JPS6316142B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an in-vivo implant material for an artificial organ or an artificial organ to be implanted in the body.

In recent years, research and development of artificial organs and organs for implantation in the body has been actively conducted. For example, many things are being researched and developed, including artificial tracheas, artificial esophagus, artificial blood vessels, shunts for hemodialysis, pacemakers, artificial valves, and artificial hearing. Since these implant materials for implantation in the body need to exert their respective functions continuously over a long period of time, materials that are stable and strong even when implanted in the body are used as their structural materials. Materials that easily decompose in the body or are toxic are not preferred. Among the materials used for these purposes, synthetic polymers such as silicone, Teflon, polycarbonate, and polyethylene have been used for many purposes and are establishing themselves as medical materials. It is the most commonly used and most important synthetic polymer due to its stability in the body, non-toxicity, processability, and physical properties.

Although such medical polymer materials do not deteriorate in vivo, they are usually hydrophobic and do not have good affinity with living tissues. However, internal implants are usually substitutes for a certain organ or tissue over a long period of time, and are used by being connected to living tissue, so the quality of the connection between the implant material and the living body is extremely important. Become. For example, silicone is used as a material for artificial tracheas and esophagus, but it does not adhere well to the living body's trachea and esophagus, and often falls off.

In order to improve these drawbacks, attempts have been made to design various physical structures for the junction between the artificial trachea and the esophagus. In addition, it is important that not only the joints at both ends of these prostheses but also the entire sidewalls adhere well to the surrounding tissue in order for the implant material to function in the correct position for a long period of time. In addition, in order to perform hemodialysis, blood must be taken out of the body, and a silicone tube (shunt) is used to create this blood extraction port, and the shunt is connected to the artery and vein and is exposed outside the body. fixed in the state. The shunt penetrates the skin and exits the body, and because the silicone surface and skin tissue adhere poorly, infection from the area around the shunt becomes a major problem. Even in such cases, the problem can be solved by modifying the surface of the shunt so that it is compatible with living tissue. In addition, there are many cases in which implants are implanted in the body and used for long periods with one end exposed outside the body, but in this case, problems similar to those of silicone shunts occur as well.

As mentioned above, improving the surface of implant materials made of medical polymer materials such as silicone to improve compatibility and adhesion with surrounding biological tissue is
This greatly contributes to the long-term stable function of the implant material.

The present invention has been made in consideration of these circumstances, and includes a sponge-like sheet whose main constituent material is atelocollagen from which telopeptides present at the terminal portions of collagen molecules have been removed. The present invention relates to an in-vivo implant material characterized by the following.

In the present invention, a sponge-like sheet made of atelocollagen may be bonded together, or a sponge-like sheet made of atelocollagen and polyvinyl alcohol may be bonded together.

In addition, in order to manufacture the implant material according to the present invention, telopeptides present at the terminal portions of collagen molecules are selectively digested and removed using a proteolytic enzyme, and the resulting liquid containing atelocollagen as a main component is then purified. An in-vivo implant characterized in that a sponge-like sheet is created by a freeze-drying method, cross-linked to this sponge-like sheet, and then this cross-linked sponge-like sheet is pasted to the surface of an in-vivo implant material body. It is important to adopt the manufacturing method of the material.

In the method according to the present invention, it is preferable to create a sponge-like sheet from an atelocollagen solution or from a mixed solution of atelocollagen and polyvinyl alcohol. Further, it is desirable to crosslink the sponge sheet by gamma ray irradiation, ultraviolet ray irradiation, or chemical reagent treatment.

The atelocollagen used in the present invention has antigenic telopeptides present at both ends of the molecule removed by pepsin treatment, and is a collagen without immunological activity. Atelocollagen has unique characteristics as a medical material; unlike synthetic polymers, it is of biological origin, so it has good compatibility with living tissues, is excellent as a scaffold for cell growth and proliferation, and attracts connective tissue. It has an effect. It is also gradually absorbed into the body and replaced by new connective tissue in the host. On the other hand, although polyvinyl alcohol is a synthetic polymer, it has been shown that it is absorbed within the body, and is attracting attention as an absorbable synthetic polymer. However, its absorption rate is much slower than that of atelocollagen. By mixing atelocollagen and polyvinyl alcohol (PVA), the in vivo absorption of atelocollagen is delayed without losing its affinity with living tissues, and the role of the mixture is sustained and stabilized. Atelocollagen or a mixture of atelocollagen and polyvinyl alcohol is molded into a sponge sheet and used for the purpose of the present invention, but surrounding living tissue, especially connective tissue, enters into the holes of the sponge to improve the adhesion effect. It is very convenient for The size of the holes in this sponge must be determined in order to allow the tissue to enter effectively.
Must have a diameter of 80 microns or more.

Next, the present invention will be explained according to one manufacturing process.

