WO2004037120A2 - Implantable medical devices using zinc - Google Patents
Implantable medical devices using zinc Download PDFInfo
- Publication number
- WO2004037120A2 WO2004037120A2 PCT/US2003/033752 US0333752W WO2004037120A2 WO 2004037120 A2 WO2004037120 A2 WO 2004037120A2 US 0333752 W US0333752 W US 0333752W WO 2004037120 A2 WO2004037120 A2 WO 2004037120A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- zinc
- containing component
- tissue
- stent
- implantable medical
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/315—Zinc compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/30—Inorganic materials
- A61L27/306—Other specific inorganic materials not covered by A61L27/303 - A61L27/32
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/082—Inorganic materials
- A61L31/088—Other specific inorganic materials not covered by A61L31/084 or A61L31/086
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
Definitions
- the present invention relates generally to U.S. Patent Application Serial No. 60/421,336, attorney docket no. 020154-001100US, entitled “Modulation of Zinc Levels to Improve Tissue Properties," and U.S. Patent Application Serial No. 60/421,278, attorney docket no. 020154-001200US, entitled “Implantable Medical Devices Using Zinc,” which are hereby fully incorporated by reference.
- the present invention relates generally to medical devices. More specifically, the invention relates to implantable medical devices coupled with zinc to inhibit plaque formation, enhance elastin production or the like.
- Blood vessel disease frequently arises when masses or plaques, called “atheromas,” accumulate on the inner walls of vascular lumens, resulting in a condition known as atherosclerosis.
- Atherosclerosis may occur in any blood vessel in the body, but is particularly common in the arteries supplying blood to the heart and the arteries supplying blood to the lower extremities. Atherosclerosis occurs naturally as a result of aging, but may also be aggravated by factors such as diet, hypertension, heredity, vascular injury and the like. Atheromas and other vascular deposits restrict blood flow and can cause a deficiency of blood in a body part—a condition known as ischemia.
- Ischemia in turn, can result in tissue death, such as a myocardial infarction (heart attack) or gangrene of the lower extremities.
- Atheromatous deposits can have widely varying properties, some being relatively soft and others being fibrous or calcified.
- One method for treating vascular disease includes placing one or more stents within a blood vessel at a site of atherosclerosis. Stents are commonly used to treat an obstructed or weakened vascular lumen by supporting the vessel wall to maintain patency of the lumen. In many procedures, a blood vessel is first dilated, using a balloon angioplasty catheter or similar device, and then one or more stents are placed across the dilated area to maintain its diameter.
- Zinc is one of the most important trace elements in human health and nutrition and plays a significant role in the function of many intracellular proteins. Zinc is crucial for gene expression and nucleic acid metabolism, which accounts in part for its importance in cellular growth and differentiation. Recent investigations indicate that zinc may actually have a regulatory role. Zinc possesses ligand-binding properties that are utilized effectively at the catalytic site of a broad range of enzymes. In addition, it has many structural roles in biological membranes [Tang et al., (2001) J. Nutr. 131: 1414-14200], cell receptors, and proteins (i.e. transcription factors and proteins involved in DNA replication). For additional description of many of the properties and characteristics of zinc, refer to U.S. Patent Application Serial No. 60/421,336, ("Modulation of Zinc Levels to Improve Tissue Properties”), previously incorporated by reference.
- zinc may have one or more beneficial effects in treating vascular disease. Therefore, it would be advantageous to have implantable medical devices and methods that use zinc to improve one or more tissue properties in a tissue such as a blood vessel, heart muscle, a venous graft or the like.
- a tissue such as a blood vessel, heart muscle, a venous graft or the like.
- zinc might be used with an implantable device in a configuration to prevent plaque formation, enhance elastin production, provide both plaque prevention and enhanced elastin production or the like. At least some of these objectives will be met by the present invention.
- Devices and methods of the present invention provide for implantable medical devices using zinc to enhance one or more properties of a tissue.
- some methods include using an implantable medical device coupled with at least one zinc-containing component to resist plaque formation, enhance elastin production or both.
- the device may be one or more stents, grafts or stent-grafts for placement in a blood vessel such as a coronary artery, peripheral blood vessel, abdominal aorta or the like.
- the device may comprise a gel or other zinc carrier substance, a catheter such as a balloon-expandable catheter, a zinc anchoring substance or device, or any other suitable device.
- the at least one zinc-containing component, and the amounts, concentrations, methods for coupling the zinc to the device and the like may be selected to provide a desired effect on a target tissue.
- a "zinc-containing component” refers to a zinc compound, complex, chelate or any other zinc-containing component.
- Target tissues may be any suitable tissues, such as blood vessels, heart muscle, aneurismal tissue, manufactured graft material, genetically-engineered tissue, animal tissue or the like.
- a method for resisting plaque formation in a tissue includes: providing at least one implantable medical device; identifying a configuration of at least one zinc-containing component which, when coupled to the at least one implantable device and implanted in the blood vessel, will inhibit plaque formation; coupling the at least one zinc- containing component to the implantable medical device in the identified configuration; and implanting the at least one device so that the zinc-containing component inhibits plaque formation.
- the tissue may include arterial tissue, venous tissue, heart tissue, natural graft tissue, man-made graft tissue or genetically engineered tissue.
- the device may be any suitable device.
- the device is a stent, a graft, a stent-graft, a gel, a carrier, a zinc-anchoring device, a compound, a balloon- expandable device or a catheter.
- the device includes a biodegradable stent.
- the at least one zinc-containing component may comprise any suitable zinc substance or combination.
- the at least one zinc-containing component comprises one or more zinc salts, such as acetate, ascorbate, aspartate, butyrate, caproate, caprylate, carbonate, chromate, citraconate, citramalate, citrate, EDTA, formate, fumarate, gallate, gluconate, halides, iodate, lactate, laurate, laureate, malate, maleate, malonate, metaphosphate, methansulfonate, monophosphate, myristate, nitrate, octoate, oleate, orotate, orthophosphate, oxalate, oxides, palmitate, permanganate, phenolsulfonate, phosphate, picolinate, propionate, pyrophosphate, salicylate, selenate, stearate, succinate, sulfate,
- zinc salts such as acetate, ascor
- a zinc-containing component for use in the present invention may be selected to provide ionic zinc when the device is implanted in the blood vessel.
- an amount of zinc may be selected to provide an ionic zinc concentration in an area of the blood vessel adjacent the implanted device of between about 1.0 picomolar and about 500 millimolar.
- a concentration or amount of zinc may be selected to provide plaque inhibition for at least a target duration.
- the target duration in one embodiment may be at least about six months.
- the configuration a zinc-containing component provides for sustained-release of ionic zinc from the device.
- Zinc-containing components may be coupled with a medical device in any suitable configuration or by any suitable means.
- the at least one zinc-containing component is selectively deposited over a portion of the device.
- the zinc- containing component may be deposited primarily on a tissue-facing surface of the device.
- an entire device maybe coupled with or coated in zinc.
- coupling the zinc-containing component to the implantable medical device includes coupling a zinc chelator to the device and releasably coupling the zinc-containing component to the chelator.
- the method may further include polymerizing the chelator.
- a method for treating a blood vessel includes: identifying a diseased location along the blood vessel for treatment; determining that the blood vessel at the diseased location is susceptible to plaque formation if treated by device implantation; selecting an implantable medical device coupled with at least one zinc-containing component in response to the determining step; and implanting the selected medical device along the diseased location such that the zinc-containing component inhibits formation of plaque.
- any suitable device, any form of zinc, any means for coupling zinc to the device, any amounts or concentrations of zinc or the like may be selected in any given embodiment to provide desired effects on a tissue.
- a method for coupling at least one zinc-containing component with an implantable medical device to enhance plaque resistance, elastin production or both, of a tissue includes coupling at least one binding agent with at least one surface of the implantable medical device and coupling the at least one zinc-containing component with the at least one binding agent.
- coupling the at least one binding agent with the at least one surface involves coupling a chelator with the surface.
- the method may further include polymerizing the chelator.
- the binding agent may be any suitable binding agent, but in one embodiment it includes allylamine linked with polyaspartate, with the zinc-containing component being coupled with the polyaspartate.
- any suitable implantable device, any suitable form or amount of zinc and any suitable means for coupling the zinc with the device may be used.
- a method for enhancing elastin production of a tissue includes: identifying an area of tissue which may benefit from enhanced elastin production; implanting at least one implantable medical device at or near the area of tissue, the device comprising at least one zinc-containing component; and promoting elastin formation at or near the area of tissue with the zinc-containing component of the implantable medical device.
- the tissue may be arterial tissue, venous tissue, heart tissue, natural graft tissue, man-made graft tissue or genetically engineered tissue in various embodiments.
- the area of tissue may comprise an area within or adjacent to an abdominal aortic aneurysm.
- any device, form or amount of zinc, or means for coupling may be used.
- the promoting step raises elastin content of the area of tissue to an enhanced elastin content which is significantly greater than a normal elastin content.
- the area of tissue has the normal elastin content prior to the implanting step.
- the identifying step comprises identifying an area of tissue which has a deficient elastin content which is significantly less than a normal elastin content.
- a device for inhibiting plaque formation, promoting elastin production, or both includes at least one implantable medical device and zinc-containing component coupled with the device.
- the device may be a graft, a stent, a stent-graft, a gel, a zinc-anchoring device, a topical compound or complex or any other suitable device.
- the zinc-containing component may be a zinc salt, as described above, or may be a zinc chelate or any other form of zinc.
- the device is configured to provide ionic zinc when the device is implanted.
