JP4686743B2 - Percutaneous terminal and medical tube - Google Patents

Description

  The present invention relates to a percutaneous terminal for preventing bacterial infection at an in-vivo insertion portion in an indwelling medical device, for example, and more particularly to a percutaneous terminal having high bioadhesion. is there.

  In recent years, indwelling medical devices such as percutaneous catheters have been used for medical treatment. For example, the percutaneous catheter is inserted into a living body from outside the living body, and medical practices such as peritoneal dialysis are performed. However, when an indwelling medical device such as a percutaneous catheter is implanted (implanted) in a living body, the living tissue recognizes the indwelling medical device as a foreign substance. Since the living tissue and the medical device are not in close contact with each other, so-called downgrowth (a phenomenon in which the epithelial tissue is invaded along the catheter surface) occurs in which the epidermis falls inward along the catheter. Become. And if this downgrowth becomes deep, disinfection will not be achieved and a bacterial infection route will be formed, causing skin inflammation and the like. And there exists a problem that the state which must finally pull out the said in-dwelling-type medical device will arise. Therefore, in order to solve such problems, various in-dwelling medical devices to which bioadhesiveness is imparted have been proposed.

  For example, a percutaneous terminal made of hydroxyapatite ceramics with high biocompatibility has been proposed as an indwelling medical device (see Non-Patent Document 1).

Further, a percutaneous catheter in which hydroxyapatite having high biocompatibility is attached to the surface by adhesion or melting has been proposed.
H. AOKI, in “Medical Applications of Hydroxyapatite” (Ishiyaku EuroAmerica Inc., 1994) p. 133

  However, the configuration disclosed in the above prior art has the following problems.

  In the configuration disclosed in Non-Patent Document 1, the percutaneous terminal is composed of only hydroxyapatite ceramics. Hydroxyapatite is a tooth component and exhibits excellent soft tissue affinity, but hydroxyapatite ceramics are hard and brittle. In addition, since this percutaneous terminal is hard, there may be a gap between the hydroxyapatite ceramic and the living tissue even when implanted in a living body, and there is a problem if the adhesion is poor. Furthermore, when the percutaneous terminal is composed of only hydroxyapatite ceramics, the size of the percutaneous terminal becomes large. Therefore, in the configuration disclosed in Non-Patent Document 1, the percutaneous terminal is likely to be damaged, and when the percutaneous terminal is implanted in a living body, the patient may be affected by the hardness of the percutaneous terminal. There is a problem that it causes a sense of incongruity.

  In addition, when hydroxyapatite with high biocompatibility is bonded or melted on the surface of the catheter, the hydroxyapatite is directly attached to the catheter, so the physical properties of the part where the hydroxyapatite is attached are different from other parts. There is a problem of being different. In particular, when hydroxyapatite is introduced into a catheter by melting, the physical properties of the catheter may be impaired and the catheter may be cut. In addition, when hydroxyapatite is directly bonded to the catheter, the hydroxyapatite is taken into the adhesive and the area where the hydroxyapatite is exposed is reduced, or if the adhesion is insufficient, the hydroxyapatite is There is a problem in that it may be detached from.

  The present invention has been made in view of the above-described problems, and an object of the present invention is to provide a percutaneous terminal having high adhesion to a living tissue and capable of fixing a medical tube in the vicinity of a percutaneous portion. Is to provide.

  The percutaneous terminal according to the present invention is a percutaneous terminal for fixing a medical tube to be inserted into a living body at an insertion position of the medical tube in order to solve the above problem, and holds the medical tube. It is characterized in that at least a part of the surface of the substrate is coated with a biocompatible ceramic composite formed by chemically bonding the base material and the biocompatible ceramic.

  The percutaneous terminal is, for example, for fixing a medical tube that connects a living body and a living body such as a catheter or a blood vessel sending / removing blood vessel of an auxiliary artificial heart (VAS) in vivo. Specifically, the percutaneous terminal is for fixing a medical tube to be inserted into the living body via the subcutaneous tissue and the living tissue in the vicinity thereof at the percutaneous portion (the subcutaneous tissue and the vicinity). .

  Here, the biocompatible ceramic refers to a ceramic having adhesiveness / affinity with living tissue, such as titanium oxide that expresses adhesiveness with a living body by treating a calcium phosphate sintered body or particle surface. That is. That is, the biocompatible ceramic indicates at least one of calcium phosphate and titanium oxide.

  The biocompatible ceramic composite is a bioactive base material (polymer base material) and biocompatible ceramics bonded together through a chemical bond, and the physical properties and biocompatibility of the base material. It has both the physical properties of the ceramics. The biocompatible ceramic has adhesiveness to a living tissue, and the base material and the substrate do not affect the living body even when implanted in the living body. And it is preferable that the said base material and a base | substrate have elasticity.

  According to said structure, at least one part of the surface of a base | substrate is coat | covered with the said biocompatible ceramic composite. Therefore, a percutaneous terminal having high adhesion to the living tissue at the percutaneous terminal portion can be provided by favorably bonding the biocompatible ceramic composite and the living tissue.

  Further, among the biocompatible ceramics, particularly calcium phosphate is excellent in adhesiveness and affinity with a living body, and therefore a calcium calcium phosphate sintered body is more preferable. The calcium phosphate sintered body will be described below. The calcium phosphate sintered body is obtained by sintering amorphous calcium phosphate at a high temperature (for example, in a temperature range of 800 ° C. to 1300 ° C.). In addition, the calcium phosphate complex is a material in which a bioactive substrate (polymer substrate) and a calcium phosphate sintered body are bonded via a chemical bond, and the physical properties of the substrate and the calcium phosphate sintered body are It has both physical properties. And the said calcium-phosphate sintered compact is excellent in adhesiveness with a biological tissue, and the said base material and a base | substrate do not affect a biological body, even when it implants in a biological body. And it is preferable that the said base material and a base | substrate have elasticity.

  Further, by treating the titanium oxide surface of the biocompatible ceramics, it is possible to develop adhesiveness / affinity with the living body. Therefore, the titanium oxide will be described below.

  The titanium oxide is a material in which a cationic functional group such as an amino group is introduced into the particle surface by chemical treatment so that the particle surface has affinity with a living tissue. In addition, the titanium oxide composite is a material in which a biologically active base material (polymer base material) and titanium oxide particles are bonded via a chemical bond, and the physical properties of the base material and the physical properties of the titanium oxide particles. It has both physical properties. That is, the titanium oxide has a cationic functional group.

  The surface-treated titanium oxide (particles) is excellent in adhesiveness with living tissue, and the base material and substrate do not affect the living body even when implanted in the living body. . And it is preferable that the said base material and a base | substrate have elasticity.

  According to said structure, at least one part of the surface of a base | substrate is coat | covered with the said biocompatible ceramic composite. Therefore, a percutaneous terminal having high adhesion to the living tissue at the percutaneous terminal portion can be provided by favorably bonding the biocompatible ceramic composite and the living tissue. In other words, with the above configuration, the biocompatible ceramics and the tissue around the medical tube can be suitably adhered, so that the insertion position of the medical tube can be suitably fixed. Growth can be suppressed. In addition, transdermal terminals coated with biocompatible ceramic composites use hard biocompatible ceramics bonded to an elastic base material, so they are damaged compared to transdermal terminals made of hydroxyapatite, for example. There is nothing to do. Furthermore, when the percutaneous terminal is implanted in a living body, the uncomfortable feeling felt by the patient can be reduced. Further, by adopting the above configuration, since the biocompatible ceramic composite is coated on a substrate different from the medical tube, the physical properties of the medical tube are not impaired. That is, it is possible to provide a percutaneous terminal capable of safely fixing a medical tube in a living body.

  Biocompatible ceramics have higher crystallinity and lower solubility than amorphous ones. Therefore, by using the above configuration, even when a percutaneous terminal is used for the purpose of implanting a medical tube in a living body for a long period of time, it can be used satisfactorily.

  In the percutaneous terminal according to the present invention, it is more preferable that the base is provided with a collar portion that suppresses movement of the base with respect to the insertion direction of the medical tube.

  According to said structure, the collar part which suppresses the movement of the said base | substrate with respect to the extending | stretching direction of the said medical tube is provided. Thereby, since the movement of the medical tube (the movement of the percutaneous terminal in the internal direction of the living body) can be further suppressed, the progress of downgrowth can be suppressed. Note that the above movement includes parallel movement and rotational movement. Therefore, when the percutaneous terminal is fixed in vivo, the buttocks fix the position of the percutaneous terminal in the living body, and the percutaneous terminal rotates (including twisting of the percutaneous terminal in the living body). ) To suppress.

