US20060067976A1 - Formation of barrier layer - Google Patents
Formation of barrier layer Download PDFInfo
- Publication number
- US20060067976A1 US20060067976A1 US11/238,532 US23853205A US2006067976A1 US 20060067976 A1 US20060067976 A1 US 20060067976A1 US 23853205 A US23853205 A US 23853205A US 2006067976 A1 US2006067976 A1 US 2006067976A1
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- Prior art keywords
- oil
- medical device
- barrier layer
- biocompatible medical
- oil composition
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Definitions
- the present invention relates to barrier layers that are able to provide anti-adhesion, anti-inflammatory, and wound healing functionality, with the potential to deliver therapeutic agents to a targeted location, while adhering to a medical device, and more specifically the application of barrier layers to biocompatible mesh structures.
- Biocompatible medical film is often used in surgical settings.
- Seprafilm® a product of Genzyme Corporation of Cambridge, Mass.
- U.S. Pat. No. 5,017,229 is directed to a water insoluble, biocompatible gel that includes the reaction product of hyaluronic acid, a polyanionic polysaccharide, and an activating agent.
- the gel described in the '229 patent can be provided in the form of an adhesion prevention composition, such as a membrane or composition suitable for incorporation into a syringe.
- the gel is described as being able to form a film by being compressed or allowed to dehydrate. When modified with polysaccharide, the film forms the above-described Seprafilm® anti-adhesion or adhesion barrier product.
- Surgical meshes also can have anti-adhesion properties.
- PCT Application Publication No. WO 2004/028583 is directed to compositions, devices, and methods for maintaining or improving the integrity of body passageways following surgery or injury.
- the delivery devices can include one or more therapeutic agents provided with a mesh wrap.
- the mesh is most often constructed of a synthetic polymer material, such as polyethylene, polytetrafluoroethylene, and polypropylene, and can include a carrier having a therapeutic agent attached thereto or coated thereon.
- the mesh structure makes it easier to handle the device without the drawbacks of film, namely tearing and folding.
- PCT Application Publication No. WO 03/028622 is directed to a method of delivering drugs to a tissue using drug coated medical devices.
- the drug coated medical device is brought into contact with the target tissue or circulation and the drugs are quickly released onto the area surrounding the device in a short period of time after contact is made. The release of the drug may occur over a period of 30 seconds, 1 minute or 3 minutes.
- the carrier of the drug is a liposome.
- Other particles described as potential drug carriers include lipids, sugars, carbohydrates, proteins, and the like. The publication describes these carriers as having properties appropriate for a quick short term release of a drug combined with the carriers.
- barrier coating mesh In applying barriers to medical devices, such as surgical meshes, coverage and uniformity are important factors in the getting optimal performance out of the barrier coated mesh. If a mesh does not have proper coverage then there may be areas of the mesh that does not have proper barrier protection which can lead to all the problems typically associated with uncoated meshes. Similar problems can arise when the coating is not uniform. Non-uniform coatings can cause inconsistent interactions, especially when a therapeutic agent is being delivered. Ideally, the barrier should be uniform over the whole mesh so that dosage and interaction with tissue can be better controlled.
- a barrier layer having uniform consistent coverage is directed toward solutions to address this need.
- a method and device for applying a barrier to a medical device, such as a surgical mesh are provided that can produce uniform consistent coverage in a repeatable and controllable manner.
- a method of applying a barrier layer to a biocompatible medical device includes providing a biocompatible medical device such as a mesh structure, providing a reservoir of biological oil or oil composition, and motivating the biocompatible medical device through the reservoir of biological oil or oil composition using a roller mechanism.
- the method further includes removing excess biological oil or oil composition from the biocompatible medical device.
- a wiping surface can be provided which the mesh can be passed over after the mesh emerges from the reservoir of biological oil or oil composition.
- the method of claim further includes curing the oil or oil composition on the biocompatible medical device to form the barrier layer.
- Curing generally refers to thickening, hardening, or drying of a material brought about by heat, UV, reactive gases, or other chemical means.
- the barrier can be applied by completely immersing the biocompatible medical device in the oil or oil composition in the reservoir.
- the barrier can be applied using an applicator.
- a roller or sponge applicator can be used to apply the oil or oil composition in the reservoir.
- the biocompatible medical device is maintained in a substantially horizontal orientation as it emerges from the reservoir.
- the barrier layer includes at least one therapeutic agent component.
- the therapeutic agent component can include an agent selected from the group consisting of antioxidants, anti-inflammatory agents, anti-coagulant agents, drugs to alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissue growth stimulants, functional protein/factor delivery agents, anti-infective agents, imaging agents, anesthetic agents, chemotherapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, analgesics, prodrugs, and antiseptics.
- the biological oil or oil composition is configured to provide controlled release of the therapeutic agent component.
- the method further includes sterilizing the barrier layer and biocompatible medical device.
- suitable methods of sterilization include ethylene oxide, gamma radiation, gas plasma, e-beam, steam, and vaporized hydrogen peroxide (VHP).
- a device for applying a barrier layer to a biocompatible medical device.
- the device includes a reservoir for holding a biological oil or oil composition for application to a biocompatible medical device, and a roller mechanism configured to motivate the biocompatible medical device through the reservoir to apply a biological oil or oil composition to the biocompatible medical device.
- the device further includes a staging surface for feeding a biocompatible medical device through the device to apply a barrier layer to the biocompatible medical device.
- the staging surface can include a spring loaded ramp for maintaining contact between the biocompatible medical device and the roller mechanism.
- the device can maintain the biocompatible medical device in a substantially horizontal orientation as the barrier layer is applied.
- the device further includes a wiping bar for removing excess biological oil or oil composition from the biocompatible medical device after application of the biological oil or oil composition to the biocompatible medical device.
- the device further includes a biological oil or oil composition reserve for replenishing the reservoir.
- the reservoir can also have an applicator for applying biological oil or oil composition to the biocompatible medical device.
- an applicator for applying biological oil or oil composition to the biocompatible medical device.
- a roller or sponge applicator can be used to apply the oil or oil composition in the reservoir.
- the roller mechanism of the device can comprise a motorized drive roller.
- the roller mechanism can also be spring loaded to maintain contact with the biocompatible medical device.
- a method for applying a barrier layer to a biocompatible medical device using an applicator device.
- the method includes providing a device for applying a barrier layer to a biocompatible medical device, the device having a reservoir for holding a biological oil or oil composition for application to a biocompatible medical device and a roller mechanism configured to motivate the biocompatible medical device through the reservoir to apply a biological oil or oil composition to the biocompatible medical device and passing the biocompatible medical device through the device to apply a barrier layer to the biocompatible medical device.
- the method further includes removing excess biological oil or oil composition from the biocompatible medical device.
- the device can have a wiping surface which the mesh can be passed over after the mesh is passed through the reservoir of biological oil or oil composition after motivating the mesh through the reservoir of biological oil or oil composition.
- the method of claim further includes curing the oil or oil composition on the biocompatible medical device to form the barrier layer.
- the curing can be performed using heat, UV, reactive gases, or other chemical means.
- FIG. 1 is a diagrammatic illustration of a barrier layer realized as a stand alone film, according to one embodiment of the present invention
- FIGS. 2A, 2B , and 2 C are cross-sectional views of the barrier layer in accordance with one aspect of the present invention.
- FIGS. 3A, 3B , 3 C, 3 D, 3 E, and 3 F are diagrammatic views of the barrier layer in accordance with another aspect of the present invention.
- FIG. 4 is a flow chart illustrating a method of making the barrier layer of the present invention, in accordance with one embodiment of the present invention
- FIGS. 5A and 5B are perspective and cross-sectional views of the barrier layer in combination with a medical device, in accordance with one embodiment of the present invention.
- FIG. 6 is a flow chart illustrating a method of combining the barrier layer with a medical device, in accordance with one embodiment of the present invention
- FIG. 7 is a flow chart illustrating another variation of the method of FIG. 6 , in accordance with one embodiment of the present invention.
- FIG. 8 is a flow chart illustrating a method of applying a barrier layer to a surgical mesh, in accordance with one embodiment of the present invention.
- FIGS. 9A, 9B , and 9 C are diagrammatic views of a device for applying a barrier layer to a surgical mesh, in accordance with various embodiments of the present invention.
- the present invention relates to the provision of a barrier layer that can exhibit anti-inflammatory properties, non-inflammatory properties, and anti-adhesion properties, and corresponding method of making.
- the barrier layer can be its own medical device (i.e., a stand alone film), or the barrier layer can be combined with another medical device to provide anti-adhesion characteristics, in addition to improved healing and delivery of therapeutic agents.
- the barrier layer is generally formed of a naturally occurring oil, or an oil composition formed in part of a naturally occurring oil.
- the oil composition can include a therapeutic agent component, such as a drug or other bioactive agent.
- the barrier layer is implantable in a patient for short term or long term applications, and can include controlled release of the therapeutic agent.
- the barrier layer is a non-polymeric cross-linked gel derived at least in part from a fatty acid compound.
- cross-linked gel refers to a gel that is non-polymeric and is derived from an oil composition comprising molecules covalently cross-linked into a three-dimensional network by one or more of ester, ether, peroxide, and carbon-carbon bonds in a substantially random configuration.
- the oil composition comprises a fatty acid molecule, a glyceride, and combinations thereof.
- bio-absorbable generally refers to having the property or characteristic of being able to penetrate the tissue of a patient's body.
- bio-absorption occurs through a lipophilic mechanism.
- the bio-absorbable substance is soluble in the phospholipid bi-layer of cells of body tissue, and therefore impacts how the bio-absorbable substance penetrates into the cells.
- Biodegradable is generally defined as capable of being decomposed by biological agents, or capable of being broken down by microorganisms or biological processes, in a manner that does not result in cellular uptake of the biodegradable substance. Biodegradation thus relates to the breaking down and distributing of a substance through the patient's body, verses the penetration of the cells of the patient's body tissue.
- Biodegradable substances such as polymers, can cause inflammatory response due to either the parent substance or those substances formed during breakdown, and they may or may not be absorbed by tissues.
- Bio-absorbable substances break down into substances or components that do not cause an inflammatory response and can be consumed by the cells forming the body tissues.
- controlled release generally refers to the release of a biologically active agent in a predictable manner over the time period of weeks or months, as desired and predetermined upon formation of the biologically active agent on the medical device from which it is being released. Controlled release includes the provision of an initial burst of release upon implantation, followed by the predictable release over the aforementioned time period.
- oils With regard to the aforementioned oils, it is generally known that the greater the degree of unsaturation in the fatty acids the lower the melting point of a fat, and the longer the hydrocarbon chain the higher the melting point of the fat.
- a polyunsaturated fat thus, has a lower melting point, and a saturated fat has a higher melting point. Those fats having a lower melting point are more often oils at room temperature. Those fats having a higher melting point are more often waxes or solids at room temperature. Therefore, a fat having the physical state of a liquid at room temperature is an oil.
- polyunsaturated fats are liquid oils at room temperature
- saturated fats are waxes or solids at room temperature.
- Polyunsaturated fats are one of four basic types of fat derived by the body from food. Other fats include saturated fat, as well as monounsaturated fat and cholesterol. Polyunsaturated fats can be further composed of omega-3 fatty acids and omega-6 fatty acids. Under the convention of naming the unsaturated fatty acid according to the position of its first double bond of carbons, those fatty acids having their first double bond at the third carbon atom from the methyl end of the molecule are referred to as omega-3 fatty acids. Likewise, a first double bond at the sixth carbon atom is called an omega-6 fatty acid. There can be both monounsaturated and polyunsaturated omega fatty acids.
- Omega-3 and omega-6 fatty acids are also known as essential fatty acids because they are important for maintaining good health, despite the fact that the human body cannot make them on its own. As such, omega-3 and omega-6 fatty acids must be obtained from external sources, such as food. Omega-3 fatty acids can be further characterized as containing eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and alpha-linolenic acid (ALA). Both EPA and DHA are known to have anti-inflammatory effects and wound healing effects within the human body.
- EPA eicosapentaenoic acid
- DHA docosahexanoic acid
- ALA alpha-linolenic acid
- Oil that is hydrogenated becomes a waxy solid. Attempts have been made to convert the polyunsaturated oils into a wax or solid to allow the oil to adhere to a device for a longer period of time.
- One such approach is known as hydrogenation, which is a chemical reaction that adds hydrogen atoms to an unsaturated fat (oil) thus saturating it and making it solid at room temperature. This reaction requires a catalyst, such as a heavy metal, and high pressure. The resultant material forms a non-crosslinked semi-solid. Hydrogenation can reduce or eliminate omega-3 fatty acids, and any therapeutic effects (both anti-inflammatory and wound healing) they offer.
- polymers For long term controlled release applications, polymers, as previously mentioned, have been utilized in combination with a therapeutic agent. Such a combination provides a platform for the controlled long term release of the therapeutic agent from a medical device.
- polymers have been determined to themselves cause inflammation in body tissue. Therefore, the polymers often must include at least one therapeutic agent that has an anti-inflammatory effect to counter the inflammation caused by the polymer delivery agent.
- patients that receive a polymer-based implant must also follow a course of systemic anti-inflammatory therapy, to offset the inflammatory properties of the non-absorbable polymer.
- Typical anti-inflammatory agents are immunosupressants and systemic delivery of anti-inflammatory agents can sometimes lead to an additional medical complications, such as infection or sepsis, which can lead to long term hospitalization or death.
- Use of the non-polymeric cross-linked gel of the inventive coating described herein may negate the necessity of anti-inflammatory therapy, and the corresponding related risks described, because there is no inflammatory reaction to the oil barrier.
- oils and more specifically oils containing omega-3 fatty acids, have been utilized as a delivery agent for the short term uncontrolled release of a therapeutic agent, so that minimal or no curing is required.
- oils containing omega-3 fatty acids for combination with a therapeutic agent in a controlled release application that makes use of the therapeutic benefits of the omega-3 fatty acids.
- some heating of the omega-3 fatty acids to cure the oil can lessen the total therapeutic effectiveness of the omega-3 fatty acids, but not eliminate the therapeutic effectiveness.
- One characteristic that can remain after certain curing by heating methods is the non-inflammatory response of the tissue when exposed to the cured omega-3 fatty acid material.
- an oil containing omega-3 fatty acids can be heated for curing purposes, and still maintain some or even a majority of the therapeutic effectiveness of the omega-3 fatty acids.
- the therapeutic agent combined with the omega-3 fatty acid and cured with the omega-3 fatty acid can be rendered partially ineffective, the portion remaining of the therapeutic agent can, in accordance with the present invention, maintain pharmacological activity and in some cases be more effective than an equivalent quantity of agent delivered with other barrier or coating materials.
- vitamin E and the term alpha-tocopherol are intended to refer to the same or substantially similar substance, such that they are interchangeable and the use of one includes an implicit reference to both.
