Nanometer coatings for resorbable metal implants

Abstract

The present disclosure relates to a method of controlling the time and rate of biodegradation of a biodegradable metal implant by applying one or more coating to the metal implant using nanosecond electrodeposition, wherein the one or more coating is nanometer and / or micrometer thick. The electrodeposited one or more coating may be applied to metal implants to control the release of harmful metal ions and particles. The one or more coating may include additional dopants to improve characteristics of the implant.

Description

Docket No. 2891.099AWONANOMETER COATINGS FOR RESORBABLE METAL IMPLANTSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No. 63 / 776,534 filed March 24, 2025, which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates generally to nanometer and micrometer thick coatings on metal implants and biodegradable metal implants.BACKGROUND OF THE INVENTION

[0003] This disclosure relates to biodegradable metal implants and metal implants.Biodegradable metal implants may biodegrade at an uncontrolled rate and release corrosion products that are harmful. Metal implants may release harmful ions and nanoparticles. The present disclosure is directed to overcoming these and other deficiencies.SUMMARY OF THE INVENTION

[0004] In one aspect the disclosure relates to a method of delaying for a period of time a metal implant from biodegrading including electrodepositing a coating on at least a surface of the metal implant, wherein the electrodepositing comprises electric pulses of about 1 to 1000 nanoseconds in duration and implanting the metal implant into a subject, wherein the metal implant biodegradation is delayed due to the coating.

[0005] In an example, the metal implant includes iron. In an example, the metal implant includes magnesium. In an example, the metal implant includes zinc.

[0006] In an example, the delaying for a period of time is at least one of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks or about 12 weeks. In an example, the delaying for a period of time is at least one of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 month, about 24 months, or about 36 months.

[0007] In an example, the electric pulse has a period range of about 0.001 Hz to 10,000 Hz. In an example, the electric pulse has a voltage range of about 10 to about 100 volts. In anDocket No. 2891.099AWOexample, the electric pulse has a voltage range of about 100 to about 1000 volts. In an example, the electric pulse has a voltage range of about 1,000 to about 10,000 volts. In an example, the electric pulse has a voltage range of about 10 kilovolts to about 100 kilovolts.

[0008] In an example, the coating thickness has a range of about 10 to 50 nanometers. In an example, the coating thickness has a range of about 50 to 500 nanometers. In an example, the coating thickness has a range of about 500 to 1000 nanometers. In an example, the coating is about 1000 to 5000 nanometers thick.

[0009] In an example, the coating includes calcium phosphate. In an example, the coating includes zinc doped calcium phosphate. In an example, the coating includes magnesium doped calcium phosphate. In an example, the coating includes manganese doped calcium phosphate. In an example, the coating includes iron doped calcium phosphate. In an example, the coating includes silica doped calcium phosphate. In an example, the coating includes silica. In an example, the coating includes calcium phosphate and one or more dopant selected from the group consisting of zinc, magnesium, silica and iron. In an example, the coating includes crystalline calcium phosphate. In an example, the coating includes amorphous calcium phosphate. In an example, the coating includes crystalline and amorphous calcium phosphate. In an example, the coating includes at least one dopant.

[0010] In an example, the delaying for a period of time correlates to a concentration of the dopant. In an example, two or more coatings are applied to the metal implant. In an example, the porosity of the metal implant includes about 1 to about 95 percent of the volume of the implant. In an example, the coating is applied internally to the porous region, to an external surface or any combination thereof. In an example, after the period of time a deposit of dopants in the metal are released to combine with and reduce the toxicity of metal ions released from the metal implant.

[0011] In an example, the coating further includes nanoparticles, microparticles or a combination thereof. In an example, the coating further includes nanoparticles comprising antimicrobials. In an example, the coating further includes nanoparticles comprising compounds to promote osteointegration selected from the group consisting of calcium phosphate, strontium ranelate, TGFpi, TGFP2, TGFP3, bone morphogenic protein (BMP)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-l, CDMP-2, and / or CDMP-3, fibroblast growth factor (FGF)-l, BMP-1, BMP -2a, BMP-2P, BMP-3b, BMP-8b, BMP- 10, BMP-11, BMP- 12, BMP-13, BMP- 14, BMP-15, TGFP4, TGFP5 and combinations thereof.Docket No. 2891.099AWO

[0012] In an example, the coating includes nanoparticles comprising anti-inflammatory compounds selected from the group consisting of acetylated salicylates (aspirin), nonacetylated salicylates (diflunisal, salsalate), anthranilic acids (meclofenamate and mefenamic acid), propionic acids (naproxen and ibuprofen), enolic acids (meloxicam and piroxicam), acetic acids (diclofenac and indomethacin), naphthylalanine (nabumetone), selective COX-2 inhibitors (celecoxib, etoricoxib) and any combination thereof.

[0013] In an example, the coating includes nanoparticles comprising compounds for preventing or treating stent restenosis selected from the group consisting of Rapamycin, Everolimus, Zotarolimu, Paclitaxel, Atorvastatin, Rosuvastatin, Dexamethasone, Clopidogrel, Ticagrelor, Prasugrel, Colchicine and any combination thereof.

[0014] In an example, after the period of time a deposit of dopants deposited inside one or more cavities of the metal implant is exposed to a cellular environment. In an example, after the period of time nanotubes comprising one or more dopants on the surface of the metal implant release one or more dopants into a body fluid after the coating biodegrades. In an example, after the period of time the metal implant begins to biodegrade and release metal ions, and wherein a dopant is released from the coating that combines with the metal ions to reduce the toxicity of the metal ions. In an example, the coating further promotes osteocyte growth.

[0015] In one aspect the disclosure relates to a method of slowing for a period of time a release of ions from a metal implant including electrodepositing a coating on at least a surface of the metal implant, wherein the electrodepositing includes: applying electric pulses with a duration in a range of about 1 to 1000 nanoseconds; and implanting the metal implant into a subject, wherein the slowing the release of the ions is due to the coating.

[0016] In an example, the metal implant includes nickel. In an example, the metal implant includes chrome. In an example, the metal implant includes cobalt. In an example, the metal implant includes vanadium.

[0017] In one aspect the disclosure relates to a method of increasing the rate of biodegradation of a metal implant including electrodepositing a coating on a least a surface of the metal implant, wherein the electrodepositing includes: applying electric pulses having a duration in a range of about 1 to 1000 nanoseconds; and implanting the metal implant into a subject, wherein increasing the rate of biodegradation of the metal implant is due to the coating.Docket No. 2891.099AWO

[0018] In an example, the increasing the rate of biodegradation includes galvanic corrosion between a less active metal in the metal implant and a more active metal in the coating. In an example, the increasing the rate of biodegradation includes galvanic corrosion between a less active metal in the coating and a more active metal in the metal implant.

[0019] In one aspect the disclosure relates to a method of slowing for a period of time the release of ions from a metal implant including electrodepositing a coating on at least a surface of the metal implant, wherein the electrodepositing includes: applying electric pulses having a duration in a range of about 1 to 1000 nanoseconds; and implanting the metal implant into a subject, wherein the slowing the release of ions due to the coating, wherein the coating includes an inner coating contacting the metal implant and an outer coating disposed over the inner coating, wherein the outer coating includes a dopant to reduce inflammation, and wherein the inner coating includes a dopant to increase a rate of biodegradation of the metal implant after the outer coating biodegrades. In an example, the inner coating increases the rate of biodegradation as the outer coating biodegrades.

[0020] In one aspect the disclosure relates to a method of controlling a rate of biodegradation of a metal implant including electrodepositing one or more coating on at least a surface of the metal implant, wherein the electrodepositing includes: applying electric pulses having a duration in a range of about 1 to 1000 nanoseconds; and implanting the metal implant into a subject, wherein the metal implant biodegradation rate is determined by one or more coatings.

[0021] In an example, controlling the rate of biodegradation determines a period of time for the metal implant to biodegrade. In an example, controlling the rate of biodegradation increases a period of time for the biodegradation of the metal implant. In an example, controlling the rate of biodegradation decreases a period of time for the biodegradation of the metal implant. In an example, a percent porosity of the metal implant and a thickness of the coating determines the rate of biodegradation of the implant. In an example, a percent porosity, a composition of the metal implant, a composition of the coating and a thickness of the coating determines the rate of biodegradation of the implant.BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate embodiments of the disclosure and together with the detailed description herein, serve to explain the principles of the disclosure. It is emphasized that, inDocket No. 2891.099AWOaccordance with the standard practice in the industry, various features are not drawn to scale. In fact, the dimensions of the various features may be arbitrarily increased or reduced for clarity of discussion. The drawings are only for purposes of illustrating preferred embodiments and are not to be construed as limiting the disclosure:

[0023] FIG. 1 shows an example of a device and / or system used for electrodeposition, in accordance with an aspect of the present disclosure;

[0024] FIG. 2 shows a scanning electron microscope (SEM) image of stainless-steel substrate without an electrodeposition material on the surface, in accordance with an aspect of the present disclosure;

[0025] FIG. 3 shows an SEM image of calcium phosphate (CaP) electrodeposition on stainless-steel, in accordance with an aspect of the present disclosure;

[0026] FIG. 4 shows a uniform layer of calcium phosphate (CaP) electrodeposited on a silica wafer, in accordance with an aspect of the present disclosure;

[0027] FIG. 5 shows an SEM image of silica electrodeposition on a stainless-steel washer (0.5 inch), in accordance with an aspect of the present disclosure;

[0028] FIG. 6 shows an SEM image of silver (Ag) electrodeposition on a stainless-steel substrate, in accordance with an aspect of the present disclosure;

[0029] FIG. 7 shows an SEM image of silver doped calcium phosphate electrodeposition on a stainless-steel substrate, in accordance with an aspect of the present disclosure;

[0030] FIG. 8 shows an SEM image of zinc oxide (ZnO) electrodeposition on a stainless-steel washer (0.5 inch), in accordance with an aspect of the present disclosure;

[0031] FIG. 9 shows an SEM image of zinc oxide (ZnO) electrodeposition on a stainless-steel washer (0.5 inch), in accordance with an aspect of the present disclosure;

[0032] FIG. 10 shows an example of amorphous calcium phosphate electrodeposition on a 316L stainless-steels washer, in accordance with an aspect of the present disclosure;

[0033] FIG. 11 shows an SEM image of crystalline calcium phosphate electrodeposition on a 316L stainless-steels washer, in accordance with an aspect of the present disclosure;

[0034] FIG. 12 shows an example of amorphous calcium phosphate electrodeposition on a 316L stainless-steels washer, in accordance with an aspect of the present disclosure;

[0035] FIG. 13 shows an SEM image of crystalline calcium phosphate electrodeposition on a 316L stainless-steels washer, in accordance with an aspect of the present disclosure;

[0036] FIGs. 14A-14D shows an example of controlled corrosion of nanometer thick coatings on metal and control metals, in accordance with an aspect of the present disclosure;Docket No. 2891.099AWO

[0037] FIGs. 15A and 15B shows an SEM image of calcium phosphate crystals, large and small, converted using basic pH solution;

[0038] FIG. 16 is a schematic of an embodiment of calcium phosphate crystal vertical orientation as compared to the surface of the substrate;

[0039] FIG. 17 shows an SEM image of low density calcium phosphate crystals;

[0040] FIG. 18 shows an SEM image of high density calcium phosphate crystals;

[0041] FIG. 19 is a graph quantifying Alizarin red on various titanium surfaces after 21 day differentiation of MSCs;

[0042] FIG. 20 is a graph quantifying Alizarin red on various stainless steel surfaces after 21 day differentiation of MSCs; and

[0043] FIG. 21 is a schematic of a metal implant with multiple coatings on a surface.DETAILED DESCRIPTION FOR CARRYING OUT THE INVENTION

[0044] This disclosure relates to nanometer and / or micrometer thick electrodeposited coatings on metal and metal alloy implants. The coatings may be used on either biodegradable metal implants and / or nonbiodegradable metal implants to modify the physical properties of the implants. The coatings may be combined with biodegradable implants to modify a rate of biodegradation or modify the rate metal ions and / or nanoparticles are released into a subject. The coating may reduce the toxicity, necrosis, disease and / or biological conditions associated with the release of metal ions and / or particles. As used herein the term “metal” may include pure metals and metal alloys. As used herein for example, metal implants are primarily biodegradable metal implants though where there is no contradiction, non-biodegradable metal implants may be included. As used herein the term “coatings” may include nanometer thick coatings, micrometer thick coatings and / or combinations thereof. The coatings may be used to modify the surface properties of the metal implants to enhance cells and tissue attachment to the implant. The coatings may modify corrosion of the metal implant. The coatings may modify biodegradation of the metal implant. The coatings may further modify the release of metal ions from the metal implant. The combination of the selected metal or alloys in combination with one or more coating may be specifically combined to manufacture a biodegradable metal implant.

[0045] In certain applications biodegradable metal implants may be used in place of traditional non-biodegradable metal implants. Biodegradable metal implants are designed to biodegrade when contacting bodily fluid. Biodegradable metal implants may be suitable forDocket No. 2891.099AWOfracture repair, fixation devices, tissue sutures, bone implants, tissue implants, organ implants, vascular stents, arterial stents as well as for cardiovascular stents. Biodegradable implants or biodegradable metal implants as described herein refer to metal implants which may include pure metals, metal alloys and composite materials that include at least one metal or alloy and biodegrade in the presence of bodily fluids. Biodegradable metal implants may include devices with at least one metal or alloy. Biodegradable implants may include metal implants or devices with at least one metal or alloy combined with cells, tissues, bodily fluids or any combinations thereof. Biodegradable metal implants may be placed in or on the body to replace, support, or enhance biological structures. Biodegradable implants may be used to correct skeletal injury that require fixation hardware to support bones during the healing period. Biological structures may include bones, teeth, arteries, veins, tissue, organs, the digestive system, the respiratory system, the circulatory / cardiovascular system, the lymphatic system, the immune system, the nervous and endocrine system, the musculoskeletal system, the reproductive system and any combination thereof.

[0046] Biodegradable metal implants may offer many improvements over traditional nonbiodegradable implants. Biodegradation of a metal implant may result in biodegradable materials being resorbed, degraded, corroded and excreted by a subject and replaced with endogenous cells and tissues. Biodegradable, or bioresorbable, materials may be temporary, nontoxic, and capable of being degraded and reabsorbed in the human body within a designated period of time.

[0047] A biodegradable metal implant may have minimum toxicity, strong structural support, adequate degradation and resorption rates and native tissue ingrowth. Biodegradation of a metal implant may take place in a variety of environments inside a subject that may be subject to change over the course of healing and repair of injuries. Biological environmental parameters such as body temperature, pH, the presence of inflammation, subject type, subject weight, subject height, subject age, the subject’s diet, cell composition at the site of injury and location of the implant may influence the rate of biodegradation of the implant. A biodegradable metal implant may biodegrade without toxicity to cells and tissues, and may release vitamins, minerals and medicines inside the subject while biodegrading. In some embodiments, a coated biodegradable metal implant may be designed to release dopants such as antimicrobials, medicines to alleviate pain, inflammation and promote healthy cell and tissue integration into the biodegrading implant for a predetermined period of time, during biodegradation or combinations thereof.Docket No. 2891.099AWO

[0048] Metals typically biodegrade through a corrosion process. The corrosion generally proceeds by an electrochemical reaction with an electrolyte to produce oxides, hydroxides, hydrogen gas, or other compounds. The physiological environment, such as bodily fluids, is highly corrosive due to the high concentration of chloride ions, which may break down the metallic hydroxide protective layer on a metal implant. When metal implants react with body fluid, it may be oxidized and release electrons and form positive ions following an anodic reaction. The generated electrons may be consumed by a cathodic reaction corresponding to water reduction for magnesium based biodegradable metals and dissolved oxygen reduction for iron based biodegradable metals. These reactions may occur on any surface of the metal implant exposed to body fluid.

