KR102172140B1 - Biodegradable polyurethane microparticles - Google Patents

Abstract

In the present invention, a polyol compound and a diisocyanate compound are used to prepare polyurethane microspheres. The polyurethane microspheres according to the present invention can control physical properties, that is, average molecular weight, melting point, Young′s modulus, tensile strength, elongation at break, hydrolysis rate and the like by adjusting the ratio of diisocyanates in a preparation process. The polyurethane microspheres according to the present invention can be used as an insert for treating arthritis, an insert for treating wrinkles, a filler for molding, a drug delivery system and the like through the adjustment of the physical properties.

Description

Biodegradable polyurethane microparticles

The present invention relates to a method for producing biodegradable polyurethane microspheres, and to a biodegradable polyurethane microsphere prepared by the method.

Polyurethanes (PU) are widely used in the biomedical field due to their unique mechanical properties and excellent biocompatibility (Refs. 1-3). Polyurethane is a segmented copolymer composed of alternating soft segments and hard segments. The soft segment is a flexible domain derived from polyol, and the hard segment is a stiff domain derived from diisocyanate. The soft segment gives the polymer an elastomeric character, while the hard segment provides additional strength due to hydrogen bonding between the PU chains (Ref. 4). Mechanical properties can be controlled simply by changing the type and ratio of polyols and isocyanates (Refs. 4-5). In addition, further improved mechanical properties can be achieved through a chain extension reaction using polyol and polyamine (Ref. 6).

However, the application of polyurethane has generally been limited to medical devices due to the non-degradability of the polyurethane.

Therefore, there is a need to prepare polyurethane having excellent mechanical properties and excellent biodegradability at the same time.

An object of the present invention is to provide a polyurethane microsphere having excellent mechanical properties and excellent biodegradability and a method for manufacturing the same.

The present invention comprises the steps of preparing a prepolymer by reacting a polyol compound and a diisocyanate compound; And

Comprising the step of preparing an emulsion by adding an oil phase containing the prepared prepolymer to an aqueous phase containing a water-soluble chain extender, and stirring the emulsion to prepare polyurethane microspheres,

The polyol compound provides a method for producing one or more polyurethane microspheres selected from the group consisting of polycaprolactone diol (PCL diol) and polycaprolactone triol (PCL triol).

In addition, the present invention provides polyurethane microspheres manufactured by the above-described method for manufacturing polyurethane microspheres.

In addition, the present invention provides a biocompatible material comprising the polyurethane microspheres described above.

The present invention uses a polyol compound and a diisocyanate compound to prepare polyurethane microspheres.

The polyurethane microspheres according to the present invention can control physical properties such as average molecular weight, melting point, Young's modulus, tensile strength, elongation at break, and hydrolysis rate by adjusting the ratio of the diisocyanate compound in the manufacturing process.

The polyurethane microspheres according to the present invention can be used in various fields such as an insert for treating arthritis, an insert for treating wrinkles, a filler for molding, and a drug delivery system through the adjustment of the physical properties.

1 shows a reaction scheme for the synthesis of polyurethane (PU).
2 shows DSC thermograms results of polyurethane prepolymers having different polyol compound/diisocyanate compound ratios.
3 shows (a) Representative strain-stress curves, (b) Young's moduli, (c) tensile strengths and (d) elongations at break of a polyurethane prepolymer film. to break) Shows the measurement result.
4A shows the results of measuring the remaining masses of the polyurethane prepolymer film in NaOH solution (1M) at 60°C over time. In addition, (b) shows photographs of the PU12 film on days 3, 6, 9 and 18.
5 shows the measurement results of DEX cumulative release profiles from polyurethane microspheres in PBS buffer (pH 7.4) and 37°C.

The present invention comprises the steps of preparing a prepolymer by reacting a polyol compound and a diisocyanate compound (hereinafter, a prepolymer preparation step); And

Including the step of preparing polyurethane microspheres by adding the oil phase containing the prepared prepolymer to the aqueous phase containing a water-soluble chain extender, and stirring the emulsion to prepare polyurethane microspheres (hereinafter, manufacturing polyurethane microspheres). It relates to a method for producing polyurethane microspheres.