  The percutaneous terminal according to the present invention preferably has a structure in which a hole is formed in the heel portion. According to said structure, the hole is formed in the said collar part. Thereby, for example, when the percutaneous terminal is embedded in a living body, the tissue in the living body passes through the hole and adheres to another tissue. Thereby, the position of the percutaneous terminal can be more firmly fixed.

  In the percutaneous terminal according to the present invention, the heel portion is provided between one end and the other end of the base, and the region including the heel portion from the one end (or the region from the one end to the heel portion). The structure in which the biocompatible ceramic composite is coated only on the above is more preferable.

  According to said structure, only the area | region containing a collar part from the end of the said base | substrate is coat | covered with biocompatible ceramics. The biocompatible ceramic composite not only has excellent adhesion to living tissue, but also exhibits good adhesion to other cells in vitro such as bacteria. Therefore, with the above configuration, for example, even when the percutaneous terminal is implanted in a state where the region of the percutaneous terminal that is not covered with the biocompatible ceramic composite is exposed outside the living body, Since the portion exposed to the outside of the living body is not covered with the biocompatible ceramic composite, the bacteria can be prevented from adhering to the percutaneous terminal. In other words, it is possible to implant in a state where a part of the percutaneous terminal is exposed outside the living body.

  In the percutaneous terminal according to the present invention, it is more preferable that the buttocks are provided so as to have a predetermined angle with respect to the insertion direction of the medical tube.

  By adopting the above configuration, when a percutaneous terminal is implanted in a living body and a medical tube is used with the percutaneous terminal, by tilting the buttocks with respect to the insertion direction of the medical tube, A medical tube that is outside the living body can be placed along the living body. Thereby, it can reduce that a medical tube becomes obstructive outside a living body.

  In addition, when the above-mentioned percutaneous terminal is embedded in the living body in the buttock of the percutaneous terminal according to the present invention, consideration is given to both the ease of implantation in the living body and the expression of high adhesive strength to the living body. A shape is required. Specifically, the percutaneous terminal has a percutaneous terminal living body inner surface and a percutaneous terminal living body outer surface with respect to the extending direction of the medical tube during in vivo implantation.

  Here, the percutaneous terminal living body inner surface refers to the percutaneous terminal surface in which the percutaneous terminal is perpendicular to the extending direction of the medical tube in the insertion direction from the center surface of the percutaneous terminal when implanted in the living body. Say. Further, the percutaneous terminal living body outer surface means a surface of the living body in the outer direction from the center surface of the percutaneous terminal where the percutaneous terminal exists perpendicular to the extending direction of the medical tube at the time of implantation in the living body.

  And when the symmetry of the shape is low, the ease of embedding differs depending on the embedding direction.

  When the medical tube and the percutaneous terminal are implanted in a living body, a part of the epithelium in the living body is partially incised, the medical tube is punctured and placed, and the medical tube is inserted into the living body. It will be. Therefore, it is more preferable that the buttocks on the inner surface of the living body of the percutaneous terminal have a narrow shape that is easy to insert (embed) and have a large area in order to obtain a bonding surface with the living body. And the structure which has the wide area in order for the edge part on the opposite side to the insertion direction in the said collar part to take an adhesive surface with a biological body is more preferable.

By adopting the above-described configuration, it is easy to insert (embed) and can improve the adhesion to the living body. A configuration in which a plurality of holes are provided so as to have a certain ratio is more preferable.

  With the above-described configuration, after the percutaneous terminal is implanted, the living tissue passes by extending the hole, and the living tissue adhered to the surface of the buttocks on the passing side and the stretched The tissue adheres and can be fixed to the living body as if the buttock of the percutaneous terminal was sewn with a thread called tissue. Thereby, the movement and rotation of the base body with respect to the insertion direction of the medical tube can be suppressed.

  The transdermal terminal according to the present invention preferably has a configuration in which at least a part of the substrate is coated with a large number of particulate biocompatible ceramic composites.

  According to said structure, at least one part of the said base | substrate is coat | covered with many particulate biocompatible ceramic composites. As a result, the surface area of the biocompatible ceramic covering the surface of the substrate can be increased, and the percutaneous terminal can be more closely adhered to the living tissue.

  The percutaneous terminal according to the present invention may be integrated with the medical tube.

  According to said structure, since the percutaneous terminal is comprised integrally with the said medical tube, the movement of a catheter can be suppressed by fixing the said percutaneous terminal.

  Hereinafter, among the biocompatible ceramics, particularly the calcium phosphate sintered body will be described.

  In the transdermal terminal according to the present invention, the calcium phosphate complex has a columnar or spherical shape in which the length in the major axis direction is in the range of 1 μm to 1 cm and the length in the minor axis direction is in the range of 1 nm to 1 mm. A configuration having a shape is more preferable.

  According to said structure, the surface area of the calcium-phosphate composite which has coat | covered the base | substrate surface can be increased by making a calcium-phosphate composite granular or fibrous.

  The transdermal terminal according to the present invention preferably has a configuration in which the substrate is silk fibroin.

  Silk fibroin has high biological activity. According to said structure, a transdermal terminal with high biocompatibility can be provided by using silk fibroin as a base material.

  The percutaneous terminal according to the present invention is a percutaneous terminal for fixing a medical tube to be inserted into a living body at an insertion position of the medical tube in order to solve the above-described problem, and holds the medical tube. It is characterized in that at least a part of the surface of the substrate is coated with silk fibroin.

  Since silk fibroin has high biocompatibility, a transdermal terminal having high biocompatibility can be provided by adopting the above-described configuration.

  Moreover, the medical tube concerning this invention is equipped with the said percutaneous terminal, It is characterized by the above-mentioned. Thereby, even when a medical tube is implanted in a living body, the medical tube can be prevented from moving.

  The percutaneous terminal according to the present invention is a percutaneous terminal for fixing a medical tube to be inserted into a living body at an insertion position of the medical tube, and is at least a part of the surface of the base for fixing the medical tube. However, it is the structure coat | covered with the calcium-phosphate complex which a base material and a calcium-phosphate sintered compact chemically bond.

  Thereby, the said calcium phosphate complex and a biological tissue adhere | attach favorably, The transdermal terminal with high adhesiveness with a biological tissue can be provided in a percutaneous terminal part.

  An embodiment of the present invention will be described as follows. That is, the percutaneous terminal according to the present embodiment is a percutaneous terminal implanted in a percutaneous part (subcutaneous tissue) of a living body, and at least a part of the surface of the substrate is composed of a base material and a biocompatible ceramic. It is the structure coat | covered with the biocompatible ceramics composite formed by chemical bonding.

  The biocompatible ceramic composite according to the present invention is a calcium phosphate composite or titanium oxide composite in which at least a part of the surface of the substrate is a calcium phosphate sintered body or titanium oxide and a base material chemically bonded, or a plurality of types. Is coated with biocompatible ceramics.

  In the following description, “a complex formed by chemically bonding calcium phosphate and a base material” will be described.

(Calcium phosphate sintered body)
Here, the calcium phosphate sintered body will be described. The calcium phosphate sintered body (also referred to as calcium phosphate ceramics) indicates calcium phosphate having high crystallinity when compared with amorphous (amorphous) calcium phosphate. Specifically, the calcium phosphate sintered body is obtained by sintering amorphous (amorphous) calcium phosphate. The calcium phosphate sintered body has at least one of calcium ions (Ca ²⁺ ), phosphate ions (PO ₄ ²⁻ ) and hydroxide ions (OH ⁻ ) on the surface of the calcium phosphate sintered body itself. Has ions.

And the said calcium-phosphate sintered compact has high bioactivity. Specific examples of the calcium phosphate sintered body include, for example, hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ), calcium triphosphate (β (α) -tricalcium phosphate (Ca ₃ (PO ₄ )). ₂ )), calcium metaphosphate (Ca (PO ₃ ) ₂ ), calcium octaphosphate (OCP), Ca ₁₀ (PO ₄ ) ₆ F ₂ , Ca ₁₀ (PO ₄ ) ₆ Cl _{2 and the} like. The calcium phosphate constituting the calcium phosphate sintered body may be artificially produced by a known production method such as a wet method, a dry method, a hydrolysis method, a hydrothermal method, Naturally derived from bones, teeth, etc. may be used. Further, the calcium phosphate sintered body may contain a compound in which a hydroxide ion and / or a part of the phosphate ion of calcium phosphate is substituted with carbonate ion, chloride ion, fluoride ion, or the like.

  And, since the calcium phosphate sintered body is higher in crystallinity than the amorphous calcium phosphate and has low solubility in the living body, even if the percutaneous terminal is implanted in the living body over a long period of time, It can be preferably used.

