Manufacturing method of biocompatible components

Abstract

To provide a method for producing a biocompatible member having high biocompatibility and easy handling property.SOLUTION: A method for producing a biocompatible member includes the steps of forming a laminated sheet by depositing fibers containing a biocompatible material, permeating 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 moisture-containing treatment.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The embodiments relate to a method for manufacturing a biocompatible component. [Background technology]

[0002] In the medical field, biocompatible materials have been developed as materials for use in living organisms or as a base for cell growth. Biocompatible materials are required to have high biocompatibility and be easy to handle. For example, biocompatible materials are required to be strong enough to maintain their shape even when held with tweezers, yet soft enough to be cut with scissors or a scalpel. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Patent No. 6450894 [Patent Document 2] Patent No. 6470327 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the embodiments is to provide a method for manufacturing a biocompatible component that is highly biocompatible and easy to handle. [Means for solving the problem]

[0005] A biocompatible component according to an embodiment includes an aggregate of fibers containing a biocompatible material bonded together, and water contained between the fibers, wherein the water content in the biocompatible component is 40% by mass or more and 90% by mass or less.

[0006] A method for manufacturing a biocompatible component according to an embodiment includes the steps of forming a laminated sheet by depositing fibers containing a biocompatible material, 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 hydration treatment. [Brief explanation of the drawings]

[0007] [Figure 1] 1 is a diagram showing a biocompatible component according to a first embodiment. FIG. [Figure 2] 1(a) and 1(b) are diagrams showing a method for manufacturing a biocompatible component according to a first embodiment. [Figure 3] 1(a) to 1(c) are diagrams showing a method for producing a biocompatible component according to a first embodiment. [Figure 4] FIG. 10 is a diagram showing a hydrostatic pressure treatment in a method for producing a biocompatible component according to a second embodiment. [Figure 5] FIG. 10 is a diagram showing a decompression process in the method for producing a biocompatible component according to the third embodiment. [Figure 6] (a) is an SEM photograph of the surface of the deposition layer formed by the electrospinning method, and (b) is an SEM photograph of the surface of the laminated sheet after ethanol treatment. [Figure 7] 10(a) and 10(b) are SEM photographs of the surface of a freeze-dried sample of a biocompatible component according to a test example. [Figure 8] 1 is a graph showing the results of differential scanning calorimetry of a laminate sheet and a biocompatible component according to a test example, with the horizontal axis representing temperature and the vertical axis representing heat flow. [Figure 9] 1 is a table showing the results of differential scanning calorimetry of a laminate sheet and a biocompatible component according to a test example. [Figure 10] 10 is a table showing the measurement results of the compressive elastic modulus of biocompatible components according to test examples. [Figure 11](a) is a graph showing the storage modulus-frequency curve of a biocompatible component according to a test example, with frequency on the horizontal axis and storage modulus on the vertical axis; (b) is a graph showing the loss modulus-frequency curve of a biocompatible component according to a test example, with frequency on the horizontal axis and loss modulus on the vertical axis. [Figure 12] 1 is a surface SEM photograph showing a cut surface of a biocompatible component according to a test example. DETAILED DESCRIPTION OF THE INVENTION

[0008] First Embodiment The first embodiment will be described below. FIG. 1 is a diagram showing a biocompatible component according to this embodiment.

[0009] 1, the biocompatible component 1 according to this embodiment includes an aggregate 12 in which a plurality of fibers 11 are bonded together, and water 13 contained between the fibers 11. The content of water 13 in the biocompatible component 1 is 40% by mass or more and 90% by mass or less.

[0010] The fiber 11 includes a biocompatible material. The biocompatible material is, for example, a bio-derived material. The bio-derived material is a material produced by biological activity or a material obtained by processing such a material. The biocompatible material does not have to be a bio-derived material, and may be, for example, a synthetic polymer, a functional protein or synthetic polypeptide obtained by artificial synthesis, or the like.

