KR101145175B1 - Biocompatible and temperature-sensitive polyethyleneglycol/polyester block copolymer with high biodegradable property - Google Patents

Abstract

The present invention is a polyalkylene glycol / polyester block copolymer composed of a hydrophilic portion composed of polyethylene glycol and a biodegradable polyester-based hydrophobic portion simultaneously containing a caprolactone segment and a lactide segment at a specific ratio, and according to temperature change. Phase change is caused by aggregation and expansion of the polymer micelle composed of hydrophilic and hydrophobic moieties to easily form a gel in a desired form in the body, and because of its excellent biodegradability, it can be decomposed without the need for surgical removal. It relates to a multifunctional polymer that can be applied as an engineering support.

Description

 Biocompatible and temperature-sensitive polyethyleneglycol / polyester block copolymer with high biodegradable property

The present invention is a polyalkylene glycol / polyester block copolymer composed of a hydrophilic portion composed of polyethylene glycol and a biodegradable polyester-based hydrophobic portion simultaneously containing a caprolactone segment and a lactide segment at a specific ratio, and according to temperature change. Phase change is caused by aggregation and expansion of the polymer micelle composed of hydrophilic and hydrophobic moieties to easily form a gel in a desired form in the body, and because of its excellent biodegradability, it can be decomposed without the need for surgical removal. It relates to a multifunctional polymer that can be applied as an engineering support.

Since the introduction of hydrogels using PHEMA (Polyhydroxyethyl Methacrylate) in 1960, various studies using hydrogels have been conducted continuously, and by 1980, the manufacture of hydrogels using calcium alginate became a big electricity in the field of biomaterials. Since then, the synthesis of hydrogels for biomaterials using natural or synthetic polymers has made great strides. A typical property of hydrogels is that they can contain large amounts of water as a network of hydrophilic polymers that can swell in water. The three-dimensional network structure of the hydrogel may be formed by various factors such as covalent bonds, hydrogen bonds, van der Waals bonds, or physical aggregation. Hydrogels can prevent degeneration of drugs from enzymes or pH in the intestine, and can also impart the characteristic properties of releasing drugs by stimulation in various human bodies. Hydrogels that contain sensory properties capable of irritating response can produce reversible volume changes or sol-gel changes within minutes of stimulation in the human body. bgtt (delete)

External stimuli can be classified into physical stimuli such as temperature, electricity, solvent change, light, pressure, sound, and magnetic force, and chemical stimuli such as ions and specific molecular recognition. The development is expected to be applicable to high-efficiency and sustained-release drug delivery systems that can minimize side effects of drugs. In addition, many studies have reported that stem cells, which are attracting attention in the field of regenerative medicine these days, are differentiated into various tissues by controlling the actions and functions of various cytokines. Based on these research backgrounds, the complexation of cells, genes, and stem cells with stimulus-sensitive hydrogels is expected to enable the formation of various organs such as cartilage, bone, and blood vessels.

In particular, temperature-stimulated sensitized hydrogels are most widely studied in tissue regenerating cell transporters and water delivery systems. This is because many polymers exhibit temperature transfer characteristics. When introducing a hydrophilic group that can dissolve or swell a general polymer in water, the polymer is dissolved or swelled by water, and the solubility in water increases with increasing temperature, but the hydrophilicity and hydrophobic part such as methyl, ethyl and propyl are increased. The polymer is composed of a low critical solution temperature (LCST) of water solubility decreases with increasing temperature. Hydrogels made of polymers with LCST, such as the polyethyleneglycol / biodegradable polyester copolymers according to the invention, are elevated temperature hydrogels which condense and become gels when the temperature increases above LCST.

Polymers composed of hydrophilic and hydrophobic moieties have a high hydrogen bonding force between the hydrophilic group and water molecules of the polymer at low temperatures, so that they dissolve in water and become sol. However, as the temperature increases, the hydrophobic portion of the polymer has a higher bond strength than the hydrogen bonding force. The hydrophobic part of the polymer aggregates and a phase transition occurs in a gel state. Therefore, the increase of the hydrophobic moiety in the polymer lowers the LCST and the LCST is changed through the control of the molecular chain of the hydrophilic and hydrophobic groups. When the polymer solution flows with the fluid in a sol state at a normal temperature, the entrapment of the drug is possible by simple mixing, and when the heat is applied above the human body temperature, the polymer hydrogel becomes a gel, in which case the drug exhibits a sustained release behavior from the gel. do. When the polymer is crosslinked, the swelling and shrinkage behavior is shown, but when the polymer is not crosslinked, the sol-gel phase transition behavior is shown. Poly (N-isopropylacrylamide) is most widely used because it has LCST near body temperature. Copolymers such as butyl methacrylate, polyethylene glycol, polypropylene glycol, and the like are changed in the human body through sol-gel change at various temperature ranges. Is being used by. Copolymer of polyethylene oxide-polypropylene oxide (PEO-PPO) is also a polymer exhibiting a sol-gel change, and many copolymers are trade names such as Pluronic, Poloxamers, and Tetronic. US Patent No. 4188373.

On the other hand, the sol-gel polymer has a disadvantage that it must be released to the body by metabolism of the human body after being used in the human body, so that a polylactide-polyglycolide copolymer (PLGA) is introduced as a biodegradable polymer chain in the hydrophobic group. Many sol-gel polymers have also been reported (US Pat. Nos. 4,882,168, 4,716,203, 4,942,035, 5,476,909, 5,548,035).

Currently, many researches on intelligent hydrogels for application to drug delivery systems and tissue engineering using physicochemical properties of polymers in response to external stimuli have been conducted. In order to apply the intelligent hydrogel for injection drug delivery and tissue regeneration, it has to have low viscosity, fast gel formation and biodegradability, and low molecular weight to be easily released to the outside of the body. In addition, in order to be used in biomaterials, it must have biocompatibility and there should be no damage to cells or metabolic organs during degradation or release.

In order to apply the temperature sensitive hydrogel as a biomaterial to the porous support for tissue engineering, the present inventors have a high solubility in water and an organic solvent as a hydrophilic polymer, nontoxic, non-responsive to immune action, and a hydrophobic biodegradable ester. When applied to a living body by chemical bonding with a series of polymers, polyethylene glycol is used to control the decomposition period by increasing the inflow of water into the copolymer, and polymerizes the caprolactone monomer and lactide monomer at a specific content ratio When the polyester block copolymer is prepared, the present invention is completed by discovering that gel formation can be confirmed near the body temperature when injected into rats, although it is in a sol state at room temperature.

Therefore, the present invention is composed of a hydrophilic portion composed of polyethylene glycol and a biodegradable polyester-based hydrophobic portion containing caprolactone segment and lactide segment at the same time, and biodegradable polyethylene glycol having a specific molar ratio of caprolactone segment and lactide segment. It is an object to provide a polyester block copolymer.

The present invention is composed of a hydrophilic portion composed of polyethylene glycol, and a biodegradable polyester-based hydrophobic portion containing caprolactone segment and lactide segment at the same time, and the molar ratio of caprolactone segment and lactide segment is 94: 6 to 99: 1. Biodegradable polyethylene glycol / polyester block copolymers in the range.

The aqueous solution of the biodegradable polyethylene glycol / polyester block copolymer according to the present invention can be phase-transformed by temperature change, thereby forming a gel in the body. In particular, because it is biodegradable and biocompatible, it can be used as a substrate of various forms for cell and tissue culture in the body, and can provide a place where cells can attach, move, and grow. Therefore, the biodegradable polyethylene glycol / polyester block copolymer according to the present invention can be widely used as a porous support for tissue engineering using the temperature-sensitive properties.

1 shows a ¹ H-NMR spectrum of a methoxy polyethylene glycol (MPEG) -polycaprolactone (PCL) -co-polylactide (PLLA) block copolymer prepared according to Example 1 of the present invention.
2 is a graph showing the sol-gel phase transition and the magnitude of the viscosity by measuring the sol-gel phase transition through the viscosity change according to the temperature change of the block copolymers prepared in Examples and Comparative Examples.
FIG. 3 is a photograph confirming gelation in vivo by injecting the aqueous block copolymer prepared in Examples 1 and 2 subcutaneously in the rat.
Figure 4 is a photograph comparing the size of the gel over time after injecting the block copolymer aqueous solution of Examples 1, 2 and Comparative Example 3 subcutaneously.
Figure 5 is a block copolymer of Examples 1, 2 and Comparative Example 3 injected into the subcutaneous of the mouse after the gel was removed over time and H & E stained picture, the red arrow shows the blood vessels formed in the gel .
6 is a photo of the block copolymer aqueous solution of Examples 1, 2 and Comparative Example 3 injected into the subcutaneous of the mouse and then removed the gel over time and ED1 immunofluorescence staining, the blue and red portions are respectively DAPI and ED1 staining are shown.

Hereinafter, the present invention will be described in detail.

The present invention is a polyalkylene glycol / polyester block copolymer composed of a hydrophilic portion composed of polyethylene glycol and a biodegradable polyester-based hydrophobic portion simultaneously containing a caprolactone segment and a lactide segment at a specific ratio, and according to temperature change. Phase change is caused by aggregation and expansion of the polymer micelle composed of hydrophilic and hydrophobic moieties to easily form a gel in a desired form in the body, and because of its excellent biodegradability, it can be decomposed without the need for surgical removal. It relates to a multifunctional polymer that can be applied as an engineering support.

In particular, the polyethylene glycol has many advantages in the field of drug delivery and tissue engineering, and typically has a high solubility in organic solvents, non-toxicity and no rejection of immune action, and shows excellent biocompatibility, easily enclosing the drug as a drug carrier, It can be released and used in the pharmaceutical formulation industry as a material approved for use by the US Food and Drug Administration for human use. In addition, since polyethylene glycol improves the biocompatibility of the polymers used for blood contact among hydrophilic polymers and has the greatest protein adsorption inhibitory effect, many applications have been made as biomaterials [J. H. Lee, J. Kopecek, and J. D. Andrade, J. Biomed. Mater. Res., 23, 351 (1989)].

In the present invention, the polyalkylene glycol is preferably used having a number average molecular weight of 350 ~ 2,000 g / mole, preferably having a molecular weight of 500 ~ 1,000 g / mole.

Biodegradable polymers of the ester series have the advantage of controlling the decomposition period by controlling the molecular weight and chemical components. Block copolymers of polyethylene glycol (PEG) and polycaprolactone (PCL), which have become basic models in the present invention, have already been applied to biomaterials as temperature-sensitive copolymers having sol-gel phase transition properties. However, caprolactone is biodegradable and compatible with many polymers and has a feature of easily crystallizing. However, high crystallinity decreases compatibility with tissues and exhibits long-term degradation behavior when applied in vivo.

Thus, in the present invention, by adding a biodegradable ester series lactide to a caprolactone at a specific ratio, the caprolactone segment and the lactide segment are irregularly present to have a biodegradable polyester-based hydrophobic portion to lower crystallinity and biodegradation. The period was adjusted. The molar ratio (mole fraction) of the caprolactone segment and the lactide segment was adjusted to be in the range of 94: 6 to 99: 1, and preferably in the range of 95: 5 to 98: 1. If the ratio of the caprolactone segment exceeds the above range, the biodegradability is low, the decomposition takes a long time after the bio-injection, and if the ratio of the lactide segment exceeds the above range, the sol-gel phase transition does not appear at the temperature there is a problem.

As an example of the polymer prepared in the present invention, a process of ring-opening polymerization of caprolactone and lactide to polyethylene glycol using a catalyst is shown in Scheme 1 below.

Scheme 1

In addition, the copolymer of the present invention is synthesized by hydrolyzing polyethylene glycol having a number average molecular weight of 350 to 2,000 g / mole with the ester-based caprolactone and lactide ring-opening copolymerization. In the synthesis method, polyethylene glycol is azeotropically distilled to dryness, and then monomers are added, and methylene chloride or toluene is used as a reaction solvent. In addition, the catalyst for the ring opening reaction is Sn (Oct) _2, trifluoromethanesulfonic acid (trifluoromethanesulfonic acid), trifluoroacetic acid (trifluoroacetic acid), TiO _2, Zn (Oct) ₂ , BF ₃ O (CH ₃ ) ₂ , Al (Acac) ₃ and the like can be used, the reaction temperature is preferably in the range of 90 ~ 150 ℃.

The aqueous solution phase of the synthesized polyethylene glycol / polyester block copolymer maintains the sol state with flow characteristics at room temperature, but forms a gel over a certain temperature range (30-50 ° C.), and again exhibits flow characteristics above the critical temperature. Sol-gel phase transition behavior. The thermal properties and crystallinity were analyzed by differential scanning calorimetry and X-ray diffractometer. In order to confirm gel formation near the body temperature, it was injected into rats to confirm the formation and integrity of gel.

In addition, in order to apply such a temperature-sensitive block copolymer as an injectable drug carrier or a functional support for tissue regeneration, it is necessary to have low viscosity, fast gel formation, and low molecular weight to be easily discharged out of the body. By introducing in a certain content ratio it was possible to reduce the crystallinity to lower the viscosity, to obtain a molecular weight close to the expected value to maintain a low viscosity and low molecular weight.

At this time, it is preferable to synthesize a biodegradable polyethylene glycol / polyester block copolymer having a total number average molecular weight of 2,000 to 3,000 g / mole, when the total molecular weight is less than 2,000 g / mole, the human body temperature which is the object of use of the present invention This is because there is a problem in that the sol-gel phase transition does not occur in the range and continues to be in a sol state, and if it exceeds 3,000 g / mole, there is a problem that it takes a long time to cause biodegradation due to its large molecular weight.

The biodegradable polyethylene glycol / polyester block copolymer according to the present invention can be applied as a drug carrier containing a support for tissue engineering or a drug, and also blood in the wound healing process such as inflammation, wound, friction, wound by surgery It can also be applied as an anti-adhesion agent that can leak and coagulate and thereby prevent adhesion caused by binding to surrounding organs or tissues.

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

Example 1: Synthesis of methoxypolyethylene glycol- (polycaprolactone-co-polylactide) block copolymer [MPEG- (PCL-co-PLLA)] (caprolactone: lactide = 95: 5)

To synthesize methoxy polyethylene glycol (MPEG) -polycaprolactone (PCL) -co-polylactide (PLLA) block copolymer of molecular weight 2,400 g / mole (1.5 g, 2 mmol, Mn) = 750 g / mole) and 80 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stock trap. After distillation, 40 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., and then purified caprolactone (CL) (4.51 g, 39.51 mmol) and lactide (LA) (0.30 g, 2.08 mmol) 40 ml of pre-purified toluene was added as a reaction solvent, 2.4 ml of Sn (Oct) ₂ was added as a polymerization catalyst, and the mixture was stirred at 110 ° C for 24 hours. All procedures were carried out under high purity nitrogen. In order to remove unreacted monomer or initiator after the reaction, the reactant was slowly precipitated in 800 ml of hexane and 200 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight to molar ratio of the constituents of the copolymer synthesized above was measured using ¹ H-NMR, and a number average molecular weight of 2,380 g / mole similar to the theoretical expected value was obtained, and the polydispersity was measured. It was confirmed by using gel permeation chromatography (GPC) to have a polydispersity of 1.41. 1 shows the ¹ H-NMR spectrum of the prepared block copolymer.

Example 2 Synthesis of Methoxypolyethyleneglycol- (polycaprolactone-co-polylactide) block copolymer [MPEG- (PCL-co-PLLA)] (caprolactone: lactide = 97: 3)

To synthesize methoxy polyethylene glycol (MPEG) -polycaprolactone (PCL) -co-polylactide (PLLA) block copolymer of molecular weight 2,400 g / mole (1.5 g, 2 mmol, Mn) = 750 g / mole) and 80 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stock trap. After distillation, 40 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., and then purified caprolactone (CL) (4.7 g, 40.8 mmol) and lactide (LA) (0.18 g, 1.26 mmol) 40 ml of pre-purified toluene was added as a reaction solvent, 2.4 ml of Sn (Oct) ₂ was added as a polymerization catalyst, and the mixture was stirred at 110 ° C for 24 hours. All procedures were carried out under high purity nitrogen. In order to remove unreacted monomer or initiator after the reaction, the reactant was slowly precipitated in 800 ml of hexane and 200 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight to molar ratio of the components of the copolymer synthesized above was measured using ¹ H-NMR, the number average molecular weight 2,420 g / mole similar to the theoretical expected value was obtained, and the polydispersity was measured It was confirmed by using gel permeation chromatography (GPC) to have a polydispersity of 1.36.

Comparative Example 1: Synthesis of methoxy polyethylene glycol- (polycaprolactone-co-polylactide) block copolymer [MPEG- (PCL-co-PLLA)] (caprolactone: lactide = 93: 7)

To synthesize methoxy polyethylene glycol (MPEG) -polycaprolactone (PCL) -co-polylactide (PLLA) block copolymer of molecular weight 2,400 g / mole (1.5 g, 2 mmol, Mn) = 750 g / mole) and 80 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stock trap. After distillation, 40 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., and then purified caprolactone (CL) (4.5 g, 39.1 mmol) and lactide (LA) (0.42 g, 2.94 mmol) 40 ml of pre-purified toluene was added as a reaction solvent, 2.4 ml of Sn (Oct) ₂ was added as a polymerization catalyst, and the mixture was stirred at 110 ° C for 24 hours. All procedures were carried out under high purity nitrogen. In order to remove unreacted monomer or initiator after the reaction, the reactant was slowly precipitated in 800 ml of hexane and 200 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight to molar ratio of the constituents of the copolymer synthesized above was measured using ¹ H-NMR, and a number average molecular weight of 2,260 g / mole similar to the theoretical expected value was obtained. It was confirmed by using gel permeation chromatography (GPC) to have a polydispersity of 1.25.

Comparative Example 2: Synthesis of methoxypolyethylene glycol- (polycaprolactone-co-polylactide) block copolymer [MPEG- (PCL-co-PLLA)] (caprolactone: lactide = 90:10)

To synthesize methoxy polyethylene glycol (MPEG) -polycaprolactone (PCL) -co-polylactide (PLLA) block copolymer of molecular weight 2,400 g / mole (1.5 g, 2 mmol, Mn) = 750 g / mole) and 80 ml of toluene were placed in a well dried 100 ml round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stock trap. After distillation, 40 ml of toluene was removed, and methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., followed by pre-purified caprolactone (CL) (4.3 g, 37.8 mmol) and lactide (LA) (0.6 g, 4.2 mmol). 40 ml of pre-purified toluene was added as a reaction solvent, 2.4 ml of Sn (Oct) ₂ was added as a polymerization catalyst, and the mixture was stirred at 110 ° C for 24 hours. All procedures were carried out under high purity nitrogen. In order to remove unreacted monomer or initiator after the reaction, the reactant was slowly precipitated in 800 ml of hexane and 200 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight to molar ratio of the constituents of the copolymer synthesized above was measured using ¹ H-NMR, and a number average molecular weight of 2,260 g / mole similar to the theoretical expected value was obtained. It was confirmed by using gel permeation chromatography (GPC) to have a polydispersity of 1.23.

Comparative Example 3 Synthesis of Methoxy Polyethylene Glycol-Polycaprolactone Block Copolymer [MPEG-PCL] (Caprolactone: Lactide = 100: 0)

To synthesize methoxy polyethylene glycol (MPEG) -polycaprolactone (PCL) block copolymers of molecular weight 2,400 g / mole, methoxypolyethylene glycol (1.5 g, 2 mmol, Mn = 750 g / mole) and toluene 80 The mL was placed in a well dried 100 mL round flask and subjected to azeotropic distillation at 130 ° C. for 3 hours using a Dean Stock trap. After distillation, 40 ml of toluene was removed, methoxy polyethylene glycol (MPEG) was cooled to 25 ° C., and prepurified caprolactone (CL) (4.8 g, 42 mmol) was added thereto, and 40 ml of toluene, which was previously purified, was added as a reaction solvent. Next, 2.4 ml of Sn (Oct) ₂ was added as a polymerization catalyst and stirred at 110 ° C. for 24 hours. All procedures were carried out under high purity nitrogen. In order to remove unreacted monomer or initiator after the reaction, the reactant was slowly precipitated in 800 ml of hexane and 200 ml of ether. The precipitate was dissolved in methylene chloride (MC), filtered through a filter paper, and the solvent was removed through a rotary evaporator and dried under reduced pressure.

