Abstract:
Flowable graft materials are provided which comprise collagen powder and a liquid in an amount sufficient to impart a flowable consistency to the material. The graft materials are sufficiently formable and pliable so as to provide both superior contact with and easier access to a surgical site than typical, more rigid grafts such as collagen sheets. These flowable materials may also be in a fluidized, paste-like and/or gel-like state and may be moldable and/or ejectable. The flowable collagen materials reduce and/or eliminate post implantation problems associated with other materials, e.g. synthetic dural sealants (hemostasis products), such as product swelling after application and implantation. The flowable graft materials are particularly useful as a dural graft.

Description:
FIELD 
       [0001]    The present application relates to flowable collagen dural graft materials for repairing, replacing, reinforcing or strengthening bodily tissue, as an adhesion barrier, or for use as a short-term body contact for moisture retention, hemostasis or tissue protection. 
       BACKGROUND 
       [0002]    The human brain and spinal cord are protected, preserved and enveloped by a meningeal system comprising meningeal membranes. A meningeal membrane is composed of an intricate network of three overlapping tissue layers: the dura mater (or dura) outermost layer, the arachnoid middle layer, and the pia mater innermost layer. The outermost layer is tough and waterproof. The innermost layer follows along and contacts the entire surface of the brain and spinal cord, carrying blood vessels to service them. The middle layer acts as a gliding system between the inner and outer surfaces. Any damage to this network causes acute problems to the central nervous system. 
         [0003]    Repairing damaged meningeal membranes has largely focused on implantable and/or resorbable constructs known as dural substitutes. These dural substitutes are grafted to the damaged dura mater and are designed to replace and/or regenerate the damaged tissue. A number of synthetic and animal based dural repair products are currently available. However, most of these are categorized into either suturable or onlay (sutureless) grafts, typically available in sponges, sheets, nonwoven matrixes or combinations thereof. In some instances, these products can be difficult to apply, and in some cases limited pliability, or moldability, may not enable them to adequately reach the entire damaged area. 
         [0004]    Synthetic gelatin and polymeric dural sealants have also been disclosed. However, with these synthetic sealants, certain problems persist as well. Some are porous, therefore not creating a tight seal. They may also be nonelastic and/or insoluble, thus leading to time consuming application. Furthermore, most are subject to swelling once applied and/or implanted because they must be hydrated or mixed at the surgical site rather than being prepared in advance of the procedure. Swelling of the material, post implantation, can be detrimental to the patient, for example, where such swelling causes compression of brain tissue, a nerve root or the spinal cord. 
         [0005]    Thus, there is a need for a dural graft material that is especially adapted for use in those areas or locations where it is difficult to apply conventional dural grafts. Furthermore, there is a need for a dural graft material which minimizes or eliminates post implantation swelling as well as reduces the quantity of implant material necessary to repair the damage. Finally, a dural graft material is needed which simplifies the procedure in terms of mateability, risks and time duration as compared with conventional dural graft products. 
       SUMMARY 
       [0006]    The present invention provides a flowable collagen graft materials useful, for example, as a dural graft. These graft materials comprise a collagen powder and a liquid in an amount effective to impart a flowable consistency for application to an area of concern. The collagen graft materials, when used as a dural graft, are sufficiently flowable so as to provide both superior contact with and easier access to a surgical site than typical, more rigid dural grafts such as collagen sheets or synthetic gelatin or polymeric dural sealants. The flowable graft materials are moldable and/or extrudable and have particular application in areas where other materials simply cannot access a site because they lack adequate pliability or moldability. 
         [0007]    The flowable collagen graft materials can also be used in applications to reduce and/or eliminate post implantation problems associated with other materials (synthetic dural sealants (hemostasis products)), such as product swelling after application and implantation. 
         [0008]    In another aspect, there is provided a method for repairing damaged dura utilizing the flowable collagen graft materials described herein. In one aspect the method involves applying a flowable dural graft material comprising a mixture of collagen and a liquid to a desired site, and conforming the dural graft material to a curvature of the site. The flowable graft material can be applied through a variety of techniques, including by ejections from a syringe and by manual spreading. 
