied only to the nanoprojections 18. With this configuration, the coating 32 iv is exposed to the maximum and released correspondingly rapidly.

[0024] Sample structures incorporating various of the above features have been fabricated and tested, as described in detail below. More specifically, ultraconformal atomically thin Cu films were deposited by ALD on silicon, planar Pt10Ir, and Pt10Ir HSS. x In one example, a Veeco Fiji ALD kit was used to fabricate an antimicrobial coating on Cu. x O ALD coating was used for deposition.

[0025] The samples were exposed to repeated cycles of Cu-containing precursors and oxidizing reactants (e.g., O3, O plasma, or HO). In each cycle, the Cu-containing precursors and gas reactants react simultaneously with the substrate in a sequential and self-limiting manner. Thus, ultraconformal Cu x A Cu precycle is grown on the sample. x The quality and properties of the O ALD coatings were evaluated by various characterization techniques: film thickness and optical properties by ellipsometry and atomic force microscopy (AFM), microstructure and nanomorphology by high-resolution scanning electron microscopy (SEM) and AFM, microscale chemical probes by energy dispersive spectroscopy (EDS), chemical composition by X-ray photoelectron spectroscopy (XPS), crystal structure and composition by grazing incidence X-ray diffraction (GIXRD), coating conformity and uniformity by optical microscopy and SEM, and mechanical durability by nanoindentation. Based on XPS, the ALD coatings by O plasma PEALD and thermal ALD with O were confirmed to be CuO.

[0026] The antimicrobial properties of the coated samples were investigated, as described in detail below. While uncoated Si and flat Pt10Ir have no antimicrobial properties, interestingly the uncoated Pt10Ir HSS sample exhibits certain inherent antimicrobial properties, likely due to the nanoscale surface sharpness. The CuO coated samples all exhibited different degrees of antimicrobial properties. The CuO coated HSS sample exhibited the highest antimicrobial properties.

[0027] [Coating procedure] Cu xO films were grown using a Veeco Fiji PEALD system. The Cu-containing precursor was (bis(dimethylamino-2-propoxide)copper(II)) and the precursor source was maintained at 125 °C using a Veeco low vapor pressure delivery (LVPD) module. Argon gas was used as the carrier gas with a constant flow rate of 30 sccm.

[0028] Two ALD deposition conditions were studied: (1) plasma-enhanced ALD (PEALD) using oxygen plasma as a co-reactant, and (2) thermal ALD using ozone (O3) as a co-reactant. The substrate temperature was maintained at 150 °C. For PEALD, each ALD cycle consisted of a 2 s copper precursor pulse and a 10 s oxygen plasma pulse, resulting in a growth per cycle (GPC) of ~0.05 nm. For O3-based ALD, each ALD cycle consisted of a 2 s Cu precursor pulse and a 0.075 s O3 pulse, resulting in a growth per cycle (GPC) of ~0.02 nm.

[0029] Three types of substrates were used: atomically flat silicon, as-received Pt10Ir, and laser-treated Pt10Ir HSS. To analyze the thickness of the ALD coating, Kapton tape was used to block / mask the ALD coating, allowing only the unmasked areas to be ALD coated.

[0030] [Materials characterization] A JAWoollam spectroscopic ellipsometer M-2000 was used to analyze the thickness and optical properties of the ALD coatings. An Olympus microscope was used to characterize the sample morphology. A Hitachi S-4800 scanning electron microscope (SEM) with EDS module was used to characterize the nanoscale morphology and EDS compositional mapping. A VersaProbe5000XPS was used for XPS compositional analysis. The XPS spot size was 200 μm and was calibrated using the CC component of the C1s peak at 284.8 eV. A Park Systems AFM was used to analyze the surface morphology and film thickness of the masked-Si samples.

[0031] [Results and Discussion] (PEALD of CuO) - 225 cycles of PEALD Cu on three different substrates x O was performed. The film thickness was measured to be 12 nm using ellipsometry, with a growth rate of ~0.05 nm / cycle. Figures 9A and 9B show SEM images of the coated Pt10Ir and Pt10Ir HSS samples, showing minimal changes in surface morphology before and after PEALD deposition, suggesting good conformity of the film on the sample surface.

[0032] The EDS spectra in Figures 10A to 10C show that Cu x The O deposition shows the expected Cu and O. Quantitative EDS analysis shows that the surface composition of Cu is 4.8 wt% for the silicon sample, 3.9 wt% for the Pt10Ir, and 13.7 wt% for the Pt10Ir HSS sample, as shown in Table 1 below.

[0033] [Table 1]

[0034] FIG. 11 shows the XPS Cu2p spectrum of the PEALD thin film, which shows that Cu2+, i.e., Cu with x=2, x This clearly indicates that O was deposited as CuO. In all samples, satellite peaks of Cu2p3 / 2, Cu2p1 / 2, and Cu2+ were observed at approximately 929.6 eV, 949.8 eV, 958.5 eV, and 937.0–939.9 eV.