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

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

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

[0014] In each layer 10, the fibers 11 are oriented in, for example, one direction. The orientation directions of the fibers 11 in two adjacent layers 10 intersect with each other, for example, are approximately perpendicular to each other. As shown in FIG. 1 , in an XYZ orthogonal coordinate system, when the thickness direction of the biocompatible component 1, i.e., the stacking direction of the layers 10, is defined as the Z direction, layers 10 oriented in the X direction and layers 10 oriented in the Y direction are stacked alternately. In each layer 10, adjacent fibers 11 are bonded to each other in a linear manner. The bonding strength between layers 10 is weaker than the bonding strength between fibers 11 within a layer 10. Voids 15 with a diameter of 10 μm or more are formed on the surface of the biocompatible component 1 at a density of 1 / mm 2 It is formed at a density of more than 10 ...

[0015] Note that FIG. 1 is a schematic diagram conceptually illustrating the configuration of the biocompatible component 1 and does not necessarily correspond to the actual configuration. For example, as described above, the diameter of the fiber 11 is approximately 1 / 1000 of the thickness of the layer 10, but in FIG. 1, the fiber 11 is depicted larger than it actually is to make the drawing easier to see. Furthermore, because the fibers 11 are bonded to each other, it is not always possible to distinguish the individual fibers 11 when observing the biocompatible component 1 under a microscope. Furthermore, the boundaries between the layers 10 are not always clearly observable. The same applies to the other figures described below.

[0016] The compressive elastic modulus of the biocompatible material 1 is 5 kPa or more. Furthermore, the biocompatible material 1 is an elastic body, and when the viscoelasticity-frequency curve is measured using a dynamic viscoelastic method, the storage elastic modulus is higher than the loss elastic modulus. The biocompatible material 1 is a solid, soft elastic body with no fluidity. Furthermore, the biocompatible material 1 is transparent or translucent.

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

[0018] First, as shown in Fig. 2(a), a fiber 11 is formed by an electrospinning method. A manufacturing apparatus 101 for the fiber 11 is provided with a nozzle 102, a roller 103, and a power supply 104. The roller 103 rotates at high speed. The power supply 104 applies a 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 a biocompatible material, for example, collagen. Immediately after being discharged from the nozzle 102, the raw material liquid 110 is stretched by electrostatic repulsion, turns into fibers 11, reaches the outer circumferential surface of the roller 103, and is taken up at high speed by the roller 103. As a result, the fibers 11 are deposited in an oriented state in the outer circumferential direction of the roller 103, and a deposited layer 10a is formed. The deposited layer 10a is a layer in which the fibers 11 are deposited in an oriented state.

[0020] Next, as shown in Fig. 2(b), a plurality of deposition layers 10a are stacked on the substrate 112. At this time, the orientation directions of adjacent deposition layers 10a are made to cross, for example, be orthogonal to each other. A laminated sheet 10b is formed from the stacked plurality of deposition layers 10a.

[0021] The composition and shape of the substrate 112 are not particularly limited, but a composition and shape that maximize adhesion to the deposition layer 10a are preferred. Examples of materials for the substrate 112 include 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; and biological tissues such as decellularized tissue, human skin, and organs. The substrate 112 may be a biocompatible material 1 that has already been manufactured, or may be a substrate, cloth, sphere, rod, tube, or other material formed by molding the biocompatible material 1. Alternatively, an artificial biological structure such as an artificial blood vessel, artificial valve, artificial joint, or artificial tooth may also be used. Additionally, the substrate 112 may include drugs, cells, blood, bodily fluids, and the like.

[0022] Next, as shown in FIG. 3(a), a volatile liquid is permeated into the laminate sheet 10b. The volatile liquid is not particularly limited, but it is preferable to use a liquid that does not dissolve the fibers 11 as much as possible. For example, water, alcohols (ethanol, methanol, isopropyl alcohol, etc.), or an alcohol-water solution may be used. For example, a cloth 113 soaked in ethanol is placed on the laminate sheet 10b placed on the substrate 112. This allows the ethanol in the cloth 113 to permeate the laminate sheet 10b.