- an ionic zinc concentration may be provided in an area adjacent the implanted device of between about 1.0 picomolar and about 500 millimolar.
- configurations of zinc, coupling methods, amount and concentrations, and the like may be varied to achieve desired effects on a tissue. The various embodiments are described in more detail below.
- Fig. 1 is a cross-sectional diagram depicting a portion of an implantable medical device with zinc bound to a surface of the device via a binding agent, according to one embodiment of the present invention.
- FIG. 2 is a cross-sectional diagram depicting a portion of an implantable medical device with zinc bound to a surface of the device via a polymerized binding agent, according to one embodiment of the present invention.
- Fig. 3 is a cross-sectional diagram depicting a portion of an implantable medical device with zinc bound to a surface of the device via multiple different binding agents, according to one embodiment of the present invention.
- Fig. 4 is a cross-sectional diagram depicting a portion of an implantable medical device with zinc coupled with a surface of the device via a electroplating or sputter-coating techniques, according to one embodiment of the present invention.
- Fig. 5 is a cross-sectional diagram depicting a portion of an implantable medical device with zinc coupled with a surface of the device via a gel, according to one embodiment of the present invention.
- Fig. 6 is a cross-sectional diagram depicting a portion of an implantable medical device with zinc coupled with a surface of the device via a gel and a binding agent, according to one embodiment of the present invention.
- Fig. 7 is a cross-sectional diagram depicting a portion of an implantable medical device with a surface modified with allylamine to form part of a zinc-binding agent, according to one embodiment of the present invention.
- Fig. 8 is a cross-sectional diagram depicting a portion of an implantable medical device with zinc coupled with a surface of the device via a binding agent formed from allylamine, as in Fig. 7, couple with polyaspartate, according to one embodiment of the present invention.
- Devices and methods of the present invention generally include at least one implantable medical device, such as a stent or graft, coupled with at least one zinc-containing component for treating a tissue, such as a blood vessel, heart tissue, a vein graft or the like.
- a tissue such as a blood vessel, heart tissue, a vein graft or the like.
- a zinc-containing component may be a zinc compound, complex, chelate, or any other suitable form of zinc or combination of forms of zinc. Different configurations of zinc may be used, for example, to inhibit plaque formation, promote elastin production, or both, in various embodiments.
- One configuration of zinc coupled with a stent may be advantageous for preventing plaque formation in a coronary artery.
- Another configuration may work well for preventing plaque formation on a vein graft.
- Yet another configuration may be advantageous for promoting elastin production in or near an aneurysm. In some embodiments, both plaque inhibition and elastin promotion may be achieved.
- any configuration of at least one zinc-containing component may be used with any implantable device, according to various embodiments.
- Devices may include any of a number of implantable devices, such as stents, grafts, stent-grafts, and the like.
- the word "device” is defined as any means for carrying or applying zinc to a tissue or other surface.
- a device may comprise a topical zinc-containing component which may be applied to a tissue to release the zinc to achieve a desired effect.
- a device may comprise a gel, a container for releasably carrying zinc, an anchoring device for anchoring zinc to a tissue or the like.
- Devices of the invention may include any means for delivering or applying zinc at a desired location.
- the location will typically be on or near a tissue.
- the tissue may be tissue of a human patient, such as heart muscle, arterial wall tissue, venous tissue, and the like, hi other embodiments, the tissue may comprise graft tissue, such as a venous graft.
- zinc may be used in a research or therapeutic context on manufactured tissue, genetically engineered tissue, animal tissue or the like. Generally, application to any tissue is contemplated, such as human, animal or other tissue in research, patient care or other suitable contexts.
- any configuration of zinc may be used with the present invention.
- devices and methods of the invention provide for delivering ionic zinc at or near a tissue for treatment.
- any suitable form of zinc may be coupled with one or more devices to deliver zinc and all forms of zinc now known or hereaf er discovered are contemplated.
- any suitable concentration, amount, chemical configuration, and the like may be used.
- zinc may be applied to a tissue- contacting surface of a stent.
- the zinc may be applied to the entire stent or some other surface of the stent.
- a device may be coated in different thicknesses of zinc, may be coupled with zinc to provide sustained-release of the zinc, may be coupled with varying concentrations of zinc or the like.
- Zinc may also be coupled with a device by any suitable means.
- Various embodiments may also employ different means for coupling zinc with a device.
- zinc chelators or other binders may be used to bind zinc to a surface of a device, zinc may be bound to a device by electroplating or any other suitable method may be used.
- any suitable medical devices and any suitable configurations, amounts, compositions, and the like may be used according to the present invention.
- zinc coupled or otherwise used with one or more devices according to the present invention may have any suitable composition.
- zinc used in the present invention is typically referred to as "at least one zinc-containing component," which may include but is not limited to at least one zinc compound, complex, chelate, a combination thereof or the like, in various embodiments.
- one or more zinc salts may be used.
