The present disclosure relates to electrodes and biomedical, implantable or diagnostic medical devices. The devices have an improved surface topography which supports a coating which imparts antibacterial, antimicrobial, or drug eluting properties.
Ageing population and a multitude of neurological and cardiovascular illnesses that cannot be mitigated by medication alone have resulted in a significant growth in the number of patients that require implantable neurostimulation devices. These range from sensors, gastric and cardiac pacemakers, cardioverter defibrillators, to deep brain, nerve, and bone stimulators. Resorbable electronics may offer excellent short-term performance without the need for surgical removal. However, most electronic materials have poor bio- and cytocompatibility, resulting in immune reactions and infections.
Infection is a serious complication of devices implanted in the human body. Deep infections, which are difficult to treat may often require removal of the infected implant to eradicate infection and this remains a serious complication of many medical procedures. Treatment of deep infections is challenging because it is difficult to supply antibiotics to the infection site, and such treatment can vary from 3 to 14 months in duration and can include secondary surgery.
Others have previously recognized the antimicrobial properties of metals and metal oxides, especially in a micro- or nanoparticulate form, and there is extensive literature reporting that effect. A common shortcoming of known metal containing coatings is that efforts to improve adherence of such coatings (e.g., to provide durability and scratch-resistance) can adversely affect their antimicrobial properties. Conversely, efforts to improve the antimicrobial efficacy of such coatings can adversely affect their ability to stably adhere to implant surfaces.
Hierarchical surface restructuring (HSR™) technology is capable of fabricating hierarchically structured surfaces (HSS) on microelectrodes for ultrahigh surface area and enhanced electrochemically-active-surface-area. However, the electrode materials (e.g., Pt10Ir) or common surface coatings (e.g. TiN or IrO2) that are deposited onto the electrode materials may not be antimicrobial. On the other hand, highly effective broad-spectrum antimicrobial materials, e.g., CuxO, are insulators with poor electrochemical properties and cannot be used as electrodes. Coating electrodes or microelectrode arrays that are hierarchically restructured on the surface with atomically thin and ultra-conformal antimicrobial material may impart antimicrobial property to the electrode or microelectrode array.
Here, the atomically thin thickness is essential for minimal effect on HSS' nanoscale morphology and functionalities (e.g., ultrahigh surface area, charge storage capacity, impedance and specific capacitance). The ultra-conformality is essential for the complete antimicrobial coverage for the complex nanostructured HSS. Here, the two essential features—ultra-conformality and atomically thin thickness—are extremely challenging for conventional coating techniques (e.g., sputtering, PVD, and CVD) due to their (1) line-of-sight effect and (2) difficulty of atomic-thickness control on sub-100 nm nanocoatings. On the contrary, atomic layer deposition (ALD) coating technique is ideal (the only one) to achieve the two essential features and ultrahigh repeatability due to its intrinsically self-limiting coating mechanism. Moreover, ALD technique has been used in modern applications with automated high parallel processing throughput.
In at least one embodiment, the present disclosure provides a medical device including a substrate structure with 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 eluding properties is applied to the substrate structure such that the coating engages within or along a surface portion of one or more of the protrusions and/or voids.
The accompanying drawings, which are incorporated herein and constitute part of this specification, illustrate the presently preferred embodiments of the invention, and, together with the general description given above and the detailed description given below, serve to explain the features of the invention. In the drawings:
In the drawings, like numerals indicate like elements throughout. Certain terminology is used herein for convenience only and is not to be taken as a limitation on the present invention. The following describes preferred embodiments of the present invention. However, it should be understood, based on this disclosure, that the invention is not limited by the preferred embodiments described herein.
Referring to
In the illustrated embodiment, the outer peripheral surface has a topography defined by a plurality of discrete macro protrusions 14 distributed about and extending outwardly from the outer peripheral surface 12 (see
A plurality of discrete micro protrusions 16 are distributed on and extend outwardly from the macro protrusions 14 (see
A plurality of discrete nano protrusions 18 are distributed on and extending outwardly from the micro protrusions 16 (see
In another embodiment of the invention, in addition to these discrete macro, micro, and nano protrusions which extend outwardly from the substrate surface, the surface structure 12 may have a laser induced array of voids 20 (see
A substrate surface 10 according to the disclosure, is produced by exposing an outer peripheral surface of a solid, monolithic substrate of a biocompatible metal to pulses of laser irradiation. In one embodiment the laser has a spot diameter ranging from about 1 μm to about 1000 μm. In another embodiment, the laser has a spot diameter ranging from about 2 μm to about 250 μm, and in yet another embodiment, the laser has a spot diameter ranging from about 5 μm to about 200 μm. In one embodiment the number of pulses of laser irradiation per spot, ranges from about 10 to about 1500 pulses. In another embodiment, the number of pulses of laser irradiation per spot ranges from about 20 to about 1000, and in yet another embodiment, the number of pulses of laser irradiation per spot ranges from about 100 to about 500. In one embodiment the laser has a pulse wavelength which ranges from about 200 nm to about 1500 nm. In another embodiment, the pulse wavelength ranges from about 400 to about 1,000, and in yet another embodiment, the pulse wavelength ranges from about 400 to about 800. In one embodiment the laser pulse width ranges from about 1 femtosecond to about 5 picoseconds. In another embodiment the laser pulse width ranges from about 1 femtosecond to about 3 picoseconds. In one embodiment the laser irradiance ranges from about 200 Watts/cm2 to about 5000 Watts/cm2. The exposing may be conducted by traversing the spot of laser radiation across the outer peripheral surface of the solid, monolithic substrate at a rate of from about 50 mm/min to about 1000 mm/min, however, the rate is not critical to the invention and only affects the cost-effective execution of the inventive method.