- vitamin E are such variations including but not limited to one or more of alpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol acetate, beta-tocopherol acetate, gamma-tocopherol acetate, delta-tocopherol acetate, alpha-tocotrienol acetate, beta-tocotrienol acetate, delta-tocotrienol acetate, gamma-tocotrienol acetate, alpha-tocopherol succinate, beta-tocop
- FIGS. 1 through 9 illustrate an example embodiment of a non-polymeric biological and physical oil barrier layer according to the present invention.
- FIGS. 1 through 9 illustrate an example embodiment of a non-polymeric biological and physical oil barrier layer according to the present invention.
- FIG. 1 illustrates a non-polymeric biological oil barrier layer 10 in accordance with one embodiment of the present invention.
- the barrier layer 10 is flexible, to the extent that it can be placed in a flat, curved, or rolled, configuration within a patient.
- the barrier layer 10 is implantable, for both short term and long term applications. Depending on the particular formulation of the barrier layer 10 , the barrier layer 10 will be present after implantation for a period of hours to days, or possibly months.
- the barrier layer 10 is formed of an oil component.
- the oil component can be either an oil, or an oil composition.
- the oil component can be a naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, or other oils having desired characteristics.
- One example embodiment of the present invention makes use of a fish oil in part because of the high content of omega-3 fatty acids, which provide healing support for damaged tissue, as discussed below.
- the fish oil also serves as an anti-adhesion agent.
- the fish oil maintains anti-inflammatory or non-inflammatory properties as well.
- the present invention is not limited to formation of the barrier layer with fish oil as the naturally occurring oil. However, the following description makes reference to the use of fish oil as one example embodiment. Other naturally occurring oils can be utilized in accordance with the present invention as described herein.
- fish oil fatty acid includes but is not limited to omega-3 fatty acid, fish oil fatty acid, free fatty acid, monoglycerides, diglycerides, triglycerides, ester of fatty acids, or a combination thereof.
- the fish oil fatty acid includes one or more of arachidic acid, gadoleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid or derivatives, analogs and pharmaceutically acceptable salts thereof.
- free fatty acid includes but is not limited to one or more of butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, analogs and pharmaceutically acceptable salts thereof.
- the naturally occurring oils, including fish oil are cured as described herein to form a hydrophobic cross-linked gel, creating the barrier layer 10 .
- FIG. 1 represents merely one embodiment of the barrier layer 10 .
- the barrier layer 10 serves as a biological oil barrier and, depending on degree of cure, can also serve as a physical barrier, as depicted.
- the biological oil barrier is represented by the application of the fatty acid based oil, such as fish oil, onto a medical device. Such a configuration provides a biological oil barrier layer that provides a non-inflammatory or anti-inflammatory barrier coating. Using a number of different methods as described below, the biological oil can be cured to create a non-polymeric cross-linked gel.
- the biological oil can be cured to the extent that the cells or pores of the mesh are substantially or completely bridged by the cured biological oil creating a physical barrier.
- a physical barrier provides anti-adhesive properties of the barrier as discussed herein. Additional embodiments can include the provision of the substantially cured oil forming the biological oil barrier layer with physical layer, and then a subsequent application of the biological oil as a top coat. This creates a more substantial biological oil barrier layer supported by the combination biological oil barrier layer and physical barrier layer.
- barrier layer 10 has anti-adhesion characteristics or properties.
- anti-adhesion what is meant is a characteristic whereby the incidence, extent, and severity of postoperative adhesions between different tissues and organs is reduced.
- the anti-adhesion characteristic results from the materials used to form the barrier layer 10 .
- the barrier layer 10 provides a lubricious and/or anti-adhesive surface against tissue.
- the barrier layer 10 itself, in its substantially cured configuration, can provide a physical anti-adhesion barrier between two sections of tissue, or the barrier layer 10 can form an anti-adhesion surface on a medical device, such as the mesh 40 .
- the use of the naturally occurring oil, such as fish oil, provides extra lubrication to the surface of the medical device, which helps to reduce injury.
- the biological oil barrier created by the fatty acid based oil derived barrier layer likewise provides anti-inflammatory and non-inflammatory properties, thus reducing the occurrence of inflammatory response and also adhesions due to inflammation.
- the oily surface of the barrier layer 10 provides the anti-adhesion characteristics.
- oils will have different anti-adhesive properties, and the oils can be modified to be more liquefied or more solid or waxy, as desired. Accordingly, the degree of anti-adhesive properties offered by the barrier layer 10 can vary.
- the modification of the oils from a more liquid physical state to a more solid, but still flexible, physical state is implemented through the curing process. As the oils are cured, especially in the case of fatty acid-based oils such as fish oil, cross-links form creating a gel. As the curing process is performed over increasing time durations and/or increasing temperature conditions or UV intensity, more cross-links form transitioning the gel from a relatively liquid gel to a relatively solid-like, but still flexible, gel structure.
- the barrier layer 10 is formed of the bio-absorbable material, such as naturally occurring fish oil, in accordance with the example embodiment described herein.
- the bio-absorbable properties of the naturally occurring oil enable the barrier layer 10 to be absorbed by the cells of the body tissue (i.e., bio-absorbable).
- the bio-absorbable barrier layer contains lipids, many of which originate as triglycerides. It has previously been demonstrated that triglyceride byproducts, such as partially hydrolyzed triglycerides and fatty acid molecules can integrate into cellular membranes and enhance the solubility of drugs into the cell.
- Whole triglycerides are known not to enhance cellular uptake as well as partially hydrolyzed triglycerides, because it is difficult for whole triglycerides to cross cell membranes due to their relatively larger molecular size. Vitamin E compounds can also integrate into cellular membranes resulting in decreased membrane fluidity and cellular uptake.
- fatty acids and cellular uptake inhibitors such as alpha-tocopherol can be used alone or in combination to provide an effective transport of a given compound to a given region or location. Both fatty acids and alpha-tocopherol are accommodated by the barrier layer of the present invention described herein. Accordingly, fatty acids and alpha-tocopherol can be combined in differing amounts and ratios to contribute to a barrier layer in a manner that provides control over the cellular uptake characteristics of the barrier layer and any therapeutic agents mixed therein.
- the amount of alpha-tocopherol can be varied in the barrier layer.
- Alpha-tocopherol is known to slow autoxidation in fish oil by reducing hydroperoxide formation, which results in a decrease in the amount of cross-linking in cured fish oil.
- alpha-tocopherol can be used to increase solubility of drugs in the fish oil forming the barrier layer.
- varying the amount of alpha-tocopherol present in the barrier layer can impact the resulting barrier layer.
- Alpha-tocopherol can actually protect the therapeutic drug during curing, which increases the resulting drug load in the barrier layer after curing.
- the increase of alpha-tocopherol in the barrier layer serves to slow and extend drug release due to the increased solubility of the drug in the alpha-tocopherol component of the barrier layer.
- This reflects the cellular uptake inhibitor functionality of alpha-tocopherol, in that the uptake of the drug is slowed and extended over time.
- the bio-absorbable nature of the barrier layer results in the barrier layer 10 being completely absorbed over time by the cells of the body tissue. There are no substances in the barrier layer, or break down products of the barrier layer, that induce an inflammatory response.
- the barrier layer 10 is generally composed of, or derived from, omega-3 fatty acids bound to triglycerides, potentially also including a mixture of free fatty acids and vitamin E (alpha-tocopherol). The triglycerides are broken down by lipases (enzymes) which result in free fatty acids that can than be transported across cell membranes. Subsequently, fatty acid metabolism by the cell occurs to metabolize any substances originating with the barrier layer.
- the bio-absorbable nature of the barrier layer of the present invention results in the barrier layer being absorbed over time, leaving only an underlying delivery or other medical device structure that is biocompatible. There is no foreign body inflammatory response to the bio-absorbable barrier layer.
- the present invention is bio-absorbable to the extent that the barrier layer 10 experiences the uptake into or through body tissues
- the exemplar oils are also lipid based oils.
- the lipid content of the oils provides a highly bio-absorbable barrier layer 10 . More specifically, there is a phospholipids layer in each cell of the body tissue.
- the fish oil, and equivalent oils contain lipids as well. There is a lipophilic action that results where the lipids are attracted by each other in an effort to escape the aqueous environment surrounding the lipids.
- a further aspect of the barrier layer 10 is that the specific type of oil can be varied, and can contain elements beneficial to healing.
- the barrier layer also provides a natural scaffold for cellular growth and remodeling with clinical applications in general surgery, spinal repair, orthopedic surgeries, tendon and ligament repairs, gynecological and pelvic surgeries, and nerve repair applications.
- the addition of therapeutic agents to the films used in these applications can be utilized for additional beneficial effects, such as pain relief or infection minimization.
- non-surgical applications include external wound care, such as a treatment for burns or skin ulcers, without therapeutics as a clean, non-permeable, non-adhesive, anti-inflammatory, non-inflammatory dressing, or with added therapeutics for additional beneficial effects.
- the film may also be used as a transdermal drug delivery patch with the addition of therapeutic agents to the film.
- the process of wound healing involves tissue repair in response to injury and it encompasses many different biologic processes, including epithelial growth and differentiation, fibrous tissue production and function, angiogenesis, and inflammation.
- the barrier layer formed of the cross-linked gel has been shown in an animal model not to produce an inflammatory response, but still provide excellent cellular overgrowth with little to no fibrous capsule formation. Accordingly, the barrier layer formed of the cross-linked gel provides an excellent material suitable for wound healing applications.
- the barrier layer 10 can contain therapeutic agents for delivery to the body tissue.
- Therapeutic agents have been delivered to a targeted location in a human utilizing a number of different methods in the past.
- agents may be delivered nasally, transdermally, intravenously, orally, or via other conventional methods. Delivery may vary by release rate (i.e., quick release or slow release). Delivery may also vary as to how the drug is administered. Specifically, a drug may be administered locally to a targeted area, or administered systemically.
- therapeutic agent(s) refers to a number of different drugs or agents available, as well as future agents that may be beneficial for use with the barrier layer of the present invention. Therapeutic agents can be added to the barrier layer 10 , and/or the medical device in combination with the barrier layer 10 as discussed herein.
- the therapeutic agent component can take a number of different forms including anti-oxidants, anti-inflammatory agents, anti-coagulant agents, drugs to alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissue growth stimulants, functional protein/factor delivery agents, anti-infective agents, anti-imaging agents, anesthetic agents, therapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, anti-septics, analgesics, prodrugs, and any additional desired therapeutic agents such as those listed in Table 1 below.
- NSAIDS dexamethazone, methylprednisolone
- leflunomide NSAIDS, ibuprofen, acetaminophen, hydrocortizone acetate, hydrocortizone sodium phosphate, macrophage-targeted bisphosphonates Growth Factor Angiopeptin, trapidil, suramin Antagonists Antiplatelet Agents Aspirin, dipyridamole, ticlopidine, clopidogrel, GP IIb/IIIa inhibitors, abcximab Anticoagulant Agents Bivalirudin, heparin (low molecular weight and unfractionated), wafarin, hirudin, enoxaparin, citrate Thrombolytic Agents Alteplase, reteplase, streptase, urokinase, TPA, citrate Drugs to Alter Lipid Fluvastatin, colestipol, lovastatin, atorvastatin, amlopidine Metabolism (e
- ACE Inhibitors Elanapril, fosinopril, cilazapril Antihypertensive Agents Prazosin, doxazosin Antiproliferatives and Cyclosporine, cochicine, mitomycin C, sirolimus Antineoplastics micophenonolic acid, rapamycin, everolimus, tacrolimus, paclitaxel, QP-2, actinomycin, estradiols, dexamethasone, methatrexate, cilostazol, prednisone, cyclosporine, doxorubicin, ranpirnas, troglitzon, valsart, pemirolast, C- MYC antisense, angiopeptin, vincristine, PCNA ribozyme, 2-chloro-deoxyadenosine Tissue growth stimulants Bone morphogeneic protein, fibroblast growth factor Promotion of hollow Alcohol, surgical sealant polymers, polyvinyl particles, polyvin
- therapeutic agents useful in the anti-restenosis realm include cerivastatin, cilostazol, fluvastatin, lovastatin, paclitaxel, pravastatin, rapamycin, a rapamycin carbohydrate derivative (for example as described in U.S. Patent Application Publication 2004/0235762), a rapamycin derivative (for example as described in U.S. Pat. No. 6,200,985), everolimus, seco-rapamycin, seco-everolimus, and simvastatin.
- the therapeutic agent is administered orally or intravenously to be systemically processed by the patient.
- an alternative to the systemic administration of a therapeutic agent is the use of a targeted local therapeutic agent delivery approach.
- the therapeutic agent is administered using a medical device or apparatus, directly by hand, or sprayed on the tissue, at a selected targeted tissue location of the patient that requires treatment.
- the therapeutic agent emits, or is otherwise delivered, from the medical device apparatus, and/or carrier, and is applied to the targeted tissue location.
- the local delivery of a therapeutic agent enables a more concentrated and higher quantity of therapeutic agent to be delivered directly at the targeted tissue location, without having broader systemic side effects.
- the therapeutic agent that escapes the targeted tissue location dilutes as it travels to the remainder of the patient's body, substantially reducing or eliminating systemic side effects.
- Targeted local therapeutic agent delivery using a medical device can be further broken into two categories, namely, short term and long term ranging generally within a matter of seconds or minutes to a few days or weeks to a number of months.
- the therapeutic agent must be combined with a delivery agent, or otherwise formed with a physical impediment as a part of the medical device, to slow the release of the therapeutic agent.
- Prior attempts to create films and drug delivery platforms such as in the field of stents, primarily make use of high molecular weight synthetic polymer based materials to provide the ability to better control the release of the therapeutic agent.
- the polymer in the platform releases the drug or agent at a predetermined rate once implanted at a location within the patient. Regardless of how much of the therapeutic agent would be most beneficial to the damaged tissue, the polymer releases the therapeutic agent based on properties of the polymer.
- the effect of the therapeutic agent is substantially local at the surface of the tissue making contact with the medical device having the coating. In some instances the effect of the therapeutic agent is further localized to the specific locations of, for example, stent struts pressed against the tissue location being treated.
- the barrier layer 10 of the present invention makes use of the natural oils to form a non-polymeric natural oil based therapeutic agent delivery platform, if desired. Furthermore, the barrier layer 10 can be formed in a manner that creates the potential for controlled long term release of a therapeutic agent, while still maintaining the benefits of the natural oil component of the barrier layer 10 .
- oil that is oxygenated becomes a waxy solid.
- One such approach applies the oil to the medical device and allows the oil to dry.
- the uptake of the therapeutic agent is facilitated by the delivery of the therapeutic agent to the cell membrane by the bio-absorbable barrier layer 10 .