[0049] In electrochemistry, the values of standard electrode potential provide a way to compare the relative ease of different metal elements to lose electrons to form ions in solutions. The more negative the standard electrode potential value is the more readily the metal biodegrades in an aqueous solution. The metals and alloys selected for biodegradable metal implants may be selected based on the electrode potential value and readiness to corrode or biodegrade in physiological conditions in a subject. The types of metals and alloys may be specific to match a predetermined period of time a metal implant should take to biodegrade in a subject. Physical characteristics, such as the coating, porosity and density of the metal implant may also affect biodegradation times and rates.

[0050] When metal implants include two different metals galvanic corrosion may occur. Galvanic corrosion is a type of corrosion that occurs when two metals with different electrode potentials come into contact with each other in the presence of an electrolyte, such as salt water or a bodily fluid. Galvanic corrosion causes one metal to corrode faster than it would otherwise on its own. Dissimilar metals and alloys have different electrode potentials, and when two or more come into contact in an electrolyte, one metal (that is more reactive) acts as anode and the other (that is less reactive) as cathode. Galvanic corrosion leads to the metal at the anode corroding more quickly than it otherwise would alone and corrosion at the cathode being inhibited. The further apart the metals in the galvanic series are the higher the rate of galvanic corrosion there is. Galvanic corrosion may occur when there is a metal in a coating that is different than the metal in the metal implant. Galvanic corrosion may occur when two different metals are in a coating on a metal implant. Galvanic corrosion may occur when a metal implant includes two different metals.Docket No. 2891.099AWO

[0051] In some embodiments, a metal included in a coating and a metal in a biodegradable metal implant will promote galvanic corrosion of the more active metal. In some embodiments, the more reactive metal will be in the coating of a biodegradable metal implant, and the less reactive metal will be the metal in the implant. In some embodiments, the more reactive metal will be in the biodegradable metal implant, and the less reactive metal will be in the coating. In some embodiments, the more reactive metal and the less reactive metal will both be in the coating. In some embodiments, the more reactive metal and less reactive metal will both be in the biodegradable metal implant. In some embodiments, the more reactive metal will be in the coating and the biodegradable metal implant, and the less reactive metal will also be in the metal implant. In some embodiments, the more reactive metal will be in both the coating and the biodegradable metal implant, and the less reactive metal will be in the coating.

[0052] In some embodiments, galvanic corrosion will increase the biodegradation rate, reduce the period of time needed for biodegradation, or both. The coating may include one or more anodic metal that is more anodic than the metal in the biodegradable metal implant, wherein the coating dissolves more quickly than the metal in the biodegradable metal implant. The coating may include one or more less anodic metal than the metal in the biodegradable metal implant, wherein the coating biodegrades more slowly than the metal in the biodegradable metal implant.

[0053] In some embodiments, it may be beneficial to have a biodegradable metal implant that biodegrades rapidly. In some embodiments, galvanic corrosion may be used to cause the biodegradable metal implant to resorb quicker. In an embodiment the addition of a metal ion into a calcium phosphate coating induces galvanic corrosion of the metal substrate of the biodegradable metal implant. In some embodiments, a biodegradable metal implant with a metal ion in a calcium phosphate coating will produce galvanic corrosion and rapidly biodegrade a biodegradable metal implant where an acute infection on a metal implant is the primary concern, and the implant is only needed for a short duration. The faster biodegrading surface wouldn’t allow for bacteria attachment compared to a more stable metal surface and thus may reduce the likelihood of bacterial infection or reduce the risk of bacterial infection. In another embodiments galvanic corrosion between the coating and the metal in the biodegradable metal implant may be useful in biodegradable metal implants such as ureter / urethral stents, staples, thin film bandages or grafts. In an embodiment galvanic corrosion between the coating and an iron based biodegradable metal implant may increaseDocket No. 2891.099AWOthe biodegradation rate of the iron which may otherwise resorb too slowly. In applications where more mechanical strength is desired than found in biodegradable metal such as magnesium, such as bone fixation devices (screws, pins, rods, plates) iron alloys could be used. Iron based metal implants may resorb or biodegrade too slowly in body fluid. In some embodiments, where the biodegradation rate of an iron or iron alloy -based metal implant needs to be increased, a coating may be applied to induce galvanic corrosion where the iron metal implant biodegrades more rapidly.

[0054] The coating may include dopants, such as metal or alloys, that biodegrade creating micrometer and / or nanometer sized holes in the coating, wherein the underlying metal may biodegrade faster than the coating due to the more anodic metal in the implant as compared to the metal or alloy in the coating. In this example, the coating remains intact on a large surface area of the metal implant and the biodegradation of the implant is controlled by the biodegradation of one or more dopants in the coating creating controlled holes or opening in the coating. The body fluid of a subject may react through the holes in the coating to release ions in the metal implant, biodegrade the metal implant, corrode the metal implant or combinations thereof. The concentrations of dopants may increase or decrease the porosity of the coating as the one or more dopants dissolves. In some embodiments, the size of the electrodeposited nanoparticles of metal in a coating determines the rate of the biodegradation and / or galvanic corrosion. Larger metal particles in a calcium phosphate coating may take longer to biodegrade than smaller metal particles. A coating of calcium phosphate may include metal nanoparticles of any of the metals disclosed herein which may biodegrade and / or undergo galvanic corrosion to manufacture a calcium phosphate coating that biodegrades after a predetermined period of time or at a predetermined rate. In some embodiments, magnesium alloys have high susceptibility to galvanic corrosion. Severe galvanic corrosion takes place when magnesium is in contact with less active metals such as Fe, Ni, or Cu. Metals such as Al, Zn, Cd, and Sn, are less likely to produce galvanic corrosion, and are favorable as alloying elements for magnesium alloys. In some embodiments, dopants of Fe with a nano particle size of about 500 nanometers are electrodeposited on a biodegradable metal implant.

[0055] A coating and a biodegradable metal implant may include one or more of the following metals in this galvanic series, which lists the metals starting a the most reactive metals to least reactive metals: Lithium, Rubidium, Potassium, Calcium, Barium, Sodium, Magnesium, Beryllium, Aluminum, Manganese, Zinc, Chromium, Tungsten, Iron, Cadmium,Docket No. 2891.099AWOCobalt, Nickel, Tin, Lead, Hydrogen, Antimony, Copper, Iodine, Silver, Mercury, Bromine, Platinum, Chlorine, Gold and Fluorine.

[0056] The physical structure of the biodegradable metal implants may affect the rate of biodegradation, ion release, hydrogen formation, corrosion, release of nanoparticles and combinations thereof. The porosity of a metal implant may determine the quantity of metal, such as mass of the metal in the implant and the surface area of a metal or alloy.Biodegradable metal implants may have a varying degree of porosity. An external surface of a metal implant may have pores, an internal surface may have pores, or a combination of internal and external surfaces may have pores, The pores may be of variable length, width or a combination thereof. The pores may be of uniform length, width or both. The pores may form an interconnected porous network. The porosity of a biodegradable metal implant may be expressed as the percentage of void space in the implant's structure. Thus, a biodegradable metal implant with 50% porosity has 50% void space in the metal of the implant. A biodegradable metal implant with 50% porosity would have about 50% the mass of the same implant with 0% porosity.

[0057] The porosity of a biodegradable metal implant can be modified to decrease or increase the rate at which a metal implant biodegrades when exposed to body fluid in a subject. If a metal or alloy biodegrades at a predictable rate the porosity of the metal may be adjusted to ensure the mass and / or thickness of the biodegradable implant matches the predetermined period of time required for biodegradation. The porosity of an implant may be adjusted depending on the length, thickness, diameter or shape of the biodegradable implant and required mass and / or void volume.

[0058] The rate of biodegradation, delay for a period of time of biodegradation, or slowing for a period of time ion release of a metal implant may be further controlled or modified by applying the disclosed electrodeposited coatings on conductive surfaces of the biodegradable metal implant. A coating on a biodegradable metal implant may have predetermined longevity and biodegradation of the metal implant may not begin until the coating biodegrades. The coating may slow the release of ions of the metal implant as some body fluid may diffuse through the coating and contact the metal implant. In some embodiments, the underlying metal may biodegrade prior to the biodegradation of the coating. The porosity of the biodegradable metal implant together with the electrodeposited coating may be used to create an implant that biodegrades at a predetermined rate, after a predetermined amount of time, delays biodegradation for a period of time, slow ion release, delays for a period of timeDocket No. 2891.099AWObulk ion release or a combination thereof. Bulk ion release may occur when an entire surface of a metal implant biodegrades and releases large amounts of ions into a body fluid. In some embodiments, the rate of biodegradation of an implant is approximately the rate at which the implant is replaced by new cells and / or tissues. In some embodiments, the rate of biodegradation can be controlled by using a coating to increase or decrease the overall time required for biodegradation of a metal implant. Increasing or decreasing a rate of biodegradation of a metal implant may be in comparison to the rate of biodegradation of the same metal implant without one or more coating, dopants or combinations thereof.

[0059] The rate of biodegradation may be calculated as loss of mass per period of time. In some embodiments, the biodegradation rate may be milligrams per month of mass loss. In some embodiments, the biodegradation rate may be in micrograms per month of mass loss.

[0060] In some embodiments, biodegradation rate may be determined by the loss of material in millimeters of thickness per day, week, month or year.

[0061] The percent porosity of a biodegradable metal implant may range from about 0 percent to about 99 percent porosity, including all ranges, subranges, and values therein, with a preferred range of about 1 percent to about 10 percent porosity, or about 10 percent to about 50 percent porosity, or about 50 percent to about 75 percent porosity or about 75 to about 95 percent porosity.

[0062] A biodegradable metal implant may biodegrade at a rate ranging from about 0.001 to about 0.01 millimeters per month, or about 0.01 to about 0.1 millimeters per month, or about 0.1 to about 1 millimeter per month, or about 1 millimeter per month to about 5 millimeters per month.

[0063] Biodegradable metal implants may result in a variety of biological responses.Biological responses following implantation may include: thrombus formation, acute and chronic inflammation, immune response, foreign body reactions and fibrous capsule formation. Often the first host response starts from plasma proteins adsorption onto the surface of the implant immediately after the injury. High level of metal ions may ultimately result in necrosis of tissues, cells organs or combinations thereof. One or more metal implant coating may act to suppress or eliminate one or more biological response that may otherwise occur in response to a metal implant.

[0064] Biodegradation, corrosion and wear of metal implants may result in two types of metal degradation products: particles and soluble (ionic) debris such as metal ions and non-metal ions. Particles may range in size of about less than 1 micrometer, which may beDocket No. 2891.099AWOswallowed by cells (pinocytosis) without phagocytosis and hinder the differentiation of macrophages into osteoclasts. Soluble metal ions may bind to serum proteins and disseminate into local and systemic environments. A high concentration of metal ions may elicit tissue inflammation, immunologic response, and cell necrosis. Implants of various metals and alloys have been implicated in numerous health conditions.

[0065] CoCrMo alloys have been used as a biomaterial for metal implants because of their high corrosion resistance and significantly lower volumetric wear. CoCrMo-based hip metal implants suffered an unexpectedly high failure rate, with many patients experiencing unexplained pain, leading to revision surgery. The metal implant failure and pain may be a result of CoCrMo alloys producing up to a trillion nanoscale particles per year per patient that are released into the body fluid triggering inflammatory immune responses. CoCrMo wear particles have been found inside macrophage cells, extracellularly in the synovial membrane, lymph nodes, bone marrow, the liver and spleen. In addition to nanoparticles from the metal alloys of implants, ions and corrosion products have been identified as being released from the metal implants which may be cytotoxic and genotoxic.

[0066] CoCrMo alloys in metal implants have been demonstrated to release Co ions, Mo ions, Cr ions, Cr phosphate-like corrosion products, un-corroded metallic particles and Cr oxide corrosion products. In some examples, species of ions released from CoCrMo alloy metal implants may include Co(II) ions which are cytotoxic and genotoxic, Cr(VI) species which are known to be carcinogenic and Mo ions which are thought to form complexes with proteins, thus potentially inhibiting their function. Other metals and alloys in metal implants may release toxic and inflammatory ions and corrosion products. Nickel titanium implants are known to release nickel ions which are potentially allergenic, carcinogenic, teratogenic, and genotoxic.

[0067] Ti-6A1-4V alloys are used for dental metal implants, hip, knee, wrist, spine, shoulder, elbow and orthodontics. However, there may be a long-term risk associated with Ti-6A1-4V alloys because of the release of Al and V may be associated with Alzheimer’s, osteomalacia and other neurological conditions.

[0068] Orthopedic implants are implants that replace a missing joint or any damaged bone. Orthopedic implants represent a large part of the implants made in the field of medical implants. Orthopedic implants may be composed of chromium, cobalt, molybdenum, nickel, titanium and zirconium alloys which may result in metal allergy, metal implant failure, and complications related to joint replacement. Other serious complications of implants includeDocket No. 2891.099AWOdevice failure, pain, metallic staining of the surrounding tissue, muscular necrosis, tissue necrosis, cell necrosis, periprosthetic fibrosis and loosening of prosthesis. Orthopedic implants used for total hip arthroplasty (THA) and total knee arthroplasty (TKA) have resulted in metal allergy and resulting device failure resulting in pain, instability, malrotation, and bacterial infection. Metal ions, metal particles and corrosion products may be responsible for the negative effects associated with orthopedic implants.

[0069] The biodegradation of some metals and alloys may lead to negative health consequences. The biodegradation of magnesium may lead to hypermagnesemia from excess magnesium, which can be linked to diseases such as arrhythmia and asystole. Hydrogen gas bubbles formed from degrading magnesium have the possibility of blocking blood vessels or causing death of the patient. Products from some Mg implants such as hydroxides, oxides, chlorides and Mg apatites may cause a “burst release” of corrosion products which may affect local cell activity. In some examples, the burst release of corrosion products leads to local alkalization in the immediate proximity of the implant. Excessive iron has been shown to generate lesions in the gastrointestinal tract, cause abdominal pain, fatigue, and liver damage, while manganese can cause manganism, which causes negative psychiatric and motor effects. Zinc overload, on the other hand, can cause neurotoxicity. Thus, there is a need to ensure biodegradable metal implants biodegrade at predictable rates that can be processed safely by the subject.

[0070] Iron and manganese ions from metal implants may cause toxicity. An excess of iron may lead to heart and liver failures as well as causing ischemia stroke. Manganese ions are of most concern because excess of Mn ions in low quantities (TC50 about 10- 100 pM) may result in neurotoxicity linked to Parkinson’s disease. In addition, Mn with ion concentrations higher than 1 mM may strongly decrease the proliferation and viability of MG63 osteoblasts.

[0071] Metal implants may release particles and ions by metal-on-metal wear, biodegradation, corrosion or combinations thereof. Particles, especially cobalt and chromium, are released from implants as they abrade against one another into the surrounding tissues. The deposition of metal ions into the periprosthetic space can lead to a wide spectrum of soft-tissue reactions including massive sterile effusions, necrosis, corrosive osteolysis, and both cystic and solid periprosthetic masses. Metallosis is defined as the accumulation and deposition of metallic particles secondary to abnormal wear from prosthetic metal implants that may be visualized as abnormal macroscopic staining of periprosthetic soft tissues. This phenomenon occurs secondary to the release of metal ions and particles from metal-on-metalDocket No. 2891.099AWOhip implants in patients with end-stage osteoarthritis. Metallosis may generate local and systemic reactions, owing to an increased release of cobalt and chromium ions in the joint space. Metallosis is a condition that arises when particles released from the articulation of metal components accumulate to a toxic concentration. Metallosis may be associated with pain and local inflammation in surrounding tissues and evidenced by dark discoloration surrounding the implant. Metallosis may be difficult to diagnose because concentrations of metal ions in serum or urine may not correlate with local metallic build-up associated with implant failure. Metal implants may release metal particles which may then be phagocytosed by cells and macrophages. This may lead to a release of intracellular metal ions and subsequent cell death. Macroscopically, this may manifest as soft tissue destruction, aseptic loosening of the implant, and osteolysis. Local metal debris may also be associated with increased serum ion levels. These levels may become grossly elevated with progressive implant loosening. This debris can disseminate through tissues and organs leading to rare systemic side effects, including cardiomyopathy, neurological changes (e.g., auditory or visual impairments), and thyroid dysfunction. Metallosis is also linked to extreme pain, localized aseptic fibrosis, necrosis, bone deterioration, and implant loosening. Systemic distribution of toxic metal ions can cause carcinogenesis and death. Treatments for metallosis may include revision surgery, which is indicated for implant malfunction or failure.Biodegradable metal implants may reduce the risk of metallosis. Coatings on metal implants may also reduce the risk of metallosis. Coatings on metal implants may reduce the risk of disease and conditions associated with the excess release of metal ions and / or particles.Coatings on metal implants may reduce metal ion release. Coatings on metal implants may delay metal ion release. Coatings on metal implants may both reduce and delay ion release. Coatings on metal implants may reduce metal allergies. Biodegradable metal implants that biodegrade at a constant rate and / or predetermined rate that is nontoxic may reduce the risk of metallosis.

