US20080208359A1 - Dural graft and method of preparing the same - Google Patents

Abstract

A dural graft is provided having improved stiffness characteristics relative to conventional dural substitutes. The dural graft can be formed from a collagen material having a stiffness between about 0.1 pounds per inch (lb./in.) and 0.25 lb./in. Relative to the collagen material forming conventional dural graft substitutes, the decreased stiffness of the collagen material of the present dural graft can provide the graft with a relatively improved or increased pliability. As a result of the increased pliability, the dural graft can sufficiently conform to a curvature of a tissue surface to which it is applied, such as the curved surface of a meningeal membrane. The reduced stiffness of the collagen material can also provide for a relatively improved or increased flexibility or elasticity of the dural graft. The increased flexibility of the dural graft minimizes tearing of the graft when handled or manipulated during an implantation procedure.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
• The present application is a divisional of U.S. patent application Ser. No. 11/238,717 filed on Sep. 29, 2005 and entitled “Dural Graft and Method of Preparing the Same” which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
• The present invention relates to a dural graft and a method of preparing the same.
BACKGROUND OF THE INVENTION
• The human brain and spinal cord are covered with meningeal membranes, the integrity of which is critical to the operation of the central nervous system. When the integrity of a person's meningeal membranes is intentionally or accidentally compromised, serious consequences may ensue, unless the membranes can be repaired. The meningeal membrane comprises three overlapping layers of tissue, which are in order from outside to inside, the dura mater (or dura), the arachnoid and the pia mater. Repairing damaged meningeal membranes has largely focused on implantable and/or resorbable constructs, known as dural substitutes, which are grafted to the damaged dura mater and are designed to replace and/or regenerate the damaged tissue.
• While dural substitutes are effective in covering and repairing damaged dura mater, the conventional dural substitutes can be relatively fragile. For example, conventional hydrated dural substitutes can be formed of a porous, sponge-like collagen structure. During handling or manipulation of these dural substitutes, the substitutes can be inadvertently pulled or placed under sufficient tension to create tears in the collagen structure, thereby destroying the dural substitute.
• Accordingly, there remains a need for a dural substitute having improved stiffness characteristics that allows for handling of the dural substitute while minimizing the risk of tearing the substitute.
SUMMARY OF THE INVENTION
• The present invention provides a dural substitute having improved stiffness characteristics relative to conventional dural substitutes. In one embodiment, a dural graft is provided having a size and shape suitable for placement to repair or replace a damaged meningeal membrane. The dural graft can be formed of a collagen material having a stiffness in a range of about 0.01 pounds per inch to 0.25 pounds per inch. In one embodiment, however, the collagen material can have a stiffness in a range of about 0.04 pounds per inch to 0.12 pounds per inch. The dural graft can include one or more biological agents such as an antibiotic, a growth factor, a hemostasis factor, an anti-adhesion agent, and an anti-cancer agent. The collagen material can be formed from a substantially fluid impermeable material.
• In one embodiment, a dural graft material is provided having a first collagen layer having opposed surfaces and a second collagen layer disposed on at least a first surface of the first collagen layer. The second collagen layer can have a stiffness in a range of about 0.01 pounds per inch to 0.25 pounds per inch.
• In another aspect, the present invention provides a method for manufacturing a dural graft substitute that includes delivering energy to a collagen material at a power level and for a period of time sufficient to reduce a stiffness of the collagen material to a stiffness in a range of about 0.01 pounds per inch to 0.25 pounds per inch. The energy can include a microwave energy applied at a power of about 700 Watts for a duration of about 30 seconds to reduce the stiffness of the collagen material. The microwave energy can also be applied at a power of about 700 Watts for a duration of about 60 seconds. Other types of energy can be delivered to the collagen material to reduce the stiffness of the collagen material. For example, radiation energy or electron beam energy can be used to irradiate the collagen material to reduce the stiffness of the material.
BRIEF DESCRIPTION OF THE DRAWINGS
• The invention can be more fully understood from the following detailed description taken in conjunction with the accompanying drawings, in which:
• FIG. 1 illustrates a top view of a dural graft;
• FIG. 2. illustrates a perspective view of the dural graft ofFIG. 1;
