KR102031346B1 - Implantable composition with improved biocompatibility - Google Patents

Abstract

The present invention relates to a polymer represented by general formula 1: [-CH_2-CR_2(CONH_2)-]_x-[-CH_2-CR_1COO(CH_2)_nOH-]_y and a method for manufacturing the same.

Description

Implantable composition with improved biocompatibility

The present invention relates to a polymer for implants having improved biocompatibility, a composition comprising the same, and a method for preparing the same.

Patients who have undergone mastectomy due to breast cancer often suffer from loss and stress, and most patients undergo breast reconstruction with artificial implants and autologous fat insertion. However, side effects from incision surgery and breast reconstruction using implants are reported at a much higher frequency than other medical devices, of which 50.2% in Korea are side effects due to silicone implants. For implants used for conventional breast reconstruction, spherical contraction occurs due to excessive film formation around the implant after insertion, which is a typical side effect of transplant surgery. As a non-surgical breast reconstruction to overcome these side effects, fillers (injectable implant compositions) have been used as replacements for implants. In this case, it is possible to reduce spherical contraction phenomena that may be caused by various reasons such as infection caused by tissue dissection to insert a silicone implant, technique of an incision operator, foreign body reaction, and toxicity of the implant itself, and thus side effects.

Alternatives to implantable prostheses, polymethyl methacrylate and polyimide, which are injectable liquid silicones, have been proposed, but have a high potential for side effects (Aesth. Plast. Surg. 29: 34-48, 2005; Aesth. Plast. Surg. 27: 354-366, 2003). Alternatives are naturally derived products (eg, collagen or hyaluronic acid) that have fast absorption and short-term effects, but they have the disadvantage of high cost and easy degradation in the body and re-injection in a short period of time. In addition, conventionally known synthetic polymer fillers are clinically licensed for topical use only, so when used in large amounts, such as for breast reconstruction, they may be induced when applied in large amounts, such as unexpected cytotoxicity and immune responses. Stability issues cannot be ruled out. Thus, there is still a need in the medical industry for implantable injection compositions, with improved biocompatibility for use in large quantities.

Accordingly, an object of the present invention is to provide a polymer represented by the following general formula (1).

<Formula 1>

[-CH ₂ -CR ₂ (CONH ₂ )-] _x -[-CH ₂ -CR ₁ COO (CH ₂ ) _n OH—] _y .

Specifically, the present invention has an object to provide a copolymer by polymerizing a monomer represented by the following formula (1) and a monomer represented by the following formula (2) in order to provide an implant composition comprising the polymer, It is an object of the present invention to provide a method for producing a polymer comprising the step of crosslinking a polymer of the crosslinking agent represented by the following formula (3).

<Formula 1>

<Formula 2>

<Formula 3>

.

.

One aspect is to provide a polymer represented by the following general formula (1):

<Formula 1>

[-CH ₂ -CR ₂ (CONH ₂ )-] _x -[-CH ₂ -CR ₁ COO (CH ₂ ) _n OH-] _y

In Formula 1, R ₁ and R ₂ are each independently hydrogen or alkyl of C _1-3 ; n is an integer from 1 to 6; And x and y may each independently be an integer from 1 to 100.

In one embodiment, the polymer is a monomer represented by the following formula (1); A monomer represented by Formula 2 below; And a polymerization of a crosslinking agent represented by Formula 3 below:

<Formula 1>

<Formula 2>

<Formula 3>

.

.

In Formulas 1 to 3, R ₁ , R ₂ , R ₃ , and R ₄ are each independently hydrogen or alkyl of C _1-3 ; And n and m may each independently be an integer from 1 to 6.

In one embodiment, the polymer may be formed of a repeating unit represented by the following formula (2).

<Formula 2>

[[-CH ₂ -CR ₂ (CONH ₂ )-] _x -[-CH ₂ -CR ₁ COO (CH ₂ ) _n OH-] _y -[-CH ₂ -CR ₁ COO-] _z ] _p

In Formula 2, R ₁ and R ₂ are each independently hydrogen or alkyl of C _1-3 ; n is an integer from 1 to 6; And z or p may be an integer from 1 to 100. In the formula [-CH ₂ -CR ₁ COO-] _z , the ester group may form a crosslinked structure through an ether bond with an ester group of a neighboring polymer. The ether bond may comprise C _1-6 alkylene. That is, the ether bond formed by the ester group is represented by the formula [-COO- (CH ₂ ) _m -OOC-], and m may be an integer of 1 to 6.

