CN111484611A

CN111484611A - Polyethylene glycol polymer containing thioester and aldehyde group, preparation method thereof, chemical crosslinking hydrogel containing thioester and aldehyde group and application of chemical crosslinking hydrogel

Info

Publication number: CN111484611A
Application number: CN202010300747.4A
Authority: CN
Inventors: 俞麟; 时家悦; 王丹妮; 丁建东
Original assignee: Fudan University; Zhuhai Fudan Innovation Research Institute
Current assignee: Fudan University; Zhuhai Fudan Innovation Research Institute
Priority date: 2020-04-16
Filing date: 2020-04-16
Publication date: 2020-08-04
Anticipated expiration: 2040-04-16
Also published as: CN111484611B

Abstract

The invention discloses a polyethylene glycol polymer containing thioester and aldehyde groups, a preparation method thereof, a chemical crosslinking hydrogel containing the same and application thereof, belonging to the field of biomedical materials. The invention firstly constructs a linear structure or multi-arm structure polyethylene glycol polymer containing thioester and aldehyde group, and then utilizes Schiff base reaction and sulfhydryl-thioester exchange reaction to design and synthesize the chemical crosslinking hydrogel containing the polyethylene glycol polymer, the precursor polymer of the hydrogel system can be stably stored, and the precursor solution can rapidly form in-situ crosslinking under physiological conditions after being mixed with the amino-containing polymer solution. The hydrogel can be attached to a wound to quickly form gel in situ to stop bleeding or protect the wound; when the hydrogel needs to be removed, the hydrogel can be quickly dissolved through a sulfhydryl-thioester exchange reaction, so that secondary damage to a wound caused by tearing is avoided, and the hydrogel is suitable for wound in-situ gelling hemostasis, wound protection and other conditions in emergency care.

Description

Polyethylene glycol polymer containing thioester and aldehyde group, preparation method thereof, chemical crosslinking hydrogel containing thioester and aldehyde group and application of chemical crosslinking hydrogel

Technical Field

The invention belongs to the field of biomedical materials, and particularly relates to a thioester and aldehyde group-containing polyethylene glycol polymer, a preparation method thereof, a chemical crosslinking hydrogel containing the thioester and aldehyde group-containing polyethylene glycol polymer and application of the chemical crosslinking hydrogel.

Background

The hydrogel is widely applied to various fields due to good biocompatibility and similarity with human soft tissues, is an important biomedical material, and is widely applied to drug carriers, cell carriers, auxiliary materials, masks, artificial cornea and the like. However, for some special biomedical requirements, such as hemostatic sealing, it is also desirable to have the ability to be quick to meet, strong, and quickly removable.

In recent years, various hydrogels have been developed for the hemostatic sealing field. Commercially available brands such as Coseal, Duraseal, Floseal, Tisseel, Bioglue, etc. have been successfully used in the clinic. Although these commercial hydrogels have good hemostatic sealing performance, the degradation time is too slow, and in case of emergency care (such as emergency hemostasis during burns or heavy bleeding), the gel needs to be cleaned away with an auxiliary traumatic tool such as a scalpel, which increases the risk of use, and also causes the residue of the hemostatic sealant, and in severe cases, the gel can be removed or adhered by external force to cause secondary injury to the wound.

In order to realize the rapid degradation of the hemostatic sealing hydrogel and solve the application limitation of the hemostatic sealing hydrogel in the field of emergency care, patent CN 108525016A discloses a PEG hydrogel based on a rapidly degradable chemical bond, wherein the hydrogel is formed by connecting polyethylene glycol amino with polyethylene glycol succinimidyl ester and polyethylene glycol aldehyde respectively through β -carbonyl amide bond and schiff base bond.

Therefore, the development of a hemostatic sealing hydrogel which can be quickly gelatinized and quickly dissolved, has mild properties, is mild in lotion properties, and does not cause secondary damage to body surface wounds is a problem to be solved by the technical personnel in the field.

Disclosure of Invention

In view of the above, the first objective of the present invention is to provide a polyethylene glycol polymer containing thioester and aldehyde groups.

In order to achieve the purpose, the invention adopts the following technical scheme:

a polyethylene glycol polymer containing thioester and aldehyde groups, wherein the average molecular weight of the polyethylene glycol polymer is 2000-40000, and the polyethylene glycol polymer is a linear structure polyethylene glycol polymer or a multi-arm structure polyethylene glycol polymer;

the structural formula of the linear structure polyethylene glycol derivative is as follows:

wherein R is₁Is composed of

R₂Is composed of

R₃Is composed of

n is a positive integer, n is more than or equal to 44 and less than or equal to 212, and c is 0, 1 and 2;

the number of arms of the multi-arm polyethylene glycol derivative is 3-8, and the structural formula is as follows:

wherein R is₁Is composed of

R₂Is composed of

R₃Is composed of

n is a positive integer, n is greater than or equal to 5 and less than or equal to 303, x is a positive integer, x is greater than or equal to 3 and less than or equal to 8, and c is 0, 1 or 2.

