News Column

Patent Issued for Biocompatible Materials for Medical Devices

July 26, 2014



By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Colorado State University Research Foundation (Fort Collins, CO) has been issued patent number 8771756, according to news reporting originating out of Alexandria, Virginia, by NewsRx editors (see also Colorado State University Research Foundation).

The patent's inventors are Reynolds, Melissa M. (Fort Collins, CO); Reynolds, Benjamin P. (Fort Collins, CO).

This patent was filed on December 28, 2010 and was published online on July 8, 2014.

From the background information supplied by the inventors, news correspondents obtained the following quote: "Each year billions of health care dollars are spent on medical devices that fail in clinical practice (e.g., intravascular and neonatal catheters, coronary artery and vascular stents and grafts, guidewires, extracorporeal membrane oxygenation circuits, heart valves, by-pass circuits, etc.). These device failures are due to the introduction of a foreign material into the body leading to a multitude of serious health risks and undesirable complications including thrombosis, inflammation, cell proliferation, infection, and tissue overgrowth on the surface of the implanted device. Over the last 50 years, much has been learned about these device failures and attempts have been made to prevent failures using (1) alternative systemic drug therapies, (2) surface modifications on the device, or (3) a combination of both approaches.

"Despite efforts to improve the efficacy of body-contacting and implantable medical devices, the incompatibility of materials within human blood and tissue still causes serious complications in patients. Thus, systemic or regional drug therapies remain necessary (e.g., use of heparin for short-term anticoagulation applications). Most often, when these drugs are administered they produce a systemic response in the patient. Systemic responses can mask blood chemistry problems and lead to a greatly increased possibility of complications and morbidity. Research studies examining alternative mechanisms are ongoing, but there is not yet an FDA-approved alternative material that overcomes all the problems associated with body-material interactions and systemic drug therapies. As such, in clinical practice today, all implanted devices eventually fail.

"To approach the aforementioned shortcomings, it is worth considering the structure and function of the ideal blood-contacting material. Preferably this material would simultaneously inhibit multiple pathways of device complication (i.e., thrombosis, inflammation, cell proliferation and migration, restenosis as well as infection) but without causing systemic side effects of its own. Such a material strategy requires not only the identification of suitable therapeutic agent(s) with appropriate biological half-lives, but the approach also requires the material's architecture to be fabricated and tailored specifically to the needs of the clinical application. Thus, the approach to an ideal body-contacting material requires a biomaterial that can be systematically and dramatically tailored for use in a wide variety of devices while promising the simultaneous reduction in complicating factors. Currently, no material substrates exist that can be modified in such diverse ways without significantly altering the chemical, physical, or cytotoxicity properties of the material and, in turn, rendering the material unsuitable for clinical use. A modular biomaterial that can simultaneously reduce or eliminate thrombosis, inflammation, cell proliferation, and infection, and also attenuate normal tissue growth upon exposure to physiological fluid, such as blood, is paramount to improve and advance the efficacy of medical devices.

"Nitric oxide is a free radical that is produced naturally by the body in several ways. Among these processes, the release and function of NO in endothelial cells (EC) has been the most extensively studied. For example, the endothelial cells that line all blood vessel walls produce NO via nitric oxide synthase (NOS) by the oxidation of L-arginine. The continuous release of NO from the EC has been shown to contribute significantly to the exceptional thromboresistivity and vascular function of a healthy vessel. For thromboresistivity, NO released from the EC into the blood stream temporarily 'anesthetizes' any platelets that come close to the surface, preventing platelet adhesion and activation. In addition, NO prevents the formation of thrombi at sites of vascular injury and thus favors the dissolution of clot.

"At the same time, NO produced by the ECs also diffuses into the underlying smooth muscle cells and acts as a vasoregulatory molecule. Results of in vivo studies have demonstrated that NO inhibits neointimal hyperplasia and causes vasorelaxation of surrounding cells. Because of these findings, agents that release nitric oxide have already been suggested as a potential pharmacological strategy for reducing intimal hyperplasia following balloon angioplasty procedures. In addition, researchers have shown NO as an effector in wound healing mechanisms and as an important regulator of angiogenesis and revascularization. Furthermore NO has been implicated in the control of sepsis, the treatment of tumors, neurotransmission, bone growth, and reproduction.

