Biocompatible material and method for manufacturing the same

Abstract

The present invention provides a biocompatible component that is highly biocompatible and easy to handle, as well as a method for manufacturing the same. [Solution] The biocompatible member comprises an aggregate of fibers containing a biocompatible material bonded together, and water contained between the fibers. The biocompatible member has a plurality of layers. Within each layer, the fibers are oriented. The orientation directions of the fibers in two adjacent layers intersect each other.

Description

Technical Field

[0001] Embodiments relate to a biocompatible member and a method for manufacturing the same.

Background Art

[0002] In the medical field, biocompatible members have been developed for use in the living body or as a material for cell growth. Biocompatible members are required to have high biocompatibility and be easy to handle. For example, it is desired that the biocompatible member has a strength such that it can maintain its shape even when held with tweezers or the like, and is soft enough to be cut with scissors or a scalpel.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] An object of the embodiments is to provide a biocompatible member having high biocompatibility and easy to handle, and a method for manufacturing the same.

Means for Solving the Problems

[0005] The biocompatible member according to the embodiments includes an aggregate in which fibers containing a biocompatible material are bonded to each other, and water contained between the fibers. The biocompatible member has a plurality of layers. In the layer, the fibers are oriented. The orientation directions of the fibers in two adjacent layers intersect each other.

[0006] A method for manufacturing a biocompatible member according to an embodiment comprises the steps of: forming a laminated sheet by pulling fibers containing a biocompatible material in one direction to form a deposit layer in which the direction of extension of the fibers is aligned, and stacking a plurality of such deposit layers so that the directions of extension of the fibers intersect in two adjacent deposit layers; impregnating the laminated sheet with a volatile liquid; volatilizing the liquid that has permeated the laminated sheet; and subjecting the laminated sheet from which the liquid has been volatilized to a water-infused treatment. [Brief explanation of the drawing]

[0007] [Figure 1] This is a diagram showing a biocompatible member according to the first embodiment. [Figure 2] (a) and (b) are diagrams showing a method for manufacturing a biocompatible member according to the first embodiment. [Figure 3] Figures (a) to (c) show a method for manufacturing a biocompatible member according to the first embodiment. [Figure 4] This figure shows a hydrostatic pressure treatment, which is one of the methods for manufacturing a biocompatible member according to the second embodiment. [Figure 5] This figure shows a reduced pressure treatment as part of the manufacturing method for a biocompatible member according to the third embodiment. [Figure 6] (a) is a surface SEM image of a deposited layer formed by electrospinning, and (b) is a surface SEM image of a laminated sheet after ethanol treatment. [Figure 7] (a) and (b) are surface SEM images of freeze-dried samples of biocompatible materials related to the test examples. [Figure 8] This graph shows the differential scanning calorimetry results for laminated sheets and biocompatible materials related to the test examples, with temperature on the horizontal axis and heat flow on the vertical axis. [Figure 9] This table shows the differential scanning calorimetry results for the laminated sheets and biocompatible materials used in the test examples. [Figure 10] This table shows the measurement results of the compressive modulus of biocompatible materials related to the test examples. [Figure 11](a) is a graph showing the storage modulus-frequency curve of the biocompatible material in the test example, with frequency on the horizontal axis and storage modulus on the vertical axis, and (b) is a graph showing the loss modulus-frequency curve of the biocompatible material in the test example, with frequency on the horizontal axis and loss modulus on the vertical axis. [Figure 12] This is a surface SEM image showing a cross-section of a biocompatible component related to a test example. [Modes for carrying out the invention]

[0008] <First Embodiment> The first embodiment will be described below. Figure 1 shows a biocompatible member according to this embodiment.

[0009] As shown in Figure 1, the biocompatible member 1 according to this embodiment includes an aggregate 12 formed by the bonding of multiple fibers 11 together, and water 13 contained between the fibers 11. The water content of the biocompatible member 1 is 40% by mass or more and 90% by mass or less.

