TWI445761B - Biodegradable-bioresorbable composite and preparing method thereof - Google Patents

Description

Biodegradable absorption composite material, preparation method thereof and application thereof

The present invention relates to a biodegradable absorbent composite, and more particularly to a biodegradable absorbent composite which can be freely shaped at room temperature and a process for preparing the same.

Since biomedical materials implanted in the human body must not adversely affect human tissues, blood, immune system, etc., the biocompatibility of materials is the first consideration in the research and design of biomedical materials.

When biocompatible materials are used in surgical implants, they can be classified into permanent and non-permanent implants depending on the tissue site requirements of the implant. Permanent implants are suitable for tissues that cannot be regenerated; non-permanent implants are suitable for temporary replacement of regenerative tissues. At present, the development of non-permanent implants tends to develop materials that can be used for recovery without being removed, that is, materials that are biodegradable and absorbable, and the materials are continuously decomposed by the organism while the tissue is growing. The most optimistic result is that the normal tissue is fully grown back when the replacement material is completely broken down.

However, biodegradable and biocompatible materials have been developed, and the rate of decomposition in the body is usually fast, and often cannot stay in the body for a long enough time to match the time course of tissue recovery.

For example, biodegradable plastic-polylactic acid (PLA) is a linear polymer having a glass transition temperature (Tg) of about 58-60 °C. Due to the high rigidity and toughness of polylactic acid, the application end is limited, and the degradation rate is too fast, and the service life is short. In addition, polylactic acid is a brittle material that cannot withstand loads, and should be composited with other materials (such as ceramic materials) for bone repair or for making bone nails and bone plates. However, the ceramic powder needs to be evenly distributed in the low-flow polylactic acid to provide better mechanical strength, and the addition of too much ceramic powder also affects the operation of injection molding, which in turn leads to instability of mechanical properties.

Polypropylene carbonate (PPC) is a biodegradable elastic material with high elongation at break, high barrier property and heat resistance of 100 °C. US Patent No. 4946884 physically blends PPC with a non-biodegradable material, polymethylmethacrylate (PMMA), to obtain a partially degradable composite. However, this composite is applied to ceramics. The linker when the material is molded is not applied to biomedical materials.

The biocompatible ceramic powder, tricalcium phosphate (TCP), is a material with mineral composition similar to bones. Its properties are easy to bond with bones and connect together to enhance the effect. Repairs the material of the bone tissue, but because the material is brittle, it cannot be used on the bone joints.

Therefore, materials that have good mechanical properties, are completely biodegradable, and have a decomposition rate that can match the growth rate of different tissue cells have not yet been developed.

Accordingly, one aspect of the present invention is to provide a biodegradable absorbent composite which is solid and has the property of being arbitrarily shaped at room temperature.

The biodegradable absorbent composite is composed of a mixture of polypropylene carbonate/β-tricalcium phosphate and polylactic acid in a weight ratio of 5:5 to 9:1. The composition wherein the polypropylene carbonate resin and the beta tricalcium phosphate are composed in a weight ratio of 9:1.

According to one or more embodiments of the present invention, the weight ratio of the mixture of the polypropylene carbonate resin/β-tricalcium phosphate to the polylactic acid is from 7:3 to 9:1, more preferably 8:2.

Another aspect of the present invention provides a method for preparing a biodegradable absorbent composite comprising forming a composite solution of a mixture of a polypropylene carbonate resin/β-tricalcium phosphate and a polylactic acid, and drying the composite solution. Forming to form a solid biodegradable absorbent composite. Wherein, the composite solution is obtained by dispersing a mixture of polypropylene carbonate resin/β-tricalcium phosphate and polylactic acid in a weight ratio of 5:5 to 9:1 in an organic solvent.

According to an embodiment of the present embodiment, a method for preparing a biodegradable absorbent composite material further comprises adding a salt to the composite solution, separating a solid mixture by salting out, removing the salt from the solid mixture, and drying the formed salt. A biodegradable absorbent composite having a porous structure is formed.

