News Column

Patent Issued for Implantable Medical Devices

July 22, 2014

By a News Reporter-Staff News Editor at Life Science Weekly -- A patent by the inventors O'Neill, Liam (Midleton, IE); O'Donoghue, John (Dungarvan, IE); O'Keeffe, Joe (Fermoy, IE); Dobbyn, Peter (Midleton, IE), filed on December 9, 2011, was published online on July 8, 2014, according to news reporting originating from Alexandria, Virginia, by NewsRx correspondents (see also Enbio Limited).

Patent number 8771782 is assigned to Enbio Limited (Dublin, IE).

The following quote was obtained by the news editors from the background information supplied by the inventors: "In general there are two plasma types, namely thermal equilibrium and non-isothermal equilibrium plasmas. Thermal equilibrium plasmas are typically hot with temperatures .about.10,000 K and are used in industry as plasma torches, jets and arcs for welding. These hot plasma systems are also used in thermal spray coating where they can be used to deposit metallic and ceramic coatings onto metal surfaces for applications as diverse as producing biocompatible hydroxyapatite coatings on medical implants to the deposition of protective coatings on gas turbine components. Despite the widespread use of thermal plasmas to produce biocompatible hydroxyapatite ceramic coatings, their applications are limited by the high thermal energy within these devices which prevent these devices from depositing temperature sensitive materials such as proteins, polysaccharides and other biomaterials.

"In contrast, non-isothermal plasmas are generally cool and can be employed in manufacturing processes including surface cleaning (removal of unwanted contaminants), etching (removal of bulk substrate material), activation (changing surface energies) and deposition of functional thin film coatings onto surfaces. Historically, these coating devices were limited to vacuum conditions and used only gas phase precursors to produce coatings. However, plasma systems have been widely used to modify surfaces to allow for subsequent attachment of biomolecules through traditional wet chemistry techniques, and this area has been extensively reviewed by Siow et al (Plasma Processes and Polymers, 2006, 3, pages 392-418).

"Recent years have seen the development of plasma devices that operate at atmospheric pressure and which can also produce functional coatings using gas phase monomers, and a typical example is seen in Allcock et al, Langmuir, 2007, 23, 8103-8107. However, the switch from vacuum systems to ambient pressure also allows for the use of precursors other than gas phase monomers in the production of thin films. U.S. Pat. No. 4,929,319 discloses a process for treating a plastic substrate in which a liquid aerosol is introduced into an atmospheric corona discharge while a flat plastic substrate is passed through the corona discharge.

"U.S. Pat. No. 7,455,892 discloses a method for producing a coating wherein a polymer forming material is atomized into a homogeneous atmospheric pressure plasma glow discharge in order to produce a polymeric coating on a substrate. The list of potential monomers disclosed includes numerous materials which are well known to polymerize under exposure to free radicals or UV radiation to produce a coating. These precursors typically contain vinyl, cyclic or other reactive groups.

"WO 2007/106212 discloses a plasma system which combines an atmospheric pressure plasma activation coupled to a vacuum deposition chamber in order to deposit a biomolecule on a surface. The idea of combing vacuum chambers and atmospheric pressure plasma jets into one system represents a complex engineering challenge.

"In traditional plasma polymerization systems, it is standard practice to use monomers that contain reactive groups that undergo free radical or ionic polymerization reactions and the presence of these groups allow the monomers to produce a dry, polymerized coatings without the use of high energy plasmas. It has been possible to plasma polymerize materials such as alkanes that do not possess reactive groups. However, this requires that the plasma is provided with sufficient energy to break chemical bonds within the monomers and this results in significant fragmentation and re-arrangement of the precursor molecules as summarized by Heyse et al (Plasma Processes and Polymers, 2007, 4, pg 145-157). As biomolecules, such as collagen, do not possess the reactive groups (e.g. vinyl) expected to take part in a low energy plasma induced polymerization, it is logical to conclude that in order to produce a coating from such a material, high energy plasma parameters would be required in order to induce bond breakage within the molecule. This would induce significant damage to the biomolecule and would be expected to render the molecule biologically inactive. Therefore, development has focused on ways to indirectly attach molecules to a plasma coated surface.

"One common method was to first deposit a plasma coating and then attach the biomolecules in a separate step via wet chemical techniques. However, this results in a multi-step process with high costs and there is therefore a requirement for a more rapid, single step approach using plasma technology. Alternatively, plasma systems have been used to deposit coatings onto which biomolecules can be subsequently attached in another multistep process. This area has been thoroughly reviewed by Kim Shyong Siow et al. in Plasma Processes and Polymers, 2006, Volume 3, pages 392-418.