  Further, at least phosphate ions or calcium ions are present on one crystal face of the calcium phosphate sintered body. Specifically, the ions present depend on the crystal plane of calcium phosphate, and calcium ions and phosphate ions exist on different crystal planes. In addition, when the calcium phosphate sintered body contains hydroxide ions, the hydroxide ions are present on at least one crystal face where the calcium ions or phosphate ions are present. Will be.

  Here, the manufacturing method of the said calcium phosphate sintered compact is demonstrated. The calcium phosphate sintered body according to the present embodiment can be obtained by sintering amorphous calcium phosphate. Specifically, a calcium phosphate sintered body can be obtained by sintering the above-exemplified calcium phosphate within a temperature range of 800 ° C. to 1300 ° C. for a predetermined time. By sintering the calcium phosphate, the crystallinity can be increased, and for example, the solubility when introduced into a living body can be reduced. The degree of crystallization of this calcium phosphate sintered body can be measured by X-ray diffraction (XRD). Specifically, the narrower the half width of the peak showing each crystal plane of the calcium phosphate complex, the higher the crystallinity.

  The lower limit of the sintering temperature at which the calcium phosphate is sintered is more preferably 800 ° C or higher, further preferably 900 ° C or higher, and particularly preferably 1000 ° C or higher. If the sintering temperature is lower than 800 ° C., sintering may not be sufficient. On the other hand, as an upper limit of sintering temperature, 1300 degreeC or less is more preferable, 1250 degreeC or less is further more preferable, and 1200 degreeC or less is especially preferable. When the sintering temperature is higher than 1300 ° C., it may be difficult to directly chemically bond with the functional group of the base material described later. Therefore, by setting the sintering temperature within the above range, a calcium phosphate sintered body that is difficult to dissolve in the living body (high crystallinity) and can be directly chemically bonded to the functional group of the substrate is manufactured. can do. In addition, the sintering time is not particularly limited, and may be set as appropriate.

  Further, for example, when a hydroxyapatite sintered body or β (α) -tricalcium phosphate is used as a material constituting the calcium phosphate sintered body, the hydroxyapatite sintered body or β (α) -tricalcium phosphate is It is suitable as a medical material because of its affinity with living tissue and excellent stability in the living environment. Further, the hydroxyapatite sintered body is difficult to dissolve in vivo. Therefore, for example, when a calcium phosphate complex is produced using the hydroxyapatite sintered body, the biological activity can be maintained for a long period in vivo.

  The calcium phosphate sintered body is more preferably in the form of particles, more preferably fine particles. Specifically, when the calcium phosphate sintered body has a spherical shape, the diameter thereof is more preferably in the range of 10 nm to 100 μm, and further preferably in the range of 50 nm to 10 μm. By using the fine particles of the calcium phosphate sintered body within the above range, elasticity can be imparted to the obtained percutaneous terminal. In this embodiment, since the calcium phosphate sintered body and the substrate are chemically bonded, even when the calcium phosphate sintered body having a particle diameter in the above range is used, the calcium phosphate sintered body is used. The physical properties are not impaired.

(Base material)
As the substrate according to the present embodiment, a polymer substrate is more preferable, a medical polymer is further preferable, and an organic polymer is particularly preferable. Specific examples of the base material include silicone polymer (which may be silicone rubber), polyethylene glycol, polyalkylene glycol, polyglycolic acid, polylactic acid, polyamide, polyurethane, polysulfone, polyether, and poly Synthetic polymers such as ether ketone, polyamine, polyurea, polyimide, polyester, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid, polymethacrylic acid, polymethyl methacrylate, polyacrylonitrile, polystyrene, polyvinyl alcohol, polyvinyl chloride; Polysaccharides such as cellulose, amylose, amylopectin, chitin and chitosan, polypeptides such as collagen, mucopolysaccharides such as hyaluronic acid, chondroitin and chondroitin sulfate, silk Natural polymers such as Iburoin and the like. Of the above-exemplified base materials, silicone polymer, polyurethane, polytetrafluoroethylene, or silk fibroin is preferably used because it has excellent properties such as long-term stability, strength, and flexibility. Further, for example, the organic polymer and the inorganic material may be combined to form a base material.

  The surface of the substrate according to the present embodiment preferably has a functional group capable of chemically bonding with the calcium phosphate sintered body itself. By having a functional group on the surface of the base material, the calcium phosphate sintered body can be chemically bonded without being subjected to chemical pretreatment. Below, the case where the functional group which can be chemically combined with the calcium-phosphate sintered compact is introduce | transduced on the base-material surface is demonstrated.

When the calcium phosphate sintered body is a hydroxyapatite sintered body, the hydroxyapatite sintered body can be chemically bonded to at least one functional group selected from the group consisting of an isocyanate group and an alkoxysilyl group. . That is, when the substrate has at least one functional group selected from the group consisting of an isocyanate group and an alkoxysilyl group, the substrate and the hydroxyapatite sintered body are chemically bonded. be able to. In addition, the said alkoxysilyl group has shown group containing Si-OR. That is, in this embodiment, the alkoxysilyl group includes ≡Si—OR, ═Si— (OR) ₂ , —Si— (OR) _{3, and the} like. In addition, “≡” and “=” in the above ≡Si—OR, ═Si— (OR) ₂ do not indicate only a triple bond or a double bond, but each bond is bonded to a different group. It may be. Accordingly, for example, —SiH— (OR) ₂ , —SiH ₂ — (OR) and the like are also included in the alkoxysilyl group. Further, R in the Si-OR represents an alkyl group or hydrogen.

  The functional group on the substrate surface may be a functional group possessed by the substrate itself, and the substrate surface may be treated by known means such as acid / alkali treatment, corona discharge, plasma irradiation, surface graft polymerization, etc. May be introduced by modifying the base material.

  Moreover, in order to introduce | transduce the said functional group, an active group may be introduce | transduced into a base material and a functional group may be introduce | transduced using this active group.

  The shape of the substrate may be a sheet or a particle, and is not particularly limited. Among them, the shape of the base material is more preferably a particle shape (spherical) or a columnar shape (columnar shape) that is remarkably smaller than the size of the substrate described later. And when the shape of a base material is a particulate form, specifically, the magnitude | size of the said base material exists in the range whose length of a major axis direction is 1 cm-1 micrometer, and the length of a minor axis direction is 1 mm. A columnar or spherical shape in the range of ˜1 nm is more preferable. Specifically, when the substrate is cylindrical, it is more preferable that the length in the major axis direction is in the range of 5 μm to 1 mm, and the minor axis direction is in the range of 100 nm to 10 nm. The case where the length in the direction is in the range of 10 μm to 200 μm and the minor axis direction is in the range of 1 μm to 50 μm is particularly preferable. When the substrate is spherical, the maximum diameter is more preferably in the range of 1 μm to 1 mm, particularly preferably in the range of 10 μm to 500 μm. By using the base material having a shape within the above range, the binding amount of the calcium phosphate sintered body on the base material can be increased, so that a calcium phosphate complex having higher bioactivity can be obtained.

(Calcium phosphate complex)
And the calcium-phosphate composite can be obtained by making the base material which has the said functional group react with a calcium-phosphate sintered compact. That is, the calcium phosphate sintered body and the base material are bonded by a chemical bond. In order to chemically bond the base material and the calcium phosphate sintered body, for example, a method of introducing a functional group capable of chemically binding to the calcium phosphate sintered body into the base material and reacting both, or a calcium phosphate sintered body A reactive functional group capable of being chemically bonded to the substrate is introduced into the substrate, and both are reacted.

When the calcium phosphate complex according to the present embodiment is, for example, a hydroxyapatite complex, the hydroxyapatite sintered body is chemically bonded to the surface of the base material. Specifically, the hydroxyl group (—OH) present in the hydroxyapatite sintered body is directly chemically bonded to the isocyanate group (—NCO) or alkoxysilyl group possessed by the substrate or the surface-modified linker. . When the alkoxysilyl group of the substrate is —Si≡ (OR) ₃ , a bond represented by the chemical formula (1) exists between the hydroxyapatite sintered body and the substrate.

(However, the above X and Y represent either a base material or a hydroxyapatite sintered body, and when X is a base material, Y is a hydroxyapatite sintered body, and X and Y are reversed. In some cases)
The silicon atom (Si) in the chemical formula (1) is a part of the alkoxysilyl group. Specifically, the silicon atom may be a part of the surface-modified graft chain of the substrate or a part of the alkoxysilyl group of the polymer chain. Further, the oxygen atom (O) in the chemical formula (1) is a part of an alkoxysilyl group or a part of a hydroxyl group of the hydroxyapatite sintered body. Further, X and Si in the chemical formula (1) may be bonded by a polymer chain, may be bonded by a low molecular chain, or may be directly bonded.