The polymers according to one aspect of the present invention may be used to replace implant implants in a non-invasive manner, by injection. The polymer is easy to control the physical properties, and despite the use of a large capacity can be maintained in the form. In addition, tissue foreign body reaction can be minimized, so biocompatibility is higher than conventional implantable implants and injectable implant compositions.

1 shows a bonding structure of a polymer according to an embodiment of the present invention.
FIG. 2 is a Fourier Transform Infrared Spectroscopy (FTIR) -attenuated total reflection (ATR) (ie IR-ATR) graph of the polymer of Example 1 (transmittance; transmittance, wavenumbers; wavenumber).
Figure 3A is a graph showing the mechanical strength of the hydrogel of Example 1 as a function of each modulus, Figure 3B is a graph showing the mechanical strength of the hydrogel of Example 1 as a composite variable of dynamic modulus, Figure 3C A graph showing the mechanical strength of a filler as a function of each modulus, and FIG. 3D is a graph showing the mechanical strength of a conventional filler as a composite variable of dynamic modulus.
4A is a graph showing the mechanical strength of skin-free adipose tissue (N) as a function of each modulus, FIG. 4B is a graph showing the mechanical strength of skin-free adipose tissue as a composite variable of dynamic modulus, and FIG. 4C is A graph showing the mechanical strength of skinned adipose tissue as a function of each modulus, and FIG. 4D is a graph showing the mechanical strength of skinned adipose tissue as a composite variable of dynamic modulus.
5A and 5B are graphs of cytotoxicity of the hydrogels of the hydrogels of Example 1 at 3 and 5 days after the hydrogel treatment diluted according to the ratio, respectively, and FIGS. 5C and 5D are Examples The cytotoxicity of the hydrogels of human 1 against human fibroblasts is shown on the 3rd and 5th day after the hydrogel treatment diluted according to the ratio, respectively.
6A and 6B are graphs in which the hydrogel of Example 1 measured cytotoxicity against human fibroblasts at 3 and 5 days after hydrogel treatment, respectively, according to each ratio, and FIGS. The graph shows the cytotoxicity against human fibroblasts measured at 3 and 5 days after control treatment diluted according to each ratio.
7A and 7B are images observed on days 3 and 5 of the effects of the hydrogel of Example 1 on fat stem cells, and FIGS. 7C and 7D are the effects of the hydrogel of Example 1 on human fibroblasts. Images observed on days 3 and 5, respectively.

DETAILED DESCRIPTION Hereinafter, exemplary embodiments of the present disclosure will be described in detail with reference to the accompanying drawings so that those skilled in the art may easily implement the present disclosure. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention. In the drawings, parts irrelevant to the description are omitted in order to clearly describe the present application.

As used throughout this specification, the terms “about”, “substantially”, and the like, are used at, or in close proximity to, numerical values when manufacturing and material tolerances inherent in the stated meanings are set forth, and the understandings herein Accurate or absolute figures are used to assist in the prevention of unfair use by unscrupulous infringers. As used throughout this specification, the term “step of” or “step of” does not mean “step for”.

Throughout this specification, the description of “A and / or B” means “A or B, or A and B”.

One aspect provides a polymer represented by the following general formula (1).

<Formula 1>

[-CH ₂ -CR ₂ (CONH ₂ )-] _x -[-CH ₂ -CR ₁ COO (CH ₂ ) _n OH-] _y

In Formula 1, R ₁ and R ₂ are each independently hydrogen or alkyl of C _1-3 ; n is an integer from 1 to 6; And x and y may each independently be an integer from 1 to 100. As defined by the structure of Formula 1, the structure of the polymer of the present invention includes a linear copolymer structure represented by Formula 1.

In one embodiment, the linear copolymer of Formula 1 may be at least partially crosslinked with each other by a crosslinking agent. Specifically, the crosslinked structure of the linear copolymer may mean an ether bond that the ester group of Formula 1 forms with the ester group of the adjacent linear copolymer.

In one embodiment, the crosslinked polymer is a monomer represented by the following formula (1); A monomer represented by Formula 2 below; And a polymerization of a crosslinking agent represented by Formula 3 below:

<Formula 1>

<Formula 2>

<Formula 3>

.

.

In Formulas 1 to 3, R ₁ , R ₂ , R ₃ , and R ₄ are each independently hydrogen or alkyl of C _1-3 ; And n and m may each independently be an integer from 1 to 6.