Molecular weight to molar ratio of the components of the copolymer synthesized above was measured using ¹ H-NMR, the number average molecular weight 2,430 g / mole similar to the theoretical expected value was obtained, the polydispersity measurement It was confirmed by using gel permeation chromatography (GPC) to have a polydispersity of 1.26.

Experimental Example 1 Determination of Sol-Gel Phase Transition Behavior with Temperature in Biodegradable Polyethylene Glycol / Polyester Block Copolymer

In order to observe the phase transition behavior of the biodegradable polyethylene glycol / polyester block copolymers, the copolymers synthesized according to the above examples and the comparative examples were dissolved in distilled water at a concentration of 20 wt%, and then equilibrated with homogeneously dispersed polymers. Refrigerated at 4 ° C. for 1 day to maintain. The sol-gel phase transition behavior was measured at each temperature by increasing the spin rate at 0.2 rpm while increasing the prepared polymer solution by 1 ° C. per 2 minutes in the range of 10 ° C. to 60 ° C. using a viscosity meter (FIG. 2).

As shown in FIG. 2, the block copolymers of Examples and Comparative Examples 3 exist in a sol state having a low viscosity at room temperature, but transition to a gel state occurs at 30 to 50 ° C., but in Comparative Examples 1 and 2 In this case, it was confirmed that the phase change did not occur and remained in the sol state. Therefore, it was confirmed that the polyethyleneglycol / polyester block copolymer of the present invention can form a gel through phase transition at a body temperature.

Experimental Example 2 of Biodegradable Polyethylene Glycol / Polyester Block Copolymer in vivo  Check gel formation

To confirm the sol-gel phase transition near the body temperature, the polyethyleneglycol / biodegradable polyester block copolymer solution of Example and Comparative Example 3 was maintained in a sol state at room temperature, and then 1 mL of rats were removed using a disposable syringe. Injected subcutaneously. After 24 hours, the injection site was excised to confirm gel formation. Therefore, it was confirmed that the polyethylene glycol / biodegradable polyester block copolymer solution was rapidly forming and maintaining the gel in vivo (FIG. 3).

In addition, the size of the gel formed at 1, 2, 4 and 6 weeks after the subcutaneous injection of the rat was compared (Fig. 4). As shown in FIG. 4, after 6 weeks, the block copolymers of Examples 1 and 2 were significantly reduced to about 25% and 50% of the gel size at 1 week, but the block copolymers of Comparative Example 3 were After 6 weeks, it was confirmed that there was little change in the size of the gel. Therefore, the block copolymer of the present invention was confirmed that biodegradation occurs at a rapid rate after the gel is formed in vivo.

Experimental Example 3 Histological Evaluation of Polyethylene Glycol / Polyester Gel

After 1, 2, 4, and 6 weeks, the gel removed from the rats was fixed in 10% formalin, and the fixed support was made of paraffin blocks, cut into 4 μm thicknesses, fixed on slides, and histologically H & E and ED1 staining was performed for evaluation. H & E staining is the most basic staining method. Hematoxylin, which is specifically stained at the nucleus of cells, and eosin, which is stained at the cytoplasm. Progress was made to confirm the behavior and morphology. Macrophage, neutrophils, lymphocytes were present in the gel through the H & E staining, it was confirmed that new blood vessels are generated (Fig. 5). In addition, ED1 (mouse anti-rat CD68; Serotec, UK) expression was confirmed in order to confirm the inflammatory response of the transplanted transplant (Fig. 6).

The experiment confirmed that the gel of the present invention is biocompatible and does not cause an immune inflammatory response, it can be seen that it can be used as a tissue engineering support.

Claims (7)

delete A copolymer composed of a hydrophilic portion composed of polyethylene glycol having a number average molecular weight of 350 to 2,000 g / mole and a biodegradable polyester hydrophobic portion containing caprolactone segment and lactide segment at the same time. The molar ratio (mole fraction) is in the range of 94: 6 to 99: 1, the sol phase at room temperature, the gel phase at 30 to 50 ° C, and the number average molecular weight in the range of 2,000 to 3,000 g / mole. Biodegradable polyethylene glycol / polyester block copolymers, characterized in that
delete delete The support for tissue engineering consisting of the block copolymer of claim 2.
An anti-adhesion agent comprising the block copolymer of claim 2.
Drug delivery system consisting of the block copolymer of claim 2.

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