  When the functional group is an isocyanate group, the hydroxyapatite sintered body and the base material are chemically bonded by a urethane bond.

  The calcium phosphate composite used in the present embodiment is obtained by introducing a functional group capable of chemically bonding with the calcium phosphate sintered body into a base material and reacting the calcium phosphate sintered body with the functional group. Are more preferred. More specifically, the calcium phosphate composite includes a base material having at least one functional group selected from the group consisting of an isocyanate group, an alkoxysilyl group, and 4-methacryloxyethyl trimerlate anhydride group, and a calcium phosphate sintered body. A structure formed by chemical bonding with (a hydroxyapatite sintered body is more preferable) is further preferable. By introducing a functional group capable of chemically bonding with the calcium phosphate sintered body into the base material and reacting the functional group with the calcium phosphate sintered body, the calcium phosphate composite is not subjected to chemical pretreatment on the calcium phosphate sintered body. Therefore, a calcium phosphate composite can be obtained without impairing the biological activity of the calcium phosphate sintered body.

  In the calcium phosphate composite according to the present embodiment, the binding amount (adsorption rate) of the calcium phosphate sintered body on the base material is more preferably 5% by weight or more. The amount of binding is preferably 7% by weight or more, more preferably 10% by weight or more, and particularly preferably 12% by weight or more. When the binding amount is 5% by weight or more, when the calcium phosphate complex is used for a medical material such as a percutaneous terminal, high biocompatibility can be exhibited.

  In the calcium phosphate composite according to the present embodiment, the calcium phosphate sintered body and the base material may be chemically bonded by ionic interaction. This will be described below.

  In the calcium phosphate composite according to the present embodiment, when the calcium phosphate sintered body is chemically bonded to the calcium phosphate sintered body and the base material by ionic interaction, the functional group is ionized on the surface of the base material. Ionic functional groups are present. When an ionic functional group is present on the surface of the substrate, the ionic functional group and the ions of the calcium phosphate sintered body itself are chemically bonded by an ionic interaction, whereby a calcium phosphate complex ( Calcium phosphate complex) will be formed.

  The ionic functional group is classified as an acidic functional group or a basic functional group.

Specific examples of the acidic functional group include —COO ⁻ , —SO ₃ ²⁻ , —SO ₃ ⁻ , —O ⁻ , R ₂ NC (S) ₂ ^{—, and the} like. Specific examples of the basic functional group include —NH ³⁺ , ethylenediamine, pyridine and the like. That is, the acidic functional group or basic functional group exemplified above is present on the surface of the substrate. In the above R ₂ NC (S) ₂ ^— , R represents an alkyl group.

  In addition, the ionic functional group may be any one that can be ionized by chemical treatment such as acid treatment or alkali treatment. Specifically, for example, carboxyl group, dicarboxyl group, dithiocarbamate ion, amine, ethylenediamine , Pyridine and the like.

  The functional group may be, for example, a nonionic functional group (neutral functional group) or the like that can bind the functional group and the calcium phosphate sintered body itself by a coordinate bond.

(Substrate)
The substrate preferably has elasticity. As the material constituting the substrate, medical plastics, elastomers and the like are preferably used. Examples of the medical plastic and elastomer include fluorine resins (fluorine-containing resins) such as polytetrafluoroethylene, silicone resins such as silicone rubber, vinyl chloride resins, vinylidene chloride resins, fluorinated silicone rubber, polyethylene, and polypropylene. , Polycarbonate, polyester, polyhydroxyethyl (meth) acrylate, polyacrylamide, polysulfone, polyethersulfone, poly-N-vinylpyrrolidone, segmented polyurethane and the like. And as a material which comprises the said base | substrate, it is more preferable that it is the same material as the medical tube inserted in the percutaneous terminal finally obtained. Further, the substrate may be subjected to surface treatment by, for example, etching, glow discharge treatment or application of a surface treatment agent in order to improve the coating of the biocompatible ceramic composite.

  Here, the shape of the substrate will be described. However, the shape is not limited to this. For example, a cylindrical substrate may be used as the substrate. A medical tube is inserted into the cylindrical interior.

  More preferably, the base body has a collar portion. In the following description, a percutaneous terminal having a buttocks will be described.

  As shown in FIGS. 2, 23, 24, and 25, the base body according to the present embodiment includes a body portion 10 and a flange portion 20. A plurality of flanges 20 may be provided. Then, a medical tube is inserted into the inside (inside) of the trunk portion 10. Moreover, the said trunk | drum 10 and the collar part 20 may be comprised with the same material, and may mutually differ. Further, the base has a structure in which a hole 30 is provided in the flange 20. At this time, a plurality of the hole portions 30 may be provided. Hereinafter, these will be described.

  The trunk portion 10 fixes the percutaneous terminal 1 to a medical tube. And the said trunk | drum 10 is the shape extended in the insertion direction of the medical tube inserted in the said trunk | drum 10. FIG. And the said trunk | drum 10 is the cylinder shape whose shape (cross-sectional shape) in the surface orthogonal to the insertion direction of a medical tube is circular or an ellipse. The length of the body 10 in the insertion direction of the medical tube differs depending on the application to be used. For example, when it is used for a pulmonary hypertension treatment catheter (long-term indwelling central vein catheter), the length is 0. It may be about 0.5 mm to 2 cm, and when used for a catheter for peritoneal dialysis, it may be about 0.5 mm to 4 cm. Moreover, the internal diameter of the trunk | drum 10 is the same grade as the thickness of the medical tube inserted in the said percutaneous terminal 1. FIG. And as thickness (thickness) of the trunk | drum 10, although it changes also with the uses to be used, when the thickness of the medical tube inserted in the said percutaneous terminal 1 is made into 100%, it exceeds 0 and is 10000%. Within the range, more preferably within the range of 100 to 5000%. By setting the thickness of the body portion 10 within the above range, the percutaneous terminal 1 can be sufficiently fixed to the medical tube.

  The said heel part 20 suppresses a movement and rotation of the said base | substrate (percutaneous terminal 1) with respect to the extending | stretching direction of the said medical tube. When the medical tube is embedded in a living body, the medical tube is in a state where the outside of the living body is connected to the inside of the living body. And the external force will be added to the said medical tube mainly in the extending | stretching direction of the said medical tube. At this time, by providing the collar portion 20 on the percutaneous terminal 1, movement of the percutaneous terminal 1 in the extending direction of the medical tube (the insertion direction of the percutaneous terminal 1 in the medical tube) can be suppressed.

  It is also known that a rolling force is applied to the medical tube in the rotational direction of the cylindrical tube of the medical tube due to external force and distortion of the medical tube due to movement of the living body. At this time, by providing the collar 20 on the percutaneous terminal 1, movement of the percutaneous terminal 1 in the rotation direction of the medical tube (the rotation direction around the trunk of the percutaneous terminal in the medical tube) can be suppressed. .

  As a shape of the said collar part 20, it may be provided in all the trunk periphery of the said trunk | drum 10, and may be provided only in a part of trunk periphery. Moreover, the said collar part 20 may be provided with two or more. Specifically, for example, the flange portion 20 may be provided at both end portions of the body portion 10, or may be provided at one end portion of the body portion 10. And the collar part 20 is provided so that the area seen from the insertion direction of the medical tube in the percutaneous terminal 1, in other words, the axial direction of the percutaneous terminal 1 may be larger than the area of the body part 10. .

  As a shape of the said collar part 20, it may be provided in the whole trunk periphery of the said trunk | drum 10, and may be provided only in a part of trunk periphery. Moreover, the said collar part 20 may be provided with two or more. Specifically, for example, the flange portion 20 may be provided at both end portions of the body portion 10, or may be provided at one end portion of the body portion 10. Further, it may be provided in the middle part of the body part 10. And the collar part 20 is provided so that the area seen from the insertion direction of the medical tube in the percutaneous terminal 1, in other words, the axial direction of the expense terminal 1 may be larger than the area of the body part 10.

  Moreover, the said collar part 20 protrudes so that it may have a predetermined angle with respect to the axial direction of the said trunk | drum 10 (axial direction of the percutaneous terminal 1). Specifically, it is more preferable that the flange portion 20 protrudes from the trunk portion 10 so as to have an angle within a range of 30 to 150 ° when viewed from the axial direction of the trunk portion 10. And when the said buttock part 20 is made to incline so that it may become a predetermined angle with respect to the axial direction of the trunk | drum 10, and when the percutaneous terminal 1 is implanted in the living body, for example, The catheter fixed to the percutaneous terminal 1 can be placed along the living body. The angle of inclination of the buttocks 20 with respect to the axial direction of the trunk 10 varies depending on the application. The inside is more preferable, and the range of 20 to 160 ° is further preferable. And from the viewpoint of the biocompatibility of the finally obtained percutaneous terminal among the tilt angles, the tilt angle is particularly preferably in the range of 60 to 120 °. From the viewpoint of implanting the percutaneous terminal in a living body, the inclination angle is particularly preferably within the range of 15 to 45 ° (135 to 165 °).