Examples of suitable lasers non-exclusively include a Coherent Libra-F Ti:Sapphire amplifier laser system, a Rofin Startfemto, and a Coherent AVIA laser. According to the disclosure, the resulting electrode has a polarization of about 1,000 mV or less, preferably about 500 mV or less, and more preferably about 200 mV or less.
Referring to
Antibacterial coatings or thin films that contain bactericidal elements such as zinc, copper and/or silver, are known to have bactericidal properties when in ion form. Most of these elements form an oxide when exposed to oxygen under specific processing and/or operating conditions and their oxides can also provide antibacterial properties. Examples include zinc oxide, silver oxide, and copper oxide.
While basic coatings are known, the laser restructuring or texturing of the substrate structure 10 configures the surface 12 such that the coating has the greatest efficacy. For example, in the embodiment illustrated in
Turning to the medical device 30′ illustrated in
With the medical device 32′″ illustrated in
Sample structures incorporating various features described above were manufactured and tested as explained in more detail hereinafter. More specifically, ultra-conformal atomically thin CuxO antimicrobial coatings were fabricated on silicon, flat Pt10Ir, and Pt10Ir HSS via ALD. As one example, a Veeco Fiji Plasma Enhanced ALD (PEALD), which is capable of depositing thermal or plasma enhanced ALD, was used to deposit CuxO ALD coatings.
The samples were exposed to repeating cycles of Cu-containing precursor as well as oxidation reactants (e.g., O3, O plasma, or H2O). For each cycle, the Cu-containing precursor and gas reactant(s) react with the substrates at a time in a sequential, self-limiting manner. Thus, an ultra-conformal CuxO pre cycle would grow on the samples. The quality and properties of the CuxO ALD coating have been characterized by various characterization techniques: thickness and optical properties by ellipsometer and atomic force microscope (AFM), microstructure and nanomorphology by high resolution scanning electron microscope (SEM) and AFM, microscale chemical probing by energy dispersive spectroscopy (EDS), chemical and composition by X-ray photoelectron spectroscopy (XPS), crystal structure and composition by grazing incidence X-ray diffraction (GIXRD), coating conformity and uniformity by optical microscope and SEM, and mechanical durability by nanoindenter. Based on XPS, it is confirmed that, via PEALD using O plasma and thermal ALD using O3, the ALD coating is CuO.
As explained in more detail hereinafter, the antimicrobial properties of the coated samples have been investigated. While the uncoated Si and flat Pt10Ir have no antimicrobial properties, the uncoated Pt10Ir HSS samples interestingly demonstrate certain intrinsic antimicrobial property, possibly due to the nanoscale surface sharpness. The CuO-coated samples all demonstrated different degrees of antimicrobial property. The CuO-coated HSS samples show the highest antimicrobial property.
Coating Procedures
CuO films were grown using a Veeco Fiji PEALD system. (Bis(dimethylamino-2-propoxide) copper (II)) was used as the Cu-containing precursor, and the precursor source was maintained at 125° C. using a Veeco Low Vapor Pressure Delivery (LVPD) module. Argon gas was used as carrier gas with a constant flow rate of 30 sccm.
Two ALD deposition conditions were studied: (1) plasma enhanced ALD (PEALD) using oxygen plasma as the co-reactant, and (2) thermal ALD using Ozone (O3) as the co-reactant. The substrate temperature was maintained at 150° C. For the PEALD, each ALD cycle consisted of a 2-sec Cu precursor pulse and then a 10-sec oxygen plasma pulse, and the growth per cycle (GPC) is ˜0.05 nm. For O3-based ALD, each ALD cycle consisted of a 2-sec Cu precursor pulse and then a 0.075-sec O3 pulse, and the growth per cycle (GPC) is ˜0.02 nm.
Three types of substrates were used: atomically flat silicon, as-received Pt10Ir, and laser-processed Pt10Ir HSS. In order to analyze the ALD coating thickness, Kapton tape was used to block/mask the ALD coatings, so that only the unmasked region can be ALD-coated.