Another aspect of the present invention provides a non-permanent tissue substitute or artificial scaffold comprising a biodegradable absorption composite formed by mixing a mixture of a polypropylene carbonate resin/β-tricalcium phosphate and polylactic acid. material.

As used herein, "non-permanent tissue substitute" means a solid that is non-permanently replacing a regenerable tissue (eg, bone, cartilage, or skin) that can be coated or padded around a living tissue. .

"Artificial stent" means the periphery of a tissue or organ that is attached to a living body and can be used to non-permanently support the solid matter of the tissue or organ. The artificial stent can be mounted between the cardiovascular wall, between the two bones, between the defective bone tissue, between the semilunar cartilage, the living tissue, and the permanent or non-permanent artificial implant.

From the above, it is understood that the biodegradable absorbent composite material to which the embodiment of the present invention is applied has the following advantages:

1. The biodegradable absorbent composite of the embodiment of the present invention is prepared by kneading three biodegradable materials, wherein the polypropylene carbonate resin is an elastic material, and the β-tricalcium phosphate has hemostasis and bone guiding property. The effect of adding polylactic acid provides composite stiffness to adjust mechanical strength and control the rate of decomposition. The above three materials are not only completely biodegradable, but also different in blending ratio according to the three biodegradable materials, resulting in different mechanical properties and their decomposition and absorption rates in the living body.

2. The biodegradable absorbing composite material of the embodiment of the invention can be pre-formed into a finished product, and then can be arbitrarily shaped at room temperature, and the finished product of appropriate shape is packed in the periphery of the regenerable structure, that is, Can be used for alternative, support or cushioning purposes.

The biodegradable absorbent composite material of the embodiment of the invention is a solid material having the property of being arbitrarily shaped at room temperature. The biodegradable absorbent composite is composed of a mixture of polypropylene carbonate resin/β-tricalcium phosphate and polyemulsion in a weight ratio of 5:5 to 9:1, and a polypropylene carbonate resin and a β-phosphate Calcium is composed of a weight ratio of 9:1.

The method for preparing the biodegradable absorption composite material of the embodiment of the invention is characterized in that the polypropylene carbonate resin, the β-tricalcium phosphate and the polylactic acid are mixed and dissolved in different weight ratios by using a solvent (for example, acetone or tetrachloromethane). Among them, a composite solution is formed.

An embodiment of the present invention comprises blending a polypropylene carbonate resin with β-tricalcium phosphate in a weight ratio of 9:1 to form a mixture of propylene carbonate resin/β-tricalcium phosphate; the propylene carbonate resin The mixture of /β-tricalcium phosphate is then blended with polylactic acid in a weight ratio of 5:5, 6:4, 7:3, 8:2 or 9:1 to form a composite solution.

In the embodiment of the present invention, a salt having a size of 40 μm or less, such as sodium chloride, is added to the composite solution by salting out to precipitate a solid mixture. The solid mixture was molded by vacuum drying at 37 ° C for 12 hours, and the solid mixture after molding was removed by a known method to form a biodegradable absorbent composite having a porous structure.

Analysis of Physical Properties of Biodegradable Absorbing Composites

According to the embodiments of the present invention, it is understood that the composite material of the embodiment of the present invention is a polypropylene-based resin (PPC) and a polylactic acid (PLA) as a main body of the biodegradable absorption composite material, and is matched with β-tricalcium phosphate ( β-TCP) provides an effect of increasing bone guiding and independently controlling the rate of biodegradation. The three materials are closely blended to obtain a solid material that can be arbitrarily shaped at room temperature.

Since the chemical structure of the two main polymers contained in the biodegradable absorption composite material of the present invention, the poly(propylene carbonate) resin (PPC) and the polylactic acid (PLA), are different, the phases of the components in the composite material are different. Capacitance affects the effect of mixing, and the degree of mutual solubility between the components will affect the physical properties of the biodegradable absorbent composite. Therefore, first confirm whether the polypropylene carbonate resin (PPC) and polylactic acid (PLA) are Two polymers that are compatible.