In the examples of the present invention, a prepolymer was prepared by varying the molar ratio of the diisocyanate compound, and mechanical properties and biodegradation properties were evaluated. In addition, polyurethane microspheres containing drugs were prepared through a solvent evaporation method, and the release behavior of DEX from the polyurethane microspheres according to the ratio of the diisocyanate compound was evaluated over time. . Polyurethane microspheres with controlled mechanical properties and biodegradability can be used not only as a tissue engineering-based scaffold, but also as an insert for treating arthritis, an insert for treating wrinkles, a filler for molding, and a material for a drug delivery system.

Hereinafter, the configuration of the present invention will be described in detail.

In the present invention, the term "polyurethanes (PU)" refers to a polymer compound containing a urethane bond (-OCONH-).

In the present invention, the term "prepolymer" refers to a polymer having a relatively low degree of polymerization in which polymerization is stopped at an intermediate stage in order to facilitate molding. The prepolymer can be prepared as a polymer (polymer) by newly performing polymerization. In the present invention, the prepolymer may be expressed as a polyurethane prepolymer. The polyurethane prepolymer may include an isocyanate group (-NCO) at the terminal, and may form a urethane bond by addition polymerization using a chain extender.

In the present invention, the term "microspheres" generally refers to a material forming a sphere shape having a diameter of 1 to 1000 µm. In this case, a sphere is only a sphere with a mathematical definition of a three-dimensional shape consisting of all points at the same distance from one point. In addition, "polyurethane microspheres" may be used in a sense of encompassing all externally rounded shapes, that is, an error range generated during measurement or manufacturing. Means.

In the present invention, the prepolymer preparation step is to prepare a prepolymer by reacting a polyol compound and a diisocyanate compound.

In one embodiment, the type of the polyol compound is not particularly limited, and one or more selected from the group consisting of polycaprolactone diol and polycaprolactone triol may be used.

In one embodiment, the type of the diisocyanate compound is not particularly limited, and 2,4- or 4,4'-methylene diphenyl diisocyanate (MDI), xylylene diisocyanate (XDI), m- or p-tetramethyl Xylylene diisocyanate (TMXDI), toluene diisocyanate (TDI), di- or tetra-alkyldiphenylmethane diisocyanate, 3,3'-dimethyldiphenyl-4,4'-diisocyanate (TODI), 1,3 -Phenylene diisocyanate, 1,4-phenylene diisocyanate, naphthalene diisocyanate (NDI), 4,4'-dibenzyl diisocyanate, hydrogenated MDI (H12MDI), 1-methyl-2,4-diisocyanate diisocyanate Hexane, 1,12-diisocyanatododecane, 1,6-diisocyanato-2,2,4-trimethylhexane,1,6-diisocyanato-2,4,4-trimethylhexane, isophorone diisocyanate (IPDI), tetramethoxybutane-1,4-diisocyanate, butane-1,4-diisocyanate, hexane-1,6-diisocyanate (HDI), dicyclohexylmethane diisocyanate, cyclohexane-1,4 -One or more selected from the group consisting of diisocyanate and ethylene diisocyanate may be used.

In one embodiment, the molar ratios of the polyol compound and the diisocyanate compound may be 1:0.1 to 1:10, 1:1 to 1:10, or 1:2 to 1:5.

In the present invention, a prepolymer may be prepared through the reaction of a polyol compound and a diisocyanate compound. An isocyanate group (-NCO) may be formed at both ends of the prepolymer.

In one embodiment, the reaction of the polyol compound and the diisocyanate compound may be carried out in the presence of a catalyst. Using the catalyst, the reaction can proceed quickly and the reaction efficiency can be improved. As such a catalyst, the catalyst used in the production of polyurethane in the art can be used without limitation, and tin (II) acetate, tin (II) octoate, tin (II) ethylhexoate, tin (II) laurate, dibutyl Tin diacetate, dibutyltin dilaurate, dibutyltin maleate and/or dioctyltin diacetate, tris-(N,N-dimethylaminopropyl)-s-hexahydrotriazine, tetramethylammonium hydroxide , At least one selected from the group consisting of sodium hydroxide, sodium N-[(2-hydroxy-5-nonylphenyl)methyl]-N-methylaminoacetate, sodium acetate, sodium octoate, potassium acetate and potassium octoate You can use

In the present invention, in the step of preparing polyurethane microspheres, an emulsion is prepared by adding an oil phase containing a prepolymer to an aqueous phase containing a water-soluble chain extender, and the emulsion is stirred to prepare a polyurethane microsphere.