The second objective of the present invention is to provide a method for preparing the above-mentioned polyethylene glycol polymer containing thioester and aldehyde group.

the preparation method of the polyethylene glycol polymer containing thioester and aldehyde group comprises the following steps:

I. preparation of carboxyl-terminated polyethylene glycol polymer: adding a polyethylene glycol macromonomer into an anhydrous dichloromethane solvent, adding a micromolecular monomer, adding a catalyst after complete dissolution for esterification reaction, performing rotary evaporation, extraction, drying, sedimentation and vacuum drying after the reaction is finished to obtain a carboxyl-terminated polyethylene glycol polymer;

II. Preparation of thioester-containing polyethylene glycol polymer: dissolving the carboxyl-terminated polyethylene glycol polymer obtained in the step I, 4-dimethylaminopyridine and a dehydrating agent in an anhydrous dichloromethane solvent, sequentially adding an activated carboxyl-terminated micromolecule monomer, a sulfhydryl donor micromolecule monomer and N, N-diisopropylethylamine for reaction, and after the reaction is finished, filtering, extracting, drying, rotary steaming, settling and vacuum drying to obtain a polyethylene glycol polymer containing thioester;

III, preparation of a polyethylene glycol polymer containing thioester and aldehyde groups: and (3) dissolving the thioester-containing polyethylene glycol polymer obtained in the step (II), a catalyst and a dehydrating agent in an anhydrous dichloromethane solvent, adding a small molecular monomer serving as an aldehyde group donor to react, filtering, extracting, drying, rotary evaporating, settling and drying in vacuum after the reaction is finished to obtain the thioester-and aldehyde-group-containing polyethylene glycol polymer.

Further, the small molecule monomer in step I comprises succinic anhydride, glutaric anhydride, phthalic anhydride, maleic anhydride, 1-cyclopentene-1, 2-dicarboxylic anhydride, 3-fluorophthalic anhydride, 4-fluorophthalic anhydride, methyl-5-norbornene-2, 3-dicarboxylic anhydride, bicyclo [2,2,1] hept-5-ene-2, 3-dicarboxylic anhydride or 3- (tert-butyldimethylsilyloxy) glutaric anhydride; the catalyst comprises 4-dimethylaminopyridine, N-hydroxysuccinimide or N-hydroxythiosuccinimide.

Further, the dehydrating agent in the step II is N, N-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; the activated carboxyl-terminated small molecule monomer comprises N-hydroxysuccinimide or N-hydroxythiosuccinimide; the sulfhydryl donor micromolecule monomer comprises thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptobutyric acid or 4-mercaptobutyric acid.

Further, the catalyst in the step III is 4-dimethylaminopyridine, N-hydroxysuccinimide or N-hydroxythiosuccinimide, the dehydrating agent is N, N-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the aldehyde donor small molecule monomer is p-hydroxymethylbenzaldehyde, 2-hydroxy-5- (hydroxymethyl) benzaldehyde, 4-hydroxy-3-hydroxymethylbenzaldehyde or 4- (2-hydroxyethyl) benzaldehyde.

It is worth mentioning that the invention firstly introduces carboxyl group at the end group of the polyethylene glycol macromonomer by esterification reaction of linear or multi-arm polyethylene glycol macromonomer with any one of succinic anhydride, glutaric anhydride, phthalic anhydride, maleic anhydride, 1-cyclopentene-1, 2-dicarboxylic anhydride, 3-fluorophthalic anhydride, 4-fluorophthalic anhydride, methyl-5-norbornene-2, 3-dicarboxylic anhydride, bicyclo [2,2,1] hept-5-ene-2, 3-dicarboxylic anhydride, 3- (tert-butyldimethylsilyloxy) glutaric anhydride under mild condition; then activating a terminal carboxyl group by introducing N-hydroxysuccinimide or N-hydroxythiosuccinimide, adding any one of thioester-containing small molecules such as thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptobutyric acid, 4-mercaptobutyric acid and the like, and further performing substitution reaction under mild conditions to introduce a thioester bond; then, introducing any one of micromolecules containing aldehyde groups such as p-hydroxymethylbenzaldehyde, 2-hydroxy-5- (hydroxymethyl) benzaldehyde, 4-hydroxy-3-hydroxymethylbenzaldehyde or 4- (2-hydroxyethyl) benzaldehyde, and performing esterification reaction under mild conditions to introduce the aldehyde groups, thereby obtaining the polyethylene glycol polymer containing thioester and aldehyde groups.

