JP7530182B2 - Biocompatible Materials - Google Patents

Description

The embodiments relate to a biocompatible component .

In the medical field, biocompatible materials are being developed as materials to be used in living organisms and as a foundation 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, and soft enough to be cut with scissors or a scalpel.

Patent No. 6450894 Patent No. 6470327

An object of the embodiments is to provide a biocompatible component that is highly biocompatible and easy to handle.

The biocompatible component according to the embodiment comprises an aggregate in which fibers containing a biocompatible material are bonded together, and water contained between the fibers. The water content in the biocompatible component is 40% by mass or more and 90% by mass or less.

The method for manufacturing a biocompatible component according to the 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.

FIG. 2 shows a biocompatible component according to a first embodiment. 3A and 3B are diagrams illustrating a method for manufacturing a biocompatible component according to the first embodiment. 3A to 3C are diagrams illustrating a method for manufacturing a biocompatible component according to a first embodiment. 13A to 13C are diagrams illustrating a hydrostatic pressure treatment in a method for producing a biocompatible component according to a second embodiment. 13A to 13C are diagrams illustrating a decompression process in a method for producing a biocompatible component according to a third embodiment. 1A is a SEM photograph of the surface of a deposition layer formed by electrospinning, and FIG. 1B is a SEM photograph of the surface of a laminate sheet after ethanol treatment. 13A and 13B are SEM photographs of the surface of a freeze-dried sample of a biocompatible component according to a test example. 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. 1 is a table showing the results of differential scanning calorimetry of a laminate sheet and a biocompatible component according to a test example. 13 is a table showing the measurement results of the compressive elastic modulus of the biocompatible components according to the test examples. 1A is a graph showing the storage modulus-frequency curve of a biocompatible material according to a test example, with frequency on the horizontal axis and storage modulus on the vertical axis; and FIG. 1B is a graph showing the loss modulus-frequency curve of a biocompatible material according to a test example, with frequency on the horizontal axis and loss modulus on the vertical axis. 1 is a surface SEM photograph showing a cut surface of a biocompatible component according to a test example.

First Embodiment
The first embodiment will be described below.
FIG. 1 is a diagram showing a biocompatible component according to the present embodiment.

As shown in FIG. 1, the biocompatible component 1 according to this embodiment includes an aggregate 12 in which multiple 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.

The fiber 11 includes 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, and may be, for example, a synthetic polymer, a functional protein obtained by artificial synthesis, or a synthetic polypeptide.

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).

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 that constitutes the fibers 11 also maintains this structure. In the aggregate 12, the fibers 11 are bonded to each other by, for example, partial welding 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.

The shape of the biocompatible component is, for example, a sheet. The biocompatible component 1 has a plurality of layers 10 stacked in the thickness direction. The layers 10 are stacked, for example, in a number of 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 component 1 is, for example, about 0.03 to 50 mm.

In each layer 10, the fibers 11 are oriented in one direction, for example. The orientation directions of the fibers 11 in two adjacent layers 10 cross 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 the Z direction, layers 10 whose orientation direction is the X direction and layers 10 whose orientation direction is the Y direction are alternately stacked. In each layer 10, adjacent fibers 11 are bonded to each other in a linear manner. The bonding force between the layers 10 is weaker than the bonding force between the fibers 11 in the layer 10. Voids 15 having a diameter of 10 μm or more are formed on the surface of the biocompatible component 1 at a density of 1 piece/ ^mm2 or more.

Note that FIG. 1 is a schematic diagram conceptually showing the configuration of the biocompatible component 1, and does not necessarily match the actual configuration. For example, as described above, the diameter of the fiber 11 is about 1/1000 of the thickness of the layer 10, but in FIG. 1, the fiber 11 is drawn larger than it actually is to make the drawing easier to see. In addition, since the fibers 11 are bonded to each other, even if the biocompatible component 1 is observed under a microscope, it is not always possible to distinguish the individual fibers 11. Furthermore, the boundaries between the layers 10 are not always clearly observable. The same applies to the other figures described below.

The compressive elastic modulus of the biocompatible component 1 is 5 kPa or more. In addition, the biocompatible component 1 is an elastic body, and when the viscoelasticity-frequency curve is measured by the dynamic viscoelastic method, the storage elastic modulus is higher than the loss elastic modulus. The biocompatible component 1 is solid as a whole, a soft elastic body, and has no fluidity. In addition, the biocompatible component 1 is transparent or translucent.

Next, a method for producing 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.

First, as shown in FIG. 2(a), fiber 11 is formed by electrospinning. A manufacturing device 101 for fiber 11 is provided with a nozzle 102, a roller 103, and a power source 104. The roller 103 rotates at high speed. The power source 104 applies a voltage to the nozzle 102.

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, becomes 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 deposition layer 10a is formed. The deposition layer 10a is a layer in which the fibers 11 are deposited in an oriented state.

Next, as shown in FIG. 2(b), a plurality of deposition layers 10a are laminated on the substrate 112. At this time, the orientation directions of adjacent deposition layers 10a are crossed, for example, perpendicular to each other. A laminated sheet 10b is formed by the stacked deposition layers 10a.

The composition and shape of the substrate 112 are not particularly limited, but a composition and shape that provides as good adhesion as possible to the deposition layer 10a are preferred. The material of the substrate 112 may be, for example, synthetic polymers such as polystyrene (PS), polyethylene (PE), polypropylene (PP), polymethylmethacrylate (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 tissues, human skin, and organs. In addition, the substrate 112 may be a biocompatible member 1 that has already been manufactured, or a member such as a substrate, cloth, sphere, rod, or tube formed by molding the biocompatible member 1, or an artificial biological structure such as an artificial blood vessel, an artificial valve, an artificial joint, or an artificial tooth. Additionally, the substrate 112 may contain drugs, cells, blood, body fluids, etc.

Next, as shown in FIG. 3(a), a volatile liquid is permeated into the laminated 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.), and alcohol aqueous solutions are used. For example, a cloth 113 soaked in ethanol is placed on the laminated sheet 10b placed on the substrate 112. This causes the ethanol in the cloth 113 to permeate into the laminated sheet 10b.

Next, as shown in FIG. 3(b), the volatile liquid that has permeated into the laminated sheet 10b is volatilized and removed from the laminated sheet 10b. As a result, the capillary force of the liquid acts to weld some of the fibers 11 together, and the fibers 11 bond 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 accumulated. Furthermore, if spaces (air bubbles) that are not filled with the volatile liquid are formed in the laminated 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 becomes about 1/3 to 1/5 times that of the laminated sheet 10b before the volatile liquid is permeated. Furthermore, the aggregate 12 becomes transparent or translucent.

The aggregate 12 formed on the substrate 112 may be peeled off from the substrate 112 and used alone, or may be used integrally with the substrate 112.

Next, as shown in FIG. 3(c), the aggregate 12 is subjected to a hydration treatment. The hydration treatment may be performed by immersing the aggregate 12 in water 116 in a container 115, pouring the water 116 into the container, contacting the aggregate 12 with a cloth soaked in the water 116, or spraying the aggregate 12 with a mist of water 116. The water 116 may be pure water or physiological saline. The water 116 may be serum such as fetal bovine serum (FBS), various liquid culture media, an aqueous solution containing protein, RNA, DNA, or a substrate, or may be a suspension of cells, body fluid, or blood. As a result, water penetrates between the fibers 11, and the fibers 11 absorb water and swell, producing the biocompatible component 1. By these hydration treatments, the biocompatible component 1 swells 2 to 5 times at room temperature.

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, even if the biocompatible component 1 is placed in a living body, it does not show toxicity. In addition, rejection reactions such as inflammation caused by the living body can be suppressed. In particular, by forming the fibers 11 from high-dimensional collagen that has not deteriorated, the rejection reaction can be more effectively suppressed. Furthermore, when the fibers 11 are formed from a biomaterial and the biocompatible component 1 is placed in a living body, the biomaterial is consumed with the metabolism of the living body, and the fibers 11 are loosened. This makes it easier for cells to enter between the fibers 11.