[0072] Coatings may be electrodeposited on any conductive surface of a metal implant. Coatings on metal implants may include nanometer thick coatings on the metal surface of a metal implant. Coatings may include micrometer thick coatings on the metal surface of a metal implant. Coatings may include nanometer thick and micrometer thick coatings on the metal surface of a metal implant. The thickness of the coating may be specific to the region of an implant. The thickness of the coating may be specific to one or more regions of a metal implant to change the biodegradation rates, metal ion release and corrosion rates of specificDocket No. 2891.099AWOregions of an implant, to prolong the release of dopants in a coating, to prolong the delay of release of metal ions and / or metal nanoparticles or any combination thereof. A region may include an entire surface, a portion of a surface, and one or more portions of surfaces.Regions of surfaces may be continuous and / or discontinuous. Regions of surfaces may be on internal surfaces, external surfaces or combinations thereof.

[0073] The electrodeposition of materials forming coatings may form nanoparticles on the surface of the conductive substrate, such as a metal implant surface, as the coating layer is formed. These nanoparticles may be characterized by their nanoscale morphology, size, optical, electrical, adhesive, magnetic, catalytic activity, hardness, corrosion resistance, biodegradation rate, ion release rate, and other physical properties.

[0074] The electrodeposition of nanocrystals allows for the introduction of new properties to substrates. Nanocrystals may exhibit superior properties to their coarse-grained material counterparts because of the reduced sizes, diverse nanoscale morphologies, and controllable exposed crystal facets. Nanomaterials are materials sized from 1 to 1000 nm in at least one dimension. Nanoparticles may be as small as the atom and molecular in scale. There are different nanoscale morphologies of nanoparticles: amorphous, semi-crystalline or crystalline, and nanocrystals may be the semi-crystalline or crystalline form of nanoparticles.

[0075] Any of the disclosed metal implants may benefit from electrochemically deposited coatings to impart new properties to the metal implant. In some embodiments, an electrochemically deposited coating may slow, delay, or prevent, for a predetermined period of time, the release of metals ions, nanoparticles, and corrosion products from a metal implant, biodegradation of a metal implant, or combinations thereof. In some embodiments, the coating characteristics such as nanoscale morphology, nanoparticle size, thickness and combinations thereof on a metal implant may slow, delay, or prevent, for a predetermined period of time, the release of metal ions, nanoparticles, and corrosion particles from a metal implant, biodegradation of a metal implant, or combinations thereof. In some embodiments, a coating may slow, delay, or prevent, for a period of time, the corrosion of a biodegradable metal implant. In some embodiments, a coating will biodegrade at a constant rate. In some embodiments, a biodegradable metal implant will biodegrade at a constant rate.

[0076] Coatings on metal implants may reduce the toxicity of the implants. The coatings may allow for a controlled rate of biodegradation. The coatings may slow the release of metal ions. The coatings may prevent a burst release of toxic ions. The coatings may result in a sustained low-level release of ions, corrosion products, nanoparticles or any combinationDocket No. 2891.099AWOthereof. The coatings may result in a delay in the release of ions, corrosion products, nanoparticles or any combination thereof. The coatings may result in an accelerated release of ions, corrosion products, nanoparticles or any combination thereof.

[0077] An electrodeposited coating may slow, delay, or inhibit, for a predetermined period of time, the release of toxic metal ions from a metal implant into the environment. An electrodeposited coating may slow, delay, or inhibit, for a predetermined period of time, the release of metal ions from a metal implant into the body fluid, surrounding cells, surrounding tissue or any combination thereof, resulting in a more bioactive and less toxic implant. In some embodiments, coatings on a metal implant may delay the release of metals ions, nanoparticles, corrosion products and combinations thereof into the surrounding environment, such as cells, tissues and / or bodily fluid.

[0078] The disclosed electrodeposited coating on biodegradable metal implants may improve their corrosion resistance in a physiological environment such as body fluid. In some embodiments, the disclosed coatings may produce corrosion resistance to maintain the mechanical integrity of biodegradable metal implants used in fixation hardware during the initial bone healing period, for a predetermined period of time, or both. Electrodeposited coatings may allow a more predictable rate of resorption of the biodegradable metal implant. In some embodiments, a coating material with a predetermined biodegradation rate first acts to prevent the biodegradation of the metal substrate. In some embodiments, the coating is applied to the metal implant including inside a porous region of the metal implant as the thickness of the coating may be less than the pore diameter. In some embodiments, a coating thickness is larger than a pore diameter of a metal implant and may not enter a porous network and thus not coat the surface within the pores. In some embodiments, a 70 percent porous metal may be used, wherein the coating delays biodegradation for a period of time, wherein after the coating biodegrades the highly porous metal biodegrades at a more rapid rate, though still within a safe toxicity level for a subject.

[0079] In some embodiments, the electrodeposition of a coating may slow the release of toxic ions, slow the release of nanoparticles, slow or delay biodegradation and formation of corrosion products from metal and metal alloy implants making them less toxic, genotoxic, inflammatory, carcinogenic, cytotoxic and genotoxic. A coating may be biocompatible with endogenous cells and tissues. A biocompatible coating may recruit healthy cells that prolong the life of the coating, shielding it from corrosive body fluid. In some embodiments, a calcium phosphate coating may shield the biodegradable metal implant, thereby delayingDocket No. 2891.099AWObiodegradation, slowing the release of ions, slowing or delaying corrosion products, slowing or delaying nanoparticles or any combination thereof. In some embodiments, the coating may include zinc doped calcium phosphate, magnesium doped calcium phosphate, manganese doped calcium phosphate, iron doped calcium phosphate, amorphous calcium phosphate, crystalline calcium phosphate, silica or any combination thereof. In some embodiments, the calcium phosphate may be doped with zinc, magnesium, manganese, iron, silicon, strontium, selenium, copper, silver, gold, palladium, platinum or any combination thereof. The dopant may be metallic, an oxide, or other chemistry, such as a halide, nitrate, sulfate carbonate or combinations thereof. The dopant may be in nanoparticle, microparticle or nanocrystalline form or in a mixture of calcium phosphate. The elements and modifying chemistries may be individual or in combination.

[0080] Biodegradable metal implants may resorb and / or biodegrade over a period of time. In an example, cardiovascular biodegradable scaffolds biodegradation time may be 6 to 12 months. In an example, orthopedic biodegradable scaffolds may require at least 6 months to biodegrade. An electrodeposited coating may biodegrade independently and at a rate or predetermined time independent of the coated metal implant. In an example, a coating may biodegrade after about four weeks and the metal implant may then begin to biodegrade and complete biodegradation after eight to twelve weeks. Two or more coatings may biodegrade at independent rates or after predetermined time intervals.

[0081] Calcium phosphate coatings may be in a variety of morphologies. When describing amorphous, crystalline and semicrystalline calcium phosphate the term calcium phosphate may be used as a way to describe each form of calcium phosphate and characteristics that may be shared by each form such as thickness and dopants. In some embodiments, the specific morphology of calcium phosphate such as amorphous, crystalline and semicrystalline will be specified. In some embodiments, nanometer thick calcium phosphate coatings may contain nanometer size features. Nanometer size features and nanometer thick coatings may be referred to as nanometer scale indicating that one or more feature of the calcium phosphate coating has dimensions on the 1 to 1000 nanometer scale. Nanometer size, nanometer, nanometer thick, nanometer thickness and nanometer scale may include dimensions of calcium phosphate coatings such as thickness, crystal dimensions such as crystal height, crystal width and crystal depth, crystal topology, substrate topology, roughness, substrate features and nanoparticles where at least one measurement is about 1 to 1000 nanometers. Calcium phosphate coatings may be nanometers in thickness, and the calcium phosphateDocket No. 2891.099AWOcrystals are nanometers in at least one dimension. The nanometer size crystals may be formed from a highly uniform single layer of amorphous calcium phosphate that is nanometers in thickness and converted with a basic solution to a highly uniform single layer of nanometer size crystalline calcium phosphate.

[0082] In some embodiments, micrometer thick calcium phosphate coatings may contain micrometer size features. Micrometer size features and micrometer thick coatings may be referred to as micrometer scale indicating that one or more feature of the calcium phosphate coating has a dimension on the 1 to 1000 micrometer scale. Micrometer size, micrometer, micrometer thick, micrometer thickness and micrometer scale may include dimensions of calcium phosphate coatings such as thickness, crystal dimensions such as crystal height, crystal width and crystal depth, crystal topology, substrate topology, roughness, substrate features and microparticles where at least one measurement is about 1 to 1000 micrometers. Calcium phosphate coatings may be micrometers in thickness, and the calcium phosphate crystals are micrometers in at least one dimension. The micrometer size crystals may be formed from a highly uniform single layer of amorphous calcium phosphate that is micrometers in thickness and converted with a basic solution to a highly uniform single layer of micrometer size crystalline calcium phosphate.

[0083] Coatings of amorphous calcium phosphate may be electrodeposited on electrically conductive substrates such as metal implants in varying ratios of calcium to phosphate. The calcium phosphate coating may have many chemical configurations. The ratio of calcium to phosphorous may be expressed as a ratio in a number of ways such as calcium : phosphorous and calcium / phosphorous. In some embodiments, the ratio of calcium to phosphorus can vary from 1:1 to 2:1. In some embodiments, the calcium phosphate coating may be hydroxyapatite (HAP) with a Ca / P = 1.5 to 1.67, tricalcium phosphate (TCP) with a Ca / P = 1.5, tetracalcium phosphate (TTCP) with a Ca / P = 2.0 and octacalcium phosphate (OCP) with a Ca / P = 1.33. In some embodiments, calcium -deficient hydroxyapatite has a Ca / P ratio between 1.67 and 1.5.

[0084] Amorphous and crystalline calcium phosphate coatings may include monocalcium phosphate monohydrate, monocalcium phosphate anhydrous, dicalcium phosphate dehydrate, dicalcium anhydrous, octacalcium phosphate, apatite, hydroxyapatite, tricalcium phosphate, heptacalcium phosphate, pentacalcium phosphate, tetracalcium phosphate, calcium pyrophosphate, calcium metaphosphate, calcium phosphinate, calcium hydroxide phosphate or combinations thereof. In some embodiments, one or more form of calcium phosphate isDocket No. 2891.099AWOelectrodeposited onto the surface of an electrically conductive substrate, such as a metal implant, as a highly uniform amorphous calcium phosphate coating which is then converted with a basic solution to a crystalline calcium phosphate with a single layer of highly uniform crystals with a vertical orientation. Nanometer scale crystalline calcium phosphate may be created from any of the forms or ratios of calcium phosphate described herein by conversion with a basic or alkaline solution. Micrometer scale crystalline calcium phosphate may be created from any of the forms or ratios of calcium phosphate described herein by conversion with a basic or alkaline solution.

[0085] Amorphous calcium phosphate may be converted to a uniform base layer of nanocrystalline surface using a base. The converting solution does not add any material to the surface, just converts what is there. Surface uniformity and thickness is preserved based on the initial amorphous coating process. The nanometer thick coatings, such as a calcium phosphate coating, has reduced risk of delamination which would lead to unpredictable release of a dopant in the coating. In some embodiments, micrometer thick amorphous calcium phosphate may be converted to micrometer thick crystalline calcium phosphate using a basic pH solution. A basic pH solution may be referred to as a basic solution or alkaline solution.

[0086] A basic pH solution may be used to convert amorphous calcium phosphate to crystalline calcium phosphate. In some embodiments, a calcium phosphate coating is soaked in basic solution. A feature of the nanometer thick amorphous calcium phosphate coating or layer being converted to a crystalline calcium phosphate coating or layer is that the crystal size and density can change based on the amorphous calcium phosphate layer thickness and the conversion step. In some embodiments, a smaller nanometer scale calcium phosphate crystal size is made using a thinner nanometer thick amorphous calcium phosphate layer followed by conversion with a relatively higher concentration of base that is heated and the conversion reaction occurs for a shorter period of time. In some embodiments, larger nanometer calcium phosphate crystals are made using a relatively thicker nanometer amorphous calcium phosphate coating that is converted more slowly with a lower concentration base that is at a cooler temperature and reacted for a longer period of time. In some embodiments, the longer the conversion process or conversion step the larger the nanometer calcium phosphate crystals produced. In some embodiments, the shorter the conversion process the smaller the nanometer calcium phosphate crystals. In some embodiments, an amorphous calcium phosphate coating is converted with a base, such asDocket No. 2891.099AWOsodium hydroxide, resulting in a conductive substrate with a surface of vertically oriented nanometer calcium phosphate crystals. The pH of the conversion solution may be used to adjust the size of the calcium phosphate crystals. For example, a very basic solution such as pH 10 may convert amorphous calcium phosphate to smaller nanometer calcium phosphate crystals. In some embodiments, the crystals are approximately 22.5 degrees vertical relative to the substrate. In some embodiments, the vertical crystals are more effective at decreasing bacterial attachment and may physically disrupt bacteria membranes, leading to contact mediated bacterial cell death. In some embodiments, the pointed crystal surface may be difficult for bacterial attachment. The plurality of nanometer crystals may act to inhibit bacterial colonization of a surface thereby producing an antimicrobial effect. This property may be especially useful for medical implants. It may also be useful for conductive surfaces that would benefit from an antimicrobial effect such as bioreactors that may be used as is known in the art such as for cell culture, antibody culture and fermentation.

[0087] An amorphous calcium phosphate coating may be converted using a base or alkaline solution. The temperature of the base may influence the crystal size. In some embodiments, the base solution for conversion of amorphous to crystalline calcium phosphate is at about 0 degrees centigrade, at about 10 degrees centigrade, at about 20 degrees centigrade, at about 30 degrees centigrade, at about 40 degrees centigrade, at about 50 degrees centigrade, at about 60 degrees centigrade, at about 70 degrees centigrade, at about 80 degrees centigrade, at about 90 degrees centigrade, or at about 100 degrees centigrade.

[0088] Amorphous calcium phosphate may be converted to a crystalline form of calcium phosphate such as hydroxyapatite. In some embodiments, amorphous calcium phosphate (ACP), octacalcium phosphate (OCP), monetite (CaHPO4), and even brushite, may be converted to crystalline calcium phosphate in alkali conditions to produce a nanometer thick coating with nanometer size calcium phosphate crystals. In other embodiments, amorphous calcium phosphate of various ratios of calcium to phosphate, as described herein, are converted to crystalline calcium phosphate to create a surface with a single layer of nanometer sized crystals that have a vertical orientation. In some embodiments, calcium deficient hydroxyapatite may be converted to nanometer crystalline calcium phosphate. Nanometer thick amorphous calcium phosphate may be formed into nanometer thick semicrystalline calcium phosphate. Semicrystalline calcium phosphate may include amorphous calcium phosphate that has not been completely converted into a crystalline surface. Nanometer thick semicrystalline calcium phosphate may include coatings bothDocket No. 2891.099AWOamorphous and crystalline calcium phosphate. Semicrystalline can also be amorphous with crystals dispersed throughout. Semicrystalline may be a crystalline and amorphous layers created with independent steps.