The polymer consists of one or more chains formed by the repetitive bonding of monomers as defined above. The monomers may further require a polymerization initiator to form a polymer. Tetramethylethylenediamine (TEMED), dimethylaminopropionitrile (DMAPN), ammonium persulfate (APS), 6,7-dimethyl-9- (D-1-ribityl) -isoaloxazine (riboflavin), sodium metabisulfite (SMBS), sodium persulfate, sodium bisulfite, potassium persulfate Etc. may be used but is not limited thereto.

The monomer represented by Formula 1 and the monomer represented by Formula 2 may be polymerized to form a linear copolymer. The polymerized linear copolymer may be a polymer represented by Formula 1.

The term 'alkyl' means a straight-chain or branched hydrocarbon moiety which may be substituted or unsubstituted, unless stated otherwise. The alkyl group may include, without limitation, a methyl group, an ethyl group, or a propyl group, and all possible isomers thereof.

In one embodiment, the polymer may be formed of repeating units represented by the following general formula 2:

<Formula 2>

[[-CH ₂ -CR ₂ (CONH ₂ )-] _x -[-CH ₂ -CR ₁ COO (CH ₂ ) _n OH-] _y -[-CH ₂ -CR ₁ COO-] _z ] _p

In Formula 2, z and p may be an integer of 1 to 100.

The polymer formed from the repeating unit can also be crosslinked and linked with neighboring polymers by ether bonds, an example of one such polymer structure being disclosed in FIG. 1.

In one embodiment, the polymer may be formed by a polymerization reaction of 2-hydroxyethylmethacrylate (HEMA) and acrylamide (Am). The 2-hydroxyethyl methacrylate and acrylamide may be in a molar ratio of about 1:10 to 1: 1, and preferably in a molar ratio of about 1: 7. In one embodiment, the crosslinking agent may be ethylene glycol dimethacrylate (EGDMA). The ethylene glycol dimethacrylate may be a molar ratio of about 1: 0.01 to 1: 0.5 on the basis of 2-hydroxyethyl methacrylate, and preferably may be a molar ratio of about 1: 0.05.

The polymer of the present invention may specifically be represented by the following general formula 3:

<Formula 3>

As can be seen from the general formulas 1 to 3, since the polymer of the present invention includes an amide group, the amide group included in one polymer may form hydrogen bonds with the amide groups of neighboring polymers. Thus, the polymers of the present invention may include one or more of the ether bonds by ester groups with neighboring polymers and / or hydrogen bond structures by amide groups.

In one embodiment, the copolymer may be hydrophilic. Thus, the polymer may be to form a hydrogel.

By the intrinsic intermolecular interactions that the linear copolymers form with each other, the polymer of the present invention may form a three-dimensional structure. Injectable implant compositions known in the art do not have sufficient binding force to form a three-dimensional structure, or are often difficult to mold or unsuitable for injection due to excessive crosslinking. However, the polymer of the present invention has both an ether bond by a crosslinking agent and a hydrogen bond by an amide group of the linear copolymer to form a sufficient three-dimensional structure to replace the implantable implant, while being water-soluble and injectable for injection. It has physical properties.

In addition, as the crosslinking agent of the polymer, a crosslinking agent of bis-methylene series (for example, N, N'-methylenebisacrylamide) is commonly used. These crosslinkers form secondary amine structures in the polymer in the course of crosslinking the polymer. However, secondary amine structures have been reported to cause cytotoxicity (Cancer research 31, 1201-1205, September 1971). Thus, the injectable implant compositions for topical use on the conventional injection (e.g., aqua-filling ^® and ahkuahyi mid ^{®; Arch Aesthetic Past Surg2015; 21} (3):... 124-126, Plast Reconstr Surg 118 (Suppl .): 85S, 2006), although these secondary amine structures have proven safe for use in vivo, are likely to cause unexpected cytotoxicity when applied to high-dose procedures such as breast reconstruction. . However, the polymer of the present invention includes only the hydrogen bond between the ether bond and the amino group by crosslinking using the crosslinking agent of Formula 3 and the specificity of the linear copolymer of the monomers of Formulas 1 and 2, There is no need to worry about cytotoxicity due to the structure, and the biocompatibility is high.

Another aspect is a monomer of Formula 1; Monomer of Formula 2; And it provides an implant composition comprising a polymer obtained from the polymerization of the crosslinking agent of the formula (3).

The term "implant" refers to a procedure for insertion into a living body, and may include both insertion by tissue incision and injection into a topical site. The composition may further comprise water, physiological saline, glucose solution, plasma, and various other biocompatible buffers so as to swell to impart proper physical properties to the polymer of the present invention. In view of the possible impact on the living body after being injected into the living body, the composition may optionally further comprise a drug.

The composition may further comprise a pharmaceutically acceptable carrier suitable for application to a living body. The 'pharmaceutically acceptable salt' is a salt that is relatively nontoxic to the patient and has a harmless effective action, in which the side effects caused by the salt do not detract from the beneficial effects of the polymer of the invention, for example as a mineral acid. Hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, and the like can be used. Luxuronic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid, alkali metal salts ( Sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.), and acid addition salts as acetates, aspartates, benzates, besylate, bicarbonates / carbonates, bisulfates / sulphates Hydrates, borates, chamlates, citrates, edsylates, ecylates, formates, fumarates, gluceptates, gluconates, glucuronates, hexafluorophosphates, hybenates, hydrochlorides / chlorides, Hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, maleate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate , Orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharide, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzatin, calcium , Choline, Diethylamine, Diolamine, Glycine, Lysine, Magnesium, Meglumine, Olamine, Potassium, Nat , Tromethamine, but are not limited to zinc and the like salts.

In one embodiment, the implant composition may be an injection. Since the polymer of the present invention has water solubility and physical properties suitable for injection into a living body as an injection, there is an advantage that a non-invasive procedure is possible because it does not require an incision for implant insertion. The injectable implant composition includes a composition for filler.

In one embodiment, the implant composition may be for implantation into tissue, anatomical internal space, body cavities, ducts, and vessels. More specifically, the implant composition may be for breast reconstruction.

Another aspect is to obtain a copolymer by polymerizing a monomer represented by the formula (1) and a monomer represented by the following formula (2):

<Formula 1>

<Formula 2>

; 및

; And

It provides a polymer manufacturing method comprising the step of crosslinking the copolymer with a crosslinking agent represented by the following formula (3).

<Formula 3>

In Formulas 1 to 3, R ₁ , R ₂ , R ₃ , and R ₄ are each independently hydrogen or alkyl of C _1-3 ; And n and m may each independently be an integer from 1 to 6.

Obtaining a copolymer from the monomer of Formula 1 and the monomer of Formula 2 may further require a polymerization initiator to form the copolymer. The polymerization initiator is as mentioned above.

The following examples illustrate in more detail the properties and effects of the polymers of the present invention and methods for their preparation. The following examples are only intended to illustrate the invention, whereby the scope of the invention is not limited.

One. Example  One: HEMA Synthesis of -Am Copolymers and Hydrogels thereof

Copolymers of 2-hydroxyethylmethacrylate (HEMA) and acrylamide (Am) and hydrogels thereof were synthesized as disclosed in FIG.

Specifically, all reactants were purchased from Aldrich (St. Louis, Mo.) unless otherwise noted. Using a Millipore Milli-Q Uitrapure Water Purification System (Bedford, Mass.), The solvent was distilled and deionized at a resistance of 18.2M. All reactions were performed at room temperature (RT). HEMA (99%) was passed through a 10 ml syringe packed with cotton swabs, aluminum oxide (Samchun chem) and sand (junsei) before use. Aqueous solutions of ammonium persulfate (APS) and tetramethylethylenediamine (TEMED) were used together as redox initiators. Ethyleneglycol dimethacrylate (EGDMA) was used for hydrogel polymerization as a cross-linking agent.

The monomer 0.24 ml (0.002 mol) HEMA, 1.0 g (0.014 mol) Am and 0.038 ml (0.0001 mol) crosslinker EGDMA were dissolved in 10 ml water by stirring under nitrogen gas for 1 hour. The solution was clear and uniform upon visual observation. To the solution was added 100 mg (0.000438 mol) of APS and TEMED, reacted with stirring under nitrogen gas for 1 hour at room temperature, gelled with hydrogel and dried under vacuum at 25 ° C. for 24 hours. The dried sample was expanded in water and dialyzed using a membrane (MW: 5000, Cellu-Sep T2) to remove unreacted reagents and monomers.

Structural characteristics of the resulting copolymers were analyzed by IR-ATR. FTIR spectra (Spectrum GX, Perkin-Elmer, USA) were acquired at 0.15 resolution in the range of 4000-400 wavenumber for 6 scans. The obtained FTIR spectra were then leveled and the major vibration bands associated with the functional groups of the polymer.

As a result, it can be seen that the polymer produced in Example 1 does not include a secondary amine structure as can be seen in FIG. 2 and Table 1 below.

Combined form IR bands (cm-1) Primary amines (CONH ₂ ) 3346.71, 3194.65 Amide C = O Stretch Peak 1660.68 Amide N-H Bond Peak 1450.72 Secondary Amine Stretch Peaks -

2. Example  2: HEMA Of mechanical strength of -Am copolymer

The mechanical strength was measured to confirm that the HEMA-Am copolymer prepared in Example 1 is suitable for use as the main component of an injectable implant composition (eg filler).

Specifically, rheological measurements were performed. Dynamic shear oscillation measurement at 10% strain was used to evaluate the viscoelastic (physical) properties of the crosslinked EGDMA hydrogel of Example 1. As a control for the evaluation of the mechanical strength, which was used for aqua-filling ^® KR Laid-Open Publication No. 10-2013-0057925), which are used clinically. Rheological measurements of vibratory shear compressions were performed with a DHR3 rheometer (TA instruments) using a 20 mm parallel plate steel and a plate-plate distance of 2 mm. The mechanical spectrum is recorded in constant compression mode while maintaining 0.1 compression in the frequency range of 0.001-1000 Hz (rad / s) at 25 ° C. The shear compression rate dependence of the storage (elastic) modulus was determined by vibratory shear compression (dynamic rheological observations) with a shear compression scan in the range of 0.01-100 (%) at constant frequency (6.3 Hz). Hydrogels were inflated in water and analyzed using a frequency sweep of 0.01 to 100 Hz. The function of storage modulus is called G 'and the function of loss modulus is G "(Figures 3A, 3C, 4A and 4C). If the missing modulus is lower than the storage modulus, it means that the sample has gel-like properties. To express this more clearly, we can use a dynamic variable of complex modulus (G *), where [G * = G '+ iG''] (i is an imaginary unit (An introduction to rheology.Elsevier: 1989; Vol. 3). 3B, 3D, 4B and 4D). In the figure, “tan” means material damping and was calculated as [Tan σ = G ″ / G ′].

For materials that need to maintain structure, mechanical strength can be an important factor. In order to use the hydrogel as an injectable use, the properties of the hydrogel that change with contact with water may be very important. The inventors have confirmed that in order to determine as having a sufficient mechanical strength as a hydrogel tissue reconstruction material of the present invention, compared to the aqua-filling ^® to be used in clinical surgically, having a similar movement modulus (Fig. 3 and 4 ). The dynamic modulus of adipose tissue was about 1 kPa at 0.01% compression (International Journal of Solids and Structures 2010, 47 (21), 2982-2990), while the dynamic modulus of hydrogels had a value of less than 1 kPa. In the case of the crosslinked hydrogel of Example 1 exhibited a storage modulus of about 30 ~ 40pa, aquafilling ^® 40 ~ 50pa it was confirmed that it has injectable properties. Thus, it can be seen that the hydrogel of Example 1 also has the physical properties of the injectable form as used in conventional fillers. Compared with adipose tissue, adipose tissue without skin tissue (ie, fat tissue without dermis) and adipose tissue with skin tissue exhibit a storage modulus of about 1 kpa. However, since the hydrogel of Example 1 has the purpose of injectable form, it is appropriate to exhibit physical properties similar to those of the conventional filler, which can be obtained by adjusting the synthesis ratio of the material.

3. Example  3: HEMA Confirmation of Biocompatibility of -Am Copolymer

In order to confirm that the HEMA-Am copolymer prepared in Example 1 has excellent biocompatibility compared to the existing product, adadiose derived stem cells (ADSC) and human fibroblasts (hFB) Cytotoxicity was assessed for.