- Suitable zinc salts include, but are not limited to acetate, ascorbate, aspartate, butyrate, caproate, caprylate, carbonate, chromate, citraconate, citramalate, citrate, EDTA, formate, fumarate, gallate, gluconate, halides, iodate, lactate, laurate, laureate, malate, maleate, malonate, metaphosphate, methansulfonate, monophosphate, myristate, nitrate, octoate, oleate, orotate, orthophosphate, oxalate, oxides, palmitate, permanganate, phenolsulfonate, phosphate, picolinate, propionate, pyrophosphate, salicylate, selenate, stearate, succinate, sulfate, sulfonate, tannate, tartrate, tetrametaphosphate, titanate, transferrin, tripolyphosphate,
- a zinc-containing component may be selected or coupled with a device in a manner to provide controlled-release or sustained-release of zinc at a desired location.
- a zinc-containing component may be coupled with a device with varying degrees of "releasability," such that some zinc will be released soon after implantation and other zinc will be released over time
- zinc may be coupled with or contained within, a degradable device such as a degradable stent, capsule, other anchoring device or the like, so that as the device degrades over time, zinc is released in a sustained or controlled manner
- a zinc-containing component may be contained within matrixes, liposomes, vesicles, microcapsules, microspheres, a solid particulate material or the like, to provide release of zinc over time.
- any suitable time period for release of zinc may be chosen, depending on the desired effect, the tissue being treated, the desired duration of treatment, and the like. In some embodiments, for example, it may be desired to cause a release of zinc very soon after implanting a device, to reach a plateau level of zinc release relatively quickly, and to sustain that level of release over a longer time period. In one embodiment, for example, a desired level of zinc at a treatment location may be reached within two weeks of implanting a device and that level may be maintained for at least six months. Any other sustained-release or controlled-release pattern is contemplated with the scope of the invention.
- the amount, concentration, composition or any other characteristic of zinc used with devices of the present invention may be selected to provide one particular effect or a combination of effects on a target tissue.
- zinc coupled with a device will be configured to inhibit plaque formation in a treatment area, such as within a coronary artery.
- zinc may be coupled with a device to enhance elastin production, for example, to enhance elastin production at or near an aneurysm.
- zinc coupled with a device may cause both plaque inhibition and enhanced elastin production. Any one or a number of variables applying to devices, zinc-containing components or both may be selected to achieve desired effects on a given tissue, while still remaining within the scope of the present invention.
- embodiments of the present invention generally include at least one implantable medical device (as device is defined herein) coupled with at least one zinc-containing component.
- Devices, zinc-containing components, and means for coupling devices and zinc are typically selected to provide for the release of ionic zinc from the device at a location to have a desired effect on a tissue or similar substance.
- devices used in various embodiments of the present invention may be made by various known techniques, such as those described in U.S. Patent Nos. 6,113,636, 6,190,407, 6,267,782 and 6,322,588, the complete contents of which are hereby incorporated by reference.
- Such techniques involve depositing a metal or compound, such as zinc or a zinc compound on the surface of a device (for instance a stent or implant) formed from a suitable biocompatible material such as stainless steel, titanium, nitinol, ceramics, polytetrafluoroethylene, silastic, polylactide, polyglycolide, polylactide-co-glycolide, and the like, acrylates, methacrylates, polyurethane, or combinations of these. Other biocompatible materials or compounds may similarly be used in such devices. Deposition may be carried out either on a device already formed or on biocompatible material that will subsequently be used for production of such a device.
- the deposition is carried out by techniques such as incubation of the device or biocompatible material with a solution of a zinc salt, as described in US Patent No. 6,113,636.
- the zinc may be deposited on the device or biocompatible material in the form of elemental zinc.
- U.S. Patent No. 6,113,636 describes processes for producing such a zinc-containing material, including chemical reduction, photochemical reduction, and electrodeposition or electroplating. Also, as described in that patent, a combination of elemental zinc and a zinc salt may be deposited on the material.
- U.S. Patent No. 6,267,782 describes additional means for producing a zinc- or zinc salt-containing biocompatible material or device, including physically impressing the elemental zinc onto the material or device, mixing elemental zinc into the substance used to form the biocompatible material, such as a polymer during its formation, and vapor deposition.
- U.S. Patent No. 6,322,588 contains additional information about deposition of metals on such biocompatible materials.
- the amount of a zinc-containing component that is coupled with a device may generally be selected to provide an effective amount of zinc ions to achieve a desired effect for a desired time period.
- embodiments of the invention typically include one or more implantable medical devices used to increase tissue zinc levels in order to prevent plaque formation or to increase tissue elasticity or elastin levels.
- implantable medical devices used to increase tissue zinc levels in order to prevent plaque formation or to increase tissue elasticity or elastin levels.