- the therapeutic agent is not freely released into the body fluids, but rather, is delivered directly to the cells and tissue.
- the drugs were released at a rate regardless of the reaction or need for the drug on the part of the cells receiving the drug.
- the process for forming the barrier layer 10 can be tailored to avoid causing detrimental effects to the beneficial properties of the omega-3 fatty acids, or at least effects too detrimental to have any lasting effect. As described herein, certain properties of the fatty acids may lose their effectiveness, however other desired properties are maintained. If there is no concern for maintaining the beneficial effects, the curing and other steps leading to the formation of the barrier layer 10 can include steps that may reduce some of the beneficial properties of the omega-3 fatty acids, as understood by one of ordinary skill in the art. Example embodiments illustrating the formation and different configurations of the barrier layer 10 are provided herein.
- the barrier layer 10 of the present invention serves as a non-polymeric biological oil barrier layer and can also serve as a physical barrier layer if sufficiently cured.
- the barrier layer is formed of a non-polymeric cross-linked gel derived from fatty acids compounds.
- the fatty acids include omega-3 fatty acids when the oil utilized to form the barrier layer is fish oil or an analog or derivative thereof.
- autoxidation occurs with the absorption of oxygen into the fish oil to create hydroperoxides in an amount dependent upon the amount of unsaturated (C ⁇ C) sites in the fish oil.
- the (C ⁇ C) bonds are not consumed in the initial reaction.
- both the hydroperoxide and (C ⁇ C) bonds can undergo secondary reactions converting them into lower molecular weight secondary oxidation byproducts including aldehydes, ketones, alcohols, fatty acids, esters, lactones, ethers, and hydrocarbons.
- the barrier layer non-polymeric cross-linked gel derived from fatty acid compounds, such as those of fish oil includes a cross-linked structure of triglyceride and fatty acid molecules in addition to free and bound glycerol, monoglyceride, diglyceride, and triglyceride, fatty acid, anhydride, lactone, aliphatic peroxide, aldehyde, and ketone molecules.
- glycerol monoglyceride
- diglyceride diglyceride
- triglyceride fatty acid
- anhydride lactone
- aliphatic peroxide aldehyde
- ketone molecules aliphatic peroxide linkages
- the barrier layer degrades into fatty acid, short and long chain alcohol, and glyceride molecules, which are all non-inflammatory and likewise consumable by cells in the soft tissue to which the barrier layer is applied.
- the barrier layer is bio-absorbable.
- FIGS. 2A, 2B , and 2 C illustrate side views of multiple different embodiments of the barrier layer 10 when cured into a flexible cross-linked gel.
- a barrier layer 10 A is shown having two tiers, a first tier 20 and a second tier 22 .
- the first tier 20 and the second tier 22 as shown are formed of different materials.
- the different materials can be different forms of fish oil, different naturally occurring oils other than fish oil, or therapeutic components as will be discussed later herein.
- the different materials bind together to form the barrier layer 10 A.
- FIG. 2B shows a barrier layer 10 B having a first tier 24 , a second tier 26 , and a third tier 28 .
- each of the tiers 24 , 26 , and 28 is formed of the same material.
- the plurality of tiers indicates the ability to create a thicker barrier layer 10 if desired. The greater the number of tiers, the thicker the resulting film.
- the thickness of the barrier layer 10 can have an effect on the overall strength and durability of the barrier layer 10 . A thicker film is generally stronger and more durable. In addition, the thickness of the barrier layer 10 can also affect the duration of time that the barrier layer 10 lasts after implantation.
- a thicker barrier layer 10 provides more material to be absorbed by the body, and thus will last longer than a thinner barrier layer 10 .
- the thickness of the barrier layer 10 can vary both by varying the thickness of each tier 24 , 26 , and 28 , and by varying the number of tiers 24 , 26 , and 28 . Accordingly, the present invention is not limited to the particular layer combinations illustrated.
- FIG. 2C shows another barrier layer 10 C, having four tiers, a first tier 30 , a second tier 32 , a third tier 34 , and a fourth tier 36 .
- the first tier 30 and the third tier 34 are formed of the same material
- the second tier 32 and the fourth tier 36 are formed of a material different from each other and different form that of the first tier 30 and the third tier 34 .
- this embodiment illustrates the ability to change the number of tiers, as well as the material used to form each of the tiers 30 , 32 , 34 , and 36 .
- the different materials can be derived from different forms of fish oil, different naturally occurring oils other than fish oil, or therapeutic components as will be discussed later herein.
- FIGS. 3A through 3F show additional embodiments or configurations of the barrier layer 10 .
- the embodiments include barrier layer 10 D in a circular configuration, barrier layer 10 E in an oval configuration, barrier layer 10 F in a U-bend configuration, barrier layer 10 G in a square configuration having a circular aperture, barrier layer 10 H in a wave configuration, and barrier layer 10 D in an irregular shape configuration.
- Each of the configurations of the barrier layer 10 D through 10 I represent different types of configurations.
- the configurations illustrated are by no means the only possible configurations for the barrier layer 10 .
- One of ordinary skill in the art will appreciate that the specific shape or configuration of the barrier layer 10 can vary as desired.
- a more prevalent configuration is the rectangular or oblong configuration of FIG. 1 .
- FIGS. 3A through 3F illustrate a number of different alternative embodiments, and indicate some of the many possible configurations.
- FIG. 4 is a flowchart illustrating one example method for the formation of the barrier layer 10 .
- a surface is provided having a release agent (step 100 ).
- the surface can be prepared by the application of the release agent, or the release agent can be pre-existing.
- the release agent can be a number of different solutions, including for example, Teflon or polyvinyl alcohol (PVA).
- PVA polyvinyl alcohol
- the release agent can be applied in a number of different ways as well, including but not limited to spraying, dipping, coating, painting, and the like. It should be noted that the release agent can be applied to the surface immediately prior to the remaining steps or well in advance of the remaining steps, so long as when the remaining steps are executed there is a release agent on the surface.
- the oil component is applied to the surface on top of the release agent (step 102 ).
- the oil component can be a naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, or other oils having desired characteristics.
- the oil component can be an oil composition, meaning a composition containing oil in addition to other substances.
- the oil composition can be formed of the oil component in addition to a solvent and/or a preservative.
- Solvents can include a number of different alternatives, including ethanol or N-Methyl-2-Pyrrolidone (NMP).
- the preservative can also include a number of different alternatives, including vitamin E compounds.
- the solvent can be useful to alter the physical properties of the oil, as well as prepare the oil for combination with a therapeutic agent as described below.
- the preservative can also be useful in altering the physical properties of the oil component, as well as protecting some of the beneficial properties of the oil component during certain curing processes. Such beneficial properties include the healing and anti-inflammatory characteristics previously mentioned.
- the oil component can be combined with one or more therapeutic agents to form an oil composition.
- the therapeutic agent(s) can be added to the oil component prior to application to the surface, along with the oil component during application to the surface (including mixing with the oil component prior to application), or after the oil component has been applied (step 104 ).
- the different alternatives for adding the therapeutic agent(s) are determined in part based on the desired effect and in part on the particular therapeutic agent(s) being added. Some therapeutic agents may have reduced effect if present during a subsequent curing step. Some therapeutic agents may be more useful intermixed with the oil component to extend the release period, or applied to the surface of the oil component, resulting in a faster release because of increased exposure.
- the present invention is not limited to the specific combinations described, but is intended to anticipate all such possible variations for adding the therapeutic agent(s).
- the remaining 20% of therapeutic agent, combined with and delivered by the barrier can be efficacious in treating a medical disorder, and in some cases have a relatively greater therapeutic effect than the same quantity of agent delivered with a polymeric or other type of coating or barrier.
- This result can be modified with the variance of alpha-tocopherol (vitamin E compound) to protect the therapeutic agent during the curing process, and then slow and extend the delivery of the therapeutic agent during absorption of the barrier layer into the tissue.
- the oil component (or composition if mixed with other substances) is then hardened into the barrier layer 10 (step 106 ).
- the step of hardening can include hardening, or curing, such as by introduction of UV light, heat, oxygen or other reactive gases, chemical curing, or other curing or hardening method.
- the purpose of the hardening or curing is to transform the more liquid consistency of the oil component or oil composition into a more solid film or barrier layer, while still maintaining sufficient flexibility to allow bending and wrapping of the film or barrier layer as desired.
- the hardening process as described herein does not refer to or include the process of hydrogenation.
- the therapeutic agent(s) is added to the barrier layer 10 (step 108 ). Subsequently, the barrier layer 10 is removed from the surface (step 110 ). Once again, there is opportunity to apply a therapeutic agent(s) to the barrier layer 10 on one or both sides of the barrier layer 10 . If such therapeutic agent(s) is desired, the therapeutic agent(s) is applied (step 112 ).
- the additional therapeutic agent can also be applied in the form of a non-cured or minimally cured oil, such as fish oil. The oil can likewise include other therapeutic agents mixed therewith.
- the resulting structure of such an application forms the underlying barrier layer 10 that is cured to form the film, with a top coating of oil and potentially additional therapeutic agent layered on top.
- This structure enables the provision of a short term release of therapeutic from the oil top layer combined with a longer term release from the cured film, which takes more time to degrade.
- the barrier layer 10 is sterilized.
- the sterilization process can be implemented in a number of different ways. For example, sterilization can be implemented utilizing ethylene oxide, gamma radiation, E beam, steam, gas plasma, or vaporized hydrogen peroxide (VHP).
- VHP vaporized hydrogen peroxide
- One of ordinary skill in the art will appreciate that other sterilization processes can also be applied, and that those listed herein are merely examples of sterilization processes that result in a sterilization of the barrier layer 10 , preferably without having a detrimental effect on the barrier layer.
- the oil component or oil composition can be added multiple times to create multiple tiers in forming the barrier layer 10 .
- additional tiers of the oil component or oil composition can be added after steps 100 , 104 , 106 , 108 , 110 , or 112 .
- Different variations relating to when the oil is hardened and when other substances are added to the oil are possible in a number of different process configurations. Accordingly, the present invention is not limited to the specific sequence illustrated. Rather, different combinations of the basic steps illustrated are anticipated by the present invention.
- FIGS. 5A and 5B illustrate the barrier layer 10 and a medical device in the form of a mesh 40 .
- the barrier layer 10 and mesh 40 are shown in exploded view, while FIG. 5B shows the barrier layer 10 coupled with the mesh 40 .
- the mesh 40 is merely one example medical device that can be coupled with the barrier layer 10 .
- the coupling of the barrier layer 10 with the mesh 40 achieves such a device.
- the properties of the mesh 40 and the barrier layer 10 can vary. There may be a requirement for the mesh 40 to have one side, or a portion of a side, that has anti-adhesion properties for a period of several days. Alternatively, multiple sides of the mesh 40 may be required to have anti-adhesion properties. As such, the barrier layer 10 can be applied to all sides, or portions of sides, or portions of one side of the mesh 40 .
- the requirement may be for the anti-adhesion properties to last several weeks, or even longer. Accordingly, the thickness of the barrier layer 10 can be varied to achieve longer or shorter term anti-adhesion properties.
- the therapeutic agent(s) can be added to the barrier layer 10 to achieve the desired controlled release of the therapeutic agent after implantation. As previously described, combinations of cured oils top coated with lesser cured or non-cured oils and therapeutic agents can form the barrier layer 10 .
- the particular properties or characteristics of the mesh 40 are determined based on the desired use of the mesh 40 .
- a common implementation is for the mesh 40 to be formed of a bio-compatible material, such as polypropylene, however other bio-compatible materials can be utilized, such as a mesh formed of the same or similar substance as the barrier layer 10 (i.e., oil based).
- FIG. 6 is a flowchart illustrating one example method for forming the mesh 40 and barrier layer 10 combination.
- the medical device is provided (step 150 ).
- the medical device can be, for example, the mesh 40 .
- An example release agent for such an application is polyvinyl alcohol.
- the medical device is then combined with the barrier layer 10 (step 154 ).
- the combination with the barrier layer 10 can be implemented more efficiently by either applying the barrier layer 10 to the medical device, or placing the medical device on the barrier layer 10 .
- the mesh 40 can be placed on top of the barrier layer 10 , or the barrier layer 10 can be placed on top of the mesh 40 .
- the medical device and the barrier layer are then cured to create a bond (step 156 ).
- the curing process can be one of several known processes, including but not limited to applying heat, or UV light, or chemical curing, to cure the barrier layer. After curing, if there is any release agent present, the release agent is washed away using water, or some other washing agent (step 158 ).
- FIG. 7 is a flowchart illustrating another example method of forming a medical device with a barrier layer.
- a surface is prepared with a release agent, such as Teflon or PVA (step 170 ).
- the medical device is placed on the surface (step 172 ).
- the medical device is the mesh 40 .
- the oil component or oil composition is applied to the medical device (step 174 ).
- the oil component or oil composition is poured or sprayed onto the mesh 40 .
- the combined oil component/composition and mesh 40 are then cured (step 176 ) using methods such as application of heat, UV light, oxygen or other reactive gases, chemical cross-linker, or hardening processes, to form the barrier layer in combination with the mesh 40 .
- the combined barrier layer and mesh are then removed from the surface (step 178 ) and the release agent is washed away (step 180 ).
- a therapeutic agent can be added to the oil component or oil composition at any point along the process forming the combined barrier layer 10 and mesh 40 , including being a component of the oil composition. As discussed previously, consideration must be given as to whether the therapeutic agent may be affected by the curing process, or other aspects of the process.
- the formation of the oil composition can be done in accordance with different alternatives to the methods described.
- a preservative and/or compatibilizer such as Vitamin E can be mixed with the naturally occurring oil component to form the oil composition.
- a solvent can be mixed with a therapeutic agent, and then added to the naturally occurring oil to form the oil composition.
- the solvent can be chosen from a number of different alternatives, including ethanol or N-Methyl-2-Pyrrolidone (NMP). The solvent can later be removed with vacuum or heat.
- FIG. 8 is a flowchart of another embodiment for applying a barrier layer 10 , particularly a biological oil or oil composition, to a mesh 40 .
- a biocompatible medical device such as a mesh structure, is provided onto which the barrier layer is to be applied (step 190 ).
- a reservoir of biological oil or oil composition is also provided (step 192 ).
- the mesh is then passed through the reservoir using a roller mechanism (step 194 ).
- excess biological oil or oil composition may be removed from the mesh ( 196 ).
- the method can also include curing the oil or oil composition on the biocompatible mesh structure to form the barrier layer ( 198 ).
- FIG. 8 The methodology of FIG. 8 may be better understood if viewed in conjunction with exemplary embodiments of a device 200 for applying a barrier layer to a biological medical device shown in FIGS. 9A, 9B and 9 C.