Compared with the synthesis thought in the prior art, the method avoids the problems of poor stability of the precursor polymer, drop of an activated group, easy oxidation and the like caused by taking a sulfhydryl group or succinimide as an end group, creatively provides the end-capping group taking an aldehyde group as the polymer, designs and completes a corresponding synthesis route, improves the stability of the precursor polymer, simultaneously avoids the drop and oxidation of the activated group, is beneficial to the subsequent application of the polyethylene glycol polymer containing thioester and aldehyde groups, and provides a new way for further chemical modification or structural design on the basis.

The third purpose of the invention is to provide the hemostatic sealing hydrogel which can be quickly gelatinized and dissolved, has mild property and mild lotion property, and does not cause secondary damage to body surface wounds.

a chemically crosslinked hydrogel containing a thioester group that dissolves rapidly, comprising: 10-40 wt% of the polyethylene glycol polymer, 2-20 wt% of the macromolecular polymer containing primary amino and the balance of the solvent.

It is worth mentioning that thiol-thioester exchange usually occurs in some biological processes in vivo, or in native chemical ligation reactions, but few researchers have applied thiol-thioester exchange for organic synthesis and building reversible molecular assemblies. Thiol-thioester exchange specifically refers to the efficient reaction of thioesters and thiolate anions in the aqueous phase to produce new thioesters and thiolates. The sulfhydryl-thioester exchange is used as a reversible reaction, and has great application prospect in the design and synthesis of functional materials.

The invention mixes the polyethylene glycol cross-linking agent containing thioester and aldehyde group with the polymer solution containing a large amount of amino at the tail end or side chain, and the chemical cross-linking hydrogel which can be quickly dissolved based on the mercapto-thioester exchange is prepared by Schiff base reaction. After the chemical crosslinking hydrogel is fully contacted with a small molecule solution containing sulfydryl, sulfydryl-thioester exchange can occur to promote complete dissolution of the hydrogel.

Further, the primary amino group-containing high molecular polymer comprises a 2-4 th generation polyethylene diamine dendrimer PAMAM, polyethyleneimine PEI with the average molecular weight of 1800-25000 or polylysine P LL with the average molecular weight of 3000-70000.

It is worth noting that the second generation PAMAM has a molecular weight of 3256 and a structural formula:

the molecular weight of the third generation PAMAM is 6909, and the structural formula is as follows:

the molecular weight of the fourth generation PAMAM is 14215, and the structural formula is as follows:

the structural formula of the polyethyleneimine PEI is shown in the specification

Wherein n is a positive integer and is not less than 4 and not more than 42;

the structural formula of the polylysine P LL is shown in the specification

Wherein n is a positive integer and n is more than or equal to 8 and less than or equal to 182.

Further, the solvent comprises one or more of pure water, water for injection, physiological saline, buffer solution, animal and plant or human body fluid, tissue culture solution and cell culture solution.

It is worth to say that the synthesized thioester and aldehyde group-containing polyethylene glycol cross-linking agent solution and the macromolecular polymer solution with the tail end or the side chain containing a large amount of amino are mixed, the in-situ chemical cross-linking hydrogel is formed through Schiff base reaction, the precursors of the two components are in a flowable solution state before mixing, and the precursors are in a gel state after mixing. The chemical crosslinking hydrogel prepared by the invention has injectability, the precursors of the two components are in a solution state before being mixed, and after being mixed and injected into a wound position or a body, the chemical crosslinking hydrogel can form an in-situ hydrogel through Schiff base reaction under the physiological condition of a warm-blooded animal (namely the pH value is about 7.4 and the temperature is about 37 ℃), is perfectly matched with the wound or a defect part, and plays a role in stopping bleeding or protecting the wound; when the hydrogel needs to be moved, the rapid dissolution of the hydrogel can be realized through the thiol-thioester exchange reaction, so that the secondary injury to the wound caused by tearing is avoided.

The fourth object of the present invention is to provide the use of the chemically crosslinked hydrogel having a sulfide bond that can be rapidly dissolved.

In order to achieve the above purpose, the invention provides the following technical scheme:

provides the application of the hydrogel in serving as or preparing a drug loading material, a tissue engineering scaffold, a medical sponge, a hemostatic sealant, a surface coating of medical implant, a surface hemostatic sealing coating of epidermis, a coating for treating burn or a material for preventing tissue adhesion.

Further, the hydrogel degrades in a body fluid environment or dissolves rapidly in a wash solution, and the wash solution includes one or more of an aqueous cysteine methyl ester solution, an aqueous cysteine solution, and an aqueous chymotrypsin solution.

