CN114907558B

CN114907558B - Low-swelling injectable hydrogel and preparation method and application thereof

Info

Publication number: CN114907558B
Application number: CN202110178402.0A
Authority: CN
Inventors: 张依晴; 孙宇
Original assignee: Shanghai Lingjiu Medical Technology Co ltd
Current assignee: Shanghai Lingjiu Medical Technology Co ltd
Priority date: 2021-02-09
Filing date: 2021-02-09
Publication date: 2024-05-07
Anticipated expiration: 2041-02-09
Also published as: CN114907558A

Abstract

The invention relates to a low-swelling injectable hydrogel, and a preparation method and application thereof. The low-swelling injectable hydrogel is prepared by mixing a component A, a component B and a solvent; the component A is a polymer derivative modified by o-phthalaldehyde molecules; the component B is water-soluble micromolecule, water-soluble natural polymer or water-soluble synthetic polymer containing one or more groups of primary amine, diamine, hydrazide and hydroxylamine, and the number of the contained groups is not less than 2. Compared with the prior art, the hydrophobic property of the prepared hydrogel is regulated and controlled through the hydrophobic modification of the polyethylene glycol skeleton in the component A, so that the preparation of the injectable hydrogel with low swelling rate (less than 30%) is realized, and the potential safety hazard caused by high swelling rate in the clinical application process of the current double-component hydrogel material is overcome. Moreover, the hydrogel provided by the invention has the advantages of simple preparation method, mild preparation conditions, controllable preparation time and very good application prospect in the biomedical field.

Description

Low-swelling injectable hydrogel and preparation method and application thereof

Technical Field

The invention belongs to the technical field of new medical materials, and particularly relates to a low-swelling injectable hydrogel and a preparation method and application thereof.

Background

The hydrogel is a high-moisture polymer material with a three-dimensional cross-linked network structure, and is widely applied to the fields of regenerative medicine and tissue engineering due to the excellent biocompatibility and the characteristic of being capable of fitting biological tissue microenvironment. The double-component hydrogel refers to a hydrogel cured by mixing two gel precursors with reactivity and then crosslinking, and in clinical application, the hydrogel can be cured in situ, has excellent tissue shaping property and has wide clinical application prospect. Among them, polyethylene glycol polymer is the most main raw material for preparing double-component hydrogel because of its excellent biocompatibility and easy chemical modification and functionalization. However, because the polyethylene glycol skeleton has extremely strong hydrophilicity, the swelling rate of the hydrogel is generally high, the mechanical property of the hydrogel is greatly reduced due to the high swelling property, surrounding tissues are pressed by volume expansion, and the gel has the risk of falling off, so that potential safety hazards exist in clinical application of the hydrogel. For example, polyethylene glycol-based sealants typified by DuraSeal and CoSeal, are commonly used in neurosurgery to prevent leakage of cerebrospinal fluid after dural suturing, and cause adverse events that may lead to paralysis of the extremities due to volume swelling of the hydrogel after absorption of body fluid to press the nerve (D Thavarajah, pde copy, R Hussain, RM REDFERN, spine.2010,35, 25-26.). Therefore, it is of great importance to develop a polyethylene glycol-based two-component hydrogel with a lower swelling rate (< 30%). Chinese patents CN202010454896.6 and CN202010455951.3 disclose a method for preparing hydrogel based on crosslinking of polyethylene glycol derivative modified by o-phthalaldehyde, which has advantages of simplicity, rapidness and mild condition, however, the hydrogel prepared based on the method still has the defect of high swelling rate, and still faces potential safety risk in practical application.

Disclosure of Invention

Aiming at the current situation that the swelling rate of the current double-component hydrogel is high, the invention provides a low-swelling injectable hydrogel and a preparation method and application thereof.

According to the invention, the hydrophilicity of the polyethylene glycol-based hydrogel is reduced by modifying the hydrophobicity of the polyethylene glycol polymer skeleton, and the polyethylene glycol-based hydrogel provided by the invention has the advantages of low swelling rate (less than 30%), simple preparation method, mild preparation conditions and controllable preparation time.