The biocompatible component 1 also 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 living organisms. This also gives the biocompatible component 1 high biocompatibility.

Furthermore, 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 piece/ ^mm2 or more. This allows living cells to easily enter the voids 15 when the biocompatible component 1 is placed in a living body. The cells that have entered the voids 15 serve as a scaffold to further enter the biocompatible component 1.

The biocompatible component 1 also has 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 in a living body and pressure or heat is applied to the biocompatible component 1 from the surrounding living tissue, the layers 10 tend to peel off and gaps are likely to form. This allows cells to enter the gaps between the layers 10, further promoting the formation of cellular tissue.

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 the biological tissue.

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

The biocompatible component 1 is made of fibers 11 made of biocompatible materials and water 13, so when the biocompatible component 1 is placed in a living body, it gradually disappears due to reactions within the body. This means that the biocompatible component 1 that has completed its role does not remain in the living body and does not interfere with cell proliferation or tissue regeneration.

In addition, in the biocompatible component 1, the fibers 11 are bonded to each other, for example, welded together, 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 has a high enough rigidity that it can maintain its shape even when picked up and lifted with tweezers or the like.

On the other hand, the biocompatible member 1 is soft enough to be cut with scissors or a scalpel. Therefore, for example, in a medical setting, the biocompatible member 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 member 1 is easy to handle. In addition, since the biocompatible member 1 is transparent or translucent, it can be easily positioned to fit tissue damage or the space left after tumor resection.

If the fibers 11 are not bonded together, the entire sheet becomes weak when it absorbs water and is unable to maintain its shape. For this reason, if the water content is adjusted to a value close to that of living tissue, the sheet becomes difficult to handle, for example becoming gel-like. Furthermore, even if the fibers 11 are bonded together, if an appropriate amount of water is not contained between the fibers 11, the flexibility of the entire sheet decreases, 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 cell tissue may be damaged when it is placed in a living body.

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, resulting in a decrease in biocompatibility.

Second Embodiment
Next, a second embodiment will be described.
This embodiment is an example in which the moisture 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.

First, the steps shown in FIG. 2(a) to FIG. 3(b) are carried out.
4, the assembly 12 from which the volatile liquid has been absorbed and then 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, 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.

Then, the pump 118 pressurizes the water 116 and the aggregate 12 through the air 120 and the sealed bag 117. The pressure is higher than atmospheric pressure (1 atm), preferably 5 MPa to 1 GPa, more preferably 100 MPa to 1 GPa, for example 500 MPa. This causes water to permeate between the fibers 11 in the aggregate 12 and into the fibers 11. Also, the 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.

According to this embodiment, by carrying out hydrostatic pressure treatment as a water-containing treatment, water can be efficiently contained in the aggregate 12. In addition, the biocompatible component 1 can be sterilized by hydrostatic pressure treatment. This also improves the biocompatibility of the biocompatible component 1. The configuration, manufacturing method, and effects of this embodiment other than those described above are the same as those of the first embodiment.

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.

First, the steps shown in FIG. 2(a) to FIG. 3(b) are carried out.
Next, as shown in Fig. 5, the laminated sheet 10b is subjected to a decompression treatment. Specifically, the laminated 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 may be performed as described in the second embodiment.

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

<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. Also, an ethanol solution was used as the volatile liquid.

In this test example, a deposition layer 10a was formed by depositing fibers 11 by electrospinning, and a laminated sheet 10b was formed by stacking multiple deposition layers 10a so that their orientation directions crossed each other. The laminated sheet 10b was then subjected to an ethanol treatment in which an ethanol solution was permeated and volatilized to the extent that only a few air bubbles remained, and then the sheet was immersed in saline to perform a hydration treatment. In this manner, a sheet-shaped biocompatible material 1 was produced. The characteristics of the biocompatible material 1 were then evaluated by the following method.