"As most biomolecules do not possess vinyl groups or other chemical functionalities that would be expected to undergo free radical style polymerization reactions, it was previously believed that in order to form a plasma coating containing such molecules it was necessary to physically entrap these molecules within a polymer film formed from traditional plasma reactive monomers containing vinyl groups or equivalent chemistry. The biomolecule was therefore mixed with the reactive monomer within the plasma and as the reactive monomer underwent film forming reactions, this allowed the biomolecule to be physically entrapped within the growing coating, as described in WO2005/110626 and WO2005/106477. The downside of this process is that the coating would contain significant amounts of chemical polymers that are not biocompatible and can induce inflammatory responses in a biological setting.

"WO 2005/110626 describes the use of a non-thermal plasma device to convert a liquid aerosol containing an active agent and a reactive monomer into a dry coating which contains both a polymer (produced by polymerising the reactive monomer) and an active agent which is physically entrapped in the polymer coating. The patent specifically refers to the coating of medical implants and refers to the incorporation of a biopolymer (collagen) as an active agent. Similarly, WO 2005/106477 describes an atmospheric pressure non-thermal plasma process to deposit biomolecule containing coatings. The process involves the introduction of reactive monomers and biomolecules (proteins, sugars, physiologically active substances, biomimetic materials) into the plasma to produce a polymerised coating of the reactive monomer which entraps the active agent on a surface through the incorporation of the biomolecule into a polymer matrix

"WO 2010/105829 discloses a technology for the deposition of biomolecules using plasma wherein the biomolecules are introduced as a vapour into the plasma. The patent discloses the concept of spraying a solution into a chamber, evaporating the solvent and then plasma polymerising the evaporated biomolecule to form a coating on a surface. The patent description mentions the use of bioactive molecules (proteins, polysaccharides, etc.) onto various surfaces, including implantable devices.

"Argon plasma coagulation (APC) is also a well known technique used in medicine and US 2007/0225700 described typical applications of this technique. The APC systems use an argon plasma to alter tissue through a combination of protein coagulation and tissue dehydration. However, no care is taken to control which proteins are present in the coagulation region and the technique has never been applied to a medical implant."

In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "One embodiment disclosed herein is directed to overcoming precursor fragmentation induced by traditional plasma devices, and the use of these traditional plasma devices to directly deposit functional coatings from high molecular weight biomolecules.

"Another embodiment discloses the use of plasma devices for the deposition of biomolecules or living cells onto a surface of a substrate, such as conductive metal substrates, overcoming previous problems with the treatment of conductive metal substrates due to the formation of high energy arcs.

"Another embodiment discloses the use of plasma devices for the deposition of biomolecules or living cells, and/or pre-polymerised biopolymers that do not undergo polymerisation when exposed to traditional polymerisation systems such as free radicals or UV light. As these molecules already have large molecule weights, even a slight degree of coagulation results in a solid coating.

"Another embodiment provides a method of depositing only a biomolecule in the absence of a reactive monomer.

"Another embodiment describes the use of plasma devices for deposition of biomolecules, overcoming prior art problems such as where the deposition is limited to gas phase systems and requires heating of the precursor solution, which is likely to denature many biomolecules.

"Also disclosed herein are surface modification techniques that allow for a single step deposition of biomolecules and/or living cells onto a surface without the use of vacuum systems or additional reactive monomers. By introducing solutions comprising biomolecules into a non-thermal atmospheric pressure plasma, it is possible to create direct binding of the biomolecules to the implant surface. This does not involve polymerisation of the biomolecule, e.g., a biopolymer, but instead involves some cross-linking of the biopolymer strands with additional formation of bonds to the activated substrate surface. In effect, the plasma can be used to initiate coagulation of the biological materials to form a coating.

"Additionally, it is possible to achieve the deposition of living cells on an implant surface with or without the presence of additional biomolecules."

URL and more information on this patent, see: O'Neill, Liam; O'Donoghue, John; O'Keeffe, Joe; Dobbyn, Peter. Implantable Medical Devices. U.S. Patent Number 8771782, filed December 9, 2011, and published online on July 8, 2014. Patent URL:

Keywords for this news article include: Chemicals, Chemistry, Technology, Enbio Limited.

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Source: Life Science Weekly

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