Polyurethane has unique mechanical properties and excellent biocompatibility. The polyurethane is a segmented copolymer composed of alternating soft segments and hard segments, and the soft segments may be derived from polyol compounds, and the hard segments may be derived from diisocyanate compounds. Can be. In the polyurethane, the soft segment may impart elastic properties, and the hard segment may impart strength due to hydrogen bonding between polyurethane chains.

In the present invention, microspheres composed of polyurethane may be prepared using a solvent evaporation method. The solvent evaporation method is one of the methods used in manufacturing microspheres, and has the advantage of a simple manufacturing process. The method refers to a method of dissolving a polymer, that is, the urethane prepolymer of the present invention, in an organic solvent with a low boiling point, emulsifying it in an aqueous solution, and evaporating the organic solvent through stirring to form microspheres.

In one embodiment, the oil phase comprises a prepolymer. Polyurethane microspheres may be prepared using the prepolymer, or may be used after dissolving the prepolymer in a separate organic solvent. At this time, dichloromethane (DCM), chloroform, acetone, tetrahydrofuran (THF), methyl ethyl ketone (MEK), or toluene may be used as the organic solvent.

The content of the organic solvent may be 10000 parts by weight or less, 5000 parts by weight or less, 100 to 3000 parts by weight, or 500 to 2000 parts by weight based on 100 parts by weight of the prepolymer.

In one embodiment, the oil phase may further contain a drug in addition to the prepolymer. The drug may impart functionality to the microspheres, and when the drug is included, microspheres having a drug therein may be prepared.

The content of the drug may be 10 parts by weight or less, 0.001 to 1 part by weight, or 0.01 to 0.1 parts by weight based on 100 parts by weight of the organic solvent.

In one embodiment, the aqueous phase comprises a water-soluble chain extender. The water-soluble chain extender can be used to add hydrophilicity to the microspheres, which can be biodegradable and can be applied to a biocompatible material.

In the present invention, a polyurethane may be prepared by addition polymerization of a prepolymer using a water-soluble chain extender. Specifically, the isocyanate group (-NOC) at the end of the prepolymer may react with a chain extender to form a urethane bond (-OCONH-).

The water-soluble chain extender may be one or more selected from the group consisting of gelatin, chitosan, diamine, diol, polyamine, and polyol. In addition, the content of the water-soluble chain extender may be 0.1 to 10 parts by weight or 0.5 to 5 parts by weight relative to the aqueous solvent, that is, water.

In one embodiment, the aqueous phase may further contain an emulsifier. The emulsifier may serve to stabilize the droplet by reducing the surface tension of the formed droplet. As such an emulsifier, an emulsifier used in the art may be used without limitation, and specifically, at least one selected from the group consisting of Tweens, polyvinyl alcohol (PVA), sodium dodecyl sulfate (SDS), and poloxamer. Water-soluble emulsifiers can be used.

In particular, in the present invention, gelatin can simultaneously play the role of a water-soluble chain extender as well as a surface modifier as an emulsifier. When using the gelatin, microspheres can be formed without using a separate emulsifier. It can be easily manufactured.

In the present invention, when the oil phase is added to the aqueous phase, that is, when the oil phase and the aqueous phase are mixed, an O/W emulsion is prepared. In the emulsion, the emulsifier may lower the interfacial tension to prevent the emulsions from agglomeration with each other. Further, when the emulsion is stirred, the organic solvent evaporates to form microspheres.

In one embodiment, the stirring may be performed at a speed of 500 to 1500 rpm or 600 to 1000 rpm, for 1 to 24 hours or 5 to 12 hours.

In the present invention, the concentration of the prepolymer, the kind of organic solvent, and the stirring speed may affect physical properties such as the shape and average particle diameter of the microsphere, and the ratio of the diisocyanate compound may affect the biodegradation rate. You can adjust it appropriately according to the intended use.

In the present invention, physical properties and biodegradability of polyurethane microspheres can be controlled through the above manufacturing method. In addition, the polyurethane microspheres may include a functional material such as a drug, and the release profile of the drug may be controlled by controlling the biodegradability (degradation rate) of the polyurethane microspheres.