  A preferable shape of the percutaneous terminal 1 for fixing the long-term indwelling central venous catheter will be described. When a long-term indwelling central venous catheter is implanted in a living body, it is implanted in the form shown in FIG. Specifically, it is implanted so that the catheter extends from the chest to the outside of the living body. At this time, by providing the collar portion 20 of the percutaneous terminal 1 on the trunk portion 10 so as to have a predetermined inclination angle as described above, the catheter can be taken out of the living body along the living body.

  Moreover, the area of the said collar part 20 seen from the insertion direction of a medical tube, in other words, the area of the collar part 20 in the cross section orthogonal to the axial direction of the trunk | drum 10 is with respect to the axial direction of the trunk | drum 10. When the area of the body portion 10 and the hollow portion in the body portion 10 in the cross section orthogonal to each other is 1, the range of more than 0 and within 10 is more preferable, and the range of 0.05 to 5 is further included. preferable.

  That is, as the shape of the base body, as shown in FIG. 2, the flange portion 20 may be provided near the center of the body portion 10 in the axial direction of the base body, and as shown in FIG. In addition, a flange portion 20 may be provided at the end of the body portion 10, and further, as shown in FIG. 4, the flange portion 20 is provided so as to have a predetermined angle with respect to the axial direction of the base body. It may be. Further, for example, the flange portions 20 may be provided at both ends of the trunk portion 10, and the flange portions 20 may be provided so as to protrude only at a part around the trunk portion 10. Furthermore, the flanges 20 provided at both ends may be provided so as to have a predetermined angle with respect to the axial direction of the base.

  The shape of the heel part 20 is required to be a shape that can be embedded in a living body and that exhibits high adhesion to the living body. Specifically, the percutaneous terminal 1 has a percutaneous terminal living body inner surface and a percutaneous terminal living body outer surface with respect to the extending direction of the medical tube during in vivo implantation. Therefore, the ease of embedding the percutaneous terminal 1 may vary depending on the shape of the heel portion 20, specifically, the symmetry of the heel portion 20. This will be described below.

  In the implantation of the medical tube and the percutaneous terminal 1 into the living body, a part of the epithelium in the living body is partially incised, the medical tube is punctured and placed, and the medical tube is inserted into the living body. . And it is preferable that the collar part 20 of the percutaneous terminal living body inner surface of the percutaneous terminal 1 has a shape with a thin tip which is easy to be inserted (embedded) into the living body when the medical tube is punctured. In addition to the above, it is preferable that the area of the collar portion 20 is large in order to obtain a wider adhesion surface with the living body.

  From these two viewpoints, it is more preferable that the shape of the heel portion 20 on the insertion side has a narrow tip so that the heel portion of the percutaneous terminal 1 can be easily inserted when inserting the medical tube into the living body. . Moreover, since the shape of the collar part 20 on the opposite side with respect to the insertion side has a wider area (a wider adhesive surface with respect to a living body), it is more preferable to protrude.

  Specifically, the shapes as shown in FIGS. 24 and 25 are preferable.

  The shape of the heel part 2 shown in FIG. 24 is such that the flying squirrel has a shape in which the film is expanded in order to obtain buoyancy from the air, and the surface of the living body inside the percutaneous terminal can be said to be the direction of the head of the flying squirrel. More specifically, the percutaneous terminal 1 shown in FIG. 24 has a shape in which four portions of the buttocks 2 further protrude, and when the percutaneous terminal 1 is inserted into a living body, the above buttocks It is the shape where the front-end | tip of 20 is thinner than another part.

  In addition, the shape of the heel part 2 shown in FIG. 25 is such that the space shuttle has a shape in which its wings are spread to obtain buoyancy from the air, and the inner surface of the percutaneous terminal living body is the flight direction of the space shuttle. it can. More specifically, the percutaneous terminal 1 shown in FIG. 25 has a shape in which two places on the rear end side in the embedding direction protrude in the living body of the heel part 2.

  By adopting the above-described configuration, it is easy to insert (embed), and the adhesion to the living body can be improved. Furthermore, the movement and rotation of the percutaneous terminal 1 with respect to the insertion direction of the medical tube can be suppressed by improving the adhesive force.

  Moreover, it is more preferable that a plurality of hole portions 30 are provided in the collar portion 20 of the percutaneous terminal 1. This will be described below.

  FIG. 23 is a drawing showing a schematic configuration of the percutaneous terminal 1 in which the hole portion 30 is provided in the collar portion 20. The hole 30 is provided to suppress the movement of the base body and the rotation of the medical tube with respect to the extending direction of the medical tube. When the medical tube is embedded in a living body, the medical tube is in a state where the outside of the living body is connected to the inside of the living body. And the external force will be added to the said medical tube mainly in the extending | stretching direction of the said medical tube. At this time, the movement of the percutaneous terminal 1 in the extending direction of the medical tube (the insertion direction of the percutaneous terminal 1 in the medical tube) is suppressed by providing the hole 30 in the collar portion 20 of the percutaneous terminal 1. be able to. Further, it is known that a rolling force is applied to the medical tube due to external force and distortion of the medical tube due to movement of the living body. Thereby, the medical tube rotates. Therefore, by providing a hole 30 in the collar portion 20 of the percutaneous terminal 1, the percutaneous terminal 1 is moved and rotated in the rotation direction of the medical tube (the rotation direction around the trunk of the percutaneous terminal 1 in the medical tube). Can be suppressed.

  More specifically, when the percutaneous terminal 1 is implanted in the living body due to the presence of the hole 30 in the heel part 20, living tissue existing in the living body is transferred to the hole 30 of the percutaneous terminal 1. Extend and pass. Then, the living tissue adhered to the surface of the buttocks 20 and the stretched tissue are adhered. Thereby, since the hole part 30 which exists in the collar part 20 of the percutaneous terminal 1 will be in the state sewn with the thread | yarn called tissue, the said percutaneous terminal 1 can be fixed to a biological body. By fixing the percutaneous terminal 1 as described above, movement and rotation of the percutaneous terminal 1 with respect to the insertion direction of the medical tube can be suppressed. That is, by providing a hole in the heel part 20 of the percutaneous terminal 1, when the percutaneous terminal 1 is implanted in a living body, the tissues existing on both sides of the heel part 20 are They are bonded to each other through the hole 30. Thereby, while being able to fix the position in the living body of the percutaneous terminal 1 implanted in the living body, it can suppress that the percutaneous terminal 1 rotates.

  The hole portion 30 may be provided only in a part of the flange portion 20 or may be provided in the entire region of the flange portion 20. Furthermore, a plurality of the hole portions 30 may be provided. Specifically, for example, the hole 30 may be provided in the middle part of the collar 20 (in the middle of the collar), or may be provided at the end of the collar 20. Further, the plurality of hole portions 30 may not be arranged symmetrically with respect to the shape of the flange portion 20.

  Moreover, 1-20 pieces are preferable, as for the number of all the hole parts 30 arrange | positioned at the collar part 20, 2-10 pieces are more preferable, and 4-8 pieces are especially preferable.

  By providing the hole 30 in the collar 20 as described above, the movement and rotation of the percutaneous terminal 1 with respect to the extending direction of the medical tube can be further suppressed.

  When the number of the hole portions 30 is too large (for example, more than 20 holes 30 are provided), the area of the collar portion 20 is reduced, and a sufficient machine for the percutaneous terminal 1 is obtained. The physical properties may not be obtained. Further, if the number of the hole portions 30 is excessively large, the size of the hole portions 30 arranged in the collar portion 20 becomes relatively small, so that the living tissue cannot sufficiently pass through the hole portions 30. The effect of suppressing the movement of the base body relative to the stretching direction of the medical tube and the rotation of the medical tube may not be sufficiently obtained.

  Moreover, it is more preferable that the plurality of hole portions 30 provided in the flange portion 20 are arranged symmetrically with respect to a line orthogonal to the stretching axis (stretching direction) of the body portion 10. And the movement and rotation of the percutaneous terminal 1 can be sufficiently suppressed by arranging the plurality of holes 30 symmetrically as described above.

  Further, the total area of all the holes 30 arranged in the collar part 20 includes the area of the collar part 20 (the area of the hole part arranged in the collar part) as seen from the insertion direction of the medical tube. In addition, the area of the cross section perpendicular to the axial direction of the body portion 10 which is flush with the collar portion is not included.) On the other hand, when the area of the collar portion 20 is 100%, it exceeds 0% and is within 40% An area within the range of 0.1 to 30% is more preferable, and an area within the range of 1 to 20% is particularly preferable.

