Systems and methods for selective coating removal for resorbable metal medical devices

Abstract

The invention relates to self-assembled organosilane coatings for resorbable medical implant devices. The coatings can be prepared from coating compositions containing organosilane and can be applied to metal or metal alloy substrates. Prior to applying the coatings, the surfaces of the substrates can be pretreated. The coatings can be functionalized with a binding compound that is coupled with an active component. The coatings can be selectively removed, e.g., patterned, to expose portions of the uncoated substrate. Selecting different patterns can provide the ability to regulate or control various properties, such as, corrosion and hydrogen generation.

Claims

1. A medical implant device, comprising: a substrate selected from the group consisting of magnesium and magnesium alloy, having a first surface and an opposing second surface; a thin film coating applied to at least one of the first and second surfaces, comprising: a self-assembled amphiphilic organosilane having a hydrophobic aliphatic tail containing a C.sub.4 to C.sub.20 backbone, and a hydrophilic silane head reactive with the substrate, comprising: an alkyltrialkoxy silane tetramethoxysilane co-polymer; a cross-linking agent combined with the co-polymer; and an aminosilane binding compound; and a pattern applied to the thin film coating in a form such that one or more selected areas of the substrate is uncoated.

2. The medical implant device of claim 1, wherein the aminosilane binding compound is aminopropyl-trimethoxy silane.

3. The medical implant device of claim 1, further comprising an active component coupled to the binding compound.

4. The medical implant device of claim 1, further comprising a pretreatment applied to at least one of the first and second surfaces, and the coating applied to the pretreatment.

5. The medical implant device of claim 1, wherein a first portion of the pattern has a first configuration and a second portion of the pattern has a different, second configuration.

6. The medical implant device of claim 1, wherein the one or more selected areas that are uncoated is effective to increase the corrosion rate of the substrate.

7. The medical implant device of claim 1, wherein a laminar structure of the thin film coating has multiple layers.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a schematic that shows various patterns formed by selectively removing a coating deposited on a magnesium or magnesium alloy substrate to expose portions of uncoated substrate for use in regulating corrosion rate, in accordance with certain embodiments of the invention;

(2) FIG. 2 shows SEM micrographs A, B and C of laser ablated substrate samples at various magnifications, i.e., A is low magnification, B is intermediate magnification and C is high magnification, wherein the coating is completely removed in the ablated areas and the underlying metal remains intact, in accordance with certain embodiments of the invention;

(3) FIG. 3 is a plot of hydrogen evolution verses time (i.e., days) for patterned Mg—OH-AS coated substrate samples, in accordance with certain embodiments of the invention; and

(4) FIG. 4 is a SEM micrograph that shows a patterned magnesium disk exposed to simulated body fluid (SBF) for a period of seven days with a bare Mg side on the left and AS coated on the right, and wherein insets show an EDS spectra from the respective areas, in accordance with certain embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

(5) The invention generally relates to self-assembled organosilane-containing coating compositions applied to, or deposited on, substrates to form patterned coatings; and methods of applying/depositing the coating compositions onto the substrates, and subsequently selectively removing a portion or part of the coatings to expose the uncoated substrates (e.g., underneath the coatings). The invention also relates to the use of the patterned coated substrates in constructing and fabricating medical implant devices for use in various surgical applications, such as, but not limited to, dental, orthopedic, craniofacial, and cardiovascular.

(6) The substrates, e.g., medical implant devices, can be composed of a wide variety of materials that are known in the art for such purposes. In accordance with the objectives of controlling the rates of corrosion of the substrates in order to reduce or minimize the production and accumulation of hydrogen resulting therefrom, and to construct medical implant devices from materials that demonstrate sufficient mechanical strength when needed and degradation over time when no longer needed, it is preferred that the substrates, e.g., medical implant devices, be composed of magnesium or magnesium alloy.

