This invention generally relates to medical or dental devices such as bone implants. In alternative embodiments, provided are products of manufacture such as medical or dental devices, e.g., bone implants, having zinc phosphate (ZnP) coatings prepared on zinc (Zn), magnesium (Mg), and iron (Fe) based biodegradable metals and other non-biodegradable substrates, e.g., stainless steel, titanium and its alloys, cobalt-chrome alloys, nickel titanium alloys, to improve surface biocompatibility and provide antibacterial properties, and to enhance vascularization, and methods of making and using them. In alternative embodiments, also provided are methods to form ZnP coatings, including ZnP coatings with a porous surface, on metal surfaces such as zinc surfaces, and Zn-, Mg-, and Fe-based biodegradable metals, and other non-biodegradable substrates.
Metallic implants play significant roles in the clinical treatment and therapy for the coronary artery and orthopedic surgery1-3. Traditional metallic implants have been applied as coronary stents, orthopedic scaffolds, and bone plates and screws, etc. They have numerous advantages, including good machinability for complex structures, low risks of restenosis, and high mechanical support and durability1, 4. However, there are non-ignorable serious side effects faced by the traditional metallic implants. Long term anti-clotting medicine is required to reduce the thrombosis risks for the inert stents, while a second removal surgery is necessary when the orthopedic tissue has recovered5, 6. In addition, chronic inflammation is a common concern for the long-term permanent implants1, 6, 7.
Compared to the conventional metallic implant materials, biodegradable metals as temporary implants have been developed to avoid a secondary surgery, thereby accelerating the entire healing process while simultaneously reducing health risks, costs and scarring1, 5. Up to now, magnesium (Mg), iron (Fe) and zinc (Zn) are the three main classes of biodegradable metals as functional but temporary implants1, 5, 8-11. Zn is considered a promising biodegradable metal thanks to its essential role in many enzymes and in cell metabolic activity and functions12-14. In addition, it has a probably more suitable degradation rate, which is more likely in line with the clinical demand15, 16.
However, one of the significant concerns about Zn as a degradable metal is its local and systemic toxicity; the recommended dietary allowance (RDA) for Zn is only 15-40 mg/day, much lower than that of Mg (300-400 mg/day)17. Moreover, notable cytotoxicity of Zn has been reported in different cells, including human bone cells18-20 and vascular cells20, 21.
To improve the surface biocompatibility of implants, calcium phosphate (CaP) has been used. CaP owns the inherent bone tissue compatibility due to their similar composition to carbonated apatite in natural bone tissue22. Therefore, CaP is applied in the orthopedic applications in the form of ceramic substrates, reinforcement in composites, bone cement, or surface bio-functional coating23-30.
As a natural phosphate of Zn-based metals, ZnP has stable chemical properties and shows biocompatibility31-32. The feasibility of ZnP coating has been explored on several biomedical metallic substrates, including Ti, Fe and Mg alloys, but not Zn-based ones33-35. ZnP coating has been shown to modify the degradation rate of biodegradable Fe- and Mg-based alloys34-35 and promote a fibroblast cell's adhesion on a Ti alloy33. Zn ion released from a Zn-based material could potentially interact with a bacteria surface to induce cell deformation and bacteriolysis36.
In alternative embodiments, provided are products of manufacture comprising a zinc phosphate (ZnP) or a ZnP-based composite coating, or a combination of a ZnP coating and a ZnP-based composite coating, on or deposited on:
In alternative embodiments, for products of manufacture as provided herein:
wherein optionally the inorganic component of the ZnP composite coating comprises between about 1% to 95%, or between about 10% and 90%, or between about 20% and 80%, by weight, mass or molar ratio of the ZnP composite coating (the remainder being ZnP);
wherein optionally the organic component of the ZnP composite coating comprises between about 1% to 95%, or between about 10% and 90%, or between about 20% and 80%, by weight, mass or molar ratio of the ZnP composite coating (the remainder being ZnP);
In alternative embodiments, provided are kits comprising a product of manufacture as provided herein.