In addition, the present invention relates to polyurethane microspheres manufactured by the above-described method for manufacturing polyurethane microspheres.

In one embodiment, the average particle diameter of the polyurethane microspheres may be 1 to 500 μm or 10 to 300 μm. It is suitable for use in vivo within the above average particle diameter range.

In one embodiment, the polyurethane microspheres may further include a functional material such as a drug. As the drug, a hydrophobic drug used in the art may be used without limitation. In the examples of the present invention, dexamethasone (DEX) was used to evaluate the release profile.

In addition, the present invention relates to a biocompatible material comprising the polyurethane microspheres described above.

The biocompatible material may be any biocompatible material in which polyurethane microspheres may be used, for example, it may be selected from the group consisting of an insert for treating arthritis, an insert for treating wrinkles, a filler for molding, and a drug delivery system. . Such a biocompatible material can properly adjust its physical properties according to its specific use.

The present invention will be described in more detail through the following examples. However, the scope of the present invention is not limited to the following examples, and those skilled in the art can understand that various modifications, modifications, or applications are possible without departing from the technical matters derived by the matters described in the appended claims. will be.

Example

<Reference> Materials

Poly(ε-caprolactone) diol (PCL diol, Mn ~ 2000), 4,4'-methylenediphenyl diisocyanate (MDI, 98%), dibutyltin dilaurate (DBTDL, 95%), gelatin (type A, from pig skin, 90-110 g bloom) was purchased from Sigma-Aldrich (St. Louis, MO, USA). Anhydrous dichloromethane (DCM) and dexamethasone (DEX) were purchased from Tokyo Chemical Industry (Tokyo, Japan).

Example 1. Biodegradable polyurethane Prepolymer synthesis

The molar ratios of PCL diol and MDI were varied to 1:2 (PU12), 1:3 (PU13), 1:4 (PU14) and 1:5 (PU15). The determined content of PCL diol and MDI was dissolved in anhydrous DCM (20 wt%, 20 g) (solution preparation), and DBTDL (catalyst, 0.1 mmol) was added to the solution. The solutions having different polyol/diisocyanate ratios were stirred at room temperature for 24 hours to polymerize. A film (polyurethane prepolymer film) was prepared in a Teflon mold by a solvent casting method.

The polymerization reaction scheme of PCL diol and MDI is shown in FIG. 1.

Example 2. Polyurethane Mythropian Produce

Polyurethane microspheres containing DEX were prepared using a single oil-in-water (O/W) emulsion and a solvent evaporation method.

4 g of the polyurethane prepolymer prepared in Example 1 and 80 mg of DEX were dissolved in 20 g of anhydrous DCM (oil phase preparation). The oily phase was emulsified in 400 ml (1 wt%) of aqueous gelatin solution. The O/W emulsion was stirred overnight at 700 rpm using a magnetic stirrer. DEX-rod PU microspheres were washed three times with water to remove excess gelatin and free drug, and then freeze-dried.

Experimental example 1. Biodegradable polyurethane Prepolymer Physical property measurement

(1) method

Gel permeation chromatography using Shimadzu SIL-20A and LC-20AD systems equipped in series with PLgel 5㎛ MIXED columns (300mm × 7.5mm) as well as Shimadzu RID-20A differential index detector. , GPC) analysis was performed. Tetrahydrofuran (THF) was used as an eluent at a flow rate of 1 mL/min.

Differential scanning calorimetry (DSC) analysis was performed using a DSC4000 (PerkinElmer) differential scanning calorimeter. In the temperature range of -50 to 200°C, the scanning rates were 10°C/min.

Mechanical properties were evaluated using a texture analyzer (Stable Micro Systems, Reading, UK) with a 5 kg load cell while using pneumatic clamps to hold the samples. The film was tested at 1 mm/s speed. Strain, stress, and Young's modulus values were obtained using package Texture Exponent 32. In order to evaluate the decomposition by hydrolysis, the films were immersed in an aqueous NaOH solution (20 mL, 1M) at 60°C. At the determined time point, the films were washed with water and dried and their weight was measured.

(2) result

The molecular weight of the prepolymer according to the PCL diol and MDI mole ratio is shown in Table 1 below.