[0023] Next, as shown in FIG. 3(b), the volatile liquid that has permeated into the laminate sheet 10b is volatilized and removed from the laminate sheet 10b. As a result, the capillary force of the liquid causes some of the fibers 11 to fuse together, bonding the fibers 11 together. As a result, an aggregate 12 is formed on the substrate 112. The aggregate 12 is a structure in which the fibers 11 are three-dimensionally assembled. Furthermore, if spaces (air bubbles) that are not filled with the volatile liquid are formed in the laminate sheet 10b, voids 15 (see FIG. 1) are formed in the aggregate 12 after the volatile liquid is removed. The thickness of the aggregate 12 is reduced to approximately 1 / 3 to 1 / 5 of the thickness of the laminate sheet 10b before the volatile liquid was permeated. Furthermore, the aggregate 12 becomes transparent or translucent.

[0024] Assembly 12 formed on substrate 112 may be peeled off from substrate 112 and used alone, or may be used integrally with substrate 112 .

[0025] Next, as shown in FIG. 3(c), the assembly 12 is subjected to a hydration treatment. The hydration treatment may be performed by immersing the assembly 12 in water 116 in a container 115, pouring the water 116 into the assembly, contacting the assembly with a cloth soaked in the water 116, or spraying the assembly 12 with a mist of water 116. The water 116 may be pure water or physiological saline. The water 116 may also be serum such as fetal bovine serum (FBS), various liquid media, an aqueous solution containing protein, RNA, DNA, or a substrate, a suspension of cells, body fluid, or blood. This allows water to penetrate between the fibers 11, which then absorb the water and swell, producing the biocompatible component 1. These hydration treatments cause the biocompatible component 1 to swell by 2 to 5 times its original size at room temperature.

[0026] Next, the effects of this embodiment will be described. The biocompatible component 1 according to this embodiment has high biocompatibility because the fibers 11 are made of a biocompatible material. For example, the biocompatible component 1 does not exhibit toxicity when placed in a living body. Furthermore, it can suppress rejection reactions, such as inflammation, caused by the living body. In particular, by forming the fibers 11 from high-dimensional collagen that has not deteriorated, it is possible to more effectively suppress rejection reactions. Furthermore, when the fibers 11 are formed from a bio-derived material and the biocompatible component 1 is placed in a living body, the bio-derived material is consumed as the body metabolizes, and the fibers 11 become loose. This makes it easier for cells to invade between the fibers 11.

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

[0028] Furthermore, the surface of the biocompatible component 1 has voids 15 with a diameter of 10 μm or more at a rate of 1 / mm 2 The voids 15 are formed at a density equal to or greater than this. This allows living cells to easily infiltrate into the voids 15 when the biocompatible component 1 is placed inside a living body. The cells that have infiltrated into the voids 15 then use them as a foothold to further infiltrate into the biocompatible component 1.

[0029] Furthermore, the biocompatible component 1 is provided with multiple layers 10, and the bonding strength between the layers 10 is weaker than the bonding strength between the fibers 11 within the layers 10. For this reason, when the biocompatible component 1 is placed inside a living body and pressure or heat is applied to the biocompatible component 1 from the surrounding biological tissue, the layers 10 tend to peel off, forming gaps. This allows cells to enter the gaps between the layers 10, further promoting the formation of cellular tissue.

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

[0031] Thus, the biocompatible material 1 is highly compatible with surrounding cell tissues. Therefore, for example, if the biocompatible material 1 is placed in the area of ​​tissue damage or the space left after tumor resection, it can be expected that the biocompatible material 1 will serve as a scaffold for cell growth, promoting wound healing and tissue reconstruction. Furthermore, if the biocompatible material 1 is used as a covering material when implanting artificial objects or drugs into the body, it can be expected to have the effect of suppressing inflammation within the body. Furthermore, if the biocompatible material 1 is used as a scaffold when growing cells and tissues outside the body, it can be expected that the cells and tissues can be grown and cultured efficiently or three-dimensionally.

[0032] Because the biocompatible component 1 is made of fibers 11 made of biocompatible materials 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 it has completed its role, and does not interfere with cell proliferation or tissue regeneration.