- the device 200 has a reservoir 210 for holding a biological oil or oil composition for application to a biocompatible mesh structure 40 and a roller mechanism 220 configured to motivate the biocompatible mesh structure 40 through the reservoir 210 to apply a biological oil or oil composition to the biocompatible mesh structure 40 .
- the reservoir 210 holds the biological oil or oil composition to be applied to the mesh 40 .
- the biological oil or oil composition can include a therapeutic agent. Examples of suitable therapeutic agents are discussed above.
- the reservoir 210 can also have a reserve supply 212 of biological oil or oil composition that replenishes the reservoir 210 as the oil or oil composition is dispensed out onto the mesh 40 .
- the reserve supply 212 is a bottle that gravity feeds the reservoir 210 as needed.
- Controlling the amount of oil or oil composition in the reservoir is one way of controlling the coverage and uniformity of the barrier layer 10 on the mesh 40 .
- the reservoir is configured to allow the biocompatible mesh structure 40 to be completely submerged in the biological oil or oil composition during application. This allows for total coverage on all sides of the mesh 40 .
- the reservoir 210 may include an applicator 214 for applying the oil or oil composition to the mesh 40 . Suitable applicators include but are not limited to roller or sponge applicators.
- the mesh 40 is passed over (or under) the applicator wherein the oil or oil composition is applied via the applicator to only the side of the mesh 40 that comes into contact with the applicator.
- Other possible application techniques include spraying or pouring the oil over the mesh as the mesh 40 passes through the reservoir 210 .
- Other possible configurations and implementations will be apparent to one skilled in the art given the benefit of this disclosure.
- the rolling mechanism 220 provides a means for propelling the mesh as the mesh 40 is passed through the reservoir 210 (step 194 ).
- the roller mechanism 220 is positioned to be in contact with the mesh 40 so as to provide the motive force for the mesh 40 as it passes through the reservoir 210 .
- the roller mechanism 220 can be spring loaded 222 to maintain contact with the mesh 40 as the mesh 40 passes through the reservoir 210 .
- the roller mechanism 220 can be motorized 224 as seen in FIG. 9B .
- the motorized roller may also have variable speed control 226 . Controlling the rate in which the mesh 40 passes through the reservoir 210 is another method of controlling the uniformity and coverage of the barrier layer 10 .
- the roller mechanism can also have a wiper 228 to remove any oil or oil composition that may get onto the roller as the mesh 40 passes through the reservoir 210 .
- the wiper 228 is a rubber squeegee that wipes off any excess oil or oil composite on the roller and returns it to the reservoir 210 .
- Other possible configurations and implementations will be apparent to one skilled in the art given the benefit of this disclosure.
- the device 200 can be provided with a staging surface 230 for feeding the biocompatible mesh structure 40 through the device 200 to apply a barrier layer 10 to the biocompatible mesh structure 40 .
- the staging surface 230 provides a flat uniform surface for supporting the mesh 40 as it is passed through the device 200 .
- the staging surface 230 includes a spring loaded ramp 232 for maintaining contact between the mesh 40 and the rolling mechanism 220 as the mesh 40 is passed through the reservoir 210 .
- the embodiments of the device in FIGS. 9A, 9B and 9 C also includes feet 234 that can be adjusted provide a stable and level work surface. Other possible configurations and implementations will be apparent to one skilled in the art given the benefit of this disclosure.
- the biocompatible medical device is kept substantially horizontal when the mesh emerges the reservoir.
- two of the factors that the present method attempt to control are uniformity and coverage of the barrier layer 10 .
- One of the aspects of dealing with biological oil or oil compositions is the viscosity of the oil or oil composition.
- the viscosity of the oil or oil composition should be such as to allow the oil to flow on, into and through the structure of the mesh 40 as to adequately coat the mesh 40 . At such viscosity, pooling can occur if the mesh 40 is not maintained in a substantially horizontal orientation. By maintaining the mesh 40 in a substantially horizontal orientation, the viscosity of the oil or oil composition allows the oil or oil composition to spread and settle uniformly across the mesh 40 .
- the method of FIG. 8 further comprises removing excess biological oil or oil composition from the mesh ( 196 ).
- This can be accomplished by passing the biocompatible mesh structure 40 over a wiping surface 240 after motivating the mesh through the reservoir 210 of biological oil or oil composition.
- a goal of the present invention is to control uniformity and coverage of the barrier layer 10 on the mesh 40 . Too much oil or oil composition, like to little oil or oil composition, can adversely affect the uniformity and coverage of the barrier layer 10 .
- a wiping surface 240 in this embodiment a wiping bar, can be provided. After being passed through the reservoir 210 , the mesh 40 is passed over the wiping surface 240 to remove any excess oil or oil composition.
- the excess oil or oil composition falls onto the oil recovery surface 245 and is directed back into the reservoir 210 .
- the wiping surface 240 can also provide the additional benefit of spreading the oil or oil composition more uniformly across the mesh 40 as the mesh 40 is passed across the wiping surface 240 .
- a wiping bar is used because it does not possess any sharp edges that could scrape or otherwise damage the mesh 40 but can still function to remove excess oil or oil composition.
- Other possible configurations and implementations will be apparent to one skilled in the art given the benefit of this disclosure.
- the wiping surface 240 can also aid in maintaining the mesh 40 in a substantially horizontal orientation as the mesh 40 is transferred to a curing rack used in curing the oil or oil composition. Techniques for curing the oil or oil composition are discussed above. Likewise, sterilization, using the techniques discussed above, can be performed.
- the oil component or oil composition can be applied multiple times to create multiple tiers in forming the barrier layer 10 . If a thicker barrier layer 10 is desired, additional tiers of the oil component or oil composition can be added with additional passes through the reservoir 210 (step 194 ).
- Different variations relating to when the oil is hardened and when other substances are added to the oil are possible in a number of different process configurations. Accordingly, the present invention is not limited to the specific sequence illustrated. Rather, different combinations of the basic steps illustrated are anticipated by the present invention.
- the resulting barrier layer 10 can maintain its bio-absorbable characteristics if the therapeutic agent component is also bio-absorbable.
- the therapeutic agent component has some form of therapeutic or biological effect.
- the oil component or oil composition component can also have a therapeutic or biological effect.
- the barrier layer 10 (and its oil constituents) enable the cells of body tissue of a patient to absorb the barrier layer 10 itself, rather than breaking down the film and disbursing by-products of the film for ultimate elimination by the patient's body.
- the barrier layer 10 is formed of a naturally occurring oil, or composition including a naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, and the like.
- a naturally occurring oil such as fish oil, cod liver oil, cranberry oil, and the like.
- the naturally occurring oil can include the essential omega-3 fatty acids in accordance with several embodiments of the present invention.
- the present description makes use of the mesh 40 as an example of a medical device that can be combined with the barrier layer 10 of the present invention.
- the present invention is not limited to use with the mesh 40 .
- any number of other implantable medical devices, such as surgical patches, can be combined with the barrier layer 10 in accordance with the teachings of the present invention.
- the method and device of the present invention allows for the application of barrier layers having uniform consistent coverage in a repeatable and controllable manner.
- the mesh is passed through a reservoir of oil or oil composition using a roller mechanism.
- the coverage, and in some cases, dosage, of the barrier layer can be controlled. Once these factors are decided upon, the process can be repeated on additional medical devices or on the original medical device to produce additional tiers for the barrier layer.
Abstract
A barrier layer and corresponding method of making provide anti-inflammatory and anti-adhesion functionality for a medical device implantable in a patient. The barrier layer can be combined with a medical device structure to provide anti-adhesion characteristics, in addition to improved healing and anti-inflammatory response. The barrier layer is generally formed of a naturally occurring oil, or an oil composition formed in part of a naturally occurring oil, that is at least partially cured forming a cross-linked gel derived from at least one fatty acid compound. In addition, the oil composition can include a therapeutic agent component, such as a drug or other bioactive agent.
Description
- This application claims priority to, and the benefit of, co-pending U.S. Provisional Application No. 60/613808, filed Sep. 28, 2004, for all subject matter common to both applications. The disclosure of said provisional application is hereby incorporated by reference in its entirety. This application also relates to co-pending U.S. patent application Ser. No. ______ (Attorney Docket No. ATA-427), filed concurrently with this application on Sep. 28, 2005.
- The present invention relates to barrier layers that are able to provide anti-adhesion, anti-inflammatory, and wound healing functionality, with the potential to deliver therapeutic agents to a targeted location, while adhering to a medical device, and more specifically the application of barrier layers to biocompatible mesh structures.
- Biocompatible medical film is often used in surgical settings. For example, Seprafilm®, a product of Genzyme Corporation of Cambridge, Mass., is used in patients undergoing abdominal or pelvic laparotomy as an adjunct intended to reduce the incidence, extent, and severity of postoperative adhesions between different tissues and organs and implantable medical devices such as soft tissue support membranes and mesh.
- U.S. Pat. No. 5,017,229 is directed to a water insoluble, biocompatible gel that includes the reaction product of hyaluronic acid, a polyanionic polysaccharide, and an activating agent. The gel described in the '229 patent can be provided in the form of an adhesion prevention composition, such as a membrane or composition suitable for incorporation into a syringe. The gel is described as being able to form a film by being compressed or allowed to dehydrate. When modified with polysaccharide, the film forms the above-described Seprafilm® anti-adhesion or adhesion barrier product.
- However, such commercially available adhesion prevention and adhesion barrier products often are difficult to handle and apply to the targeted location due to their chemical make up and bio-dissolvable properties. The composition and structural properties of these bio-dissolvable products require that they be handled with dry hands or instruments, which can be difficult during most surgical intervention operations. Furthermore, many of these bio-dissolvable films are made intentionally to be thin to minimize tissue disruption and consequently end up being structurally weak (i.e., easily torn or folded during handling).
- Surgical meshes also can have anti-adhesion properties. PCT Application Publication No. WO 2004/028583 is directed to compositions, devices, and methods for maintaining or improving the integrity of body passageways following surgery or injury. The delivery devices can include one or more therapeutic agents provided with a mesh wrap. The mesh is most often constructed of a synthetic polymer material, such as polyethylene, polytetrafluoroethylene, and polypropylene, and can include a carrier having a therapeutic agent attached thereto or coated thereon. The mesh structure makes it easier to handle the device without the drawbacks of film, namely tearing and folding.
- Some of these film and mesh devices also include therapeutic agents in combination with the anti-adhesion properties. PCT Application Publication No. WO 03/028622 is directed to a method of delivering drugs to a tissue using drug coated medical devices. The drug coated medical device is brought into contact with the target tissue or circulation and the drugs are quickly released onto the area surrounding the device in a short period of time after contact is made. The release of the drug may occur over a period of 30 seconds, 1 minute or 3 minutes. In one embodiment described in the publication, the carrier of the drug is a liposome. Other particles described as potential drug carriers include lipids, sugars, carbohydrates, proteins, and the like. The publication describes these carriers as having properties appropriate for a quick short term release of a drug combined with the carriers.
- In applying barriers to medical devices, such as surgical meshes, coverage and uniformity are important factors in the getting optimal performance out of the barrier coated mesh. If a mesh does not have proper coverage then there may be areas of the mesh that does not have proper barrier protection which can lead to all the problems typically associated with uncoated meshes. Similar problems can arise when the coating is not uniform. Non-uniform coatings can cause inconsistent interactions, especially when a therapeutic agent is being delivered. Ideally, the barrier should be uniform over the whole mesh so that dosage and interaction with tissue can be better controlled.
- What is desired is a barrier layer having uniform consistent coverage. The present invention is directed toward solutions to address this need. In accordance with the present invention a method and device for applying a barrier to a medical device, such as a surgical mesh, are provided that can produce uniform consistent coverage in a repeatable and controllable manner.
- In accordance with one embodiment of the present invention, a method of applying a barrier layer to a biocompatible medical device is provided. The method includes providing a biocompatible medical device such as a mesh structure, providing a reservoir of biological oil or oil composition, and motivating the biocompatible medical device through the reservoir of biological oil or oil composition using a roller mechanism.
- In accordance with certain aspects of the present invention, the method further includes removing excess biological oil or oil composition from the biocompatible medical device. For example, a wiping surface can be provided which the mesh can be passed over after the mesh emerges from the reservoir of biological oil or oil composition.
- In accordance with other aspects of the present invention, the method of claim further includes curing the oil or oil composition on the biocompatible medical device to form the barrier layer. Curing with respect to the present invention generally refers to thickening, hardening, or drying of a material brought about by heat, UV, reactive gases, or other chemical means.
- In accordance with further aspects of the present invention, the barrier can be applied by completely immersing the biocompatible medical device in the oil or oil composition in the reservoir. Alternatively, the barrier can be applied using an applicator. For example, a roller or sponge applicator can be used to apply the oil or oil composition in the reservoir.
- In accordance with further aspects of the present invention, the biocompatible medical device is maintained in a substantially horizontal orientation as it emerges from the reservoir.
- In accordance with further aspects of the present invention, the barrier layer includes at least one therapeutic agent component. The therapeutic agent component can include an agent selected from the group consisting of antioxidants, anti-inflammatory agents, anti-coagulant agents, drugs to alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissue growth stimulants, functional protein/factor delivery agents, anti-infective agents, imaging agents, anesthetic agents, chemotherapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, analgesics, prodrugs, and antiseptics. In certain aspects the biological oil or oil composition is configured to provide controlled release of the therapeutic agent component.
- In accordance with further aspects of the present invention, the method further includes sterilizing the barrier layer and biocompatible medical device. Examples of suitable methods of sterilization include ethylene oxide, gamma radiation, gas plasma, e-beam, steam, and vaporized hydrogen peroxide (VHP).
- In accordance with one embodiment of the present invention, a device is provided for applying a barrier layer to a biocompatible medical device. The device includes a reservoir for holding a biological oil or oil composition for application to a biocompatible medical device, and a roller mechanism configured to motivate the biocompatible medical device through the reservoir to apply a biological oil or oil composition to the biocompatible medical device.
- In accordance with certain aspects of the present invention, the device further includes a staging surface for feeding a biocompatible medical device through the device to apply a barrier layer to the biocompatible medical device. The staging surface can include a spring loaded ramp for maintaining contact between the biocompatible medical device and the roller mechanism.
- In accordance with further aspects of the present invention, the device can maintain the biocompatible medical device in a substantially horizontal orientation as the barrier layer is applied.
- In accordance with further aspects of the present invention, the device further includes a wiping bar for removing excess biological oil or oil composition from the biocompatible medical device after application of the biological oil or oil composition to the biocompatible medical device.
- In accordance with further aspects of the present invention, the device further includes a biological oil or oil composition reserve for replenishing the reservoir. The reservoir can also have an applicator for applying biological oil or oil composition to the biocompatible medical device. For example, a roller or sponge applicator can be used to apply the oil or oil composition in the reservoir.
- In accordance with further aspects of the present invention, the roller mechanism of the device can comprise a motorized drive roller. The roller mechanism can also be spring loaded to maintain contact with the biocompatible medical device.