[0089] A basic or alkali solution may be used to convert nanometer thick amorphous calcium phosphate to nanometer sized crystalline calcium phosphate. In some embodiments, a basic or alkali solution made from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, guanidine, barium hydroxide, cesium hydroxide, strontium hydroxide, lithium hydroxide, rubidium hydroxide, Sodium amide, Sodium hydride, and combinations thereof may be used. In some embodiments, a weak base may be used to convert amorphous calcium phosphate to crystalline calcium phosphate. In other embodiments, a strong base may be used to convert amorphous calcium phosphate to crystalline calcium phosphate. In some embodiments, heat in addition to a basic or alkali solution is used to convert nanometer thick amorphous calcium phosphate into nanometer thick crystalline calcium phosphate. In some embodiments, a combination of a weak base and strong base may be used for conversion of amorphous calcium phosphate to crystalline calcium phosphate. In some embodiments, conversion of a micrometer thick amorphous calcium phosphate coating may require a basic pH solution and heat and increased pressure to form micrometer sized crystalline calcium phosphate. The concentration of the base or alkaline solution may influence the speed of conversion of amorphous calcium phosphate to crystalline calcium phosphate. In some embodiments, the concentration of the base or alkaline solution used is about O.lmM, about 0.5 mM, about 1 mM, about 2 mM, about 5 mM, about 10 mM, about 20 mM, about 50 mM, about 100 mM, about 250 mM, about 500 mM, about 1 M, about 2 M, about 5 M, or about 10 M.

[0090] The total conversion time may be dependent on the desired density and / or size of nanometer sized crystals. The total conversion time for converting amorphous calcium phosphate to nanometer sized crystalline calcium phosphate may be about 30 seconds, about 1 minute, about 5 minutes, about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 24 hours, about 36 hours about 48 hours, about 96 hours, about 144 hours, about 1 week, about 2 weeks, about 4 weeks or about 6 weeks.

[0091] In some embodiments, calcium phosphate conversion may involve surface treatment, such as cleaning the conductive surface before the coating process. In some embodiments, aDocket No. 2891.099AWOpost-treatment, after conversion, such as thermal annealing and additional alkaline treatment to improve the property of coatings and crystals.

[0092] The nanometer and / or micrometer thickness also makes it possible for some dopants to be added to the coating by diffusing into the coating. In some embodiments, diffusion of dopants will occur on an outer surface of a coating. Diffusing molecules into a coating may be done in a liquid or gas. Molecules may be added to coating by ion substitution or inclusion through the entire coating surface area. Dopants may bond to ions and nanoparticles present in the coating. In some embodiments, pulsed nanosecond electrodeposition is used to deposit calcium phosphate coatings and to co-deposit dopants. During electrodeposition dopants such as ions may be integrated into the coating. Dopants may include divalent cations. Divalent cations may be used as dopants in ionic substitutions of calcium phosphate coatings. Some divalent cation dopants used for ionic substitutions include Co2+, Cu2+, Mg2+, Mn2+, Sr2+ and Zn2+. Dopants may include monovalent cations such as K+, Ag+ and Na+ ions. Dopants may include anions such as CO2-, F-. Cl- and SiO4- ions. Dopants may impart biological activity to a conductive surface. Cobalt may promote angiogenesis. Copper may have antibacterial properties. Magnesium may promote bone densification. Manganese may regulate osteoblast differentiation and promote cell adhesion. Strontium may stimulate bone formation and inhibit bone resorption. Zinc may provide antibacterial, anti-inflammatory properties and promote growth of bone. Ionic dopants are discussed in Drevet et al., Electrodeposition of Calcium Phosphate Coatings on Metallic Substrates for Bone Implant Applications: A Review. Coatings 2022, 72, 539, which is hereby fully incorporated by reference.

[0093] The disclosed coatings may be used to release dopants at a specific rate based on the rate of dissolution of the nanometer thick coating. The rate of dissolution may be referred to as rate of decay or rate of biodegradation of the coating. The nanometer thick coating may dissolve at a pH dependent rate. The coating may dissolve at a rate dependent on the local environment. In some embodiments, coatings may include a homogenous concentration of dopants. In some embodiments, coatings may include a heterogeneous concentration of dopants. In some embodiments, dopants may be concentrated near the surface of the metal implant. In some embodiments, dopants may be concentrated at the very surface of the coating in contact with the environment. In some embodiments, coatings may include a gradient of dopants. A gradient of dopant may be created by soaking a nanometer thick coating into a dopant where the dopant is integrated into the coating at decreasingDocket No. 2891.099AWOconcentrations with increasing depth into the coating. In an embodiment, a zinc gradient is formed by soaking the nanometer thick calcium phosphate crystalline surface in a solution of zinc where the zinc substitutes for calcium and the highest concentration of zinc is at the surface of the coating and the concentration of zinc decreases with increasing depth into the coating.

[0094] The coating may modify harmful metal ions and reduce their toxicity by reducing the rate of the release of the ions. The coating may include a dopant, such as a chelating agent, that can combine with metal ions to form a less toxic complex that can be excreted from the body, resorbed, biodegraded or any combination thereof. Chelating agents may be included in the coating or be a dopant added to one or more coating. Chelating agents may include N-acetyl cysteine (NAC), di ethylenetriaminepentaacetic acid (DTP A), and dimercaptosuccinic acid (DMSA). Chelating agents may include edetate calcium disodium (calcium disodium EDTA), sodium 2, 3 -dimercaptopropane sulfonate (DMPS), ethylenediamine tetraacetic acid (EDTA) and dimercaprol.

[0095] Coatings with dopants, such as chelators, may reduce metal ion concentration in blood, urine, body fluid, saliva, in tissues, cells or any combination thereof. Bodily fluids are electrochemically active and react with biomedical implants.

[0096] The coating may include one or more coatings. In some embodiments, coatings may be described as layers from the inner layer contacting the metal implant to the outer layer exposed to the body fluid. In some embodiments, nanosecond electrodeposition is performed to create one or more coatings such that each layer may be defined by thickness, the inclusion of one or more dopant, one or more nanoparticles, and if present one or more calcium to phosphate ratio or combinations thereof. One or more coatings may include one or more dopant. One or more dopants may be present at different thickness of the coating as measured from the metal implant. Dopants at different thicknesses may be accomplished by changing the electrodeposition solution used to create the coating, wherein after some period of time the solution is changed one or more time to include one or more dopant at one or more distance from the metal implant or from the body fluid. In some embodiments, specific dopants are included at specific thickness of the coating, such as the outermost layer which contacts the environment, and thereby releases a first dopant for a period of time and then a coating below the outermost coating may release a second dopant for a period of time and a coating below may release a third dopant for a period of time, a coating below may release a fourth dopant for a period of time, a coating below may release a fifth dopant for a period ofDocket No. 2891.099AWOtime, a coating below may release sixth dopant for a period of time, a coating below may release a seventh dopant for a period of time and so on for any desired amount of dopants and periods of time. In some embodiments, coatings may be termed coating layers where more than one coating is present. Dopants may be slow release or release in bursts. In some embodiments, a slow release of dopant may be a low concentration dopant homogenized in the coating. In some embodiments, a dopant is released in burst when it is highly concentrated to a specific layer of the coating. In some embodiments, a first layer contacts the metal implants. In some embodiments, an outer layer contacts the bodily fluid. A first layer may contact a metal implant. A last layer may contact the body fluid. In some embodiments, a surface of a metal implant may be described as a conductive substate or a substrate herein.

[0097] A metal implant may include a first coating of silica, which contacts the metal implant, a second coating of calcium phosphate over the coating of silica, which contacts the bodily fluid. A metal implant may include a first coating of calcium phosphate, which contacts the metal implant, and a second coating or layer of silica, which contacts the bodily fluid. A metal implant may include a first coating layer of zinc doped calcium phosphate, which contacts the metal implant, and a second coating layer of calcium phosphate in contact with the bodily fluid. A metal implant may include one or more layer of calcium phosphate, zinc doped calcium phosphate, iron doped calcium phosphate, magnesium doped calcium phosphate, silica doped calcium phosphate, silica, magnesium, iron, zinc, or any combination thereof.

[0098] The size of a nanoparticle, crystal, the thickness of a coating and / or a nanoparticle coating on a metal implant may be about 1 nm, about 5 nanometers, about 10 nanometers, about 20 nanometers, about 30 nanometers, about 40 nanometers, about 50 nanometers, about 60 nanometers, about 70 nanometers, about 80 nanometers, about 90 nanometers, about 100 nanometers, about 110 nanometers, about 120 nanometers, about 130 nanometers, about 140 nanometers, about 150 nanometers, about 200 nanometers, about 300 nanometers, about 400 nanometers, about 500 nanometers, about 600 nanometers, about 700 nanometers, about 800 nanometers, about 900 nanometers or about 1000 nanometers.

[0099] The size of a nanoparticle, a crystal, the thickness of a coating and / or a nanoparticle coating on a metal implant may be about 1 micrometer, about 5 micrometer, about 10 micrometers, about 20 micrometers, about 30 micrometers, , about 40 micrometers, about 50 micrometers, about 60 micrometers, about 70 micrometers, about 80 micrometers, about 90 micrometers, about 100 micrometers, about 150 micrometers, about 200 micrometers, aboutDocket No. 2891.099AWO300 micrometers, about 400 micrometers, about 500 micrometers, about 600 micrometers, about 700 micrometers, about 800 micrometers, about 900 micrometers or about 1000 micrometers.

[0100] In some embodiments, biodegradation, resorption or both of a coated biodegradable implant may be complete in about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months about 24 months, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 15 years or about 20 years.

[0101] Coatings may delay biodegradation of a coated metal or metal alloy implant for a predetermined period of time. Coatings may delay ion release from a coated metal implant for a period of time. In some embodiments, a predetermined period of time may be about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 18 weeks, 24 weeks, 36 weeks, or about 48 weeks, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years, or about 10 years, or about 15 years or about 20 years.

[0102] Coatings, dopants or combination thereof may modify one or more characteristics of a metal or metal alloy implant for a predetermined period of time. In some embodiments, a predetermined period of time may be about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 18 weeks, 24 weeks, 36 weeks, or about 48 weeks, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years or about 10 years.

[0103] Coatings on a metal implant may reduce metal ion release, nanoparticle release or a combination thereof for a predetermined period of time. In some embodiments, a predetermined period of time may be about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 18 weeks, 24 weeks, 36 weeks, or about 48 weeks, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years or about 10 years.

[0104] The coating may increase the overall length of time for biodegradation of a metal implant by about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days a week, two weeks, threeDocket No. 2891.099AWOweeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, 11 months, a year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years or about 10 years.

[0105] The coating may decrease the overall length of time for biodegradation of a metal implant by about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, 11 months, a year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years or about 10 years.

[0106] Percent porosity may reduce the period of time required for biodegradation by about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 18 weeks, 24 weeks, 36 weeks, or about 48 weeks, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years or about 10 years.

[0107] In some embodiments, a minimum percentage of the surface of a biodegradable metal implant is coated with a coating. In some embodiments, a surface of a biodegradable metal implant may be covered by a range of about 5 percent to about 10 percent, or about 10 percent to about 25 percent, or about 25 percent to about 50 percent, or about 50 percent to about75 percent or about 75 percent to about 100 percent.

[0108] Nanometer calcium phosphate crystals.

[0109] The crystalline calcium phosphate coating includes nanometer sized crystals that have a vertical orientation as compared to the surface of the substrate. Nanocrystal vertical orientation may be an angle measured from a central axis of a crystal to the surface of the substrate. In some embodiments, a vertical orientation of 90 degrees from the surface of the substrate represents the greatest measured angle from the surface of the substrate. In some embodiments, having a maximum 90-degree vertical orientation allows all crystal vertical orientation to be described in angles of 90 degrees or less from the surface of the substrate regardless of the direction of the crystal. Thus, where crystals face north, south, east or west, where north is the top of the image, the vertical orientation will be described relative to a perpendicular angle to the surface of the substrate where 90 degrees represents the greatest vertical orientation relative to the surface of the substrate. In some embodiments, crystalline calcium phosphate may be micrometer in size. In some embodiments, both nanometer and micrometer sized calcium phosphate crystals are in a coating.

[0110] A vertical orientation and vertically oriented may be used to describe an angle from a central axis of a crystal to the surface of a substrate. In some embodiments, a verticalDocket No. 2891.099AWOorientation expressed as an angle from a central axis of a nanocrystal to the surface of the substrate represents an average vertical orientation of each calcium phosphate nanocrystal of the plurality of nanocrystals. In some embodiments, a plurality of calcium phosphate nanocrystals may be described by a minimum vertical orientation, expressed by an angle from the surface of the substrate to a central axis of a plurality of crystals, wherein each nanocrystal of the plurality of nanocrystals exceeds the minimum vertical angle. In some embodiments, nanometer size crystals are vertically oriented at least 20 or more degrees from the surface. In some embodiments, the calcium phosphate crystals are vertically oriented at least 22.5 degrees vertically from the surface.[oni] The vertical nature of the crystals on the disclosed calcium phosphate coatings imparts unique physical properties into the coating. The disclosed vertical crystals result in more free bonding atoms available to react with the environment. In some embodiments, crystals project nanometers from the substrate surface and create a unique vertical crystal topology of available binding atoms.

[0112] In some embodiments, a percentage of the plurality of nanometer sized calcium phosphate crystals are vertically oriented. In some embodiments, a percentage of the plurality of nanometer sized calcium phosphate crystals have a vertical orientation. In some embodiments, the percentage of the plurality nanometer calcium phosphate crystals with a vertical orientation may be in a range of about 30 percent to about 50 percent, or about 50 percent to about 90 percent.

[0113] In some embodiments, a percentage range of the plurality of nanometer sized calcium phosphate crystals are vertically oriented. In some embodiments, the percentage range of the plurality of nanometer calcium phosphate crystals vertically oriented may be about 30 percent or greater, about 40 percent or greater, about 50 percent or greater, about 60 percent or greater, about 70 percent or greater, about 80 percent or greater about 90 percent or greater or about 100 percent.

[0114] In some embodiments, a percentage of the surface of the conductive metal implant is coated with a single layer of calcium phosphate nanocrystals. In some embodiments, a percentage of the surface of the conductive metal implant is coated with a single layer of calcium phosphate crystals. In some embodiments, a surface includes an exterior surface of metal implant. In some embodiments, a surface includes an internal surface of a metal implant. In some embodiments, a surface includes an internal surface, an exterior surface, or a combination of both surfaces of a metal implant. In some embodiments, a porous externalDocket No. 2891.099AWOsurface results in an external surface of a conductive surface of a metal implant having a greater percentage of the surface coated with a single layer of calcium phosphate nanocrystals than an interior surface. In some embodiments, a percentage of a surface coated with a single layer of calcium phosphate nanocrystals may be in a range of about 1 percent to about 10 percent, about 20 percent to about 40 percent, about 50 percent about 75 percent or about 80 percent to about 100 percent.

[0115] In some embodiments, a plurality of calcium phosphate nanocrystals may be vertically orientated where the vertical orientation includes a minimum vertical angle. A minimum vertical angle may include a minimum angle exceeded by each crystal. A minimum vertical angle may include a minimum angle, wherein each crystal meets or exceeds the minimum vertical angle. In some embodiments, a plurality of calcium phosphate crystals are vertically oriented with a minimum vertical angle of about 10 degrees, about 15 degrees, about 20 degrees, about 22.5 degrees, about 25 degrees, about 30 degrees, about 35 degrees, about 40 degrees, about 45 degrees, about 50 degrees, about 55 degrees, about 60 degrees, about 65 degrees, about 70 degrees, about 75 degrees, about 80 degrees, about 85 degrees or about 90 degrees from the surface of the substrate.

[0116] In some embodiments, crystal vertical orientation is determined based on images. In some embodiments, crystal vertical orientation is determined using computer software analysis of the images.

[0117] The calcium phosphate crystals may have an aspect ratio that describes the length of the crystal as compared to the width. An aspect ratio of 1 unit of length to 1 unit of width is 1 : 1 and would be spherical in shape. An aspect ratio may be the shortest dimension to the longest dimension. In some embodiments, the width may be the dimension that is the shortest dimension and the length the longest dimension. In some embodiments, the length is measured as the distance the crystal extends from the surface. In some embodiments, the aspect ratio of the calcium phosphate crystal can be controlled during the conversion process. In some embodiments, a crystal with a higher ratio than 1 : 1 such as 1 :2 or 1 :3 may be created using a weaker base that is cooled. In some embodiments, a crystal aspect ratio that is lower than 1 :2 or such as 1 : 1.2 or 1 : 1.3 may be created using a stronger base that is heated. The disclosed nanometer scale calcium phosphate crystals may have aspect ratios in a range of about of about 1 : 1 to about 1 :2, or about 1 :2 to about 1 :3, or about 1 :4 to about 1 :8, or about 1:9 to about 1:10.Docket No. 2891.099AWO

[0118] The density of nanometer calcium phosphate crystals may include the number of crystals per square unit of area and a number of grams of calcium phosphate per unit of square area. The density of the crystals may be increased or decreased. In some embodiments, increasing or decreasing crystal density is to achieve a desired binding effect, such as binding capacity, as the crystals have many free atoms available for binding. Crystal density may be controlled by the thickness of the initial electrodeposited amorphous calcium phosphate coating. In some embodiments, increasing the amorphous calcium phosphate coating from 100 to 500 nanometers increases the density of nanometer size calcium phosphate crystals formed during the conversion of amorphous calcium phosphate into crystalline calcium phosphate using a basic solution.

[0119] The density of nanometer calcium phosphate crystals may be in a range of about 5 crystals per square micron to about 100 crystals per square micron, or about 125 crystals per square micron to about 500 crystals per square micrometer.

[0120] The density of nanometer calcium phosphate may be in square meters per gram. The density of nanometer calcium phosphate may be in a range of about 300 square meters per gram to about 1000 square meters per gram, or about 2000 square meters per gram to about 10,000 square meters per gram.

[0121] The coatings may be applied to a conductive substrate such as a metal implant using electrodeposition. Electrodeposition may be carried out using a power supply connected to electrodes in a conductive liquid, electrolyte or solution. The electrodeposition system includes an anode and cathode, where the substrate to be coated is electrically connected to either the anode or the cathode. The electrodeposition substrate may act as either the anode or cathode. The counter electrode, the electrode not electrically connected to the substrate, is electrically connected to the deposition liquid. In an example, a power supply is connected to a pulse generator such that electric pulses are provided to electrodes which are electrically connected to the substrate and the liquid and the charged substrate attracts material of the opposite charge in the liquid which is electrodeposited on the surface.

[0122] In some embodiments, the electric pulses may have a period range of about 0.001 Hz to 10,000 Hz, including all ranges, subranges, and values therein.

[0123] In some embodiments, the electric pulses may have an amplitude of about 1 to 200,000 volts, including all ranges, subranges, and values therein. Some embodiments may utilize a voltage in the range of 100 to 200,000 volts and may be called high voltage examples as the voltages used are high compared to traditional electrodeposition.Docket No. 2891.099AWO

[0124] In some embodiments, the electric pulses may have a duration of about 10 to 1000 nanoseconds, including all ranges, subranges, and values therein. The disclosed systems and methods allow for more controllable electrodeposition of materials onto the surfaces of electrically conductive substrates.

[0125] The electrodeposition liquid, also referred to as liquid, electrolyte or solution herein, may be any suitable liquid that is conductive. Electrodeposition is commonly carried out in aqueous fluids but is not limited to aqueous systems. For example, electrodeposition liquid can include molten salts, solvents, gels, alcohols, acids, bases and combinations thereof. The electrodeposition liquid may include additional salts. The additional salts may provide additional conductivity to the deposition liquid while not playing an active role in the deposition chemistry. An electrodeposition liquid that lacks conductivity may become conductive with additional salts. Salts may be used to increase or decrease the ionic concentration of the liquid. Salts and ionic compounds may be included in the liquid to increase or decrease the ionic concentration of the liquid. Salts and ionic compounds are well known in the art, any of which may be suitable for use in the liquid. In an example, one or more ionic compound may be used for electrodeposition material. The concentration of the electrodeposition material may increase or decrease the ionic concentration of the liquid. The electrodeposition material, salts, additives or any combination thereof may be used to increase or decrease the ionic concentration of the liquid. Additives may include acids, bases, alcohols, solvents, buffers, salts, ionic compounds, polymers, antioxidants, gels, oxidants, doping compounds and combinations thereof. Any one or more material disclosed herein may be used as a doping compound. In example, the liquid is a gel. In another example, the liquid is a gel with an additional electrolyte.

[0126] The electrodes may include one or more cathode and one or more anode. The cathode may be characterized by a negative charge. The anode may be characterized by a positive charge. The electrodes may be of the same material or different material. The electrodes may be alloys of two or more materials such as metals. The electrodes can be made of any suitable conductive material such as metal or a semiconductor. The materials that may be used for electrodes may also be used for substrates and for electrodeposition materials. An electrode may have a positive or negative charge. A counter electrode may be referred to as an electrode of opposite charge to the reference electrode. In an example, one or more electrode is referred to by its charge, positive or negative. In an example, a cathode is an electrode from which the current exits a polarized electrical device and an anode is an electrode from whichDocket No. 2891.099AWOa current enters into a polarized electrical device. In an example, one or more electrode is referred to as positive or negative as opposed to cathode or anode.

[0127] Examples of materials for electrodes and metal implants include but are not limited to stainless steel (SS), SS 316, SS 316L, SS 304, SS304L, SS 303, SS 321, SS 347, SS 410, SS 416, SS 440C, SS 2205, SS 2207, SS 13-8, SS 15-5, SS 17-4, 17-4PH and combinations and alloys thereof. Graphite and carbon nanotubes may be used for electrodes and substrates. In another example, silica may be an electrode or a substrate. Inconel, monel, brass, and bronze may be electrodes and substrates.

[0128] The voltage used for electrodeposition as disclosed herein may be in a range of about 1 volt to about 20,000 volts, including all ranges, subranges, and values therein. In some embodiments, the voltage used for electrodeposition may be in the range of about 1 volt to about 12 volts, about 10 volts to about 1000 volts, about 12 volts to about 100 volts, about 100 volts to about 1000 volts, about 1,000 volts to about 5,000 volts, about 1,000 volts to about 10,000 volts, about 5,000 volts to about 10,000 volts, about 10,000 volts to about 20,000 volts, etc. In a non-limiting example, the voltage used is 4000 volts. In a non-limiting example, the voltage used is 5000 volts. In a non-limiting example, the voltage used is 8000 volts.

[0129] The frequency of the electric pulses as disclosed herein may be measured in cycles per second referred to as hertz. In some embodiments, the frequency of the electric pulses ranges from about 0.001 hertz to about 1000 hertz, including all ranges, subranges, and values therein. The frequency of the electric pulses may be in a range of about 0.001 hertz to about 0.01 hertz, or about 0.01 hertz to about 0.1 hertz, or about 0.1 hertz to about 1 hertz, or about 1 hertz to about 10 hertz, or about 10 hertz to about 100 hertz, or about 100 hertz to about 1000 hertz. In a non-limiting example, the electric pulses have a frequency of 5 hertz.

[0130] The electric pulses as disclosed herein may have a duration in a range of about 1 nanosecond to about 1000 nanoseconds, including all ranges, subranges, and values therein. In some embodiments, the electric pulses have a duration of about 1 nanoseconds to about 300 nanoseconds, or about 300 nanoseconds to about 900 nanoseconds, or about 300 to about 1000 nanoseconds.

[0131] The ionic concentration of the liquid, the material concentration in the solution, or any combination thereof may be in the range of about 1 millimolar to about 10 molar, including all ranges, subranges, and values therein. In some embodiments, the ionic concentration of the liquid, the material concentration in the solution, or any combination thereof may beDocket No. 2891.099AWOabout 1 millimolar, or about 20 millimolar, or about 40 millimolar, or about 60 millimolar, or about 80 millimolar, or about 100 millimolar, or about 300 millimolar, or about 500 millimolar, or about 700 millimolar, or about 900 millimolar, or about 1 molar, or about 2 molar, or about 3 molar, or about 4 molar, or about 5 molar, or about 6 molar, or about 7 molar, or about 8 molar, or about 9 molar, or about 10 molar.

[0132] Nanosecond electrodeposition of calcium phosphate coatings on metal implants may occur at temperatures that do not inactive dopants. Nanosecond electrodeposition of a coating may occur at a temperature in the range of about -20 degrees centigrade to about 13- degrees centigrade, including all ranges, subranges, and values therein. In some embodiments, nanosecond electrodeposition of a coating may occur at a temperature of about -20 degrees centigrade, about -10 degrees centigrade, about 0 degrees centigrade, about 10 degrees centigrade, about 20 degrees centigrade, about 30 degrees centigrade, about 40 degrees centigrade, about 50 degrees centigrade, about 60 degrees centigrade, about 70 degrees centigrade, about 80 degrees centigrade, about 90 degrees centigrade, about 100 degrees centigrade, about 110 degrees centigrade, about 120 degrees centigrade, about 130 degrees centigrade or at one or more of the foregoing temperatures.

[0133] The metal implant may have one or more processes, treatments and pretreatments done prior to electrodeposition of the material or after electrodeposition of material and may have cycles of electrodeposition of one or more material with one or more processing steps repeated as many times as desired. The substrate may receive one or more pretreatments prior to electrodeposition of material on to the surface of the substrate or after electrodeposition of material. Pretreatments, treatments and processes include, but are not limited to, ultrasonic IPA cleaning, plasma cleaning, light acid etching, chemical bonding of materials, nonchemical bonding of materials, electropolishing, chemical polishing, physical polishing, laser ablation, polishing with slurries, evaporative deposition of materials, ultraviolet light treatment, contact with acid, contact with base, contact with solvent or any combination thereof. In an example, one or more material is bonded to a substrate prior to the electrodeposition of one or more materials. In a further example, an abrasive such as diamond, polycrystalline diamond (PCD), cubic boron nitride (cBN), and polycrystalline cubic boron nitride (PCBN), zirconia or any combination thereof is bonded to a substrate prior to electrodeposition.

[0134] A coating may be applied to a surface of a metal implant, a region of an implant, multiple regions of an implant, may be applied in patterns, may be applied to regions ofDocket No. 2891.099AWOporosity, regions of bulk metal, regions where failure may occur prematurely, or any combination there. Portions of metal implants may be masked to be nonconductive such that electrochemical deposition of a nanometer thick coating does not occur on the masked region or portion.

[0135] One or more metal surface of a biodegradable metal implant may be masked to prevent electrodeposition of a coating to the masked surface. The masked surface may be removed to produce regions of thinner electrodeposited coating on the biodegradable implant. In some embodiments, an outer surface is masked preventing a coating from being applied to an outer surface or to apply a thinner coating to the outer surface. In some embodiments, an inner surface is masked to prevent a coating from being applied over the inner coating or to apply a thinner inner coating on some portions of the metal implant. In some embodiments, the pores created interconnected networks with a large surface are internal to the metal implant. This porous surface may be coated with one or more coating while the external surface of the metal implant is coated with a different one or more coating. In some embodiments, one or more coating is applied to both the inner porous surface and the external surface. One or more inner coating may contact the metal implant. One or more outer coating may coat or cover one or more inner coating.

[0136] Dopants as described herein may include a variety of drugs, nanoparticles, medicines, antimicrobials, metals, ions and any other dopant as so described herein. Any one or more dopants may be combined with another one or more dopants. Combinations of dopants described herein are embodiments of dopants that may be used with the disclosed coatings. In some embodiments, metals dopants are combined with nanoparticles dopants, antiinflammatory dopants and pain medicine dopants to create a desired dopant for use with the disclosed calcium phosphate coating. In some embodiments, nanoparticles contain dopants and they are adhered to the substrate of the metal implant followed by applying the nanometer thick coating over the nanoparticles and as the coating dissolves the nanoparticles release dopants. In other embodiments, nanoparticles containing dopants are co-deposited with the coating where the nanoparticles act to release dopants immediately and for a predetermined period of time. In some embodiments, a nanometer thick coating contains dopants such as bone growth hormones, proteins, anti-inflammatory medicine, and antimicrobials.

[0137] Dopants may include nanoparticles, microparticles or combinations thereof.Nanoparticles may be any particle of any disclosed material that is of nanometer size.Docket No. 2891.099AWOMicroparticles may be any particle of any disclosed material that is of micrometer size. In some embodiments, both nanometer size and micrometer size nanoparticle dopants are included in a coating. In some embodiments, nanoparticles, microparticles or combinations thereof may be in an electrodeposition solution and are co-deposited into the coating. In some embodiments, pre-existing nanoparticles, microparticles or combinations thereof can be added to a substrate or surface before the coating. In some embodiments, during the pulsed deposition process the coating will cover and integrate the nanoparticles, microparticles or combinations thereof into the coating and be physically retained. In some embodiments, nanoparticles, microparticles or combinations thereof are adhered to a conductive substrate using adhesive or other chemical bonding that does not affect the conductivity of the substrate such that the coating is uniformly deposited trapping the nanoparticles. In some embodiments, nanoparticles, microparticles, or a combination thereof are added after the formation of the coating. In some embodiments, nanoparticles, microparticles or combinations thereof are conductive metals that are coated using nanosecond electrodeposition as described herein. In some embodiments, nanoparticles, microparticles or combinations thereof are coated with dopants. In some embodiments, nanoparticles, microparticles or combinations thereof are coated with calcium phosphate including dopants. In some embodiments, nanoparticles, microparticles or combinations thereof are already coated using nanosecond electrodeposition and are then coated onto a metal implant using nanosecond electrodeposition. In some embodiments, nanoparticles, microparticles or combinations thereof are coated with silica. In some embodiments, nanoparticles, microparticles or combinations thereof are coated with silica and dopants. Additionally, preformed nanoparticles, microparticles or combinations thereof can be incorporated into the coating. In some embodiments, the nanoparticles, microparticles or combinations thereof are released as the coating dissolves. The nanoparticles and microparticles may include dopants. The nanoparticles and microparticles may be metal nanoparticles. Nanoparticles may include carbon nanotubes, fullerenes, such as C60 and C70 fullerenes, metal nanoparticles, ceramic nanoparticles, and polymeric nanoparticles. The size of the nanoparticles may influence the optical properties of surfaces or coatings due to the size of the wavelength of light they absorb.

[0138] The coating may include dopants such as metal ions known to have antimicrobial or antibacterial effects, such as silver, copper, or zinc that create an antimicrobial effect for a predetermined length of time. A dopant or combination of dopants may be in a coating. ADocket No. 2891.099AWOdopant or combination of dopants may produce a biological effect. In some embodiments, a biological effect may last for at about a week, two weeks, three weeks, one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months or about twelve months. In some embodiments, a biological effect may last at about one year, about two years, about three years, about four years or about five years. In some embodiments, a biological effect may be about a week, about two weeks, about three weeks or about four weeks. A biological effect may include promoting or inhibiting osteoblasts, osteocytes, osteoclasts and bone lining cells, stem cells, cellular receptors and cellular pathways. A biological effect may include inhibiting microorganisms such as bacteria, viruses, parasites, fungi and protozoa. A biological effect may include bio resorption, cell adhesion activity, cell proliferation activity, cell migration activity, cell differentiation activity, anti-bacterial activity, bactericidal activity, anti-inflammatory activity, osseointegration activity, biocorrosion activity, cell differentiation activity, immuno-modulating activity during acute or chronic inflammation or any combination of these. Biological effects may include the nanometer calcium phosphate crystal size of the coating, thereby encouraging mesenchymal stem cells to differentiate into osteoblast. Additional biological effects include osteoblasts excreting extracellular matrix to form bone on growth. Biological effects include osteointegration of a coated implant. In some embodiments, a nanometer thick crystalline calcium phosphate coating includes dopants to promote osteointegration.