[0033] Furthermore, in the biocompatible component 1, the fibers 11 are bonded to one another, for example, by welding, to form an aggregate 12. Therefore, even if water 13 is contained within the fibers 11 in the aggregate 12, the strength of the entire biocompatible component 1 can be maintained. For example, the biocompatible component 1 has a compressive modulus of elasticity of 5 kPa or more, and a storage modulus higher than the loss modulus. Therefore, the biocompatible component 1 is sufficiently rigid that it can maintain its shape even when picked up with tweezers or the like.

[0034] On the other hand, the biocompatible component 1 is soft enough to be cut with scissors or a scalpel. Therefore, for example, in a medical setting, the biocompatible component 1 can be processed by holding it 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 component 1 is easy to handle. Furthermore, because the biocompatible component 1 is transparent or translucent, it can be easily positioned to fit the space at the site of tissue damage or after tumor resection.

[0035] If the fibers 11 are not bonded to each other, the entire sheet will become brittle when it absorbs water and will not be able to maintain its shape. Therefore, 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. Furthermore, 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. Furthermore, if the flexibility of the biocompatible component 1 is low, there is a possibility that the surrounding cellular tissue will be damaged when placed in a living body.

[0036] It is also possible to bond the fibers 11 together by heating or chemical cross-linking, but in this case, the biomaterial may be denatured or become toxic due to heat, which may reduce biocompatibility.

[0037] <Second embodiment> Next, a second embodiment will be described. This embodiment is an example in which the water impregnation treatment in the first embodiment is replaced with hydrostatic pressure treatment. The method for producing a biocompatible component according to this embodiment will be described below. FIG. 4 is a diagram showing the hydrostatic pressure treatment in the method for producing a biocompatible component according to this embodiment.

[0038] First, the steps shown in FIG. 2(a) to FIG. 3(b) are carried out. Next, as shown in Fig. 4, the assembly 12 from which the volatile liquid has been absorbed and 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 the water 116, such as physiological saline. The sealed bag 117 is then placed in a chamber 119 connected to a pump 118. Air 120 is introduced into the chamber 119 outside the sealed bag 117.

[0039] Then, the pump 118 pressurizes the water 116 and the aggregate 12 via the 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 causes water to permeate between and into the fibers 11 in the aggregate 12. Additionally, air that was present in the voids 15 is removed from the aggregate 12. Air released from the voids 15 may accumulate in the sealed bag 117 after the hydrostatic pressure treatment. In this manner, the biocompatible component according to this embodiment is manufactured.

[0040] According to this embodiment, by performing hydrostatic pressure treatment as a hydration treatment, water can be efficiently contained in the aggregate 12. Furthermore, the biocompatible component 1 can be sterilized by the hydrostatic pressure treatment. This also improves the biocompatibility of the biocompatible component 1. Other configurations, manufacturing methods, and effects of this embodiment 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 moisture impregnation treatment in the first embodiment is replaced with a reduced pressure treatment. The method for producing a biocompatible component according to this embodiment will be described below. FIG. 5 is a diagram showing the decompression process in the method for producing a biocompatible component according to this embodiment.

[0042] First, the steps shown in FIG. 2(a) to FIG. 3(b) are carried out. Next, as shown in Fig. 5, the laminate sheet 10b is subjected to a decompression treatment. Specifically, the laminate sheet 10b is placed in a 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 decompression 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 assembly 12. Other configurations, manufacturing methods, and effects of this embodiment are the same as those of the first embodiment.

[0044] <Test example> Next, a test example of the first embodiment will be described. In this test example, a biocompatible component 1 was actually manufactured by the manufacturing method according to the first embodiment. In this test example, collagen, which is a biomaterial, was used as the biocompatible material. An ethanol solution was used as the volatile liquid.

[0045] That is, in this test example, a deposition layer 10a was formed by depositing fibers 11 by electrospinning, and multiple deposition layers 10a were stacked so that their orientation directions alternated to form a laminated sheet 10b. This was then subjected to an ethanol treatment in which an ethanol solution was infiltrated and evaporated to the extent that only a few air bubbles remained, and then the sheet was immersed in physiological saline for a hydration treatment. In this way, a sheet-like biocompatible component 1 was produced. The properties of the biocompatible component 1 were then evaluated by the following method.