• FIG. 3 illustrates a side view of the dural graft ofFIG. 1;
• FIG. 4 is a graph showing stiffness ranges for conventional collagen devices and the dural graft ofFIG. 1;
• FIG. 5 is a sectional view of a portion of a cranium having the dural graft ofFIG. 1 implanted therein;
• FIG. 6 illustrates a side view of a multi-layer dural graft material that includes the dural graft ofFIG. 1; and
• FIG. 7 illustrates a perspective view of the multi-layer dural graft material ofFIG. 6.
DETAILED DESCRIPTION OF THE INVENTION
• 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. One or more examples of these embodiments are illustrated in the accompanying drawings. Those of ordinary skill 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 of the present invention is defined solely by the claims. The features illustrated or described in connection with one exemplary embodiment may be combined with features of other embodiments. Such modifications and variations are intended to be included within the scope of the present invention.
• The present invention provides a dural graft suitable to repair or replace damaged meningeal membranes. In general, a dural graft can be formed from a collagen material having a stiffness between about 0.1 pounds per inch (lb./in.) and 0.25 lb./in. Relative to the collagen material forming conventional dural graft substitutes, the decreased stiffness of the collagen material of the present dural graft can provide the graft with a relatively improved or increased pliability. As a result of the increased pliability, the dural graft can sufficiently conform to a curvature of a tissue surface to which it is applied, such as the curved surface of a meningeal membrane. The reduced stiffness of the collagen material can also provide for a relatively improved or increased flexibility or elasticity of the dural graft. The increased flexibility of the dural graft minimizes tearing of the graft when handled or manipulated during an implantation procedure.
• FIGS. 1-3 illustrate an embodiment of adural graft10. Thedural graft10 can be formed of a collagen material having a desired shape, such as a generally rectangular geometry as shown, and having a desiredthickness11, such as athickness11 within the range of about 0.020 inches and 0.240 inches. In one embodiment, thedural graft10 has a thickness in the range of about 0.120 inches and 0.129 inches. For example, thedural graft10 can be formed having atop surface12, abottom surface14 andperipheral edge16. Theedge16 of thedural graft10 defines the generally rectangular shape of thegraft10. In one embodiment, theedge16 of thedural graft10 can be chamfered to allow a smooth profile of theedge16 when it is wetted in situ, as shown inFIGS. 1-3. Theedge16 can be chamfered at anangle18 of approximately 30 to 75 degrees relative to thetop surface12. While thedural graft10 is shown as having a generally rectangular geometry, one skilled in the art will appreciate that thedural graft10 can be formed into other geometries as well. For example, thedural graft10 can be formed into a circle, triangle, or other geometries. In one embodiment, thedural graft10 can have
• The collagen material that forms thedural graft10 can be produced according to the process described in U.S. patent application Ser. No. 10/955,835, filed Sep. 30, 2004 and entitled COLLAGEN AND METHOD OF PREPARING THE SAME, the contents of which are expressly incorporated herein by reference in their entirety. A summary of the process is provided below.
• A collagen powder is mixed with purified water for a period of time sufficient to form a mixture. The ratio of collagen to purified water can be between approximately 0.4% to 5.0% w/w. The pH of the mixture is then adjusted to a pH level sufficient to substantially solubilize the collagen. A predetermined amount of the mixture is then placed into a container. The mixture is then formed into a collagen sheet by a lyophilizing process. The mixture could also be formed into a block, cylinder, or other desired shape, which will hereinafter be referred to collectively as a collagen sheet. The collagen sheet is then cross-linked. During the cross-linking, the collagen sheet is preferably exposed to a liquid or vapor form of a cross-linking agent, such as formaldehyde or glutaraldehyde. Thereafter, the collagen sheet can be ventilated if the cross-linking agent is vapor or relyophilized if it is liquid. The resulting collagen material has a plurality of pores wherein a majority of the pores (e.g., greater than approximately 80% of the pores) have a diameter of less than 10 μm.
• Once the collagen material has been formed, the material has a particular stiffness. Generally, the stiffness of a material is defined as ratio of the displacement or stretching of the material relative to a change in load applied to the material (e.g., stiffness=change in load/displacement). The relationship between load and displacement for a material can be plotted on a Cartesian coordinate system (e.g., with displacement being a function of load) to produce a load-displacement curve. Generally, a slope of the curve representing the load-displacement relationship of the material relates to the stiffness for that material. Typically, the steeper the slope of the curve (e.g., the larger the slope value), the stiffer the material.
• For example,FIG. 4 illustrates agraph20 showing an average load-displacement relationship orcurve21 for a conventional collagen material (e.g., as formed in the process described above). In one embodiment, the average slope of the load-displacement curve21 for conventional collagen materials is about 4.0 lb./in. As indicated above, the slope of thecurve21 relates to the stiffness of the collagen material. With the stiffness of the collagen material being about 4.0 lb./in., the collagen material can be considered as a relatively stiff material (e.g., as having a relatively high stiffness). As a result, grafts formed from such collagen materials can be considered as relatively inelastic in that minimal stretching of the graft when the graft is handled or manipulated can cause the graft to tear.
• In one embodiment, the stiffness for a conventional collagen material can fall within arange24 of values represented on thegraph20 by anupper threshold26 and alower threshold28. The slopes of thesethresholds26,28 represent the range of stiffness values for the conventional collagen materials. For example, in one embodiment theupper threshold26 can represent a collagen material stiffness of approximately 7.30 lb./in. while thelower threshold28 can represent a collagen material stiffness of approximately 0.60 lb./in. With the stiffness of the collagen material falling within such arange24, the collagen material can be considered as a relatively stiff material (e.g., as having a relatively high stiffness).
• In order to reduce the relative inelasticity and increase the pliability and flexibility of the collagen material, the stiffness of the collagen material forming thedural graft10 can be reduced. For example, reduction of the stiffness below thelower threshold28 of 0.60 lb./in. can and increase the pliability and flexibility of the collagen material. In one embodiment, to affect a reduction of the stiffness, energy can be applied to the collagen material.
• In one embodiment, microwave energy can be used to reduce the stiffness of the collagen material. For example, the collagen material, which may be wetted or moist, can be placed in the vicinity of a microwave emitting device, such as within a microwave oven, and exposed to the microwave energy emitted by the device. As a result of such exposure, the microwave energy can change the material properties of the material and reduce the stiffness of the collagen material below the lower threshold28 (e.g., approximately 0.60 lb./in.) as illustrated inFIG. 4. For example,FIG. 4 illustrates a load-displacement curve29 representing the stiffness for a conventional collagen material exposed to a microwave energy of approximately 700 Watts. As illustrated, the stiffness of the collagen material is below thelower threshold28. In one embodiment, the average stiffness for the collagen material exposed to the microwave energy source is about 0.09 lb./in.
• One skilled in the art will appreciate that while microwave energy can be used to reduce the stiffness the collagen material, other energy forms can be used as well. In one embodiment, heat can be applied to the collagen material in a moist environment to reduce the stiffness of the material. By way of non-limiting example, the collagen material can be exposed to a heated fluid, such as heated water, or to heated steam. In another example, the collagen material can be exposed to an energy source, such as a heat lamp, in a moist environment. In such an embodiment, the collagen material can be wetted, moist, or dry. In another embodiment, other types of energies can be applied to the collagen material such as, for example, radiation energy from a radiation source or energy from an electron beam.
• While the application of energy to the collagen material can decrease the stiffness of the material, other factors related to the energy application can affect the decrease in stiffness. In one embodiment, the power level of the energy applied to the collagen material and the duration of application of the energy can affect the reduction in stiffness of the collagen material. By way of non-limiting example, the following describes the stiffness changes in a collagen material after application of microwave energy for varying durations of time.
• Collagen material taken from 11 inch×11 inch sheets was formed into substantially rectangular shaped sheets, each having a length of approximately 3 inches, a width of approximately 3 inches, and an average thickness of approximately 0.146 inches (e.g., within the range of approximately 0.12 inches and 0.19 inches). Nine of the collagen sheets were exposed to a microwave energy at a power or energy level of approximately 700 Watts for a duration of approximately 30 seconds and ten of the collagen sheets were exposed to a microwave energy at a power level of approximately 700 Watts for a duration of approximately 60 seconds. Tensile loads were applied to each of the sheets and the resulting displacements measured. The stiffness of each collagen sheet was then calculated from the corresponding load—displacement data and the stiffness range (e.g., average stiffness+/−standard deviation) for each group (e.g., 30 second group or 60 second group) was determined.
• One skilled in the art will appreciate that the duration of exposure to energy and the power level of applied energy can vary depending on a number of factors, including the amount of material to be treated and the desired stiffness level. In addition, the type of energy used to treat the collagen material can also vary. For collagen materials treated according to the invention by exposure to microwave energy, the power level can be in the range of about 50 to 1200 Watts, and more preferably in the range of about 200 to 800 Watts. The material can be exposed to such microwave energy for a time period in the range of about 5 seconds to 180 seconds and more preferably for a period of time in the range of about 15 seconds to 60 seconds.
• With respect to the above-reference example,FIG. 4 illustrates a first range of stiffness values30 for the collagen material (e.g., as described above) exposed to the microwave energy for the duration of approximately 30 seconds. In one embodiment, as a result of such exposure, the collagen material can have a stiffness in a range of about 0.04 lb./in., as indicated bylower curve32, and 0.12 lb./in, as indicated byupper curve34.FIG. 4 also illustrates a second range of stiffness values36 for the collagen material exposed to the microwave energy for the duration of approximately 60 seconds. In one embodiment, as a result of such exposure, the collagen material can have a stiffness in a range of about 0.01 lb./in., as indicated bylower curve38, and 0.25 lb./in. as indicated by upper curve40. In either case, exposure of the collagen material to a microwave energy at a substantially constant power level for a period of time (e.g., 30 seconds or 60 seconds) can decrease the stiffness of the collagen material.
• In one embodiment, for a substantially constant power level, changing the duration of a collagen material's exposure to microwave energy can affect a decrease in the stiffness of the material. For example, increasing an amount to time that a collagen material is exposed to a microwave energy can further reduce the stiffness of the collagen material (e.g., below 0.01 lb./in). In another embodiment, either the power level, the duration of time, or a combination of both can be adjusted in order to affect the decrease in the stiffness of the collagen material. For example, in one embodiment, over a substantially constant duration of time, changing the power level of the energy applied to the collagen material can affect the decrease in the stiffness of the collagen material.
• The above example also indicates that for collagen material formed into sheets having a particular dimension (e.g., a length of approximately 3 inches, a width of approximately 3 inches, and an average thickness of approximately 0.146 inches), application of microwave energy at a constant power level and for varying durations of time can reduce the stiffness of the collagen material to a particular level, as shown inFIG. 4. In one embodiment, for relatively larger or smaller amounts of collagen material, the power level and the duration of exposure can be adjusted to reduce the stiffness of the collagen material to the particular level (e.g., the power level of the energy source and the duration of exposure can be a function of the amount of collagen material used). For example, for a relatively larger amounts of collagen material, (e.g., relative to the amounts used in the above-described example), the power level of the energy source, the duration of exposure, or a combination of both, can be increased in order to reduce the stiffness of the collagen material to the stiffness range illustrated inFIG. 4. In another embodiment, the power level of the microwave energy can vary over a given period of time to reduce the stiffness of a collagen material. For example, the collagen material can be exposed to a linearly increasing, linearly decreasing, or cyclically changing power over a time interval.
• While the application of energy to the collagen material can decrease the stiffness of the collagen material, the applied energy can also alter or adjust other properties of the material. In one embodiment, application of energy to the collagen material can adjust the fluid impermeability of the material. For example, collagen material has a substantially porous, sponge-like structure that, while resistant to the passage of fluid such as cerebrospinal spinal fluid (CSF), is not completely fluid impervious. When exposed to a microwave energy, the energy can cause the collagen material to shrink to approximately ⅓ of its original size (e.g., original volume) and can adjust the porous, sponge-like structure of the collagen material such that the material becomes less porous and more membrane-like (e.g., the collagen material takes on a membrane-like material “feel”). As a result of such physical changes, the microwave energy can reduce the ability for fluids to pass through the collagen material and can increase the fluid imperviousness of the material.
• Returning toFIG. 1, while thedural graft10 can be formed of a collagen material, thedural graft10 can include other materials as well. In one embodiment, one or more biological or biologically active agents can be incorporated within thedural graft10. For example, the biological agents can include antibiotics, growth factors, hemostasis factors, autologous cells, bone marrow, anti-adhesion agents, anti-cancer agents, or gene and DNA constructs.
• In use, thedural graft10 can be placed in contact with bodily tissue for use as an adhesion barrier, for short-term body contact for moisture retention, or for tissue protection or repair. When used as an implant, thedural graft10 can be resorbed by the body in a range of about 8 months and 12 months time. In one embodiment, thedural graft10 can be utilized during a surgical procedure to repair or replace damaged meningeal membranes.
• For example,FIG. 5 illustrates a portion of acranium50 having a damageddura mater site52. During implantation, thedural graft10 is inserted through anopening54 of theskull56 of thecranium50 and is placed in contact with ameningeal membrane58 at thesite52. For example, thedural graft10 is placed at thesite52 such that anedge60 of thedural graft10 overlaps a portion of themeningeal membrane58 and contacts a non-damaged portion of thedura mater62. With thedural graft10 having a relatively small stiffness and a relatively large amount of flexibility, thedural graft10 can be manipulated or maneuvered during implantation at thesite52 with minimal, if any, tearing of thegraft10.
• As thedural graft10 contacts thedura mater62, thedural graft10 substantially conforms to a general curvature of themeningeal membrane58. For example, as shown inFIG. 5, thedural graft10 forms a curved shape substantially similar to a curvature of themeningeal membrane58. With thedural graft10 having a reduced stiffness and an increased of pliabilility, thedural graft10 can sufficiently conform to the curved surface of ameningeal membrane58. The conformance of thedural graft10 minimizes the presence of gaps between thedural graft10 and themeningeal membrane58 thereby allowing thedural graft10 to substantially contain cerebrospinal fluid (CSF) within the brain132 after implantation of thegraft10.
• In one embodiment, the conformability of thedural graft10 relative to themeningeal membrane58 allows thedural graft10 to be used as an onlay graft. As such, sutures would not be required to secure thedural graft10 to themeningeal membrane58. Instead, the weight of thedural graft10 maintains the relative positioning of thedural graft10 relative to thesite52. In another embodiment, however, thedural graft10 can be secured to themeningeal membrane58 using sutures.
• Thedural graft10 has been shown as a single layer sheet. In one embodiment, thedural graft10 can be used as a component of a multi-layer sheet, such as illustrated inFIGS. 6 and 7.
• In one embodiment, as shown inFIGS. 6 and 7, thedural graft10 can be combined with acollagen sheet80 to form adural graft material82. Thedural graft10 is configured to augment or improve one or a number of characteristics of thecollagen sheet80 such as fluid impermeability or handling characteristics of thecollagen sheet80. For example, as indicated above, conventional collagen sheets are formed from a porous, sponge-like structure that are not fluid impervious. When used in combination with thecollagen sheet80, thedural graft10 can provide a level of fluid impermeability to thecollagen sheet80 as part of thedural graft material82.
• As shown inFIGS. 6 and 7, thedural graft10 is positioned adjacent to thecollagen sheet80. In one embodiment, the surface tension of a body fluid (e.g., cerebral spinal fluid) in contact with thedural graft material82 maintains contact between thedural graft10 and thecollagen sheet80 during implantation. In another embodiment, thedural graft10 and thecollagen sheet80 can be physically joined together after implantation. For example, sutures can be applied to thedural graft material82 to attach thedural graft material82 to a meningeal membrane and to physically couple thedural graft10 and thecollagen sheet80.
• With respect toFIGS. 6 and 7, while thedural graft material82 is shown as having a singledural graft layer10 and a singlecollagen sheet layer80 one skilled in the art will appreciate that thedural graft material82 can be configured in any number of ways. For example, in one embodiment, thedural graft material82 can include adural graft10 disposed between two collagen sheet layers80. In another embodiment, thedural graft material82 can include acollagen sheet layer80 disposed between two dural graft layers10.
• One skilled in the art will appreciate further features and advantages of the invention based on the above-described embodiments. Accordingly, the invention 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.

Claims (15)

1. A dural graft, comprising:

a bioimplantable dural graft having a size and shape suitable for placement to repair or replace a damaged meningeal membrane, the dural graft being formed of a collagen material having a stiffness in a range of about 0.01 pounds per inch to 0.25 pounds per inch.

2. The dural graft ofclaim 1, wherein the collagen material has the stiffness in a range of about 0.04 pounds per inch to 0.12 pounds per inch.

3. The dural graft ofclaim 1, wherein the collagen material comprises a substantially fluid impermeable material.

4. The dural graft ofclaim 1, wherein the collagen material comprises a cross-linked collagen material having a plurality of pores, at least a portion of the pores having a diameter of less than about 10 micrometers.

5. The dural graft ofclaim 1, further comprising at least one biological agent incorporated within the dural graft.

6. The dural graft ofclaim 5, wherein the at least one biological agent is selected from the group consisting of an antibiotic, a growth factor, a hemostasis factor, an anti-adhesion agent, and an anti-cancer agent.

7. The dural graft ofclaim 1, wherein the graft is configured to substantially conform to a curvature of a tissue at a site of implantation.

8. A dural graft material, comprising:

a first collagen layer having opposed surfaces; and

a second collagen layer disposed on at least a first surface of the first collagen layer, the second collagen layer having a stiffness in a range of about 0.01 pounds per inch to 0.25 pounds per inch.

9. The dural graft material ofclaim 8, wherein the second collagen layer has the stiffness in a range of about 0.04 pounds per inch to 0.12 pounds per inch.

10. The dural graft material ofclaim 8, wherein second collagen layer comprises a substantially fluid impermeable material.

11. The dural graft material ofclaim 8, wherein the second collagen layer comprises a cross-linked collagen material having a plurality of pores, at least a portion of the pores having a diameter of less than about 10 micrometers.

12. The dural graft material ofclaim 8, wherein the first collagen layer comprises a cross-linked collagen material having a plurality of pores, at least a portion of the pores having a diameter of less than about 10 micrometers.

13. The dural graft material ofclaim 8, further comprising at least one biological agent incorporated within the dural graft material.

14. The dural graft material ofclaim 13, wherein the at least one biological agent is selected from the group consisting of an antibiotic, a growth factor, a hemostasis factor, an anti-adhesion agent, and an anti-cancer agent.

15. The dural graft material ofclaim 8, wherein the dural graft material is configured to substantially conform to a curvature of a tissue at a site of implantation.

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