     
    
     DETAILED DESCRIPTION  
       [0009]    Certain exemplary embodiments will now be described to provide an overall understanding of the principles of the structure, function, manufacture, and use of the devices and methods disclosed herein. Those skilled in the art will understand that the devices and methods specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and that the scope is defined solely by the claims. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present application. 
         [0010]    One aspect of the invention provides a dural graft material that can be dispensed in a flowable, fluidized, gel-like and/or paste-like form and, during application, shaped to conform to and remain in place in a desired location. In use as a dural substitute or adhesion barrier, or for short-term body contact for moisture retention, hemostasis, or tissue protection, the flowable dural graft material may be placed in contact with the desired bodily tissue. Once implanted at the desired site, contact between the flowable collagen material and the bodily tissues is maintained as a result of the paste-like consistency of the material. Over time, usually about 3 to 6 months, the flowable collagen material will be fully resorbed. 
         [0011]    A flowable collagen material in accordance with the present application can be formed from a collagen powder and a liquid in an amount effective to impart a flowable consistency to the resulting product. This flowable product, which is gel-like and/or paste-like in consistency, can be applied to the desired location by a number of techniques, as described below. Further, as a result of being a flowable material, the dural graft material described herein can be molded such that it is able to substantially conform to the geometery of the anatomical site at which it is implanted, e.g., the curvature of the site of dura damage. 
         [0012]    The collagen source for the flowable dural substitute described herein can be obtained from a variety of sources as known to those skilled in the art. By way of example, such collagen sources may include, bovine collagen, such as Type 1 bovine collagen, as well as porcine collagen, porcine small intestine submucosa, and fetal bovine skin. 
         [0013]    Generally, the collagen material is in a powdered form, however the powder can be derived from sheets of a collagen material that are ground to a powder having the desired particle size distribution. Exemplary collagen materials can be crosslinked, either before or after grinding the collagen to a powder form, but before combining with a liquid to form a flowable material. Alternatively, the flowable collagen graft material may be crosslinked by a variety of known techniques, including vapor crosslinking or solution crosslinking. Exemplary crosslinking agents include formaldehyde, glutaraldehyde, carbodiimides, and difunctional succinimides. The flowable collagen graft material may also be crosslinked by dehydrothermal crosslinking or UV radiation. 
         [0014]    The particle size of the collagen material can vary depending on factors such as the desired use of the material as well as the properties desired of the flowable material. In one embodiment, the particle size of the collagen powder of the flowable dural graft material is in the range of about 0.1 to 10,000 microns. In another embodiment, collagen powder has a particle size in the range of about 10 to 1,000 microns. In yet another embodiment, the collagen powder has a particle size in the range of about 50 to 800 microns. In further embodiment, collagen powder has a particle size in the range of about 100 to 400 microns. 
         [0015]    One skilled in the art will appreciate that a variety of biocompatible liquids can be mixed with the collagen material to form the flowable graft material. Exemplary liquids include water (e.g., purified water), saline, blood, plasma, collagen gels, and any other biocompatible solvents commonly used in the art. 
         [0016]    The relative amounts of collagen and liquid used to form the flowable dural graft material can vary depending on the desired applications and properties. One skilled in the art can readily determine the appropriate ratios of these components to achieve a flowable graft material that is suitable for a desired use and application technique. For example, flowable materials that are to be injectable, such as through a conventional syringe, should generally be less viscous than a flowable dural graft material that is to be applied by other techniques, such as by manual application. One skilled in the art will appreciate that conventional syringes have a standard luer lock at the distal end. However, a custom syringe with a different size opening can be designed to allow a thicker, more viscous material to be delivered. Consistent with these qualifications, the collagen powder component can generally be present in an amount of about 25% wt/wt %. In another embodiment, the collagen powder component can be present in an amount of about 20% wt/wt %. In a further embodiment, the collagen powder component can be present in an amount of about 11% wt/wt %. In yet another embodiment, the collagen powder component can be present in an amount of about 6% wt/wt %. 