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

[0047] FIG. 6(a) is an SEM photograph of the surface of the deposition layer 10a formed by electrospinning, and (b) is an SEM photograph of the surface of the laminated sheet 10b after the ethanol treatment.

[0048] As shown in Figure 6(a), in the deposition layer 10a formed by the electrospinning method and before the ethanol treatment, many fibers 11 were extending in roughly the same direction. This confirmed that the deposition layer 10a had orientation. Furthermore, as shown in Figure 6(b), the treatment of penetrating and volatilizing the ethanol caused some of the fibers 11 to fuse together and become integrated, resulting in a smooth surface.

[0049] 7(a) and (b) are SEM photographs of the surface of a frozen sample of biocompatible component 1 according to this test example, in which collagen was crosslinked with glutaraldehyde and the ice was sublimated using a cooling SEM. As shown in FIGS. 7(a) and 7(b), the surface of the biocompatible component 1 has voids 15 with a diameter of 10 μm or more at a rate of 1 / mm. 2 It was formed at a density of more than

[0050] (Polarized FT-IR-ATR method) In a stretched polymeric material, the direction in which the long axes of the molecules (molecular axes) extend tends to be the direction in which the polymeric material (fibers) extend. Therefore, by examining the direction in which the long axes of the molecules extend on the surface of the biocompatible component 1, the direction in which the fibers 11 extend can be estimated, and therefore, whether the fibers 11 are oriented or not can be determined.

[0051] The direction of the molecular long axis can be determined by a structure determination method appropriate for 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 test 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, the direction of the molecular long axis can be determined, for example, by using polarized FT-IR-ATR (Fourier Transform-Infrared Spectroscopy-Attenuated Total Reflectance), a type of infrared spectroscopy.

[0052] The analysis method using the polarized FT-IR-ATR method will be described below. Wave number: 1640cm -1 The absorption intensity of light is T1, and the wave number is 1540 cm -1The absorption intensity of light is defined as T2. Absorption intensity T1 is the absorption intensity in a 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 is small, it can be seen that there are many molecules extending in that polarization direction.

[0053] Then, for a sample obtained by freeze-drying the biocompatible material 1 after the hydration treatment, the absorbance ratio (T1 / T2) is measured while changing the angle with the polarization direction. The absorbance ratio with the maximum value is defined as R1, and the absorbance ratio with the minimum value is defined as R2. For example, the orientation of the biocompatible material 1 at which the absorbance ratio R2 is obtained is rotated 90° from the orientation of the biocompatible material 1 at which the absorbance ratio R1 is obtained. The ratio (R1 / R2) is then defined as the orientation parameter. The larger the orientation parameter (R1 / R2), the higher the degree of orientation.

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

[0055] (Differential Scanning Calorimetry) Differential scanning calorimetry (DSC) was performed on the laminated sheet 10b before the hydration treatment and the freeze-dried sample of the biocompatible component 1 after the hydration treatment.

[0056] FIG. 8 is a graph showing the results of differential scanning calorimetry of the laminated sheet and biocompatible component according to this test example, with the horizontal axis representing temperature and the vertical axis representing heat flow. FIG. 9 is a table showing the differential scanning calorimetry results. For comparison, the measurement results for untreated collagen powder are also shown in Figure 9. Collagen powder has a 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 temperature range of 20°C to 100°C in the laminate sheet 10b and the biocompatible component 1, and a second endothermic peak P2 appeared in the temperature range of 200°C to 240°C. This is presumably due to an endothermic reaction that occurs when collagen molecules, which have 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 laminate sheet 10b and the biocompatible component 1 before heating is the original high-dimensional structure.

[0058] Furthermore, the heat quantity of the endothermic peak P1 of the biocompatible component 1 was greater than that of the laminate sheet 10b. Specifically, the endothermic peak P1 of the laminate sheet 10b was approximately 16 to 19 J / g, while the endothermic peak P1 of the sample 1s was approximately 27 J / g. This suggests that the triple helix structure of the collagen molecules was maintained.