- In accordance with another embodiment of the present invention, a method is provided for applying a barrier layer to a biocompatible medical device using an applicator device. The method includes providing a device for applying a barrier layer to a biocompatible medical device, the device having a reservoir for holding a biological oil or oil composition for application to a biocompatible medical device and a roller mechanism configured to motivate the biocompatible medical device through the reservoir to apply a biological oil or oil composition to the biocompatible medical device and passing the biocompatible medical device through the device to apply a barrier layer to the biocompatible medical device.
- In accordance with certain aspects of the present invention, the method further includes removing excess biological oil or oil composition from the biocompatible medical device. For example, the device can have a wiping surface which the mesh can be passed over after the mesh is passed through the reservoir of biological oil or oil composition after motivating the mesh through the reservoir of biological oil or oil composition.
- In accordance with other aspects of the present invention, the method of claim further includes curing the oil or oil composition on the biocompatible medical device to form the barrier layer. The curing can be performed using heat, UV, reactive gases, or other chemical means.
- The aforementioned features and advantages, and other features and aspects of the present invention, will become better understood with regard to the following description and accompanying drawings, wherein:
-
FIG. 1 is a diagrammatic illustration of a barrier layer realized as a stand alone film, according to one embodiment of the present invention; -
FIGS. 2A, 2B , and 2C are cross-sectional views of the barrier layer in accordance with one aspect of the present invention; -
FIGS. 3A, 3B , 3C, 3D, 3E, and 3F are diagrammatic views of the barrier layer in accordance with another aspect of the present invention; -
FIG. 4 is a flow chart illustrating a method of making the barrier layer of the present invention, in accordance with one embodiment of the present invention; -
FIGS. 5A and 5B are perspective and cross-sectional views of the barrier layer in combination with a medical device, in accordance with one embodiment of the present invention; -
FIG. 6 is a flow chart illustrating a method of combining the barrier layer with a medical device, in accordance with one embodiment of the present invention; -
FIG. 7 is a flow chart illustrating another variation of the method ofFIG. 6 , in accordance with one embodiment of the present invention; -
FIG. 8 is a flow chart illustrating a method of applying a barrier layer to a surgical mesh, in accordance with one embodiment of the present invention; and -
FIGS. 9A, 9B , and 9C are diagrammatic views of a device for applying a barrier layer to a surgical mesh, in accordance with various embodiments of the present invention. - The present invention relates to the provision of a barrier layer that can exhibit anti-inflammatory properties, non-inflammatory properties, and anti-adhesion properties, and corresponding method of making. The barrier layer can be its own medical device (i.e., a stand alone film), or the barrier layer can be combined with another medical device to provide anti-adhesion characteristics, in addition to improved healing and delivery of therapeutic agents. The barrier layer is generally formed of a naturally occurring oil, or an oil composition formed in part of a naturally occurring oil. In addition, the oil composition can include a therapeutic agent component, such as a drug or other bioactive agent. The barrier layer is implantable in a patient for short term or long term applications, and can include controlled release of the therapeutic agent. As implemented herein, the barrier layer is a non-polymeric cross-linked gel derived at least in part from a fatty acid compound.
- It should be noted that the term cross-linked gel, as utilized herein with reference to the present invention, refers to a gel that is non-polymeric and is derived from an oil composition comprising molecules covalently cross-linked into a three-dimensional network by one or more of ester, ether, peroxide, and carbon-carbon bonds in a substantially random configuration. In various preferred embodiments, the oil composition comprises a fatty acid molecule, a glyceride, and combinations thereof.
- As utilized herein, the term “bio-absorbable” generally refers to having the property or characteristic of being able to penetrate the tissue of a patient's body. In certain embodiments of the present invention bio-absorption occurs through a lipophilic mechanism. The bio-absorbable substance is soluble in the phospholipid bi-layer of cells of body tissue, and therefore impacts how the bio-absorbable substance penetrates into the cells.
- It should be noted that a bio-absorbable substance is different from a biodegradable substance. Biodegradable is generally defined as capable of being decomposed by biological agents, or capable of being broken down by microorganisms or biological processes, in a manner that does not result in cellular uptake of the biodegradable substance. Biodegradation thus relates to the breaking down and distributing of a substance through the patient's body, verses the penetration of the cells of the patient's body tissue. Biodegradable substances, such as polymers, can cause inflammatory response due to either the parent substance or those substances formed during breakdown, and they may or may not be absorbed by tissues. Bio-absorbable substances break down into substances or components that do not cause an inflammatory response and can be consumed by the cells forming the body tissues.
- The phrase “controlled release” generally refers to the release of a biologically active agent in a predictable manner over the time period of weeks or months, as desired and predetermined upon formation of the biologically active agent on the medical device from which it is being released. Controlled release includes the provision of an initial burst of release upon implantation, followed by the predictable release over the aforementioned time period.
- With regard to the aforementioned oils, it is generally known that the greater the degree of unsaturation in the fatty acids the lower the melting point of a fat, and the longer the hydrocarbon chain the higher the melting point of the fat. A polyunsaturated fat, thus, has a lower melting point, and a saturated fat has a higher melting point. Those fats having a lower melting point are more often oils at room temperature. Those fats having a higher melting point are more often waxes or solids at room temperature. Therefore, a fat having the physical state of a liquid at room temperature is an oil. In general, polyunsaturated fats are liquid oils at room temperature, and saturated fats are waxes or solids at room temperature.
- Polyunsaturated fats are one of four basic types of fat derived by the body from food. Other fats include saturated fat, as well as monounsaturated fat and cholesterol. Polyunsaturated fats can be further composed of omega-3 fatty acids and omega-6 fatty acids. Under the convention of naming the unsaturated fatty acid according to the position of its first double bond of carbons, those fatty acids having their first double bond at the third carbon atom from the methyl end of the molecule are referred to as omega-3 fatty acids. Likewise, a first double bond at the sixth carbon atom is called an omega-6 fatty acid. There can be both monounsaturated and polyunsaturated omega fatty acids.
- Omega-3 and omega-6 fatty acids are also known as essential fatty acids because they are important for maintaining good health, despite the fact that the human body cannot make them on its own. As such, omega-3 and omega-6 fatty acids must be obtained from external sources, such as food. Omega-3 fatty acids can be further characterized as containing eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and alpha-linolenic acid (ALA). Both EPA and DHA are known to have anti-inflammatory effects and wound healing effects within the human body.
- Oil that is hydrogenated becomes a waxy solid. Attempts have been made to convert the polyunsaturated oils into a wax or solid to allow the oil to adhere to a device for a longer period of time. One such approach is known as hydrogenation, which is a chemical reaction that adds hydrogen atoms to an unsaturated fat (oil) thus saturating it and making it solid at room temperature. This reaction requires a catalyst, such as a heavy metal, and high pressure. The resultant material forms a non-crosslinked semi-solid. Hydrogenation can reduce or eliminate omega-3 fatty acids, and any therapeutic effects (both anti-inflammatory and wound healing) they offer.
- For long term controlled release applications, polymers, as previously mentioned, have been utilized in combination with a therapeutic agent. Such a combination provides a platform for the controlled long term release of the therapeutic agent from a medical device. However, polymers have been determined to themselves cause inflammation in body tissue. Therefore, the polymers often must include at least one therapeutic agent that has an anti-inflammatory effect to counter the inflammation caused by the polymer delivery agent. In addition, patients that receive a polymer-based implant must also follow a course of systemic anti-inflammatory therapy, to offset the inflammatory properties of the non-absorbable polymer. Typical anti-inflammatory agents are immunosupressants and systemic delivery of anti-inflammatory agents can sometimes lead to an additional medical complications, such as infection or sepsis, which can lead to long term hospitalization or death. Use of the non-polymeric cross-linked gel of the inventive coating described herein may negate the necessity of anti-inflammatory therapy, and the corresponding related risks described, because there is no inflammatory reaction to the oil barrier.
- In addition, some curing methods have been indicated to have detrimental effects on the therapeutic agent combined with the omega-3 fatty acid, making them partially or completely ineffective. As such, oils, and more specifically oils containing omega-3 fatty acids, have been utilized as a delivery agent for the short term uncontrolled release of a therapeutic agent, so that minimal or no curing is required. However, there are no known uses of oils containing omega-3 fatty acids for combination with a therapeutic agent in a controlled release application that makes use of the therapeutic benefits of the omega-3 fatty acids. Further, some heating of the omega-3 fatty acids to cure the oil can lessen the total therapeutic effectiveness of the omega-3 fatty acids, but not eliminate the therapeutic effectiveness. One characteristic that can remain after certain curing by heating methods is the non-inflammatory response of the tissue when exposed to the cured omega-3 fatty acid material. As such, an oil containing omega-3 fatty acids can be heated for curing purposes, and still maintain some or even a majority of the therapeutic effectiveness of the omega-3 fatty acids. In addition, although the therapeutic agent combined with the omega-3 fatty acid and cured with the omega-3 fatty acid can be rendered partially ineffective, the portion remaining of the therapeutic agent can, in accordance with the present invention, maintain pharmacological activity and in some cases be more effective than an equivalent quantity of agent delivered with other barrier or coating materials.
- It should be noted that as utilized herein to describe the present invention, the term vitamin E and the term alpha-tocopherol, are intended to refer to the same or substantially similar substance, such that they are interchangeable and the use of one includes an implicit reference to both. Further included in association with the term vitamin E are such variations including but not limited to one or more of alpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol acetate, beta-tocopherol acetate, gamma-tocopherol acetate, delta-tocopherol acetate, alpha-tocotrienol acetate, beta-tocotrienol acetate, delta-tocotrienol acetate, gamma-tocotrienol acetate, alpha-tocopherol succinate, beta-tocopherol succinate, gamma-tocopherol succinate, delta-tocopherol succinate, alpha-tocotrienol succinate, beta-tocotrienol succinate, delta-tocotrienol succinate, gamma-tocotrienol succinate, mixed tocopherols, vitamin E TPGS, derivatives, analogs and pharmaceutically acceptable salts thereof.
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FIGS. 1 through 9 , wherein like parts are designated by like reference numerals throughout, illustrate an example embodiment of a non-polymeric biological and physical oil barrier layer according to the present invention. Although the present invention will be described with reference to the example embodiments illustrated in the figures, it should be understood that many alternative forms can embody the present invention. One of ordinary skill in the art will additionally appreciate different ways to alter the parameters of the embodiments disclosed, such as the size, shape, or type of elements or materials, in a manner still in keeping with the spirit and scope of the present invention. -
FIG. 1 illustrates a non-polymeric biologicaloil barrier layer 10 in accordance with one embodiment of the present invention. Thebarrier layer 10 is flexible, to the extent that it can be placed in a flat, curved, or rolled, configuration within a patient. Thebarrier layer 10 is implantable, for both short term and long term applications. Depending on the particular formulation of thebarrier layer 10, thebarrier layer 10 will be present after implantation for a period of hours to days, or possibly months. - The
barrier layer 10 is formed of an oil component. The oil component can be either an oil, or an oil composition. The oil component can be a naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, or other oils having desired characteristics. One example embodiment of the present invention makes use of a fish oil in part because of the high content of omega-3 fatty acids, which provide healing support for damaged tissue, as discussed below. The fish oil also serves as an anti-adhesion agent. In addition, the fish oil maintains anti-inflammatory or non-inflammatory properties as well. The present invention is not limited to formation of the barrier layer with fish oil as the naturally occurring oil. However, the following description makes reference to the use of fish oil as one example embodiment. Other naturally occurring oils can be utilized in accordance with the present invention as described herein. - It should be noted that as utilized herein, the term fish oil fatty acid includes but is not limited to omega-3 fatty acid, fish oil fatty acid, free fatty acid, monoglycerides, diglycerides, triglycerides, ester of fatty acids, or a combination thereof. The fish oil fatty acid includes one or more of arachidic acid, gadoleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid or derivatives, analogs and pharmaceutically acceptable salts thereof. Furthermore, as utilized herein, the term free fatty acid includes but is not limited to one or more of butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, analogs and pharmaceutically acceptable salts thereof. The naturally occurring oils, including fish oil, are cured as described herein to form a hydrophobic cross-linked gel, creating the
barrier layer 10. - It should further be noted that
FIG. 1 represents merely one embodiment of thebarrier layer 10. Thebarrier layer 10 serves as a biological oil barrier and, depending on degree of cure, can also serve as a physical barrier, as depicted. The biological oil barrier is represented by the application of the fatty acid based oil, such as fish oil, onto a medical device. Such a configuration provides a biological oil barrier layer that provides a non-inflammatory or anti-inflammatory barrier coating. Using a number of different methods as described below, the biological oil can be cured to create a non-polymeric cross-linked gel. In the instance of the medical device taking the form of a surgical mesh, the biological oil can be cured to the extent that the cells or pores of the mesh are substantially or completely bridged by the cured biological oil creating a physical barrier. With such a configuration there remains some biological oil that is not cured but is interdispersed within the cured oil and maintains the biological oil barrier layer as well. Thus, substantial curing creates both a biological oil barrier layer and a physical barrier. The physical barrier provides anti-adhesive properties of the barrier as discussed herein. Additional embodiments can include the provision of the substantially cured oil forming the biological oil barrier layer with physical layer, and then a subsequent application of the biological oil as a top coat. This creates a more substantial biological oil barrier layer supported by the combination biological oil barrier layer and physical barrier layer. - One aspect of the
barrier layer 10 mentioned above is that it has anti-adhesion characteristics or properties. By anti-adhesion, what is meant is a characteristic whereby the incidence, extent, and severity of postoperative adhesions between different tissues and organs is reduced. The anti-adhesion characteristic results from the materials used to form thebarrier layer 10. - More specifically, the
barrier layer 10 provides a lubricious and/or anti-adhesive surface against tissue. Thebarrier layer 10 itself, in its substantially cured configuration, can provide a physical anti-adhesion barrier between two sections of tissue, or thebarrier layer 10 can form an anti-adhesion surface on a medical device, such as themesh 40. The use of the naturally occurring oil, such as fish oil, provides extra lubrication to the surface of the medical device, which helps to reduce injury. The biological oil barrier created by the fatty acid based oil derived barrier layer likewise provides anti-inflammatory and non-inflammatory properties, thus reducing the occurrence of inflammatory response and also adhesions due to inflammation. The oily surface of thebarrier layer 10 provides the anti-adhesion characteristics. One of ordinary skill in the art will appreciate that different oils will have different anti-adhesive properties, and the oils can be modified to be more liquefied or more solid or waxy, as desired. Accordingly, the degree of anti-adhesive properties offered by thebarrier layer 10 can vary. The modification of the oils from a more liquid physical state to a more solid, but still flexible, physical state is implemented through the curing process. As the oils are cured, especially in the case of fatty acid-based oils such as fish oil, cross-links form creating a gel. As the curing process is performed over increasing time durations and/or increasing temperature conditions or UV intensity, more cross-links form transitioning the gel from a relatively liquid gel to a relatively solid-like, but still flexible, gel structure. - Another aspect of the present invention is that the
barrier layer 10 is formed of the bio-absorbable material, such as naturally occurring fish oil, in accordance with the example embodiment described herein. The bio-absorbable properties of the naturally occurring oil enable thebarrier layer 10 to be absorbed by the cells of the body tissue (i.e., bio-absorbable). In example embodiments of the present invention, the bio-absorbable barrier layer contains lipids, many of which originate as triglycerides. It has previously been demonstrated that triglyceride byproducts, such as partially hydrolyzed triglycerides and fatty acid molecules can integrate into cellular membranes and enhance the solubility of drugs into the cell. Whole triglycerides are known not to enhance cellular uptake as well as partially hydrolyzed triglycerides, because it is difficult for whole triglycerides to cross cell membranes due to their relatively larger molecular size. Vitamin E compounds can also integrate into cellular membranes resulting in decreased membrane fluidity and cellular uptake. - Compounds that move too rapidly through a tissue may not be effective in providing a sufficiently concentrated dose in a region of interest. Conversely, compounds that do not migrate in a tissue may never reach the region of interest. Cellular uptake enhancers such as fatty acids and cellular uptake inhibitors such as alpha-tocopherol can be used alone or in combination to provide an effective transport of a given compound to a given region or location. Both fatty acids and alpha-tocopherol are accommodated by the barrier layer of the present invention described herein. Accordingly, fatty acids and alpha-tocopherol can be combined in differing amounts and ratios to contribute to a barrier layer in a manner that provides control over the cellular uptake characteristics of the barrier layer and any therapeutic agents mixed therein.