(7) In certain embodiments, the coating composition is directly applied to, or deposited on, the surface of the substrate, e.g., medical implant device, in the absence of any pretreatment or pre-coating of the surface, to form a coating thereon. However, in other embodiments, for the purpose of improving the adherence and/or adhesion of the coating to the surface of the substrate, a pretreatment or pre-coating is applied to the surface of the substrate prior to applying the coating composition. Suitable pretreatments or pre-coatings include those known in the art for use with magnesium or magnesium alloy substrates to improve adherence and/or adhesion of a coating to the surface of the substrates.

(8) Following the application of the coating composition and formation of the resultant coating on the surface of the substrate, the coating is partially removed. The partial removal of the coating from the surface of the substrates can be selectively conducted by forming various patterns of coated and uncoated substrate. In certain areas of the pattern, the uncoated surface of the substrate is exposed and in other areas, the surface has the coating applied thereto. The selective removal, e.g., pattern, can be effective to regulate or control certain properties of the substrate, such as, corrosion rate and hydrogen generation.

(9) Without intending to be bound by any particular theory, it is believed that the patterned coatings are effective to modify various properties and characteristics of the underlying magnesium/magnesium-containing substrate of the a medical implant device. For example, a patterned coating can be effective to control one or more of the following properties of the magnesium/magnesium-containing substrate: corrosion rate, production/accumulation of hydrogen, rate of resorption, tissue integration and osteoconduction. In certain embodiments, the patterned coating can be effective to reduce or preclude the corrosion rate and, in turn, the production/accumulation of hydrogen. Further, the surface of the coated portions of the substrate can include covalent bonding with different molecules, including bioactive molecules, such as proteins and peptides.

(10) Surface chemistry modifications can provide the ability to control different physical chemical properties of the coating, including but not limited to, hydrophobicity and charge, as well as bioactivity. Furthermore, the patterned, substrate surface including coated and uncoated portions or parts can be used to control or regulate pre-selected or desired properties.

(11) Conventional apparatus and techniques are generally known for preparing and applying/depositing a silane coating composition onto a substrate, modifying or functionalizing the surface of the formed silane coating, and selectively removing a portion of the coating formed. For example, various amphiphilic organosilanes are used to form nanostructured films for glass coating applications, and the application of organosilanes for corrosion control are known. However, there is a need in the art to develop organosilane-containing compositions for use in coating resorbable metallic, e.g., magnesium and magnesium alloy, substrates, such as medical implant devices. In particular, the coatings for medical implant devices require special properties, including the ability to adapt to the intrinsically unstable physical and chemical environment of a corroding metal substrate, as well as the ability to be functionalized with bioactive molecules.

(12) In general, self-assembled coatings, e.g., monolayers, are thin films produced by deposition of materials, such as, organosilanes. The coatings are formed, e.g., spontaneously, on a surface of a substrate by adsorption and include a head group, tail and functional end groups. The head group can be in a vapor phase or a liquid phase. The head group assembles onto the substrate surface, while the tail group organizes and assembles farther from the surface of the substrate. The substrate and head group are selected to react with each other. In certain embodiments, a hydrophilic end (e.g., head group) may bond with the substrate surface while a hydrophobic end may be opposite the hydrophilic end.

(13) In accordance with the invention, the self-assembled coating compositions include organosilane, such as, hybrid organosilanes. In certain embodiments, the coating compositions include amphiphilic organosilanes having an aliphatic tail containing a backbone of 4 to 20 carbon atoms (i.e., C.sub.4 to C.sub.20) and a silane head. A non-limiting example of suitable organosilanes include alkylsilanes, such as, alkyltrialkoxysilanes including, but not limited to, decyltriethoxysilane. In certain embodiments, the alkyltrialkoxysilanes, such as, but not limited to, decyltriethoxysilane, are co-polymerized with another polymer component, such as, but not limited to, tetramethoxysilane (TMOS). Further, in certain embodiments, the alkyltrialkoxysilanes are combined with a crosslinking material, such as, but not limited to, a UV crosslinking agent.