- Such devices include, for example, vascular devices such as stents, grafts, stent-grafts, catheters, gels, topical compounds, zinc anchoring devices, and the like, which may be implanted to reverse elastin degradation states, treat atherosclerotic vascular diseases, repair or prevent aneurysmal disease or the like.
- intravascular stents are coated with one or more zinc-containing components to prevent or treat plaque progression or restenosis.
- zinc is coupled with a device so as to provide a desired concentration of zinc ions at a given location on or in a tissue.
- at least one zinc-containing component is coupled with a device so that a zinc concentration at or adjacent to a target tissue, upon implantation of the device, will be from about 1.0 picomolar to about 500 millimolar, and more preferably from about 100 picomolar to about 50 millimolar.
- concentration ranges are approximated at the tissue-device interface, but may also occur in an area around or adjacent to that interface.
- the ranges listed above may have plaque inhibition effects, elastin promotion effects, or both, in various settings. Other ranges may be selected to provide other or additional effects on a target tissue.
- any suitable means for delivering or applying zinc to a tissue is contemplated.
- zinc is applied directly to a venous bypass graft for implantation to bypass a coronary artery. It has been found that zinc, applied once to a venous graft after implantation, may enhance elastin production in or near the graft and thereby prevent graft atherosclerosis. It may be applied as a gel, another form of topical compound, or any other suitable delivery agent coupled with zinc. Furthermore, a zinc gel or other applicable compound may be delivered via any suitable means.
- Zinc- containing components used for inhibiting plaque formation in venous grafts may provide any suitable zinc concentration at the tissue-device interface, but in one embodiment provide a concentration from about 1.0 picomolar to about 500 millimolar, and more preferably from about 100 picomolar to about 50 millimolar.
- zinc ions may be released from a gel composition with or without other active agents.
- ionic zinc could be released from a gel composed of cross-linked 30% polyethylene glycol dimethacrylate in phosphate buffered saline including anchoring to the surface of the stent covalently.
- Zinc would be included in the form of zinc acetate with phosphate buffer added to the final composition.
- Methacrylates would be introduced to the stent surface using a silane with a methacrylate arm (United Chemical). The gel would be UV crosslinked and anchored to the reactive stent methacrylates.
- polylactide-co-glycolide microspheres containing ionic zinc and preferably a pH buffer could be incorporated into the gel or otherwise anchored to the stent (for example, following methods described in "Development of a Platform to Evaluate and Limit in-Stent Restenosis,” Elkins et al., Tissue Eng.. 2002 Jun;8(3):395-407).
- zinc may be used to increase heart elastin content and improve compliance
- a gel, patch or other device coupled with zinc is used to increase tissue free ionic zinc levels in order to enhance elastin production in or increase compliance of heart tissue.
- the concentration range of the zinc-containing substance is from about 1.0 picomolar to about 1000 millimolar, and preferably from about 100 picomolar to about 900 millimolar.
- zinc could be applied via a gel (with or without another device), a patch applied outside the heart or any other device applied to the heart.
- the zinc can be metal (applied by sputtering, plating, or other means), chelate (including poly-binding agents as above) or salt.
- the zinc-containing component can be mechanically or chemically adhered so that ionic zinc is made available to the tissue over time.
- endoscopic delivery of a sterile 20% pluronic f-127 (BASF) gel containing buffered bioerodable PLGA microspheres loaded with zinc acetate could be accomplished with injection into the myocardium just deep to the pericardium.
- BASF pluronic f-127
- zinc ions could be released during infarct remodeling so that the scarred tissue would be elastic and provide an inward force to assist the remaining myocardium in ejecting blood.
- symptoms of heart failure might be reduced.
- the same approach could be accomplished through a variety of techniques including intracardiac delivery through endovascular access. These approaches could be combined with laser or other techniques and therapeutic agents as well.
- stent 10 may be a stent, graft or any other suitable implantable device useable with zinc.
- Zinc ions 14 may comprise any of the zinc-containing components described above, or any combination of zinc-containing components.
- binding agents 12 may include any suitable binding elements for coupled zinc ions with one or more surfaces 11 of stent 10.
- binding agents 12 comprise one or more zinc chelators.
- Figure 2 shows a similar cross section to that in Figure 1, except that zinc ions 14 are bound to surface 11 via chains of binding agents 12. Such chains of binding agents 12 allow larger numbers of zinc ions 14 to be bound to stent 10 per unit surface area of surface
- Figure 3 demonstrates that multiple different binding agents 12a-c may be used to bind zinc ions 14 to one or more surfaces 11 of the same stent 10. Use of multiple binding agents 12a-c may allow stent 10 to release zinc ions 14 at different rates, to provide for timed- or sustained-release of zinc at a treatment area.
- Figure 4 shows a similar stent 10 in cross section, however zinc ions 14 have been electroplated or sputter-coated onto surface 11.
- the portion of stent 10 to the right of the vertical dotted line shows that when a stent plated or sputter-coated with zinc 14 is placed in an in- vivo environment, in which there is oxidative stress, zinc ions 14 are released from stent 10.