After pulverizing the dermal part of the skin of a young cow and washing it with 5% saline and water, 0.005 (weight ratio) pepsin is added to 1 part dry dermis, and the mixture is solubilized at pH 3 under stirring for 7 days. The solubilized collagen solution is passed through a cloth, the pH is adjusted to 10 to inactivate pepsin, and the mixture is centrifuged to a pH of 7 to collect the atelocollagen precipitate. After redissolving in acid, it is reprecipitated at pH 7 and collected by centrifugation to purify atelocollagen. This purified atelocollagen is dissolved in HCl of PH3 to make a 2% solution. After adjusting this 2% atelocollagen solution to pH7, atelocollagen-PVA was added as shown below.
Create a sponge similar to the mixture. On the other hand, refining
Create a 2% aqueous solution of PVA. The respective 2% solutions were mixed and adjusted so that the total concentration of atelocollagen and PVA was 2%. The mixing ratio of atelocollagen and PVA is
PVA can be used in a range of 100:10 to 10:100, preferably 100:100 is ideal. In this case, equal amounts of each 2% solution may be mixed. After mixing, adjust the pH to 7 with NaOH solution.

This mixed solution is poured into a flat stainless steel container to a thickness of 1 to 3 mm, and then vacuum freeze-dried to obtain a sponge sheet. Alternatively, a sponge sheet can be obtained by freeze-drying the sponge to a thickness of 10 to 20 mm and cutting it with a band knife to a thickness of 1 to 3 mm. The thickness of the sponge sheet is most preferably 2 mm. Next, the sponge sheet was irradiated with a 30W ultraviolet germicidal light from a distance of 10cm for 1 hour each on the front and back sides.
Introducing crosslinking. Gamma rays instead of ultraviolet rays
Crosslinking can be similarly introduced by irradiation with 10 ⁶ rad.
Furthermore, aldehydes such as formaldehyde and glutaraldehyde can also be used to introduce crosslinking. In the case of formaldehyde, it is appropriate to treat at pH 7.0 and formaldehyde concentration 0.1% for 10 minutes. For glutaraldehyde, PH6.0,
Treatment with glutaraldehyde concentration of 0.01% for 10 minutes is appropriate. In the case of treatment with aldehydes,
After treatment, it is washed repeatedly with water, lightly dehydrated using a centrifugal dehydrator, and then freeze-dried again. As the crosslinking operation, ultraviolet irradiation is the simplest and preferred.

After the crosslinking treatment, the sponge sheet is compressed and crushed using a glass rod. The sponge sheet thus obtained is applied to an implant whose surface is made of silicone or other synthetic polymers. For example, in the case of a silicone artificial esophagus, medical grade one-component RTV silicone is applied as an adhesive to the outer wall, and the sponge sheet is pasted on top of this. In the case of a hemodialysis shunt, it is attached to the part that enters the body using the same method as above. Furthermore, when a metal wire or the like is inserted into the body from the outside, it is sufficient to first cover the metal with silicone and then affix it to the silicone surface in the same manner as above. After adhering the sponge sheet, apply 1% atelocollagen solution (PH
3. Apply HCl (acidic) to the sponge surface, neutralize with 1% ammonia solution, wash with water, and air dry. To introduce crosslinks into the newly applied atelocollagen,
Ultraviolet light is irradiated for 1 hour under the same conditions as above.

The implant material obtained in this way has a sponge layer of atelocollagen or atelocollagen on the outermost layer, that is, the surface that comes into contact with living tissue.
Covered with a thin sponge layer made of PVA,
The surface of the sponge and the surface of the holes are covered with a very thin layer of atelocollagen. When such an implant material is implanted into the body, the surrounding tissue enters the sponge, improving the close contact between the implant material and the living tissue, and conveniently fixing the implant material. This prevents the implant material from falling off and infection from the interface between the implant and the living body, and greatly contributes to the long-term performance of the implant material.

Claims (1)

[Scope of Claims] 1. An in-vivo implant material characterized in that a sponge-like sheet whose main constituent material is atelocollagen from which telopeptides present at the terminal portions of collagen molecules have been slowly removed is laminated on its surface. 2. The in-vivo implant material described in claim 1, which is bonded with a sponge-like sheet made of atelocollagen. 3. The in-vivo implant material as set forth in claim 1, wherein a sponge-like sheet made of atelocollagen and polyvinyl alcohol is laminated. 4. Selectively digest and remove telopeptides present at the terminal portions of collagen molecules using proteolytic enzymes, and freeze-dry the resulting liquid containing atelocollagen as its main component. 1. A method for producing an in-vivo implant material, comprising subjecting a sponge-like sheet to cross-linking treatment and then bonding the cross-linked sponge-like sheet to the surface of a main body of the in-vivo implant material. 5. The method described in claim 4, wherein a sponge-like sheet is created from atelocollagen liquid. 6. The method according to claim 4, wherein a sponge-like sheet is created from a mixed solution of atelocollagen and polyvinyl alcohol. 7. The method according to any one of claims 4 to 6, wherein the sponge-like sheet is crosslinked by gamma ray irradiation, ultraviolet irradiation, or chemical reagent treatment.