KR19990068916A - Medical Biodegradable Polymer Materials - Google Patents

Abstract

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical biodegradable polymer material, and more particularly, to plasma the surface of a biodegradable polymer material such as polylactic acid (PLLA), polyglycolic acid (PGA) or polylactic acid-polyglycolic acid copolymer (PLGA). Hydrophilization by treatment, corona discharge, chemical treatment with acid, chemical treatment with alkali, gamma irradiation, etc. improves affinity with bone tissue during implantation into the body, thereby improving adhesion and promoting bone tissue growth. The present invention relates to a biodegradable polymer material for medical use, in which fractures are fixed and bone tissue regeneration is obtained.

Description

Medical Biodegradable Polymer Materials

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical biodegradable polymer material, and more particularly, to plasma the surface of a biodegradable polymer material such as polylactic acid (PLLA), polyglycolic acid (PGA) or polylactic acid-polyglycolic acid copolymer (PLGA). Hydrophilization by treatment, corona discharge, chemical treatment with acid, chemical treatment with alkali, gamma irradiation, etc. improves affinity with bone tissue during implantation into the body, thereby improving adhesion and promoting bone tissue growth. The present invention relates to a medical biodegradable polymer material, which has a great effect on fracture fixation and bone tissue regeneration.

Conventionally, a metal device in the form of a plate, screw or pin is used to join a fractured bone in orthopedic surgery. However, these metallic materials must be removed before they lose their function because they become corrosive or loose in the body. In addition, the metal material is very hard, causing osteoporosis in the lower portion of the bonding material, there is a problem that the end of the plate is broken.

Therefore, in order to improve this problem, studies have recently been made to use biodegradable polymers as bone bonding materials [D. K. Gilding, et al., Polymer, 20, 1459, 1979; A. M. Reed, et al., Polymer, 22, 494, 1981.

Medical devices using biodegradable polymer materials have been developed and used, for example, matrices for controlling the release of low molecular weight drugs for treatment, absorbent sutures, artificial curtains, artificial skin, bone bonding materials, and cartilage treatment materials [R. Langer, et al., J. Macromol. Sci.-Rev. Macromol. Chem. Phys., C 23, 61, 1983; S. Higashi, et al., Biomterials, 7, 183, 1986; US Patent No. 3,739,773].

Biodegradability and biocompatibility are required in order to use the polymeric material for implantation in the body. In addition, the degradation products should not be toxic, and the required mechanical strength should be maintained while degrading at an appropriate rate depending on the purpose of use.

Therefore, many biodegradable polymer materials have been considered as bone bonding materials because they satisfy the above conditions. Among them, polylactic acid (PLLA), polyglycolic acid (PGA) and polylactic acid-polyglycolic acid copolymers (PLGA) have suitable mechanical strength, biocompatibility, biodegradability and processability, which are actually used in clinical practice. . The bone bonding material using polyglycolic acid loses its mechanical strength after 6 weeks, whereas polylactic acid is hydrophobic and has a higher glass transition temperature than polyglycolic acid. Availability may be greater [S. Vainionpaa, et al., Prog, Polym. Sci., 14, 679, 1989; D. Cam, et al., Bimaterials, 16, 833, 1995].

Studies of biodegradable implants published to date indicate that the implant material is difficult to maintain chemical and mechanical stability in vivo during treatment because the rate of treatment of damaged tissue does not match the rate of degradation of the implanted polymeric material. The only purpose was to improve.

Therefore, the conventionally disclosed implants are weak in the adhesion of the bone tissue and the implant in the body, it takes a lot of time to grow the bone tissue, it is not improved the difficulty of fracture fixation or bone tissue regeneration.

In the present invention, in order to solve the above problems, when the surface of the biodegradable polymer material that has been commonly applied to the human body is hydrophilized, low molecular weight hydrophilic groups containing oxygen are formed on the surface of the biodegradable implants to form bone tissue The purpose of the present invention is to provide a biodegradable polymer material for medical use, which improves adhesion between the implant and bone tissue as well as promotes the growth of bone tissue, thereby greatly improving the fixation of bone and regeneration of the bone tissue. .

The present invention is characterized by a medical biodegradable polymer material obtained by hydrophilizing the surface of the biodegradable polymer material.

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

The present invention is a base for regenerating damaged bone tissue in orthopedic or plastic surgery because it is decomposed by enzymatic or non-enzymatic hydrolysis in the body to produce no toxic substances and also maintains mechanical stability during the treatment period. And medical biodegradable polymeric materials useful as fracture fixation implants. The medical biodegradable polymer material according to the present invention improves affinity with bone tissue when applied to the human body in clinical practice, adheres well to bone tissue and promotes bone tissue growth, thereby exerting a great effect on fracture fixation or bone tissue regeneration. .

