Biocompatible materials

Abstract

To provide a biocompatible component that can be easily integrated with biological tissue. [Solution] A biocompatible member in which at least a part of the surface is composed of a porous material, The present invention provides a biocompatible member in which the porous body is an aggregate of polymer particles.

Description

Technical Field

[0001] The present invention relates to a biocompatible member.

Background Art

[0002] Conventionally, biocompatible members such as artificial blood vessels and artificial skin have been used. As biocompatible members, in addition to tubular ones such as artificial blood vessels and sheet-like ones such as artificial skin, those used as constituent members of devices equipped with subcutaneous implantable access ports as described in Patent Document 1 below are also known.

[0003] For materials for constructing this type of biocompatible member, polymers with excellent biocompatibility such as polytetrafluoroethylene (PTFE) and silicone-based polymers are adopted. Among them, a material made porous by stretching polytetrafluoroethylene is widely used under the name of ePTFE or the like.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] If the biocompatible member is such that the contact state with the living body is not sufficiently good and a gap where air or body fluid can stay is formed between the biocompatible member and the living tissue, bacteria may breed in the gap, so it is desired to easily integrate with the living tissue. However, such a desire has not been fully satisfied. Therefore, an object of the present invention is to provide a biocompatible member that can easily integrate with living tissue.

Means for Solving the Problems

[0006] To solve the above problems, the present invention provides: A biocompatible member in which at least a portion of the surface is composed of a porous material, The present invention provides a biocompatible member in which the porous body is an aggregate of polymer particles. [Effects of the Invention]

[0007] According to the present invention, a biocompatible member that can be easily integrated with biological tissue can be provided. [Brief explanation of the drawing]

[0008] [Figure 1] Figure 1 is a schematic perspective view showing an artificial blood vessel. [Figure 2] Figure 2 is a diagram (scanning electron microscope image) showing a cross-section of the porous material that constitutes the biocompatible component. [Figure 3a] Figure 3a is a schematic diagram showing the mold used in the manufacture of corrugated tubing, which constitutes an artificial blood vessel. [Figure 3b] Figure 3b is a schematic diagram showing the manufacturing process of corrugated tubing, which is a component of artificial blood vessels. [Figure 4a] Figure 4a is a schematic perspective view showing the pre-assembly, segmented form of corrugated tubing that can be used to manufacture artificial blood vessels. [Figure 4b] Figure 4b is a schematic perspective view showing the assembled, segmented corrugated tubing that can be used to manufacture artificial blood vessels. [Figure 4c] Figure 4c is a schematic perspective view showing the disassembly of a corrugated tube after its manufacture. [Figure 5] Figure 5 is a partially cutaway schematic front view showing a vascular access device. [Figure 6] Figure 6 is a schematic diagram of the rat implantation evaluation. [Figure 7a] Figure 7a is a scanning electron microscope (SEM) image of a cross-section of a sample made of a sintered body of polyester polymer particles. [Figure 7b]Figure 7b is a diagram showing the mapping of Si element in the observation area in Figure 7a. [Figure 8] Figure 8 is a diagram showing the state of a specimen for rat implantation evaluation. [Figure 9a] Figure 9a is a diagram showing the overall state of the implanted and evaluated sample 1-1. [Figure 9b] Figure 9b is a diagram showing the detailed state of the implanted and evaluated sample 1-1. [Figure 9c] Figure 9c is a diagram showing the detailed state of the implanted and evaluated sample 1-1. [Figure 9d] Figure 9d is a diagram showing the detailed state of the implanted and evaluated sample 1-1. <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Figure 12a shows the overall appearance of samples 1-4 that were evaluated after being planted. [Figure 12b] Figure 12b shows the detailed appearance of samples 1-4 that were evaluated after being implanted. [Figure 12c] Figure 12c shows the detailed appearance of samples 1-4 that were evaluated after being implanted. [Figure 12d] Figure 12d shows the detailed appearance of samples 1-4 that were evaluated after being implanted. [Figure 12e] Figure 12e shows the detailed appearance of samples 1-4 that were evaluated after being implanted. [Figure 13a] Figure 13a shows the overall appearance of sample 2-1, which was evaluated after being planted. [Figure 13b] Figure 13b shows a detailed view of sample 2-1, which was evaluated after being implanted. [Figure 13c] Figure 13c shows a detailed view of sample 2-1, which was evaluated after being implanted. [Figure 13d] Figure 13d shows the detailed appearance of sample 2-1, which was evaluated after being implanted. [Figure 13e] Figure 13e shows the detailed features of sample 2-1, which was evaluated after being planted. [Figure 14a] Figure 14a shows the overall appearance of sample 2-2, which was evaluated after being planted. [Figure 14b] Figure 14b shows a detailed view of sample 2-2, which was evaluated after being planted. [Figure 14c] Figure 14c shows a detailed view of sample 2-2, which was evaluated after being planted. [Figure 14d] Figure 14d shows the detailed appearance of sample 2-2, which was evaluated after being implanted. [Figure 14e] Figure 14e shows a detailed view of sample 2-2, which was evaluated after being planted. [Figure 15a] Figure 15a shows the overall appearance of samples 2-3 that were evaluated after being planted. [Figure 15b] Figure 15b shows the detailed appearance of sample 2-3, which was evaluated after being planted. [Figure 15c]Figure 15c shows the detailed appearance of sample 2-3, which was evaluated after being implanted. [Figure 15d] Figure 15d shows the detailed appearance of samples 2-3 that were evaluated after being implanted. [Figure 15e] Figure 15e shows the detailed appearance of sample 2-3, which was evaluated after being implanted. [Figure 16a] Figure 16a shows the overall appearance of sample 2-4, which was evaluated after being planted. [Figure 16b] Figure 16b shows the detailed appearance of sample 2-4, which was evaluated after being implanted. [Figure 16c] Figure 16c shows the detailed appearance of sample 2-4, which was evaluated after being implanted. [Figure 16d] Figure 16d shows the detailed appearance of sample 2-4, which was evaluated after being implanted. [Figure 16e] Figure 16e shows the detailed appearance of sample 2-4, which was evaluated after being implanted. [Figure 17a] Figure 17a shows the overall appearance of sample 3-1, which was evaluated after being buried. [Figure 17b] Figure 17b shows a detailed view of sample 3-1, which was evaluated after being planted. [Figure 17c] Figure 17c shows a detailed view of sample 3-1, which was evaluated after being planted. [Figure 17d] Figure 17d shows the detailed appearance of sample 3-1, which was evaluated after being implanted. [Figure 17e] Figure 17e shows a detailed view of sample 3-1, which was evaluated after being implanted. [Figure 18a] Figure 18a shows the overall appearance of sample 3-2, which was evaluated after being planted. [Figure 18b] Figure 18b shows a detailed view of sample 3-2, which was evaluated after being planted. [Figure 18c] Figure 18c shows the detailed appearance of sample 3-2, which was evaluated after being implanted. [Figure 18d] Figure 18d shows the detailed appearance of sample 3-2, which was evaluated after being implanted. [Figure 18e]Figure 18e shows the detailed features of sample 3-2, which was evaluated after being implanted. [Figure 19a] Figure 19a shows the overall appearance of sample 3-3, which was evaluated after being planted. [Figure 19b] Figure 19b shows a detailed view of sample 3-3, which was evaluated after being planted. [Figure 19c] Figure 19c shows a detailed view of sample 3-3, which was evaluated after being implanted. [Figure 19d] Figure 19d shows a detailed view of sample 3-3, which was evaluated after being implanted. [Figure 19e] Figure 19e shows a detailed view of sample 3-3, which was evaluated after being implanted. [Figure 20a] Figure 20a shows the overall appearance of samples 3-4 that were evaluated after being planted. [Figure 20b] Figure 20b shows the detailed appearance of samples 3-4 that were evaluated after being planted. [Figure 20c] Figure 20c shows the detailed appearance of samples 3-4 that were evaluated after being planted. [Figure 20d] Figure 20d shows the detailed appearance of samples 3-4 that were evaluated after being implanted. [Figure 20e] Figure 20e shows the detailed appearance of samples 3-4 that were evaluated after being planted. [Figure 21a] Figure 21a shows the overall appearance of sample 4-1, which was evaluated after being planted. [Figure 21b] Figure 21b shows a detailed view of sample 4-1, which was evaluated after being planted. [Figure 21c] Figure 21c shows the detailed features of sample 4-1, which was evaluated after being implanted. [Figure 21d] Figure 21d shows the detailed appearance of sample 4-1, which was evaluated after being implanted. [Figure 21e] Figure 21e shows a detailed view of sample 4-1, which was evaluated after being implanted. [Figure 22a] Figure 22a shows the overall appearance of sample 4-2, which was evaluated after being planted. [Figure 22b]Figure 22b shows a detailed view of sample 4-2, which was evaluated after being planted. [Figure 22c] Figure 22c shows a detailed view of sample 4-2, which was evaluated after being implanted. [Figure 22d] Figure 22d shows the detailed appearance of sample 4-2, which was evaluated after being implanted. [Figure 22e] Figure 22e shows a detailed view of sample 4-2, which was evaluated after being planted. [Figure 23a] Figure 23a shows the overall appearance of sample 4-3, which was evaluated after being planted. [Figure 23b] Figure 23b shows a detailed view of sample 4-3, which was evaluated after being planted. [Figure 23c] Figure 23c shows a detailed view of sample 4-3, which was evaluated after being planted. [Figure 23d] Figure 23d shows the detailed appearance of sample 4-3, which was evaluated after being implanted. [Figure 23e] Figure 23e shows the detailed features of sample 4-3, which was evaluated after being planted. [Figure 24a] Figure 24a shows the overall appearance of sample 4-4, which was evaluated after being planted. [Figure 24b] Figure 24b shows a detailed view of sample 4-4, which was evaluated after being planted. [Figure 24c] Figure 24c shows a detailed view of sample 4-4, which was evaluated after being implanted. [Figure 24d] Figure 24d shows the detailed appearance of sample 4-4, which was evaluated after being implanted. [Figure 24e] Figure 24e shows a detailed view of sample 4-4, which was evaluated after being planted. [Modes for carrying out the invention]

