JPS62176454A - Bone analogous molded article - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a bone-like molded article useful as a plastic surgery material.

[Prior art and its problems] In recent years, in order to improve medical welfare, there are expectations for the development of "biomedical materials or biomaterials" that function under conditions of direct or indirect contact with living organisms. . A living body can only exist when the various organs that make up the living body perform their unique functions while maintaining relationships with each other, and are continuously maintained. , biomedical materials based on biopolymer models have been developed.

Depending on the purpose of use, biomedical materials may be used for permanent implantation, for promoting the formation of a pseudoendometrium on the surface of the material to perform its original function, or for the period until the original organ regenerates on its own. Things that take over functions and collapse and disappear after regeneration, etc.
Various properties are desired depending on the intended application.

In addition, biomedical materials generally include direct or indirect
Because it comes into contact with living organisms or biologically derived substances,
When an artificial material that requires consideration for biocompatibility, biodegradability, antithrombotic properties, and safety comes into contact with a living body, the living body is affected by the artificial material, and at the same time, the artificial material is also affected by the living organism. . Living organisms generally dislike contact with foreign substances and reject the invasion of foreign substances, leading to necrosis of biological tissue cells due to foreign body reactions.Also, on the side of artificial materials, in-vivo deterioration and decomposition of the material has become a problem, and it is important to consider the safety of the products of the deterioration and decomposition process.

Currently, there are many types of biomedical materials used, but the biomedical materials according to the present invention are used for forming artificial noses, artificial ear shells, prosthetic materials such as artificial breasts, and percutaneous access devices. It is a bone-like molded product intended for in-vivo implantation to replace cartilage attached to hard tissues of bones, joints, etc.

Until now, medical polymer materials for the purpose of forming
Development of materials that were thought to be inert to living organisms, such as silicone and Teflon, and hybrid composite materials that have excellent biocompatibility by applying high energy to the material surface or by surface modification, such as various hydrogels. Attempts have been made.

However, none of them has been able to sufficiently achieve their objectives in terms of biocompatibility and safety.

The present inventors focused on the biocompatibility and in vivo anti-deterioration properties of sintered hydroxyapatite (hereinafter referred to as rHAPJ), which is used in artificial hard tissues such as artificial bones, artificial tooth roots, and bone cement. As a result of extensive research, we have arrived at the creation of a new bone-like molded material that is easy to mold, has high elasticity, and is safe, in addition to being biocompatible and antibiotic-resistant.

[Structure of the Invention] The bone-like molded product of the present invention is characterized by being made by combining OHA P, glycosaminoglycan (hereinafter referred to as "GAG"), glucomannan, and epihalohydrin.

HAP used in the present invention is a main component of hard bones and dentary bones represented by the following formula: Caz (POa)a (OH) 1 For example, in the wet method, it is represented by the following formula: C
a (NOI) 2 + (NH4) 2 HPO4
pH 8-10 □Ca, oCPOa ) a (OH)2 In the dry method, it is synthesized by the following formula: Caz P2 07 +CaCO3 and other known methods, and in order to use it as an artificial tooth root or artificial bone, it is further formed into a cake-like apatite after molding. 1000-1250°
It is used after being sintered with C to increase its mechanical strength.

GAGs used in the present invention include chondroitin sulfates, hyaluronic acid, heparin, heparan sulfate, etc., and chondroitin sulfate A and chondroitin sulfate C are particularly preferred, and those of quality that are reprinted as pharmaceuticals are usually used.

As the glucomannan used in the present invention, reprinted glucomannan powder is usually used, but if it contains many impurities, purification is required.

Examples of the epihalohydrin used in the present invention include epichlorohydrin and ebibromohydrin.

The amount of HAP, GAG and glucomannan used is
Preferably, the amount is 100 parts by weight, GAG 100 to 5 parts by weight, and glucomannan 200 to 5 parts by weight.

The amount of epihalohydrin used is preferably 10 times the number of moles of the repeating sugar constituting GAG.

The bone-like molded article of the present invention can be manufactured, for example, as follows.

That is, HAP, GAG, glucomannan, and epihalohydrin are added to an alkaline aqueous solution, preferably pH 10-12, and kneaded to form a homogeneous cake, which is then molded according to the purpose. The amount of alkaline aqueous solution used at this time is 1tooz in total of HAP, GAG, and glucomannan.
10 to 5 per part! ! ! Preferably, it is in parts by weight.

The molded kneaded cake is usually reacted at room temperature to 150°C, preferably room temperature to 100°C, for 1 hour to 48 hours to form a cartilage-like product with high elasticity by performing matrix-like crosslinking through the hydroxyl groups between the constituent components. A molded product can be obtained.

[Effects of the Invention] According to the present invention, it is possible to provide a bone-like molded product that is easy to mold and has high elasticity and resistance to enzymatic degradation.

[Examples of the Invention] Hereinafter, the present invention will be explained in more detail with reference to Examples and Test Examples, but these are not intended to limit the scope of the present invention in any way.

Example 1 5 g of sodium chondroitin sulfate and 5 g of glucomannan were added to 0.0 g of sodium chondroitin sulfate and 5 g of glucomannan. OIN NaOH aqueous solution 100%/
After kneading, 5 g of HAP and 9.25 g of epichlorohydrin were added to make a clay cake. The cake was molded into the desired shape using a wooden mold and reacted for 2 hours in a hot bath at 40°C.Then, the mold was removed and boiled for 5 minutes in boiling water for 5 minutes. After being immersed in a 1N NaOH aqueous solution overnight, it was washed with sterile water and dried with warm air aseptically to obtain 18.7 g of cartilage-like material. The analytical values of the cartilage-like substance are shown in the table.

Ca 9.1%P
5.7% Moisture 25.0% Glucuronic acid content 7.8% Examples 2 to 9 The reaction was carried out according to Example 1 by changing the quantitative ratio of the constituent components of HAP, sodium chondroitin sulfate, and glucomannan. A piece of cartilage-like material measuring 1 cm x 1 cm x 1 ff1 m was prepared.

In addition, in order to examine the influence of GAG and epichlorohydrin in the following test example, a composition reaction product of HAP and glucomannan was prepared according to the example and used as Comparative Example 1.

Example 10 HAP 5g, sodium chondroitin sulfate 5g,
Sodium hyaluronate (molecular weight approximately 100,000) 0.5g
, glucomannan 5g and epichlorohydrin 9.25g
g to 0. The mixture was kneaded in OIN NaOH aqueous solution 100- and reacted according to Example 1 to obtain 18.3 g of cartilage-like material.

Analysis value Ca 9.1%P
5.5% glucuronic acid equivalent uronic acid value 7.2% water 28.7% Test Example 1 Resistance to enzymatic degradation As a model of deterioration reaction during biological implantation, resistance to hyaluronidase, a mucopolysaccharide degrading enzyme, was investigated.

1 g of the cartilage-like substance obtained in Example 1 was cut into pieces of approximately 1 am", and the pieces were mixed with 0.1 M acetate buffer (pH 5, 0) at 50-
1 g of Gyufumaru hyaluronitase (Seikagaku Kogyo ■ken reagent grade) O was added thereto, and the mixture was stirred and digested at 50° C. for 24 hours.

The pieces of cartilage-like material were taken from house to house, and the furnace solution was measured by the carbazole sulfuric acid method, but no uronic acid was found in the furnace solution. This revealed that this sample was not easily degraded by hyaluronidase and was not easily degraded in vivo.

2. Blood compatibility test As an indicator of biocompatibility, blood coagulation reaction and platelet aggregation are measured by whole blood coagulation time measurement (Significance and Interpretation of Clinical Tests (2nd edition) p. 86, supervised by Kazu Yoshiri, Igaku Shuin Publishing). The effect of this sample on the reaction and hemagglutination reaction was qualitatively evaluated.

The bottom of a polyethylene tube with a diameter of 0.7 cm and a length of 4 cm was clamped and filled with 30 square pieces of cartilage-like material of 1 mm3 prepared in Example 1, and freshly collected human venous blood 1-2- added. The control clotting time was measured by adding the main sample and blood to a glass tube of the same size as the tube. Each tube and glass tube was heated to 37°C and tilted every 30 seconds to check blood fluidity. The end point of the coagulation time was defined as the time when the entire blood turned into gel. Control-1 was obtained by treating only blood in the same manner without adding the main sample. The results are shown in the table.

It showed exactly the same results as Control-1 and was found to have blood compatibility.

3. An example of an adult cat abdominal subcutaneous implantation test? , Example 1O1 l of Comparative Example 1, Oc layer x 1
, 0 cω
It was implanted subcutaneously in the abdomen. After 2 weeks and 4 weeks, the histopathological findings of the explants and surrounding tissues were observed for three animals each. The results are shown in the table.

From the above histopathological findings, the bone-like molded product of the present invention underwent an initial mild foreign body reaction and ended up in a tissue-compatible state. On the other hand, it can be seen that the sample of Comparative Example 1, which does not contain GAG, is completely degraded and decomposed after a strong foreign body reaction and inflammatory reaction.

Claims (1)

[Claims] A bone-like molded product characterized by being made by reacting hydroxyapatite, glycosaminoglycan, glucomannan, and epihalohydrin.