Implants using polymer materials are in direct contact with bone tissue in the body, so when the affinity with bone tissue is not good, it takes a lot of time to grow bone tissue because of weak adhesion between the bone tissue and the implant. Due to fatigue, not only dissociation and cracking occur in the fixing material, but also biodegradable polymers are gradually decomposed in the body, so that dissociation occurs between the fixing material and the living bone and thus, fracture fixation or bone tissue regeneration is difficult. On the contrary, the medical biodegradable polymer material according to the present invention is hydrophilized on the surface thereof, and thus has excellent affinity with bone tissue, thereby easily bonding the implant with the bone tissue, and greatly affecting the growth of the bone tissue.

Biodegradable polymer material that can be applied in the present invention may be used as long as the biodegradable polymer is generally applied to the human body. Among them, it is particularly preferable to use polylactic acid (PLLA), polyglycolic acid (PGA), polylactic acid-polyglycolic acid copolymer (PLGA), since they have suitable mechanical strength, biocompatibility, degradability and processability. In orthopedic or plastic surgery, it is used as a basis for reconstructing the damaged bone tissue and the joint for bonding the fractured bone.

In addition, in the present invention, as a method for hydrophilizing the surface of the biodegradable polymer materials, at least one selected from methods such as plasma treatment, corona discharge, chemical treatment with acid, chemical treatment with alkali and gamma irradiation It is used as a basis for rejuvenating damaged bone tissue and as a binder for bonding fractured bones because of the formation of low molecular weight hydrophilic groups that contain oxygen on the surface of biodegradable implants to improve hydrophilicity. Because.

The background theory behind the above reason is as follows.

"Tissue cells generally adhere and grow better on hydrophilic surfaces than hydrophobic surfaces, and glass, hydrophilized polystyrene, and the like have excellent cell affinity by their hydrophilic surfaces" [C. F. Amstein, et al., J. Clin. Micromol., 46, 1975]. In other words, the increased hydrophilicity of the surface of the biodegradable polymer materials used as implants improves the affinity with the bone tissues because these biodegradable polymer materials are in direct contact with the bone tissues in the body. Of course, it promotes bone tissue growth and serves to improve fracture fixation or bone tissue regeneration.

In addition, the decomposition rate of the biodegradable polymer material having improved hydrophilicity by surface treatment according to the present invention is biodegradable polymer having improved hydrophilicity by surface treatment for about 4 weeks as compared with biodegradable polymer materials which are not surface treated. The decomposition rate of the materials was fast but there was no big difference after that. The reason is that low-molecular-weight hydrophilic groups containing oxygen formed by surface treatment are formed only on the extreme surface layer of the biodegradable polymer material. This is because the hydrophilic surface is lost by decomposition and has almost the same surface state as undegraded biodegradable materials. That is, the above fact means that the physical properties of the biodegradable polymer materials are not significantly changed by the surface treatment, and the hydrophilicity improvement of the biodegradable polymer materials by the surface treatment method has a great influence on the mechanical strength of the implant. And only affects the affinity with bone tissue cells.

In addition, the medical biodegradable polymer material according to the present invention is also used as an implant, the implant is a surgical suture, a base or fracture fixation material for regenerating damaged bone tissue in any form of screws, pins or plates Can be used.

Therefore, the surface of the hydrophilized implant improves the affinity with the bone tissue cells, as well as the bone tissue cells in contact with the surface of the implant, as well as promote the growth of bone tissue cells.

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

Examples 1-3

Polylactic acid (PLLA) chips, polyglycolic acid (PGA) chips, and polylactic acid-polyglycolic acid copolymer (PLGA) chips were melted at 240 ° C., respectively, and then prepared in a plate form and dried at room temperature. The plates were then washed with ethanol and placed in a vacuum dryer to dry. The plates thus prepared were placed in a bell jar type plasma discharge device connected to a 13.56 MHz high frequency generator and subjected to plasma treatment for 5 seconds under a vacuum of 0.1 Torr to hydrophilize the surfaces of the plates. The plates treated as above were then sterilized with ethylene oxide gas.

Examples 4-6

Polylactic acid (PLLA) chip, polyglycolic acid (PGA) chip and polylactic acid-polyglycolic acid copolymer (PLGA) chip were prepared in the form of plate using the same method as in Example 1, and then 1 cm per second in the air. The surface of the plates was made hydrophilic by performing corona discharge treatment at a speed of. The plates thus treated were sterilized with ethylene oxide gas.