"Despite the known uses of NO, NO materials that can be used clinically to release therapeutic amounts of NO at levels required to prevent thrombosis, restenosis, inflammation, and infection have not been reported. A primary problem with current approaches to incorporating NO therapeutic agents into medical devices is that the materials provide inadequate NO loading dosages. As a result, the currently available materials limit the length of time for useful NO fluxes to only a few days in most systems. While this may be suitable for some limited short-term medical applications, it is not viable for most implanted and blood-contacting medical devices. While this may be suitable for some limited short-term medical applications, it is not viable for most implanted and fluid-, tissue-, or cell-contacting medical devices, such as blood-contacting medical devices.

"A significant cause of this issue is the structure and type of compound substrate upon which the NO moiety is currently attached. These substrates are organic compounds that are chemically limited in their capacity for loading NO and their ability to be structurally modified. High degrees of modification in the organic substrates to attempt to increase the NO loading amounts often lead to major changes in the physical, chemical, and mechanical properties of the material and render the material unsuited for use in medical applications. Further, many of these organic substrates are prone to decomposition, especially under physiological conditions, which leads to significant cytotoxicity issues due to the leaching of the decomposition byproducts. Further modifications to eliminate these problems often result in other structural inadequacies that render them unsuitable for clinical applications. To overcome these fundamental limitations, NO materials are needed that (1) produce significantly high levels of NO for long periods of time and (2) allow systematic modification while maintaining the structural properties that make them suitable for clinical applications.

"There is a great need for a truly biocompatible material that minimizes biofouling and other deleterious side effects and simultaneously increases the lifetime of the medical device in a safe and efficacious manner. The result of such a material would decrease healthcare costs, improve the quality of care for patients, and decrease the time physicians spend repeating procedures.

"In addition, there is a need for effective methods for using the material to treat clinically relevant disorders which this disclosure encompasses. Finally, a need exists to develop the coating method that allows for applying the material in a range of thicknesses or as encapsulated particles to broaden the utility of the material as outlined in this disclosure."

Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "Disclosed herein is a modular biomaterial that accomplishes the properties mentioned above. Specifically, the approach focuses on the utilization of nitric oxide (NO) as a therapeutic agent capable of concurrently achieving many of the aims of an ideal physiological fluid-contacting material. Nitric oxide has been shown to regulate cell responses via biochemical, structural, and physical mechanisms. Among the naturally occurring compounds that could possibly be employed as a therapeutic agent, nitric oxide has been shown to simultaneously decrease platelet adhesion and aggregation (thrombosis), decrease smooth muscle cell migration and proliferation (intimal hyperplasia), and reduce infection and inflammation. Thus, due to its ability to singularly invoke multiple desirable therapeutic responses, NO is a broadly applicable molecule for the treatment of disease states.

"The present disclosure describes compounds comprised of a metal bound to organic linkers that are capable of overcoming biofouling or treating diseases, for example, but not limited to, by producing NO.

"The present disclosure describes the combination of metal organic compounds with and without secondary therapeutic agents that are capable of overcoming biofouling or treating diseases.

"The present disclosure describes compositions of compounds comprised of metals bound to organic linkers combined with another material or matrix such as a polymer.

"The present disclosure describes a number of methods of making the subject compositions.

"The present disclosure describes the use of these materials for the treatment of clinically relevant diseases or complications.

"The present disclosure describes the use of these materials as coatings and material compositions for fabricating medical devices.