When the area of the hole 30 is larger than 40%, the ratio of the hole 30 in the flange 20 is too large, so that the percutaneous terminal 1 itself cannot obtain sufficient mechanical properties. In addition, since the area per hole 30 is increased, even when the tissue passing through the hole 30 adheres to another living tissue, a sufficient force to fix the percutaneous terminal 1 can be obtained. In some cases, the effect of suppressing the movement and rotation of the percutaneous terminal 1 with respect to the extending direction of the medical tube may not be sufficiently obtained. Also, the shape of all the holes 30 arranged in the collar 20 For example, the shape may be a round shape, an elliptical shape, a triangular shape, a quadrangular shape, or the like, or an indefinite shape.

  Furthermore, the shape of all the hole portions 30 arranged in the flange portion 20 may not be the same, and the shapes of the plurality of hole portions 30 may be different from each other.

(Percutaneous terminal)
And the percutaneous terminal 1 concerning this Embodiment can be obtained by coat | covering the base-material surface with the said biocompatible ceramic composite.

  Hereinafter, implementation of calcium phosphate in the biocompatible ceramic will be described.

  The transdermal terminal 1 according to the present embodiment can be obtained by coating the surface of the substrate with the calcium phosphate complex. Further, the percutaneous terminal 1 can be obtained by coating the surface of the substrate with silk fibroin. That is, the surface of the transdermal terminal 1 according to the present embodiment is coated with a biocompatible ceramic composite (calcium phosphate composite) and / or silk fibroin. The biocompatible ceramic composite (calcium phosphate composite) and / or silk fibroin and the substrate may be physically joined using, for example, an adhesive, or may be joined by chemical bonding. Good. Specific examples of the adhesive used when the calcium phosphate complex and the substrate are bonded using the adhesive include, for example, silicone adhesive, polyethylene-vinyl acetate copolymer, polyester, nylon, urethane. An elastomer, vinyl acetate, an acrylic resin, etc. are mentioned.

  And the surface of the transdermal terminal 1 other than the surface in contact with the medical tube is coated with the calcium phosphate complex.

  For example, as shown in FIG. 20, the calcium phosphate complex may cover the entire surface of the percutaneous terminal 1, and for example, as shown in FIGS. 5: Only the collar part 20 and FIG. 6; a part of the collar part 20 and the trunk | drum 10) may be coat | covered. For example, you may coat | cover only the said collar part 20 with a calcium-phosphate complex. Further, a part of the percutaneous terminal 1 may be coated with a calcium phosphate complex, and the other part may be coated with silk fibroin.

  Moreover, for example, as shown in FIG. 7, the calcium phosphate complex may be covered beyond the region of the flange 20.

  Specific examples of the method for coating the surface of the substrate with the calcium phosphate complex include, for example, a method of physically bonding using an adhesive or the like, a method of bonding the substrate and the calcium phosphate complex by chemical bonding, and the like. In addition, when combining a base | substrate and a calcium-phosphate complex with a chemical bond, it is the same as the method of chemically bonding the said calcium-phosphate sintered compact and a base | substrate, and detailed description is abbreviate | omitted.

  When the calcium phosphate complex is bonded to the substrate surface using an adhesive, a sheet-like calcium phosphate complex may be attached to the substrate surface, or a particulate calcium phosphate complex may be attached to the substrate surface. Further, a fibrous calcium phosphate complex may be attached to the substrate surface. Then, by attaching the particulate or fibrous calcium phosphate composite to the substrate surface, the surface area of the calcium phosphate sintered body existing on the surface of the percutaneous terminal 1 terminal is increased, so that the biocompatibility of the percutaneous terminal 1 is further increased. Can be improved. Furthermore, when the fibrous calcium phosphate complex is attached to the substrate surface, when the transdermal terminal 1 is transplanted into the living body, the tissue enters between the fibrous calcium phosphate complexes, so that the biocompatibility is further increased. Therefore, the percutaneous terminal 1 can be suitably fixed in vivo (entanglement effect). Note that the base material of the sheet-like, particulate, and fibrous calcium phosphate composites has the above shape, and the calcium phosphate sintered body has a remarkably smaller particle diameter than the above base material. That is, the shape of the calcium phosphate complex is the same as the shape of the substrate. The fibrous or particulate calcium phosphate complex is a columnar or spherical shape having a major axis length in the range of 1 μm to 1 cm and a minor axis direction length in the range of 1 nm to 1 mm. The shape is shown.

  Furthermore, when the calcium phosphate complex is coated on the surface of the substrate, it is more preferable to coat the calcium phosphate complex so that the substrate is raised. Since the surface area of the calcium phosphate sintered body in the percutaneous terminal 1 can be increased by coating the substrate with the calcium phosphate composite so as to be in a raised state, the percutaneous terminal 1 can be well fixed to the subcutaneous tissue. can do.

  As described above, the percutaneous terminal 1 according to the present embodiment has a configuration in which the substrate surface is coated with the calcium phosphate complex formed by chemically bonding the calcium phosphate sintered body and the base material. By setting it as said structure, the transdermal terminal 1 with high biocompatibility can be provided. Moreover, since the calcium phosphate sintered compact is couple | bonded with the base material through the chemical bond, the physical property of a calcium phosphate sintered compact and a base material is not impaired. Furthermore, since the whole percutaneous terminal 1 can be made elastic by using an elastic material as the base and / or the base, the patient feels uncomfortable when the percutaneous terminal 1 is implanted. It can be further reduced. Further, when the percutaneous terminal 1 is used by being inserted into a medical tube, the percutaneous terminal 1 can be used easily and safely as compared with the conventional configuration in which calcium phosphate is fused to the medical tube. Moreover, since the said percutaneous terminal 1 uses the calcium-phosphate composite which combined the hard calcium-phosphate sintered compact with the base material which has elasticity, it is damaged compared with the percutaneous terminal 1 which consists of hydroxyapatite, for example. There is nothing.

  In addition, the same material may be sufficient as the base material which comprises the calcium-phosphate complex, and the said base | substrate may be mutually different materials. Moreover, you may form the said percutaneous terminal 1 and a medical tube integrally.

  Here, the case where the percutaneous terminal 1 is transplanted (implanted) in a living body will be described. When implanting the percutaneous terminal 1 in a living body, it is more preferable to implant so that a portion of the percutaneous terminal 1 covered with the calcium phosphate sintered body is in the living body. Further, the entire percutaneous terminal 1 may be implanted in the living body. For example, even when implanting so that a part of the percutaneous terminal 1 is exposed, the part of the calcium phosphate complex coated on the percutaneous terminal 1 is implanted outside the living body. It is possible to prevent bacteria and the like from adhering to the portion of the percutaneous terminal 1 that is being used.

  Further, as a method of implanting the percutaneous terminal 1, specifically, as shown in FIG. 1, the entire percutaneous terminal 1 is implanted, and the buttocks 20 come between the subcutaneous tissue and the skin. As shown in FIG. 8, there is a method of implanting so that the buttock 20 is placed in the subcutaneous tissue. Further, when the shape of the percutaneous terminal 1 is such that the heel portion 20 of the percutaneous terminal 1 has a predetermined inclination with respect to the axial direction of the substrate, as shown in FIG. There are a method of implanting so as to be disposed between and a method of implanting so that the heel portion 20 becomes a subcutaneous tissue as shown in FIGS. When the heel portion 20 of the percutaneous terminal 1 has a predetermined inclination with respect to the axial direction of the base body, the heel portion 20 is implanted so as to be parallel to the boundary surface between the subcutaneous tissue and the skin. do it.

  And the percutaneous terminal 1 concerning this Embodiment can be inserted and used for various medical tubes. Specific applications of the percutaneous terminal 1 include, for example, a pulmonary hypertension treatment catheter (long-term indwelling central venous catheter), a peritoneal dialysis catheter, and an artificial heart (VAS) for blood transfusion and devascularization. Suitable for site, colostomy, urinary bladder, high calorie catheter, gastric fistula, percutaneous electrode, external shunt, blood access.

In the above description, the case where the biocompatible ceramic is calcium phosphate is described, but the same applies to the case of titanium oxide. The percutaneous terminal according to the present embodiment is a percutaneous terminal for fixing a medical tube to be inserted into a living body at an insertion position of the medical tube, and is provided on the surface of the substrate holding the medical tube It is more preferable that at least a part is coated with a biocompatible ceramic composite formed by chemically bonding a base material and at least one of calcium phosphate and titanium oxide.
〔Example〕
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples and a comparative example.
Example 1
(Method for producing hydroxyapatite sintered body)
First, a method for producing a hydroxyapatite sintered body according to this example will be described.