(14) The self-assembled coating compositions are applied or deposited onto the magnesium or magnesium alloy surface, e.g., of the medical implant device. The magnesium alloy may be selected from a wide variety of magnesium alloys known in the art for constructing medical implant devices. Non limiting examples of suitable magnesium alloys include those magnesium-containing compositions described in PCT Application having International Application No. PCT/US2012/058939 entitled “Biodegradable Metal Alloys” filed on Oct. 5, 2012, published as US20140248288 on Sep. 4, 2014, and issued as U.S. Pat. No. 9,510,932 on Dec. 6, 2016, and based on U.S. Provisional Patent Application 61/544,127 entitled “Biodegradable Metal Alloys” filed on Oct. 6, 2011, which are incorporated in their entirety herein by reference.

(15) In certain embodiments, the magnesium alloys include elemental magnesium and one or more other elemental components, such as, but not limited to, iron, zirconium, manganese, calcium, yttrium and zinc. The amount of each of the components can vary and, in general, the amounts are selected such that the resulting magnesium alloys are within acceptable non-toxic limits, sufficiently biocompatible and degradable over a period of time.

(16) In general, the self-assembled organosilane coatings can be formed using known apparatus and conventional coating techniques, including, but not limited to, physical vapor deposition, electro-deposition or electro-less deposition. For example, a self-assembled coating can be formed on a magnesium or magnesium alloy substrate at ambient conditions by spinning, dipping or spraying techniques, which are known in the art. In certain embodiments, a coating is formed by employing a deep-coating process at ambient conditions. This process includes combining organosilane and solvent, e.g., water, to form a solution and applying the solution to a magnesium or magnesium alloy substrate by dipping/immersing the substrate into a bath of the solution. The immersion can be for a time period ranging from minutes to hours and, typically includes sufficient time to allow the organosilane to bond to the substrate. As previously described, the solution can be applied directly to the substrate (in the absence of pretreating or pre-coating) or the solution can be applied to a pretreated or pre-coated substrate. Subsequent evaporation of the solvent, by conventional methods, induces the organosilane to self-assemble into micro- or nano-structures and thin film. The resulting coating, e.g., thin film, is rigid, uniform and has a thickness that can vary from about 100 nanometers to tens of micrometers

(17) The coating thickness can depend on various factors including the organosilane composition components, the process conditions and the intended use of the coated substrate. In one embodiment, the coating has a thickness of about 1 um. Further, the coating, e.g., laminar structure, can include multiple layers. In certain embodiments, the coating may be composed of about 30 nm thick layers. Furthermore, the coating can be hydrophobic which may be particularly beneficial for cardiovascular applications.

(18) The coating process in accordance with the invention can optionally include pre-treating or pre-coating the surface of the substrate prior to applying/depositing the organosilane coating composition thereto. The pre-treatment or pre-coating is applied to, or deposited on, the bare, e.g., uncoated, surface of the magnesium or magnesium alloy substrate. The pre-treatment/pre-coating step can vary and may be selected from known pretreatment compounds/compositions, techniques and processes that are employed to improve adherence or adhesion of a coating to the surface of a substrate. In certain embodiments, the pretreatment includes polishing and/or etching the uncoated substrate with nitric acid, and/or passivating with sodium hydroxide. Without intending to be bound by any particular theory, it is believed that pretreating the substrate prior to applying the coating composition, e.g., solution, results in a more uniform coating having improved adhesion or adherence properties, as compared to coatings that are formed in the absence of pretreating the substrate.

(19) The coating in accordance with the invention has numerous advantages as compared to conventional coatings, including, but not limited to, for example, tunability and controllability. The thickness of the coating and its mechanical properties can be tuned or controlled. For example, using organosilanes with UV crosslinkable groups provides the ability to increase stiffness simply by exposure to a UV source. Further, copolymerizing organosilanes with tetramethoxysilane produces liquid-like coatings having increased flexibility, which may be particularly useful for cardiovascular applications.