- For example, the amount of alpha-tocopherol can be varied in the barrier layer. Alpha-tocopherol is known to slow autoxidation in fish oil by reducing hydroperoxide formation, which results in a decrease in the amount of cross-linking in cured fish oil. In addition alpha-tocopherol can be used to increase solubility of drugs in the fish oil forming the barrier layer. Thus, varying the amount of alpha-tocopherol present in the barrier layer can impact the resulting barrier layer. Alpha-tocopherol can actually protect the therapeutic drug during curing, which increases the resulting drug load in the barrier layer after curing. Furthermore, with certain therapeutic drugs, the increase of alpha-tocopherol in the barrier layer serves to slow and extend drug release due to the increased solubility of the drug in the alpha-tocopherol component of the barrier layer. This reflects the cellular uptake inhibitor functionality of alpha-tocopherol, in that the uptake of the drug is slowed and extended over time.
- It should further be emphasized that the bio-absorbable nature of the barrier layer results in the
barrier layer 10 being completely absorbed over time by the cells of the body tissue. There are no substances in the barrier layer, or break down products of the barrier layer, that induce an inflammatory response. Thebarrier layer 10 is generally composed of, or derived from, omega-3 fatty acids bound to triglycerides, potentially also including a mixture of free fatty acids and vitamin E (alpha-tocopherol). The triglycerides are broken down by lipases (enzymes) which result in free fatty acids that can than be transported across cell membranes. Subsequently, fatty acid metabolism by the cell occurs to metabolize any substances originating with the barrier layer. The bio-absorbable nature of the barrier layer of the present invention results in the barrier layer being absorbed over time, leaving only an underlying delivery or other medical device structure that is biocompatible. There is no foreign body inflammatory response to the bio-absorbable barrier layer. - Although the present invention is bio-absorbable to the extent that the
barrier layer 10 experiences the uptake into or through body tissues, in the specific embodiment described herein formed using naturally occurring oils, the exemplar oils are also lipid based oils. The lipid content of the oils provides a highlybio-absorbable barrier layer 10. More specifically, there is a phospholipids layer in each cell of the body tissue. The fish oil, and equivalent oils, contain lipids as well. There is a lipophilic action that results where the lipids are attracted by each other in an effort to escape the aqueous environment surrounding the lipids. - A further aspect of the
barrier layer 10 is that the specific type of oil can be varied, and can contain elements beneficial to healing. The barrier layer also provides a natural scaffold for cellular growth and remodeling with clinical applications in general surgery, spinal repair, orthopedic surgeries, tendon and ligament repairs, gynecological and pelvic surgeries, and nerve repair applications. The addition of therapeutic agents to the films used in these applications can be utilized for additional beneficial effects, such as pain relief or infection minimization. In addition, non-surgical applications include external wound care, such as a treatment for burns or skin ulcers, without therapeutics as a clean, non-permeable, non-adhesive, anti-inflammatory, non-inflammatory dressing, or with added therapeutics for additional beneficial effects. The film may also be used as a transdermal drug delivery patch with the addition of therapeutic agents to the film. - The process of wound healing involves tissue repair in response to injury and it encompasses many different biologic processes, including epithelial growth and differentiation, fibrous tissue production and function, angiogenesis, and inflammation. The barrier layer formed of the cross-linked gel has been shown in an animal model not to produce an inflammatory response, but still provide excellent cellular overgrowth with little to no fibrous capsule formation. Accordingly, the barrier layer formed of the cross-linked gel provides an excellent material suitable for wound healing applications.
- Another aspect of the
barrier layer 10 mentioned above is that thebarrier layer 10 can contain therapeutic agents for delivery to the body tissue. Therapeutic agents have been delivered to a targeted location in a human utilizing a number of different methods in the past. For example, agents may be delivered nasally, transdermally, intravenously, orally, or via other conventional methods. Delivery may vary by release rate (i.e., quick release or slow release). Delivery may also vary as to how the drug is administered. Specifically, a drug may be administered locally to a targeted area, or administered systemically. - As utilized herein, the phrase “therapeutic agent(s)” refers to a number of different drugs or agents available, as well as future agents that may be beneficial for use with the barrier layer of the present invention. Therapeutic agents can be added to the
barrier layer 10, and/or the medical device in combination with thebarrier layer 10 as discussed herein. The therapeutic agent component can take a number of different forms including anti-oxidants, anti-inflammatory agents, anti-coagulant agents, drugs to alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissue growth stimulants, functional protein/factor delivery agents, anti-infective agents, anti-imaging agents, anesthetic agents, therapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, anti-septics, analgesics, prodrugs, and any additional desired therapeutic agents such as those listed in Table 1 below.TABLE 1 CLASS EXAMPLES Antioxidants Alpha-tocopherol, lazaroid, probucol, phenolic antioxidant, resveretrol, AGI-1067, vitamin E Antihypertensive Agents Diltiazem, nifedipine, verapamil Antiinflammatory Agents Glucocorticoids (e.g. dexamethazone, methylprednisolone), leflunomide, NSAIDS, ibuprofen, acetaminophen, hydrocortizone acetate, hydrocortizone sodium phosphate, macrophage-targeted bisphosphonates Growth Factor Angiopeptin, trapidil, suramin Antagonists Antiplatelet Agents Aspirin, dipyridamole, ticlopidine, clopidogrel, GP IIb/IIIa inhibitors, abcximab Anticoagulant Agents Bivalirudin, heparin (low molecular weight and unfractionated), wafarin, hirudin, enoxaparin, citrate Thrombolytic Agents Alteplase, reteplase, streptase, urokinase, TPA, citrate Drugs to Alter Lipid Fluvastatin, colestipol, lovastatin, atorvastatin, amlopidine Metabolism (e.g. statins) ACE Inhibitors Elanapril, fosinopril, cilazapril Antihypertensive Agents Prazosin, doxazosin Antiproliferatives and Cyclosporine, cochicine, mitomycin C, sirolimus Antineoplastics micophenonolic acid, rapamycin, everolimus, tacrolimus, paclitaxel, QP-2, actinomycin, estradiols, dexamethasone, methatrexate, cilostazol, prednisone, cyclosporine, doxorubicin, ranpirnas, troglitzon, valsarten, pemirolast, C- MYC antisense, angiopeptin, vincristine, PCNA ribozyme, 2-chloro-deoxyadenosine Tissue growth stimulants Bone morphogeneic protein, fibroblast growth factor Promotion of hollow Alcohol, surgical sealant polymers, polyvinyl particles, 2- organ occlusion or octyl cyanoacrylate, hydrogels, collagen, liposomes thrombosis Functional Protein/Factor Insulin, human growth hormone, estradiols, nitric oxide, delivery endothelial progenitor cell antibodies Second messenger Protein kinase inhibitors targeting Angiogenic Angiopoetin, VEGF Anti-Angiogenic Endostatin Inhibitation of Protein Halofuginone, prolyl hydroxylase inhibitors, C-proteinase Synthesis/ECM formation inhibitors Antiinfective Agents Penicillin, gentamycin, adriamycin, cefazolin, amikacin, ceftazidime, tobramycin, levofloxacin, silver, copper, hydroxyapatite, vancomycin, ciprofloxacin, rifampin, mupirocin, RIP, kanamycin, brominated furonone, algae byproducts, bacitracin, oxacillin, nafcillin, floxacillin, clindamycin, cephradin, neomycin, methicillin, oxytetracycline hydrochloride, Selenium. Gene Delivery Genes for nitric oxide synthase, human growth hormone, antisense oligonucleotides Local Tissue perfusion Alcohol, H2O, saline, fish oils, vegetable oils, liposomes Nitric oxide Donor NCX 4016 - nitric oxide donor derivative of aspirin, Derivatives SNAP Gases Nitric oxide, compound solutions Imaging Agents Halogenated xanthenes, diatrizoate meglumine, diatrizoate sodium Anesthetic Agents Lidocaine, benzocaine Descaling Agents Nitric acid, acetic acid, hypochlorite Anti-Fibrotic Agents Interferon gamma -1b, Interluekin - 10 Immunosuppressive/Immu- Cyclosporine, rapamycin, mycophenolate motefil, nomodulatory Agents leflunomide, tacrolimus, tranilast, interferon gamma-1b, mizoribine Chemotherapeutic Agents Doxorubicin, paclitaxel, tacrolimus, sirolimus, fludarabine, ranpirnase Tissue Absorption Fish oil, squid oil, omega 3 fatty acids, vegetable oils, Enhancers lipophilic and hydrophilic solutions suitable for enhancing medication tissue absorption, distribution and permeation Anti-Adhesion Agents Hyaluronic acid, human plasma derived surgical sealants, and agents comprised of hyaluronate and carboxymethylcellulose that are combined with dimethylaminopropyl, ehtylcarbodimide, hydrochloride, PLA, PLGA Ribonucleases Ranpirnase Germicides Betadine, iodine, sliver nitrate, furan derivatives, nitrofurazone, benzalkonium chloride, benzoic acid, salicylic acid, hypochlorites, peroxides, thiosulfates, salicylanilide Antiseptics Selenium Analgesics Bupivicaine, naproxen, ibuprofen, acetylsalicylic acid - Some specific examples of therapeutic agents useful in the anti-restenosis realm include cerivastatin, cilostazol, fluvastatin, lovastatin, paclitaxel, pravastatin, rapamycin, a rapamycin carbohydrate derivative (for example as described in U.S. Patent Application Publication 2004/0235762), a rapamycin derivative (for example as described in U.S. Pat. No. 6,200,985), everolimus, seco-rapamycin, seco-everolimus, and simvastatin. With systemic administration, the therapeutic agent is administered orally or intravenously to be systemically processed by the patient. However, there are drawbacks to a systemic delivery of a therapeutic agent, one of which is that the therapeutic agent travels to all portions of the patient's body and can have undesired effects at areas not targeted for treatment by the therapeutic agent. Furthermore, large doses of the therapeutic agent only amplify the undesired effects at non-target areas. As a result, the amount of therapeutic agent that results in application to a specific targeted location in a patient may have to be reduced when administered systemically to reduce complications from toxicity resulting from a higher dosage of the therapeutic agent.
- Accordingly, an alternative to the systemic administration of a therapeutic agent is the use of a targeted local therapeutic agent delivery approach. With local delivery of a therapeutic agent, the therapeutic agent is administered using a medical device or apparatus, directly by hand, or sprayed on the tissue, at a selected targeted tissue location of the patient that requires treatment. The therapeutic agent emits, or is otherwise delivered, from the medical device apparatus, and/or carrier, and is applied to the targeted tissue location. The local delivery of a therapeutic agent enables a more concentrated and higher quantity of therapeutic agent to be delivered directly at the targeted tissue location, without having broader systemic side effects. With local delivery, the therapeutic agent that escapes the targeted tissue location dilutes as it travels to the remainder of the patient's body, substantially reducing or eliminating systemic side effects.
- Targeted local therapeutic agent delivery using a medical device can be further broken into two categories, namely, short term and long term ranging generally within a matter of seconds or minutes to a few days or weeks to a number of months. Typically, to achieve the long term delivery of a therapeutic agent, the therapeutic agent must be combined with a delivery agent, or otherwise formed with a physical impediment as a part of the medical device, to slow the release of the therapeutic agent.
- Prior attempts to create films and drug delivery platforms, such as in the field of stents, primarily make use of high molecular weight synthetic polymer based materials to provide the ability to better control the release of the therapeutic agent. Essentially, the polymer in the platform releases the drug or agent at a predetermined rate once implanted at a location within the patient. Regardless of how much of the therapeutic agent would be most beneficial to the damaged tissue, the polymer releases the therapeutic agent based on properties of the polymer. Accordingly, the effect of the therapeutic agent is substantially local at the surface of the tissue making contact with the medical device having the coating. In some instances the effect of the therapeutic agent is further localized to the specific locations of, for example, stent struts pressed against the tissue location being treated. These prior approaches can create the potential for a localized toxic effect.
- The
barrier layer 10 of the present invention, however, makes use of the natural oils to form a non-polymeric natural oil based therapeutic agent delivery platform, if desired. Furthermore, thebarrier layer 10 can be formed in a manner that creates the potential for controlled long term release of a therapeutic agent, while still maintaining the benefits of the natural oil component of thebarrier layer 10. - More specifically, it is known that oil that is oxygenated becomes a waxy solid. Attempts have been made to convert the polyunsaturated oils into a wax or solid to allow the oil to adhere to a device for a longer period of time. One such approach applies the oil to the medical device and allows the oil to dry.