In alternative embodiments, provided are use of: a product of manufacture as provided herein, or a kit as provided herein, for: increasing cell adhesion to the product of manufacture in situ or in vivo, enhancing vascularization in situ or in vivo, or increasing the rate of osteogenic differentiation of pre-osteoblasts to osteoblasts.
In alternative embodiments, products of manufacture and/or kits as provided herein are used for: increasing cell adhesion to the product of manufacture in situ or in vivo, enhancing vascularization in situ or in vivo, or increasing the rate of osteogenic differentiation of pre-osteoblasts to osteoblasts.
In alternative embodiments, provided are methods for: increasing cell adhesion to a product of manufacture in situ or in vivo, enhancing vascularization in situ or in vivo, or increasing the rate of osteogenic differentiation of pre-osteoblasts to osteoblasts, comprising: implanting in vivo a product of manufacture as provided herein.
The details of one or more exemplary embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
All publications, patents, patent applications cited herein are hereby expressly incorporated by reference for all purposes.
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
The drawings set forth herein are illustrative of exemplary embodiments provided herein and are not meant to limit the scope of the invention as encompassed by the claims.
as discussed in detail in Example 1, below.
Like reference symbols in the various drawings indicate like elements.
In alternative embodiments, provided are products of manufacture such as medical or dental devices, e.g., implants such as bone implants, having zinc phosphate (ZnP) coatings prepared on zinc- (Zn-), magnesium- (Mg-), and iron- (Fe)-based biodegradable metals and other non-biodegradable substrates, e.g., stainless steel, titanium and its alloys, cobalt-chrome alloys, nickel titanium alloys, to improve surface biocompatibility of the medical or dental devices, e.g., implants, with cells such as pre-osteoblasts; and, to provide antibacterial properties, and methods of making and using them. In alternative embodiments, also provided are methods for making the ZnP coatings, e.g., on metal (e.g., zinc) surfaces, such as zinc (Zn)-based biodegradable or biocompatible metals and other substrates. In alternative embodiments, provided are products of manufacture such as medical or dental devices, e.g., implants comprising a ZnP coating on a metal surface, e.g., a Zn metal surface, or other biodegradable metal surfaces, to improve the biocompatibility and antibacterial properties. In alternative embodiments, provided are products of manufacture as provided herein are used for orthopedic and/or vascular applications.
In alternative embodiments, methods as provided herein comprise optimization or modification of the ZnP coating morphology by controlling or modifying the pH and compositions of coating solutions for different substrates; the result being that methods as provided herein can produce a homogeneous micro-/nano-ZnP coating structure or surface, e.g., on a metal surface, or on a product of manufacture surface, e.g., on an implant surface. In alternative embodiments, ZnP coatings as provided herein or ZnP coatings made by methods as provided herein result in: significantly increased the cell (e.g., pre-osteoblast or osteoblast) viability; increased cell adhesion to a product of manufacture surface, e.g., an implant surface; and/or, increased or faster rate of osteogenic differentiation of pre-osteoblasts to osteoblasts. In alternative embodiments, ZnP coatings as provided herein or ZnP coatings made by methods as provided herein result in: enhanced vascular cell attachment to a product of manufacture surface, e.g., an implant surface; and/or, increased cell growth and proliferation. In alternative embodiments, ZnP coatings as provided herein or ZnP coatings made by methods as provided herein result in: a reduction of platelet adhesion to a product of manufacture surface, e.g., an implant surface, and a reduction in platelet activation. In alternative embodiments, ZnP coatings as provided herein or ZnP coatings made by methods as provided herein have anti-bacterial properties, e.g., to reduce potential infection after an implantation of a medical or dental device.
In alternative embodiments, provided are products of manufacture such as medical or dental devices, e.g., implants such as bone implants, having a ZnP coating on a biodegradable metal alloy, e.g., a Zn based biodegradable metal alloys or other biodegradable metal alloy, including but not limited to Mg-based biodegradable metal alloys and Fe-based biodegradable metal alloys.
In alternative embodiments, provided are products of manufacture such as medical or dental devices, e.g., implants such as bone implants, having a ZnP coating on a biocompatible alloy, e.g., an inert biomedical metallic alloy such as a stainless steel, titanium and its alloys, cobalt-chrome alloys and/or nickel titanium alloys.