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

[0060] FIG. 10 is a table showing the measurement results of the compressive modulus of elasticity of the biocompatible component according to this test example. As shown in FIG. 10, the compressive elastic modulus was 7.5 to 74.8 kPa in the measurement results for the 12 samples.

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

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

[0063] 11(a) and (b), the storage modulus was higher than the loss modulus over the entire measured frequency range, which indicates that the biocompatible component 1 has strong elastic properties.

[0064] (Structural changes in vivo) We simulated the structural changes of biocompatible material 1 due to stress from the living body when it is placed inside a living body. Specifically, collagen in biocompatible material 1 was cross-linked with glutaraldehyde, and the material was cut with a razor while still unfrozen. The shear force from the razor simulated the stress that biocompatible material 1 would experience inside a living body. Next, the ice was sublimated using a cooling SEM, and the surface of the cut surface was observed using an SEM.

[0065] FIG. 12 is a surface SEM photograph showing a cut surface of the biocompatible component 1 after the above-described treatment. As shown in Figure 12, gaps 16 between the layers 10 were observed on the cut surface of the biocompatible component 1. This is thought to be because the layers 10 were displaced from each other due to the shear force applied to the biocompatible component 1 in the thickness direction (Z direction) when it was cut with a razor. On the other hand, no gaps 16 between the layers 10 were observed on the cross section formed by cutting with a knife in a frozen and high vacuum state.

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

[0067] Condition 1: The test specimen was immersed in saline and stored at 5°C. Condition 2: The test specimen was immersed in saline and stored at 37°C. Condition 3: The test specimen was immersed in FBS (fetal bovine serum) and stored at 5°C. Condition 4: The test specimen was immersed in FBS and stored at 37°C.

[0068] As a result, peeling between layers 10 was observed in a high temperature environment of 37°C regardless of the type of immersion liquid. On the other hand, peeling between layers 10 was not observed in a low temperature environment of 5°C.

[0069] These results indicate that in the biocompatible component 1, the bonding strength between the layers 10 is weaker than the bonding strength between the fibers 11 within the layers 10. It was also estimated that when stress or heat is applied to the biocompatible component 1 in a living body, gaps 16 are formed between the layers 10. As described above, when cells enter these gaps 16, the fusion between the biocompatible component 1 and the living body improves.

[0070] (Subcutaneous implantation in rats) Biocompatible material 1 was implanted subcutaneously into a rat, and the condition was then visually observed. As a result, one to two days after implantation, biocompatible material 1 became gel-like and lost its elasticity. Seven days after implantation, biocompatible material 1 disappeared. During this time, no rejection reaction such as inflammation was observed.

[0071] According to the embodiment described above, a biocompatible material that is highly biocompatible and easy to handle, and a method for producing the same, can be realized.

[0072] Although several embodiments of the present invention have been described above, these embodiments are presented as examples and are not intended to limit the scope of the invention. These novel embodiments can be embodied 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 modifications are included within the scope and spirit of the invention, and are also included in the scope of the invention and its equivalents as defined in the claims. [Explanation of symbols]

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

Claims

1. a step of forming a deposited layer in which the fibers containing a biocompatible material are pulled in one direction, and the fibers are aligned in the same direction, and laminating a plurality of the deposited layers to form a laminated sheet; Permeating the laminated sheet with a volatile liquid; a step of bonding the fibers together by volatilizing the liquid that has permeated the laminated sheet; a step of subjecting the laminated sheet from which the liquid has been evaporated to a moisture-containing treatment; A method for manufacturing a biocompatible component comprising:

2. The method for producing a biocompatible component according to claim 1 , wherein the step of forming the laminated sheet comprises a step of forming the fibers by an electrospinning method.

3. The method for producing a biocompatible component according to claim 1 or 2, wherein in the step of infiltrating the volatile liquid, a space that is not filled with the volatile liquid is formed.

4. The method for producing a biocompatible component according to any one of claims 1 to 3, wherein the volatile liquid is an aqueous ethanol solution.

5. The method for producing a biocompatible component according to any one of claims 1 to 4, wherein the biocompatible material is collagen.

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