"In one aspect the disclosure provides a method of producing nitric oxide comprising (i) providing a composition comprising a metal-organic framework, and (ii) exposing the composition to a nitric oxide-releasing compound to produce nitric oxide. In various embodiments, the aforementioned method is provided wherein the metal-organic framework has a repeating structure in 1-dimension, 2-dimensions, 3-dimensions, or a mixture thereof. In various embodiments, an aforementioned method is provided wherein the metal-organic framework comprises a polydentate organic linker.

"In various embodiments an aforementioned method is provided wherein the metal-organic framework comprises a polydentate organic linker having a formula I, II, III, IV, or V:

"##STR00001## wherein X.sup.1, X.sup.2, X.sup.4, X.sup.5, and X.sup.6 are each independently selected from the group consisting of NH.sub.2, CO.sub.2H, SH, nitrogen-containing heteroaromatic compounds, and nitrogen-containing heterocycles; X.sup.3 is selected from the group consisting of NH.sub.2, CO.sub.2H, SH, nitrogen-containing heteroaromatic compounds, nitrogen-containing heterocycles, C(.dbd.O)NHR', C(.dbd.O)OR', C(.dbd.O)SR', N(H)C(.dbd.O)R', OC(.dbd.O)R', and SC(.dbd.O)R'; R is selected from the group consisting of aromatic compounds, heteroaromatic compounds, cycloalkanes, and heterocycles, and R' is a therapeutic agent having one or more functional groups selected from the group consisting of NH.sub.2, OH, SH, C(.dbd.O)NH.sub.2, C(.dbd.O)OH, and C(.dbd.O)SH.

"In various embodiments an aforementioned method is provided wherein the metal-organic framework comprises a polydentate organic linker having a formula XXIV: R.sup.a--X.sup.7 XXIV; wherein X.sup.7 is selected from the group consisting of H, NH.sub.2, CO.sub.2H, SH, nitrogen-containing heteroaromatic compounds, nitrogen-containing heterocycles, C(.dbd.O)NHR', C(.dbd.O)OR', C(.dbd.O)SR', N(H)C(.dbd.O)R', OC(.dbd.O)R', and SC(.dbd.O)R'; R.sup.a is selected from the group consisting of heteroaromatic compounds and heterocycles; and R' is a therapeutic agent having one or more functional groups selected from the group consisting of NH.sub.2, OH, SH, C(.dbd.O)NH.sub.2, C(.dbd.O)OH, and C(.dbd.O)SH; with the proviso that when X.sup.7 is H, R.sup.a comprises at least two heteroatoms.

"In various embodiments an aforementioned method is provided wherein the metal-organic framework comprises a metal selected from the group consisting of copper, zinc, iron, cobalt, manganese, vanadium, molybdenum, tungsten, chromium, nickel, aluminum, and mixtures thereof. In various embodiments, the metal-organic framework comprises at least first and second metal atoms, and the oxidation state of the first metal atom is different from the oxidation state of the second metal atom.

"In various embodiments an aforementioned method is provided wherein the metal-organic framework comprises Cu.sub.3(1,3,5-benzenetricarboxylic acid).sub.2.

"In various embodiments an aforementioned method is provided wherein the metal-organic framework comprises metal atoms and polydentate organic linkers. In various embodiments an aforementioned method is provided wherein the metal-organic framework comprises at least two metal atoms and at least two molecules of a polydentate organic linker. In still other embodiments, an aforementioned method is provided wherein at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 metal items and at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 molecules of a polydentate organic linker are provided.

"In various embodiments an aforementioned method is provided wherein the metal-organic framework has a porous structure. In various embodiments, an aforementioned method is provided wherein the metal-organic framework has a porous structure comprising pores having an average size of about 5 .ANG. to about 500 .ANG. in diameter.

"In other embodiments an aforementioned method is provided wherein the nitric oxide-releasing compound comprises a functional group selected from the group consisting of S-nitrosothiol, diazeniumdiolate, nitrate, nitrite, nitroso, and nitrosyl.

"In various embodiments an aforementioned method is provided wherein the exposing step comprises contacting the composition with blood. In various embodiments an aforementioned method is provided wherein the nitric oxide-releasing compound is present in blood.