In alternative embodiments, provided are products of manufacture having a coating that is partly, substantially or completely comprising a ZnP coating; for example, a product of manufacture as provided herein can cover between about 1% to 100%, or between about 10% and 90%, of the surface of the product of manufacture, e.g., biomedical or dental device such as an implant. For example, products of manufacture as provided herein can be a zinc phosphate-based composite (i.e., a mixed ingredient) coating comprising one or more other inorganic coating compositions, e.g., comprising zinc oxide, zinc hydroxide, calcium phosphates and/or hydroxyapatite (HA), and the like, or mixtures thereof. In alternative embodiments, provided are products of manufacture having a ZnP based coating that is a composite with an organic compound, e.g., an organic coating composition such as a collagen, chitosan, gelatin, hyaluronic acid, polylactic acid and/or polylactide, and the like, or mixtures thereof. In alternative embodiments, the inorganic and/or organic component of the coating can comprise between about 1% to 95%, or between about 10% and 90%, or between about 20% and 80%, by weight, mass or molar ratio of the coating (the remainder being ZnP).
In alternative embodiments, a Zn coating is between about 0.5 to 100 μm, or between about 1.0 to 50 μm, where the average Zn coating thickness on a Zn metal using a chemical method of deposition is between about 3 to 6 μm, as shown in
In alternative embodiments, Zn coatings are multi-layered, e.g., Zn coatings can comprise other coatings to form a composite coating. In alternative embodiments, a metallic substrate can affect a coating composition in a multi-layered structure, e.g. the inner layer of a coating can comprise a Mg alloy, where the Mg alloy can comprise magnesium hydroxide and/or magnesium phosphate.
In alternative embodiments, the ZnP based coatings as provided herein can significantly improve the biocompatibility of the product of manufacture. For example, the ZnP based coatings as provided herein are cyto-compatible and can provide improved or enhanced cell (e.g., pre-osteoblast or osteoblast) adhesion to the product of manufacture; and use of ZnP based coatings as provided herein can result in improved or enhanced cell viability, proliferation and differentiation. In alternative embodiments, the ZnP based coatings as provided herein are hemo-compatible, resulting in decreased platelet adhesion and hemolysis rate.
In alternative embodiments, the ZnP based coatings as provided are antibacterial, and can provide or significantly improve on antibacterial properties, for example, by decreasing or preventing the surface adhesion of the bacteria, thereby decreasing the surrounding bacterial numbers. In alternative embodiments, the ZnP based coatings are antibacterial against Staphylococcus, e.g., Staphylococcus aureus, and/or gram negative bacteria, e.g., Escherichia coli.
In alternative embodiments, the ZnP based coatings as provided act as a biomedical coating on a biodegradable or a non-biodegradable metal or metal alloy.
In alternative embodiments, ZnP-comprising surface coatings have enhanced biocompatibility in vivo, e.g., with cells, e.g., they enhance vascularization, and promote cell adhesion and osteoblast differentiation.
In alternative embodiments, ZnP-comprising surface coatings as provided herein have antibacterial properties.
In alternative embodiments, ZnP-comprising surface coatings as provided herein and products of manufacture as provided herein can be used in biomedical applications such as in orthopedic, dental, craniofacial and cardiovascular applications and related surgeries.
In alternative embodiments, ZnP-comprising surface coatings are applied onto biodegradable metal alloys, which can comprise Zn-, Mg- and Fe-based biodegradable metal alloys.
In alternative embodiments, the Zn alloy can comprise aluminum, iron, magnesium, calcium, strontium, silver, copper, titanium, manganese or lithium or any combination thereof; and can have a proportion of the following compositions including but not limited to:
and a balance of zinc, based on the total weight of the composition.
In alternative embodiments, the magnesium (Mg) alloy can comprise aluminum, zinc, calcium, strontium, silver, copper, titanium, manganese or lithium or any combination thereof; and can have a proportion of the following compositions including but not limited to:
and a balance of zinc, based on the total weight of the composition.