         [0017]    One skilled in the art will appreciate that a variety of additives can be incorporated into the flowable graft material. Examples of such additives include, in effective amounts, antimicrobial agents, bioactive compounds, growth factors, immunosuppressive agents, permeation enhancers, antiviral agents, antitumor agents, and gelling agents. The flowable graft material may also include effective amounts of meningeal tissue growth factors. 
         [0018]    The flowable graft material described herein can be used as dural graft, or it can be used in a variety of other applications, including as an adhesion barrier, for short-term body contact for moisture retention, hemostasis, and tissue protection. Although the flowable graft and its method of use is primarily described in the context of a dural graft, one skilled in the art will understand the additional uses and applications of such a material. Independent of the intended use, the flowable collagen material can be deliverable in a fluidized, paste or gel state. One exemplary method for applying the material is by ejection from a delivery device such as a syringe. The material can be applied by ejection from a delivery device in the desired pattern or it can be applied by other techniques (e.g., manually or by other handling tools) and subsequently shaped to the desired pattern. For example, for thicker pastes, the material may be ejected with a caulking gun or similar type system 
         [0019]    In one embodiment, the dural graft material is prepared before it is applied to a surgical site. However, the material may also be prepared simultaneously with application to the surgical site. 
         [0020]    One use of the flowable collagen graft is in a surgical procedure as a dural graft material to repair or protect damaged meningeal membranes. The graft material can be implanted by applying an effective amount of the flowable collagen graft by the desired application technique (e.g., by ejection from a delivery device) through an opening of the cranium and is placed in contact with the meningeal membrane at the area of concern. An effective amount of the flowable collagen dural graft material may comprise a volume sufficient to slightly overlap with and contact a portion of non-damaged meningeal membrane. The flowable nature of the graft material enables it to substantially conform to the curvature of the meningeal membrane. In addition, the flowable graft material provides a superior seal and advantageously effectively avoids gaps between the graft material and the meningeal membrane. Further advantages of this material as a dural graft include its fluid impermeable nature and its ability to be implanted in a sutureless manner. 
       EXAMPLE 
       [0021]    A non-limiting example illustrating the preparation of a flowable dural graft material in accordance with the present invention is provided below. Bovine collagen (Type I Tendon sheet) is ground into powder having an average particle size of 100-500 microns. The collagen powder is then added to saline in the following four ratios to determine the weight percent lower limit for applying the material to the site of dural damage in a conventional 60 ml syringe: 
         [0022]    (A) 25% wt/wt % collagen powder ( 0.511 g bovine collagen powder to 2.0 ml saline); 
         [0023]    (B) 20% wt/wt % collagen powder (0.511 g bovine collagen powder to 2.5 ml saline); 
         [0024]    (C) 11% wt/wt % collagen powder (0.511 g bovine collagen powder to 4.5 ml saline); 
         [0025]    (D) 6% wt/wt % collagen powder (0.511 g bovine collagen powder to 8.5 ml saline). The product resulting from sample (A) is a thick paste that is too thick to be suitable for ejection from a conventional 60 ml syringe and it is not moldable. The product resulting from sample (B) is a balled thick paste that is moldable and it likewise is not ejectable from a conventional 60 ml syringe. However, this material may be applied to the site of dura damage by other application techniques such as using a custom syringe with a larger opening, delivering the material as a log shape and then spreading over the defect, or using a delivery system with mechanical advantage such as a caulking gun. The product resulting from sample (C) is not tacky, resists “wash away” when some additional saline is added to the material, and is both moldable and ejectable from a conventional 60 ml syringe. The product resulting from sample (D) is also moldable and ejectable from a conventional 60 ml syringe. 
         [0026]    One skilled in the art will appreciate further features and advantages based on the above-described embodiments. Accordingly, the disclosure is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety.