JPH0611312B2 - Percutaneous implant body - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a percutaneous implant body comprising a microporous hollow fiber fitted with an affinity member.

A conventional biomedical terminal, such as a cannula (intubation), has one end on the skin of the living body and the other end buried under the skin, and is used for infusion or injection of various medicinal solutions or the like through the through hole for renal dialysis. It is used as a blood flow extraction / injection port, etc., and it has already been proposed that it is mainly made of a so-called bio-inert material such as silicone rubber or fluororesin.

However, since these are nothing but foreign substances to the living body, the living body attachment site is left in a state of some kind of trauma, so it can withstand long-term use due to bacterial infection from the gap between the two. Not only can it not be obtained, but it also has some problems such as fear of bleeding due to rocking due to poor bio-fixability, so it has not yet been sufficiently spread.

For example, in the so-called drug treatment (drug delivery) system whose development is remarkable recently, such as in artificial pancreas (see "Drug Delivery System" by Klaus Haleman, published by Ikuyakuyaku Publishing Co., Ltd. in 1983), insulin Problems such as drug injection route and ultra-quantitative injection method have not been solved (see Journal of Medical Device, 1983, Vol. 53, No. 2, pp. 90 et seq.), And it is semi-permanent and safe as a drug injection port. It can be said that the demand for biometric terminals that can be used is increasing more and more today.

On the other hand, recently, the excellent biocompatibility and further osteoinductivity of a skin tissue-affinity member composed of an apatite-based material such as a hydroxyapatite sintered body and a ceramic-based material such as a calcium phosphate compound sintered body have been elucidated, and its burning has been revealed. Although the use of a sintered body for artificial tooth roots and artificial bones has been proposed and put to practical use, the physiological reactivity of the sintered body with skin tissue has not been clarified at all in the prior art.

In view of the above, as a result of intensive studies by the present inventors, the fact that the above-mentioned skin tissue-affinity member not only has affinity for skin tissues but also tightly and integrally joins these tissues and the quantitative determination The present inventors have found that the injection can be easily solved by arranging a microporous hollow fiber constituted by a barrier layer in contact with a biological tissue, which inhibits spontaneous diffusion of a drug as much as possible, and arrived at the present invention. .

Hereinafter, the material composition and manufacturing method of the skin tissue affinity member and the microporous hollow fiber of the biological terminal of the present invention,
The shape and structure, the mode of use, etc. will be explained in detail.

Material composition and manufacturing method 1. The skin tissue affinity member in the present invention is classified into "apatite-based material" and "ceramic-based material", and the respective material composition manufacturing methods are described.

(a) the at "apatitic material" in the present invention not only hydroxyapatite its chemical composition is represented by _{Ca 10 (PO 4) 6 (} OH) 2, 1~10% of the carbonate in place of OH ions (CO ₃ ) ion, fluorine ion, chlorine ion or its various ion-substituted compounds which may contain Mg instead of Ca, or whose main component is to improve sinterability, strength, porosity, etc. to which the _{Ca 3 (PO 4) 2,} Ca 4 O (PO 4) 2, Mg
O, Na ₂ O, K ₂ O, CaF ₂ , Al ₂ O ₃ , SiO ₂ , CaO, Fe ₂ O ₃ , MnO,
It also includes a mixture of well-known various additives such as MnO ₂ , ZnO, C, SrO, PbO, BaO, TiO ₂ , ZrO ₂ or various polymer materials.

Here, when it is used as a composite agent with a polymer, polyethylene, polypropylene, polymethylmethacrylate, polyurethane, polyester, ABS resin, fluorine resin, polycarbonate, polysulfone, epoxy resin, silicone resin, diallyl phthalate resin, which is relatively less toxic ，
A resin such as furan resin can be selected.

On the other hand, examples of the manufacturing method include a so-called sintering method on a base material such as a unit or a metal, and a plasma spraying method on a base material such as a metal. Apatite powder is compression-molded into a so-called shape under a pressure of about 500 to 3,000 kg / cm ² by a mold or a rubber press, and then sintered at a temperature of about 700 to 1,300 ° C. However, the following known techniques are referred to for more details including other production methods and compositions. That is, JP-A-51-40400 and JP-A-52-64
199, the same 52-82893, the same 52-142707,
52-147606, 52-149895, 53
-28997, ibid 53-75209, ibid 53-1110.
00, same 53-118411, same 53-141494,
53-1110999, 54-158099, 55
-51751, 55-130854, 55-140.
756, the same 56-45814, the same 56-166843,
JP-B-57-40776 and JP-A-57-40803.

The relative density (based on the density of the hydroxyapatite single crystal) of the sintered body that is particularly useful in the present invention from the viewpoint of the bondability with the skin tissue is 60 to 99.5%, more preferably 85 to 95%. %.

(b) In the present invention, the "ceramic material" means a sintered body containing tricalcium phosphate and / or tetracalcium phosphate as a main raw material, or a support such as metal or ceramic, which is sprayed or sintered. It is a coating material formed by coating with MgO, Na ₂ O, K ₂ O, Ca in order to improve its sinterability, strength, porosity, etc.
_{F 2, Al 2 O 3,} SiO 2, CaO, Fe 2 O 3, MnO, MnO 2, ZnO, C, Sr
It includes a mixture of various additives such as O, PbO, BaO, TiO ₂ and ZrO ₂ .

On the other hand, examples of the manufacturing method include a so-called sintering method on a base material such as a single substance or a metal, and a plasma spraying method on a base material such as a metal. For example, the single sintered body is generally phosphoric acid. A raw material consisting of tricalcium or tetracalcium phosphate is 500-3,000 kg / c by a mold or rubber press.
It is obtained by compression molding into a desired shape under a pressure of about m ² and then sintering this at a temperature of about 700 to 1,300 ° C., but more detailed including other manufacturing methods and compositions. The following known techniques are referred to.

That is, JP-A-55-140756, JP-A-55-42240, 55-56062, 54-94512, 56-18864, 56-143156, 56-166843, 53-28997, 53-75209, and JP-B-58-39533. Incidentally, the relative density (based on the density of tricalcium phosphate) of the sintered body and the covering material which are particularly useful in the present invention from the viewpoint of the bondability with the skin tissue is 60 to 99.5%, More preferably, it is about 85 to 95%.

2. The microporous hollow fiber in the present invention is
It functions as a barrier layer against invasion of living tissue into the drug solution passage and diffusion of natural concentration of drug, and also has a function of extracting body fluid. Furthermore, selective extraction of body fluid to various places in the body is performed. In addition, it has various functions and functions such as flexibility of the microporous hollow fiber for directional drug administration. The material forming the microporous hollow fiber has an average pore size of regenerated cellulose, polypropylene, PVA (polyvinyl alcohol), etc.
It is preferable to use a porous member having a size within the range of 007 μ to 0.2 μ, but generally, the implant site, the depth and the molecular weight and concentration of the drug used and the body fluid to be extracted, as well as the energy form used for drug injection, in vivo It can be changed depending on the purpose of use.

As described above in detail, the present invention, the form of the microporous hollow fiber in which the skin tissue affinity member is formed in the contact portion with the skin tissue can be made as desired depending on the purpose of use, and the typical drawings thereof will be referred to in the accompanying drawings. The details will be described with reference to FIG.

That is, FIG. 1 is a cross-sectional view showing an example of the biomedical terminal of the present invention, in which biomedical terminal 1 used as a drug injection port.
Is integrally formed with a terminal head portion 2 and a bottom portion 3 both made of a skin tissue affinity member, and has a pore diameter of, for example, 0.2 μm inside or at the end portion thereof, such as PVA (polyvinyl alcohol). A microporous hollow fiber 4 formed of a porous member such as, and a porous member 5 of the same quality as the microporous hollow fiber 4 is bonded to the tip of the microporous hollow fiber 4, for example. A desired drug is injected into the living body through the microporous hollow fiber 4, and various sensor elements are introduced.

FIG. 2 is a sectional view showing a second embodiment of the biological terminal of the present invention. This is configured such that, depending on the type of desired drug, the drug is likely to be contaminated and the effect is rapidly reduced, and the drug can be constantly circulated or flushed with an antibiotic. In the figure, a living body terminal II in which a drug injection port 9 is further provided at a drug injection port 9 is formed by integrally connecting a terminal head portion 6 and a bottom portion 7 made of a skin tissue affinity member, as in FIG. For example, a microporous hollow fiber 8 using a member similar to that of the first embodiment is mounted inside and at the extreme end of the microporous hollow fiber 8, and the desired drug enters the living body through the microporous hollow fiber 8. After being injected, the drug circulates in the body and is taken out of the body. In the embodiment shown in FIG. 1 and FIG. 2 above, only the microporous hollow fiber can be replaced in the biomedical terminal composed of the skin tissue compatibility member and the microporous hollow fiber, and it is possible to endure long-term use.

In addition, in the biological terminal made of a skin tissue compatible member,
Although the drug injection port and the drug injection port are integrally formed, the region between FIGS. 2A and 2B may be separated according to the purpose of use such as expansion of the drug administration area.

On the other hand, since the porous member can achieve a predetermined purpose if it is interposed in the contact portion with the skin tissue, only the main portion of the microporous hollow fiber, that is, the contact portion with the skin tissue is covered with the apatite sintered coating material (Japanese Patent Laid-Open Publication No. Sho. 52-82893, 53
No. 75209 and No. 53-118411, etc.). Further, it may be a bio-terminal formed by forming a hydroxyapatite sprayed or sintered layer on a microporous hollow fiber.

Further, the tip of the microporous hollow fiber may be sealed by heat welding or the like as shown at 11 in FIG.

As is clear from the above, the biomedical terminal of the present invention can have various shapes, structures, and dimensions, and is not limited to a specific form.

Hereinafter, the present invention will be described in detail with reference to experimental examples.

Experimental Example I 1. Manufacture of biological terminal For hydroxyapatite powder, 0.5 mol / calcium hydroxide and 0.3 mol / phosphoric acid solution are gradually dropped,
Synthesis was carried out by reacting at 37 ° C. for 1 day, and this was obtained by filtration and drying. This synthetic powder was filled in a mold and compression-molded at a pressure of 800 kg / cm ² to have a through hole with a diameter of 2 mm and a bulk density of 1.6.
A green compact of g / cm ³ was obtained. This was cut and processed into a terminal head shape (see FIG. 1) with a lathe and a dental diamond bar. Similarly, the synthetic powder was filled in a mold, compression-molded, and cut to obtain a terminal bottom portion (see FIG. 1). Next, the through holes of both green compacts were joined together, and further, water was previously added between the two and the gel apatite powder well kneaded in a mortar was applied and adhered.
This is sintered at 1,250 ° C for 1 hour to obtain compressive strength of 5,
000kg / cm ^2, bending strength 1,200 kg / cm ^2, the relative density 9
A bio-terminal as shown in FIG. 1 was obtained in which 5% and the bonded portion were evenly sintered.

Here, the terminal bottom has a diameter of 5.4 mm, a thickness of 2 mm, and the terminal head neck has a diameter of 4 mm and an inner diameter of 2 mm.

In addition, in the sintered body obtained when the sintering temperature is 1,100 ° C., the relative density is 85%, the compressive strength is 3,000 kg.
The bending strength was 700 kg / cm ² and the bending strength was 700 kg / cm ² . A microporous hollow fiber (PVA (polyvinyl alcohol) having an average pore diameter of 0.2 μ) was mounted in the terminal as shown in FIG. 1 to prepare a sample.

2. Animal experiment The above-mentioned biological terminal was embedded in the flank skin of a mongrel dog and observed over time. As a result, the terminal was strongly bonded and adhered to the skin tissue at the bottom and neck about 2 weeks after the operation and removed even when pulled. After a lapse of one year, no abnormal findings such as an inflammatory reaction were visually observed.

In addition, no inflammatory cells were found in the usual histological examination.

On the other hand, with the silicone rubber terminal having the same shape as the control, no adhesion to the skin was observed at 4 weeks after the operation, and inflammatory redness was already observed. In addition, inflammation progressed and suppuration began in the second month, and shed in the third month.

Experimental Example II Ca ₃ (PO) was added to the hydroxyapatite powder as an additive.
₄ ) ₂ 7%, MgO 0.8%, Na ₂ O 1.8%, K ₂ O 0.2%, and CaFe 0.2% were used as the starting materials, except that the mixed powder was used as the starting material. 0.3 mm, outer diameter 2.0 mm, length 8 mm
A small cylindrical sintered body including the gold pipe of No. 1 was manufactured, and this was subjected to polishing treatment with an abrasive, and the terminal bottom portion shown in FIG.
A small tubular terminal with a diameter of 4 mm, a thickness of 2 mm and a diameter of the neck portion of the terminal head was obtained.

The length of the sintered body portion of this terminal was 8 mm.

Next, a microporous hollow fiber made of PVA (polyvinyl alcohol) having an average pore size of 0.2 μ
After connecting as shown in the figure, it was pierced and embedded in the chest of an adult dog in two places so that the tips were located subcutaneously.
After a week, these terminals were completely bonded and fixed to the skin tissue.

Therefore, one end of the terminal was joined to a conduit filled with physiological saline and the DC resistance was measured (as an indifferent conductor, an electrode for electrocardiogram made by Advanced Electrode Co., Ltd.
Attached using ^R to other shaved chest), the value of 1.7kΩ were obtained. In contrast to the skin resistance through the stratum corneum which is usually about 100 kΩ, a marked decrease in resistance is observed.

Next, a microneedle type glucose sensor element having a diameter of 0.5 mm and a length of 20 mm was inserted from the other terminal end, and the reaction of glucose was confirmed.

[Brief description of drawings]

FIG. 1 attached is a schematic cross-sectional view of the biomedical terminal of the present invention. FIGS. 2, 3, and 4 attached herewith are cross-sectional views showing an embodiment of the present invention. I, II, IV ... Biological terminal (skin tissue affinity member), III ... Skin tissue affinity member, 2,6,14 ... Terminal head (skin tissue affinity member), 3,7,17 ... ... Terminal bottom (skin tissue affinity member), 4,8,12 ... microporous hollow fiber, 13 ... skin tissue, 5,16 ... porous member, 15 ... metal tube, 11 ... welded portion, 9 ... Drug injection port, 10 ... Drug injection port.

Claims (1)

[Claims] 1. A percutaneous implant body comprising at least a contact portion with a skin tissue, which is made of a calcium phosphate-based member and is made of a microporous hollow fiber.