The compatibility of polymer blending is mainly determined by differential scanning calorimetry (DSC), and the compatibility of the blending system is evaluated by whether the blended composite has a single glass transition temperature. . If the blending system is compatible, it will exhibit a single glass transition temperature, usually between the glass transition temperatures of the two component polymers; conversely, the incompatible system will be due to the two component polymers Separated while presenting two glass transition temperatures.

In addition, in order to understand the physical properties of the biodegradable absorbent composite material of the embodiment of the present invention, the flexural strength (unit MPa) test is performed according to the ASTM D790 standard, and the sample is placed at a certain distance by a three-point test method. On a fixed anvils, and then pressurize from the top to the bottom of the two fulcrum points until the sample breaks or exceeds a certain limit, which can be used to determine the bending properties of the plastic. The flexural strength was tested by ASTM D790 and the results are shown in Table 1 below:

The results of Table 1 show that, in the embodiment of the present invention, when the above three materials are blended in an appropriate ratio, the (PPC/TCP): PLA addition ratio increases, the bending strength of the test material is higher, and PPC or PLA is used alone. The composite material of the embodiment of the present invention has better bending strength than the plastic.

Table 2 below is a result of the physical property test results of the biodegradable absorbent composite material of the above-described embodiment of the present invention.

It can be seen from Table 2 that after blending with polypropylene carbonate resin/β-tricalcium phosphate (PPC/TCP) and polylactic acid (PLA), a single glass transition temperature can be obtained, indicating that the embodiment of the present invention is selected to be polycarbonate. The propylene ester resin is blended with the polylactic acid, and the blending system is compatible.

Furthermore, a polypropylene carbonate resin having a low glass transition temperature (Tg) (Tg of pure PPC is 29.82 ° C) is blended with polylactic acid having a relatively high glass transition temperature (Tg of pure PLA is 59.24 ° C). The Tg value between the individual glass transition temperatures of the two component polymers can be obtained, and as the polylactic acid addition amount increases, the glass transition temperature can reach 36.42-49.37 ° C, thereby adjusting the ratio of the two to obtain Finished glass with proper glass transfer temperature.

The data of the elastic modulus of Table 2 was measured using the ASTM D790 standard. The modulus of elasticity can be calculated by the following formula:

E _B =L ³ m/4bd ³

Where E _B is the elastic modulus (MPa), L is the span of the two support ends in the measurement method (support span, mm), b is the width of beam tested, and d is the depth of the test sample. (depth of beam tested, mm), m is the slope of the tangent to the initial straight-line portion of the load-deflection curve (N/mm).

It can also be seen from Table 2 that as the polylactic acid addition ratio increases, the elastic modulus of the composite material also increases, that is, the softness of the material is inversely proportional to the polylactic acid addition ratio, and the polypropylene carbonate resin/β The mixture of tricalcium phosphate is directly proportional, and the addition ratio of polylactic acid is preferably not more than 50% by weight. The elastic modulus is the ratio of stress to strain within the elastic limit. The larger the elastic modulus, the greater the stress required to reach the same strain. Conversely, the smaller the strain under the same stress, ie the modulus The smaller the more "soft", the harder the modulus is.

Therefore, in the embodiment of the present invention, two kinds of high-molecular polymers having a large difference between "soft" and "hard" are used to achieve the effect of adjusting mechanical properties. Since the polypropylene carbonate resin is an elastic material having a high elongation at break, and the polylactic acid is a material which is brittle and brittle, the embodiment of the present invention uses an elastic material of a polypropylene carbonate resin (the elastic modulus is 290.59 MPa, good toughness), blended with rigid material polylactic acid (elastic modulus 3505.2 MPa, poor toughness) in different proportions, can adjust the toughness and elasticity of the composite, can be arbitrarily molded at room temperature Shaped biodegradable absorbent composites.