Examples 7-9

Polylactic acid (PLLA) chip, polyglycolic acid (PGA) chip and polylactic acid-polyglycolic acid copolymer (PLGA) chip were prepared in the form of plate using the same method as in Example 1, and then 30% of 60 ° C. The surface of the plates was hydrophilized by putting in an aqueous sulfuric acid solution for about 20 minutes. The plates thus treated were washed three times or more with ultrapure water, and then dried in a vacuum dryer. The plates were then sterilized with ethylene oxide gas.

Examples 10-12

Polylactic acid (PLLA) chip, polyglycolic acid (PGA) chip and polylactic acid-polyglycolic acid copolymer (PLGA) chip were prepared in the form of plate using the same method as in Example 1, and then 1N hydroxide at 60 ° C. The surface of the plates was hydrophilized by hydrolysis of the surfaces of the plates in about 30 minutes in an aqueous sodium solution. The plates thus treated were washed three times or more with ultrapure water, and then dried in a vacuum dryer. The plates were then sterilized with ethylene oxide gas.

Examples 13-15

Polylactic acid (PLLA) chips, polyglycolic acid (PGA) chips and polylactic acid-polyglycolic acid copolymer (PLGA) chips were prepared in the form of plates using the same method as in Example 1, and then 50 KCi Co in air. The surface of the plates was hydrophilized by gamma irradiation with a total dose of 40 KGy using a −60 source. The plates were then sterilized with ethylene oxide gas.

Comparative Examples 1 to 3

Polylactic acid (PLLA) chips, polyglycolic acid (PGA) chips, and polylactic acid-polyglycolic acid copolymer (PLGA) chips were melted at 240 ° C., respectively, and then prepared in a plate form and dried at room temperature. The plate was then washed with ethanol and placed in a vacuum dryer to dry.

Experimental Example 1 Measurement of Water Contact Angle

The water contact angle was measured to determine the hydrophilicity of each of the plates prepared in Examples 1 to 15 and Comparative Examples 1 to 3. At this time, the water contact angle was measured by dropping a certain amount (1 μl) of ultrapure water on the surface of the material and measuring the angle between the surface and water droplets using a conventional method, and the results are shown in Table 1 below.

division Biodegradable Polymer Materials Hydrophilization Method Water contact angle of plate surface (°) Example 1 PLLA Plasma treatment 42.0 ± 4.0 Example 2 PGA Plasma treatment 43.7 ± 3.9 Example 3 PLGA Plasma treatment 44.5 ± 2.7 Example 4 PLLA Corona discharge 45.3 ± 2.9 Example 5 PGA Corona discharge 47.0 ± 3.7 Example 6 PLGA Corona discharge 46.5 ± 3.2 Example 7 PLLA Chemical treatment by acid 53.0 ± 4.2 Example 8 PGA Chemical treatment by acid 51.2 ± 3.9 Example 9 PLGA Chemical treatment by acid 55.4 ± 3.2 Example 10 PLLA Chemical treatment with alkali 56.4 ± 2.8 Example 11 PGA Chemical treatment with alkali 53.2 ± 3.9 Example 12 PLGA Chemical treatment with alkali 54.5 ± 2.9 Example 13 PLLA Gamma irradiation 50.3 ± 3.2 Example 14 PGA Gamma irradiation 49.7 ± 4.0 Example 15 PLGA Gamma irradiation 51.4 ± 3.7 Comparative Example 1 PLLA - 70.0 ± 2.5 Comparative Example 2 PGA - 67.2 ± 2.8 Comparative Example 3 PLGA - 69.7 ± 4.2

Experimental Example 2 Graft Culture of Bone Tissue Cells

Culture experiments of bone tissue cells were carried out using the plates prepared in Examples 1 to 15 and Comparative Examples 1 to 3.

Bone tissue cells were extracted from the skull of the mice using the enzyme method, and then cultured for three generations, transplanted into the prepared plate, and cultured at 37 ° C. under a carbon dioxide gas atmosphere of 5%. At this time, the initial concentration of the bone tissue cells used for the culture was 4 × 10 ⁴ cells / ㎠, the culture period was 2 hours, 72 hours, 168 hours respectively. After the cell culture, the proliferated cell number was examined using a hemocytometer after treatment with trypsin. The results are shown in Table 2.

