KR100201874B1 - An artificial organ having a porous and biodegradable character and its manufacturing method - Google Patents

Abstract

The present invention relates to a porous and biodegradable artificial organs and a method of manufacturing the same, and more particularly, a porous body having a uniform diameter distribution prepared by emulsion freeze-drying a biodegradable polymer in a mold of the required form, vascular endothelial cells in the human body Or, it is easy to attach and grow skin tissue cells, and after the growth of cells is completed, it is naturally biodegradable and absorbed by the human body. It is about a method.

Description

Porous and biodegradable artificial organs and preparation method thereof

The present invention relates to a porous and biodegradable artificial organs and a method of manufacturing the same, and more particularly, a porous body having a uniform diameter distribution prepared by emulsion freeze-drying a biodegradable polymer in a mold of the required form, vascular endothelial cells in the human body Or, it is easy to attach and grow skin tissue cells, and after the growth of cells is completed, it is naturally biodegradable and absorbed by the human body. It is about a method.

In particular, research is being actively conducted on the development of artificial blood vessels in artificial organs. In general, diseases caused by vascular circulatory diseases such as arteriosclerosis, angina pectoris, and varicose veins are generally impossible to perform surgery or pharmacological healing. The procedure to do is widely performed. As an artificial blood vessel material, metals such as gold and platinum were used in the early stages, but as polymer materials were developed, the application of the artificial blood vessels became easier. In the early 1950s, the artificial blood vessels that had been attempted were coagulated with nylon or acrylonitrile. Currently, polyethylene terephthalate (PET, Dacron) and polytetrafluoroethylene (PTFE, Gore Tex) were applied. ) Two polymer materials have been mainly used.

In order to be applied to artificial organs such as artificial blood vessels, such polymer materials should be implanted in the human body and there should be no bio-rejection reaction. In addition, in order to be used as an artificial blood vessel, blood clots and embolisms must not be generated in the inner wall of blood vessels, and enduring contraction / expansion must be able to withstand considerable pressure from the blood vessels as well as flexibility to withstand the flowing blood flow. It must have mechanical and physical properties.

The artificial blood vessels of PET and PTFE materials that are currently commercialized can only be large diameters of 6 mm or more because PET and PTFE materials themselves easily cause blood clots and embolism. In addition, since PET and PTFE are non-biodegradable, there is a problem of remaining and accumulating in vivo.

As a result, a porous tube using a biodegradable polymer that can be biodegraded after a certain period of time without accumulating in vivo has been manufactured [D. J. Mooney, C. Breuer, K. McNamara, J. P. Vacanti, and R. Langer, Tissue Engineering, 1 (2), 107-118 (1995)], and their methods are outlined as follows.

First, in order to make the biodegradable polymer into a porous site, a 250 µm salt single crystal and a biodegradable polymer solution are mixed and molded to a desired thickness, and then salt is dissolved in water to form pores in the polymer sheet. The porous sheet thus prepared is dried and then rolled into a cylindrical shape having a desired diameter to bond the sock end with an adhesive to produce a porous tube.

The tubular porous and biodegradable artificial blood vessels produced by this manufacturing method have a very large size distribution of the pore size due to the non-uniform size distribution of the salt single crystal, and the pores in the process of dissolving salt with water and drying. There is a problem that the structure is separated a lot, especially the rolled porous sheet is bonded to the end of the socks with an adhesive to produce a tube form, there is a problem that the mechanical and chemical properties of the adhesive surface is changed.

As described above, in the case of artificial blood vessels made of conventional non-biodegradable polymers, there are limitations in the application to artificial blood vessels because they are large diameters and remain in the water forever after transplantation. In the case of artificial blood vessels made of conventional biodegradable polymers, the flat sponges are rolled up when manufactured in the form of tubes, so that seams are formed at both ends, and the size or distribution of pores is not easily controlled. there was.

In the present invention, using a biodegradable polymer material that biodegradation occurs for a certain period of time when implanted in the human body, and filled with an emulsion solution containing a solution in which the biodegradable polymer is dissolved in a mold of the required form and their incompatible liquid and frozen The present invention has been completed by fabricating a porous and biodegradable artificial organ using a so-called emulsification freeze drying method of drying this.

Accordingly, an object of the present invention is to provide an artificial organ that is excellent in bioadaptability and is naturally biodegraded and absorbed by the human body after a certain period of time, and a method of manufacturing the same.

1 is a photograph of a mold for producing an artificial blood vessel in the form of a tube,

2 is a photograph of a porous biodegradable artificial blood vessel produced by the manufacturing method of the present invention,

3 is an electron microscope (× 600) of a porous biodegradable artificial blood vessel manufactured in the present invention.

The present invention is characterized by a method for producing a porous, biodegradable artificial organ which is emulsified and freeze-dried by putting an emulsion solution composed of a biodegradable polymer, an organic solvent and water into a mold.

In addition, it includes a porous, biodegradable artificial organs prepared by the manufacturing method as described above, any artificial organs can be applied as long as the organs, such as artificial blood vessels, phosphorus space can be recovered.

The present invention will be described in more detail as follows.

The present invention relates to an artificial organ prepared by emulsification freeze drying of a biodegradable polymer and a method of manufacturing the same. The artificial organ has a certain size distribution porosity, which enables the growth and recovery of tissue cells, and also for a certain period of time. When this elapses, there is no fear of being naturally decomposed and absorbed in vivo and accumulating in the human body.

Hereinafter, the manufacturing process of the artificial organ according to the present invention will be described in detail. That is, a mixed solution containing 1.5 to 18% of a biodegradable polymer in an emulsion solution containing 30 to 90% by weight of an organic solvent and 10 to 70% by weight of water is made into a fully emulsified solution using an ultrasonic or homogenizer. The complete emulsified solution is immediately put into a mold of a certain type and lyophilized to prepare a porous and biodegradable artificial organ.

The porous biodegradable artificial organ according to the present invention is composed of a biodegradable polymer in the form of a sponge, which is slowly biodegraded by hydrolysis and absorbed into the human body when implanted into the human body. Therefore, a feature of the present invention is in the selection of biodegradable polymers, the biodegradable polymers that can be used in the present invention should be harmless to the human body and have properties that can be biodegraded within a desired period of time.

Biodegradable polymers having such characteristics include albumin, collagen, gelatin, fibrinogen, casein, fibrin, hemoglobin, and transferrin. ), Chitin, chitosan, hyaluronic acid, heparin, chondroitin, keratin sulfate, alginic acid, starch, dextrin, dextran , Citric acid, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, polyhydroxyzybutyric acid, polycaprolactone, polyanhydride and polyalkylcyano acrylate acrylate) at least one selected from. These biodegradable polymers have been found to be naturally biodegradable after a certain period of time in the human body by hydrolysis and various enzymes in the human body [Langer. R Vacanti J. P., Science 260, 920, 1993].

In addition, in order to perform the emulsifying freeze drying method (Emulsifying Freeze Drying Method) which is the main point of the present invention, a tubular artificial blood vessel type mold as shown in FIG. 1 is required. The mold is made of materials such as teflon, polyethylene, ultra high molecular weight polyethylene, and various changes are possible depending on the shape of the artificial organ. It should be noted, however, that the biodegradable polymer in the emulsified state should not be attached. For example, when the material of the mold is made of stainless steel, copper, aluminum, polymethyl methacrylate, polycarbonate, etc., the biodegradable polymer in the porous form is strongly adhered from the mold due to the property of attaching to the biodegradable polymer. It is not easily separated.

The emulsion solution used in the present invention is composed of an organic solvent and water, preferably consisting of 30 to 90% by weight of the organic solvent and 10 to 70% by weight of water.

The biodegradable polymer is dissolved in an emulsion solution having the composition described above, and the biodegradable polymer is dissolved in an emulsion solution in which an organic solvent and water are mixed, or dissolved in an organic solvent and water is added thereto, or water After dissolving in, an organic solvent may be added. The method of dissolving the biodegradable polymer or the selection of the organic solvent can be varied by conventional methods well known in the art depending on the characteristics and circumstances. For example, in the case of lactic acid-glycolic acid copolymer, it is particularly preferable to use one selected from acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dioxane and methylene chloride as an organic solvent. The biodegradable polymer is dissolved in the concentration of 0.003 to 27% in the emulsion solution, and more preferably in the concentration of 1.5 to 18%. If the concentration is less than 1.5%, the biodegradable polymer concentration is too low, so the porous tissue state is too weak. If the concentration exceeds 18%, the porous tissue state is too dense, which may hinder the growth of tissue cells. to be. The emulsion solution containing the biodegradable polymer is completely prepared as an emulsion solution by ultrasonic or homogenizer. In this case, the pore size, pore size distribution, porosity, etc. may be variously changed according to the type of artificial organ to be manufactured, which is possible by controlling the composition ratio of the biodegradable polymer, organic solvent and water used.

Poured quickly into a mold containing a biodegradable polymer prepared as described above, and then frozen in liquid nitrogen for 0.5 ~ 1 company, to a temperature of less than -35 ℃, and dried by a lyophilizer. Finally, by separating the dried porous body from the mold, a porous biodegradable artificial organ, which is the object of the present invention, is obtained. In addition, the artificial organs manufactured in the present invention are applicable to any organs capable of growing and restoring tissue cells such as artificial blood vessels, artificial urethra, artificial small intestine, artificial bronchus, human space, artificial kidney, and artificial cartilage.

The porous and biodegradable artificial organs prepared as described above have no seams on both sides because of the use of molds, and the diameter and diameter of the outer and inner diameters, the pore size, the pore size distribution, and the porosity are the ratios of the solution and water containing the biodegradable polymer. There is an advantage that can be adjusted appropriately by adjusting. In addition, the biodegradation period of the porous and biodegradable artificial organs implanted in the human body may be longer because the larger the molecular weight of the biodegradable polymer used and the larger the fraction of either component of lactide or glycolide, It is adjustable.

Hereinafter, the present invention will be described in detail with reference to the following Examples, the present invention is not limited by the Examples.

Example 1

The copolymer was prepared by mixing lactic acid and glycolic acid (glycolic acid) at a ratio of 75: 25% by weight and thermally polymerizing in the presence of a catalyst (150 ppm, stanous octoate) at 170 ° C. and 100 rpm for 4 hours. The molecular weight of the prepared copolymer (hereinafter referred to as PLGA 75) using gel permeation chromatography (Gel Permeation Chromatography) was 110 kg / mol.

0.8 g of the prepared PLGA 75 was evenly dissolved in 8 ml of methylene chloride, and this solution was mixed with water in a ratio of 60:40, and then an emulsion solution was prepared for 30 seconds using an ultrasonic mixer of 40w intensity. The emulsion solution was quickly poured into a tubular mold of an outer diameter of 8 mm, an inner diameter of 4 mm and a teflon material, and immersed in liquid nitrogen at -196 ° C to freeze instantly.

After leaving for one day in this, using a lyophilizer was dried under a pressure of -78 ℃, 0.1 torr. Separation of the dried tubular artificial blood vessel from the mold yielded the form as shown in FIG. 2.

In order to measure the physical properties such as pore size, pore size distribution and total pore area, a mercury porosimeter (AutoPore II, Micromeritrics) was used to measure the physical properties of these pore electron micrographs. . Physical properties of the tubular porous artificial blood vessel manufactured by Example 1 are shown in Table 1.

Example 2

PLGA 75 was polymerized in the same manner as in Example 1, at which time 30 ppm of catalyst was added. As a result of GPC measurement, the molecular age was 370 kg / mol. 0.8 g of PLGA 75 was evenly dissolved in 80 ml of methylene chloride, and the solution was mixed with water in a ratio of 70:30, and an emulsion solution was prepared using an ultrasonic mixer. It was carried out in the same manner as in Example 1 below. As a result, these physical properties are shown in Table 1.

Example 3

0.8 g of polyhydroxybutyric acid (PHB) having a molecular weight of 15 kg / mol was dissolved in 8 ml of chloroform, and the solution was mixed with water in a ratio of 50:50, and an emulsion solution was prepared using an ultrasonic mixer. It was carried out in the same manner as in Example 1 below. As a result, these physical properties are shown in Table 1.

Example 4

1.2 g of polycaprolactone (PCL) having a molecular weight of 37 kg / mol was dissolved in 8 ml of dioxane, the solution was mixed with distilled water at a ratio of 40:60, and an emulsion solution was prepared using an ultrasonic mixer. It was carried out in the same manner as in Example 1 below. As a result, these physical properties are shown in Table 1.

Example 5

1 g of low viscosity alginic acid was dissolved in 10 ml of distilled water, the solution was mixed with dichloromethane in a ratio of 50:50, and an emulsion solution was prepared using an ultrasonic mixer. It was carried out in the same manner as in Example 1 below. As a result, these physical properties are shown in Table 1.

Example 6

An aqueous solution containing 6% glucose, 70% textran, and 0.06% citric acid was mixed with acetonitrile in a ratio of 90:10, and an emulsion solution was prepared using an ultrasonic mixer. It was carried out in the same manner as in Example 1 below. As a result, these physical properties are shown in Table 1.

[Comparative Example]

A tubular porous artificial blood vessel was prepared in the same manner as in Example 1, except that the ratio of the biodegradable polymer organic solution and water was mixed at a weight ratio of 10:90.

According to the above results, the porous and biodegradable artificial organs according to the present invention have an average pore size of about 15 μm, but when the ratio of water in the emulsion solution is excessive, as in the comparative example, the artificial organs are not manufactured. This is because it is below the critical concentration at which voids must be achieved.

As described above, the porous artificial organ made of the biodegradable polymer of the present invention has an appropriate pore size, so that material transfer such as nutrient solution, oxygen, and carbon dioxide is effectively carried out between the blood and the skin, and the connection between the pores is a biodegradable polymer. It is easy to attach and grow vascular endothelial cells or skin tissue cells in the human body, and since the growth of these washes is completed, they are naturally biodegradable and absorbed by the body. .

Claims (8)

A method of producing a porous, biodegradable artificial organ, characterized in that the emulsion freeze-dried by putting an emulsion solution and a biodegradable polymer consisting of an organic solvent and water into a mold (mold). The method of claim 1, wherein the biodegradable polymer is polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, albumin, collagen, gelatin, fibrinogen, casein, fibrin, hemoglobin, transferrin, chitin, chitosan, high At least one selected from aruronic acid, heparin, chondroitin, keratin sulfate, alginic acid, starch, dextrin, dextran, citric acid, polyhydroxybutyric acid, polycaprolactone, polyanhydride and polyalkylcyanoacrylate Method for producing porous, biodegradable artificial organs. The method according to claim 1 or 2, wherein the biodegradable polymer is contained in an emulsion solution at a concentration of 1.5 to 18%. The method of claim 1, wherein the emulsion solution comprises 30 to 90% by weight of an organic solvent and 10 to 70% by weight of water. The method of claim 1 or 4, wherein the organic solvent is at least one selected from acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dioxane, and methylene chloride. The method of claim 1, wherein the freeze-dried emulsion is a process for freezing and drying to less than -35 ° C and dried. The method of claim 1, wherein the mold is a method for producing a porous biodegradable artificial organ, characterized in that at least one material selected from Teflon, polyethylene and ultra high molecular weight polyethylene. A porous, biodegradable artificial organ, which is prepared by the method of claim 1.

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