It is worth to be noted that the chemical crosslinking hydrogel provided by the invention can generate a sulfhydryl-thioester exchange reaction after being fully contacted with one or a combination of a cysteine methyl ester aqueous solution, a cysteine aqueous solution and a chymotrypsin aqueous solution, thereby realizing the controllable dissolution of the hydrogel.

Compared with the prior art, the invention has the advantages that:

1. the invention avoids the defect that the traditional method takes sulfydryl or succinimide as the end group, designs the synthetic route of the aldehyde-terminated polyethylene glycol polymer containing thioester and aldehyde, improves the stability of the hydrogel precursor polymer, and avoids the problems of drop of an activating group, easy oxidation and the like. And the precursor solution can quickly form an in-situ cross-linked hydrogel system under physiological conditions after being mixed, and is suitable for wound in-situ gelling hemostasis, wound protection and other conditions in emergency care.

2. The chemical crosslinking hydrogel prepared by the invention has good biocompatibility, gel flexibility, high gelling speed and high mechanical strength up to 1.3 × 10⁵Pa, the hydrogel can keep integrity all the time after reaching swelling equilibrium in 48h, and the adhesiveness on the surface of skin tissue is goodAnd after one or a combination of a cysteine methyl ester aqueous solution, a cysteine aqueous solution and a chymotrypsin aqueous solution is added, sulfhydryl-thioester exchange can be carried out to realize the rapid dissolution of the hydrogel.

3. The chemically crosslinked hydrogel provided by the invention can be used as a liquid band-aid and an emergency hemostatic material. The results of the chemical crosslinking hydrogel in animal experiments of SD rat skin surface wound models and femoral artery models show that the hydrogel system meets the requirements of emergency hemostatic materials in both mechanical property and controllable dissolution, and has good potential for hemostatic application.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.

FIG. 1 is a diagram of the mechanism of formation and controlled dissolution of a chemically crosslinked hydrogel based on thiol-thioester exchange reaction for rapid dissolution provided by the present invention.

FIG. 2 is a nuclear magnetic representation of linear polyethylene glycol polymers containing thioester and aldehyde groups in example 1.

FIG. 3 is a nuclear magnetic representation of the multi-arm polyethylene glycol polymer containing thioester and aldehyde groups of example 2.

Fig. 4 is a graph of rheological measurements in experimental example 1.

FIG. 5 is a graph showing the dissolution behavior in Experimental example 5.

Fig. 6 is an adhesion test chart in experimental example 9.

Fig. 7 is a schematic view of the liquid band-aid in experimental example 10.

Fig. 8 is a femoral artery hemostasis model of the emergency hemostatic material in experimental example 11.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The present invention will be further specifically illustrated by the following examples for better understanding, but the present invention is not to be construed as being limited thereto, and certain insubstantial modifications and adaptations of the invention by those skilled in the art based on the foregoing disclosure are intended to be included within the scope of the invention.

Example 1

A preparation method of a polyethylene glycol polymer containing thioester and aldehyde groups comprises the following steps:

I. under argon atmosphere, linear polyethylene glycol (PEG 2000) and Succinic Anhydride (SA) in a molar ratio of 1: 3 are added into a 250m L eggplant-shaped bottle, 40m L of anhydrous dichloromethane is added, magnetons are stirred until the mixture is completely dissolved, then a catalyst 4-Dimethylaminopyridine (DMAP) is weighed, wherein the molar ratio of the DMAP to the PEG2000 is 2: 1, the mixture is dissolved into 10m L of anhydrous dichloromethane, the mixture is slowly injected into the reaction system through a micro injection pump, an ice-water bath is carried out for reaction for 4 hours, then the ice-water bath is removed, the reaction is continued for 24 hours at normal temperature, after the reaction is finished, most of dichloromethane is removed by rotary evaporation, 150m L of deionized water is added, the mixture is uniformly stirred, the pH is adjusted to be about 3 by hydrochloric acid, a large amount of dichloromethane is added for extraction, the mixture is washed by saturated salt water, anhydrous sodium sulfate is dried for 12 hours, then most of dichloromethane is removed by rotary evaporation, a large amount of anhydrous ether is added, the dichloromethane is precipitated for 24 hours at the temperature of-20 ℃, supernatant.