- With the present invention, and in the field of soft tissue applications, and in part because of the lipophilic mechanism enabled by the bio-absorbable lipid based
barrier layer 10 of the present invention, the uptake of the therapeutic agent is facilitated by the delivery of the therapeutic agent to the cell membrane by thebio-absorbable barrier layer 10. Further, the therapeutic agent is not freely released into the body fluids, but rather, is delivered directly to the cells and tissue. In prior configurations using polymer based coatings, the drugs were released at a rate regardless of the reaction or need for the drug on the part of the cells receiving the drug. - In addition, when the oil provided to form the
barrier layer 10 is a naturally occurring oil containing the omega-3 fatty acids (including DHA and EPA), the process for forming thebarrier layer 10 can be tailored to avoid causing detrimental effects to the beneficial properties of the omega-3 fatty acids, or at least effects too detrimental to have any lasting effect. As described herein, certain properties of the fatty acids may lose their effectiveness, however other desired properties are maintained. If there is no concern for maintaining the beneficial effects, the curing and other steps leading to the formation of thebarrier layer 10 can include steps that may reduce some of the beneficial properties of the omega-3 fatty acids, as understood by one of ordinary skill in the art. Example embodiments illustrating the formation and different configurations of thebarrier layer 10 are provided herein. - To summarize, the
barrier layer 10 of the present invention serves as a non-polymeric biological oil barrier layer and can also serve as a physical barrier layer if sufficiently cured. In accordance with the example embodiments described herein, the barrier layer is formed of a non-polymeric cross-linked gel derived from fatty acids compounds. The fatty acids include omega-3 fatty acids when the oil utilized to form the barrier layer is fish oil or an analog or derivative thereof. As liquid fish oil is heated, autoxidation occurs with the absorption of oxygen into the fish oil to create hydroperoxides in an amount dependent upon the amount of unsaturated (C═C) sites in the fish oil. However, the (C═C) bonds are not consumed in the initial reaction. Concurrent with the formation of hydroperoxides is the isomerization of (C═C) double bonds from cis to trans in addition to double bond conjugation. It has been demonstrated that hydroperoxide formation increases with temperature. Heating of the fish oil allows for cross-linking between the fish oil unsaturated chains using a combination of peroxide (C—O—O—C), ether (C—O—C), and hydrocarbon (C—C) bridges. The formation of the cross-links results in gelation of the barrier layer after the (C═C) bonds have substantially isomerized into the trans configuration. The (C═C) bonds can also form C—C cross-linking bridges in the glyceride hydrocarbon chains using a Diels-Alder Reaction. In addition to solidifying the barrier layer through cross-linking, both the hydroperoxide and (C═C) bonds can undergo secondary reactions converting them into lower molecular weight secondary oxidation byproducts including aldehydes, ketones, alcohols, fatty acids, esters, lactones, ethers, and hydrocarbons. - Accordingly, the barrier layer non-polymeric cross-linked gel derived from fatty acid compounds, such as those of fish oil, includes a cross-linked structure of triglyceride and fatty acid molecules in addition to free and bound glycerol, monoglyceride, diglyceride, and triglyceride, fatty acid, anhydride, lactone, aliphatic peroxide, aldehyde, and ketone molecules. There are a substantial amount of ester bonds remaining after curing in addition to peroxide linkages forming the majority of the cross-links in the gel. The barrier layer degrades into fatty acid, short and long chain alcohol, and glyceride molecules, which are all non-inflammatory and likewise consumable by cells in the soft tissue to which the barrier layer is applied. Thus, the barrier layer is bio-absorbable.
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FIGS. 2A, 2B , and 2C illustrate side views of multiple different embodiments of thebarrier layer 10 when cured into a flexible cross-linked gel. InFIG. 2A , abarrier layer 10A is shown having two tiers, afirst tier 20 and asecond tier 22. Thefirst tier 20 and thesecond tier 22 as shown are formed of different materials. The different materials can be different forms of fish oil, different naturally occurring oils other than fish oil, or therapeutic components as will be discussed later herein. The different materials bind together to form thebarrier layer 10A. -
FIG. 2B shows abarrier layer 10B having afirst tier 24, asecond tier 26, and athird tier 28. In the embodiment shown, each of thetiers thicker barrier layer 10 if desired. The greater the number of tiers, the thicker the resulting film. The thickness of thebarrier layer 10 can have an effect on the overall strength and durability of thebarrier layer 10. A thicker film is generally stronger and more durable. In addition, the thickness of thebarrier layer 10 can also affect the duration of time that thebarrier layer 10 lasts after implantation. Athicker barrier layer 10 provides more material to be absorbed by the body, and thus will last longer than athinner barrier layer 10. One of ordinary skill in the art will appreciate that the thickness of thebarrier layer 10 can vary both by varying the thickness of eachtier tiers -
FIG. 2C shows anotherbarrier layer 10C, having four tiers, afirst tier 30, asecond tier 32, athird tier 34, and afourth tier 36. In this example embodiment, thefirst tier 30 and thethird tier 34 are formed of the same material, while thesecond tier 32 and thefourth tier 36 are formed of a material different from each other and different form that of thefirst tier 30 and thethird tier 34. Accordingly, this embodiment illustrates the ability to change the number of tiers, as well as the material used to form each of thetiers -
FIGS. 3A through 3F show additional embodiments or configurations of thebarrier layer 10. The embodiments includebarrier layer 10D in a circular configuration,barrier layer 10E in an oval configuration,barrier layer 10F in a U-bend configuration,barrier layer 10G in a square configuration having a circular aperture,barrier layer 10H in a wave configuration, andbarrier layer 10D in an irregular shape configuration. Each of the configurations of thebarrier layer 10D through 10I represent different types of configurations. The configurations illustrated are by no means the only possible configurations for thebarrier layer 10. One of ordinary skill in the art will appreciate that the specific shape or configuration of thebarrier layer 10 can vary as desired. A more prevalent configuration is the rectangular or oblong configuration ofFIG. 1 . However,FIGS. 3A through 3F illustrate a number of different alternative embodiments, and indicate some of the many possible configurations. -
FIG. 4 is a flowchart illustrating one example method for the formation of thebarrier layer 10. A surface is provided having a release agent (step 100). The surface can be prepared by the application of the release agent, or the release agent can be pre-existing. The release agent can be a number of different solutions, including for example, Teflon or polyvinyl alcohol (PVA). The release agent can be applied in a number of different ways as well, including but not limited to spraying, dipping, coating, painting, and the like. It should be noted that the release agent can be applied to the surface immediately prior to the remaining steps or well in advance of the remaining steps, so long as when the remaining steps are executed there is a release agent on the surface. - An oil component is applied to the surface on top of the release agent (step 102). As noted previously, the oil component can be a naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, or other oils having desired characteristics. In addition, the oil component can be an oil composition, meaning a composition containing oil in addition to other substances. For example, the oil composition can be formed of the oil component in addition to a solvent and/or a preservative. Solvents can include a number of different alternatives, including ethanol or N-Methyl-2-Pyrrolidone (NMP). The preservative can also include a number of different alternatives, including vitamin E compounds. One of ordinary skill in the art will appreciate that there are a number of different solvents and preservatives available for use with the oil component to form the oil composition, and as such the present invention is not limited to only those listed in the examples herein. The solvent can be useful to alter the physical properties of the oil, as well as prepare the oil for combination with a therapeutic agent as described below. The preservative can also be useful in altering the physical properties of the oil component, as well as protecting some of the beneficial properties of the oil component during certain curing processes. Such beneficial properties include the healing and anti-inflammatory characteristics previously mentioned.
- The oil component can be combined with one or more therapeutic agents to form an oil composition. Thus, if the added therapeutic benefit of a particular therapeutic agent or agents is desired, the therapeutic agent(s) can be added to the oil component prior to application to the surface, along with the oil component during application to the surface (including mixing with the oil component prior to application), or after the oil component has been applied (step 104). The different alternatives for adding the therapeutic agent(s) are determined in part based on the desired effect and in part on the particular therapeutic agent(s) being added. Some therapeutic agents may have reduced effect if present during a subsequent curing step. Some therapeutic agents may be more useful intermixed with the oil component to extend the release period, or applied to the surface of the oil component, resulting in a faster release because of increased exposure. One of ordinary skill in the art will appreciate that a number of different factors, such as those listed above in addition to others, can influence when in the process the therapeutic agent is added to the oil component, or the
barrier layer 10. Accordingly, the present invention is not limited to the specific combinations described, but is intended to anticipate all such possible variations for adding the therapeutic agent(s). - For example, if 80% of a therapeutic agent is rendered ineffective during curing, the remaining 20% of therapeutic agent, combined with and delivered by the barrier can be efficacious in treating a medical disorder, and in some cases have a relatively greater therapeutic effect than the same quantity of agent delivered with a polymeric or other type of coating or barrier. This result can be modified with the variance of alpha-tocopherol (vitamin E compound) to protect the therapeutic agent during the curing process, and then slow and extend the delivery of the therapeutic agent during absorption of the barrier layer into the tissue.
- The oil component (or composition if mixed with other substances) is then hardened into the barrier layer 10 (step 106). The step of hardening can include hardening, or curing, such as by introduction of UV light, heat, oxygen or other reactive gases, chemical curing, or other curing or hardening method. The purpose of the hardening or curing is to transform the more liquid consistency of the oil component or oil composition into a more solid film or barrier layer, while still maintaining sufficient flexibility to allow bending and wrapping of the film or barrier layer as desired. However, the hardening process as described herein does not refer to or include the process of hydrogenation.
- After the
barrier layer 10 has formed, another determination is made as to whether therapeutic agents should be applied to the film. If desired, the therapeutic agent(s) is added to the barrier layer 10 (step 108). Subsequently, thebarrier layer 10 is removed from the surface (step 110). Once again, there is opportunity to apply a therapeutic agent(s) to thebarrier layer 10 on one or both sides of thebarrier layer 10. If such therapeutic agent(s) is desired, the therapeutic agent(s) is applied (step 112). The additional therapeutic agent can also be applied in the form of a non-cured or minimally cured oil, such as fish oil. The oil can likewise include other therapeutic agents mixed therewith. The resulting structure of such an application forms theunderlying barrier layer 10 that is cured to form the film, with a top coating of oil and potentially additional therapeutic agent layered on top. This structure enables the provision of a short term release of therapeutic from the oil top layer combined with a longer term release from the cured film, which takes more time to degrade. - After application of the therapeutic agent(s), or after the
barrier layer 10 is removed from the surface, thebarrier layer 10 is sterilized. The sterilization process can be implemented in a number of different ways. For example, sterilization can be implemented utilizing ethylene oxide, gamma radiation, E beam, steam, gas plasma, or vaporized hydrogen peroxide (VHP). One of ordinary skill in the art will appreciate that other sterilization processes can also be applied, and that those listed herein are merely examples of sterilization processes that result in a sterilization of thebarrier layer 10, preferably without having a detrimental effect on the barrier layer. - It should be noted that the oil component or oil composition can be added multiple times to create multiple tiers in forming the
barrier layer 10. For example, if athicker barrier layer 10 is desired, additional tiers of the oil component or oil composition can be added aftersteps -
FIGS. 5A and 5B illustrate thebarrier layer 10 and a medical device in the form of amesh 40. InFIG. 5A , thebarrier layer 10 andmesh 40 are shown in exploded view, whileFIG. 5B shows thebarrier layer 10 coupled with themesh 40. Themesh 40 is merely one example medical device that can be coupled with thebarrier layer 10. In the instance of themesh 40, it can be useful to have one side of the mesh support a rougher surface to encourage tissue in-growth, and the other side of the mesh with an anti-adhesion, non-inflammatory, and anti-inflammatory surface to prevent the mesh from injuring surrounding tissue or causing inflammation. The coupling of thebarrier layer 10 with themesh 40 achieves such a device. - As understood by one of ordinary skill in the art, the properties of the
mesh 40 and thebarrier layer 10 can vary. There may be a requirement for themesh 40 to have one side, or a portion of a side, that has anti-adhesion properties for a period of several days. Alternatively, multiple sides of themesh 40 may be required to have anti-adhesion properties. As such, thebarrier layer 10 can be applied to all sides, or portions of sides, or portions of one side of themesh 40. - In addition, the requirement may be for the anti-adhesion properties to last several weeks, or even longer. Accordingly, the thickness of the
barrier layer 10 can be varied to achieve longer or shorter term anti-adhesion properties. In addition, there may be a desire to include a therapeutic agent to reduce inflammation, provide antibiotic therapy, or other therapeutic measures, in combination with the use of themesh 40. Accordingly, the therapeutic agent(s) can be added to thebarrier layer 10 to achieve the desired controlled release of the therapeutic agent after implantation. As previously described, combinations of cured oils top coated with lesser cured or non-cured oils and therapeutic agents can form thebarrier layer 10. - The particular properties or characteristics of the
mesh 40 are determined based on the desired use of themesh 40. A common implementation is for themesh 40 to be formed of a bio-compatible material, such as polypropylene, however other bio-compatible materials can be utilized, such as a mesh formed of the same or similar substance as the barrier layer 10 (i.e., oil based). -
FIG. 6 is a flowchart illustrating one example method for forming themesh 40 andbarrier layer 10 combination. The medical device is provided (step 150). The medical device can be, for example, themesh 40. - A determination is made as to whether a release agent should be added to the medical device to aid in removing the device from its location (e.g., on a surface) after combination with the
barrier layer 10. If a release agent is required, the release agent is applied to the medical device (step 152). An example release agent for such an application is polyvinyl alcohol. - The medical device is then combined with the barrier layer 10 (step 154). Depending on the particular medical device, the combination with the
barrier layer 10 can be implemented more efficiently by either applying thebarrier layer 10 to the medical device, or placing the medical device on thebarrier layer 10. For example, in the case of themesh 40, themesh 40 can be placed on top of thebarrier layer 10, or thebarrier layer 10 can be placed on top of themesh 40. - The medical device and the barrier layer are then cured to create a bond (step 156). The curing process can be one of several known processes, including but not limited to applying heat, or UV light, or chemical curing, to cure the barrier layer. After curing, if there is any release agent present, the release agent is washed away using water, or some other washing agent (step 158).