division Number of bone tissue cells (# / ㎠, × 10,000) Incubation time 2 hours 72 hours 168 hours Example 1 2.3 ± 0.2 6.7 ± 0.3 7.0 ± 0.2 Example 2 2.4 ± 0.3 6.8 ± 0.4 7.1 ± 0.3 Example 3 2.4 ± 0.3 6.7 ± 0.3 7.0 ± 0.2 Example 4 2.1 ± 0.2 6.5 ± 0.1 7.8 ± 0.6 Example 5 2.2 ± 0.4 6.8 ± 0.4 7.9 ± 0.4 Example 6 2.1 ± 0.4 6.5 ± 0.3 7.8 ± 0.3 Example 7 1.8 ± 0.2 5.9 ± 0.2 6.8 ± 0.3 Example 8 2.0 ± 0.5 6.0 ± 0.3 6.8 ± 0.4 Example 9 1.8 ± 0.3 5.9 ± 0.2 6.9 ± 0.3 Example 10 2.2 ± 0.4 5.7 ± 0.4 6.5 ± 0.5 Example 11 2.1 ± 0.3 5.9 ± 0.2 6.7 ± 0.2 Example 12 2.1 ± 0.2 5.8 ± 0.4 6.7 ± 0.3 Example 13 2.0 ± 0.2 5.5 ± 0.3 6.3 ± 0.3 Example 14 2.2 ± 0.5 5.7 ± 0.4 6.3 ± 0.1 Example 15 2.1 ± 0.3 5.6 ± 0.3 6.4 ± 0.4 Comparative Example 1 0.9 ± 0.1 2.7 ± 0.3 3.2 ± 0.1 Comparative Example 2 1.1 ± 0.1 2.9 ± 0.2 3.3 ± 0.2 Comparative Example 3 1.0 ± 0.1 2.9 ± 0.3 3.3 ± 0.2

As shown in Table 2 above, as a result of examining the change in the number of cells, the growth rate of the cells in the example was significantly faster than that of the comparative example.

Experimental Example 3 Measurement of Protein Production and Calcium Production

Protein production and calcium production were measured using the plates prepared in Examples 1 to 15 and Comparative Examples 1 to 3. In this experiment, calcium production was investigated to investigate the production of inorganic material. The results are shown in Table 3. At this time, the amount of protein production was investigated using the ultraviolet absorbance (Bio-Red protein micreassay) method, the amount of calcium was measured using an elemental analyzer.

division Protein production amount (㎍ / ㎠) Calcium production amount (㎍ / ㎠) Example 1 9.65 ± 0.2 0.80 ± 0.05 Example 2 10.5 ± 0.32 0.79 ± 0.04 Example 3 9.82 ± 0.25 0.81 ± 0.05 Example 4 13.5 ± 0.28 0.90 ± 0.03 Example 5 14.2 ± 0.38 0.91 ± 0.05 Example 6 13.7 ± 0.25 0.89 ± 0.03 Example 7 8.7 ± 0.43 0.76 ± 0.04 Example 8 9.0 ± 0.31 0.77 ± 0.05 Example 9 8.8 ± 0.2 0.76 ± 0.05 Example 10 8.5 ± 0.1 0.72 ± 0.01 Example 11 8.7 ± 0.4 0.74 ± 0.05 Example 12 8.6 ± 0.15 0.72 ± 0.05 Example 13 8.3 ± 0.2 0.70 ± 0.02 Example 14 8.4 ± 0.5 0.70 ± 0.03 Example 15 8.4 ± 0.1 0.71 ± 0.04 Comparative Example 1 5.24 ± 0.21 0.30 ± 0.05 Comparative Example 2 5.30 ± 0.23 0.31 ± 0.02 Comparative Example 3 5.25 ± 0.31 0.30 ± 0.03

As shown in Table 3, the results of protein and calcium production after 1 week of cell culture showed that the amount of protein and calcium produced in the hydrophilized plate was significantly higher than in the plate without hydrophilization.

In addition, after culturing the bone tissue cells for 2 hours, the cell morphology was examined by electron microscopy. As a result, the cells attached to the hydrophilized plate had a lot of gastric limbs and spreaded a lot, but the cells attached to the non-hydrophilized plate retained the unmodified initial form.

As in the results of the above experimental example, biodegradable polymers such as hydrophilized polylactic acid (PLLA), polyglycolic acid (PGA) and polylactic acid-polyglycolic acid copolymer (PLGA) by the surface treatment method according to the present invention The materials can be seen that the adhesion and growth of bone tissue cells is significantly improved compared to the biodegradable polymer implants without hydrophilization treatment.

Claims (3)

A biodegradable polymer material for medical use, characterized in that the surface of the biodegradable polymer material is hydrophilized. According to claim 1, wherein the biodegradable polymer material of the medical biodegradable polymer material characterized in that the use of polylactic acid (PLLA), polyglycolic acid (PGA) or polylactic acid-polyglycolic acid copolymer (PLGA). Manufacturing method. The method of claim 1, wherein the surface treatment for hydrophilization is biodegradable for medical use, characterized in that at least one selected from plasma treatment, corona discharge, chemical treatment with acid, chemical treatment with alkali and gamma irradiation method. Polymer materials.