In alternative embodiments, the iron (Fe) alloy can comprise aluminum, zinc, calcium, strontium, silver, copper, titanium, manganese or lithium or any combination thereof; and can have a proportion of the following compositions including but not limited to:
and a balance of zinc, based on the total weight of the composition.
In alternative embodiments, ZnP-comprising coatings as provided herein, or the ZnP-comprising coatings used on the surface of products of manufacture as provided herein, have as a main or primary composition ZnP or a composite composition of ZnP with other inorganic and organic materials, including but not limited to: zinc oxide, zinc hydroxide, calcium phosphates, and hydroxyapatite (HA), and collagen, chitosan, gelatin, hyaluronic acid, polylactic acid, polylactide, and the like or mixtures thereof. In alternative embodiments, the ZnP content of the ZnP-comprising coatings as provided herein, or the ZnP-comprising coatings used on the surface of products of manufacture as provided herein, is between about 50.1% to 100%, or between about 55% and 95%, or between about 60% and 90%, by weight of the ZnP-comprising coating or the ZnP-comprising coating used on the surface of the product of manufacture.
In alternative embodiments, ZnP-comprising coatings as provided herein, or the ZnP-comprising coatings used on the surface of products of manufacture as provided herein, have a nonporous structure or a porous structure, depending on the different coating methods (a porous structure is formed automatically using certain coating method and is related to ceramic crystal nucleation and growth). A nonporous structure can improve the coating stability and improve the cell growth and compatibility. A micro- and/or nano-sized porous structure (which can be a homogeneous micro-/nano-sized porous structure) can improve the coating's adhesion properties to other inorganic and organic coating layers, biological substances or cells such as vascular cells, fibroblasts or osteoblasts.
In alternative embodiments, ZnP-comprising coatings as provided herein, or the ZnP-comprising coatings used on the surface of products of manufacture as provided herein, have a porous structure, e.g., a homogeneous micro- and/or nano-sized porous structure, to improve the ZnP-comprising coating's biocompatibility, for example: cytocompatibility to improve the cell adhesion, viability, proliferation, and differentiation, hemocompatibility to decrease the platelets adhesion and hemolysis rate, and the like.
ZnP-comprising coatings as provided herein, or porous ZnP-comprising coatings as provided herein, can be prepared and/or deposited on substrates using various methods and processes. For example, to produce porous coatings non-limiting examples of such processes include: hydrothermal, anodization, electrochemical deposition, and combinations thereof. To produce nonporous coatings, non-limiting examples of such processes include: spray deposition, pulsed laser deposition, sputter deposition, and combinations thereof to produce nonporous coatings.
Provided are kits comprising products of manufacture as described herein, optionally including instructions for use comprising methods as provided herein.
Any of the above aspects and embodiments can be combined with any other aspect or embodiment as disclosed here in the Summary, Figures and/or Detailed Description sections.
As used in this specification and the claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.
Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and”.
Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12% 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.”
Unless specifically stated or obvious from context, as used herein, the terms “substantially all”, “substantially most of”, “substantially all of” or “majority of” encompass at least about 90%, 95%, 97%, 98%, 99% or 99.5%, or more of a referenced amount of a composition.
The entirety of each patent, patent application, publication and document referenced herein hereby is incorporated by reference. Citation of the above patents, patent applications, publications and documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. Incorporation by reference of these documents, standing alone, should not be construed as an assertion or admission that any portion of the contents of any document is considered to be essential material for satisfying any national or regional statutory disclosure requirement for patent applications. Notwithstanding, the right is reserved for relying upon any of such documents, where appropriate, for providing material deemed essential to the claimed subject matter by an examining authority or court.
Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the invention has been described in substantial detail with reference to one or more specific embodiments, those of ordinary skill in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, and yet these modifications and improvements are within the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of”, and “consisting of” may be replaced with either of the other two terms. Thus, the terms and expressions which have been employed are used as terms of description and not of limitation, equivalents of the features shown and described, or portions thereof, are not excluded, and it is recognized that various modifications are possible within the scope of the invention. Embodiments of the invention are set forth in the following claims.