II. Under the same argon atmosphere, adding carboxyl-terminated modified polyethylene glycol 1a in the step I into a 500m L eggplant-shaped bottle, weighing N-hydroxysuccinimide NHS, wherein the molar ratio of NHS to PEG2000 is 5: 1, adding into the eggplant-shaped bottle, adding 200m L anhydrous dichloromethane, stirring until the N-hydroxysuccinimide NHS is completely dissolved, weighing a dehydrating agent N, N-dicyclohexylcarbodiimide DCC and a catalyst 4-dimethylaminopyridine DMAP, wherein the molar ratio of DCC to PEG2000 is 2.4: 1, the molar ratio of DMAP to PEG2000 is 0.6: 1, adding 10m L anhydrous dichloromethane for dissolving, slowly adding into the reaction system through a micro-injection pump, reacting in an ice-water bath for 4 hours, removing the ice-water bath, continuing to react for 24 hours at normal temperature, adding mercaptoacetic acid and the catalyst N, N-diisopropylethylamine EA into the reaction system after the DCC and PEG2000 react for 24 hours, adding a large amount of mercaptoacetic acid and the catalyst N, N-diisopropylethylamine EA into the reaction system, drying after the DCC is finished, adding a large amount of anhydrous acetic acid and stirring, adding a large amount of anhydrous sodium sulfate, drying, and distilling the obtained sodium sulfate solution, and drying, adding a saturated sodium chloride solution for 24 hours, and obtaining a saturated sodium sulfate solution, after the most of the saturated sodium chloride solution, and distilling the saturated sodium chloride solution, and drying, wherein the saturated sodium sulfate solution is obtained by adding the saturated sodium chloride solution, the saturated sodium sulfate solution, the saturated sodium chloride solution, the saturated sodium sulfate is obtained by adding and drying, the saturated sodium chloride solution after the saturated sodium sulfate is obtained by vacuum distillation for.

III, under the same argon atmosphere, adding thioester-containing polyethylene glycol 2a in the step II into a 250m L eggplant-shaped bottle, then adding p-hydroxymethylbenzaldehyde, wherein the molar ratio of the p-hydroxymethylbenzaldehyde to the thioester-containing polyethylene glycol 2a is 2.2: 1, and 40m L anhydrous dichloromethane, adding a magnet, stirring until the p-hydroxymethylbenzaldehyde is completely dissolved, weighing a dehydrating agent N, N-Dicyclohexylcarbodiimide (DCC), a catalyst 4-Dimethylaminopyridine (DMAP), wherein the molar ratio of the DCC to the thioester-containing polyethylene glycol 2a is 2.4: 1, the molar ratio of the DMAP to the thioester-containing polyethylene glycol 2a is 0.6: 1, adding 10m L anhydrous dichloromethane, slowly adding the mixture into the reaction system through a micro-injection pump, carrying out an ice water bath reaction for 4 hours, then removing the ice water bath, continuing the reaction for 48 hours at normal temperature, adding a few drops of deionized water after the reaction is finished, converting excessive DCC in the reaction system into insoluble Dicyclohexylurea (DCU) salt, filtering, removing most of the filtrate, steaming the thioester-containing solvent, carrying out a large amount of modification, adding a large amount of dichloromethane, carrying out a vacuum distillation for 24 hours, and carrying out a vacuum precipitation for 24 hours, and obtaining a supernatant liquid with an aldehyde group yield of aldehyde group of 2a yield as shown in a result, wherein the calculation is 85% and the.

Example 2

I. under argon atmosphere, adding four-arm polyethylene glycol PEG4000 and succinic anhydride SA in a molar ratio of 1: 6 into a 250m L eggplant-shaped bottle, adding 40m L of anhydrous dichloromethane, stirring magnetons until complete dissolution, then weighing a catalyst 4-dimethylaminopyridine DMAP, wherein the molar ratio of DMAP to PEG4000 is 4: 1, dissolving into 10m L of anhydrous dichloromethane, slowly injecting into the reaction system through a micro-injection pump, reacting in an ice-water bath for 4 hours, removing the ice-water bath, continuing to react for 24 hours at normal temperature, removing most of dichloromethane through rotary evaporation after the reaction is finished, adding 150m L of deionized water, stirring uniformly, adjusting the pH to 3 with hydrochloric acid, adding a large amount of dichloromethane for extraction, washing with saturated salt water, drying with anhydrous sodium sulfate for 12 hours, then removing most of dichloromethane through rotary evaporation, adding a large amount of anhydrous ether, settling for 24 hours at-20 ℃, pouring supernatant and drying in vacuum for 24 hours to obtain polyethylene glycol 1b with modified terminal carboxyl groups, and the yield is about 97%.

II. Under the same argon atmosphere, adding polyethylene glycol 1b modified by end carboxyl in the step I into a 500m L eggplant-shaped bottle, weighing N-hydroxysuccinimide NHS, wherein the molar ratio of NHS to PEG4000 is 10: 1, adding into the eggplant-shaped bottle, adding 200m L anhydrous dichloromethane, stirring until the N-hydroxysuccinimide NHS is completely dissolved, weighing a dehydrating agent N, N-dicyclohexylcarbodiimide DCC and a catalyst 4-dimethylaminopyridine DMAP, wherein the molar ratio of DCC to PEG4000 is 4.8: 1, the molar ratio of DMAP to PEG4000 is 1.2: 1, adding 10m L anhydrous dichloromethane for dissolving, slowly adding into the reaction system through a micro-injection pump, reacting in an ice-water bath for 4 hours, removing the ice-water bath, continuing to react for 24 hours at normal temperature, adding mercaptoacetic acid and a catalyst N, N-diisopropylethylamine EA into the system after the reaction is finished, wherein the molar ratio of mercaptoacetic acid to PEG4000 is 6: 1, the molar ratio of DIPEA to PEG4000, the thioester is 8: 1, adding a large amount of mercaptoacetic acid and the catalyst N, drying after the reaction is finished, adding a large amount of DCC, adding a saturated sodium sulfate solution, stirring, drying, adding a large amount of distilled sodium sulfate solution containing a large amount of distilled water, adding into the saturated sodium chloride solution containing sodium chloride, distilling the saturated sodium chloride solution for 24 hours, and drying, and obtaining a large amount of a saturated sodium chloride solution containing DCC, and drying, and obtaining a large amount of the saturated sodium sulfate solution containing 20 hours, and drying, and obtaining a large amount of the saturated sodium chloride after the saturated sodium chloride solution, and drying.

III, under the same nitrogen atmosphere, adding thioester-containing polyethylene glycol 2b in the step II into a 250m L eggplant-shaped bottle, then adding p-hydroxymethylbenzaldehyde, wherein the molar ratio of the p-hydroxymethylbenzaldehyde to the thioester-containing polyethylene glycol 2b is 4.4: 1, and 40m L anhydrous dichloromethane, adding a magnet to stir until the p-hydroxymethylbenzaldehyde is completely dissolved, weighing a dehydrating agent N, N-Dicyclohexylcarbodiimide (DCC) and a catalyst 4-Dimethylaminopyridine (DMAP), wherein the molar ratio of the DCC to the thioester-containing polyethylene glycol 2b is 4.8: 1, the molar ratio of the DMAP to the thioester-containing polyethylene glycol 2b is 1.2: 1, adding 10m L anhydrous dichloromethane to dissolve, slowly adding the mixture into the reaction system through a micro injection pump, carrying out an ice water bath reaction for 4 hours, then removing the ice water bath, continuing the reaction for 48 hours at normal temperature, adding a few drops of deionized water to convert excessive DCC in the reaction system into insoluble Dicyclohexylurea (DCU) salt after the reaction is finished, filtering, removing most of the thioester solvent, steaming, carrying out a large amount of modification on the dichloromethane, adding 24 hours, carrying out vacuum sedimentation, and obtaining a supernatant, and pouring the yield of aldehyde group of 24 hours, wherein the supernatant is calculated as shown in a result that the aldehyde group yield is 3% of the nuclear magnetic aldehyde group of the nuclear magnetic aldehyde.

Example 3

I. adding six-armed polyethylene glycol (PEG 5500) and Succinic Anhydride (SA) in a molar ratio of 1: 9 into a 250m L eggplant-shaped bottle under argon atmosphere, adding 40m L of anhydrous dichloromethane, stirring magnetons until complete dissolution, then weighing a catalyst 4-Dimethylaminopyridine (DMAP), wherein the molar ratio of the DMAP to the PEG5500 is 6: 1, dissolving into 10m L of anhydrous dichloromethane, slowly injecting into the reaction system through a micro-injection pump, reacting in an ice-water bath for 4 hours, removing the ice-water bath, continuing to react for 24 hours at normal temperature, removing most of dichloromethane by rotary evaporation after the reaction is finished, adding 150m L of deionized water, stirring uniformly, adjusting the pH to be about 3 by using hydrochloric acid, adding a large amount of dichloromethane for extraction, washing with saturated salt water, drying for 12 hours by using anhydrous sodium sulfate, then removing most of dichloromethane by rotary evaporation, adding a large amount of anhydrous ether, settling for 24 hours at-20 ℃, pouring supernatant and drying for 24 hours in vacuum to obtain polyethylene glycol (1 c) with modified terminal carboxyl groups, and the yield is about 95%.

II. Under the same argon atmosphere, adding polyethylene glycol 1c modified by terminal carboxyl in the step I into a 500m L eggplant-shaped bottle, weighing N-hydroxysuccinimide NHS, wherein the molar ratio of NHS to PEG5500 is 15: 1, adding into the eggplant-shaped bottle, adding 200m L anhydrous dichloromethane, stirring until the N-hydroxysuccinimide NHS is completely dissolved, weighing a dehydrating agent N, N-dicyclohexylcarbodiimide DCC and a catalyst 4-dimethylaminopyridine DMAP, wherein the molar ratio of DCC to PEG5500 is 7.2: 1, the molar ratio of DMAP to PEG5500 is 1.8: 1, adding 10m L anhydrous dichloromethane for dissolving, slowly adding into the reaction system through a micro injection pump, reacting in an ice water bath for 4 hours, removing the ice water bath, continuing to react for 24 hours at normal temperature, adding mercaptoacetic acid and a catalyst N, N-diisopropylethylamine after the reaction is completed, wherein the molar ratio of mercaptoacetic acid to PEG5500 is 9: 1, the molar ratio of DIPEA to PEG5500 is 12, adding a large amount of sodium sulfate, filtering, adding a large amount of saturated sodium sulfate solution containing sodium sulfate, drying, reacting, adding into the saturated sodium sulfate solution, stirring and drying, adding into the saturated solution, drying, adding the saturated solution containing DCC, distilling the saturated sodium sulfate, and drying, and adding into the saturated solution, wherein the saturated solution containing sodium chloride, the saturated sodium sulfate is calculated for 24 hours, and distilling, and the supernatant after the saturated sodium sulfate is calculated for 24 hours, and the saturated sodium sulfate is calculated for three times, and the saturated sodium sulfate is calculated for obtaining a large amount of the supernatant after the saturated sodium sulfate is 20 hours, the saturated sodium sulfate, the saturated sodium.

III, under the same argon atmosphere, adding polyethylene glycol 2c containing thioester in the step II into a 250m L eggplant-shaped bottle, then adding p-hydroxymethyl benzaldehyde, wherein the molar ratio of the p-hydroxymethyl benzaldehyde to the polyethylene glycol 2c containing thioester is 6.6: 1, and 40m L anhydrous dichloromethane, adding a magnet, stirring until the p-hydroxymethyl benzaldehyde is completely dissolved, weighing a dehydrating agent N, N-Dicyclohexylcarbodiimide (DCC), a catalyst 4-Dimethylaminopyridine (DMAP), wherein the molar ratio of the DCC to the polyethylene glycol 2c containing thioester is 7.2: 1, the molar ratio of the DMAP to the polyethylene glycol 2c containing thioester is 1.8: 1, adding 10m L anhydrous dichloromethane, slowly adding the mixture into the reaction system through a micro-injection pump, carrying out an ice water bath reaction for 4 hours, then removing the ice water bath, continuing to react for 48 hours at normal temperature, adding a few drops of deionized water after the reaction is finished, converting the excessive DCC in the reaction system into insoluble Dicyclohexylurea (DCU) salt, filtering, removing most of the thioester solvent, steaming the dichloromethane, carrying out a large amount of modification, adding a large amount of dichloromethane, carrying out a vacuum sedimentation for 24 hours, and carrying out vacuum drying to obtain a supernatant containing 24 hours, wherein the yield of the aldehyde group is calculated for 24 hours.

Example 4

I. under argon atmosphere, adding eight-arm polyethylene glycol PEG40000 and glutaric anhydride with the molar ratio of 1: 12 into a 250m L eggplant-shaped bottle, adding 40m L of anhydrous dichloromethane, stirring magnetons until complete dissolution, then weighing a catalyst 4-dimethylaminopyridine DMAP with the molar ratio of 8: 1 of DMAP to PEG40000, dissolving into 10m L of anhydrous dichloromethane, slowly injecting into the reaction system through a micro-injection pump, carrying out an ice-water bath reaction for 4 hours, removing the ice-water bath, continuing to react for 24 hours at normal temperature, carrying out rotary evaporation to remove most of dichloromethane, adding 150m L of deionized water, stirring uniformly, adjusting the pH to 3 with hydrochloric acid, adding a large amount of dichloromethane for extraction, washing with saturated salt solution, drying for 12 hours with anhydrous sodium sulfate, then carrying out rotary evaporation to remove most of dichloromethane, adding a large amount of anhydrous ether, settling for 24 hours at 20 ℃, pouring supernatant and carrying out vacuum drying for 24 hours to obtain polyethylene glycol 1d with modified terminal carboxyl groups, wherein the yield is about 94%.