Using dodecane as a continuous oil phase and pentaethylene glycol dodecyl ether at 31 ° C. as a nonionic surfactant as a nonionic surfactant, 40 ml of a continuous oil layer containing 0.5 g of the nonionic surfactant was prepared. Next, 10 ml of Ca (OH) ₂ dispersed aqueous solution (2.5 mol%) was added to the adjusted continuous oil layer. Then, after sufficiently stirring the obtained dispersion, 10 ml of 1.5 mol% KH ₂ PO ₄ solution was added to the water / oil (W / O) emulsion, and the reaction temperature was 50 ° C. The reaction was allowed to stir for 24 hours. Hydroxyapatite was obtained by separating the obtained reaction product by centrifugation. And the particle | grains (henceforth HAp particle | grains) of the hydroxyapatite sintered compact were obtained by heating the said hydroxyapatite on 800 degreeC conditions for 1 hour. The HAp particles were a single crystal and had a major axis of 300 to 400 nm.

(Method for producing hydroxyapatite composite particles)
First, fibrous silk fibroin as a base material (manufactured by Fujimura Yarn Co., Ltd., product name: Haeda, hereinafter referred to as SF fiber) has an average length of 100 μm in the major axis direction and an average length of 10 μm in the minor axis direction. Disconnected. The obtained SF fibers (hereinafter referred to as cutSF) were subjected to extraction removal of non-volatile components with a Soxhlet extractor.

  Next, 600 mg of cut SF extracted with Soxhlet was put into a doctor test tube, and then 82 mg of ammonium peroxodisulfate (APS) dissolved in 18 ml of pure water and 1088 μl of γ-methacryloxypropyltriethoxysilane (KBE503). Was added to 292 μl of pentaethylene glycol dodecyl ether and well stirred. The operations of freezing, degassing, thawing, and nitrogen replacement with liquid nitrogen were repeated twice.

  Next, the reaction was performed by heating the reaction solution in a 50 ° C. hot water bath for 60 minutes. Thereafter, the reaction solution was filtered using qualitative filter paper (retained particle diameter: 5 μm). As a result, silk fibroin fibers (filter cake) having alkoxysilyl groups introduced on the surface of cutSF were separated from the polymerized KBE and molecules (filtrate) esterified with silyl groups. Further, in order to separate the polymerized KBE, the silk fibroin fiber having an alkoxysilyl group introduced on the surface of cutSF was subjected to ultrasonic treatment (output 20 kHz, 35 W) for 1 minute in ethanol, and further for 2 hours. After washing with stirring, the mixture was filtered with qualitative filter paper. Thereafter, vacuum drying was performed to obtain a silk fibroin fiber grafted with a polymer chain having an alkoxysilyl group at the end, that is, an alkoxysilyl group-introduced silk fibroin fiber (hereinafter referred to as KBE-cutSF). In addition, the alkoxysilyl group introduction rate during the reaction time was 8.3% by weight. The introduction rate was determined by the following equation (3), where Ag is the weight of untreated cutSF and Bg is the weight of cutSF after the reaction (KBE-cutSF).

Introduction rate (% by weight) = ((B−A) / A) × 100 (3)
On the other hand, 300 mg of the HAp particles were added to 15 ml of a solvent (toluene: methanol = 8.6: 1), and the mixture was dispersed by sonication for 20 seconds, and then allowed to stand for 30 minutes to 1 hour.

  Further, while the HAp particles were allowed to stand, about 300 mg of KBE-cutSF was dispersed in 15 ml of a solvent (toluene: methanol = 8.6: 1) in 30 ml of Erlenmeyer.

  Then, the supernatant solvent in which the HAp particles were dispersed was gently transferred to an Ellenmeyer in which KBE-cutSF was dispersed with a Pasteur pipette. Thereafter, the dispersion solvent in which KBE-cutSF and HAp particles were mixed was gently stirred with a spoid every minute.

  Then, after the above-described mixing operation was repeated 10 times, KBE-cutSF (hereinafter referred to as KBE-cutSF-HAp) on which HAp particles were adsorbed was separated from HAp particles that were not adsorbed on the qualitative filter paper. Specifically, supernatant HAp particles were filtered, and then precipitated KBE-cutSF-HAp was recovered.

  Thereafter, the separated KBE-cutSF-HAp was stirred and washed in ethanol for 2 hours, sonicated for 1 minute, and then filtered through the qualitative filter paper.

  The filtered KBE-cutSF-HAp was dried at 60 ° C. and then treated at 120 ° C. and 1 mmHg for 2 hours. Thereby, hydroxyapatite composite particles (KBE-cutSF-HAp) were synthesized. As a result of analyzing the synthesized hydroxyapatite composite particles using FT-IR (diffuse reflection method), it was found that the HAp particles were bonded to the substrate.

(Cell adhesion test)
Next, a cell adhesion test of the hydroxyapatite composite particles (KBE-cutSF-HAp) was performed. This will be described below.

Mouse fibroblasts (L929) were seeded at 1 × 10 ⁶ cells / well on the above KBE-cutSF-HAp and untreated fibers (SF fibers) placed in a 24-multiwell dish. Then, culture was performed overnight using α-MEM medium (containing 10% bovine serum, 50 IU penicillin, 50 μg / ml streptomycin, 2.550 μg / ml amphotericin B) as a culture solution.

  After culturing, the KBE-cutSF-HAp and untreated fibers were sufficiently washed with a phosphate buffer, and after fixing the cells, both were observed with a scanning electron microscope. Specifically, FIG. 11 shows the case of KBE-cutSF-HAp, and FIG. 12 shows the case of untreated fibers. From this result, it can be seen that in the case of the hydroxyapatite composite, the cell adhesiveness is remarkably improved as compared with the case of the untreated fiber.

(Transdermal terminal manufacturing method)
Hereinafter, a method for producing a percutaneous terminal by coating a substrate with hydroxyapatite composite particles (KBE-cutSF-HAp) will be described. In addition, about the method of coat | covering a sheet-like hydroxyapatite complex and manufacturing a percutaneous terminal, the sheet-like hydroxyapatite complex was only affixed on the base | substrate, and detailed description is abbreviate | omitted.

  First, a cover tape was wound around a portion of the surface of the substrate that was not covered with the hydroxyapatite composite particles (other than the covered portion).

  Next, a silicone adhesive (non-corrosive quick-drying adhesive sealant, TSE-399) manufactured by GE Toshiba Silicone Co., Ltd. is used as the base while rotating at 360 rpm around the direction in which the catheter is inserted into the base of the silicon rubber. After the application, the excess adhesive was removed by rotating at 5600 rpm for 10 seconds.

  Then, the hydroxyapatite composite particles were uniformly applied while rotating the substrate coated with the adhesive at 360 rpm, and then the excess hydroxyapatite composite particles were removed.

  Thereafter, the substrate coated with the hydroxyapatite composite particles was dried at 85 ° C. for 5 minutes and removed from the rotating rod after 5 minutes. Then, drying was performed at 120 ° C. for 2 hours under reduced pressure (133 Pa (1 mmHg)).

Next, the substrate was washed by immersing the substrate in pure water and irradiating with ultrasonic waves (output 20 kHz, 35 W) for 3 minutes. Further, after the irradiation with ultrasonic waves, the substrate was stirred and washed in pure water for 1 hour, dried, and allowed to stand for 24 hours to produce a transdermal terminal according to the present invention. FIG. 13 shows a drawing showing a scanning electron microscope image of the percutaneous terminal thus obtained. The cover tape was removed after the hydroxyapatite composite particles were attached to the substrate on which the adhesive was applied.
(Example 2)
A transdermal terminal having a surface coated with silk fibroin was produced in the same manner as in Example 1 except that cutSF extracted with Soxhlet was used instead of the calcium phosphate complex.
(Example 3)
By the same operation as in Example 1, a transcutaneous terminal in which all of the buttocks and the trunk were covered with the calcium phosphate composite was manufactured. This percutaneous terminal is shown in FIG. FIG. 21 shows the percutaneous terminal attached to a medical tube.

(Animal implantation experiment)
Below, the effect of implanting a transdermal terminal coated with a hydroxyapatite complex and a transdermal terminal coated with silk fibroin on an animal was investigated. Specifically, the effect of implanting this transdermal terminal in rats and rabbits was examined. This will be described in detail below. In the following experiment, a percutaneous terminal (Example 1) in which the entire surface of the substrate was coated with a hydroxyapatite composite and a percutaneous terminal (Example 2) in which the entire surface of the substrate was coated with silk fibroin were used. ing.