Material Characterization
A J.A.Woollam M-2000 spectroscopic ellipsometer was used to analyze the thickness and optical properties of 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 also EDS compositional mapping. A Versa Probe 5000 XPS was used for XPS compositional analysis; the XPS spot size was 200 μm and calibration was performed using C—C component of C is peak at 284.8 eV. A Park System AFM was used to analyze surface morphology and the film thickness for the masked-Si sample.
Results and Discussion
PEALD of CuO—225 cycles of PEALD CuxO were conducted on the three types of substrates. Ellipsometry was used to test the film thickness as 12 nm, indicating a growth rate of ˜0.05 nm/cycle.
EDS spectra as in
O3-ALD of CuO—950 cycles of O3-based ALD deposition were conducted on the three types of substrates. Ellipsometry was used to test the film thickness as 22 nm, indicating a growth rate of ˜0.05 nm/cycle.
EDS spectra (not shown) also indicates Cu and O as expected for CuxO deposition on all three kinds of substrates. As shown in Table 2 below, quantitative EDS analysis as in Table 1 indicates that the surface compositions of Cu are 69.2 wt % for silicon sample, 2.5 wt % for Pt10Ir, and 31.5 wt % for Pt10Ir HSS sample. It should be noted that these are surface compositions of a coated surface.
XPS was conducted to check the composition of the O3-ALD copper oxide films.
The ˜22 nm O3-ALD CuO coating can be easily identified by optical images, SEM images, and EDS mappings around the masking boundary as in
EDS mapping (
Detailed Analysis
Ion release from surfaces—coated and bare substrates (as controls) were tested for static release of copper ions based on the coating composition as provided. The experimental design was as follows: samples were submerged in 10 ml of liquid media (either sterile distilled H2O or sterile LB media used for bacterial growth) and incubated at 37° C. At time=0 minutes and at 10-minute intervals subsequently, 500 ml aliquots 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 detection of copper ions.
The initial experiment set was performed using silicon substrates without CuO coatings. These results are shown in
The second experiment set was performed using platinum substrates with and without CuO coatings. This was also diversified by comparing untreated or “flat” Pt substrates with or without CuO coatings to Pt HSS substrates where the surface was laser restructured before coating with CuO. The results of these ICP-MS experiments are shown in
Bacterial adhesion—coated materials were tested for bacterial adhesion and contact-dependent antibacterial activity based on the coating composition as provided. The experimental design involved the deposition of a known quantity of bacteria on the surfaces (10 ml of a bacterial culture titered to 1×105 CFU/ml). After incubation for 60 min at 37° C., the surface is swabbed to isolate any remaining viable bacteria using a sterile cotton swab. This swab was then used to inoculate a solid-medium LB-agar plate, and subsequently submerged in 3 ml of sterile LB media for a final inoculation. Both the LB-agar petri dish and the liquid culture were allowed to incubate for 18 h at 37° C., with the liquid samples shaking at 250 rpm to maximize growth. After 18 h, the plates were photographed to determine colony growth while the turbidity of the liquid samples were measured using OD600. The same procedure was used for both bacterial strains of E. coli (Gram negative) and S. aureus (Gram positive).
The initial experiment set was performed using silicon substrates with and without CuO coatings. These results are shown in
Again, the second set of experiments was performed using platinum substrates with and without CuO coatings. This was also diversified by comparing untreated or “flat” Pt substrates with or without CuO coatings to Pt HSS substrates where the surface was laser restructured before coating with CuO. Results are shown in
While specific structures and coating patterns are illustrated, the disclosure is not limited to the illustrated embodiments. The laser restructuring or texturing will configure the surface such that the antibacterial/drug eluting coating has the greatest efficacy, for example, having pockets or ledges that protect the coating or delay the exposure/release of the coating. The structure may also be configured to facilitate multiple coatings or mixtures of the oxides or multi-layer coating materials.
The coatings may be applied utilizing various techniques, for example, physical vapor deposition, chemical vapor deposition, or atomic layer deposition. Additionally, the laser restructuring may take place before or after the coating is applied. As one example, a metal coating, e.g. silver or copper, may be applied to the surface using a coating technique and then the laser restructuring is carried out in an oxygen rich environment such that a metal oxide coating is created in-situ during laser restructuring.
These and other advantages of the present invention will be apparent to those skilled in the art from the foregoing specification. Accordingly, it will be recognized by those skilled in the art that changes or modifications may be made to the above-described embodiments without departing from the broad inventive concepts of the invention. It should therefore be understood that this invention is not limited to the particular embodiments described herein, but is intended to include all changes and modifications that are within the scope and spirit of the invention as defined in the claims.
This application claims the benefit of U.S. Prov. Appln. No. 63/254,752, filed on Oct. 12, 2021, the contents of which are incorporated herein by reference.
Number | Date | Country | |
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63254752 | Oct 2021 | US |