(Appearance Observation)
Samples at each stage in the manufacturing process of the biocompatible component 1 were observed by a SEM (Scanning Electron Microscope).

Figure 6 (a) is a SEM photograph of the surface of the deposition layer 10a formed by the electrospinning method, and (b) is a SEM photograph of the surface of the laminated sheet 10b after ethanol treatment.

As shown in FIG. 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. In addition, as shown in FIG. 6(b), the treatment of penetrating and volatilizing the ethanol caused some of the fibers 11 to fuse together and become one, resulting in a smooth surface.

7(a) and (b) are SEM photographs of the surface of a frozen sample of the 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 ), voids 15 with diameters of 10 μm or more were formed on the surface of the biocompatible component 1 at a density of 1 void/mm ² or more.

(Polarized FT-IR-ATR method)
In the stretched polymeric material, the direction in which the long axis of the molecule extends (molecular axis) tends to be the direction in which the polymeric material (fiber) extends. Therefore, the long axis of the molecule on the surface of the biocompatible component 1 By examining the direction in which the fibers 11 extend, the direction in which the fibers 11 extend can be estimated, and it can be determined whether the fibers 11 are oriented or not.

The direction in which the long axis of the molecule extends can be determined by a structure determination method appropriate for the type of polymer material. For example, Raman spectroscopy can be used in the case of polystyrene, and polarized absorbance analysis can be used in the case of polyimide. In this test example, as an example, a case will be described in which 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 in which the long axis of the molecule extends can be determined by using, for example, polarized FT-IR-ATR (Fourier Transform-Infrared Spectroscopy- Attenuated Total Reflectance), a type of infrared spectroscopy.

The analysis method using the polarized FT-IR-ATR method will be described below.
The absorption intensity of light with a wave number of 1640 cm ^-1 is T1, and the absorption intensity of light with a wave number of 1540 cm ^-1 is T2. The absorption intensity T1 is the absorption intensity in a direction perpendicular to the direction in which the long axis of the molecule extends. The 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 certain polarization direction is small, it can be seen that there are many molecules extending in that polarization direction.

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 designated as R1, and the absorbance ratio with the minimum value is designated as R2. For example, the orientation of the biocompatible material 1 at which the absorbance ratio R2 is obtained is rotated 90° relative to the orientation of the biocompatible material 1 at which the absorbance ratio R1 is obtained. The ratio (R1/R2) is then designated as the orientation parameter. The larger the orientation parameter (R1/R2), the higher the degree of orientation.

In a sample obtained by freeze-drying the biocompatible material 1 after the hydration treatment, the orientation parameter (R1/R2) was approximately 1.10. In this way, it was confirmed that the fibers 11 were oriented in the biocompatible material 1 after the hydration treatment.

(Differential Scanning Calorimetry)
Differential scanning calorimetry (DSC) was performed on the laminate sheet 10b before the hydration treatment and on samples obtained by freeze-drying the biocompatible member 1 after the hydration treatment.

FIG. 8 is a graph showing the results of differential scanning calorimetry of the laminate 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 of untreated collagen powder are also shown in Figure 9. Collagen powder has a triple helix structure, which is the original structure of collagen molecules.

As shown in Figures 8 and 9, in the laminate sheet 10b and the biocompatible component 1, a first endothermic peak P1 appeared 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, 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.

The heat quantity of the endothermic peak P1 of the biocompatible component 1 was greater than that of the endothermic peak P1 of the laminated sheet 10b. Specifically, the endothermic peak P1 of the laminated 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.

(Compressive Elastic Modulus)
The compressive elastic modulus was measured for the biocompatible member 1. The thickness of the biocompatible member 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.

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

(Dynamic viscoelasticity measurement)
The viscoelasticity-frequency curve of the biocompatible member 1 was measured by dynamic viscoelasticity. The thickness of the biocompatible member 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 member 1, and the elastic modulus was measured. The frequency of the sinusoidal wave force was set to 1 to 100 Hz.

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

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

(Structural changes in vivo)
A simulation was performed to simulate structural changes in the biocompatible component 1 due to stress from the living body when the biocompatible component 1 is placed in the living body. Specifically, collagen in the biocompatible component 1 was crosslinked with glutaraldehyde, and the biocompatible component 1 was cut with a razor while in an unfrozen state. The shear force from the razor simulated the stress that the biocompatible component 1 would experience in the living body. Next, the ice was sublimated using a cooling SEM, and the surface of the cut surface was observed with the SEM.

FIG. 12 is a surface SEM photograph showing a cut surface of the biocompatible component 1 after the above-mentioned treatment.
12, gaps 16 between the layers 10 were observed on the cut surface of the biocompatible component 1. This is believed 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.

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.

Condition 1: The test specimen was immersed in physiological saline and stored at 5°C. Condition 2: The test specimen was immersed in physiological 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.

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, no peeling between layers 10 was observed in a low-temperature environment of 5°C.

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 is improved.

(Subcutaneous implantation in rats)
The biocompatible material 1 was implanted subcutaneously into a rat, and the condition was then visually observed. As a result, 1-2 days after implantation, the biocompatible material 1 became gel-like and lost its elasticity. 7 days after implantation, the biocompatible material 1 disappeared. During this time, no rejection reaction such as inflammation was observed.

The above-described embodiment makes it possible to realize a biocompatible material that is highly biocompatible and easy to handle, and a method for producing the same.

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 gist of the invention. These embodiments and their modifications are included within the scope and gist of the invention, and are included in the scope of the invention and its equivalents as set forth in the claims.

1: Biocompatible material 10: Layer 10a: Deposited layer 10b: Laminated sheet 11: Fiber 12: Assembly 13: Water 15: Void 16: Gap 101: Manufacturing device 102: Nozzle 103: Roller 104: Power source 110: Raw material liquid 112: Substrate 113: Rag 115: Container 116: Water 117: Sealed bag 118: Pump 119: Chamber 120: Air 121: Chamber 122: Water P1, P2: Endothermic peak

Claims (6)

An aggregate in which collagen -containing fibers are bonded to each other;
Water contained between the fibers;
Equipped with
The water content is 40% by mass or more and 90% by mass or less,
Voids having a diameter of 10 μm or more are formed on the surface at a density of 1/mm2 or ^more ,
It has multiple layers,
The bonding strength between the layers is weaker than the bonding strength between the fibers within the layers;
Within the layer, the fibers are oriented,
A biocompatible component in which the orientation directions of the fibers in two adjacent layers cross each other . 2. The biocompatible component according to claim 1, wherein when analyzed by differential scanning calorimetry after freeze-drying, a first endothermic peak appears in a temperature range of 20°C or higher and 100°C or lower, a second endothermic peak appears in a temperature range of 200°C or higher and 240°C or lower, and the amount of heat absorbed by the first endothermic peak is 10 times or more greater than the amount of heat absorbed by the second endothermic peak. The biocompatible component according to claim 1 or 2 , wherein in each of the layers, the fibers are oriented and adjacent fibers are bonded to each other linearly. 4. The biocompatible component according to claim 1, which has a compressive modulus of elasticity of 5 kPa or more . 5. The biocompatible component according to claim 1, wherein the storage modulus is higher than the loss modulus. The biocompatible material according to any one of claims 1 to 5, wherein the absorption intensity of light having a wave number of 1640 cm ^-1 is T1, the absorption intensity of light having a wave number of 1540 cm ^-1 is T2, the absorbance ratio is T1/T2, the maximum absorbance ratio obtained when the angle with the polarization direction is changed and measured is R1, and the minimum absorbance ratio obtained when the angle with the polarization direction is changed and measured is R2, and the orientation parameter is R1/R2, and when the surface is analyzed by polarized FT-IR-ATR method after freeze-drying, the orientation parameter is 1.05 or more .

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