- Figure 5 illustrates a cross section of stent 10 having a gel coating 13 which includes zinc ions 14.
- zinc ions 14 will be released in vivo over time, either as a result of oxidative processes, due to gel degradation or both, hi still other embodiments, as shown in Figure 6, zinc may be bound to surface 11 of stent 10 by a combination of gel coating 13 and one or more binding agents 12. Such combinations may achieve advantageous zinc release patterns or timing to enhance treatment.
- Figure 7 shows one possible embodiment of a binding agent for zinc ions 14.
- allylamine 15 may first be bound to surface 11 to generate a reactive primary amine which may then be coupled with a single aspartate 17 via an amide linkage. Aspartate 17 then serves as a binding agent to bind zinc 14.
- Figure 8 shows surface 11 modified with allylamine 15 to generate a reactive primary amine which is then coupled to polyaspartate 16 via an amide linkage. Each aspartate can then serve as a zinc binding agent. As designated by the subscript letters "n" and "m", the number of zinc ions does not necessarily equal the number of aspartates.
- Example 1 Zinc anchored to a stent through chemical binders or chelates for ontrolled release after stent deployment
- a commercially available Cordis BX-NelocityTM stent (Cordis, Miami, FL) was used as a starting device, though any suitable stent device could be used.
- Stents were pretreated in a plasma chamber at 400 watts for 3 minutes in an Argon atmosphere, then derivatized in plasma for 4 minutes with a 18 milliliters/hour allylamine flow in an Argon atmosphere at 400 watts, followed by an argon flush for 3 minutes. This treatment generated reactive amine sites on the surface of the stent, as depicted schematically in Figure 7.
- a suitable linker was then used to anchor a zinc binding agent to the reactive amines on the stent surface, as shown schematically in Figures 7-8.
- a chain of linkers could be used to bind multiple zinc atoms per chain to remove constraints of surface area and increase total zinc dose.
- These chelators release zinc ions over time, with time course dependant primarily upon the identity of the chelating agent. Secondary impact of local pH and oxidative stress after injury can be used to add a "smart" environment sensitive component to zinc release.
- zinc compounds particularly useful in the compositions and methods of this invention are zinc salts, including acetate, ascorbate, aspartate, butyrate, caproate, caprylate, carbonate, chromate, citraconate, citramalate, citrate, EDTA, formate, fumarate, gallate, gluconate, halides, iodate, lactate, laurate, laureate, malate, maleate, malonate, metaphosphate, methansulfonate, monophosphate, myristate, nitrate, octoate, oleate, orotate, orthophosphate, oxalate, oxides, palmitate, permanganate, phenolsulfonate, phosphate, picolinate, propionate, pyrophosphate, salicylate, selenate, stearate, succinate, sulfate, sulfonate, tannate, tartrate, tetrametaphosphate,
- chelates of zinc and other types of zinc-containing chemical substances such as complexes, such as complexes of zinc with amino acids such as methionine.
- zinc binding agents with fewer than 6 carbon atoms per zinc atom provide rapid release of zinc.
- Combinations of different binding agents (some short and some long) as well as chains of binding agents can accomplish longer term delivery of zinc atoms with complex release curves as desired.
- particularly useful as linkers are any carboxylate-containing compounds, which can be used to form an amide linkage to the stent free amine groups.
- the stent was immersed in polyaspartate (Ajinomoto, Japan) after appropriate pretreatment with EDC and NHS.
- Example 2 Local application of a zinc formulation to create a plaque-resistant artery after arterial stent deployment
- the stent design is based on the Palmaz-Schatz coronary stent. Stents were either electroplated with zinc or left untreated. Electroplating was accomplished via immersion of the stent as the cathode in a 1.5 molar zinc acetate solution and running at fixed current mode at 270 milliamps (controls at 300 watts and 300 volts, but current limiting) for 5 minutes. Plated stents were rinsed in deionized water 5 times, inspected on a metallurgical microscope, mounted on balloons, and lyophilized overnight. Sputtering of zinc or deposition of zinc- containing compound would accomplish the same end in a more controlled fashion.
- polishing of the surface would be desirable to allow less irritation on implantation in vivo.
- polishing often requires a thicker deposition of zinc to offset losses during polishing. It is often desirable to minimize pH reducing effects in vivo, through either avoidance of acid or through buffering or neutralizing acid during these processes.
- Methods of plating implantable stents are well known in the art, for example, as described in U.S. Patent Application Serial Nos. 366022 and 803843 and U.S. Patent No. 6,099,561.
- stents were deployed in the infra-renal abdominal aorta. Stents were post-dilated at 8 atmospheres with a 5 millimeter angioplasty balloon (Jupiter, Cordis, Miami, FL) to a final lumen size of 125% above the baseline with care taken to ensure that no branches were present within the stent segment. Pre- and post-deployment digital subtraction angiograms were recorded for the blank procedural control and angiostatin treatment groups. The rabbits were fed a 0.25% cholesterol diet after the intervention.