"In various embodiments an aforementioned method is provided wherein the compositions disclosed herein comprise one or more therapeutic agents. In various embodiments the compositions disclosed herein comprise one or more polymers.

"In various embodiments an aforementioned method is provided wherein the method further comprises administering the compositions disclosed herein in a sufficient amount to a patient in need thereof. In various embodiments an aforementioned method is provided wherein the method further comprises administering the compositions disclosed herein in a sufficient amount to a patient in need thereof to treat any number of diseases, disorders, or conditions. In various embodiments an aforementioned method is provided wherein the composition produces nitric oxide for an extended period of time.

"In another aspect the disclosure provides methods for producing nitric oxide comprising providing a composition comprising a metal-organic framework, wherein the metal-organic framework is covalently attached to a nitric oxide-releasing functional group. In various embodiments an aforementioned method is provided wherein the metal-organic framework has a repeating structure in 1-dimension, 2-dimensions, 3-dimensions, or a mixture thereof. In various embodiments an aforementioned method is provided wherein the nitric oxide-releasing functional group is selected from the group consisting of S-nitrosothiol, diazeniumdiolate, nitrate, nitrite, nitroso, and nitrosyl. In various embodiments an aforementioned method is provided wherein the metal-organic framework comprises a polydentate organic linker selected from the group consisting of

"##STR00002## In various embodiments, an aforementioned method is provided wherein the method further comprises contacting the composition with physiological fluids or with an aqueous buffer and light. In various embodiments an aforementioned method is provided wherein the composition produces nitric oxide for an extended period of time.

"In another aspect the disclosure provides nitric oxide-producing compositions comprising (i) a polymer and (ii) a metal-organic framework. In various embodiments the metal-organic framework has a repeating structure in 1-dimension, 2-dimensions, 3-dimensions, or a mixture thereof. In various embodiments, an aforementioned composition is provided wherein the metal-organic framework is covalently attached to a nitric oxide-releasing functional group. In various embodiments, an aforementioned composition is provided wherein the composition having a covalently attached nitric oxide-releasing functional group produces nitric oxide when contacted with physiological fluids or with an aqueous buffer and light. In various other embodiments an aforementioned composition is provided wherein the composition produces nitric oxide when exposed to a nitric oxide-releasing compound. In various embodiments an aforementioned composition is provided wherein the composition produces nitric oxide for an extended period of time. In various embodiments an aforementioned composition is provided wherein the polymer is selected from the group consisting of polyurethane (PU), polyesters, polyethers, silicones, silicates, poly(vinyl chloride) (PVC), acrylates, methacylates, dextran, synthetic rubber (cis-polyisoprene), polyvinyl acetate, Bakelite, polychloroprene (neoprene), nylon, polystyrene, polyethylene, polypropylene, polyacrylonitrile, polyvinyl butyral (PVB), poly(vinylidene chloride), fluorinated polymers, polytetrafluoroethylene (PTFE), and mixtures and copolymers thereof. In various embodiments an aforementioned composition is provided wherein the nitric oxide-releasing functional group is selected from the group consisting of S-nitrosothiol, diazeniumdiolate, nitrate, nitrite, nitroso, and nitrosyl. In various embodiments an aforementioned composition is provided wherein the nitric oxide-releasing compound comprises a functional group selected from the group consisting of S-nitrosothiol, diazeniumdiolate, nitrate, nitrite, nitroso, and nitrosyl.