[0009] Embodiments of the present invention will be described below with reference to the drawings. Two embodiments, the first and second embodiments, will be described below. Specifically, examples of the biocompatible member of the present invention will be illustrated below, including its use in artificial blood vessels and in vascular access devices. However, the specific embodiments of the biocompatible member of the present invention are not limited to these.

[0010] (First Embodiment) First, a first embodiment of the biocompatible member will be described with reference to Figure 1. Figure 1 shows an artificial blood vessel 1, which is a biocompatible member of the first embodiment. The artificial blood vessel 1 illustrated in the figure comprises a main vessel 11 and branch vessels 12 branched from the main vessel 11. The artificial blood vessel 1 illustrated in the figure comprises a plurality of branch vessels 12, including a first branch vessel 121, a second branch vessel 122, and a third branch vessel 123.

[0011] The artificial blood vessel 1 is composed of a polymer composition with excellent flexibility, and is highly elastic and bendable. The main tube 11 and the branch tubes 12 are straight when placed on a horizontal surface without any stress applied (natural state). The three branch tubes 12 are straight in their natural state and are smaller in diameter than the main tube 11. The main tube 11 and the branch tubes 12 are corrugated tubes, and have a bellows-like shape with large diameter sections 11L and 12L that define their outer diameters, and small diameter sections 11S and 12S that are smaller in diameter than the large diameter sections 11L and 12L and define the inner diameters of the main tube 11 and the branch tubes 12, respectively, arranged alternately in the longitudinal direction. The corrugated pipe may be a ring-type corrugated pipe in which the larger diameter sections 11L, 12L and the smaller diameter sections 11S, 12S are each independent ring-shaped and arranged alternately in the longitudinal direction, or it may be a spiral-type corrugated pipe in which the larger diameter sections 11L, 12L and the smaller diameter sections 11S, 12S are spiral-shaped and extend radially so that they form a double helix. The main pipe 11 and the branch pipe 12 not only exhibit elasticity and flexibility due to the flexibility of the material itself, but also exhibit excellent elasticity and flexibility from a structural standpoint.

[0012] The three branch vessels 12 of the artificial blood vessel 1 branch off in a direction perpendicular to the longitudinal direction of the main vessel 11, roughly in the longitudinal center of the main vessel 11, and each branch extends in the same direction, with the branching points arranged in a line from one end 11a to the other end 11b of the main vessel 11.

[0013] The artificial blood vessel 1, as illustrated in Figure 1, can be used, for example, to substitute for the aortic arch by curving the main vessel 11 into an arc. More specifically, the artificial blood vessel 1 illustrated in Figure 1 can be used to substitute for the aortic arch by having one end 11a of the main vessel 11 connected to the ascending aorta a and the other end 11b connected to the descending aorta a. In this artificial blood vessel 1, the branching point of the first branch 121 is located closer to the one end 11a of the main vessel 11 than the second branch 122 and the third branch 123, and can be used, for example, to connect to the brachiocephalic artery c. The branching point of the third branch 123 is located closer to the other end 11b of the main vessel 11 than the first branch 121 and the second branch 122, and can be used, for example, to connect to the left subclavian artery d. The second branch canal 122 is positioned such that its branching point is between the first branch canal 121 and the third branch canal 123, and can be used, for example, to connect to the left common carotid artery e.

[0014] In the artificial blood vessel 1 illustrated in Figure 1, the main tube 11 and the branch tubes 12 are made of a common polymer composition. The artificial blood vessel 1 is a porous body 100 made of a polymer composition. The porous body 100 is a aggregate of polymer particles, and more specifically, a sintered body obtained by heating polymer particles to a temperature close to their melting point and sintering them. In the artificial blood vessel 1 illustrated in Figure 1, the voids between the polymer particles constituting the porous body 100 are open to the outer surface 1s1 and the inner surface 1s2, respectively.

[0015] The artificial blood vessel 1 is constructed by individually manufacturing four corrugated tubes (porous materials) that make up one main tube 11 and three branch tubes 12, and then connecting them together.

[0016] Figure 2 is an SEM image of a cross-section of a porous body 100, which is composed of polyester polymer particles, the same as the sample used as an evaluation sample in the later examples, after it has been cut. As shown in this figure, the porous body 100 is a solidified body in which polymer particles are solidified into a three-dimensional network. The porous body 100 has a polymer portion P composed of solidified polymer particles and void portions V which are the spaces between the polymer particles. The artificial blood vessel 1 has excellent elasticity and flexibility due to its macroscopic structural characteristics, such as its bellows-like shape, and also exhibits excellent elasticity and flexibility in terms of its microscopic structural characteristics, such as the fact that the polymer portion P is a three-dimensional network structure.

[0017] Each of the multiple polymer particles constituting the porous body 100 is bonded to some of the polymer particles of adjacent polymer particles in a direction parallel to the outer surface 1s1 (planar direction) or in a direction perpendicular to the outer surface 1s1 (depth direction), leaving a wide gap between it and the remaining polymer particles. These gaps between particles are continuous in the planar and depth directions, forming interconnected pores. Moreover, these interconnected pores are formed in a meandering and branching manner, and in a complementary relationship with the polymer portion P, which is a three-dimensional network structure, they form a three-dimensional network-like void portion V that fills a single space. That is, the void portion V is formed in a complex, interwoven state and extends from the surface of the porous body 100 in the depth direction.

[0018] In conventional biocompatible materials, ePTFE has voids formed between fibrils parallel to the stretching direction that extend long in the stretching direction. That is, the opening shape of the voids in ePTFE is a slit shape with an extremely short width relative to its length. Also, the voids in ePTFE are relatively monotonous in the depth direction. The porous body 100 that constitutes the artificial blood vessel 1 of this embodiment is formed by the bonding of polymer particles, and the opening shape is wide, making it easy for cells to penetrate. For example, as shown by the double-headed arrows No. 1 to No. 3 in Figure 2, the width of the voids in the cross-section of the porous body 100 (the distance between the cross-sections of adjacent polymer parts P) is several tens of μm to several hundred micrometers. Furthermore, in a polymer particle aggregate, the voids V are connected in an intricate manner that extends deep into the material, making it difficult for cells that have penetrated to escape from the voids V. For example, if biological tissue in contact with the outer surface 1s1 of the artificial blood vessel 1 is subjected to stress in a direction that moves it away from the outer surface 1s1, and if the voids are formed linearly in the depth direction, cells that have already invaded may be pulled back, and in some cases may even fall out completely. However, in the artificial blood vessel 1 of this embodiment, the voids V are interconnected in an intricate manner that extends deep into the tissue, so even in such cases, changes that would reduce the depth of cell invasion are less likely to occur. Therefore, the artificial blood vessel 1 of this embodiment, which is composed of a polymer particle aggregate, can integrate with the biological tissue it comes into contact with more quickly than conventional artificial blood vessels made of ePTFE.