(20) Furthermore, the surface of the coatings can be modified or functionalized to attach or bind an active component. A binding compound, such as, but not limited to amine, carboxyl, thiol, hydroxyl and mixtures thereof, is used to bind one or more active components to the coatings. In certain embodiments, the binding compound is attached to the surface of the coating. For example, a plurality of molecules containing silane groups, e.g., aminosilanes, such as, but not limited to aminopropyl-trimethoxysilane, can be covalently attached to the surface of the coating to provide chemistry for attachment of the active component, such as, but not limited to alkaline phosphatase, or for modifying hydrophobicity of the surface. In certain other embodiments, the binding compound can be permeated or encapsulated within the composition that is applied to the substrate to form the coating.

(21) As used herein, the term “active component” and related terms refer to at least one molecule, compound, complex, adduct and/or composite that exhibits one or more beneficial activities, such as, therapeutic activity, diagnostic activity, biocompatibility, corrosion-resistance, and the like. Active components that exhibit a therapeutic activity can include bioactive agents, pharmaceutically active agents, drugs and the like. Non-limiting examples of bioactive agents include, but are not limited to, bone growth promoting agents, such as growth factors, drugs, proteins, antibiotics, antibodies, ligands, DNA, RNA, peptides, enzymes, vitamins, cells and the like, and combinations thereof.

(22) With the binding of one or more active components, the coatings and coated magnesium or magnesium alloy substrates, can be effective to combine anti-corrosion properties with bioactive surface modifications, which can facilitate improved tissue integration and induce desired biological responses in resulting medical implant devices.

(23) Moreover, the coatings, e.g., thin films, formed as a result of the self-assembled coating compositions applied or deposited onto the magnesium or magnesium alloy surface, e.g., of the medical implant device, can be partially, e.g., selectively, removed to regulate or control various properties, such as, corrosion. The selective removal of the coating to expose portions or parts underneath, e.g., uncoated substrate, can be performed by employing various conventional techniques and apparatus known in the art. For example, selective removal of a coating can be conducted using one or more of laser ablation, ion etching and electron beam etching. In certain embodiments, the selective removal can include forming various patterns in the coating. The patterns can include a plurality of lines or grooves. The number, width and configuration of the lines or grooves can vary, and may correspond to, or depend on, a pre-determined amount of exposed uncoated surface necessary to achieve pre-selected or desired properties. Further, the pattern can be formed on one or more surfaces of the substrate. For example, wherein the substrate has upper and lower surfaces, the pattern can be formed on one or both of these surfaces.

(24) Without intending to be bound by any particular theory, it is believed that selective removal of the coating eliminates inhibition of the corrosion in the exposed areas of the substrate and increases the rate of corrosion. By changing size, density and spatial distribution of exposed areas of the substrate, the corrosion rate of the entire substrate, e.g., medical implant device, or portions or parts thereof can be controlled or tuned.

(25) FIG. 1 is a schematic showing a plurality of coated substrates A, B, C, D and E, having a given surface area and various removal patterns formed by lines, e.g., grooves, applied to the surface. As shown in FIG. 1, substrate B has a greater density of grooves, e.g., a higher number of grooves or less spacing between the grooves, in the pattern as compared to substrate A. Substrate C has a greater density of grooves in the pattern as compared to both substrates A and B. In substrate A, there are four, 1-um wide grooves spaced apart by a distance of 100 um. Substrate B has five grooves and shows a spacing of 50 um, and substrate C has 11 grooves with a spacing of 25 um. An increase in the density, e.g., higher number of grooves or less spacing between the grooves, results in an increase in the exposed area of the uncoated substrate and therefore, an increase in the rate of corrosion. A similar effect may be achieved by varying the width of the exposed areas, e.g., grooves, without changing their density. In FIG. 1, substrates D and E show that the rate of corrosion can be spatially regulated in different portions or parts, e.g., of a medical implant device, by having the density of the grooves be different for certain portions or parts. That is, the pattern for substrate D has a lesser density of grooves on the left-side portion of the disk and a greater density of grooves toward the right side portion of the disk. From left to right, the spacing is shown to decrease from 100 um to 25 um. Similarly, the pattern for the screw E has a lesser density of grooves at the top portion of the shaft and a greater density of grooves toward the lower portion of the shaft. From top to bottom, the spacing is shown to decrease from 100 um to 25 um.