[0035] (O3-ALD of CuO) - 950 cycles of O3-based ALD deposition were performed on the three substrates. The film thickness was measured to be 22 nm using ellipsometry, and the growth rate was ~0.05 nm / cycle. Figure 12 shows SEM images of the coated Si, Pt10Ir, and Pt10Ir HSS samples, suggesting minimal changes in surface morphology before and after O3-ALD.

[0036] EDS spectra (not shown) also showed that Cu x The O deposition shows that it is Cu and O as expected. As shown in Table 2 below, quantitative EDS analysis similar to that in Table 1 showed that the surface composition of Cu was 69.2 wt% for the silicon sample, 2.5 wt% for the Pt10Ir, and 31.5 wt% for the Pt10Ir HSS sample. Note that these are the compositions of the coating surface.

[0037] [Table 2]

[0038] XPS was performed to confirm the composition of the O3-ALD copper oxide film. Figure 13 shows the Cu2p spectrum, which also indicates the oxidation state of Cu2+, i.e., the O3-ALD coating film is CuO.

[0039] Figures 14A-D show AFM scans of the O3-ALD coated, Kapton tape masked Si sample at the interface, indicating a film thickness of ~24 nm, in good agreement with the ellipsometry measurement of ~22 nm. It is interesting to see a 22 nm coating on the Si substrate.

[0040] The ~22 nm O3-ALD CuO coating can be easily identified by optical images, SEM images, and EDS mapping around the masking boundary, as shown in Figures 15-17. Optical images at different magnifications (Figures 15A-15D) show the color contrast between the coated and uncoated regions. The coated side appears darker than the uncoated side. SEM images of the HSS sample (Figures 16A-16E) show an abrupt change in the structure of the sample near the masked boundary. Figures 16D and 16E show that the 22 nm CuO coating conformally coats the HSS nanostructure well and causes a blunting effect compared to the uncoated HSS structure.

[0041] EDS mapping (Figures 17A-F) was performed near the border between the masked and unmasked areas, where the masked area is on the left and the coated area is on the right. It can be seen that platinum and iridium are present throughout the sample. Cu is present on the right and absent from the masked area. This is further evidence proving the effectiveness of the masking of the surface with Kapton tape and the CuO coating.

[0042] [Detailed analysis] (Ion emission from the surface) -Coated and bare substrates (as control) were tested for static release of copper ions based on the coating composition provided. The experimental design was as follows: samples were immersed in 10 ml of liquid medium (either sterile distilled H2O or sterile LB medium for bacterial growth) and incubated at 37°C. At time=0 min and at 10 min intervals thereafter, aliquots of 500 ml were removed from the solution and immediately mixed with 4.5 ml of 2% nitric acid. These samples were then injected into an ICP-MS tuned for copper ion detection.

[0043] The first set of experiments was performed using silicon substrates without a CuO coating. These results are shown in Figures 18 and 19. The uncoated silicon samples were found to have very low levels of Cu present in the samples; they were between 50 and 70 ppb at the final time point. It is unclear where the Cu ions in these samples originated from, but the signal was consistently 2-3 times higher than the background derived from the liquid medium.

[0044] A second set of experiments was performed using platinum substrates with and without a CuO coating. The experiments were also diversified by comparing untreated or "flat" Pt substrates with and without a CuO coating, and Pt HSS substrates whose surfaces were laser reconstructed before CuO coating. The results of these ICP-MS experiments are shown in Figures 20 and 21. These results clearly show a rapid and massive release of Cu ions from the coated Pt HSS substrates in both water and LB medium. This release is an order of magnitude higher compared to the "flat" Pt substrates (~1900 ppb vs. ~200 ppb at the end of the experiment). Notably, the CuO-coated "flat" substrates released some Cu ions compared to the background (~200 ppb vs. ~60 ppb).

[0045] (Bacterial adhesion) -The coated materials were tested for bacterial adhesion and contact-dependent antibacterial activity based on the coating composition provided. The experimental design involved depositing a known amount of bacteria (10 ml of bacterial culture adjusted to 1 x 105 CFU / ml) on the surface. After 60 minutes of incubation at 37°C, the surface was wiped using a sterile cotton swab to isolate any remaining viable bacteria. The swab was used to inoculate a solid medium, an LB agar plate, which was then immersed in 3 ml of sterile LB medium for the final inoculation. Both the LB agar dish and the liquid culture were incubated at 37°C for 18 hours, with the liquid samples being shaken at 250 rpm to maximize growth. After 18 hours, the plates were photographed to confirm colony growth and the turbidity of the liquid samples was measured using OD600. The same procedure was used for both bacterial strains, E. coli (gram-negative) and Staphylococcus aureus (gram-positive).

[0046] The first set of experiments was performed using silicon substrates with and without CuO coating. The results are shown in Figures 22 and 23. Figure 22 shows the agar plate inoculated after wiping the CuO-coated Si substrate, and Figure 23 shows the OD600 after inoculation with liquid culture. The data shows that E. coli was killed by contact with the CuO surface, as evidenced by the absence of colonies on the plate and no light scattering observed in the liquid culture. In contrast, S. aureus was not killed by contact with the CuO-coated surface, as evidenced by the presence of colonies on the dish and high levels of scattering observed in the liquid culture.