-
FIG. 7 is a flowchart illustrating another example method of forming a medical device with a barrier layer. A surface is prepared with a release agent, such as Teflon or PVA (step 170). The medical device is placed on the surface (step 172). In the example embodiment, the medical device is themesh 40. The oil component or oil composition is applied to the medical device (step 174). In the instance of themesh 40, the oil component or oil composition is poured or sprayed onto themesh 40. The combined oil component/composition andmesh 40 are then cured (step 176) using methods such as application of heat, UV light, oxygen or other reactive gases, chemical cross-linker, or hardening processes, to form the barrier layer in combination with themesh 40. The combined barrier layer and mesh are then removed from the surface (step 178) and the release agent is washed away (step 180). - As with the method of
FIG. 6 , if desired, a therapeutic agent can be added to the oil component or oil composition at any point along the process forming the combinedbarrier layer 10 andmesh 40, including being a component of the oil composition. As discussed previously, consideration must be given as to whether the therapeutic agent may be affected by the curing process, or other aspects of the process. - Furthermore, the formation of the oil composition can be done in accordance with different alternatives to the methods described. For example, prior to forming the
barrier layer 10, a preservative and/or compatibilizer, such as Vitamin E can be mixed with the naturally occurring oil component to form the oil composition. A solvent can be mixed with a therapeutic agent, and then added to the naturally occurring oil to form the oil composition. The solvent can be chosen from a number of different alternatives, including ethanol or N-Methyl-2-Pyrrolidone (NMP). The solvent can later be removed with vacuum or heat. -
FIG. 8 , is a flowchart of another embodiment for applying abarrier layer 10, particularly a biological oil or oil composition, to amesh 40. A biocompatible medical device, such as a mesh structure, is provided onto which the barrier layer is to be applied (step 190). A reservoir of biological oil or oil composition is also provided (step 192). The mesh is then passed through the reservoir using a roller mechanism (step 194). In certain embodiments, excess biological oil or oil composition may be removed from the mesh (196). In additional embodiments the method can also include curing the oil or oil composition on the biocompatible mesh structure to form the barrier layer (198). - The methodology of
FIG. 8 may be better understood if viewed in conjunction with exemplary embodiments of adevice 200 for applying a barrier layer to a biological medical device shown inFIGS. 9A, 9B and 9C. Thedevice 200 has areservoir 210 for holding a biological oil or oil composition for application to abiocompatible mesh structure 40 and aroller mechanism 220 configured to motivate thebiocompatible mesh structure 40 through thereservoir 210 to apply a biological oil or oil composition to thebiocompatible mesh structure 40. - The
reservoir 210 holds the biological oil or oil composition to be applied to themesh 40. In certain embodiments, the biological oil or oil composition can include a therapeutic agent. Examples of suitable therapeutic agents are discussed above. In certain embodiments thereservoir 210 can also have areserve supply 212 of biological oil or oil composition that replenishes thereservoir 210 as the oil or oil composition is dispensed out onto themesh 40. In the illustrative embodiment thereserve supply 212 is a bottle that gravity feeds thereservoir 210 as needed. - Controlling the amount of oil or oil composition in the reservoir is one way of controlling the coverage and uniformity of the
barrier layer 10 on themesh 40. For example, in the embodiment ofFIGS. 9A and 9B , the reservoir is configured to allow thebiocompatible mesh structure 40 to be completely submerged in the biological oil or oil composition during application. This allows for total coverage on all sides of themesh 40. In other embodiments, such as inFIG. 9C , when it is desired to coat only one side of themesh 40, thereservoir 210 may include anapplicator 214 for applying the oil or oil composition to themesh 40. Suitable applicators include but are not limited to roller or sponge applicators. In such embodiments themesh 40 is passed over (or under) the applicator wherein the oil or oil composition is applied via the applicator to only the side of themesh 40 that comes into contact with the applicator. Other possible application techniques include spraying or pouring the oil over the mesh as themesh 40 passes through thereservoir 210. Other possible configurations and implementations will be apparent to one skilled in the art given the benefit of this disclosure. - The
rolling mechanism 220 provides a means for propelling the mesh as themesh 40 is passed through the reservoir 210 (step 194). In certain embodiments theroller mechanism 220 is positioned to be in contact with themesh 40 so as to provide the motive force for themesh 40 as it passes through thereservoir 210. Theroller mechanism 220 can be spring loaded 222 to maintain contact with themesh 40 as themesh 40 passes through thereservoir 210. In some embodiments theroller mechanism 220 can be motorized 224 as seen inFIG. 9B . The motorized roller may also havevariable speed control 226. Controlling the rate in which themesh 40 passes through thereservoir 210 is another method of controlling the uniformity and coverage of thebarrier layer 10. The roller mechanism can also have a wiper 228 to remove any oil or oil composition that may get onto the roller as themesh 40 passes through thereservoir 210. In the embodiment ofFIG. 9B , the wiper 228 is a rubber squeegee that wipes off any excess oil or oil composite on the roller and returns it to thereservoir 210. Other possible configurations and implementations will be apparent to one skilled in the art given the benefit of this disclosure. - In certain embodiments, the
device 200 can be provided with astaging surface 230 for feeding thebiocompatible mesh structure 40 through thedevice 200 to apply abarrier layer 10 to thebiocompatible mesh structure 40. Thestaging surface 230 provides a flat uniform surface for supporting themesh 40 as it is passed through thedevice 200. In this embodiment, thestaging surface 230 includes a spring loadedramp 232 for maintaining contact between themesh 40 and therolling mechanism 220 as themesh 40 is passed through thereservoir 210. The embodiments of the device inFIGS. 9A, 9B and 9C also includesfeet 234 that can be adjusted provide a stable and level work surface. Other possible configurations and implementations will be apparent to one skilled in the art given the benefit of this disclosure. - In certain embodiments, the biocompatible medical device is kept substantially horizontal when the mesh emerges the reservoir. As mentioned above, two of the factors that the present method attempt to control are uniformity and coverage of the
barrier layer 10. One of the aspects of dealing with biological oil or oil compositions is the viscosity of the oil or oil composition. Ideally, the viscosity of the oil or oil composition should be such as to allow the oil to flow on, into and through the structure of themesh 40 as to adequately coat themesh 40. At such viscosity, pooling can occur if themesh 40 is not maintained in a substantially horizontal orientation. By maintaining themesh 40 in a substantially horizontal orientation, the viscosity of the oil or oil composition allows the oil or oil composition to spread and settle uniformly across themesh 40. - As mentioned above, in certain embodiments the method of
FIG. 8 further comprises removing excess biological oil or oil composition from the mesh (196). This can be accomplished by passing thebiocompatible mesh structure 40 over a wipingsurface 240 after motivating the mesh through thereservoir 210 of biological oil or oil composition. As mentioned above, a goal of the present invention is to control uniformity and coverage of thebarrier layer 10 on themesh 40. Too much oil or oil composition, like to little oil or oil composition, can adversely affect the uniformity and coverage of thebarrier layer 10. Thus, a wipingsurface 240, in this embodiment a wiping bar, can be provided. After being passed through thereservoir 210, themesh 40 is passed over the wipingsurface 240 to remove any excess oil or oil composition. The excess oil or oil composition falls onto theoil recovery surface 245 and is directed back into thereservoir 210. The wipingsurface 240 can also provide the additional benefit of spreading the oil or oil composition more uniformly across themesh 40 as themesh 40 is passed across the wipingsurface 240. In the example ofFIGS. 9A, 9B and 9C a wiping bar is used because it does not possess any sharp edges that could scrape or otherwise damage themesh 40 but can still function to remove excess oil or oil composition. Other possible configurations and implementations will be apparent to one skilled in the art given the benefit of this disclosure. - In some embodiments, wherein the method of
FIG. 8 includes curing the oil or oil composition on the biocompatible medical device to form the barrier layer (step 198) thewiping surface 240 can also aid in maintaining themesh 40 in a substantially horizontal orientation as themesh 40 is transferred to a curing rack used in curing the oil or oil composition. Techniques for curing the oil or oil composition are discussed above. Likewise, sterilization, using the techniques discussed above, can be performed. - In addition, it should again be noted that the oil component or oil composition can be applied multiple times to create multiple tiers in forming the
barrier layer 10. If athicker barrier layer 10 is desired, additional tiers of the oil component or oil composition can be added with additional passes through the reservoir 210 (step 194). Different variations relating to when the oil is hardened and when other substances are added to the oil are possible in a number of different process configurations. Accordingly, the present invention is not limited to the specific sequence illustrated. Rather, different combinations of the basic steps illustrated are anticipated by the present invention. - Depending on the type of therapeutic agent component added to the
barrier layer 10, the resultingbarrier layer 10 can maintain its bio-absorbable characteristics if the therapeutic agent component is also bio-absorbable. - The therapeutic agent component, as described herein, has some form of therapeutic or biological effect. The oil component or oil composition component can also have a therapeutic or biological effect. Specifically, the barrier layer 10 (and its oil constituents) enable the cells of body tissue of a patient to absorb the
barrier layer 10 itself, rather than breaking down the film and disbursing by-products of the film for ultimate elimination by the patient's body. - As previously stated, and in accordance with embodiments of the present invention, the
barrier layer 10 is formed of a naturally occurring oil, or composition including a naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, and the like. A characteristic of the naturally occurring oil is that the oil includes lipids, which contributes to the lipophilic action described later herein, that is helpful in the delivery of therapeutic agents to the cells of the body tissue. In addition, the naturally occurring oil can include the essential omega-3 fatty acids in accordance with several embodiments of the present invention. - It should also be noted that the present description makes use of the
mesh 40 as an example of a medical device that can be combined with thebarrier layer 10 of the present invention. However, the present invention is not limited to use with themesh 40. Instead, any number of other implantable medical devices, such as surgical patches, can be combined with thebarrier layer 10 in accordance with the teachings of the present invention. - The method and device of the present invention allows for the application of barrier layers having uniform consistent coverage in a repeatable and controllable manner. The mesh is passed through a reservoir of oil or oil composition using a roller mechanism. By controlling the amount of oil or oil composition, the application technique, and the speed of the roller mechanism motivating the mesh through the reservoir, the coverage, and in some cases, dosage, of the barrier layer can be controlled. Once these factors are decided upon, the process can be repeated on additional medical devices or on the original medical device to produce additional tiers for the barrier layer.
- Numerous modifications and alternative embodiments of the present invention will be apparent to those skilled in the art in view of the foregoing description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the best mode for carrying out the present invention. Details of the structure may vary substantially without departing from the spirit of the invention, and exclusive use of all modifications that come within the scope of the appended claims is reserved. It is intended that the present invention be limited only to the extent required by the appended claims and the applicable rules of law.
Claims (37)
1. A method of applying a barrier layer to a biocompatible medical device, the method comprising:
providing a biocompatible medical device;
providing a reservoir of biological oil or oil composition; and
motivating the biocompatible medical devicethrough the reservoir of biological oil or oil composition using a roller mechanism.
2. The method of claim 1 wherein the biocompatible medical device comprises a mesh structure.
3. The method of claim 1 , further comprising removing excess biological oil or oil composition from the biocompatible medical device.
4. The method of claim 3 , wherein removing excess biological oil or oil composition comprises passing the biocompatible medical device over a wiping surface after the mesh emerges from the reservoir of biological oil or oil composition.
5. The method of claim 1 , further comprising curing the oil or oil composition on the biocompatible medical device to form the barrier layer.
6. The method of claim 5 , wherein curing comprises applying a curing mechanism selected from a group of curing mechanisms comprising heat, UV light, chemicals, and reactive gases.
7. The method of claim 1 , wherein motivating the biocompatible medical device through the reservoir of biological oil or oil composition comprises completely immersing the biocompatible medical device in the oil or oil composition.
8. The method of claim 1 , wherein the reservoir comprises an applicator for applying the oil or oil composition to the biocompatible medical device.
9. The method of claim 8 , wherein the applicator comprises a rolling applicator.
10. The method of claim 8 , wherein the applicator comprises a sponge.
11. The method of claim 1 wherein the roller mechanism comprises a motorized roller mechanism.
12. The method of claim 1 wherein the biocompatible medical device is kept substantially horizontal in orientation after emerging from the reservoir.
13. The method of claim 1 , wherein the biological oil or oil composition comprises at least one therapeutic agent component.
14. The method of claim 13 , wherein the therapeutic agent component comprises an agent selected from the group consisting of antioxidants, anti-inflammatory agents, anti-coagulant agents, drugs to alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissue growth stimulants, functional protein/factor delivery agents, anti-infective agents, imaging agents, anesthetic agents, chemotherapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, analgesics, prodrugs, and antiseptics.
15. The method of claim 13 , wherein the biological oil or oil composition is configured to provide controlled release of the therapeutic agent component.
16. The method of claim 1 , wherein the biological oil or oil composition is bio-absorbable.
17. The method of claim 1 , wherein the biological oil barrier layer maintains anti-inflammatory and non-inflammatory properties.
18. The method of claim 1 , wherein the biological oil or oil composition further comprises alpha tocopherol or a derivative or analog thereof.
19. The method of claim 1 , further comprising sterilizing the barrier layer and biocompatible medical device with a method of sterilization selected from a group of methods of sterilization comprising ethylene oxide, gamma radiation, e-beam, steam, gas plasma, and vaporized hydrogen peroxide (VHP).
20. A device for applying a barrier layer to a biocompatible medical device, the device comprising:
a reservoir for holding a biological oil or oil composition for application to a biocompatible medical device; and
a roller mechanism configured to motivate the biocompatible medical device through the reservoir to apply the biological oil or oil composition to the biocompatible medical device.
21. The device of claim 20 , further comprising a staging surface for feeding the biocompatible medical device through the device to apply the barrier layer to the biocompatible medical device.
22. The device of claim 21 , wherein the staging surface comprises a spring loaded ramp for maintaining contact between the biocompatible medical device and the roller mechanism.
23. The device of claim 20 , further comprising a wiping surface for removing excess biological oil or oil composition from the biocompatible medical device after application of the biological oil or oil composition to the biocompatible medical device.
24. The device of claim 20 , wherein a biocompatible mesh is maintained in a substantially horizontal orientation after emerging from the reservoir.
25. The device of claim 20 , further comprising a biological oil or oil composition reserve positioned to replenish the reservoir.
26. The device of claim 20 , wherein the reservoir comprises an applicator for applying biological oil or oil composition to the biocompatible medical device.
27. The device of claim 26 , wherein the applicator comprises a rolling applicator.
28. The device of claim 26 , wherein the applicator comprises a sponge.
29. The device of claim 20 , wherein the roller mechanism comprises a motorized drive roller.
30. The device of claim 20 , wherein the roller mechanism comprises a spring loaded roller for maintaining contact with the biocompatible medical device.
31. The device of claim 20 , further comprising a wiper configured to remove biological oil or oil composition from the roller mechanism.
32. A method of applying a barrier layer to a biocompatible mesh using an applicator device, the method comprising:
providing a device for applying a barrier layer to a biocompatible medical device, the device comprising a reservoir for holding a biological oil or oil composition for application to a biocompatible medical device and a roller mechanism for motivating the biocompatible medical device through the reservoir to apply a biological oil or oil composition to the biocompatible medical device; and
passing a biocompatible medical device through the device to apply barrier layer to the biocompatible medical device.
33. The method of claim 32 , further comprising removing excess biological oil or oil composition from the biocompatible medical device.
34. The method of claim 32 , further comprising curing the oil or oil composition on the biocompatible medical device to form the barrier layer.
35. The method of claim 34 , wherein curing comprises applying a curing mechanism selected from a group of curing mechanisms comprising heat, UV light, chemicals, and reactive gases.
36. The method of claim 32 , wherein passing the biocompatible medical device through the device comprises completely immersing the biocompatible medical device in the oil or oil composition of the reservoir.
37. The method of claim 32 , wherein the biocompatible medical device is kept substantially horizontal in orientation as it emerges from the reservoir.
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