- a gel is applied directly to the artery.
- the same method can be accomplished by gel-based release from a stent-graft or a vascular graft.
- Such a strategy could anchor gel or even a direct zinc binding agent as in the stent examples above directly to the graft surface, the stent surface or both where appropriate.
- Zinc could be covalently bound or mechanically adhered as desired.
- zinc acetate is used, but any source of zinc ions including polymerized zinc binding agents (as in the stent example above) could be applied and such agents could be covalently or noncovalently attached to the gel components themselves or the graft/stent surfaces.
- Example 4 Local application of a zinc formulation to create a plaque-resistant or stenosis-resistant venous segment
- a 3 centimeter segment of left superficial femoral vein was dissected through a transversal incision in the groin. All side branches were ligated with 10-0 nylon suture (Ethilon 2820G, Ethicon Inc., NJ) and divided. The animal was heparinized (200 Ul/kilograms) and the vein clamped proximally and distally. The vein was catheterized with a 27 gauge needle. Three centimeter of the right superficial femoral artery was dissected through a transversal incision in the groin. At the end of the incubation period the vein was harvested and rinsed with normal saline.
- the right Superficial Femoral Artery was clamped just below the deep femoral artery and tied 1.5 centimeter below the proximal clamp with a 6-0 polypropylene suture (Prolene, Ethicon Inc., NJ).
- a proximal longitudinal arteriotomy was performed between the clamp and the stitch and the vein anastomosed in a reversed end-to-side fashion using interrupted 10-0 nylon suture (Ethilon 2820G, Ethicon Inc., NJ).
- the SFA was then clamped distally and the distal anastomosis was performed 1.5 centimeter below the proximal anastomosis using the same technique.
- the clamps were removed, lidocaine 0.5% was applied locally to reduce spasm and the wounds were closed in two layers.
- animals were maintained on a diet containing 0.25% cholesterol until vein graft harvest at 28 days. Similar effects could be obtained by using any of the stent- or graft-based devices for anti- plaque or pro-elastin deposition in veins.
- These approaches, particularly stent-based release of ionic zinc according to the methods described herein are also particularly relevant to venous access stenoses and venous coronary bypass grafts.
- Routine methods were employed for the Verhoeff von Gieson-Masson trichrome double staining.
- a Diagnostic Instruments SPOT Diagnostic Instruments, Sterling Heights, MI
- true-color digital camera was used to record noninterpolated microscopic images of each slide at high resolution as displayed on a Nikon E600 epifluorescence microscope with plan apochromat lenses.
- the resulting images were analyzed using the Image-pro Plus analysis system (Media Cybernetics, Silver Spring, MD) to determine the intima to media ratio of each based upon area measurements.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2003/033752 WO2004037120A2 (en) | 2002-10-25 | 2003-10-22 | Implantable medical devices using zinc |
JP2004547124A JP2006503657A (en) | 2002-10-25 | 2003-10-22 | Implantable medical device using zinc |
EP03777868A EP1560543A2 (en) | 2002-10-25 | 2003-10-22 | Implantable medical devices using zinc |
AU2003286660A AU2003286660A1 (en) | 2002-10-25 | 2003-10-22 | Implantable medical devices using zinc |
CA002503492A CA2503492A1 (en) | 2002-10-25 | 2003-10-22 | Implantable medical devices using zinc |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US42133602P | 2002-10-25 | 2002-10-25 | |
US42127802P | 2002-10-25 | 2002-10-25 | |
US60/421,336 | 2002-10-25 | ||
US60/421,278 | 2002-10-25 | ||
PCT/US2003/033752 WO2004037120A2 (en) | 2002-10-25 | 2003-10-22 | Implantable medical devices using zinc |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004037120A2 true WO2004037120A2 (en) | 2004-05-06 |
WO2004037120A3 WO2004037120A3 (en) | 2005-04-07 |
Family
ID=39273388
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2003/033752 WO2004037120A2 (en) | 2002-10-25 | 2003-10-22 | Implantable medical devices using zinc |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1560543A2 (en) |
JP (1) | JP2006503657A (en) |
AU (1) | AU2003286660A1 (en) |
CA (1) | CA2503492A1 (en) |
WO (1) | WO2004037120A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3689385A4 (en) * | 2017-09-30 | 2021-07-07 | Biotyx Medical (Shenzhen) Co., Ltd. | Implantable device |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6620194B2 (en) * | 1995-04-19 | 2003-09-16 | Boston Scientific Scimed, Inc. | Drug coating with topcoat |