  The percutaneous terminal (Example 1) whose surface was coated with a hydroxyapatite complex obtained by the above production method (Example 1), and the percutaneous terminal (Example 2) whose surface was coated with silk fibroin were not coated. The percutaneous terminal (substrate only) was sterilized with an autoclave and then implanted in rats, and the progress was observed. The transdermal terminals of Example 1 and Example 2 were sterilized with an autoclave and then implanted in rabbits, and the progress was observed.

  FIG. 14 shows the results of implantation in rats for 8 weeks (2 weeks in the case of the substrate alone). Further, FIG. 15 shows the result of implantation in a rabbit for 3 weeks, and FIG. 16 shows the result of implantation for 10 weeks. In FIGS. 14 to 16, the experimental results in the percutaneous terminal (a) of Example 1 and the percutaneous terminal of Example 2 are shown in (b), and the experimental results in the percutaneous terminal of the substrate alone are shown in (c). .

  As can be seen from FIGS. 14 (a) to 14 (c), in the case of the transdermal terminal (Example 1) whose surface was coated with KBE-cutSF-HAp, and the transdermal terminal whose surface was coated with silk fibroin (Example 2). In the case of), it can be seen that the adhesion is improved as compared with the base material alone (comparative example). In the case of only the above-mentioned base material, it was detached after 2 weeks after being implanted in the rat. Further, as shown in FIGS. 15 and 16, it can be seen that the percutaneous terminals of Example 1 and Example 2 are in close contact with the skin tissue, and redness, inflammation and the like are not observed.

Moreover, the catheter (medical tube) provided with the percutaneous terminal according to Example 3 was also implanted in a rabbit in the same manner as described above. FIG. 22 shows a rabbit skin surface image when the rabbit is embedded for 6 months. From this result, it can be seen that the percutaneous terminal is in close contact with the living tissue and no inflammation or the like is observed.
(Cell adhesion test 2)
Hereinafter, a cell adhesion test between a hydroxyapatite complex and silk fibroin will be described.

Mouse fibroblasts (L929) were seeded at 1 × 10 ⁶ cells / well on hydroxyapatite complex (KBE-cutSF-HAp) and silk fibroin (SF fiber) placed in 24 multiwell dishes. And it culture | cultivated for 48 hours, using 10% FCS as a culture solution.

  Then, after discarding the culture solution, 1 ml of PBS was injected and discarded. Then 1 ml of 1% glutaraldehyde was injected. Then, after fixing with bakelite, the adhesion part of an adhesive cell (L929 cell) and SF and SF-HAp complex was cut | disconnected, and what observed the cut surface with the transmission electron microscope (TEM) was evaluated. . The results are shown in FIGS. As a result, in the case of the hydroxyapatite complex, as shown in FIG. 18, HAp is in direct contact with the SF surface and the L929 cells in many places (anchoring effect is observed). On the other hand, SF fibers and L929 cells adhered as shown in FIG. 19, but a divergence was observed at regular intervals. Therefore, it turns out that the hydroxyapatite composite_body | complex adheres to a cell more firmly than SF fiber. That is, in the case of a transdermal terminal having a hydroxyapatite complex, it can adhere to cells more firmly than a transdermal terminal in which only silk fibroin is coated on the substrate surface.

  The percutaneous terminal according to the present invention can be suitably used as a percutaneous terminal for fixing a medical catheter that is implanted in a living body for a long period of time.

It is sectional drawing which shows a mode that the percutaneous terminal is implanted so that a buttock may come between a subcutaneous tissue and skin. It is a perspective view which shows the shape of the base material which comprises the percutaneous terminal concerning this Embodiment. It is the top view (a) and front view (b) which show the other shape of the base material which comprises the percutaneous terminal concerning this Embodiment. It is the top view (a) and front view (b) which show another shape of the base material which comprises the percutaneous terminal concerning this Embodiment. It is drawing which shows the percutaneous terminal by which only the buttocks are coat | covered with the calcium-phosphate complex. It is drawing which shows the percutaneous terminal by which the collar part and a part of trunk | drum are coat | covered with the calcium-phosphate complex. It is drawing which shows the percutaneous terminal by which the calcium-phosphate complex was coat | covered beyond the area | region of the buttocks. It is sectional drawing which shows a mode that the percutaneous terminal is implanted so that a buttock may be arrange | positioned to a subcutaneous tissue. It is sectional drawing which shows the other mode which has implanted the percutaneous terminal so that a buttock may come between a subcutaneous tissue and skin. It is sectional drawing which shows the other mode which has implanted the percutaneous terminal so that a buttock may be arrange | positioned in a subcutaneous tissue. It is drawing which shows the scanning electron microscope image which shows the result of having performed the cell adhesion test using the calcium-phosphate complex of Example 1. FIG. It is drawing which shows the scanning electron microscope image which shows the result of having performed the cell adhesion test using only the base material which has not combined the calcium-phosphate sintered compact. It is drawing which shows the scanning electron microscope image of a percutaneous terminal. Drawing which shows the image at the time of implanting the percutaneous terminal (a) of Example 1, the percutaneous terminal (b) of Example 2, and the base | substrate (c) which has not couple | bonded the calcium phosphate sintered compact with a rat, respectively. It is. It is drawing which shows the image at the time of implanting the percutaneous terminal of Example 1 and Example 2 in the rabbit for 3 weeks. It is drawing which shows the image at the time of implanting the percutaneous terminal of Example 1 and Example 2 in the rabbit for 10 weeks. It is drawing which shows the attachment position in the living body of the percutaneous terminal in the case of fixing the long-term indwelling type central venous catheter for prostacyclin home continuous intravenous infusion therapy in the treatment of pulmonary hypertension. It is drawing which shows the scanning electron microscope image which shows the result of having performed the cell adhesion test 2 using the hydroxyapatite composite_body | complex. It is drawing which shows the scanning electron microscope image which shows the result of having performed the cell adhesion test 2 using silk fibroin. It is drawing which shows the percutaneous terminal by which all the buttocks and the trunk | drum were coat | covered with the calcium-phosphate composite. It is drawing which shows the medical tube provided with the percutaneous terminal of Example 3. FIG. It is drawing which shows the image at the time of implanting the percutaneous terminal of Example 3 in the rabbit for 6 months. (A) is a top view which shows schematic structure of the percutaneous terminal by which the hole was formed in the collar part, (b) is a side view. (A) is a top view which shows schematic structure of a flying squirrel type percutaneous terminal, (b) is a side view. (A) is a top view which shows schematic structure of a space shuttle type percutaneous terminal, (b) is a side view. It is sectional drawing which shows the other aspect which has implanted the percutaneous terminal so that a buttocks may be arrange | positioned in a subcutaneous tissue.

Explanation of symbols

1 percutaneous terminal 10 trunk 20 buttock 30 hole

Claims (12)

A percutaneous terminal for fixing a medical tube to be inserted into a living body at an insertion position of the medical tube,
At least a part of the surface of the substrate holding the medical tube is coated with a biocompatible ceramic composite formed by chemically bonding the base material and the biocompatible ceramic;
The transdermal terminal, wherein the biocompatible ceramic composite is a multiparticulate biocompatible ceramic composite.   The percutaneous terminal according to claim 1, wherein the base is provided with a collar portion that suppresses movement of the base with respect to the insertion direction of the medical tube.   The percutaneous terminal according to claim 2, wherein a hole is formed in the collar.   The collar portion is provided between one end and the other end of the base, and only the region including the collar portion from the one end is covered with the biocompatible ceramic composite. The percutaneous terminal according to claim 2.   The transcutaneous terminal according to claim 2, wherein the collar is provided so as to have a predetermined angle with respect to the insertion direction of the medical tube. The shape of the flange portion has a shape tapering the insertion side leading end of the living body of the collar, and that anti Department of the insertion direction of the living body of the flange portion opposite a shape that extends toward the distal end The percutaneous terminal according to any one of claims 2 to 5, wherein:   The percutaneous terminal according to any one of claims 1 to 6, wherein the percutaneous terminal is integrated with the medical tube.   The transdermal terminal according to any one of claims 1 to 7, wherein the biocompatible ceramic is calcium phosphate.   The calcium phosphate composite in which the biocompatible ceramic is calcium phosphate has a columnar or spherical shape having a major axis length in the range of 1 μm to 1 cm and a minor axis direction in the range of 1 nm to 1 mm. The percutaneous terminal according to claim 8, wherein:   The transdermal terminal according to any one of claims 1 to 9, wherein the substrate is silk fibroin.   The transdermal terminal according to any one of claims 1 to 10, wherein the biocompatible ceramic composite is coated so as to be raised with respect to the substrate.   A medical tube comprising the percutaneous terminal according to any one of claims 1 to 11.