As shown in Table 1, as the ratio of MDI increased, the average molecular weight decreased from 127 kDa (PU12) to 79 kDa (PU15). The decrease in average molecular weight is due to crosslinking between diisocyanates. The allophanate reaction interferes with the formation of linear polymers, resulting in the formation of a dense network. The PU12 was relatively transparent and less viscous compared to other polyurethane prepolymers.

The DSC profile of the polyurethane prepolymer is shown in FIG. 2. The polyurethane prepolymer has a melting point of 41 to 45°C. The polyurethane prepolymer having a high diisocyanate ratio showed a high melting point due to the allophanate reaction. Although the glass transition temperature was not observed in the experimental range, it may be -50°C (Ref. 12). The polyurethane prepolymer did not dissolve into a liquid due to three-dimensional crosslinking.

3 shows the tensile stress-strain curve and tensile properties of the polyurethane prepolymer.

The tensile properties were greatly influenced by the diisocyanate ratio. The polyurethane prepolymer having a high diisocyanate ratio increased Young's modulus, decreased tensile strength, and decreased elongation at break. PU12 showed more ductile properties than other polyurethane prepolymer films. This tendency is due to the high proportion of hard segments and the allophanate reaction.

The degradation of hydrolysis plays a key role in the development of biomaterials applied to the biomedical field. Hydrolysis of ester-based polymers involves three stages: the first stage is the incubation stage, where water absorption takes place. The second step is the induction stage in which the polymer chain is broken through ester bonds. Finally, there is an erosion stage with a corresponding polymer mass loss. In order to evaluate the biodegradation behavior of the polyurethane prepolymer in an accelerated manner, the polyurethane prepolymer film was immersed in an aqueous NaOH solution at 60°C.

Figure 4a shows the remaining amount of the polyurethane prepolymer film over time. The PU12, which has a low diisocyanate ratio, decomposes faster than other polyurethane prepolymers. The high decomposition rate of PU12 is mainly due to the rapid and easy penetration of water molecules into the PCL chain. 4B shows an optical picture of a PU12 film immersed in an aqueous NaOH solution over time. The PU12 film retained its original shape until the 3rd day, uniformity occurred on the 6th, and turned into fragments on the 9th. After 9 days, it was difficult to measure the weight. These results suggest that the rate of biodegradation can be controlled by changing the ratio of diisocyanate.

Experimental example 2. Polyurethane (PU) Microsphere Average particle diameter And DEX Measurement of emission behavior

(1) method

DEX release profiles were measured by suspending 0.4 g of DEX-loaded polyurethane microspheres in 10 ml of PBS (pH 7.4).

Samples were incubated at 37°C while shaking at 70 rpm in an incubator. At a predetermined time point, after centrifuging the polyurethane microsphere suspension, the supernatant was collected and analyzed, and then replaced with fresh PBS.

The concentration of DEX was determined by measuring absorbance at 242 nm using a UV/VIS/NIR spectrometer (Lambda1050, Perkin Elmer).

(2) result

The prepared polyurethane microspheres had a smooth surface and a diameter of 93.1±35.5 μm. In particular, polyurethane microspheres can be used as injectable fillers for cartilage treatment. DEX is known as a synthetic adrenal corticosteroid that has strong anti-inflammatory properties, and is often used not only for cartilage regeneration, but also for the treatment of rheumatoid arthritis (Refs. 13-14). Thus, DEX can be selected as a model drug.

5 shows the release profile of DEX from polyurethane microspheres. The initial burst release of DEX was observed in all polyurethane microspheres. It was expected that PU15 microspheres with a higher isocyanate ratio would have a more dense network structure and thus release DEX in a more sustained manner. However, DEX was released in a sustained manner from PU12 microspheres. In general, there are many factors that influence the release profile, such as molecular weight, crosslinking density, molecular interaction, functional groups, etc. (Ref. 15). In PU15, the rapid release of DEX in microspheres can be attributed to high molecular weight as well as high crosslinking structure. DEX molecules cannot be incorporated between the highly cross-linked structures of the PU15 chain even in solution prior to microsphere production.

In summary, biodegradable polyurethane microspheres with different isocyanate ratios have been successfully synthesized using PCL diol as polyol. Polyurethane microspheres with high diisocyanate ratio showed low average molecular weight, high melting point, high Young's modulus, low tensile strength, low elongation at break, low hydrolysis rate and fast DEX release profile. These results can be used to optimize properties to suit specific applications.