[0019] The ratio of polymer portion P to the total volume of void portion V and polymer portion P (apparent volume calculated from the external shape of the porous body 100) is advantageous if it is below a certain level, considering the ease with which cells can penetrate. This ratio is, for example, 90 vol% or less. This ratio may also be 80 vol% or less, 70 vol% or less, or 60 vol% or less. On the other hand, considering strength, it is considered advantageous if this ratio is above a certain level. This ratio is, for example, 25 vol% or more. This ratio may also be 30 vol% or more, or 35 vol% or more.

[0020] As shown in Figure 2, where a circle is denoted by X, if the diameter D of the largest circle that can be drawn in a location within the cross-section of the porous body 100 such that it encloses only the cross-section of the void portion V without enclosing the cross-section of the polymer portion P is taken as the opening diameter of the void portion V at that location, then considering the ease with which cells can penetrate, it may be advantageous for the opening diameter to be above a certain level. On the other hand, in terms of exhibiting excellent sealing properties to suppress leakage and bacterial permeation, it is considered advantageous for the opening diameter (D) to be below a certain level. The opening diameter (D) is, for example, 5 μm or more and 500 μm or less. The opening diameter (D) may be, for example, 10 μm or more, or 15 μm or more. The opening diameter (D) may be, for example, 400 μm or less, or 300 μm or less.

[0021] The polymer portion P and the void portion V preferably have a shape that allows multiple (two or more) circles of the above-mentioned size to be drawn without overlapping within a randomly set square area with sides of 1 mm in the cross-section of the porous body 100. The polymer portion P and the void portion V in the porous body 100 may have a shape that allows three or more circles of the above-mentioned size to be drawn within a 1 mm square area, or it may have a shape that allows four or more circles to be drawn, or it may have a shape that allows five or more circles to be drawn. The number of circles that can be drawn within a square area with sides of 1 mm may be, for example, 100 or less, or 50 or less.

[0022] The polymer particles that make up the porous body 100 may consist of a single polymer species, may contain multiple types of polymers, or may contain additives other than polymers. The porous body 100 may consist of a solidified body in which polymer particles are directly joined, or it may contain a binder that adheres the polymer particles together. The porous body 100 may also be a sintered body in which polymer particles are heat-fused together.

[0023] The type of polymer contained in the polymer particles is not particularly limited as long as it can be used in biocompatible materials, but examples include polyethylene such as ultra-high molecular weight polyethylene; polypropylene such as homopolypropylene and copolymerized polypropylene (e.g., block copolymers or random copolymers of propylene and ethylene); and polyolefin-based thermoplastic elastomers with polyethylene or polypropylene as the hard segment and ethylene-propylene rubber as the soft segment. Other examples of polymers contained in the polymer particles include polyesters such as polyethylene terephthalate; and polyester-based thermoplastic elastomers with polybutylene terephthalate or polybutylene isophthalate as the hard segment and polyethers such as polytetramethylene glycol as the soft segment. Polystyrene-based polymers such as polystyrene, poly-α-methylstyrene, acrylonitrile-styrene-butadiene copolymer (ABS), and styrene-based thermoplastic elastomers which are block copolymers of polystyrene blocks and polyolefins are also possible. The polymers contained in the polymer particles may also be silicone-based polymers, polysulfones, polytetrafluoroethylene, polymethyl methacrylate, polyvinyl chloride, etc. The polymer contained in the polymer particles may be polyamide polymers such as polyamide; amide-based thermoplastic elastomers with polyamide as the hard segment and polyester, polyether, etc. as the soft segment. Other polymers that can be contained in the polymer particles include, for example, polyurethane; polyurethane-based thermoplastic elastomers with polyurethane containing short-chain diols and polyisocyanates as repeating units as the hard segment and polyurethane containing long-chain diols and polyisocyanates as repeating units as the soft segment.

[0024] The polymer contained in the polymer particles may, for example, exhibit a melt viscosity of 300 Pa·s or more at 200°C. The melt viscosity of the polymer at 200°C may be 400 Pa·s or more, 500 Pa·s or more, or 600 Pa·s or more. The melt viscosity of the polymer contained in the polymer particles at 200°C may be, for example, 2000 Pa·s or less. The melt viscosity of the polymer can be measured, for example, by heating the polymer sufficiently to the measurement temperature (200°C) using a flow tester equipped with a die with a diameter of 1 mmφ and a length of 10 mm, and then applying a load of 10 kgf. The melt viscosity of the polymer can be determined as the arithmetic mean of multiple measurements (e.g., 5 measurements).

[0025] Among the polymers exemplified above, ultra-high molecular weight polyethylene and thermoplastic elastomers (olefin-based thermoplastic elastomers, ester-based thermoplastic elastomers, styrene-based thermoplastic elastomers, amide-based thermoplastic elastomers, urethane-based thermoplastic elastomers, etc.) are suitable because their high melt viscosity makes it difficult for the polymer particles to soften excessively when preparing a solidified body (sintered body) under heating and pressure, thus making it easier to secure the desired void space. The porous body is preferably configured to contain one or more of the aforementioned polymer particles selected from the group consisting of polyethylene particles, polypropylene particles, polyester-based polymer particles, polystyrene-based polymer particles, polyetheretherketone particles, and polyurethane particles.

[0026] Of the polymers mentioned above, for silicone-based polymers, for example, all parts of the molecule except the two ends are essentially D units (R2SiO 2 / 2 It may consist only of D units, and in addition to T units (RSiO 3 / 2 ) and Q units (SiO 4 / 2) may also contain such as. In other words, the silicone polymer may have a chain-like molecular structure, commonly referred to as silicone oil, or a branched molecular structure, commonly referred to as silicone resin. Regarding what siloxane units are contained in such silicone polymers, 29 This can be determined by Si-NMR. Examples of substituents (R) in the siloxane unit include alkyl groups such as methyl groups and aryl groups such as phenyl groups.

[0027] For example, the silicone oil may be a dimethyl silicone oil with dimethylsiloxane as the main repeating unit; a methylphenyl silicone oil with dimethylsiloxane and diphenylsiloxane as the main repeating units; or a methylhydrogen silicone oil with dimethylsiloxane and monomethylsiloxane as the main repeating units. Furthermore, the silicone oil may be a modified product, for example, a modified product that has been modified to impart reactive functional groups such as amino modification, epoxy modification, carboxy modification, carbinol modification, methacrylic modification, mercapto modification, or phenol modification, or a modified product that has been modified to impart non-reactive functional groups such as polyether modification, methylstyryl modification, alkyl modification, higher fatty acid ester modification, or fluorine modification.

[0028] As a binder used to bind polymer particles together, for example, a polymer solution obtained by dissolving the polymer in an organic solvent or the like, or a precursor of the polymer, can be used. For example, silicone polymers can be obtained by curing a one-component curable silicone or a two-component curable silicone by an addition reaction or a condensation reaction, and such a curable silicone may be used as a binder. The curable silicone may be a low-viscosity liquid fluid that flows by gravity alone without the application of external force at room temperature (25°C), or it may be a high-viscosity paste-like fluid that does not exhibit fluidity by gravity alone.

[0029] By incorporating such a coagulant into the raw materials of the porous body 100 together with polymer particles, it is possible to suppress the scattering of the raw materials of the porous body 100 or their adhesion to unwanted areas due to static electricity, thereby improving the manufacturing efficiency of the porous body 100.

[0030] When a curable silicone is used as a binder, the curable silicone may be an addition-reaction type having a polysiloxane skeleton in its main chain and vinyl groups bonded to the main chain or side chains. When a curable silicone is used as a binder, the curable silicone may be a condensation-reaction type having hydroxyl groups or alkoxy groups instead of vinyl groups in the addition-reaction type curable silicone.

[0031] On the surface of a porous body 100 made using curable silicone and particles of a polymer other than silicone-based polymers, such as polyester particles, both the silicone-based polymer, which is the cured product of the curable silicone, and the polyester particles will be exposed. That is, the surface of the porous body 100 may be formed with a first region composed of silicone-based polymers and a second region formed by the exposure of polyester particles on the surface. While it is usually possible to finely disperse common polymers such as polyester and silicone-based polymers, they do not typically dissolve at the molecular level. As a result, a microphase separation structure consisting of the first region and the second region is observed on the surface of the porous body 100. Depending on the type of polymer other than the silicone-based polymer and the ratio of curable silicone, one of the first and second regions may constitute a continuous phase (matrix), and the other may constitute a dispersed phase (domain).

[0032] Microphase separation on the surface of the porous body 100 as described above can be achieved not only when using curable silicone, but also by forming the porous body 100 with polymer particles containing multiple types of polymers, such as silicone-based polymers like silicone oil and silicone resin, and polymers other than silicone-based polymers. Furthermore, the formation of a first region formed of silicone-based polymer and a second region formed of polymers other than silicone-based polymers on the surface of the porous body 100 can also be achieved, for example, by forming the porous body 100 with multiple types of polymer particles, such as silicone-based polymer particles and polymer particles other than silicone-based polymers.

[0033] The porous body 100 comprises a first polymer, which is a silicone-based polymer, and a second polymer, which is not a silicone-based polymer. By exposing both the first and second polymers on the surface of the porous body 100, which forms the outer surface 1s1 and inner surface 1s2 of the artificial blood vessel 1, the biocompatibility of each polymer can be expressed, resulting in good biocompatibility. In the porous body 100, it is preferable that the silicone-based polymer (first region) constitutes a dispersed phase, and the second polymer (second region), which is not a silicone-based polymer, constitutes a continuous phase.

[0034] When using a curable silicone as the raw material for the porous body 100, a condensation-type curable silicone, which hardens by a condensation reaction, is preferable to an addition-type curable silicone, which hardens by an addition reaction, because it is easier to control the reactivity during hardening. Since water and alcohol are generated as by-products in the hardening reaction of a condensation-type curable silicone, it is possible to interpose water and alcohol between the particles during heat molding, thereby suppressing excessive fusion between polymer particles and ensuring the continuity of the voids (forming continuum).

[0035] Even when the first polymer in the raw materials of the porous body 100 is not a cured product of curable silicone but rather a silicone oil, the silicone oil can suppress excessive fusion between polymer particles, which is advantageous in ensuring the continuity of the voids (forming continuum pores).

[0036] The artificial blood vessel 1 of this embodiment can be manufactured by general molding methods such as extrusion molding using an extruder or mold molding using a mold, as will be described later. The artificial blood vessel 1 of this embodiment, which is a porous body 100 with a silicone polymer exposed on its surface, exhibits excellent release properties in extrusion molding and mold molding, and therefore also offers excellent production efficiency.

[0037] The artificial blood vessel 1 of this embodiment is, for example, (S1) Raw material preparation process for preparing raw materials containing polymer particles, (S2) A molding process in which molded products (corrugated tubes) that will become the main tubes and branches of artificial blood vessels are produced by molding using the raw materials prepared in the raw material preparation process. (S3) Post-processing step in which post-processing is performed on the molded product produced in the molding process. It can be manufactured by carrying out the following steps in order.

[0038] In the raw material preparation process, for example, raw materials may be prepared using only one type of polymer particles, raw materials containing multiple types of polymer particles, raw materials containing a binder in addition to polymer particles, or raw materials containing silicone oil that functions as a mold release agent in addition to polymer particles.

[0039] Raw materials containing a coagulant can be prepared by mixing polymer particles and the coagulant using a common mixing and stirring device such as a Henschel mixer or ribbon blender. A specific method for this is to place the polymer particles in the mixing and stirring device, stir (fluidize) the polymer particles with a stirring blade or similar device, add a predetermined amount of coagulant, and continue stirring to uniformly disperse the coagulant. The coagulant can be added using a feeder or spray nozzle. It is preferable to spray the coagulant onto the polymer particles, as this makes it easier to disperse the coagulant relatively uniformly.

[0040] Raw materials containing a release agent can also be prepared using common mixing and stirring devices such as Henschel mixers and ribbon blenders to create raw materials containing polymer particles. A specific method for this is to place the polymer particles in a mixing and stirring device, stir (fluidize) the polymer particles with a stirring blade or similar device, add a predetermined amount of release agent, and continue stirring to uniformly disperse the release agent. The release agent can be added using a feeder or spray nozzle. It is preferable to spray the release agent onto the polymer particles, as this makes it easier to disperse the release agent relatively uniformly.

[0041] The polymer particles used as raw materials may, for example, have an average particle diameter of 5 μm or more and 500 μm or less. The average particle diameter of the polymer particles may be, for example, 10 μm or more, or 20 μm or more. The average particle diameter of the polymer particles may be, for example, 300 μm or less, or 100 μm or less. The average particle diameter of the polymer particles can be determined, for example, as the median diameter (D50) on a volume basis using the laser diffraction scattering method.

[0042] The shape of the polymer particles used as raw materials may be, for example, spherical, needle-shaped, plate-shaped, or irregularly shaped. The polymer particles are preferably spherical or irregularly shaped, and more preferably irregularly shaped, as this is advantageous for the formation of voids V.

[0043] The molding process may be divided into, for example, primary molding, in which the raw material is molded into a straight tubular body, and secondary molding, in which the tubular body obtained in the primary molding process is molded into a bellows shape. One possible method for this is to use equipment similar to that used for manufacturing corrugated pipes, such as those used for flexible electrical conduits. Specifically, corrugated pipes that make up main pipes and branch pipes can be manufactured by, for example, primary molding, in which the raw material is extruded into a straight tubular shape from an extruder equipped with an annular discharge port, and secondary molding, in which a bellows shape is given using a corrugating machine installed immediately after the discharge port of the extruder, and then cutting the resulting long corrugated pipe to a predetermined length.

[0044] Corrugated pipes that make up the main pipe and branch pipes can be manufactured using a molding die instead of the method described above. When the corrugated pipe is a spiral corrugated pipe, as shown in Figures 3a and 3b, it can be manufactured using a molding die M1 having a screw-groove-shaped molding surface MP corresponding to the shape of the outer surface of the corrugated pipe, and an inner die that is slightly narrower than the cavity MV which is the space defined by the molding surface MP of the molding die M1, and has a screw-shaped surface that faces the molding surface MP. In this method, the core pin (inner die M2) is set in the cavity MV of the molding die M1 so that a molding space corresponding to the corrugated pipe is formed between the molding surface MP and the core pin (inner die M2), raw material 100' containing polymer particles is placed in the molding space, and the corrugated pipe can be manufactured by heating the raw material through the molding die M1 and the core pin (inner die M2). The mold M1 shown in Figures 3a and 3b is composed of multiple segmented molds with a plane containing the central axis CX of the cavity MV as the mating surface, which facilitates the removal of the corrugated tube after molding. In addition, the core pin (internal mold M2) can be extracted axially by rotating it relative to the fabricated corrugated tube around the central axis CX.

[0045] When the corrugated pipes constituting the main pipe and branch pipes are ring-shaped corrugated pipes, the aforementioned molding die M1 is used as the outer mold, and an inner mold M2 is constructed using a divided mold as shown in Figures 4a, 4b, and 4c, which is smaller than the outer mold by the thickness of the corrugated pipe. The inner mold M2 is then set in the cavity MV, and the raw material for the corrugated pipe is filled into the gap between the inner mold M2 and the outer mold to perform molding. Furthermore, by constructing the inner mold M2 using divided molds M21, M22, M23, M24, and M25 as shown in Figures 4a, 4b, and 4c, it is possible to easily remove the inner mold M2 from the corrugated pipe after molding.

[0046] Corrugated tubing can also be manufactured, for example, by powder injection molding.

[0047] In this molding process for producing corrugated tubes from raw materials containing polymer particles, the shape and volume ratio of the voids V can be adjusted by controlling temperature and pressure conditions, thereby preparing the corrugated tubes to a state suitable for early integration with biological tissue.

[0048] In the post-processing step after the molding process, the artificial blood vessel 1 is fabricated by drilling holes for branching to the branch pipes 12 in the corrugated pipe for the main pipe 11 manufactured in the molding process, or by connecting the corrugated pipe for the branch pipes 12 to these holes. Various methods can be used to connect the corrugated pipes, such as adhesive bonding, heat fusion, and ultrasonic welding. Generally, it is not easy to bond silicone-based polymers with high adhesive strength. Therefore, as mentioned above, forming a continuous phase on the surface of the corrugated pipe with a polymer other than a silicone-based polymer makes it easier to connect the main pipe 11 and the branch pipes 12.

[0049] Thus, in this embodiment, an artificial blood vessel 1 with excellent biocompatibility that can integrate with biological tissue at an early stage can be easily fabricated.

[0050] Next, we will describe an embodiment different from the artificial blood vessel 1 described in the first embodiment, with reference to Figure 5. (Second Embodiment) Figure 5 illustrates biocompatible components used as building blocks for the vascular access device 2. The vascular access device 2 illustrated in Figure 5 is an in-vivo implantable device used by being implanted in the wearer's body (biological lo), and more specifically, a subcutaneous implantable device used by being implanted beneath the wearer's epidermis SK.

[0051] The vascular access device 2 comprises an access port 21, which is a container for storing a drug solution to be supplied to the device wearer's blood vessel BV (more specifically, vein), and a catheter 22, which is a highly flexible tube. The vascular access device 2 is able to supply the drug solution to the device wearer's blood flow by connecting the storage space 21a of the access port 21, which contains the drug solution, with the inside of the blood vessel BV via the catheter 22.

[0052] The access port 21 is embedded subcutaneously, with its position determined in the depth direction D1 such that the entire port is not exposed from the body surface, when the direction normal to the epidermis SK (body surface) of the device wearer is defined as the depth direction D1, and the direction perpendicular to the depth direction D1 is defined as the planar direction D2. The housing space 21a of the access port 21 is a flattened cylindrical shape that extends a short distance in the depth direction D1, and its dimensions in the depth direction D1 are shorter than its dimensions (diameter) in the planar direction D2.

[0053] The access port 21 has a bottomed cylindrical housing 211 that defines the bottom and side edges of the accommodation space 21a. The housing 211 is positioned so that its upper opening faces the body surface of the device wearer. The access port 21 further comprises a disc-shaped septum 212 that closes the upper opening of the housing 211 and defines the upper edge of the accommodation space 21a. In the vascular access device 2 illustrated in the figure, the septum 212 is fitted inside the opening of the housing 211.

[0054] The access port 21 is embedded subcutaneously with the upper opening of the housing 211 facing the body surface of the device wearer, and has a nozzle portion 21b extending in a planar direction at its bottom, at which the catheter 22 is connected. In other words, the catheter 22 is connected to the access port 21 at one end in the longitudinal direction, and the other end opposite to the one end is inserted into the blood vessel BV, and communicates the blood vessel BV with the containment space 21a, forming a flow path for the drug solution contained in the containment space 21a to the blood vessel BV.

[0055] In this embodiment, the housing 211 comprises an inner housing 211a that defines the containment space 21a and constitutes the part that comes into contact with the liquid medicine, and an outer housing 211b that is arranged to cover the bottom of the inner housing 211a. The opening into which the septum 212 is fitted has a single-layer structure of the inner housing 211a, while the bottom of the nozzle portion 21b has a double-layer structure of the inner housing 211a and the outer housing 211b.

[0056] The upper end of the inner housing 211a, which constitutes the opening of the housing 211, is provided with a circumferential groove for fitting the septum 212. Specifically, the inner housing 211a is provided with a larger diameter portion 2111 located deeper than the opening edge 211e and having a larger diameter than the opening diameter at the opening edge, and is provided with a circumferential groove into which the septum 212 can be fitted.

[0057] The vascular access device 2 is configured to allow the supply of a drug solution to the access port 21 from outside the body, and the septum 212 is made of a material through which an injection needle can be inserted. The septum 212 constitutes the needle-insertion portion into which an injection needle for supplying a drug solution to the vascular access device 2 is inserted, and is a porous body with excellent elastic deformability composed of a polymer particle aggregate, similar to the artificial blood vessel 1 in the first embodiment.

[0058] The septum 212 will be described in detail below as a biocompatible member in the second embodiment, but the biocompatible member composed of a polymer particle aggregate is not limited to the septum 212, and may also be an inner housing 211a, an outer housing 211b, a catheter 22, etc.

[0059] Septum 212 is positioned so that the direction of insertion of the injection needle is in the thickness direction. The front surface of Septum 212, relative to the direction of injection needle insertion, is the bio-contact surface that comes into contact with the biological LO, while the opposite end surface, in the direction of injection needle insertion, is the drug solution contact surface that comes into contact with the drug solution supplied by the injection needle.

[0060] Furthermore, the septum 212 constituting the needle insertion site of the vascular access device 2 is required to have elastic deformation recovery that can occlude the needle mark (through hole) after puncture, and to have self-occluding properties after puncture. The self-occluding properties of the septum 212 can be confirmed, for example, by applying water pressure (e.g., 100 mm hydrohead pressure) to the site from the biological contact surface side after withdrawing an injection needle that has been inserted so as to penetrate in the thickness direction, and confirming that water does not pass through the puncture mark to the drug solution contact surface side.

[0061] The self-occlusive properties of Septum 212 may be exhibited, for example, with a 16G needle or a thinner needle at room temperature (25°C). The self-occlusive properties of Septum 212 may also be exhibited, for example, with a 23G or larger needle at room temperature (25°C). The self-occlusive properties of Septum 212 may also be exhibited with a 22G or larger needle, a 21G or larger needle, a 20G or larger needle, a 19G or larger needle, or a 18G or larger needle.

[0062] The porous material constituting the septum 212 preferably exhibits the above-described self-occluding properties at a thickness of 3.0 mm, more preferably at a thickness of 2.5 mm, even more preferably at a thickness of 2.0 mm, and particularly preferably at a thickness of 1.5 mm.

[0063] In this embodiment, the septum 212 can, for example, have a diameter larger than the opening edge 211e of the inner housing 211a when viewed in the depth direction, and less than or equal to the diameter of the enlarged portion 2111 of the inner housing 211a. The septum 212 may also have a diameter larger than the diameter of the enlarged portion 2111 of the inner housing 211a into which it is fitted. In that case, the septum 212 will receive a pressing force from the inner housing 211a toward its radial center, thereby more reliably exhibiting self-closing properties.

[0064] If the circumference of the large diameter portion 2111 of the inner housing 211a is "L1 (mm)", and the circumference of the septum 212 at the portion in contact with the large diameter portion 2111 (circumference in its natural state, not compressed by the inner housing 211a) is "L2 (mm)", and the ratio of the circumference of the septum 212 (L2) to the circumference of the large diameter portion 2111 (L1) (L2 / L1) is defined as the compression ratio, then the septum 212 can have a size that allows it to be fitted into the inner housing 211a with a compression ratio of, for example, 1.01 or higher. The septum 212 may also have a size that allows it to be fitted into the inner housing 211a with a compression ratio of, for example, 1.02 or higher, or 1.05 or higher, or 1.10 or higher. The septum 212 may have a size that allows it to be fitted into the inner housing 211a with a compression ratio of 1.30 or less.

[0065] The septum 212 is the same as the biocompatible member in the first embodiment in that it has voids that open to the biological contact surface and the drug solution contact surface. The preferred ratio of voids to polymer parts and the constituent materials, such as polymer particles and coagulants, are also the same as the biocompatible member in the first embodiment, so a detailed explanation will not be repeated here. Furthermore, the fact that the septum 212 has a complex three-dimensional network of voids extending in the thickness direction from the biological contact surface facilitates early integration with biological tissue, which is also the same as described in the first embodiment, so a detailed explanation will not be repeated here. In addition, the septum 212 can be manufactured by methods such as mold molding and powder injection molding, which is also the same as the artificial blood vessel 1, so a detailed explanation will not be repeated here.

[0066] (Other embodiments) The need for early integration between the contacting biological tissue and the component is not limited to this vascular access device 2 or the aforementioned artificial blood vessel 1. Other applications of biocompatible components composed of porous materials, which are aggregates of polymer particles, include, for example, artificial skin.

[0067] Although the above provides a detailed explanation of biocompatible components with specific examples, the present invention is not limited in any way to the above-mentioned examples. Furthermore, this specification includes the following disclosures.

[0068] (1) A biocompatible member in which at least a portion of the surface is composed of a porous material, The porous body is a biocompatible material in which polymer particles are aggregated.

[0069] (2) The biocompatible member according to (1), wherein the porous body is a sintered body of polymer particles.

[0070] (3) The porous body It comprises a first polymer, which is a silicone-based polymer, and a second polymer, which is not a silicone-based polymer. The biocompatible member according to (1) or (2), wherein both the first polymer and the second polymer are exposed on the surface.

[0071] The porous body A biocompatible material according to any one of (1) to (3), comprising one or more polymer particles selected from the group consisting of polyethylene particles, polypropylene particles, polyester polymer particles, polystyrene polymer particles, polyether ether ketone particles, and polyurethane particles. [Examples]

[0072] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0073] To evaluate the integration performance of biocompatible materials with biological tissues, implantation tests were conducted in rats. The following samples were prepared for the burial experiment.

[0074] [Table 1]

[0075] Each sample was sterilized using electrolysis (EO) and then implanted into rats. For samples 1-1 and 2-4, the same disc-shaped samples with a diameter of 20 mm and a thickness of 3.5 mm were prepared using ePTFE. However, as shown in Figure 6, the implantation positions in the rats were different. The same applies to samples 3-1 and 4-4. For samples 3-4 and 4-1, the same implantation test was performed as for samples 1-1 and 2-4, except that the sterilization method was autoclave sterilization. For Sample 1-2 and Sample 2-3, we prepared disc-shaped ePTFE samples similar to those used in Sample 1-1, with polyester threads sewn onto each. However, different polyester threads were used for Sample 1-2 and Sample 2-3. For Sample 1-4, samples were prepared by compressing ePTFE to reduce the volume fraction of the voids compared to Sample 1-1 and others. Sample 3-2 was a porous sintered sheet (porosity approximately 60%, aperture diameter approximately 20 μm) made by molding ultra-high molecular weight PE particles in a mold. A disc-shaped sample with a diameter of 20 mm and a thickness of 3 mm was prepared. Sample 4-2 was tested in the same manner as sample 3-2, except that the sample thickness was changed from 3 mm to 2 mm and the embedding position was changed as shown in Figure 6. Sample 3-3 was a porous sintered sheet (porosity approximately 60%, aperture diameter approximately 20 μm) made by molding polyester polymer particles in a mold. A strip-shaped sample measuring 20 mm in length, 5 mm in width, and 3 mm in thickness was prepared. The sample was prepared by adjusting the material to contain a small amount of silicone oil. Sample 3-3 was prepared by first creating a thick sample and then cutting it to the specified thickness. The cut surface was then heated to solidify it.

[0076] For sample 3-3, the cross-section was observed using a scanning electron microscope (SEM). The obtained SEM image is shown in Figure 7a. This figure also shows that in sample 3-3, which is a sintered polymer particle body, the particles are joined together to form a three-dimensional network structure, and large voids with a wide opening area are intricately interwoven in the depth direction, forming a continuous chain. Furthermore, the Si element was mapped in the same field of view using energy-dispersive X-ray fluorescence spectroscopy (EDX). The resulting mapping image is shown in Figure 7b (white areas indicate the presence of Si). From this mapping image, a microphase separation structure was observed on the surface of sample 3-3, revealing that a silicone-based polymer constituted the dispersed phase and a polyester-based polymer resin constituted the continuous phase.

[0077] Each of the samples described above was implanted in rats at the location shown in Figure 6. After 28 days, the samples were removed from the rats, and observation specimens were prepared from the removed samples.

[0078] (Specimen preparation) A specimen was cut from approximately the center of each sample in the head-to-tail direction (except for #3-3, which was cut in the left-to-right direction), and a cross-sectional image was photographed (Figure 8). Since the specimens were not fully fixed, they were re-fixed with NBF, then dehydrated using a dehydration and infiltration apparatus (Tissue-Tek VIP 6 AI; Sakura Finetek Japan CO. LTD, Tokyo, Japan) in an increasing concentration series of 70-100% ethanol, replaced with xylene, and infiltrated with paraffin Parabet 60 GR (#43257; Muto pure chemicals CO. LTD, Tokyo, Japan) with a melting point of 58-60°C to create paraffin-embedded blocks. Thin sections were prepared from this block using a sliding microtome (LS113; YAMATO-KOHKI industrial CO.LTD, Asaka, Saitama, Japan) to a set thickness of 4 mm. These sections were mounted on standard glass slides (#5116; Muto pure chemicals) coated with 3-aminopropyltrimethoxysilane (APS) as defined in Japanese Industrial Standards (JIS R 3703 / ISO8255-1), dried overnight at 37°C, and then stained with hematoxylin-Eosin (HE).

[0079] (Observation and image capture) A COOLPIX B600 (NIKON Corporation, Tokyo, Japan) was used to capture cross-sectional images of the test specimens. The prepared specimens were observed using an optical microscope BX-43 (OLYMPUS Corporation, Tokyo, Japan), and the primary evaluations were made of infiltration into the sample and signs of inflammation in the surrounding tissue. Invasion within the sample was classified into tissue invasion accompanied by tissue structures such as fibers and blood vessels, and cellular invasion consisting only of free cells. In the display of the results, the word "fiber" was used for bio-derived fibers and "fiber" for artificial fibers (descriptions regarding other parts and directions are shown in Figure 9a (overall image of sample 1-1)). Furthermore, the microscope images were captured using the DP-22 (OLYMPUS) imaging device. The whole image of the specimen was created by tiling and combining microscope images at 20x magnification using the Multiple Image Alignment (MIA) function of CellSens (OLYMPUS). (result) <Sample 1-1: ePTFE (control)> Sample 1-1 was a stretched PTFE (ePTFE) porous material implanted directly beneath the dermal muscle layer and used as a control sample. It was slightly curved toward the epidermal side, and the caudal end was somewhat rounded as if the corners had been trimmed, but otherwise there was no significant distortion or fracture in shape, and the rectangular cross-section of an almost disc-shaped sample was maintained (Figure 9a). The sample was surrounded by a thin, relatively dense fibrous tissue mainly composed of fibroblasts, and while capillary proliferation was observed on the outside, no strong inflammatory cell infiltration, granulation tissue formation, bleeding, or calcification was observed in the surrounding tissue. Furthermore, on the cranial (left and right) short sides of the sample (hereinafter referred to as the "vertical ends"), a very small number of macrophages, including multinucleated giant cells, were observed lined up along the ePTFE fiber ends, and fibrous infiltration accompanied by fibrous components (presumably collagen fibers) was observed in some areas, eroding the sample (Figure 9b: arrow). In other areas, including the epidermal-deep (upper and lower) long sides of the sample (hereinafter referred to as the "horizontal ends"), widespread cellular infiltration (exudation), mainly of lymphocytes, was observed, seeping into the lattice-like spaces of the ePTFE fibers from the surrounding tissue, but these cellular infiltrations were centered on the sample. It did not extend to the department (Figures 9b, 9c, 9d, 9e).

[0080] <Sample 1-2: Sewing with ePTFE-polyester thread> In sample 1-2, similar to sample 1-1, the implanted sample beneath the muscular layer of the skin was surrounded by fibrous tissue. The fibrous tissue appeared slightly thicker than in sample 1-1 (especially in the area directly beneath the muscular layer), but no strong inflammatory cell infiltration, granulation tissue formation, or bleeding was observed in the surrounding tissue. The sample was slightly curved towards the epidermis and had three large fractures at its horizontal end (Figure 10a). At two of these fractures, closer to the cranial (left and right) ends, bundles of polyester fibers accompanied by macrophages were observed on both the upper and lower sides of the sample, and polyester fibers were also found within the ePTFE fibers (Figure 10b: Polyester fibers are labeled "PET"). In addition, polyester fiber bundles accompanied by macrophages were observed to penetrate ePTFE fibers from the epidermal-deep (upper and lower) side in several locations (Figure 10e: Polyester fibers are labeled "PET"). On the other hand, in the slightly larger fracture area in the center of the horizontal end, polyester fibers were not observed. Instead, a somewhat edematous and loose fibrous tissue with capillaries infiltrated and proliferated, almost bridging the ePTFE fibers from the epidermal-deep (upper and lower) side, but no strong inflammatory cell infiltration or granulation tissue formation was observed (Figures 10c and 10d). Furthermore, macrophages and lymphocytes, including a small number of multinucleated giant cells (Figure 10e: arrow), were found to have infiltrated somewhat widely into the voids within the sample (Figure 10e). In other areas, cell infiltration from the surrounding tissue into the ePTFE fibers was observed, similar to sample 1-1, but deep infiltration into the central part of the sample, excluding the fractured area, was scarce.

[0081] <Sample 1-3: ePTFE-polyester thread sewn on - low cleanliness> Samples 1-3 were located beneath the dermal muscle layer and surrounded by a thin layer of fibrous tissue. They were slightly curved toward the epidermis and appeared somewhat compressed and concave near the center of their horizontal ends (Figure 11a). This recessed area appears to be slightly compressed by the surrounding tissue, but unlike samples 1-2, there was no evidence of ePTFE fiber rupture due to deep fibrous tissue infiltration from the surrounding tissue. Furthermore, no significant inflammatory cell infiltration, granulation tissue formation, or bleeding was observed in the surrounding tissue. In samples 1-3, similar to samples 1-2, bundles of polyester yarn were observed to penetrate the ePTFE fibers from above and below (Figure 11b: polyester fibers are labeled "PET"), and polyester fibers were also observed within the fractures (Figure 11c: polyester fibers are labeled "PET"), but the number and size (degree) of fractures were fewer than in samples 1-2. Slight fibrous infiltration was observed at the cranial vertical end (Figure 11d: arrow), and mild cellular infiltration, mainly lymphocytes including some macrophages, was observed in the surrounding tissue on all sides, including between polyester fibers and ePTFE fibers, and in the voids within the ePTFE fibers (Figure 11e: polyester fibers are labeled "PET"). However, the infiltration depth hardly extended to the center of the sample.

[0082] <Sample 1-4: ePTFE-Low porosity> In samples 1-4, the horizontal ends (especially the epidermal side) of the ePTFE samples implanted beneath the dermal muscle layer were irregularly and significantly indented, as if partially compressed, resulting in an irregular shape (Figure 12a). Within the ePTFE fibers, layers with different void densities were observed stacked in a striped pattern in the direction of compression (Figures 12b and 12c). The outer periphery of the sample was covered with a thin layer of fibrous tissue, and mild proliferation of capillaries was observed in the tissue outside of this layer. However, no strong inflammatory cell infiltration, granulation tissue formation, or bleeding was observed in the surrounding tissue. No significant fibrous proliferation was observed in the depressed areas on the epidermal side, and mild edema was seen in a small area (Figures 12b, 12c, and 12d: arrows). Mild cellular infiltration, mainly lymphocytes, was observed in the surrounding tissues, seeping into the voids within the ePTFE fibers, but the infiltration did not extend far into the center of the sample (Figure 12e). Cellular infiltration from the epidermal tissue was particularly minor.

[0083] <Sample 2-1: ePTFE - Low porosity - Different implantation location from Sample 1-4> In sample 2-1, which was implanted beneath the dermal muscle layer, two large depressions were observed at the horizontal end on the epidermal side, similar to sample 1-4 (Figure 13a). Within the ePTFE fibers, layers with different void densities were observed stacked in a striped pattern in the direction of compression (Figures 13b and 13c). The sample was surrounded by fibrous tissue that was slightly thicker than that of samples 1-4, and capillary proliferation was observed at its outer edge. However, no strong inflammatory cell infiltration, granulation tissue formation, or bleeding was observed in the surrounding tissue. Unlike samples 1-4, sample 2-1 did not show edema in the surrounding tissue of the depressed area. Although there was some fibrous tissue proliferation, there was no strong fibrous tissue infiltration from the surrounding tissue. Furthermore, macrophages were observed in a thin, lined fashion along the edges of the depressions, but cell infiltration into the ePTFE fibers was limited (Figure 13d). On the other hand, on the opposite side of the epidermis (i.e., the side without depressions), cellular infiltration, mainly lymphocytes, was observed, with cells seeping from the surrounding tissue into the voids within the ePTFE fibers (Figure 13e).

[0084] <Sample 2-2: ePTFE - polyester thread sewn - low cleanliness - different implantation position from Samples 1-3> Sample 2-2, implanted beneath the dermal muscle layer, was surrounded by relatively thin fibrous tissue. However, near the center of its horizontal end, it was fragmented over a relatively wide area by loosely fibrous connective tissue with capillaries (in other words, some of the fibers were replaced). This area was the second largest among the samples studied, after sample 4-3 (Figures 14a and 14b). Within the fibrous connective tissue, fragmentary clumps of ePTFE fibers were observed, resembling the rounded edges of sandbars in river mouths, smoothed by water currents. Some macrophages, arranged around these clumps, infiltrated the surrounding tissue, including fibrous tissue containing capillaries, and separated the ePTFE fibers (Figure 14d: arrows). However, no necrosis, hemorrhage, severe granulation tissue formation, or inflammatory cell infiltration was observed. On the other hand, at the head and tail ends (left and right) of the sample, bundles of polyester fibers were observed sandwiching the ePTFE fibers from both above and below, and were embedded within the ePTFE fibers (Figure 14c). This involved the infiltration of fibrous tissue that extended continuously from the tissue between the polyester fibers and ePTFE fibers (Figure 14e). In addition, cell infiltration from surrounding tissues was observed in other areas.

[0085] <Sample 2-3: ePTFE - sewn with polyester thread - different polyester thread from Sample 1-2> In samples 2-3, the ePTFE samples implanted beneath the dermal muscle layer were slightly curved and surrounded by fibrous tissue, but no bleeding, strong granulation tissue formation, or inflammatory cell infiltration was observed in the surrounding tissue (Figure 15a). Similar to samples 1-3, bundles of polyester yarn were observed at the horizontal ends, sandwiching the ePTFE fibers from both above and below, compressing the ePTFE fibers, and some of them even embedded within the ePTFE fibers (Figure 15b). However, compared to samples 1-2 and 2-2, the polyester fibers had a significantly smaller cross-sectional diameter, and there were few findings indicating foreign body reactions such as macrophage infiltration around the fibers. Furthermore, infiltration of fibrous tissue accompanied by capillaries into the ePTFE fibers was observed from the surrounding tissue near the polyester fiber bundles (Figure 15c: Polyester fibers are labeled "PET"). This fibrous tissue infiltration progressed deep into the ePTFE fibers, tearing them apart, and also infiltrated finely into the interior from the sides of the ePTFE fibers (Figure 15d: polyester fibers labeled "PET", Figure 15e). Fragmented ePTFE fibers were also observed (Figure 15d: arrows).

[0086] <Sample 2-4: ePTFE - Different implantation location from Sample 1-1> Similar to sample 1-1, sample 2-4, which was implanted beneath the dermal muscle layer, was surrounded by a thin layer of fibrous tissue, slightly curved toward the epidermis, and had a somewhat rounded edge on one side of its vertical end, as if the corner had been smoothed. However, no bleeding, strong granulation tissue formation, or inflammatory cell infiltration was observed in the surrounding tissue (Figure 16a). However, near the center of the horizontal end of the sample on the epidermal side, it was indented due to compression by the surrounding fibrous tissue, and striped density differences due to compression were observed within the ePTFE fibers, as in samples 1-4 (Figure 16b). At the vertical end of the sample, we observed areas where a portion of the surrounding fibrous tissue had slightly infiltrated the ePTFE fibers in an incision-like or wedge-like manner (Figure 16c: arrow), as well as areas where a portion of the ePTFE fibers had been finely divided by thin fibrous tissue along with cellular infiltration into the fibers (Figure 16d: arrow). Furthermore, macrophages were observed along the ePTFE fibers in the compressed depressions at the horizontal ends, but no multinucleated giant cells were found, and cell infiltration into the ePTFE fibers was minimal (Figure 16e).

[0087] <Sample 3-1: ePTFE - Same as Sample 1-1 (Control)> Sample 3-1, implanted beneath the dermal muscle layer, was surrounded by fibrous tissue and slightly curved toward the epidermis. However, it resembled sample 2-4 more than sample 1-1, exhibiting a depression due to compression near the center of the horizontal end on the epidermal side and a striped pattern due to differences in void density within the ePTFE fibers (Figure 17a). Microscopic findings were similar to those of samples 2-4, with very slight incision-like fibrous tissue infiltration at the vertical end (Figure 17b: arrow) and rounded corners, and a small number of macrophages were observed along the depression at the horizontal end (Figure 17c). At both horizontal ends, lymphocyte-dominant cellular infiltration from the surrounding tissue into the ePTFE void was observed, but the degree was slightly stronger than in sample 2-1 and weaker than in sample 1-1 (Figures 17d and 17e). No bleeding, severe granulation tissue formation, or inflammatory cell infiltration was observed in the surrounding tissue, including the fibrous tissue enclosing the sample and the capillary proliferation area outside of it.

[0088] <Sample 3-2: Coagulated PE particles> Sample 3-2, implanted beneath the dermal muscle layer, was completely encased in fibrous tissue with a relatively high tissue density. No warping or rupture was observed in the sample, and no significant deformation was seen at either the horizontal or vertical ends (Figure 18a). Furthermore, no bleeding, strong granulation tissue formation, or inflammatory cell infiltration was observed in the surrounding tissue. Unlike the ePTFE fibers in the groups of samples 1-1 to 1-4 and 2-1 to 2-4, which have a network of voids, the internal structure of the sample showed small vacuoles, presumably traces of compressed powder, clustered together in a foamy manner throughout. However, no obvious foreign matter remained. The spaces between these foamy vacuoles were finely infiltrated throughout the sample by macrophages containing multinucleated giant cells, lymphocytes, and fibrous tissue containing capillaries, and relatively large granulation tissue formation was observed near the center of the sample (Figures 18b, 18c, 18d, and 18e). Capillary congestion was observed, but no severe tissue bleeding or necrosis was found.