[0010] The fiber 11 contains a biocompatible material. The biocompatible material is, for example, a bio-derived material. A bio-derived material is a material produced by life activities, or a material obtained by processing such a material. The biocompatible material does not have to be a bio-derived material; for example, it may be a synthetic polymer, a functional protein or synthetic polypeptide obtained by artificial synthesis, etc.

[0011] Biocompatible materials include, for example, proteins such as collagen, laminin, and gelatin, nucleic acids such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), and polysaccharides such as chitosan, chitin, chitosan, hyaluronic acid, alginic acid, and heparin. Synthetic polymers include, for example, polyethylene (PE), polypropylene (PP), polymethyl methacrylate (PMMA), poly(2-hydroxyethyl methacrylate) (PHEMA), poly(N-isopropylacrylamide) (PNIPAAm), polyvinyl alcohol (PVA), polycyanoacrylate ester, polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polyethylene glycol (PEG), polyethylene oxide (PEO), polyhydroxy acids such as polylactic acid (PLA), polyglycolic acid, and polycaprolactone, and silicones such as polydimethylsiloxane (PDMS) and polydimethylsiloxane (PDMS).

[0012] For example, the fiber 11 is composed of collagen with a high-dimensional, i.e., three-dimensional structure. The structure of the original collagen molecule is a triple helix structure, and the collagen constituting the fiber 11 also maintains this structure. In the aggregate 12, the fibers 11 are bonded to each other by being partially welded, for example, by non-covalent interactions. Examples of non-covalent interactions include intermolecular forces, hydrophobic interactions, and hydrogen bonds. The diameter of the fiber 11 is, for example, about 60 nm to 3 μm.

[0013] The shape of the biocompatible member is, for example, sheet-like. In the biocompatible member 1, a plurality of layers 10 laminated in the thickness direction are provided. The layers 10 are laminated, for example, about 2 to 100 layers, and the thickness of each layer 10 is, for example, about 5 to 500 μm. The overall thickness of the biocompatible member 1 is, for example, about 0.03 to 50 mm.

[0014] Within each layer 10, the fibers 11 are oriented, for example, in one direction. The orientation directions of the fibers 11 in two adjacent layers 10 intersect each other, and for example, are substantially orthogonal to each other. As shown in FIG. 1, in the XYZ orthogonal coordinate system, when the thickness direction of the biocompatible member 1, that is, the stacking direction of the layers 10, is the Z direction, the layer 10 with the orientation direction in the X direction and the layer 10 with the orientation direction in the Y direction are stacked alternately. Within each layer 10, adjacent fibers 11 are linearly joined together. The bonding force between the layers 10 is weaker than the bonding force between the fibers 11 within the layer 10. On the surface of the biocompatible member 1, voids 15 with a diameter of 10 μm or more are formed at a density of 1 piece / mm 2 or more.

[0015] Note that FIG. 1 is a schematic diagram conceptually showing the configuration of the biocompatible member, and does not necessarily match the actual configuration. For example, as described above, the diameter of the fiber 11 is about one-thousandth of the thickness of the layer 10, but in FIG. 1, for ease of viewing the figure, the fiber 11 is drawn larger than the actual size. Also, since the fibers 11 are joined together, even when the biocompatible member 1 is observed with a microscope, the individual fibers 11 may not always be distinguishable. Furthermore, the boundary between the layers 10 may not always be clearly observable. The same applies to other figures described later.

[0016] The compression elastic modulus of the biocompatible member 1 is 5 kPa or more. Also, the biocompatible member 1 is an elastic body, and when a viscoelastic - frequency curve is measured by the dynamic viscoelastic method, the storage elastic modulus is higher than the loss elastic modulus. The biocompatible member 1 is a solid as a whole, a soft elastic body, and has no fluidity. Also, the biocompatible member 1 is transparent or translucent.

[0017] Next, a method for manufacturing the biocompatible member 1 according to the present embodiment will be described. FIGS. 2(a) and (b), FIGS. 3(a) to (c) are diagrams showing a method for manufacturing the biocompatible member 1 according to the present embodiment.