The aim of the invention can be achieved by the following technical scheme:

in a first aspect of the present invention, there is provided a polymer derivative modified with a phthalaldehyde molecule, comprising two parts: the polymer part P and the dialdehyde molecule part have the structure of formula 1:

In the formula 1, P is a two-arm or multi-arm polyethylene glycol derivative containing a hydrophobic structure modification, wherein the hydrophobic structure refers to a structural unit which is insoluble in water or poor in water solubility and is selected from a carbon chain, polypropylene glycol or polytetrahydrofuran;

r ₁、R₂、R₃、R₄ is independently selected from a hydrogen atom, a halogen atom, an amine group, an imine group, a hydroxyl group, a mercapto group, a nitro group, a cyano group, an aldehyde group, a ketone group, a carboxyl group, a sulfonic group, an alkyl group, an alkylene group, a modified alkyl group or a modified alkylene group, wherein the modified alkyl group is an alkyl group containing a double bond, a triple bond, an ether bond, a thioether bond, an imine bond, a ketone bond, an amide bond or a urea bond on a molecular chain, and the modified alkylene group is an alkylene group containing a double bond, a triple bond, an ether bond, a thioether bond, an imine bond, a ketone bond, an amide bond, a carbamate bond or a urea bond on a molecular chain;

P is connected with one or more groups in R ₁、R₂、R₃、R₄ through ether bond, thioether bond, amide bond, carbamate bond, urea bond, alkane chain or modified alkane chain; the modified alkane chain refers to an alkane chain containing double bonds, triple bonds, ether bonds, thioether bonds, imine bonds, ketone bonds, amide bonds, carbamate bonds or urea bonds on a molecular chain;

n≥2。

In one embodiment of the present invention, formula 1 is further preferably a structure represented by formula 2 below:

In the formula 2, the components are mixed,

P is a two-arm or multi-arm polyethylene glycol derivative modified by a hydrophobic structure, wherein the hydrophobic structure refers to a structural unit insoluble in water or poorly water-soluble, and the two-arm or multi-arm polyethylene glycol derivative comprises: carbon chains, polypropylene glycols or polytetrahydrofuran;

R ₅、R₆ is independently selected from a hydrogen atom, a halogen atom, an amine group, an imine group, a hydroxyl group, a mercapto group, a nitro group, a cyano group, an aldehyde group, a ketone group, a carboxyl group, a sulfonic group, an alkyl group, an alkylene group, a modified alkyl group or a modified alkylene group, wherein the modified alkyl group is an alkyl group containing a double bond, a triple bond, an ether bond, a thioether bond, an imine bond, a ketone bond, an amide bond or a urea bond on a molecular chain, and the modified alkylene group is an alkylene group containing a double bond, a triple bond, an ether bond, a thioether bond, an imine bond, a ketone bond, an amide bond, a carbamate bond or a urea bond on a molecular chain;

P is connected with one or two of R ₅ or R ₆ through an amide bond, an ether bond, a thioether bond, a carbamate bond, a urea bond, an alkane chain or a modified alkane chain; the modified alkane chain refers to an alkane chain containing double bonds, triple bonds, ether bonds, thioether bonds, imine bonds, ketone bonds, amide bonds, carbamate bonds or urea bonds on a molecular chain;

n≥2。

In one embodiment of the invention, the P is selected from carbon chain modified polyethylene glycol, a copolymer of polytetrahydrofuran and polyethylene glycol or a copolymer of polypropylene glycol and polyethylene glycol.

When P is selected from carbochain modified polyethylene glycol, the formula 2 is selected from the following components A-1 to A-4:

when P is selected from the group consisting of polytetrahydrofuran and polyethylene glycol copolymers, formula 2 is selected from the group consisting of the following components A-5 to A-6:

when P is selected from a copolymer of polypropylene glycol and polyethylene glycol, formula 2 is selected from the following components A-7 to A-8:

In the structure, m, h and k are the repeated unit numbers, m is more than or equal to 2 and less than or equal to 1000,2, h is more than or equal to 1000,2 and k is more than or equal to 30;

n is the branching degree of the multi-arm macromolecule, and n is selected from 2, 3, 4, 5, 6 or 8;

when n=2, R is a two-arm branching center selected from one of the following structures:

When n=3, R is a three-arm branching center selected from one of the following structures:

When n=4, R is a four-arm branching center selected from one of the following structures:

When n=5, R is a five-arm branching center selected from one of the following structures:

when n=6, R is a six-arm branching center selected from one of the following structures:

when n=8, R is an eight-arm branching center selected from one of the following structures:

in a second aspect of the present invention, there is provided a low swelling injectable hydrogel prepared by mixing component A, component B and a solvent;

the component A is a macromolecule derivative modified by the o-phthalaldehyde molecules;

the component B is a water-soluble small molecule, a water-soluble natural polymer or a water-soluble synthetic polymer containing one or more groups of primary amine, diamine, hydrazide and hydroxylamine, and the number of the groups containing one or more groups of primary amine, diamine, hydrazide and hydroxylamine is not less than 2.

In one embodiment of the present invention, the component B is selected from polyamino amino acid compounds such as polylysine, amino terminated two or more arm polyethylene glycol, lysine modified hyaluronic acid, hydrazide modified hyaluronic acid or chitosan.

In one embodiment of the invention, the solvent is selected from the group consisting of water, physiological saline, buffer solution, acellular matrix, or cell culture media solution.

In a third aspect of the invention, there is provided a method of preparing the low swelling injectable hydrogel: and respectively dissolving the component A and the component B in a solvent to obtain a component A solution and a component B solution, and mixing the solution A and the solution B to obtain the low-swelling injectable hydrogel.

In one embodiment of the invention, the solids content of component A in the component A solution is from 0.5 to 20% by weight and the solids content of component B in the component B solution is from 0.1 to 20% by weight.

In one embodiment of the invention, the hydrogel is prepared at a temperature of 0-80 ℃; the pH is 3-12.

In a fourth aspect of the invention there is provided the use of said low swelling injectable hydrogel selected from the following applications:

the use of said low swelling injectable hydrogel as a material for the preparation of a dural trauma repair;

the use of said low swelling injectable hydrogel as a material for preparing a dural wound repair;

The application of the low-swelling injectable hydrogel in preparing a vascular plugging material;

The use of the low-swelling injectable hydrogel as a preparation of a renal hemostatic material;

The application of the low-swelling injectable hydrogel in preparing a pulmonary plugging material;

the use of said low swelling injectable hydrogel for the preparation of pericardial anti-adhesion materials.

Compared with the prior art, the invention provides the low-swelling injectable hydrogel, which is prepared by mixing the component A, the component B and the solvent; the hydrophobic property of the prepared hydrogel is regulated and controlled through the hydrophobic modification of the polyethylene glycol skeleton in the component A, so that the preparation of the injectable hydrogel with low swelling rate (less than 30%) is realized, and the potential safety hazard caused by high swelling rate in the clinical application process of the current double-component hydrogel material is overcome. Moreover, the hydrogel provided by the invention has the advantages of simple preparation method, mild preparation conditions, controllable preparation time and very good application prospect in the biomedical field.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a polypropylene glycol-polyethylene glycol copolymer in example eight.

FIG. 2 is a comparison of swelling ratios of hydrogels prepared in example eleven.

Fig. 3 shows the results of the hydrogel prepared in example fourteen applied to the test group (left) and the control group (right) for vascular occlusion.

Fig. 4 shows the results of the hydrogels prepared in example fifteen applied to the experimental (left) and control (right) groups of renal hemostasis.

Detailed Description

The invention will now be described in detail with reference to the drawings and specific examples.

Embodiment one: synthesis of representative Compounds of component A-1 component A-1.1 (m=230, k=10, n=4)

(1) Synthesis of Compound 1: synthetic procedure reference Chun Ling Tung, clarence T.T.Wong, eva Yi Man Fung, xuechen Li, org.Lett.2016,18,11,2600-2603. Methods disclosed .¹H NMR(400MHz,CDCl₃):δ＝7.30(m,2H),7.23(s,1H),6.29(s,1H),6.03(s,1H),3.66(s,3H),3.43(m,6H),3.00(t,J＝7.7,2H),2.63(t,J＝7.7,2H).

(2) Synthesis of Compound 2: compound 1 (1.0 g) and decamethylene diamine (4.36 g) were dissolved in 5ml of methanol, and stirred at room temperature for 2 hours. After the completion of the reaction, most of the solvent was removed, the residual compound was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation, and the obtained crude product was purified by silica gel chromatography to give compound 2 (1.04 g, yield 80％).¹H NMR(400MHz,CDCl₃):δ＝7.30(m,2H),7.22(s,1H),6.29(s,1H),6.04(s,1H),3.60(m,4H),3.44(m,6H),3.01(t,J＝7.6,2H),2.69(m,4H),2.50(m,4H),1.52(m,2H),1.30(m,6H).

(3) Synthesis of component A-1.1: 4-arm polyethylene glycol (2 g) was dissolved in anhydrous CH ₂Cl₂ (100 mL), 4-dimethylaminopyridine (DAMP; 0.005 g) and triethylamine (0.101 g) were added, and the above mixed solution was added dropwise to a solution of phenyl 4-nitrochloroformate (0.1 g) in anhydrous CH ₂Cl₂ (3 mL), and stirred at room temperature for 12 hours. After the completion of the reaction, the solvent was removed under reduced pressure, the mixture was redissolved with deionized water, small molecular impurities were removed by dialysis and lyophilized, the resulting product was dissolved with anhydrous CH ₂Cl₂, 10% trifluoroacetic acid was added, stirring was carried out at room temperature for 12 hours, trifluoroacetic acid was removed by rotary evaporation, dissolved with a small amount of CH ₂Cl₂, and poured into Et ₂ O to give a pale yellow solid component A-1.1 (1.8 g), yield 90%. The product is identified by ¹ H NMR spectrum, the peaks at 7.2 and 7.3ppm are the peaks of hydrogen atoms on benzene ring, and 3.4-3.6 o-phthalaldehyde molecules are connected to each polyethylene glycol molecule through the integral ratio of the peak of hydrogen atoms on polyethylene glycol skeleton .¹H NMR(400MHz,D₂O):δ＝10.58(s,4H),10.52(s,4H),7.80(m,8H),7.72(s,4H),3.70(m,3636H),3.60(m,16H),3.01(t,J＝7.6,8H),2.69(m,14H),2.50(m,16H),1.52(m,8H),1.30(m,24H).

Embodiment two: synthesis of representative Compound component A-2.1 of component A-2 (m=230, k=10, n=4)

(1) Synthesis of Compound 3: synthetic procedures are described in Schmidt P, zhou L, tishinov K, et al, ANGEWANDTE CHEMIE International Edition,2014,53,10928-10931 .¹H NMR(400MHz,D₆-DMSO):δ＝8.05(d,J＝7.6Hz,1H),7.93(s,1H),7.81(brs,1H),7.55(d,J＝7.6Hz,1H),6.36(s,1H),6.11(s,1H),3.66(s,3H),3.37-3.32(m,6H).

(2) Synthesis of Compound 4: compound 3 (1 g) was dissolved in anhydrous DMF and bromoethanol (0.87 ml) and 2-fold equivalent of potassium carbonate (1.2 g) were added. The solution was stirred at room temperature for 5 hours. Removing the organic solvent after the reaction is completed, and purifying the obtained crude product by a chromatographic column to obtain the compound 4(1.3g,90％).¹H NMR(400MHz,CDCl₃):δ＝7.81(brs,1H),7.30(m,2H),7.23(s,1H),6.29(s,1H),6.03(s,1H),3.95(t,J＝4.8Hz,2H),3.81(m,2H),3.43(m,6H),2.86(brs,1H).

(3) Synthesis of Compound 5: compound 4 (1 g) was dissolved in dry DCM, triethylamine (0.87 mL) and a catalytic amount of DMAP (50 mg) were added, and the above mixed solution was added dropwise to a solution of phenyl 4-nitrochloroformate (1.7 g) in anhydrous CH ₂Cl₂ (10 mL). The solution was stirred at room temperature for 5 hours, after the reaction was completed, the organic solvent was removed, and the obtained crude product was directly used for the next reaction. Dissolving the dried crude product with anhydrous DCM, adding decanediamine (0.5 g) into the reaction system, stirring at room temperature for 2 hours, removing the reaction solvent, purifying with silica gel chromatographic column to obtain the compound 5(1.3g,90％).¹H NMR(400MHz,CDCl₃):δ＝7.50(m,2H),7.20(s,1H),6.29(s,1H),6.02(s,1H),3.81(m,2H),3.95(t,J＝4.8Hz,2H),3.63(m,4H),3.44(m,6H),1.82(m,2H),1.52(m,2H),1.30(m,6H).

(4) Synthesis of component A-2.1: the synthesis procedure refers to the synthesis of component A-1.1. The product is identified by ¹ H NMR spectrum, the peaks at 7.2 and 7.5ppm are the peaks of hydrogen atoms on benzene ring, and 3.4-3.6 o-phthalaldehyde molecules are connected on each polyethylene glycol molecule through the integral ratio of the peak of hydrogen atoms on polyethylene glycol skeleton .¹H NMR(400MHz,D₂O):δ＝10.60(s,4H),10.52(s,4H),7.90(m,8H),7.79(s,4H),3.81(m,2H),3.95(t,J＝4.8Hz,2H),3.72(m,3636H),1.82(m,8H),1.52(m,8H),1.30(m,24H).

Embodiment III: synthesis of representative Compound component A-3 of component A-3.1 (m=230, k=10, n=4)

(1) Synthesis of Compound 6: synthesis procedure reference compound 3 Synthesis .¹H NMR(400MHz,D₆-DMSO):δ＝13.21(brs,1H),8.05(d,J＝7.6Hz,1H),7.93(s,1H),7.55(d,J＝7.6Hz,1H),6.36(s,1H),6.11(s,1H),3.37-3.32(m,6H).

(2) Synthesis of Compound 7: synthesis procedure reference compound 2 Synthesis .¹H NMR(400MHz,CDCl₃):δ＝7.50(m,2H),7.22(s,1H),6.29(s,1H),6.04(s,1H),3.60(m,4H),3.44(m,6H),1.52(m,2H),1.30(m,6H).

(3) Synthesis of component A-3.1: the synthesis procedure refers to the synthesis of component A-1.1. The product is identified by ¹ H NMR spectrum, the peaks at 7.2 and 7.5ppm are the peaks of hydrogen atoms on benzene ring, and 3.4-3.6 o-phthalaldehyde molecules are connected to each polyethylene glycol molecule through the integral ratio of the peak of hydrogen atoms on polyethylene glycol skeleton .¹H NMR(400MHz,D₂O):δ＝10.57(s,4H),10.48(s,4H),7.80(m,8H),7.66(m,4H),3.72(m,3636H),3.60(m,16H),1.52(m,8H),1.30(m,24H).

Embodiment four: synthesis of representative Compounds of component A-4 component A-4.1 (m=230, k=10, n=4)

(1) Synthesis of Compound 8: the synthesis procedure refers to the synthesis of compound 3. ¹H NMR(400MHz,CDCl₃ ) δ=7.49 (s, 1H), 6.94 (s, 1H), 3.43 (m, 6H), 3.00 (s, j= 7.7,2H),

(2) Synthesis of compound 9: the synthesis procedure refers to the synthesis of compound 4. ¹H NMR(400MHz,CDCl₃ ) δ=7.64 (m, 1H), 7.01 (s, 1H), 3.63 (m, 4H), 3.03 (t, j= 7.6,2H).

(3) Synthesis of Compound 10: synthesis procedure reference compound 2 Synthesis .¹H NMR(400MHz,CDCl₃):δ＝7.65(m,1H),7.05(s,1H),3.63(m,4H),3.03(t,J＝7.6,4H),2.69(m,2H),1.52(m,2H),1.30(m,6H).

(4) Synthesis of component A-4.1: the synthesis procedure refers to the synthesis of component A-1.1. The product is identified by ¹ H NMR spectrum, the peaks at 7.6 and 7.0ppm are the peaks of hydrogen atoms on benzene ring, and 3.4-3.6 o-phthalaldehyde molecules are connected to each polyethylene glycol molecule through the integral ratio of the peak of hydrogen atoms on polyethylene glycol skeleton .¹H NMR(400MHz,D₂O):δ＝10.58(s,4H),10.52(s,4H),7.64(m,4H),7.02(s,4H),3.70(m,3636H),3.60(m,16H),3.01(t,J＝7.6,8H),2.69(m,8H),2.50(m,16H),1.52(m,8H),1.30(m,24H).

Fifth embodiment: synthesis of representative Compound component A-5 of component A-5.1 (h=170, m=10, n=4)

(1) Synthesis of Compound 11: synthesis procedure reference compound 2 Synthesis .¹H NMR(400MHz,CDCl₃):δ＝7.30(m,2H),7.22(s,1H),6.29(s,1H),6.04(s,1H),3.60(m,4H),3.44(m,6H),3.01(t,J＝7.6,2H),2.69(m,4H),2.50(m,4H).

(2) Synthesis of component A-5.1: in the synthesis process, referring to the synthesis of the component A-1.1, the product is identified by ¹ H NMR spectrum, the peaks at 7.2 and 7.3ppm are the peaks of hydrogen atoms on benzene rings, and 3.4-3.6 o-phthalaldehyde molecules are connected to each polyethylene glycol molecule through the integral ratio of the peaks of hydrogen atoms on a polyethylene glycol skeleton .¹H NMR(400MHz,D₂O):δ＝10.57(s,4H),10.48(s,4H),7.80(m,8H),7.66(m,4H),3.72(m,3636H),3.40(m,160H),3.60(m,16H),3.01(t,J＝7.6,8H),2.69(m,16H),2.50(m,8H),1.62(m,160H).

Example six: synthesis of representative Compounds of component A-6 component A-6.1 (h=10, m=170, n=4)

Synthesis of component A-6.1: in the synthesis process, referring to the synthesis of the component A-1.1, the product is identified by ¹ H NMR spectrum, the peaks at 7.2 and 7.3ppm are the peaks of hydrogen atoms on benzene rings, and 3.4-3.6 o-phthalaldehyde molecules are connected to each polyethylene glycol molecule through the integral ratio of the peaks of hydrogen atoms on a polyethylene glycol skeleton .¹H NMR(400MHz,D₂O):δ＝10.57(s,4H),10.48(s,4H),7.80(m,8H),7.66(m,4H),3.72(m,3636H),3.40(m,160H),3.60(m,16H),3.01(t,J＝7.6,8H),2.69(m,16H),2.50(m,8H),1.62(m,160H).

Embodiment seven: synthesis of representative Compounds of Components A-7 Synthesis of component A-7.1 (h=170, m=45, n=4)

Synthesis of component A-7.1: synthesis procedure reference is made to the synthesis of component A-1.1 .¹H NMR(400MHz,D₂O):δ＝10.57(s,4H),10.48(s,4H),7.80(m,8H),7.66(m,4H),3.72(m,350H),3.01(t,J＝7.6,8H),2.69(m,16H),2.50(m,8H),1.52(m,8H),1.30(m,24H),1.01(s,2000H).

Example eight: synthesis of representative Compound component A-8 of component A-8.1 (h=45, m=170, n=4)

Synthesis of component A-8.1: synthesis procedure reference is made to the synthesis of component A-1.1 .¹H NMR(400MHz,D₂O):δ＝10.60(s,4H),10.52(s,4H),7.88(m,8H),7.72(s,4H),3.52(m,170),3.70(m,2087H),3.01(t,J＝7.6,8H),2.67(t,J＝7.6,8H),1.01(m,540H).

In the eighth embodiment, the nuclear magnetic resonance hydrogen spectrum of the polypropylene glycol-polyethylene glycol copolymer is shown in fig. 1.

Example nine: structure of polyethylene glycol derivative (control group for use in the present invention) disclosed in chinese patent CN202010454896.6

Example ten: hydrogel component ratio

According to the method of the present invention, different hydrogel precursor solutions were prepared, for example as shown in Table 1, by operating at 37 ℃.

TABLE 1

The wt% in Table 1 represents the solids content of the solution, and the preferred mass concentration range for hydrogels is shown in the table.

Mixing the A and the B to obtain the hydrogel with different proportions. Different gel materials have different physical properties and biological effects, and the composition and the proportion of the gel materials can be selected pertinently according to different applications.

Example eleven: hydrogel swelling Property test

TABLE 2

The inventors performed a swelling ratio test on the hydrogels of the present technology and compared them with those disclosed in chinese patents CN202010454896.6 and CN202010455951.3 (hydrogels No. 17 and No. 18). The specific detection method comprises the following steps: the component A solution and the component B solution in Table 2 were sprayed into a special silicone tube by a twin mixer, and after curing for 10min, they were cut into cylindrical gel pieces of similar quality by a surgical blade. The gel pieces were weighed and transferred to 50ml centrifuge tubes, added to a DPBS buffer solution at pH 7.4 (which had been heated to 37.+ -. 1 ℃ C. In advance), then placed in a 37.+ -. 1 ℃ incubator, samples were taken every 2 hours, and weighed after surface moisture was removed by filter paper until the weight was no longer increased. The test was ended and the gel swell ratio was calculated as follows:

Swelling ratio = [ (sample mass after swelling-sample mass before swelling)/sample mass before swelling ] ×100%.

The swelling ratios obtained by the above test are shown in the following table:

TABLE 3 Table 3

/>

From the above experimental results, it was found that the introduction of the hydrophobic structure can effectively inhibit the swelling of the gel (fig. 2). Compared to hydrogels starting from polyethylene glycol which has not been hydrophobically modified (hydrogels No. 17 and 18), hydrogels prepared according to the invention have a lower swelling ratio (< 30%).

Embodiment twelve: application of low-swelling hydrogel to dural trauma occlusion

Male beagle dogs are selected, and the dural trauma plugging experiments are carried out in two groups: low swelling hydrogel treatment group (group a): formulation 9; hydrogel group (b group) disclosed in chinese patent CN 202010454896.6: formulation 17. After general inhalation anesthesia, beagle dogs made a curvilinear incision in the left frontal top area, and a 2mm defect was cut in the dura mater, resulting in spontaneous cerebrospinal fluid leakage. Then, the hydrogel precursor solution was sprayed at the defect by a twin mixer, and both sets of hydrogels were able to seal the leak. After 14 days, animals were sacrificed and dissected, and both beagle wounds healed without any more cerebrospinal fluid leakage. The gels of the group a and the group b are taken out and weighed respectively, the hydrogel of the group a does not swell obviously, and the swelling rate of the gel of the group b is close to 100%. Therefore, the hydrogel provided by the invention has low swelling rate, and the potential risk of adverse reaction caused by pressing nerves after the hydrogel swells is avoided.

Other hydrogel systems of different material compositions can be equally applied to dural trauma occlusion.

Embodiment thirteen: application of low-swelling hydrogel to dural mater wound occlusion

Beagle dogs were selected and used for dura mater wound repair experiments in two groups: hydrogel treatment group (a) according to the invention: formulation 8; hydrogel group (b group) disclosed in chinese patent CN 202010454896.6: formulation 17. After anesthetizing beagle, the back was opened to expose the subspinal dura, and a2 mm gap was established in the dura, resulting in spontaneous leakage of spinal fluid. Then, two groups of hydrogel precursor solutions are sprayed at the gap through a double liquid mixer, and the two groups of hydrogels can seal leakage. 21 days after surgery, the animals were sacrificed and dissected, and both beagle wounds healed without ridge fluid leakage. The gels of the group a and the group b are taken out and weighed respectively, the hydrogel of the group a does not swell obviously, and the swelling rate of the gel of the group b is close to 100%. Therefore, the hydrogel provided by the invention has low swelling rate, and the potential risk of adverse reaction caused by pressing nerves after the hydrogel swells is avoided.

Other hydrogel systems composed of different materials can be applied to dural trauma occlusion as well.

Fourteen examples: application of low-swelling hydrogel in vascular occlusion

And (3) selecting a male beagle dog for a vascular occlusion experiment, and evaluating the effect of the hydrogel on vascular occlusion. Experiments were performed in two groups: hydrogel treatment group (a): formulation 12; suture group (group b). After anesthesia and blood heparinization of beagle dogs, separating subcutaneous connective tissue to expose arteries and stripping fat tissues around the arteries; the arterial vessel was clamped using a non-invasive vessel clamp and a 27 gauge needle was used to perforate the artery. Spraying hydrogel precursor solution of formula 12 at the break through a duplex liquid mixer for 1min to form gel and stop bleeding; group b was sutured using surgical threads. Both groups removed the vessel clamps simultaneously, no bleeding occurred in group a (left in fig. 3) and bleeding occurred in group b (right in fig. 3). After 2 weeks of operation, the animals were sacrificed and dissected, and both beagle dogs had wound healed without blood leakage. And the gel in the group a is taken out and weighed, and the swelling ratio is smaller than 10%, so that the hydrogel prepared by the invention can realize the blocking of vascular bleeding, has lower swelling ratio, and can not press or separate peripheral tissues.

Other hydrogel systems of different material compositions can be applied to vascular occlusion as well.

Example fifteen: application of low-swelling hydrogel in kidney hemostasis

SD rats are selected to evaluate the hemostatic effect of the hydrogel, and kidney hemostasis experiments are carried out in two groups: hydrogel treatment group (a): formulation 1; blank control (b). After deep anesthesia of the experimental SD rats, mao Tiguang of the abdomen of the SD rats was sterilized with iodine using a shaver. The abdominal cavity is then opened along the flank portion, exposing the kidney region. An incision of the injury is established in the kidney: spraying hydrogel precursor solution of formula 1 at the incision by a double liquid mixer for 1min to form gel and stop bleeding; group b did not undergo any treatment and the kidneys were returned to the abdominal cavity after aspiration of the blood with gauze. After several hours, the SD rats in group b die from blood loss (right in fig. 4), while the SD rats in group a stopped from blood, without abnormal reaction (left in fig. 4). 7 days after operation, animals in group a were sacrificed and dissected, the kidney incision healed, no adhesion with surrounding tissues was observed, and the gel was taken out and weighed without significant swelling.

Other hydrogel systems of different material compositions can be equally applied to renal hemostasis.

Example sixteen: application of low-swelling hydrogel in blocking and preventing air leakage after local injury operation of lung

SD rats are selected to evaluate the blocking effect of the hydrogel, and the lung local injury blocking experiments are carried out in two groups: hydrogel treatment group (a): formulation 13; suture group (group b). After deep anesthesia of the experimental SD rats, a respirator was connected, and after confirmation of respiratory stabilization, the chest was opened by opening on the right outer side of the fifth intercostal space. The lungs were inflated using a syringe system prior to surgery to confirm that the preoperative lungs were free of leaks. Subsequently, 3mm long lung incisions were created with a surgical blade, and all animal wounds were air-bubbled and blood-filled. Subsequently, group a sprayed the hydrogel precursor solution to the incision site by a twin mixer. Group b was sutured with a Z needle using a 6-0 polypropylene suture. Before closing the chest, all rats adopt the same syringe system as before operation to check the tightness of the injured part, and the group a rats have no air leakage; partial rats in group b had air leakage. After 14 days, rats were sacrificed and dissected, the lung lesions of group a rats healed, were not adhered to surrounding tissues, and the hydrogel of group a was taken out and weighed without significant swelling. The low-swelling hydrogel disclosed by the invention can be applied to blocking lung injury to prevent air leakage.

Other hydrogel systems composed of different materials can be applied to the blocking of lung injury to prevent air leakage.

Example seventeenth: application of low-swelling hydrogel in pericardium anti-adhesion after heart operation

And (3) selecting beagle dogs for anti-adhesion experiments, and evaluating the anti-adhesion effect of the hydrogel. Experiments were performed in two groups: hydrogel treatment group (a): formulation 15; blank control (b). After the animals are fully anesthetized, left side chest opening operation is carried out in a fifth rib clearance, after pericardium within the range of 3.0cm multiplied by 3.0cm is cut off, sterile gauze is used for rubbing 20 times at myocardial tissue, the hydrogel precursor solution is sprayed to the wound by a double-fluid mixer in group a, and the treatment is not carried out in group b. 4 weeks after the operation, animals are sacrificed and dissected, the macroscopic adhesion phenomenon does not occur in group a, and the adhesion is serious in group b; group a hydrogels were then removed and weighed without significant swelling. The result shows that the low-swelling hydrogel can effectively prevent pericardial adhesion after cardiac operation.

Other hydrogel systems composed of different materials can be applied to pericardium anti-adhesion after cardiac operation.

The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.

Claims

1. The phthalic dicarboxaldehyde molecule modified macromolecule derivative is characterized by comprising a component A-1.1, a component A-2.1, a component A-3.1, a component A-4.1, a component A-5.1, a component A-6.1, a component A-7.1 or a component A-8.1;

2. A low-swelling injectable hydrogel, which is prepared by mixing a component A, a component B and a solvent;

The component A is a polymer derivative modified by the phthalaldehyde molecules according to claim 1;

The component B is selected from the component B-1, the component B-2 or the component B-3,

Component B-1: hydrazide modified hyaluronic acid, molecular weight 340k;

component B-2: the end group is amino modified four-arm polyethylene glycol with a molecular weight of 20k;

Component B-3: polylysine.

3. The low swelling injectable hydrogel of claim 2, wherein the solvent is selected from the group consisting of water, physiological saline, buffer solution, acellular matrix, and cell culture media solution.

4. The method for preparing the low-swelling injectable hydrogel according to claim 2, wherein the component A and the component B are dissolved in a solvent to obtain a component A solution and a component B solution, respectively, and the solution A and the solution B are mixed to obtain the low-swelling injectable hydrogel.

5. The method for producing a low-swelling injectable hydrogel according to claim 4, wherein the solid content of component A in the component A solution is 0.5 to 20% by weight and the solid content of component B in the component B solution is 0.1 to 20% by weight.

6. The method of preparing a low swelling injectable hydrogel according to claim 4, wherein component B is selected from the group consisting of component B-1: hydrazide modified hyaluronic acid, molecular weight 340k;

the solid content of the component A in the component A solution is 3wt%, and the solid content of the component B in the component B solution is 1wt%.

7. The method of preparing a low swelling injectable hydrogel according to claim 4, wherein component B is selected from the group consisting of component B-2: the end group is amino modified four-arm polyethylene glycol with a molecular weight of 20k;

the solid content of the component A in the component A solution is 3wt%, and the solid content of the component B in the component B solution is 2wt%.

8. Use of a low swelling injectable hydrogel according to claim 2, selected from the following applications: