Biological tissue reinforcement material

Abstract

The biological tissue reinforcement material comprises: a base material layer having at least one of a film, a nonwoven fabric, a knitted fabric, and a woven fabric; and two sponge-like adhesive layers laminated on both sides of the base material layer. The base material layer is composed of a base material composition containing a biodegradable material, and the two adhesive layers are composed of a sponge composition containing a protein.

Description

Biotissue Reinforcement

[0001] The present disclosure relates to biological tissue reinforcement materials.

[0002] Patent Document 1 discloses a biological tissue reinforcement material. The biological tissue reinforcement material is a medical material that is used to compensate for contracted or missing tissue in a living body and is placed in the body (for this reason, the biological tissue reinforcement material can also be referred to as a "biological tissue prosthesis"). An example of a biological tissue reinforcement material is an artificial dura mater for replacing the dura mater. The dura mater is a hard membrane that surrounds the brain and spinal cord of mammals. Its primary function is to protect the brain and spinal cord from infection and trauma and to prevent leakage of cerebrospinal fluid. The artificial dura mater is used to suture dura mater after surgical incision or trauma. A biological tissue reinforcement material, including an artificial dura mater, is required to have a low risk of infection or other problems when placed in the body, to have mechanical properties and liquid-tightness equivalent to those of living tissue, and to be easy to handle during surgery. The biological tissue reinforcing material disclosed in Patent Document 1 has tissue adhesive properties and is advantageous in that it does not require suturing to biological tissue or adhesion with an adhesive such as fibrin glue.

[0003] International Publication No. 2017 / 171549

[0004] The biological tissue reinforcement material disclosed in Patent Document 1 includes a foam layer of a polymer blend at least partially covered with a sheet layer. The foam layer is made of a polymer blend having tissue-adhesive properties and can adhere to biological tissue. The sheet layer is made of, for example, a polyurethane based on D,L-lactide / ε-caprolactone copolyester prepolymer, and reinforces the liquid-tightness and pressure resistance of the foam layer.

[0005] In order for the biological tissue reinforcement material to properly exhibit its tissue adhesiveness and liquid-tightness, it must be used with the foam layer facing the biological tissue and the sheet layer facing the opposite side. In other words, those involved in surgery using the biological tissue reinforcement material must be sure to understand the orientation of the biological tissue reinforcement material in the treatment site and use it appropriately. For this reason, there has been a demand for a biological tissue reinforcement material that is easier to handle.

[0006] The present disclosure aims to provide a biological tissue reinforcement material that is easier to handle in the treatment field.

[0007] A biological tissue-reinforcement material according to a first aspect of the present disclosure comprises a substrate layer having at least one of a film, a nonwoven fabric, a knitted fabric, and a woven fabric, and two sponge-like adhesive layers laminated on both sides of the substrate layer. The substrate layer is made of a substrate composition containing a biodegradable material, and the two adhesive layers are made of a sponge composition containing a protein.

[0008] A biological tissue reinforcing material according to a second aspect of the present disclosure is the biological tissue reinforcing material according to the first aspect, wherein the sponge composition contains collagen.

[0009] A biological tissue reinforcement material according to a third aspect of the present disclosure is a biological tissue reinforcement material according to the first or second aspect, wherein the base material layer has one of the films, and the two adhesive layers are laminated adjacent to both sides of the film.

[0010] A biological tissue reinforcement material according to a fourth aspect of the present disclosure is a biological tissue reinforcement material according to any one of the first to third aspects, wherein the base layer has one nonwoven fabric and two films laminated adjacent to both sides of the nonwoven fabric, and the two adhesive layers are laminated adjacent to one side of each of the films so as to sandwich the base layer.

[0011] A biological tissue reinforcement material according to a fifth aspect of the present disclosure is a biological tissue reinforcement material according to any one of the first to fourth aspects, wherein the thickness of each adhesive layer is 0.5 mm or more and 7 mm or less.

[0012] A biological tissue reinforcing material according to a sixth aspect of the present disclosure is the biological tissue reinforcing material according to any one of the first to fifth aspects, wherein the thickness of each film is 30 μm or more and 100 μm or less.

[0013] A biological tissue reinforcing material according to a seventh aspect of the present disclosure is the biological tissue reinforcing material according to any one of the first to sixth aspects, wherein the sponge composition contains animal-derived collagen.

[0014] A biological tissue reinforcing material according to an eighth aspect of the present disclosure is the biological tissue reinforcing material according to any one of the first to seventh aspects, wherein the base material composition contains a biodegradable synthetic polymer.

[0015] A biological tissue reinforcing material according to a ninth aspect of the present disclosure is the biological tissue reinforcing material according to any one of the first to eighth aspects, wherein the synthetic polymer is heat-meltable.

[0016] A biological tissue reinforcement material according to a tenth aspect of the present disclosure is the biological tissue reinforcement material according to any one of the first to ninth aspects, and is applied to supplement the dura mater of a mammal.

[0017] According to the present disclosure, a biological tissue reinforcement material that is easier to handle in the treatment field is provided.

[0018] 1 is a schematic cross-sectional view of a biological tissue reinforcing material according to one embodiment; FIG. 2 is a schematic cross-sectional view of a biological tissue reinforcing material according to a modified example; FIG. 3 is a schematic view of a jig used in an experiment; and FIG. 4 is a graph showing the experimental results.

[0019] Hereinafter, a biological tissue reinforcement material according to one embodiment of the present disclosure will be described with reference to the drawings. For the sake of convenience, some components may be omitted from the drawings. Furthermore, the scales of the components shown in the drawings may not necessarily correspond to the scales of the actual components.

[0020] 1 is a cross-sectional schematic diagram of a biological tissue reinforcement material 1 (hereinafter also simply referred to as "reinforcement material 1") according to this embodiment. The reinforcement material 1 is a medical material that is used to compensate for contracture or loss in tissue in a living body and is placed in the living body. The reinforcement material 1 can be applied, for example, to an artificial dura mater for replenishing the dura mater of a mammal.

[0021] Conventional artificial dura maters include films and nonwoven fabrics made of polymeric compounds such as bioabsorbable polymers. Some are used by suturing the natural dura mater, while others are used by adhering to the natural dura mater with adhesives such as fibrin glue. Suturing the artificial dura mater to the natural dura mater requires a tight enough suturing process to prevent leakage of cerebrospinal fluid, which is time-consuming. Furthermore, when adhesives are used, the preparation process is complicated and there are limitations on the amount of fibrin glue that can be used. Therefore, artificial dura maters that do not require suturing or gluing have been developed. This type of artificial dura mater is made of a sponge-like material with a porous structure and develops adhesiveness to the dura mater when immersed in liquid. Such artificial dura maters require sufficiently high liquid-tightness and pressure resistance (burst strength as specified in ASTM F2392-04). Furthermore, differences in adhesiveness occur between the front and back surfaces of the sponge-like material due to the formation process of the sponge-like material. For this reason, in such artificial dura mater, one of the surfaces is designated as the adhesive surface to be attached to the dura mater, but there is a concern that it is not easy to distinguish the adhesive surface.

[0022] The concern that it is difficult to distinguish the adhesive surface also applies to biological tissue reinforcement materials in which a sheet layer is laminated on one side of a sponge-like material (for example, the biological tissue reinforcement material disclosed in Patent Document 1). Patent Document 1 recommends coloring the sheet layer and the foam layer with different colors to distinguish them. Reinforcement material 1 provides an artificial dura mater that has sufficient pressure resistance and does not require distinguishing between adhesive surfaces. Below, an example will be described in which reinforcement material 1 is configured as an artificial dura mater.

[0023] 1 , the reinforcing material 1 includes a base layer 2 and two adhesive layers 3 laminated adjacent to each other on both sides of the base layer 2. The base layer 2 and the adhesive layers 3 are integrated without the use of an adhesive or the like. The method of laminating the adhesive layers 3 onto the base layer 2 and integrating them will be described later.

[0024] [Substrate Layer] The substrate layer 2 is a portion of the reinforcing material 1 that primarily functions to ensure liquid-tightness and enhance pressure resistance. The substrate layer 2 according to this embodiment includes one film 20. The film 20 is composed of a film composition containing a biodegradable material (note that the film composition is an example of a substrate composition in the present disclosure). Biodegradable materials are materials that gradually decompose in vivo and are eventually incorporated into the metabolic cycle of the body. Specific examples of biodegradable materials include polysaccharides, biodegradable inorganic substances, biodegradable polymers, and composites thereof. Examples of polysaccharides include starch, alginic acid, hyaluronic acid, chitin, pectic acid, and derivatives thereof. Examples of biodegradable inorganic substances include magnesium and magnesium alloys.

[0025] Biodegradable polymers include natural polymers and synthetic polymers. Natural polymers include proteins such as hydrophobized gelatin, collagen, albumin, and fibrin. Synthetic polymers are preferably heat-meltable, and further preferably have a relatively low melting point in order to ensure the flexibility required for an artificial dura mater and facilitate integration with the adhesive layer 3. Specific examples include lactide-ε-caprolactone copolymer, poly-ε-caprolactone, polylactide, and polydioxanone. Lactides include L-lactide, D-lactide, D,L-lactide, and stereocomplexes of L-lactide and D-lactide. Among polylactides, poly-D-lactide is preferred due to its relatively low melting point.

[0026] The film composition according to this embodiment is a lactide-ε-caprolactone copolymer. The molar ratio of lactide to ε-caprolactone in the film composition is preferably within the range of 45:55 to 55:45, and more preferably close to 50:50. When the molar ratio is close to 50:50, the film 20 can be imparted with flexibility suitable for an artificial dura mater, and the melting point of the film composition does not become too high, facilitating integration with the adhesive layer 3. The molar ratio can be appropriately changed within a range that allows for film formation. However, as the molar ratio of lactide increases, the film 20 becomes harder. Furthermore, the higher the melting point of the film composition, the more difficult it becomes to integrate with the adhesive layer 3. Furthermore, as the molar ratio of ε-caprolactone increases, the film 20 also becomes harder.

[0027] The film composition may contain two or more types of biodegradable materials. In addition to the biodegradable materials, the film composition may also contain additives, etc., as needed.

[0028] The thickness of each film 20 (sheet) in the reinforcing material 1 is preferably 30 μm or more and 100 μm or less, more preferably 35 μm or more and 90 μm or less, and even more preferably 45 μm or more and 55 μm or less. If the thickness of the film 20 exceeds 100 μm, the reinforcing material 1 becomes too hard. If the thickness of the film 20 is too thin, the fixing strength between the film 20 and the adhesive layer 3 may be weakened. Note that, in the integration step described below, the film 20 in the reinforcing material 1 may become slightly thinner than the film 20 before integration because the film composition softens or melts.

[0029] [Adhesive Layer] The adhesive layer 3 is a portion that exhibits adhesiveness to the dura mater when immersed in a liquid. Each adhesive layer 3 according to this embodiment is sponge-like and has a porous structure with micro-sized pores (approximately 10 μm to 200 μm) formed throughout. Each adhesive layer 3 is laminated adjacent to both sides of the film 20. The sponge composition constituting the adhesive layer 3 contains protein. As described below, when the sponge composition is molded into a sponge using a mold, differences in the porous structure occur between the bottom side of the mold and the top opening side of the mold in the molded sponge-like object 30. This results in differences in adhesive performance between the front and back surfaces of the sponge-like object 30. In this regard, the adhesive layer 3 is laminated on the film 20 so that the surface more suitable for adhesion faces outward. Therefore, there is no difference in adhesive performance between the front surface 10 and the back surface 11 of the reinforcing material 1, and either the front surface 10 or the back surface 11 can be used as an adhesive surface.

[0030] Furthermore, the inventors have found that the pressure resistance of the reinforcement material 1 is improved by laminating adhesive layers 3 on both sides of the base layer 2. When the reinforcement material 1 is used as an artificial dura mater, both the front surface 10 and the back surface 11 are immersed in a liquid such as cerebrospinal fluid, regardless of its orientation. In other words, the adhesive layer 3, which is located on the opposite side of the base layer 2 from the dura mater, is also exposed to the liquid, and the liquid is stored in the micropores. It is believed that the adhesive layer 3 in this state further supports the base layer 2, improving the pressure resistance of the reinforcement material 1 as a whole.

[0031] Examples of proteins constituting the sponge composition include the natural polymers described above. The sponge composition according to this embodiment is collagen. The collagen is preferably derived from an animal. The collagen according to this embodiment mainly contains type 1 collagen with a three-dimensional helical structure, but may also contain other types of collagen. The collagen may also be atelocollagen from which the telopeptide region has been removed.

[0032] The thickness of each adhesive layer 3 in the reinforcing material 1 is preferably 0.5 mm or more and 7 mm or less, more preferably 0.7 mm or more and 6 mm or less, and even more preferably 0.9 mm or more and 5 mm or less.

[0033] [Overall] The overall thickness of the reinforcing material 1 is preferably 2 mm or more and 20 mm or less. This thickness is the maximum height of the reinforcing material 1 relative to the flat surface when the reinforcing material 1 is placed on a flat surface with one side of the adhesive layer 3 facing upward and the other side facing the flat surface. Furthermore, the reinforcing material 1 is preferably configured so that when immersed in liquid, it has a thickness equivalent to that of the dura mater of the target mammal.

[0034] <3. Manufacturing Method of Reinforcing Material> The reinforcing material 1 can be manufactured, for example, but not limited to, by integrating one film 20 and two sponge-like materials 30 that have been individually molded. The manufacturing method of the reinforcing material 1 will be described below.

[0035] [Film Forming Process] The film forming process is a process for forming the film 20. First, the above-described film composition is prepared. Next, the film composition is formed into a film-like material having a thickness of about 50 μm. Although the forming method is not particularly limited, extrusion forming using a T-die is preferred. Next, the extruded film-like material is heat-treated at a constant temperature for several hours. This results in the film 20.

[0036] [Sponge-like Material Forming Process] The sponge-like material forming process is a process for forming a sponge-like material 30. The following describes the formation of a collagen sponge-like material 30. First, the above-described collagen (powdered) is prepared as a sponge composition. Next, the collagen is dissolved in a solvent to prepare a collagen solution with a predetermined concentration (approximately 0.3% to 3% by mass). In this embodiment, the solvent is water, but an appropriate solvent can be used depending on the collagen used. Next, the mold into which the collagen solution has been poured is placed in an ultra-low temperature freezer, and the collagen solution is frozen within the mold. The thickness of the adhesive layer 3 can be adjusted by adjusting the depth of the collagen solution in the mold. Next, the mold is placed in a freeze dryer, and the frozen material within the mold is freeze-dried. The freeze dryer sublimes the water in the frozen material under vacuum, and then heats the frozen material to remove the water from the frozen material. After freeze-drying, the frozen material is removed from the mold and cut as necessary to obtain the sponge-like material 30.

[0037] [Integration Step] The film forming step and the sponge-like material forming step may be performed in either order, or may be performed simultaneously in parallel. After these steps are completed, an integration step is carried out to integrate the obtained film 20 with the two sponge-like materials 30.

[0038] In the integration process, a laminate is produced by stacking the first sponge-like material 30, the film 20, and the second sponge-like material 30 in this order. The adhesive surface of each sponge-like material 30 faces away from the film 20. The laminate is then placed on a horizontal surface with one sponge-like material 30 facing downward and the other sponge-like material 30 facing upward. A weight is then placed on the laminate, preferably so that uniform pressure is applied to the entire laminate. The thickness of the adhesive layer 3 and the reinforcing material 1 can also be adjusted by adjusting the weight's mass. When the laminate in this state is heated under vacuum for several hours, a portion of the film composition softens or melts at the interface with the sponge-like material 30 and penetrates into the porous structure of the sponge-like material 30. At the same time, thermal crosslinking of the collagen occurs. This fuses the film 20 and the sponge-like material 30, integrating the three layers to a degree that prevents them from easily separating. The heating temperature is preferably a temperature at which the collagen undergoes thermal crosslinking without thermal denaturation and at which at least a portion of the surface of the film 20 is softened or melted. After heating is completed, the edges of the laminate are cut as necessary to obtain the reinforcing material 1 in which the two sponge-like materials 30 and the film 20 are integrated.

[0039] <4. Features> (1) The reinforcement material 1 according to the above embodiment is made entirely or almost entirely of a biodegradable material. This reduces the risk of problems caused by leaving the reinforcement material 1 in the body, and eliminates the need for surgery to remove the reinforcement material 1. This reduces the burden on the living body.

[0040] (2) The reinforcing material 1 according to the above embodiment can be adhered to the dura mater without the need for suturing or mixing adhesive, and both the front surface 10 and the back surface 11 can be used as adhesive surfaces. This allows the dura mater to be easily closed. Furthermore, there is no risk of mistaking the adhesive surface for another adhesive surface, even without the need for coloring or other measures to distinguish the adhesive surface.

[0041] (3) As will be explained later, the reinforcing material 1 according to the above embodiment has higher pressure resistance than a sponge-like material alone or a laminate in which a sponge-like material and a film are integrated. This reduces the risk of leakage of cerebrospinal fluid after placement in the body. Furthermore, it can be applied to a wider range of cases.

[0042] 5. Modifications Although one embodiment of the present disclosure has been described above, the present disclosure is not limited to the above embodiment, and various modifications are possible without departing from the spirit of the present disclosure. For example, the following modifications are possible. Furthermore, the gist of the following modifications can be combined as appropriate.

[0043] (1) The reinforcing material 1 can be used not only as an artificial dura mater, but also for purposes such as compensating for contracture or loss of tissue in a living body, such as an organ, and preventing leakage of body fluids.

[0044] (2) The configuration of the reinforcing material 1 is not limited to that of the above embodiment. Fig. 2 is a cross-sectional view showing the configuration of a reinforcing material 1A according to a modified example. The reinforcing material 1A has the same configuration of the adhesive layer 3 as the reinforcing material 1, but the configuration of the base material layer 2A is different from that of the base material layer 2. Hereinafter, the same reference numerals will be used to designate components common to the reinforcing material 1A and the reinforcing material 1, and descriptions thereof will be omitted.

[0045] The substrate layer 2A has one nonwoven fabric 21 and two films 20 laminated adjacent to each other on both sides of the nonwoven fabric 21. The nonwoven fabric 21 and the films 20 are integrated without the use of an adhesive or the like. The nonwoven fabric composition constituting the fibers of the nonwoven fabric 21 contains a biodegradable material, preferably a biodegradable polymer (note that the nonwoven fabric composition is an example of a substrate composition of the present disclosure). The biodegradable material is as described above. In addition to the synthetic polymers described above, examples of biodegradable polymers include polyglycolic acid, glycolic acid-ε-caprolactone copolymer, glycolic acid-lactide copolymer, glycolic acid-trimethylene carbonate, and the like. In this embodiment, the nonwoven fabric composition is polyglycolic acid. The nonwoven fabric composition may contain two or more types of biodegradable materials.

[0046] The adhesive layers 3 are laminated adjacent to one side of each of the films 20 so as to sandwich the base layer 2A from both sides. The base layer 2A and the adhesive layers 3 are each integrated without the use of an adhesive or the like.

[0047] The manufacturing method of the reinforcing material 1A includes the above-mentioned film forming process and sponge-like material forming process, as well as a nonwoven fabric manufacturing process and an integration process. The nonwoven fabric manufacturing process is a process of manufacturing the nonwoven fabric 21 from a fibrous nonwoven fabric composition that constitutes the nonwoven fabric 21, and is performed before the integration process. The manufacturing method of the nonwoven fabric 21 is not particularly limited, and may include electrospinning, meltblowing, needle punching, spunbonding, flash spinning, hydroentanglement, airlaid, thermal bonding, resin bonding, wet methods, dry methods, etc. Note that through holes may be formed as appropriate in the manufactured nonwoven fabric 21. The formation of through holes makes it easier to integrate the film 20 and the nonwoven fabric 21 in the subsequent integration process.

[0048] In the integration step for reinforcing material 1A, a first sponge-like material 30, a first film 20, a nonwoven fabric 21, a second film 20, and a second sponge-like material 30 are stacked in this order to produce a laminate. Thereafter, the same procedure as in the integration step for reinforcing material 1 is followed to obtain reinforcing material 1A, in which two sponge-like materials 30, two films 20, and a nonwoven fabric 21 are integrated. In the integration step, the film composition of film 20 penetrates into the three-dimensional structure of nonwoven fabric 21 or penetrates nonwoven fabric 21 to weld each other and also to adjacent sponge-like materials 30. This integrates the five layers to such an extent that they do not easily separate.

[0049] It is also possible to omit the preparation of the film 20, coat both sides of the nonwoven fabric 21 with molten lactide-ε-caprolactone copolymer (film composition), and then laminate the sponge-like material 30 thereon to carry out the integration step. That is, instead of the film 20, a biodegradable polymer that has adhesive properties to the sponge-like material 30 may be used as an adhesive between the sponge-like material 30 and the nonwoven fabric 21.

[0050] In this manner, the adhesive layer 3 may be laminated adjacent to both sides of the substrate layer, or may be laminated via a biodegradable polymer that is adhesive to at least the sponge-like material 30. In this case, the substrate layer may have a structure (excluding the sponge-like material) composed of a composition containing a biodegradable material, such as at least one of a film, nonwoven fabric, knitted fabric, and woven fabric. Appropriate through-holes may be formed in at least one of the film, nonwoven fabric, knitted fabric, and woven fabric. In this embodiment, the flexibility of the substrate layer can be more easily adjusted, while the adhesive biodegradable polymer ensures liquid-tightness. Each of the compositions that constitute these structures is an example of the substrate composition of the present disclosure.

[0051] The following describes experiments conducted by the inventors and their results, but the present disclosure is not limited thereto.

[0052] 1. Preparation of Examples and Comparative Examples A reinforcing material having a three-layer structure as shown in FIG. 1 (Example), a single-layer sponge-like material (Comparative Example 1), and a two-layer laminate consisting of a sponge-like material and a film (Comparative Example 2) were prepared. The base layer of the reinforcing material was a film composed of lactide-ε-caprolactone copolymer (molar ratio 50:50), and the adhesive layer was a sponge-like material composed of collagen (medical collagen derived from pigskin, obtained by digesting telopeptides with pepsin) laminated on both sides of the film. The reinforcing material was produced using the manufacturing method according to the above embodiment. The sponge-like material was the same as the sponge-like material constituting the adhesive layer of the reinforcing material. The laminate was a reinforcing material with one adhesive layer omitted, with the adhesive layer laminated adjacent to only one side of the film. The reinforcing material, sponge-like material, and laminate were each cut to the same dimensions to prepare three test pieces.

[0053] Each test piece was adhered to a substrate simulating biological tissue, and the substrate was set in the jig shown in Figure 3. The jig was specified in ASTM F2392-04. The substrate was circular with a diameter of 30 mm and had a 3 mm circular through-hole in the center. Using the jig, saline was poured into the circular through-hole at a rate of 2 mL / min, and the pressure (mmHg) at which the test piece burst was taken as the pressure resistance.

[0054] <2. Results> The results are shown in the graph in Figure 4. As can be seen from the results, the Examples tended to have higher pressure resistance than Comparative Examples 1 and 2. This confirmed that a reinforcing material comprising at least three layers of a sponge-like material, a film, and a sponge-like material, as in the Examples, is not only easy to handle but also advantageous in terms of pressure resistance.

[0055] 1, 1A Reinforcing material 2, 2A Base layer 3 Adhesive layer 20 Film 21 Nonwoven fabric

Claims

1. A biological tissue reinforcement material comprising a base layer having at least one of a film, a nonwoven fabric, a knitted fabric, and a woven fabric, and two sponge-like adhesive layers laminated on both sides of the base layer, wherein the base layer is composed of a base composition containing a biodegradable material, and the two adhesive layers are composed of a sponge composition containing protein.

2. The biological tissue reinforcing material according to claim 1, wherein the sponge composition contains collagen.

3. The biological tissue reinforcement material according to claim 1 or 2, wherein the base layer has one of the films, and the two adhesive layers are laminated adjacent to both sides of the film.

4. A biological tissue reinforcement material as described in claim 1 or 2, wherein the base layer has one of the nonwoven fabrics and two of the films laminated adjacent to both sides of the nonwoven fabric, and the two adhesive layers are laminated adjacent to one side of each of the films so as to sandwich the base layer.

5. The biological tissue reinforcing material according to claim 1 or 2, wherein the thickness of each of the adhesive layers is 0.5 mm or more and 7 mm or less.

6. The biological tissue reinforcing material according to claim 1 or 2, wherein the thickness of each film is 30 μm or more and 100 μm or less.

7. The biological tissue reinforcing material according to claim 2, wherein the sponge composition contains collagen derived from an animal.

8. The biological tissue reinforcing material according to claim 1 or 2, wherein the base material composition contains a biodegradable synthetic polymer.

9. The biological tissue reinforcement material according to claim 8, wherein the synthetic polymer is heat-meltable.

10. The biological tissue reinforcement material according to claim 1 or 2, which is used to supplement the dura mater of a mammal.

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