[0018] First, as shown in Figure 2(a), the fibers 11 are formed by the electrospinning method. The fiber manufacturing apparatus 101 is equipped with a nozzle 102, a roller 103, and a power supply 104. The roller 103 rotates at high speed. The power supply 104 applies voltage to the nozzle 102.

[0019] In this state, the charged raw material liquid 110 is discharged from the nozzle 102. The raw material liquid 110 contains biocompatible materials, such as collagen. Immediately after being discharged from the nozzle 102, the raw material liquid 110 is stretched by electrostatic repulsion and becomes fibers 11, which reach the outer surface of the roller 103 and are wound up at high speed by the roller 103. As a result, the fibers 11 are deposited in an orientation toward the outer surface of the roller 103, forming a deposited layer 10a. The deposited layer 10a is a layer in which the fibers 11 are deposited in an oriented state.

[0020] Next, as shown in Figure 2(b), multiple deposit layers 10a are stacked on the substrate 112. At this time, the orientation directions of adjacent deposit layers 10a are crossed, for example, perpendicular. The stacked deposit layers 10a form a laminated sheet 10b.

[0021] The composition and shape of the base material 112 are not particularly limited, but a composition and shape that provides the best possible adhesion to the deposited layer 10a is preferred. The material of the base material 112 may be, for example, synthetic polymers such as polystyrene (PS), polyethylene (PE), polypropylene (PP), polymethyl methacrylate (PMMA), polylactic acid (PLA), polyethylene oxide (PEO), polyvinyl alcohol (PVA), polyacrylonitrile (PAN), polyethylene terephthalate (PET), polycarbonate (PC), polyurethane (PU), and silicone; natural polymers such as collagen, gelatin, laminin, chitosan, and chitin; decellularized tissue; or biological tissue such as human skin or organs. The base material 112 may also be a biocompatible member 1 that has already been manufactured, or a substrate, cloth, sphere, rod, tube, or other component formed by molding the biocompatible member 1, or an artificial biological structure such as an artificial blood vessel, artificial valve, artificial joint, or artificial tooth. Furthermore, the base material 112 may contain drugs, cells, blood, body fluids, etc.

[0022] Next, as shown in Figure 3(a), a volatile liquid is impregnated into the laminated sheet 10b. The volatile liquid is not particularly limited, but it is preferable to use one that does not dissolve the fibers 11 as much as possible. For example, water, alcohols (ethanol, methanol, isopropyl alcohol, etc.), or an aqueous alcohol solution can be used. For example, a cloth 113 impregnated with ethanol is placed on the laminated sheet 10b which is placed on the substrate 112. This causes the ethanol in the cloth 113 to penetrate into the laminated sheet 10b.

[0023] Next, as shown in Figure 3(b), the volatile liquid that has permeated the laminated sheet 10b is removed from within the laminated sheet 10b by volatilization. As a result, the capillary forces of the liquid cause some of the fibers 11 to fuse together, and the fibers 11 become bonded to each other. Consequently, an aggregate 12 is formed on the substrate 112. The aggregate 12 is a structure in which the fibers 11 are three-dimensionally accumulated. Furthermore, if spaces (bubbles) that are not filled with volatile liquid are formed within the laminated sheet 10b, voids 15 (see Figure 1) will be formed in the aggregate 12 after the volatile liquid is removed. The thickness of the aggregate 12 becomes about (1 / 3) to (1 / 5) times thinner than the laminated sheet 10b before the volatile liquid was permeated. The aggregate 12 also becomes transparent or translucent.

[0024] The aggregate 12 formed on the substrate 112 may be peeled off from the substrate 112 and used independently, or it may be used integrally with the substrate 112.

[0025] Next, as shown in Figure 3(c), the aggregate 12 is subjected to a water-reinforcement treatment. The water-reinforcement treatment can be performed by immersing it in water 116 in a container 115, pouring water 116 into it, bringing it into contact with a cloth soaked in water 116, or spraying water 116 in a mist. The water 116 may be pure water or physiological saline. The water 116 may also be an aqueous solution containing serum such as fetal bovine serum (FBS), various liquid culture media, proteins, RNA, DNA, or substrates, or it may be a suspension of cells, body fluid, or blood. As a result, water penetrates between the fibers 11, the fibers 11 absorb the water and swell, and the biocompatible member 1 is produced. Due to these water-reinforcement treatments, the biocompatible member 1 swells to 2 to 5 times its original size at room temperature.

[0026] Next, the effects of this embodiment will be described. The biocompatible member 1 according to this embodiment exhibits high biocompatibility because its fibers 11 are made of biocompatible material. For example, even when the biocompatible member 1 is placed in the body, it does not exhibit toxicity. Furthermore, it can suppress rejection reactions such as inflammation by the body. In particular, by forming the fibers 11 with high-dimensional collagen that has not undergone degradation, rejection reactions can be suppressed more effectively. Moreover, when the fibers 11 are formed from bio-derived material and the biocompatible member 1 is placed in the body, the bio-derived material is consumed by the body's metabolism, and the fibers 11 loosen up. This makes it easier for cells to enter between the fibers 11.

[0027] Furthermore, the biocompatible component 1 contains water 13 at a concentration of 40% to 90% by mass. This water content is close to the water content in living organisms. This also contributes to the high biocompatibility of the biocompatible component 1.

[0028] Furthermore, the surface of the biocompatible component 1 contains voids 15 with a diameter of 10 μm or more, at a rate of 1 void / mm². 2 It is formed with the above density. This makes it easier for the body's cells to enter the void 15 when the biocompatible member 1 is placed in a living body. The cells that have entered the void 15 use it as a scaffold to further enter the biocompatible member 1.

[0029] Furthermore, the biocompatible member 1 is provided with multiple layers 10, and the bonding force between the layers 10 is weaker than the bonding force between the fibers 11 within each layer 10. Therefore, when the biocompatible member 1 is placed in a living body and pressure or heat is applied to it from the surrounding biological tissue, the layers 10 tend to separate, creating gaps. This allows cells to enter the gaps between the layers 10, further promoting the formation of cell tissue.

[0030] Furthermore, since the fibers 11 of the biocompatible member 1 are oriented, the biocompatibility of the biocompatible member 1 can be further improved by aligning the orientation direction of the fibers 11 with the direction of the biological tissue.

[0031] Thus, the biocompatible component 1 exhibits high compatibility with surrounding cell tissues. Therefore, for example, if the biocompatible component 1 is placed in a tissue-damaged area or in the space after tumor resection, it is expected that the biocompatible component 1 will serve as a scaffold for cell proliferation, promoting wound healing and tissue reconstruction. Furthermore, if used as a covering material when implanting artificial materials or drugs into the body, it is expected to have an effect of suppressing inflammation within the body. Moreover, if the biocompatible component 1 is used as a scaffold material when proliferating cells and tissues outside the body, it is expected that cells and tissues can be proliferated and cultured efficiently or three-dimensionally.

[0032] Since the biocompatible component 1 is formed from fibers 11 made of biocompatible material and water 13, when the biocompatible component 1 is placed in a living body, it gradually disappears due to reactions within the body. As a result, the biocompatible component 1 does not remain in the living body after fulfilling its role, and does not interfere with cell proliferation or tissue regeneration.

[0033] Furthermore, in the biocompatible member 1, the fibers 11 are bonded to each other, for example, by welding, to form an aggregate 12. Therefore, even if water 13 is included in the fibers 11 within the aggregate 12, the overall strength of the biocompatible member 1 can be maintained. For example, the biocompatible member 1 has a compressive modulus of 5 kPa or more, and its storage modulus is higher than its loss modulus. Therefore, the biocompatible member 1 has high rigidity, to the extent that it can maintain its shape even when picked up with tweezers or the like.

[0034] On the other hand, the biocompatible material 1 is soft enough to be cut with scissors or a scalpel. Therefore, for example, in a medical setting, the biocompatible material 1 can be processed by picking it up with tweezers and cutting it with scissors or a scalpel, or by bending it to fit the shape of a wound. In this way, the biocompatible material 1 is easy to handle. In addition, since the biocompatible material 1 is transparent or translucent, it is easy to position it to fit the tissue damage area or the space after tumor resection.

[0035] Furthermore, if the fibers 11 are not bonded to each other, the entire sheet will become fragile when water is added, and will not be able to maintain its shape. For this reason, if the water content is adjusted to a value close to that of biological tissue, the sheet will become gel-like, making it difficult to handle. Also, even if the fibers 11 are bonded to each other, if an appropriate amount of water is not contained between the fibers 11, the flexibility of the entire sheet will be low, making it difficult to cut with scissors or a scalpel. In addition, if the flexibility of the biocompatible material 1 is low, there is a possibility that the surrounding cell tissue may be damaged when placed in a living body.

[0036] It is also conceivable to bond the fibers 11 together by heating or chemical crosslinking, but in this case, the biocompatibility may decrease as the bio-derived material may denature or become toxic due to the heat.

[0037] <Second Embodiment> Next, a second embodiment will be described. This embodiment is an example in which the water absorption treatment in the first embodiment is replaced with a hydrostatic treatment. The method for manufacturing a biocompatible member according to this embodiment will be described below. Figure 4 shows the hydrostatic pressure treatment, one of the methods for manufacturing a biocompatible member according to this embodiment.

[0038] First, the process shown in Figures 2(a) to 3(b) is carried out. Next, as shown in Figure 4, the aggregate 12, after the volatile liquid has been removed, is sealed in a sealed bag 117 together with water 116. As described in the first embodiment, various forms of water can be used as water 116; for example, physiological saline can be used. The sealed bag 117 is then placed in a chamber 119 connected to a pump 118. Air 120 is introduced outside the sealed bag 117 in the chamber 119.

[0039] Then, the pump 118 pressurizes the water 116 and the aggregate 12 via air 120 and the sealed bag 117. The pressure is higher than atmospheric pressure (1 atmosphere), preferably 5 MPa to 1 GPa, more preferably 100 MPa to 1 GPa, for example, 500 MPa. This allows water to penetrate between and into the fibers 11 in the aggregate 12. Also, the air that was present in the void 15 is removed from the aggregate 12. After the hydrostatic treatment, air released from the void 15 may accumulate in the sealed bag 117. In this way, the biocompatible member according to this embodiment is manufactured.

[0040] According to this embodiment, by applying hydrostatic pressure treatment as a water-inclusion treatment, water can be efficiently incorporated into the aggregate 12. Furthermore, the biocompatible member 1 can be sterilized by the hydrostatic pressure treatment. This also improves the biocompatibility of the biocompatible member 1. The configuration, manufacturing method, and effects of this embodiment other than those described above are the same as those of the first embodiment.

[0041] <Third Embodiment> Next, a third embodiment will be described. This embodiment is an example in which the water absorption treatment in the first embodiment is replaced with a reduced-pressure treatment. The method for manufacturing a biocompatible member according to this embodiment will be described below. Figure 5 shows the reduced pressure treatment, which is part of the manufacturing method for the biocompatible member according to this embodiment.

[0042] First, the process shown in Figures 2(a) to 3(b) is carried out. Next, as shown in Figure 5, the laminated sheet 10b is subjected to a reduced pressure treatment. Specifically, the laminated sheet 10b is placed in the chamber 121 and immersed in water 122. In this state, the pressure inside the chamber 121 is reduced. The pressure inside the chamber 121 is set to less than 1 atmosphere. After the reduced pressure treatment, a hydrostatic pressure treatment as described in the second embodiment may be performed.

[0043] This also allows water 13 to be contained between the fibers 11 of the aggregate 12. The configuration, manufacturing method, and effects in this embodiment other than those described above are the same as in the first embodiment.

[0044] <Example Test> Next, a test example of the first embodiment will be described. In this test example, the biocompatible component 1 was actually manufactured using the manufacturing method according to the first embodiment. In this test example, collagen, a bio-derived material, was used as the biocompatible material. In addition, an ethanol solution was used as the volatile liquid.

[0045] In this test example, a deposited layer 10a was formed by depositing fibers 11 using the electrospinning method, and a laminated sheet 10b was formed by stacking multiple deposited layers 10a so that their orientation directions alternately intersected. An ethanol treatment was then performed by permeating the sheet with an ethanol solution until only a few air bubbles remained, and then a water treatment was performed by immersing it in physiological saline. In this way, a sheet-like biocompatible material 1 was manufactured. The properties of the biocompatible material 1 were then evaluated by the following method.

[0046] (External observation) Samples from each stage of the manufacturing process of biocompatible component 1 were observed using a Scanning Electron Microscope (SEM).

[0047] Figure 6(a) is a surface SEM image of the deposited layer 10a formed by the electrospinning method, and (b) is a surface SEM image of the laminated sheet 10b after ethanol treatment.

[0048] As shown in Figure 6(a), in the deposited layer 10a formed by the electrospinning method and before ethanol treatment, numerous fibers 11 extended in roughly one direction. This confirmed that the deposited layer 10a had orientation. Furthermore, as shown in Figure 6(b), the treatment involving the penetration and volatilization of ethanol caused some of the fibers 11 to fuse together and become integrated, resulting in a smooth surface.

[0049] Figures 7(a) and (b) are SEM images of the surface of a sample of biocompatible material 1 related to this test example, in which collagen was crosslinked with glutaraldehyde and then frozen, and observed by sublimating the ice using a cooled SEM. As shown in Figures 7(a) and (b), the surface of the biocompatible member 1 has one void 15 with a diameter of 10 μm or more per mm². 2 It was formed at the above density.

[0050] (Polarization FT-IR-ATR method) In stretched polymer materials, the direction in which the long axis of the molecule extends (molecular axis) tends to be the direction in which the polymer material (fiber) extends. Therefore, by examining the direction in which the long axis of the molecule extends on the surface of the biocompatible component 1, the direction in which the fiber 11 extends can be estimated, and consequently, it can be determined whether or not the fiber 11 is oriented.

[0051] The direction in which the long axis of a molecule extends can be determined by structural determination methods appropriate to the type of polymer material. For example, Raman spectroscopy can be used for polystyrene, and polarized absorbance analysis can be used for polyimide. In this example, we will explain the case where the polymer material is an organic compound having an amide group, such as collagen. In the case of an organic compound having an amide group, for example, the direction in which the long axis of the molecule extends can be determined using polarized FT-IR-ATR (Fourier Transform-Infrared Spectroscopy-Attenuated Total Reflectance), a type of infrared spectroscopy.

[0052] The following describes the analysis method using the polarized FT-IR-ATR method. Wavelength: 1640cm -1 Let T1 be the light absorption intensity, and the wavenumber be 1540 cm⁻¹. -1Let T2 be the absorption intensity of light. Absorption intensity T1 is the absorption intensity in the direction perpendicular to the direction in which the long axis of the molecule extends. Absorption intensity T2 is the absorption intensity in the direction in which the long axis of the molecule extends. Therefore, if the absorbance ratio (T1 / T2) in a given polarization direction becomes small, it can be seen that there are many molecules extending in that polarization direction.

[0053] Next, the absorbance ratio (T1 / T2) of the freeze-dried biocompatible material 1 after water treatment is measured while changing the angle with respect to the polarization direction. The absorbance ratio that yields the maximum value is defined as R1, and the absorbance ratio that yields the minimum value is defined as R2. For example, the orientation of the biocompatible material 1 that yields absorbance ratio R2 is rotated by 90° relative to the orientation of the biocompatible material 1 that yields absorbance ratio R1. The ratio (R1 / R2) is then defined as the degree of orientation parameter. The larger the degree of orientation parameter (R1 / R2), the higher the degree of orientation.

[0054] In the freeze-dried sample of biocompatible material 1 after water treatment, the orientation parameter (R1 / R2) was approximately 1.10. Thus, it was confirmed that the fibers 11 were oriented in biocompatible material 1 after water treatment.

[0055] (Differential scanning calorimetry) Differential scanning calorimetry (DSC) was performed on samples of the laminated sheet 10b before water absorption treatment and the biocompatible material 1 after water absorption treatment, which were freeze-dried.

[0056] Figure 8 is a graph showing the differential scanning calorimetry results for the laminated sheet and biocompatible material related to this test example, with temperature on the horizontal axis and heat flow on the vertical axis. Figure 9 is a table showing the differential scanning calorimetry results. Figure 9 also shows the measurement results for untreated collagen powder for comparison. Collagen powder retains the triple helix structure, which is the original structure of collagen molecules.

[0057] As shown in Figures 8 and 9, a first endothermic peak P1 appeared in the laminated sheet 10b and biocompatible member 1 in the temperature range of 20°C to 100°C, and a second endothermic peak P2 appeared in the temperature range of 200°C to 240°C. This is presumed to be due to an endothermic reaction that occurs when collagen molecules with a high-dimensional, i.e., three-dimensional molecular structure are decomposed by heating. Therefore, the presence of endothermic peaks P1 and P2 suggests that the molecular structure of collagen molecules in the laminated sheet 10b and biocompatible member 1 before heating was its original high-dimensional structure.

[0058] Furthermore, the heat energy of the endothermic peak P1 of the biocompatible material 1 was greater than that of the laminated sheet 10b. Specifically, the endothermic peak P1 of the laminated sheet 10b was approximately 16-19 J / g, while the endothermic peak P1 of sample 1s was approximately 27 J / g. This suggests that the triple helix structure of the collagen molecule is maintained.

[0059] (Compression modulus) The compressive modulus of biocompatible material 1 was measured. The thickness of biocompatible material 1 was set to four levels: 0.3 mm, 0.9 mm, 1.3 mm, and 1.9 mm. Three samples were prepared for each level and measured.

[0060] Figure 10 is a table showing the measurement results of the compressive modulus of the biocompatible material related to this test example. As shown in Figure 10, the compressive modulus of the 12 samples measured ranged from 7.5 to 74.8 kPa.

[0061] (Dynamic viscoelasticity measurement) The viscoelasticity-frequency curve of biocompatible material 1 was measured using the dynamic viscoelastic method. The thickness of biocompatible material 1 was set to four levels: 0.3 mm, 0.9 mm, 1.3 mm, and 1.9 mm, and the temperature was set to room temperature. A sinusoidal force was applied to biocompatible material 1, and the elastic modulus was measured. The frequency of the sinusoidal force was set to 1 to 100 Hz.

[0062] Figure 11(a) is a graph showing the storage modulus-frequency curve of the biocompatible material in this test example, with frequency on the horizontal axis and storage modulus on the vertical axis, and (b) is a graph showing the loss modulus-frequency curve of the biocompatible material in this test example, with frequency on the horizontal axis and loss modulus on the vertical axis.

[0063] As shown in Figures 11(a) and (b), the storage modulus was higher than the loss modulus throughout the entire measured frequency range. Therefore, it can be said that the biocompatible member 1 has strong elastic properties.

[0064] (Structural changes within the body) This study simulated the structural changes of biocompatible component 1 due to stress from the living body when the biocompatible component 1 was placed inside a living body. Specifically, collagen was crosslinked with glutaraldehyde in biocompatible component 1, and the unfrozen component was cut with a razor blade. The shear force applied by the razor blade simulated the stress that biocompatible component 1 would experience in a living body. Next, the ice was sublimated using a cooled SEM, and the surface of the cut surface was observed with an SEM.

[0065] Figure 12 is a surface SEM image showing a cross-section of the biocompatible member 1 after the above-described treatment. As shown in Figure 12, gaps 16 between layers 10 were observed in the cross-section of the biocompatible member 1. This is thought to be because the shear force in the thickness direction (Z direction) was applied to the biocompatible member 1 by cutting with a razor, causing the layers 10 to shift. On the other hand, gaps 16 between layers 10 were not observed in the cross-section formed by cutting with a knife under frozen and high vacuum conditions.

[0066] Next, a sheet-like biocompatible material 1 was punched out into 5 mm diameter test pieces. These test pieces were divided into four groups and placed in PS culture dishes, and stored under the following four conditions. Changes in the test pieces were then observed before and after storage.

[0067] Condition 1: Immerse the test specimen in physiological saline solution and store at a temperature of 5°C. Condition 2: Immerse the test specimen in physiological saline solution and store at a temperature of 37°C. Condition 3: Immerse the test specimen in FBS (Fetal bovine serum) and store at 5°C. Condition 4: Immerse the test specimen in FBS and store at a temperature of 37°C.

[0068] As a result, delamination between layers 10 was observed in a high-temperature environment of 37°C, regardless of the type of immersion solution. On the other hand, no delamination between layers 10 was observed in a low-temperature environment of 5°C.

[0069] These results indicate that in the biocompatible member 1, the bonding force between layers 10 is weaker than the bonding force between fibers 11 within layers 10. Furthermore, it was hypothesized that when stress or heat is applied to the biocompatible member 1 in vivo, gaps 16 are formed between the layers 10. As described above, when cells enter these gaps 16, the fusion between the biocompatible member 1 and the living body improves.

[0070] (Subcutaneous transplantation in rats) Biocompatible material 1 was implanted subcutaneously into rats, and its subsequent condition was visually observed. The results showed that 1-2 days after implantation, biocompatible material 1 became gel-like and lost its elasticity. 7 days after implantation, biocompatible material 1 disappeared. During this period, no rejection reactions such as inflammation were observed.

[0071] According to the embodiments described above, it is possible to realize a biocompatible material that is highly biocompatible and easy to handle, as well as a method for manufacturing the same.

[0072] Although several embodiments of the present invention have been described above, these embodiments are presented as examples only and are not intended to limit the scope of the invention. These novel embodiments can be implemented in various other forms, and various omissions, substitutions, and modifications can be made without departing from the spirit of the invention. These embodiments and their variations are included in the scope and spirit of the invention, as well as in the claims of the invention and its equivalents. [Explanation of symbols]

[0073] 1: Biocompatible material 10: layer 10a: Sedimentary layer 10b: Laminated sheet 11: Fibers 12: Accumulation 13:Water 15: Void 16: Gap 101: Manufacturing equipment 102: Nozzle 103: Laura 104: Power supply 110: Raw material liquid 112: Base material 113: Wipes 115: Container 116:Water 117: Sealed bag 118: Pump 119: Chamber 120: Air 121: Chamber 122:Water P1, P2: Endothermic peaks

Claims

1. An aggregate of fibers containing biocompatible materials bonded together, The water contained between the fibers, Equipped with, It has multiple layers, Within the aforementioned layer, the fibers are oriented, A biocompatible member in which the orientation directions of the fibers in two adjacent layers intersect each other.

2. The biocompatible member according to claim 1, wherein the biocompatible material is collagen.

3. The biocompatible member according to claim 1 or 2, wherein the bonding force between the layers is weaker than the bonding force between the fibers within the layers.

4. A step of forming a laminated sheet by pulling fibers containing a biocompatible material in one direction to form a deposit layer in which the direction of extension of the fibers is aligned, and stacking a plurality of such deposit layers so that the directions of extension of the fibers intersect in two adjacent deposit layers, A step of impregnating the laminated sheet with a volatile liquid, A step of volatilizing the liquid that has permeated the laminated sheet, A step of subjecting the laminated sheet, from which the aforementioned liquid has been evaporated, to a water-reinforcement treatment, A method for manufacturing a biocompatible component equipped with [the necessary components].

5. The method for manufacturing a biocompatible member according to claim 4, wherein the water absorption treatment is carried out at a pressure higher than atmospheric pressure.

6. The method for manufacturing a biocompatible member according to claim 4, wherein the water absorption treatment is carried out at a pressure lower than atmospheric pressure.

7. A method for manufacturing a biocompatible member according to any one of claims 4 to 6, wherein the biocompatible material is collagen.

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