[0139] Dopants may include one or more fluorescent dye, photoluminescent dye, fluorescent protein, radiochemical, radiopaque chemicals, reporter molecule or combinations thereof. Marker chemicals and reporter molecules may be used to monitor aspects of the coating. In some embodiments, fluorescent dyes may monitor the dissolution of a coating. In other embodiments, fluorescent dyes may monitor cell growth over the nanometer thick coating, such as bone growth, bone fixation, osteoblast growth, osteoclast growth and combinations of cells and cell activity. In some embodiments, using an infrared dye that penetrates tissue, without the need for invasive surgery, will allow monitoring of fixation of medical implants and potential bacterial infections without the risk of introducing new bacteria into the implant. In some embodiments, dopants may include fluorescent dyes that bind to bacteria to non-invasively evaluate if a bacterial infection is at the site of the metal implant.Docket No. 2891.099AWO

[0140] Radiochemicals may include one or more radionuclides such as 14C, 89Zr, 1251, 32P, 33P, 35S, 3H and 51Cr. Radiopaque compounds may include one or more barium sulfate, iodine, tungsten and tantalum.

[0141] Fluorescent dyes may include, for example, cyanine 3, cyanine 5, Cy7, Cy7.5, rhodamine-based dye molecules, squarylium-based dye molecules, cyanine-based dye molecules, aromatic ring-based dye molecules, oxazine-based dye molecules, carbopyronine-based dye molecules and pyrromethene-based dye molecules. Energy transfer dyes may be used. In some embodiments, fluorescent tagged cells or cells expressing fluorescent proteins may be identified by energy transfer from dyes present in a nanometer thick coating.

[0142] A dopant may include one or more therapeutic materials, bioactive molecules, biomaterials, biological agents, biominerals, hydroxyapatite, bioactive calcium phosphate, antibiotics, medicaments, antibacterial agents, anti-viral agents, cariostatics, antiinflammatory agents, anti-oxidants, organic and mineral fraction of bones and teeth, biologic factors, bioactive substances and cells, drugs, proteins, hormones, enzymes, antigens, antibody, antibody drug conjugate, immunogens, cytotoxins, neurotransmitters, interferons, interleukins, chemokines, cytokines, extracellular matrix components, ligands and peptides, osteoinductive factors, and combinations thereof.

[0143] Vitamins and minerals are also beneficial to bone growth and remodeling and can be included in calcium phosphate coatings as dopants. A dopant may include one or more of vitamin A (beta-carotene), vitamin Bl (Thiamine HC1), vitamin B2, riboflavin, riboflavin 5'-monophosphate, vitamin B3 (niacin), vitamin B5 (calcium D-pantothenate), vitamin B6, pyridoxine HC1, pyridoxal 5'-phsophate, vitamin B 12 (hydroxycobalamin), vitamin C (L-ascorbate), vitamin D3 (cholecalciferol), vitamin E (as mixed tocopherols), vitaminKI (phylloquinone), vitamin K2 (menatetranone, MK-4), biotin, folate (folic acid), PABA, boron (boron ascorbate), calcium (calcium citrate), chromium, chromium picolinate, chromium ascorbate, copper (copper citrate), magnesium (as magnesium citrate, magnesium malate or magnesium succinate), manganese (manganese ascorbate), molybdenum (molybdenum ascorbate), potassium (potassium citrate), selenium (L-selenomethianone), vanadium (vanadium ascorbate), zinc (zinc picolinate) and combinations thereof. In some embodiments, dopants, including vitamins and minerals, are slowly released from a calcium phosphate coating to promote cell attachment and growth.

[0144] Dopants may include systemic factors that affect bone remodeling include the parathyroid hormone (PTH), calcitriol, sex hormones, glucocorticoids, and thyroid hormones,Docket No. 2891.099AWOcytokines, prostaglandins, tumor growth factor-beta (TGF-P), and certain morphogenetic proteins.

[0145] Dopants may include bone growth proteins such as TGFpi, TGFP2, TGFP3, bone morphogenic protein (BMP)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-l, CDMP-2, and / or CDMP-3, fibroblast growth factor (FGF)-l, BMP-1, BMP-2a, BMP-2P, BMP-3b, BMP-8b, BMP- 10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, TGFP4, TGFP5 and combinations thereof

[0146] Dopants may include metals such as Lithium (Li), Beryllium (Be), Sodium (Na), Magnesium (Mg), Aluminum (Al), Potassium (K), Calcium (Ca), Scandium (Sc), Titanium (Ti), Vanadium (V), Chromium (Cr), Manganese (Mn), Iron (Fe), Cobalt (Co), Nickel (Ni), Copper (Cu), Zinc (Zn), Gallium (Ha), Rubidium (Rb), Strontium (Sr), Yttrium (Y), Zirconium (Zr), Niobium (Nb), Molybdenum (Mo), Technetium (Tc), Ruthenium (Ru), Rhodium (Rh), Palladium (Pd), Silver (Ag), Cadmium (Cd), Indium (In), Tin (Sn), Cesium (Cs), Barium (Ba), Lanthanum (La), Cerium (Ce), Praseodymium (Pr), Neodymium (Nd), Promethium (Pm), Samarium (Sm), Europium (Eu), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho), Erbium (Er), Thulium (Tm), Ytterbium (Yb), Lutetium (Lu), Hafnium (Hf), Tantalum (Ta), Tungsten (W), Rhenium (Re), Osmium (Os), Iridium (Ir), Platinum (Pt), Gold (Au), Mercury (Hg), Thallium (Tl), Lead (PB), Bismuth (Bi), Polonium (Po), Francium (Fr), Radium (Ra), Actinium (Ac), Thorium (Th), Protactinium (Pa), Uranium (U), Neptunium (Np), Plutonium (Pu), Americium (Am), Curium (Cm), Berkelium (Bk), Californium (Cf), Einsteinium (Es), Fermium (Fm), Mendelevium (Md), Nobelium (No), Lawrencium (Lr), Rutherfordium (Rf), Dubnium (Db), Seaborgium (Sg), Bohrium (Bh), Hassium (Hs), Meitnerium (Mt), Darmstadtium (Ds), Roentgenium (Rg), Copemicium (Cn), Ununtrium (Uut), Flevorium (Fl), Livermorium (Lv) and alloys and combinations thereof. Alloys may include the combination of two or more metals.

[0147] Dopants may include antibiotics such as aminoglycoside antibiotic, an ansamycin antibiotic, a beta-lactam antibiotic, a glycopeptide antibiotic, a lincosamide antibiotic, a lipopeptide antibiotic, a macrolide antibiotic, a monobactam antibiotic, a nitrofuran antibiotic, an oxazolidinone antibiotic, a quinolone antibiotic, a fluoroquinolone antibiotic, a sulfonamide antibiotic, a tetracycline antibiotic, pexiganan, fusidic acid, mupirocin, tobramycin, streptomycin, rifampicin, vancomycin, clindamycin, daptomycin, erythromycin, linezolid, penicillin, minocycline, pexiganan, fusidic acid, mupirocin, bacitracin, neomycin, polymixin B, metronidazole, silver, zinc, copper, and any combination thereof.Docket No. 2891.099AWO

[0148] Dopants may include anti-inflammatory, pain medicines and combinations of both. Dopants may include acetylated salicylates (aspirin), non-acetylated salicylates (diflunisal, salsalate), anthranilic acids (meclofenamate and mefenamic acid), propionic acids (naproxen and ibuprofen), enolic acids (meloxicam and piroxicam), acetic acids (diclofenac and indomethacin), naphthylalanine (nabumetone), selective COX-2 inhibitors (celecoxib, etoricoxib), Oxycodone, Hydrocodone, dihydrocodeinone, Morphine, Codeine, Fentanyl, Hydromorphone, Meperidine, Oxymorphone and combinations thereof. In some embodiments, one or more anti-inflammatory and one or more pain medicine are slowly released as the calcium phosphate coating dissolves in body fluid.

[0149] Dopants may include one or more antiproliferative, antiplatelet, anticoagulant agents such as paclitaxel, calcium channel antagonists, inhibitors of angiotensin converting enzyme, corticosteroids, doxorubicin, vinblastine, and paclitaxel.

[0150] Dopants may include one or more steroid, hormone, growth hormone, estrogen, testosterone, calcitonin, and glucocorticoids.

[0151] Dopants may include one or more polymer, biodegradable polymer, conductive polymers, poly(3,4-ethylenedi oxythiophene) (PEDOT), polyacetylene; polyphenylene vinylene; polypyrrole, polythiophene, polyaniline, and polyphenylene sulfide.

[0152] Dopants may include one or more antirestenotic agent such as Rapamycin, Everolimus, Zotarolimu, Paclitaxel, Atorvastatin, Rosuvastatin, Dexamethasone, Clopidogrel, Ticagrelor, Prasugrel, Colchicineor and any combination thereof.

[0153] Dopants may include antidiabetic, analgesic, anti-inflammatory agent, antirheumatic, anti-hypotensive agent, antihypertensive agent, psychoactive drug, tranquillizer, antiemetic, muscle relaxant, glucocorticoid, agent for treating ulcerative colitis or Crohn's disease, antiallergic, antibiotic, antiepileptic, anticoagulant, antimycotic, antitussive, arteriosclerosis remedy, diuretic, protein, peptide, enzyme, enzyme inhibitor, gout remedy, hormone and inhibitor thereof, cardiac glycoside, immunotherapeutic agent and cytokine, laxative, lipid-lowering agent, migraine remedy, mineral product, otological, anti-Parkinson agent, thyroid therapeutic agent, spasmolytic, platelet aggregation inhibitor, vitamin, cytostatic and metastasis inhibitor, phytopharmaceutical, chemotherapeutic agent and amino acid, acarbose, antigen, beta-receptor blocker, non-steroidal anti-inflammatory drug (NSAIDs), cardiac glycosides acetylsalicylic acid and any combinations thereof.

[0154] The coating may include at least one dopant of a particular atomic percentage. In some embodiments, the atomic percentage of the dopant within the coating is in a range ofDocket No. 2891.099AWOabout 0.05% to about 6%. In some embodiments, the atomic percentage of at least one dopant is about 0.05% to about 0.1%, or about 0.1% to about 1%, or about 1% to about 6%.

[0155] The coating may include one or more dopant of a particular weight percentage of the coating. In some embodiments, the coating includes the dopant at about 0.1% to about 50%, based on the weight of the coating, including all ranges, subranges, and values therein. In some embodiments, the weight percentage of the dopant within the coating is about 0.1 percent weight, about 0.5 percent weight, about 1 percent weight, about 5 percent weight, about 10 percent weight, about 15 percent weight, about 20 percent weight, about 30 percent weight or about 50 percent weight of the coating.

[0156] The coating may release one or more dopant for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, about 1 moth, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 15 years or about 20 years.

[0157] The coating may delay release of one or more dopant for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, about 1 moth, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years or about 5 years.

[0158] Metals may be used for electrodeposition materials, coatings, dopants, metal implants and electrodes. Examples of metals that may be used for electrodes, metal implants, electrodeposition materials, coatings and combinations thereof include but are not limited to Lithium (Li), Beryllium (Be), Sodium (Na), Magnesium (Mg), Aluminum (Al), Potassium (K), Calcium (Ca), Scandium (Sc), Titanium (Ti), Vanadium (V), Chromium (Cr), Manganese (Mn), Iron (Fe), Cobalt (Co), Nickel (Ni), Copper (Cu), Zinc (Zn), Gallium (Ha), Rubidium (Rb), Strontium (Sr), Yttrium (Y), Zirconium (Zr), Niobium (Nb), Molybdenum (Mo), Technetium (Tc), Ruthenium (Ru), Rhodium (Rh), Palladium (Pd), Silver (Ag), Cadmium (Cd), Indium (In), Tin (Sn), Cesium (Cs), Barium (Ba), Lanthanum (La), Cerium (Ce), Praseodymium (Pr), Neodymium (Nd), Promethium (Pm), Samarium (Sm), Europium (Eu), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho), Erbium (Er), Thulium (Tm), Ytterbium (Yb), Lutetium (Lu), Hafnium (Hf), Tantalum (Ta), Tungsten (W),Docket No. 2891.099AWORhenium (Re), Osmium (Os), Iridium (Ir), Platinum (Pt), Gold (Au), Mercury (Hg), Thallium (Tl), Lead (PB), Bismuth (Bi), Polonium (Po), Francium (Fr), Radium (Ra), Actinium (Ac), Thorium (Th), Protactinium (Pa), Uranium (U), Neptunium (Np), Plutonium (Pu), Americium (Am), Curium (Cm), Berkelium (Bk), Californium (Cf), Einsteinium (Es), Fermium (Fm), Mendelevium (Md), Nobelium (No), Lawrencium (Lr), Rutherfordium (Rf), Dubnium (Db), Seaborgium (Sg), Bohrium (Bh), Hassium (Hs), Meitnerium (Mt), Darmstadtium (Ds), Roentgenium (Rg), Copemicium (Cn), Ununtrium (Uut), Flevorium (Fl), Livermorium (Lv) and alloys and combinations thereof. Alloys may include the combination of two or more metals.

[0159] Electrodeposition materials, electrodes, metal implants, coatings, dopants, metal implants and substrates include alloys including but not limited to Nickel (Ni) and Tungsten (W); Iron (Fe) and Molybdenum (Mo); Iron (Fe) and Tungsten (W); Nickel (Ni) and Molybdenum (Mo); Nickel (Ni) and Phosphorous (P); Nickel (Ni), Tungsten (W) and Boron (B); Iron (Fe), Nickel (Ni) and Carbon (C); Iron (Fe), Chromium (Cr), Phosphorous (P) and Carbon (C); Cobalt (Co) and Tungsten (W); Chromium (Cr) and Phosphorous (P); Copper (Cu) and Silver (Ag); Copper (Cu) and Zinc (Zn); Cobalt (Co), Zinc (Zn), carbon (C), silicon (Si), germanium (Ge), tin (Sn), lead (Pb), boron (B), aluminum (Al), gallium (Ga), indium (In), thallium (Tl) and nihonium (Nh), alloys and combinations thereof.

[0160] The biodegradable metal implants and nonbiodegradable metal implants disclosed herein may be implanted in a subject. A subject may include a patient, a human, dog, cat, horse, pig, bird, mouse, rat, rabbit, sheep, goats, monkeys, apes, primates, vertebrates, fish, mammals, reptiles, hamsters, amphibians and one or more of the foregoing. A subject may be of a particular age group, particular weight group, a particular disease group or any combination thereof.

[0161] Bodily fluids may include blood, cerebrospinal fluid, lymph, plasma, urine, saliva, tears, mucus, semen, sweat, bile, amniotic fluid, pericardial fluid, peritoneal fluid, synovial fluid or any combination thereof.EXAMPLES

[0162] The following examples are intended to illustrate particular embodiments of the present disclosure but are by no means intended to limit the scope thereof.

[0163] Although some examples have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the presentDocket No. 2891.099AWOdisclosure and these are therefore considered to be within the scope of the present disclosure as defined in the claims that follow. Embodiments and examples may be both singular and plural unless explicitly stated otherwise. Embodiments and examples may be combined with other embodiments and examples unless explicitly stated otherwise. Embodiments may not be to scale to allow for demonstration of aspects of the embodiments.

[0164] It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail herein (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are contemplated as being part of the inventive subject matter disclosed herein and may be used to achieve the benefits and advantages described herein.

[0165] As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ±1 or ±10% , or any point therein, and remain within the scope of the disclosed embodiments.