US6716444B1 (en) * | 2000-09-28 | 2004-04-06 | Advanced Cardiovascular Systems, Inc. | Barriers for polymer-coated implantable medical devices and methods for making the same |
US6776792B1 (en) * | 1997-04-24 | 2004-08-17 | Advanced Cardiovascular Systems Inc. | Coated endovascular stent |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2777193B1 (en) * | 1998-04-14 | 2001-06-08 | Coletica | PARTICLE WITH A CHELATING HYDROXAMIC GROUP OF METAL IONS AND THEIR USE IN COSMETICS OR PHARMACY |
IT1303735B1 (en) * | 1998-11-11 | 2001-02-23 | Falorni Italia Farmaceutici S | CROSS-LINKED HYALURONIC ACIDS AND THEIR MEDICAL USES. |
US7182953B2 (en) * | 1999-12-15 | 2007-02-27 | Celgene Corporation | Methods and compositions for the prevention and treatment of atherosclerosis restenosis and related disorders |
-
2003
- 2003-10-22 EP EP03777868A patent/EP1560543A2/en not_active Withdrawn
- 2003-10-22 CA CA002503492A patent/CA2503492A1/en not_active Abandoned
- 2003-10-22 WO PCT/US2003/033752 patent/WO2004037120A2/en active Application Filing
- 2003-10-22 JP JP2004547124A patent/JP2006503657A/en active Pending
- 2003-10-22 AU AU2003286660A patent/AU2003286660A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6620194B2 (en) * | 1995-04-19 | 2003-09-16 | Boston Scientific Scimed, Inc. | Drug coating with topcoat |
US6776792B1 (en) * | 1997-04-24 | 2004-08-17 | Advanced Cardiovascular Systems Inc. | Coated endovascular stent |
US6716444B1 (en) * | 2000-09-28 | 2004-04-06 | Advanced Cardiovascular Systems, Inc. | Barriers for polymer-coated implantable medical devices and methods for making the same |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3689385A4 (en) * | 2017-09-30 | 2021-07-07 | Biotyx Medical (Shenzhen) Co., Ltd. | Implantable device |
Also Published As
Publication number | Publication date |
---|---|
EP1560543A2 (en) | 2005-08-10 |
JP2006503657A (en) | 2006-02-02 |
CA2503492A1 (en) | 2004-05-06 |
AU2003286660A1 (en) | 2004-05-13 |
WO2004037120A3 (en) | 2005-04-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9993583B2 (en) | High-density lipoprotein coated medical devices and methods of treatment using the devices | |
US7169404B2 (en) | Biologically absorbable coatings for implantable devices and methods for fabricating the same | |
CA2623123C (en) | Graft with bioabsorbable support frame | |
US4082507A (en) | Prosthesis and method for making the same | |
JP3816802B2 (en) | Medical equipment | |
JP5936231B2 (en) | Fast-absorbing or dissolving coating | |
US20040131700A1 (en) | Implantable medical devices using zinc | |
US20040037836A1 (en) | Use of nitric oxide adducts | |
JP2008504890A (en) | Drug delivery stent formulation for restenosis and vulnerable plaque | |
JP2007502135A (en) | Intraluminal prosthesis comprising a therapeutic agent | |
Cox et al. | Effect of local delivery of heparin and methotrexate on neointimal proliferation in stented porcine coronary arteries | |
JP2009526605A (en) | Medical devices that generate nitric oxide | |
Gao et al. | The mechanical property and corrosion resistance of Mg-Zn-Nd alloy fine wires in vitro and in vivo | |
Vashisht et al. | Long‐term reduction of intimal hyperplasia by the selective alpha‐1 adrenergic antagonist doxazosin | |
US9339593B2 (en) | Drug-eluting coronary artery stent coated with anti-platelet-derived growth factor antibodies overlaying extracellular matrix proteins with an outer coating of anti-inflammatory (calcineurin inhibitor) and/or anti-proliferatives | |
van der Giessen et al. | Coronary stenting with polymer-coated and uncoated self-expanding endoprostheses in pigs | |
Konstantinos et al. | Sirolimus-eluting stents: a review of experimental and clinical findings | |
EP1560543A2 (en) | Implantable medical devices using zinc | |
Storck et al. | Absorbable suture in vascular surgery | |
JP2005538756A (en) | Medical device comprising a protein-tyrosine kinase inhibitor for inhibiting restenosis | |
WO2006068516A1 (en) | Implantable medical devices coated with or containing copper chelating compounds | |
JP2006503605A (en) | Medical equipment | |
JP2015535246A (en) | Dual variable region (DVD) immunoglobulin to reduce major adverse cardiovascular events (MACE) in diabetic patients following stenting | |
CN112316134A (en) | Application of PD-1 as medicine for preventing intimal hyperplasia after vein graft operation | |
van Beusekom et al. | Stenting or balloon angioplasty of stenosed autologous saphenous vein grafts in pigs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2503492 Country of ref document: CA Ref document number: 2003286660 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003777868 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004547124 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2003777868 Country of ref document: EP |