(26) Patterned, organosilane-coated, magnesium or magnesium-containing substrates, in accordance with the invention, are generally effective for tissue regeneration and, in particular, bone regeneration, within a body of a patient. These substrates can be employed as materials of construction for various medical implant devices. Non-limiting examples of suitable medical devices include, but are not limited to, scaffolds, plates, meshes, staples, screws, pins, tacks, rods, suture anchors, tubular mesh, coils, x-ray markers, catheters, endoprostheses, pipes, shields, bolts, clips or plugs, dental implants or devices, such as but not limited to occlusive barrier membranes, graft devices, bone-fracture healing devices, bone replacement devices, join replacement devices, tissue regeneration devices, cardiovascular stents, nerve guides, surgical implants and wires.

(27) It will be appreciated by those skilled in the art that changes can be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed and the following examples conducted, but it is intended to cover modifications that are within the spirit and scope of the invention.

EXAMPLES

Example 1—Pattering of Coated Mg Samples

(28) A plurality of Mg—OH-AS (wherein AS represents alkylsilane) coated substrate samples were patterned with the use of laser ablation. Several 0.2 mm-wide lines were etched on each of the top and bottom surfaces of AS-coated disks by laser ablation (as shown in views A, B and C of FIG. 2). The laser ablation was conducted using a low energy setting such that the treatment removed only the AS coating and the underlying substrate remained intact.

Example 2—Hydrogen Evolution

(29) Four experimental groups of three samples each were assembled, including: (a) bare Mg—OH disks (absent of a coating), (b) Mg—OH-AS coated disks with 6-line patterns, (c) Mg—OH-AS coated disks with 4-line patterns, and (d) fully-coated Mg—OH-AS disks (absent of a pattern). Hydrogen evolution experiments were conducted over a seven-day period. As shown in FIG. 3, the results of these experiments demonstrated that the presence of patterning increased the corrosion rate of the Mg—OH-AS samples (i.e., (b) and (c)) as compared to the Mg—OH-AS sample absent of patterning (i.e., (d)). However, the rate of corrosion was significantly lower for the patterned substrates (i.e., (b) and (c)) as compared to the bare Mg—OH substrate (i.e., (a)). The differences among the four groups were highly statistically significant (p<0.0001). Furthermore, the initial corrosion burst was prevented in the patterned Mg—OH-AS samples (i.e., (b) and (c)). These results demonstrate that the corrosion rate of the substrate, e.g., medical implant device, can be fine-tuned by partial removal of the coating from the substrate.

Example 3—Prevention of Calcium Phosphate Deposition

(30) It was determined that local pH increase in an area around the corroding Mg devices led to spontaneous calcium phosphate precipitation. This is a highly undesirable outcome, especially in cardiovascular applications (e.g., stents and other devices). The present data indicated that the AS coatings effectively prevented calcium phosphate precipitation and therefore, may be effective to reduce calcium phosphate formation in the area of a medical implant device constructed of the substrate in accordance with the invention.

Example 4—Elemental Analysis

(31) Elemental analysis of the patterned Mg samples containing AS coated and non-coated areas was conducted and revealed the presence of calcium and phosphate on exposed areas while these elements were not detected on the coated areas (see FIG. 4). The results of the elemental composition are shown in Table 1 below.

(32) TABLE-US-00001 TABLE 1 The elemental composition of the AS coated and uncoated areas of a Mg sample Element Corroded Area Coated Area K edge Weight % Atomic % Weight % Atomic % O 48.79 62.24 25.81 35.57 Mg 29.69 24.93 50.88 46.14 P 8.76 5.77 — — Cl 8.57 4.93 — — Ca 4.19 2.13 — — Si — — 23.31 18.30