[0166] FIG. 1 shows an example of a substrate 120 in a deposition liquid 125 in a container 130 holding the deposition liquid 125 where a power supply 105 provides pules of electricity between a cathode 110 and anode 115 and a material in the deposition liquid 125 is electrodeposited onto the surface of the substrate 120. In another example the substrate 120 is attached to the anode 110 and the cathode 115 provides the counter electrode. In an example the container 130 is plastic. In another example, the container 130 is any non-conductive substance or material. In an example, the container is made of a conductive material acting as the cathode or anode in the system.

[0167] FIG. 2 shows an example of an SEM image of a stainless-steel substrate. No material has been electrodeposited onto the substrate and the image is an example of a stainless-steel substrate without any electrodeposition material.

[0168] FIG. 3 shows an example of cathodic deposition of calcium phosphate onto a stainless-steel substrate. Stainless-steel was electrically connected to the cathode and thereby negatively charged during the electrical pulses. The electric pulse voltage was 4,000 volts, the electric pulse duration was 300 nanoseconds, the electric pulse period was 5 hertz, and the total number of electric pulses was 2000. The concentration of the electrodeposition liquid was 25 mM CaCh, 3 mM NH4H2PO4, and 50 mM NaCl. The NaCl acts as a bystander ion toDocket No. 2891.099AWOadjust the solution conductivity. The amorphous calcium phosphate layer has an approximate 200 nm thickness with a texture less than 200 nm.Sample Substrate Deposition Total Volts Pulse Pulse charge liquid pulse nanoseconds frequency numberStainless Cathode CaCl25mM 2000 4000 300 5 hertz steel Negative NH4H2PO4charge 3mMNaCl 50 mM

[0169] FIG. 4 shows an example of calcium phosphate deposited onto a silica wafter substrate. Uniform color indicates uniform thickness based on light refraction through the deposited layer. Top of wafter (top of image) shows a line where the wafter exited the electrodeposition solution and was not coated. The silica wafer was electrically connected to the cathode and thereby negatively charged during the electrical pulses. The electric pulse voltage was 8,000 volts, the electric pulse duration was 300 nanoseconds, the electric pulse period was 2 hertz and the total number of electric pulses was 10,000. The concentration of the electrodeposition liquid was 5 mM CaCh, 3 mM NH4H2PO4, and 50 mM NaCl. The uniform color of the silica wafer indicates a uniform thickness of the electrodeposition material based on light refraction through the deposited layer. The uniform optical property of the substrate demonstrates uniform electrodeposition of calcium phosphate. As seen in the top of the image of FIG. 4, there is a line where the silica wafter exited the electrodeposition liquid and was not coated above the line showing a clear distinction between the coated and non-coated substrate in terms of optical characteristics. The optical characteristics of the silica wafer were modified with the electrodeposition of material onto the substrate. The color is attributed to the thin film interference associated with uniform films in the nanometer thickness range.Sample Substrate Deposition Total Volts Pulse Pulse charge liquid pulse nanoseconds frequency numberSilica Cathode CaCl25mM 10,000 8,000 300 2 hertz wafer Negative NH4H2PO4charge 3mMNaCl 50 mMDocket No. 2891.099AWO

[0170] FIG. 5 shows an example of silica deposited on a stainless-steel washer. A solution of 3M NaOH with 1 M SiC>2 dissolved to saturation is further diluted to a 0.01M solution of deposition liquid. The material being electrodeposited is silica and the stainless-steel substrate is electrically connected to the cathode and thereby negatively charged. The electric pulse is 8,000 volts, the pulse duration is 300 nanoseconds, the pulse frequency is 2 hertz with a total of 5,000 pulses. The silica can be seen on the surface of the stainless-steel substrate. In the SEM image the distance between each line of the scale represents 500 nanometers. The deposited silica is uniform in coverage and uniform in thickness and size. The nanoscale morphology of the deposited silica is consistent. This example represents nanometer scale electrodeposition of silica onto a substrate in an aqueous liquid. The percentage of coverage is consistent as is the nanomorphology and size of the electrodeposited nanoparticles.Sample Substrate Deposition liquid Total Volts Pulse Pulse charge pulse duration frequency number nanoseconds Stainless Cathode 3M NaOH with 5,000 8,000 300 2 hertz steel Negative IM SiO2charge dissolved tosaturation.Dilute to 0.0 IMsolution.

[0171] FIG. 6 shows an example of silver deposition on a stainless-steel substrate. The deposition liquid was 10 mM AgNCh, the electric pulse voltage was 4,000 volts, the pulse duration was 300 nanoseconds, and the pulse period was 5 hertz. The total number of electric pulses was 1,000. The substrate was electrically connected to the cathode and thereby negatively charged. This is an example of nanoscale electrodeposition of silver where crystals form at dispersed nucleation sites instead of a uniform thickness at the nanometer scale.Sample Substrate Deposition Total Volts Pulse Pulse charge liquid pulse duration frequency number nanoseconds Stainless Cathode lOmM 1,000 4,000 300 5 hertz steel Negative AgNChchargeDocket No. 2891.099AWO

[0172] FIG. 7 shows an example of silver doped calcium phosphate electrodeposition. The deposition liquid consisted of 3mMNH4H2PO4, 4.5 mM Ca(NO3)2 4H2O and 0.5M AgNCh. The electric pulse voltage was 4,000 volts. The pulse duration was 300 nanoseconds. The pulse period was 5 hertz. The total number of pulses was 500. The stainless-steel substrate was electrically connected to the cathode and thereby negatively charged. The nanoscale semi-crystalline morphology is very consistent. A uniform coating of similar sized nanoparticles of silver doped calcium phosphate can be observed.Sample Substrate Deposition liquid Total Volts Pulse Pulse charge pulse duration frequency number nanoseconds Stainless Cathode 3mM NH4H2PO4 500 4,000 300 5 hertz steel Negative 4.5mMcharge Ca(NO3)24H2O0.5M AgNO3

[0173] FIG. 8 shows an example of the electrodeposition of zinc oxide (ZnO) on a stainless-steel substrate. The electrodeposition liquid was 0.17g / L ZnNO3+ 0.5g / L NaCl. The electric pulse voltage was 5,000 volts. The pulse duration was 300 nanoseconds. The pulse period was 5 hertz. The total number of electric pulses was 1,000. The substrate was electrically connected to the anode and thereby positively charged. The conditions in this example are the same as FIG. 9, except the concentration of the material in the electrodeposition liquid. The lower concentration of material in the liquid resulted in electrodeposited material being less thick, smaller and of a different nanoscale morphology in FIG. 8 as compared to FIG. 9. The dilute concentration of material in the electrodeposition liquid resulted in smaller nanocrystals of electrodeposited material. The smaller nucleation sites and smaller deposited nanoparticles resulted in different optical properties of the coated substrate. The substrate in FIG. 8 absorbs light and appears black. The substrate in FIG. 9 reflects light and appears bright.Sample Substrate Deposition liquid Total Volts Pulse Pulse charge pulse duration frequency number nanoseconds Stainless Anode 0.17g / L ZnNO31,000 5,000 300 5 hertz steel Positive +charge 0.5g / LNaClDocket No. 2891.099AWO

[0174] FIG. 9 shows an example of zinc oxide (ZnO) electrodeposited on a stainless-steel substrate. The electrodeposition liquid was 1.7g / L ZnNCh. The electric pulse voltage was 5,000 volts. The pulse duration was 300 nanoseconds. The pulse period was 5 hertz. The total number of pulses was 1,000. The substrate was electrically connected to the anode and thereby positively charged. The nanoscale size and morphology of the electrodeposition of zinc changes the optical properties of the substrate. The larger zinc electrodeposition material in FIG. 9 reflects light and the substrate appears bright as compared to FIG. 8 where the smaller zinc electrodeposition particles absorbs light and appears dark. The concentration of the material in the electrodeposition liquid of FIG. 9 was 10 times higher than FIG. 8. The modification of the electrodeposition liquid modified the size of the electrodeposition material, the morphology and the thickness (compare FIG. 8 and FIG. 9).Sample Substrate Deposition Total Volts Pulse Pulse charge liquid pulse duration frequency number nanoseconds Stainless Anode 1.7g / L ZnNO31,000 5,000 300 5 hertz steel Positivecharge

[0175] FIG. 10 shows an example of amorphous calcium phosphate electrodeposition on 316L stainless-steel washer. This amorphous stage morphology becomes crystalline calcium phosphate after treatment in a basic solution. Thin uniform film corresponding to the pre-NaOH soak surface of Fig. 11. The colorful appearance on the washer is from the uniform nanometer thick film which causes light interference. This is an example of modification of the optical properties on the surface of a substrate.

[0176] FIG. 11 shows an example of an SEM image of amorphous base calcium phosphate electrodeposition on stainless-steel washer from FIG. 10 then post processed to a crystalline state. The electrodeposition liquid was CaCh 5mM, NH4H2PO43mM and NaCl 50mM. The electric pulse voltage was 4,000 volts. The electric pulse duration was 300 nanoseconds. The total number of pulses was 1,500. The washer was electrically connected to the cathode and thereby negatively charged. After electrodeposition the substrate was treated in a bath of NaOH 0.5M for 2 hours at 65°C. This sodium hydroxide treatment converts amorphous deposition to crystalline deposition. The nanoscale morphology of the electrodeposition material is small as compared to FIG. 13, which has similar conditions except the pulse number is higher and the concentration of the NaOH is ten-fold less concentrated in FIG. 13.Docket No. 2891.099AWOConditions:Sample Substrate Deposition Total Volts Pulse Pulse frequency charge liquid pulse durationnumber nanoseconds316 Cathode CaCh 5mM 1,500 4,000 300 5 hertz Washer Negative NH4H2PO43mMSmall charge NaCl 50mMTexturePost electrodeposition substrate treatment:NaOH ConversionTime0.5M 2hr @65C

[0177] FIG. 12 shows an example of amorphous calcium phosphate electrodeposition on stainless-steel washer. This amorphous stage morphology of crystalline calcium phosphate is a medium thickness film corresponding to the pre-NaOH soak surface of Fig. 13. The thicker nanometer film of the electrodeposition material in FIG. 12 has different optical characteristics as compared to FIG. 10 due to the wavelength of light interference corresponding to the film thickness.

[0178] FIG. 13 shows an example of crystalline calcium phosphate electrodeposition on stainless-steel. The surface is a crystalline calcium phosphate including a medium texture, medium size nanomaterial deposited on surface. The electrodeposition liquid was CaCh 5mM, NH4H2PO43mM and NaCl 50mM. The electric pulse voltage was 4,000 volts. The electric pulse duration was 300 nanoseconds. The total number of pulses was 2,500. The substrate was electrically connected to the cathode and thereby negatively charged. After electrodeposition the substrate was treated in a bath of NaOH 0.05M for 2 hours at 65°C. This sodium hydroxide treatments converts the amorphous deposition nanoscale morphology to a crystalline nanoscale morphology The nanoscale morphology of the electrodeposition material is larger than FIG. 11 which has similar conditions except for the total count of electric pulses was 1,500 in FIG. 11 and the concentration of the post processing NaOH was ten-fold higher in FIG. 11. The larger topology of the surface having altered biological properties compared to FIG. 11.Conditions:Docket No. 2891.099AWOSample Substrate Deposition Total Volts Pulse Pulse charge liquid pulse duration frequency number nanoseconds316 Cathode CaCl25mM 2,500 4,000 300 5 hertz Washer Negative NH4H2PO43mMMedium charge NaCl 50mMTexturePost electrodeposition substrate treatment:NaOH ConversionTime0.05M 2hr @65C

[0179] FIGS. 14A-14D illustrates an example of controlled corrosion of nanometer thick coatings on metal and control metals. Top left control magnesium alloy, Top right magnesium alloy with thin zinc doped calcium phosphate coating. The pins with the zinc doped calcium phosphate were produced with the pulsed deposition method using cathodic deposition a quantity of 500, 300ns l,000v pulses delivered at 5hz in 12.5 mM of NH4H2PO4, 17.6 mM of Ca(NO3)24H2O, 3.2 mM of Zn(NO3)26H2O solution.

[0180] The bottom row is after a corrosion test performed in 0.15M NaCl at 37 Celsius for 7 days. The bottom left if the control which shows large amounts of white magnesium oxide corrosion products on the surface that is beginning to sluff off the surface. Bottom right shows the zinc doped calcium phosphate layer largely intact slowing the underlying surface corrosion.

[0181] This was quantified with pH taken from the supernatant where the control was 9.92 and the sample with the coating was 9.33. The more basic pH from the control is due to higher levels of corrosion products in the solution.

[0182] FIGS. 15A and 15B shows various embodiments of SEM images demonstrating the conversion of nanometer thick amorphous calcium phosphate (ACP) to nanometer thick crystalline calcium phosphate by soaking the ACP in a basic pH solution for a period of time. The left panel shows small nanocrystals on the ACP surface. The right panel shows large nanocrystals after the ACP surface has been soaked in the basic pH solution converting the small ACP nanocrystals to larger nanocrystals. The small calcium phosphate crystal size is made with a thinner ACP layer with a higher concentration heated base soak. The large calcium phosphate crystals are made with a thicker ACP layer then converted slower with a lower concentration cooler base soak. The thinner ACP layer allows for the crystal densityDocket No. 2891.099AWOand orientation to remain the same when varying size. In some embodiments, the crystal density and orientation may be determined by the thickness of the ACP coating.

[0183] FIG. 16 shows an embodiment of a conductive substrate 200 with a plurality of calcium phosphate nanocrystals 220 where the vertical orientation of the crystals 220 is relative to the conductive substrate 200 with the greatest vertical orientation being a 90 degree angle perpendicular 230 to the substrate 200 as measured by a central axis of the crystal. In some embodiments, crystals have a 90 degree vertical orientation 240 to the substrate 200. In some embodiments, a plurality of calcium phosphate crystals, or a proportion or percentage thereof, have a minimum vertical angle 210 as measured from the substrate 200 to a central axis 205 of the crystals 220. In some embodiments, a plurality of calcium phosphate crystals have a minimum vertical angle 210 of at least 22.5 degrees. In some embodiments, a plurality of calcium phosphate crystals have a minimum vertical angle of at least 20 degrees. In some embodiments, about 50 percent of the plurality of the crystals have a minimum vertical angle of at least 22.5 degrees. In some embodiments, about 75 percent of the plurality of crystals have a minimum vertical angle of at least 22.5 degrees. In some embodiments, about 95 percent of the plurality of crystals has a minimum vertical angle of at least 22.5 degrees.

[0184] FIG. 17 is an SEM image of low density crystals of calcium phosphate. Crystal density as described herein refers to the numbers of crystals per unit of area. As seen by comparing FIGs. 18 and 19 the density of crystals can be tuned or controlled based on the nanometer thickness of the amorphous calcium phosphate coating and the conversion process used. FIG. 17 has a thinner nanometer thick amorphous calcium phosphate layer as compared to FIG. 18 and has fewer crystals per square micrometer. In some embodiments, electrodepositing about 100-250 nanometers of amorphous calcium phosphate results in less crystal density than electrodepositing about 250-500 nanometers of amorphous calcium phosphate. In some embodiments, electrodepositing 1-50 nanometers of amorphous calcium phosphate leads to less dense vertical crystals than electrodepositing 50-100 nanometers of amorphous calcium phosphate.