"In another aspect the disclosure provides nitric oxide-producing coatings comprising (i) a polymer and (ii) a metal-organic framework. In various embodiments the metal-organic framework has a repeating structure in 1-dimension, 2-dimensions, 3-dimensions, or a mixture thereof. In various embodiments an aforementioned coating is provided wherein the metal-organic framework is covalently attached to a nitric oxide-releasing functional group. In various embodiments an aforementioned coating is provided wherein the coating comprising a metal-organic framework having a covalently attached nitric oxide-releasing functional group produces nitric oxide when contacted with physiological fluids or with an aqueous buffer and light. In various other embodiments an aforementioned coating is provided wherein the coating produces nitric oxide when exposed to a nitric oxide-releasing compound. In various embodiments an aforementioned coating is provided wherein the coating produces nitric oxide for an extended period of time. In various embodiments an aforementioned coating is provided wherein the polymer is selected from the group consisting of polyurethane (PU), polyesters, polyethers, silicones, silicates, poly(vinyl chloride) (PVC), acrylates, methacylates, dextran, synthetic rubber (cis-polyisoprene), polyvinyl acetate, Bakelite, polychloroprene (neoprene), nylon, polystyrene, polyethylene, polypropylene, polyacrylonitrile, polyvinyl butyral (PVB), poly(vinylidene chloride), fluorinated polymers, polytetrafluoroethylene (PTFE), and mixtures and copolymers thereof. In various embodiments the nitric oxide-releasing functional group is selected from the group consisting of S-nitrosothiol, diazeniumdiolate, nitrate, nitrite, nitroso, and nitrosyl. In various embodiments an aforementioned coating is provided wherein the nitric oxide-releasing compound comprises a functional group selected from the group consisting of S-nitrosothiol, diazeniumdiolate, nitrate, nitrite, nitroso, and nitrosyl.

"In another aspect the disclosure provides medical devices comprising a nitric oxide-producing coating comprising (i) a polymer and (ii) a metal-organic framework. In various embodiments the metal-organic framework has a repeating structure in 1-dimension, 2-dimensions, 3-dimensions, or a mixture thereof. In various embodiments an aforementioned medical device is provided wherein the metal-organic framework is covalently attached to a nitric oxide-releasing functional group. In various embodiments an aforementioned medical device is provided wherein the medical device comprises a metal-organic framework having a covalently attached nitric oxide-releasing functional group produces nitric oxide when contacted with physiological fluids or with an aqueous buffer and light. In various other embodiments an aforementioned medical device is provided wherein the medical device produces nitric oxide when exposed to a nitric oxide-releasing compound. In various embodiments an aforementioned medical device is provided wherein the medical device produces nitric oxide for an extended period of time. In various embodiments an aforementioned medical device is provided wherein the polymer is selected from the group consisting of polyurethane (PU), polyesters, polyethers, silicones, silicates, poly(vinyl chloride) (PVC), acrylates, methacylates, dextran, synthetic rubber (cis-polyisoprene), polyvinyl acetate, Bakelite, polychloroprene (neoprene), nylon, polystyrene, polyethylene, polypropylene, polyacrylonitrile, polyvinyl butyral (PVB), poly(vinylidene chloride), fluorinated polymers, polytetrafluoroethylene (PTFE), and mixtures and copolymers thereof. In various embodiments the nitric oxide-releasing functional group is selected from the group consisting of S-nitrosothiol, diazeniumdiolate, nitrate, nitrite, nitroso, and nitrosyl. In various embodiments an aforementioned medical device is provided wherein the nitric oxide-releasing compound comprises a functional group selected from the group consisting of S-nitrosothiol, diazeniumdiolate, nitrate, nitrite, nitroso, and nitrosyl."

For the URL and additional information on this patent, see: Reynolds, Melissa M.; Reynolds, Benjamin P.. Biocompatible Materials for Medical Devices. U.S. Patent Number 8771756, filed December 28, 2010, and published online on July 8, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8771756.PN.&OS=PN/8771756RS=PN/8771756

Keywords for this news article include: Anions, Polyenes, Chemistry, Chlorides, Hematology, Polyvinyls, Hyperplasia, Hydrocarbons, Inflammation, Legal Issues, Nitric Oxide, Therapeutics, Free Radicals, Nitrogen Oxides, S-Nitrosothiols, Vinyl Compounds, Hydrochloric Acid, Organic Chemicals, Vascular Diseases, Cell Proliferation, Sulfhydryl Compounds.

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Source: Obesity, Fitness & Wellness Week


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