According to the above embodiment, it can be known that the mixture of the polypropylene carbonate resin/β-tricalcium phosphate and the polylactic acid is blended in a weight ratio of 5:5 to 9:1, and the double advantages of good elasticity and mechanical strength can be obtained. The composite material can be adjusted for suitable elasticity and mechanical strength depending on the application, and can be applied to a regenerable tissue substitute, for example, as a bone filling material, or as a support body and a artificial support for cartilage.

Table 3 shows the porosity of the biodegradable absorbent composite of different formulation ratios according to an embodiment of the present invention. In the embodiment of the present invention, the method for controlling the size and distribution of the pores by using the salting out method is to screen out the salt having a size of 40 μm or less by using a sieve, and then estimating the proportion of the salt and the material in the salting out method by using the predetermined porosity:

The composite solution and the salt in the weight ratio described in the above examples were placed in an acetone solution and stirred, and after the homogenization, the acetone solvent was removed to obtain a solid mixture containing the salt having a weight of M1. Then, the salt is dissolved and removed by using water, and after drying, a composite material having a porous structure is obtained, and the weight thereof is M2. The true porosity can be obtained using the following formula:

The calculated results show that the blend of the polypropylene carbonate resin, the β-tricalcium phosphate and the polylactic acid can be obtained by the method of the embodiment of the present invention to obtain a finished product having a high porosity of 85.04-87.04%, and the formula is formulated. The difference in proportion has little effect on the porosity of the finished product.

Referring to Fig. 1, there is shown an electron micrograph of a biodegradable absorbent composite according to an embodiment of the present invention. 1(A) is a photograph showing the appearance of a biodegradable absorbent composite material according to an embodiment of the present invention; the blending ratio of the biodegradable absorbent composite material of the present embodiment is (PPC/TCP): PLA=8:2, wherein PPC :TCP-9:1. Fig. 1(B) is a photograph showing the pore form and distribution of the biodegradable absorbent composite at a magnification of 50 times. Fig. 1(C) is a photograph showing the pore form and distribution of the biodegradable absorbent composite at a magnification of 300 times. It can be seen from the photographs of Figs. 1(B) and (C) that the biodegradable absorbent composite material of the embodiment of the present invention has a pore size of about 1-2 mm. In general, the smallest hole of the cell scaffold is 100 μm, but when the hole is larger than 300 μm, it is more suitable for the growth of bone cells. Therefore, the pores of the biodegradable absorbent composite material of the embodiment of the present invention are not too small for the growth of bone cells.

According to Table 3 and Figure 1, the biodegradable absorbent composite of the embodiment of the present invention can be made into a porous structure. In general, a surgical implant with porosity accelerates the absorption of nutrients by the tissue and promotes tissue repair. For example, a growth factor such as collagen, bone morphogenetic protein (BMP, etc.) may be coated on a cartilage scaffold made of a composite material according to an embodiment of the present invention by a dip-coating technique. ), can promote the growth of fibrocartilage cells.

Biocompatibility of biodegradable absorbent composites

To confirm the biocompatibility of the biodegradable absorbent composite of the examples of the present invention, the results of the biocompatibility test are explained below. Animal experiments including cytotoxicity tests and skin irritation tests.

The cytotoxicity test test method is carried out in accordance with the test standard of ISO 10993-5 (2009), and tests whether the biodegradable absorption composite material of the embodiment of the present invention has cytotoxicity, and the blending ratio is (PPC/TCP). : PLA=8:2 biodegradable absorption composite as an example, where PPC: TCP = 9:1. The test included a reagent control group (cultured in 5 ml of MEM medium containing bovine serum), a negative control group (PE membrane was extracted at 37 ° C for 24 hours at a ratio of 6 cm ² /ml), a positive control group (0.2% phenol) and a test. group. The biodegradable absorbent composite extract of the present invention was prepared according to the ISO 10993-12 standard, and the test substance was cut into 120 cm ² and extracted with MEM at 37 ° C for 24 hours at a ratio of 6 cm ² /ml.