[references]

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[2] Dong S. Huh, Stuart L. Cooper, Polym. Eng. Sci., 11(5), 369 (1971).

[3] T.G. Grasel, D.C. Lee, A.Z. Okkema, T.J. Slowinski, S.L. Cooper, Biomaterials., 9(5), 383 (1988).

[4] L. Tatai, T.G. Moore, R. Adhikari, F. Malherbe, R. Jayasekara, I. Griffiths, P.A. Gunatillake, Biomaterials., 28(36), 5407 (2007).

[5] G.R. da Silva, A. da Silva-Cunha, F. Behar-Cohen, E. Ayres, R.L. Orιfice, Polym. Degrad. Stabil., 95(4), 491 (2010).

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[12] Shan-hui Hsu, Cheng-Wei Chen, Kun-Che Hung, Yi-Chun Tsai and Suming Li, Polymers-Basel., 8(7), 252 (2016).

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Claims (10)

Preparing a prepolymer by reacting a polyol compound and a diisocyanate compound; And
Comprising the step of preparing an emulsion by adding an oil phase containing the prepared prepolymer to an aqueous phase containing a water-soluble chain extender, and stirring the emulsion to prepare polyurethane microspheres,
The polyol compound includes at least one selected from the group consisting of polycaprolactone diol (PCL diol) and polycaprolactone triol (PCL triol),
The water-soluble chain extender is gelatin, a method for producing polyurethane microspheres.
The method of claim 1,
Diisocyanate compounds include 2,4- or 4,4'-methylene diphenyl diisocyanate (MDI), xylylene diisocyanate (XDI), m- or p-tetramethylxylylene diisocyanate (TMXDI), toluene diisocyanate ( TDI), di- or tetra-alkyldiphenylmethane diisocyanate, 3,3'-dimethyldiphenyl-4,4'-diisocyanate (TODI), 1,3-phenylene diisocyanate, 1,4-phenylene Diisocyanate, naphthalene diisocyanate (NDI), 4,4'-dibenzyldiisocyanate, hydrogenated MDI (H12MDI), 1-methyl-2,4-diisocyanatocyclohexane, 1,12-diisocyanatododecane, 1,6-diisocyanato-2,2,4-trimethylhexane,1,6-diisocyanato-2,4,4-trimethylhexane, isophorone diisocyanate (IPDI), tetramethoxybutane-1,4 -Selected from the group consisting of diisocyanate, butane-1,4-diisocyanate, hexane-1,6-diisocyanate (HDI), dicyclohexylmethane diisocyanate, cyclohexane-1,4-diisocyanate and ethylene diisocyanate A method for producing polyurethane microspheres comprising one or more.
The method of claim 1,
The method for producing polyurethane microspheres in which the molar ratio of the polyol compound and the diisocyanate compound is 1:2 to 1:5.
The method of claim 1,
The reaction of the polyol compound and the diisocyanate compound is carried out in the presence of a catalyst,
The catalyst is tin (II) acetate, tin (II) octoate, tin (II) ethylhexoate, tin (II) laurate, dibutyltin diacetate, dibutyltin dilaurate, dibutyltin maleate, and /Or dioctyltin diacetate, tris-(N,N-dimethylaminopropyl)-s-hexahydrotriazine, tetramethylammonium hydroxide, sodium hydroxide, sodium N-[(2-hydroxy-5 -Nonylphenyl)methyl]-N-methylaminoacetate, sodium acetate, sodium octoate, potassium acetate and potassium octoate. A method for producing polyurethane microspheres comprising at least one selected from the group consisting of.
The method of claim 1,
The oil phase additionally contains drugs,
The content of the drug is 10 parts by weight or less based on 100 parts by weight of the organic solvent, a method for producing polyurethane microspheres.
delete delete The method of claim 1,
Polyurethane microspheres average particle diameter of 1 to 500 μm method for producing polyurethane microspheres.
A biocompatible material comprising polyurethane microspheres manufactured by the method of manufacturing polyurethane microspheres according to claim 1.
The method of claim 9,
The biocompatible material is a biocompatible material selected from the group consisting of an arthritis treatment insert, a wrinkle treatment insert, a cosmetic filler, and a drug delivery system.

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