[0047] A second set of experiments was performed, again using platinum substrates with and without a CuO coating. The experiments were also diversified by comparing untreated or "flat" Pt substrates, with and without a CuO coating, with Pt HSS substrates whose surfaces were laser reconstructed before CuO coating. The results are shown in Figures 24-27. In these experiments, E. coli was not able to grow in any of the surface conditions. However, S. aureus was only able to grow on the "flat" surfaces, regardless of the presence or absence of a CuO coating. Most importantly, no growth of S. aureus colonies was observed in samples obtained from the laser reconstructed samples, indicating a significantly improved bactericidal effect of these surfaces.

[0048] Figures 28 and 29 show data from liquid cultures inoculated from the same swabs as in Figures 24-27. Swabs from uncoated platinum samples showed the same patterns as seen in the agar plate assays, with one exception: one of the S. aureus cultures showed moderate growth in liquid culture (Figure 28). This indicates that there were likely a small number of viable S. aureus cells on the swab (i.e., the surface), but those cells did not transfer to the solid medium. However, the coated sample showed a growth pattern identical to the plate assay (Figure 29). Taken together, these data indicate that S. aureus cannot be completely eradicated on uncoated structured samples, but can be completely eradicated by the combination of the laser reconstructed surface and CuO coating.

[0049] Although specific structures and coating patterns are shown, the disclosure is not limited to the illustrated embodiments. Laser restructuring or texturing allows the surface to be configured to maximize the effectiveness of the antimicrobial / drug eluting coating, for example, with pockets or ledges to protect or delay the exposure / release of the coating. The structure can also be configured to facilitate multiple coatings or oxide blends, or multi-layer coating materials.

[0050] The coating can be applied using a variety of techniques, such as, for example, physical vapor deposition, chemical vapor deposition, atomic layer deposition, etc. Furthermore, the laser restructuring can occur before or after the coating is applied. As an example, a metal coating, such as silver or copper, can be applied to a surface using a coating technique, followed by laser restructuring in an oxygen-rich environment to form a metal oxide coating in situ during the laser restructuring.

[0051] These and other advantages of the present invention will be apparent to those skilled in the art from the foregoing specification. It will therefore be appreciated by those skilled in the art that changes or modifications may be made to the above-described embodiments without departing from the broad inventive concept of the present invention. It is therefore understood that the present invention is not limited to the particular embodiments described herein, but is intended to cover all such changes and modifications within the scope and spirit of the present invention as defined in the appended claims.

Claims

1. a substrate structure having a surface, the surface being laser treated to define at least one protrusion and / or at least one void extending relative to the surface; and a coating having antibacterial, antimicrobial and / or drug-eluting properties applied to the substrate structure so as to engage within or along a surface portion of one or more of the protrusions and / or voids; medical devices, including

2. The medical device of claim 1 , wherein the surface has a hierarchical laser reconstructed topography.

3. The medical device of claim 2 , wherein the surface topography comprises nanoprotrusions extending from the microprotrusions.

4. The medical device of claim 3 , wherein the surface topography is further defined by macroprotrusions from which the microprotrusions extend.

5. The medical device of claim 1 , wherein the coating is applied along the entire surface.

6. The medical device of claim 1 , wherein the coating has an atomically thin thickness.

7. The medical device of claim 1 , wherein the coating comprises zinc, copper and / or silver.

8. The coating is Cu ｘ The medical device of claim 1 , comprising O.

9. The medical device of claim 1 , wherein the coating is applied using a vapor deposition process.

10. The medical device of claim 1 , wherein the coating is applied using an atomic layer deposition process (ALD).

11. 11. The medical device of claim 10, wherein the coating is applied using plasma-enhanced ALD or thermal ALD.

12. 10. The medical device of claim 1, wherein the substrate structure comprises platinum, steel, a platinum-iridium alloy, a nickel-cobalt alloy, titanium, a titanium alloy, tantalum, or a combination thereof.

13. 1. A method for manufacturing a medical device having a substrate structure with a surface, comprising: laser treating the surface to define at least one protrusion and / or at least one void extending relative to the surface; a coating application step of applying a coating having antibacterial, antimicrobial and / or drug eluting properties to the substrate structure to engage within or along a surface portion of one or more of the protrusions and / or voids; A method for manufacturing a medical device, comprising:

14. The method of claim 13 , wherein the surface has a hierarchical laser reconstructed topography.

15. The method of claim 13 , wherein the coating is applied along the entire surface.

16. The method of claim 13 , wherein the coating has an atomically thin thickness.

17. The method of claim 13 , wherein the coating comprises zinc, copper and / or silver.

18. The method of claim 13 , wherein the coating is applied using a vapor deposition process.

19. 20. The method of claim 18, wherein the coating is applied using an atomic layer deposition process (ALD).

20. 20. The method of claim 19, wherein the coating is applied using plasma-enhanced ALD or thermal ALD.

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