The design of the biodegradable absorbent composite extract was co-cultured with mouse fibroblast cell line L-929 (NCTC clone 929) for 48 hours (5% CO ₂ , 37 ° C), and the cell type was observed by an inverted microscope. Cell lysis (qualitative analysis); cell survival number determination by trypan blue (semi-quantitative analysis); cell survival number measurement (quantitative analysis) by cell survival assay (MTT assay).

Qualitative test results showed that the cell type of the control group, the negative control group and the test group were normal, and no cell lysis and fragmentation were observed. According to the ISO 10933-5 cytotoxicity interpretation standard, the cytotoxicity number was 0. The positive control group had a cytotoxicity level of 4.

In the semi-quantitative analysis of trypan blue, the number of cells in each group was 1.70±0.13×10 ⁶ cells/ml in the control group, 1.70±0.01×10 ⁶ cells/ml in the negative control group, and 1.11 in the positive control group. ±0.38×10 ⁴ cells/ml; the number of cells in the test group was 1.68±0.13×10 ⁶ cells/ml. The number of positive control cells decreased by 99.3% compared with the negative control group; the number of cells in the test group decreased by 0.9% compared with the negative control group.

The results of MTT cell survival analysis showed that the absorbance values measured at 570 nm were: 1.72 ± 0.06 in the control group and 1.59 ± 0.03 in the negative control group. There was no significant difference between the experimental group and the negative control group at 1.58±0.09, but the positive control group and the negative control group were significantly different (P<0.05).

According to the above test results, it is understood that the biodegradable absorbent composite of the embodiment of the present invention is not cytotoxic.

The biodegradable absorption composite extract extracted with physiological saline and cottonseed oil was injected into the experimental animal, and the average value of the stimulation score minus the average of the stimulation score of the blank control solution was 0.

Table 4 shows the results of animal experiments on the skin irritation test of the biodegradable absorbent composite of the examples of the present invention.

It can be seen from Table 4 that the test site and the control site of the bio-stimulation experiment did not show any local irritating reaction, and the average value of the stimulation score was zero. The biodegradable absorbent composite materials of different formula ratios in the examples of the present invention have no obvious irritating reaction on the skin of the test animal.

Biodegradation rate test of biodegradable absorbent composites

To understand the biodegradation rate of the biodegradable absorbent composite of the present invention, the in vitro decomposition rate of the hydrolytically degradable polymer and its made implant implant was tested using the ASTM F1635-04a standard.

The test method is to take a mixture of different ratios of polypropylene carbonate resin/β-tricalcium phosphate and three samples of polylactic acid composite materials, and weigh them into a 50 ml test tube. 10 ml of physiological saline (PBS) having a pH of 7.4 was added to the test tube, and then the test tube was placed in a constant temperature water bath at 37 ° C for 8 weeks.

At a fixed time each week, the test tube was taken out and the pH value in the solution was measured, and the change in acidity and alkalinity was recorded, and the sample in each test tube was taken out and dried to measure the change in weight. By the pH change after the experiment and the weight loss rate (%), the biodegradation rate of the mixture of the polypropylene carbonate resin/β-tricalcium phosphate and the polylactic acid composite material in different ratios can be calculated.

Table 5 below shows the biodegradation rate test results of the biodegradable absorbent composites of different formulation ratios according to the examples of the present invention.

The results of Table 5 confirm that the biodegradable absorbent composite of the embodiment of the present invention is biodegradable and bioresorbable, and can be decomposed and absorbed in the living body.

From the results of Table 5, as the amount of polylactic acid added increases, the rate at which the composite material is decomposed and absorbed increases. Therefore, the composition and proportion of the composite material suitable for a specific tissue can be adjusted by the known tissue growth rate, so that the tissue growth rate and the tissue substitute made of the biodegradable absorption composite material can cooperate with each other. Tissue substitutes are also decomposed and absorbed in the body at similar rates.