[0185] FIG. 18 is an SEM image of high density crystals of calcium phosphate. The thickness of the amorphous calcium phosphate layer may determine the density of calcium phosphate crystals on a surface, where the density of crystals as described herein refers to the numbers of crystals per unit of area. In some embodiments, a thicker nanometer amorphous calcium phosphate layer on a surface will be converted into more densely clustered nanometerDocket No. 2891.099AWOcalcium phosphate crystals. In other embodiments, a thinner nanometer layer of amorphous calcium phosphate will be converted to less dense clusters of nanometer thick calcium phosphate crystals. Electrodeposition of a thicker nanometer amorphous calcium phosphate coating allows for the conversion process to produce more densely packed nanometer size calcium phosphate crystals. In some embodiments, the thicker the nanometer thick amorphous calcium phosphate coating the larger more dense crystals can be created during the conversion process. In some embodiments, the relatively thicker amorphous calcium phosphate coating is capable of larger more dense calcium phosphate crystals, but a quick conversion process can produce a less dense smaller calcium phosphate crystal. In some embodiments, electrodepositing 100-250 nanometers of amorphous calcium phosphate leads to more dense nanometer calcium phosphate crystals the electrodepositing 1-50 nanometers of amorphous calcium phosphate. In some embodiments, high density calcium phosphate nanocrystals of FIG. 18 have a greater vertical orientation than less dense calcium phosphate nanocrystals FIG.17. In some embodiments, increasing the density of calcium phosphate nanocrystals increases the vertical orientation about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30 degrees from the surface of the substrate as compared to a less dense calcium phosphate nanocrystal surface. In some embodiments, increasing the crystal density increases the minimum vertical orientation angle.

[0186] FIG. 19 is a graph showing Alizarin red quantification on titanium surfaces 21 days post differentiation of mesenchymal stem cells (MSCs). Alizarin red is a stain used to identify calcium containing osteocytes in differentiated MSCs. The absorbance at 490 nanometer wavelength corresponds to the amount of signal from Alizarin red which directly correlates to the number of osteocytes on a specific surface. FIG. 19 shows the untreated control surface has the least osteocytes on titanium while the addition of a nanometer thick coatings of amorphous calcium phosphate with nanometer scale topology on the titanium result in greater osteocyte differentiation. An embodiment of the nanotubes morphology with a nanometer thick amorphous calcium phosphate coating as used in this embodiment can be found in FIG. 12. The addition of nanometer thick zinc calcium phosphate to the nanotubes shows a further increase in the number of osteocytes on the surface with osteocytes increasing with concentration of zinc in the surface coating. In some embodiments, other dopants may be used.Docket No. 2891.099AWO

[0187] FIG. 20 is a graph showing Alizarin red quantification on stainless steel surfaces 21 days post differentiation of mesenchymal stem cells (MSCs). The absorbance at 490 nm wavelength corresponds to the amount of signal from Alizarin red which directly correlates to the number of osteocytes on a specific surface. The control stainless steel surface without a nanometer thick crystalline calcium phosphate coating has the lowest number of osteocytes as indicated by absorbance at 490 nm while the nanometer thick crystalline octacalcium phosphate has the highest Alizarin red signal followed by nanometer thick crystalline octacalcium phosphate with 10% zinc and crystalline octacalcium phosphate with 1% zinc. The results demonstrate nanometer thick crystalline octacalcium phosphate coating is a preferable environment for osteocytes but the inclusion of 1% to 10% zinc is still preferable for osteocyte growth than a surface without a nanometer thick crystalline calcium phosphate coating.

[0188] FIG. 21 is a schematic of a metal implant with multiple coatings on a surface. A metal implant 300 may include a surface 305 with an inner coating 325 with dopants 330 and an outer coating 335 with dopants 340. Dopants may be specific to an inner or outer coating. In some embodiments, additional coating with or without dopants may be between inner coating 325 and outer coating 335. In some embodiments, a metal implant 300 includes a coating 325 on surfaces 305, 310, 315 and 320. In some embodiments, a metal implant includes an inner coating 325 and outer coating 335 on all surfaces 305, 310, 315 and 320. In some embodiments, a first external environment 345 may be bone and one or more coating may require specific dopants to promote bone cell attachment and growth. In some embodiments, a second external environment 350 may be body fluid and require one or more coating with specific dopants to delay the release of ions from the metal implant 300 into the body fluid. In some embodiments, one or more coating on one or more surface of a metal implant may delay for a period of time biodegradation of a metal implant 300. In some embodiments, a metal implant 300 may include an outer coating 335 may include dopants 340 to reduce inflammation and an inner coating 325 with dopants 330 that produce galvanic corrosion to accelerate and increase the rate of biodegradation of the metal implant 300. In some embodiments, a metal implant 300 will have at one or more surfaces 305, 310, 315 and 320 with a coating specific to an external environment 345 and / or 350. In some embodiments, a metal implant 300 will include an outer coating 335 with dopants 340 and an inner coating 325 with dopants 330 where the dopants 330 are a more reactive metal to an external environment 350, such as body fluid, than the metal implant 300 causing the dopants 330 toDocket No. 2891.099AWObiodegrade more rapidly and exposing the metal implant to the external environment 350. In some embodiments, a metal implant 300 will include an outer coating 335 with dopants 340 and an inner coating 325 with dopants 330 where the dopants 330 are a less reactive metal to an external environment 350, such as body fluid, than the metal implant 300 causing the metal implant 300 to biodegrade more rapidly. In some embodiments, a metal implant 300 includes a coating 325 with dopants 330, wherein the dopants are combinations of two or more dopants. In some embodiments, a metal implant 300 includes a coating 325 with dopants 330 that are concentrated near the implant or an external environment 350.

[0189] Metal implant compositions.Metal Percent Metal alloys and Other Rate of composition percent biodegradation Iron 95% 1-5% CaP coatingmagnesiumMagnesium 5-25% 75-95% iron CaP coatingZinc 5-25% 75-95% iron CaP coatingAluminum 5-25% 75-95% iron CaP coatingOxide coating

[0190] Metal implant physical characteristics.Metal implant Percent porosity Pore sizes Thickness of Rate of implant biodegradation Iron 50 Outer pores 100 4 centimetersuM connected toinner pores 1 uM.Iron 40 Mixture of 20% 1 2 centimeters.mM pores and20% 500 uMpores.

[0191] Coatings.Coating Composition Other Period of time delay of biodegradation Calcium phosphate Ca / P ratio 1.67 Zinc dopedCalcium phosphate Crystalline CaPAmorphous calcium Ca / P amorphous 1.3 Dopant concentrationphosphate outer Ca / P crystalline 1.6coating with antiinflammatory dopant;inner coatingnanocrystallinecalcium phosphateDocket No. 2891.099AWO

[0192] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprise” (and any form of comprise, such as “comprises” and “comprising”), “have” (and any form of have, such as “has”, and “having”), “include” (and any form of include, such as “includes” and “including”), and “contain” (and any form of contain, such as “contains” and “containing”) are open-ended linking verbs. As a result, a method or device that “comprises,” “has,” “includes,” or “contains” one or more steps or elements possesses those one or more steps or elements, but is not limited to possessing only those one or more steps or elements. Likewise, a step of a method or an element of a device that “comprises,” “has,” “includes,” or “contains” one or more features possesses those one or more features, but is not limited to possessing only those one or more features. Furthermore, a device or structure that is configured in a certain way is configured in at least that way, but may also be configured in ways that are not listed.

[0193] The disclosure has been described with reference to the preferred embodiments. It will be understood that the architectural and operational embodiments described herein are exemplary of a plurality of possible arrangements to provide the same general features, characteristics, and general system operation. Modifications and alterations will occur to others upon a reading and understanding of the preceding detailed description. It is intended that the disclosure be construed as including all such modifications and alterations.

Claims

Docket No. 2891.099AWOCLAIMSWhat is claimed:

1. A method comprising:electrodepositing a coating on a metal implant, wherein the metal implant has at least one surface and the coating is electrodeposited onto the at least one surface; and implanting the metal implant into a subject;wherein electrodepositing comprises electric pulses having a duration of about 1 to 1000 nanoseconds; andwherein biodegradation of the metal implant is delayed for a period of time due to the coating.

2. The method of claim 1, wherein the metal implant comprises iron.

3. The method of claim 1 or claim 2, wherein the metal implant comprises magnesium.

4. The method of any one of the preceding claims, wherein the metal implant comprises zinc.

5. The method of any one of the preceding claims, wherein the period of time is at least one of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks or about 12 weeks.

6. The method of any one of the preceding claims, wherein the period of time is at least one of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 month, about 24 months, or about 36 months.

7. The method of any one of the preceding claims, wherein the electric pulses have a period range of about 0.001 Hz to 10,000 Hz.

8. The method of any one of the preceding claims, wherein the electric pulse has a voltage range of about 10 to about 100 volts.

9. The method of any one of the preceding claims, wherein the electric pulse has a voltage range of about 100 to about 1000 volts.Docket No. 2891.099AWO10. The method of any one of the preceding claims, wherein the electric pulse has a voltage range of about 1,000 to about 10,000 volts.

11. The method of any one of the preceding claims, wherein the electric pulse has a voltage range of about 10 kilovolts to about 100 kilovolts.

12. The method of any one of the preceding claims, wherein the coating has a thickness in the range of about 10 to 50 nanometers.

13. The method of any one of the preceding claims, wherein the coating has a thickness in the range of about 50 to 500 nanometers.

14. The method of any one of the preceding claims, wherein the coating has a thickness in the range of about 500 to 1000 nanometers.

15. The method of any one of the preceding claims, wherein the coating has a thickness in the range of about 1000 to 5000 nanometers.

16. The method of any one of the preceding claims, wherein the coating comprises calcium phosphate.

17. The method of any one of the preceding claims, wherein the coating comprises zinc doped calcium phosphate.

18. The method of any one of the preceding claims, wherein the coating comprises magnesium doped calcium phosphate.

19. The method of any one of the preceding claims, wherein the coating comprises manganese doped calcium phosphate.

20. The method of any one of the preceding claims, wherein the coating comprises iron doped calcium phosphate.

21. The method of any one of the preceding claims, wherein the coating comprises silica doped calcium phosphate.

22. The method of any one of the preceding claims, wherein the coating comprises silica.

23. The method of any one of the preceding claims, wherein the coating comprises calcium phosphate and one or more dopant selected from the group consisting of zinc, magnesium, manganese, iron, and silica.Docket No. 2891.099AWO24. The method of any one of the preceding claims, wherein the coating comprises crystalline calcium phosphate.

25. The method of any one of the preceding claims, wherein the coating comprises amorphous calcium phosphate.

26. The method of any one of the preceding claims, wherein the coating comprises crystalline and amorphous calcium phosphate.

27. The method of any one of the preceding claims, wherein the coating comprises at least one dopant.

28. The method of any one of the preceding claims, wherein the period of time correlates to a concentration of the dopant.

29. The method of any one of the preceding claims, wherein one or more additional coatings are applied to the metal implant.

30. The method of any one of claims 1 to 29, wherein the porosity of the metal implant comprises about 1 to about 95 percent of the volume of the implant.

31. The method of any one of claims 1 to 29, wherein the coating is applied internally to the porous region, to an external surface, or a combination thereof.

32. The method of any one of the preceding claims, wherein after the period of time a deposit of dopants in the coating are released to combine with and reduce the toxicity of metal ions released from the metal implant.

33. The method of any one of the preceding claims, wherein the coating further comprises nanoparticles, microparticles, or a combination thereof.

34. The method of any one of the preceding claims, wherein the coating further comprises nanoparticles comprising antimicrobials.

35. The method of any one of the preceding claims, wherein the coating further comprises nanoparticles comprising compounds to promote osteointegration selected from the group consisting of calcium phosphate, strontium ranelate, TGFpi, TGFP2, TGFP3, bone morphogenic protein (BMP)-2, BMP-3, BMP -4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-l, CDMP-2, and / or CDMP-3, fibroblast growth factor (FGF)-l, BMP-1, BMP-2a, BMP-2P, BMP-3b, BMP-8b, BMP- 10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, TGFP4, TGFP5 and combinations thereof.Docket No. 2891.099AWO36. The method of any one of the preceding claims, wherein the coating further comprises nanoparticles comprising anti-inflammatory compounds selected from the group consisting of acetylated salicylates (aspirin), non-acetylated salicylates (diflunisal, salsalate), anthranilic acids (meclofenamate and mefenamic acid), propionic acids (naproxen and ibuprofen), enolic acids (meloxicam and piroxicam), acetic acids (diclofenac and indomethacin), naphthylalanine (nabumetone), selective COX-2 inhibitors (celecoxib, etoricoxib) and any combination thereof.

37. The method of any one of the preceding claims, wherein the coating further comprises nanoparticles comprising compounds for preventing or treating stent restenosis selected from the group consisting of Rapamycin, Everolimus, Zotarolimu, Paclitaxel, Atorvastatin, Rosuvastatin, Dexamethasone, Clopidogrel, Ticagrelor, Prasugrel, Colchicine and any combination thereof.

38. The method of any one of the preceding claims, wherein after the period of time a deposit of dopants deposited inside one or more cavities of the metal implant is exposed to a cellular environment.

39. The method of any one of the preceding claims, wherein after the period of time nanotubes comprising one or more dopants on the surface of the metal implant release one or more dopants into a body fluid after the coating biodegrades.

40. The method of any one of the preceding claims, wherein after the period of time the metal implant begins to biodegrade and release metal ions, and wherein a dopant is released from the coating and combines with the metal ions to reduce the toxicity of the metal ions.

41. The method of any one of the preceding claims, wherein the coating further promotes osteocyte growth.

42. A method comprising:electrodepositing a coating on a metal implant, wherein the metal implant has at least one surface and the coating is electrodeposited onto the at least one surface; and implanting the metal implant into a subject;wherein electrodepositing comprises applying electric pulses having a duration of about 1 to 1000 nanoseconds; andwherein the release of ions from the metal implant is slowed for a period of time due to the coating.Docket No. 2891.099AWO43. The method of claim 42, wherein the metal implant comprises nickel.

44. The method of claim 42 or 43, wherein the metal implant comprises chrome.

45. The method of any one of claims 42 to 44, wherein the metal implant comprises cobalt.

46. The method of any one of claims 42 to 45, wherein the metal implant comprises vanadium.

47. A method comprising:electrodepositing a coating on a metal implant, wherein the metal implant has at least one surface and the coating is electrodeposited onto the at least one surface; and implanting the metal implant into a subject;wherein electrodepositing comprises applying electric pulses having a duration of about 1 to 1000 nanoseconds; andwherein the rate of biodegradation of the metal implant is increased due to the coating.

48. The method of claim 47, wherein increasing the rate of biodegradation comprises galvanic corrosion between a less active metal in the metal implant and a more active metal in the coating.

49. The method of claim 47, wherein increasing the rate of biodegradation comprises galvanic corrosion between a less active metal in the coating and a more active metal in the metal implant.

50. A method comprising:electrodepositing a coating on a metal implant, wherein the metal implant has at least one surface and the coating is electrodeposited onto the at least one surface; and implanting the metal implant into a subject;wherein electrodepositing comprises applying electric pulses having a duration of about 1 to 1000 nanoseconds;wherein the release of ions from the metal implant is slowed for a period of time due to the coating; andDocket No. 2891.099AWOwherein the coating comprises an inner coating in contact with the metal implant and an outer coating disposed over the inner coating, wherein the inner coating comprises a dopant to increase the rate of biodegradation of the metal implant after the outer coating biodegrades, and wherein the outer coating comprises a dopant to reduce inflammation.

51. The method of claim 50, wherein the inner coating increases the rate of biodegradation as the outer coating biodegrades.

52. A method comprising:electrodepositing one or more coating on a metal implant, wherein the metal implant has at least one surface and the one or more coating is electrodeposited onto the at least one surface; andimplanting the metal implant into a subject;wherein a rate of biodegradation of the metal implant is determined by the one or more coatings.

53. The method of claim 52, wherein the rate of biodegradation of the metal implant determines a period of time for the metal implant to biodegrade.

54. The method of claim 53, wherein the period of time for the metal implant to biodegrade is increased.

55. The method of claim 53, wherein the period of time for the metal implant to biodegrade is decreased.

56. The method of any one of claims 52 to 55, wherein the rate of biodegradation of the metal implant is further determined by a percent porosity of the metal implant and a thickness of the coating.

57. The method of any one of claims 52 to 55, wherein the rate of biodegradation of the metal implant is further determined by a percent porosity of the metal implant, a composition of the metal implant, a composition of the coating, and a thickness of the coating.

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