The invention will be further described with reference to the examples described herein; however, it is to be understood that the invention is not limited to such examples.
This example provides data demonstrating that the ZnP based coatings as provided herein are cyto-compatible and can provide improved or enhanced cell (e.g., pre-osteoblast or osteoblast) adhesion to the product of manufacture; and use of ZnP based coatings as provided herein can result in improved or enhanced cell viability, proliferation and differentiation. In alternative embodiments, the ZnP based coatings as provided herein are hemo-compatible, resulting in decreased platelet adhesion and hemolysis rate.
Non-porous or porous ZnP coatings as provided herein can be prepared and/or deposited on substrates using various methods and processes. For example, non-limiting examples of such processes include: hydrothermal, anodization, electrochemical deposition, and combinations thereof to produce porous coatings. Non-limiting examples of such processes include: spray deposition, pulsed laser deposition, sputter deposition, and combinations thereof to produce nonporous coatings.
One exemplary coating method comprises: Zn samples were polished using #1500 sandpaper, cleaned by sonication in acetone for 5 to 20 min, then immersed in coating solution (20-100 mL/cm2 ratio to the sample surface area) at room temperature (RT) for 2 to 20 min followed by rinsing with deionized water and drying in air before characterization. The coating solution was composed of 0 to 0.1 M Zn(NO3)2 and 0.1 to 0.3 M H3PO4 and the pH value was adjusted to pH 2 to 3, respectively. The main coating characterizations are shown in
In alternative embodiments, products of manufacture or coatings as provided herein are sterilized using, e.g., irradiation, e.g., gamma or beta irradiation, or by using chemicals, e.g., using alcohol, e.g., 75% alcohol solutions, or gases, e.g., ethylene oxide.
In alternative embodiments, products of manufacture or coatings as provided herein are corrosion resistant or have substantial corrosion resistance, e.g., to control the degradation rate of the biodegradable metal alloys and protect the inert metal alloys from degradation. A coating as provided herein can decrease the corrosion rate of an product of manufacture of an implant placed in vivo by between about 1 to 3 orders of magnitude, see e.g.,
In alternative embodiments, products of manufacture or coatings as provided herein have coating stability; e.g., during the degradation in vivo they can degrade uniformly, thus gradually providing a stable short-time biocompatibility and pH stability for the degradable metal alloys, and long-term protection and biocompatibility for non-degradable metal alloys, as illustrated in
In alternative embodiments, surface ZnP-based coatings as provided herein have good hemocompatibility, as evidenced by decreased platelets adhesion at the sample surface, which significantly keeps the hemolysis rate under 5%, as illustrated in
In alternative embodiments, surface ZnP based coatings as provided herein have good cytocompatibility to significantly improve the surface cell viability, as compared to non-coated substrate materials. For example, the ZnP coating can improve cell viability on a Zn surface from 10 to 20% to 80 to 100% for pre-osteoblasts, and from 55% to 105% at day 5 for endothelial cells, as illustrated in
In alternative embodiments, surface ZnP based coatings as provided herein have good cytocompatibility to improve cell (e.g., pre-osteoblasts) adhesion and cell spreading on a material's surface, as compared to non-coated substrate materials, as illustrated in
In alternative embodiments, surface ZnP based coatings as provided herein have good cytocompatibility to improve the differentiation of osteoblast cells, e.g. improve alkaline phosphatase (ALP) activity and calcific deposition of pre-osteoblasts, as illustrated in
In alternative embodiments, surface ZnP based coatings as provided herein have good antibacterial properties to significantly decrease or prevent surface adhesion bacteria to the substrate, as illustrated in
A number of embodiments of the invention have been described. Nevertheless, it can be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.
This U.S. Utility patent application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application Ser. No. 62/816,638 filed Mar. 11, 2019. The aforementioned application is expressly incorporated herein by reference in its entirety and for all purposes.
This invention was made with government support under National Institutes of Health (NIH), DHHS, grant no. R01HL140562. The government has certain rights in the invention.
Number | Date | Country | |
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62816638 | Mar 2019 | US |