It can be seen from the above embodiments of the present invention that the application of the present invention has the following advantages:

1. The embodiment of the present invention selects a mixture of polypropylene carbonate resin/β-tricalcium phosphate and polylactic acid to be blended, and the components in the blending system have high compatibility, so that the processing is easy and the finished product has good properties. Characteristics of physical properties and thermal properties.

Second, the embodiment of the present invention selects a mixture of polypropylene carbonate resin/β-tricalcium phosphate mixed with polylactic acid, and can adjust the mechanical strength and biodegradation rate of the implant by formula ratio adjustment and control. Surgical implants with optimal decomposition rate and mechanical strength can be made according to different parts of the tissue to achieve the best auxiliary recovery effect.

3. The biodegradable absorbent composite of the embodiment of the present invention is confirmed by an animal test to have no allergic reaction, has good biocompatibility, and is biodegradable and bioabsorbable.

4. The composite material of the embodiment of the invention has good elasticity and mechanical strength, and has the characteristics of being arbitrarily moldable at room temperature, so that it can be pre-made, and can be applied to fill bone defects in different shapes and different parts. In contrast to the general liquid bone filling material "bone cement", there is no disadvantage that "bone cement" is brittle (low elasticity) and low mechanical strength (about 20 MPa).

Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention, and the present invention can be modified and modified without departing from the spirit and scope of the present invention. The scope is subject to the definition of the scope of the patent application attached.

No component symbol

The above and other objects, features, advantages and embodiments of the present invention will become more apparent and understood.

Fig. 1 is an electron micrograph of a biodegradable absorbent composite material according to an embodiment of the present invention.

Claims (11)

A biodegradable absorbing composite material which can be arbitrarily shaped at room temperature, the biodegradable absorbing composite material being composed of a polypropylene carbonate/β-tricalcium phosphate and a mixture of β-tricalcium phosphate and β-tricalcium phosphate Polylactic acid is composed of a weight ratio of 5:5 to 9:1, wherein the polypropylene carbonate resin and beta tricalcium phosphate are composed in a weight ratio of 9:1. The biodegradable absorbent composite according to claim 1, wherein the weight ratio of the mixture of the polypropylene carbonate resin/β-tricalcium phosphate to the polylactic acid is from 7:3 to 9:1. The biodegradable absorbent composite according to claim 1, wherein the weight ratio of the mixture of the polypropylene carbonate resin/β-tricalcium phosphate to the polylactic acid is 8:2. A method for preparing a biodegradable absorbent composite according to claim 1, comprising: blending a mixture of polypropylene carbonate resin/β-tricalcium phosphate with polylactic acid in a weight ratio of 5:5 to 9:1 Mixing and dissolving in an organic solvent to form a composite solution; and drying and forming the composite solution to form a solid biodegradable absorbent composite. The method for producing a biodegradable absorbent composite according to claim 4, wherein the weight ratio of the mixture of the polypropylene carbonate resin/β-tricalcium phosphate to the polylactic acid is from 7:3 to 9:1. The method for producing a biodegradable absorbent composite according to claim 4, wherein the weight ratio of the mixture of the polypropylene carbonate resin/β-tricalcium phosphate to the polylactic acid is 8:2. A method of preparing a biodegradable absorbent composite according to claim 4, wherein the organic solvent is acetone or tetrachloromethane. A method of preparing a biodegradable absorbent composite according to claim 4, wherein the method of dry molding is dry molding or vacuum forming. The method for preparing a biodegradable absorbent composite according to claim 4, further comprising: adding a salt in the composite solution for salting out to precipitate a solid mixture; removing the salt from the solid mixture to form a biodegradable absorbent composite material having a porous structure; and a dry-formed biodegradable absorbent composite material having a porous structure. A non-permanent tissue substitute comprising the biodegradable absorbent composite of claim 1. An artificial stent comprising the biodegradable absorbent composite of claim 1.