, France)에 유지하였고, 인간의 복부지방조직으로부터 유래한 지방유래줄기세포 및 인간의 피부로부터 유래한 인간 섬유아세포를 각각 37 ℃에서 24 시간 동안 배양함으로써 세포 생존률을 평가하였다. 세포는 24 웰 플레이트에 분주하여 37 ℃에서 밤새 배양하였다. DMEM 배양액 1ml을 희석된 방출 용액 (releasing solution)과 함께 세포에 처리하고, 24 시간, 72 시간 (3일) 및 120 시간 (약 5일) 동안 배양하였다. Ez-cytox (Dogen Bio Inc., Seoul, Korea)를 4 시간 동안 적용하여 반응시키고, 450 nm (Spectramax plus 384; MolecularDevices, Sunnyvale,CA, USA)에서 흡광도를 측정하는 방식으로 세포 독성을 평가하였다. 통계적 차이는 Tukey's test를 사용하여 결정되었다. p <0.05의 값은 통계적으로 유의한 것으로 간주되고, 데이터를 표준 편차와 함께 각 조건에 대한 값의 평균으로 나타냈다.Specifically, 0.2 g / mL Example A hydrogel filler and a control group of 1 different dilution degree of the conventional filler in aqua peeling ^®, based on the culture medium (1: 1, 1: 3, 1: 5, 1: 10, 1 : 20, 1:50 and 1: 100). Cells were cultured in DMEM (biowest, Nuaill

, France), and cell viability was evaluated by culturing adipose derived stem cells derived from human abdominal adipose tissue and human fibroblasts derived from human skin for 24 hours at 37 ° C. Cells were aliquoted into 24 well plates and incubated overnight at 37 ° C. 1 ml of DMEM culture was treated with the cells with diluted releasing solution and incubated for 24 hours, 72 hours (3 days) and 120 hours (about 5 days). Ez-cytox (Dogen Bio Inc., Seoul, Korea) was applied for 4 hours to react, and cytotoxicity was evaluated by measuring absorbance at 450 nm (Spectramax plus 384; Molecular Devices, Sunnyvale, CA, USA). Statistical differences were determined using Tukey's test. Values of p <0.05 are considered statistically significant and data are presented as the mean of the values for each condition with standard deviations.

In addition, fluorescence images were obtained using confocal microscopy (CLSM, LSM 710, Carl Zeiss) with respect to cell survival. Cell viability was determined by using image J to divide into survival (green) and death (red), counting them respectively. Specifically, the hydrogel of Example 1 was treated to human adipose derived stem cells and fibroblasts at a dilution ratio as shown in FIG. 7 and incubated for 3 days and 5 days.

As a result, FIGS. 5A to 5D show the cell viability of the hydrogel of Example 1. FIG. The hydrogel of Example 1 did not show a significant difference in cell viability with time, and thus it was confirmed that the hydrogel did not exhibit toxicity within the concentration range used for cytotoxicity. However, on the 5th day of the high concentration condition, the survival rate was about 70%. This result was not interpreted as a decrease in viability due to the toxicity of the material, but the viscosity was increased in the high concentration solution. The eluate may be present in a layered form, which appears to be an in vitro phenomenon caused by oxygen permeability or by blocking the supply of nutrients.

6A to 6D show the cell viability of the hydrogel of Example 1 compared with the conventional filler. The treatment of the hydrogel of Example 1 showed little reduction in survival rate on both day 3 and day 5 (FIGS. 6A and 6B), but the existing fillers were observed to tend to significantly reduce survival (FIG. 6C and 6D). Therefore, the hydrogel of the present invention can be seen that the cytotoxicity is significantly lower than the conventional filler product.

In addition, as observed in FIG. 7, no significant difference in dilution magnification was found in the results of adipose derived stem cells and fibroblasts evaluated for 3 days and 5 days. Moreover, dead cells (red) are rarely observed, indicating that biocompatibility is better.

Therefore, it can be seen that the polymer of the present invention is significantly less likely to cause unexpected cytotoxicity even when injected in large amounts.

Claims (12)

delete delete A monomer represented by Formula 1 below;
A monomer represented by Formula 2 below; And
Obtained from polymerization of a crosslinking agent of the formula
Implant composition comprising a polymer represented by the following formula 1 and a molar ratio of the monomer represented by the formula (2) is 1: 1 to 1:10:
<Formula 1>

<Formula 2>

<Formula 3>

In Chemical Formulas 1 to 3,
R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen or alkyl of C _1-3 ; And
n and m are each independently an integer of 1-6. delete delete delete The composition of claim 3, wherein the polymer is formed by the polymerization of 2-hydroxyethylmethacrylate and acrylamide. The composition of claim 3, wherein the polymer is hydrophilic. delete The composition of claim 3, which is an injection. The composition of claim 3 for implantation into tissue, anatomical internal space, body cavities, ducts, and vessels. delete

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