[0089] <Sample 3-3: Coagulated material of silicone-added polyester particles> The cutaneous muscle layer at the implantation site was compressed and slightly narrowed by sample 3-3, which was implanted directly beneath the cutaneous muscle layer. The sample was surrounded by fibrous tissue with a relatively high tissue density, and was bisected approximately in the middle of its horizontal edge by thin fibrous tissue continuous with this tissue, resulting in two rectangular cross-sections (Figures 19a and 19b). Furthermore, this sample appeared to be relatively inflexible, and a fairly large gap was observed between it and the fibrous tissue (Figure 19c). In particular, the surrounding tissue was sparse outside the fibrous tissue at the horizontal end, and capillary proliferation was less pronounced compared to sample 3-2, but no strong granulation tissue formation or inflammatory cell infiltration was observed. The internal structure of the sample showed no obvious foreign matter residue, similar to sample 3-2. Vacuoles, presumably traces of compressed powder, were observed throughout in a foamy manner. Fibrous tissue, accompanied by macrophages, lymphocytes, and capillaries, infiltrated the gaps between the foamy vacuoles more continuously and finely than the surrounding tissue. However, compared to sample 3-2, the fused vacuolar portions were larger, resulting in a higher area ratio of vacuoles. Consequently, the formation of relatively large granulation tissue within the sample, as seen in sample 3-2, was poor (Figures 19d and 19e).

[0090] <Sample 3-4: ePTFE - Different sterilization method from Sample 3-1> Samples 3-4, implanted beneath the dermal muscle layer, were slightly curved toward the epidermis, and showed mild depressions at the center of the horizontal end, indicating compression from both the top and bottom (Figure 20a). In the depressed areas, the voids within the ePTFE fibers appeared to be compressed, resulting in an irregularly high fiber density, but no tissue infiltration from the surrounding tissue was observed (Figures 20c, 20d). The sample was surrounded by fibrous tissue, and mild proliferation of capillaries was observed on the outside of it, but there was no bleeding, severe granulation tissue formation, or inflammatory cell infiltration. Slight thickening of the surrounding tissue was observed at the vertical end of the sample, and very slight fibrous tissue infiltration was seen at the end of the ePTFE fibers (Figure 20b). Mild cellular infiltration, mainly lymphocytes, was also observed at the horizontal end (Figure 20e).

[0091] <Sample 4-1: ePTFE - Different implantation location from Sample 3-4> Sample 4-1, which was implanted beneath the dermal muscle layer, was slightly curved toward the epidermis and its four corners were slightly rounded, but no compression of the outer edge, striped appearance due to differences in void density, or ruptures were observed (Figure 21a). The sample was surrounded by fibrous tissue, and slight capillary proliferation was observed outside of this, but there was no bleeding, strong granulation tissue formation, or inflammatory cell infiltration in the surrounding tissue. At the vertical end, the fibrous tissue was slightly thickened, and the ends of the ePTFE fibers were slightly jagged (Figure 21b). At the horizontal end, the surrounding fibrous tissue was thin, a small number of macrophages were observed along the ePTFE fibers, and cell infiltration, mainly lymphocytes, was observed in the voids within the ePTFE fibers (Figures 21c, 21d, and 21e).

[0092] <Sample 4-2: Agglomerated PE particles - Different thickness from Sample 3-2> Sample 4-2, implanted beneath the dermal muscle layer, was completely encased in fibrous tissue with a relatively high tissue density, similar to sample 3-2. No warping or rupture was observed in the sample, and no significant deformation was seen at either the horizontal or vertical ends (Figure 22a). Furthermore, no bleeding, severe granulation tissue formation, or inflammatory cell infiltration was observed in the surrounding tissue, including the fibrous tissue and the mildly proliferated capillaries outside it. The internal structure of the sample was almost identical to that of sample 3-2, with small, foamy vacuoles, likely remnants of compressed powder, observed throughout. However, no obvious foreign matter was found. In the spaces between these foamy vacuoles, fibrous tissue containing macrophages, lymphocytes, and capillaries, including multinucleated giant cells, was finely infiltrated throughout the sample, continuing from the surrounding tissue. However, compared to sample 3-2, there was a scarcity of large granulation tissue (Figures 22b, 22c, 22d, and 22e). Mild congestion was observed in some capillaries, but no severe bleeding or necrosis was seen.

[0093] <Sample 4-3: Coagulated PE particles - Different burial location from Sample 3-2> Sample 4-3, implanted beneath the dermal muscle layer, was relatively widely fractionated in the central part of its horizontal end by sparsely fibrous connective tissue with capillaries and multinucleated giant cells, resulting in a cross-section separated into two pieces, craniocaudal (left and right) (Figure 23a). The entire sample was covered with a somewhat dense, membrane-like fibrous tissue, but this was absent in the broad, sparse fibrous connective tissue portion separating the two, which distinguished it from samples 2-2 and 3-3 (Figure 23b). The absence of this capsular fibrous tissue suggests that the sample was not originally a single piece that was split into left and right halves, but rather that it was originally separate and not continuous, meaning there was some gap between the two and it was mobile. In any case, no bleeding, strong granulation tissue formation, or inflammatory cell infiltration was observed in the surrounding tissue (Figure 23c). The internal structure of both samples was almost identical to that of sample 3-2, and no obvious foreign matter remained. However, small, foamy vacuoles, which appear to be traces of compressed powder, were observed throughout. In the gaps of the foamy vacuoles, macrophages containing multinucleated giant cells, lymphocytes, and fibrous tissue containing capillaries were finely infiltrated from the loose fibrous connective tissue and the surrounding capsule-like fibrous tissue into the sample. However, there was no formation of relatively large granulation tissue as in sample 3-2, and tissue infiltration was less pronounced in the center of the sample (Figures 23d and 23e).

[0094] <Sample 4-4: ePTFE - Different implantation location from Sample 3-1> Sample 4-4 was closer to sample 3-1 than to sample 1-1, and like the other ePTFE samples, the sample implanted beneath the dermal muscle layer was slightly curved toward the epidermis, with a depression observed near the center of the horizontal end on the epidermal side. The sample was covered with a membrane-like fibrous tissue, and the fibrous tissue was slightly thinner at the vertical end than in sample 3-1 (Figure 24b). However, no bleeding, strong granulation tissue formation, or inflammatory cell infiltration was observed in the surrounding tissue, including the fibrous tissue and the mild capillary proliferation area outside of it (Figure 24a). Similar to sample 3-1, the interior of the sample also showed a striped pattern due to differences in void density in the depressed areas (Figure 24c), but some of the macrophages observed along the surface of the depressed areas had slightly infiltrated into the ePTFE (Figure 24d: arrow). Furthermore, while a slightly higher number of macrophages were observed along the horizontal edges of the ePTFE, cellular infiltration into the ePTFE fibers from there was mainly lymphocytes, which were relatively scattered and only found within the voids (Figure 24e).

[0095] As described above, while cell infiltration in ePTFE is limited to the surface, when polymer particle aggregates are implanted, cell infiltration is observed even within the tissue, demonstrating superior integration with biological tissue. Therefore, it can be understood that the present invention can provide a biocompatible material that easily integrates with biological tissue. [Explanation of Symbols]

[0096] 1: Artificial blood vessel 1s1:Outer surface 1s2: Inner surface 2: Vascular access devices 11: Master 11L, 12L: Large diameter part 11S, 12S: Small diameter section 11a: One end 11b: Other end 12: Branch pipe 121: 1st branch, 122:Second branch, 123:Third branch 21: Access Port 21a: Containment space 21b: Nozzle section 22: Catheter 100: Porous material 211: Housing 211a: Inner housing 211b: Outer housing 211e: Opening edge 212: Septum 2111: Large diameter section BV: Blood vessel CX: Central axis D1: Depth direction D2: Planar direction LO: Living organism M1: Molding mold (outer mold) M2: Internal type (core pin) M21, M22, M23, M24, M25: Split type MP: molding surface MV: Cavity P: Polymer part SK: epidermis V: Void

Claims

1. A biocompatible member in which at least a portion of the surface is composed of a porous material, The porous body is a biocompatible material in which polymer particles are aggregated.

2. The biocompatible member according to claim 1, wherein the porous body is a sintered body of polymer particles.

3. The porous body It comprises a first polymer which is a silicone-based polymer and a second polymer which is not a silicone-based polymer. The biocompatible member according to claim 1 or 2, wherein both the first polymer and the second polymer are exposed on the surface.

4. The porous body The biocompatible member according to claim 1 or 2, comprising one or more polymer particles selected from the group consisting of polyethylene particles, polypropylene particles, polyester polymer particles, polystyrene polymer particles, polyether ether ketone particles, and polyurethane particles.

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