II. Under the same argon atmosphere, adding polyethylene glycol 1d modified by terminal carboxyl in the step I into a 500m L eggplant-shaped bottle, weighing N-hydroxy thiosuccinimide Sulfo-NHS, wherein the molar ratio of Sulfo-NHS to PEG40000 is 2: 1, adding into the eggplant-shaped bottle, adding 200m L anhydrous dichloromethane, stirring until the N-hydroxy thiosuccinimide Sulfo-NHS is completely dissolved, weighing 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC and a catalyst 4-dimethylaminopyridine DMAP, wherein the molar ratio of EDC to PEG40000 is 9.6: 1, the molar ratio of DMAP to PEG40000 is 2.4: 1, adding 10m L anhydrous dichloromethane for dissolving, slowly adding into the reaction system through a micro-injection pump, performing ice water bath reaction for 4h, removing ice, continuing the reaction for 24h at normal temperature, adding mercaptopropionic acid and the catalyst N, N-diisopropyl ethylamine EA, wherein the molar ratio of mercaptopropionic acid to PEG40000 is 12h, adding a large amount of sodium sulfate-containing sodium sulfate, performing vacuum filtration, drying, adding a large amount of sodium sulfate-containing sodium sulfate and stirring until the molar ratio of PEG40000 is equal to 20 h, adding a large amount of saturated sodium sulfate, performing vacuum distillation, drying to obtain a supernatant, and obtaining a supernatant after the supernatant, and performing vacuum distillation for 24h, and the precipitation, wherein the supernatant of the supernatant is 20 h, the supernatant, and the supernatant is obtained by adding.

III, under the same argon atmosphere, adding thioester-containing polyethylene glycol 2d in the step II into a 250m L eggplant-shaped bottle, then adding 2-hydroxy-5- (hydroxymethyl) benzaldehyde, wherein the molar ratio of 2-hydroxy-5- (hydroxymethyl) benzaldehyde to thioester-containing polyethylene glycol 2d is 8.8: 1, and 40m L anhydrous dichloromethane, adding a magnet and stirring until the mixture is completely dissolved, weighing a dehydrating agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC and a catalyst 4-dimethylaminopyridine DMAP, wherein the molar ratio of EDC to thioester-containing polyethylene glycol 2d is 9.6: 1, the molar ratio of DMAP to thioester-containing polyethylene glycol 2d is 2.4: 1, adding 10m L anhydrous dichloromethane and dissolving, slowly adding the mixture into the reaction system through a micro injection pump, carrying out ice-ice bath reaction for 4 hours, then removing ice-water bath, continuing the reaction for 48 hours at normal temperature, filtering anhydrous, adding a large amount of dichloromethane for three times of extraction, carrying out saturated salt washing, adding a modification, drying for 12 hours, removing a large amount of sodium sulfate, carrying out vacuum rotary evaporation and sedimentation on a supernatant liquid containing 24 hours, and obtaining a majority of aldehyde group after the supernatant, and carrying out nuclear magnetic precipitation, wherein the yield of the supernatant is calculated for 24 hours.

Example 5

I. under argon atmosphere, adding eight-arm polyethylene glycol PEG20000 and maleic anhydride with a molar ratio of 1: 12 into a 250m L eggplant-shaped bottle, adding 40m L of anhydrous dichloromethane, stirring magnetons until complete dissolution, then weighing a catalyst 4-dimethylaminopyridine DMAP with a molar ratio of 8: 1 of DMAP to PEG20000, dissolving into 10m L of anhydrous dichloromethane, slowly injecting into the reaction system through a micro-injection pump, reacting in an ice-water bath for 4 hours, removing the ice-water bath, continuing to react for 24 hours at normal temperature, removing most of dichloromethane through rotary evaporation, adding 150m L of deionized water, stirring uniformly, adjusting the pH to about 3 with hydrochloric acid, adding a large amount of dichloromethane for extraction, washing with saturated salt solution, drying for 12 hours with anhydrous sodium sulfate, then removing most of dichloromethane through rotary evaporation, adding a large amount of anhydrous ether, settling for 24 hours at-20 ℃, pouring supernatant and drying for 24 hours in vacuum to obtain polyethylene glycol 1e with modified terminal carboxyl groups with a yield of about 92%.

II. Under the same argon atmosphere, adding polyethylene glycol 1e modified by terminal carboxyl in the step I into a 500m L eggplant-shaped bottle, weighing N-hydroxy thiosuccinimide Sulfo-NHS, wherein the molar ratio of Sulfo-NHS to PEG20000 is 2: 1, adding into the eggplant-shaped bottle, adding 200m L anhydrous dichloromethane, stirring until the mixture is completely dissolved, weighing 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC and a catalyst 4-dimethylaminopyridine DMAP, wherein the molar ratio of EDC to PEG20000 is 9.6: 1, the molar ratio of DMAP to PEG20000 is 2.4: 1, adding 10m L anhydrous dichloromethane for dissolving, slowly adding into the reaction system through a micro-injection pump, carrying out ice water bath reaction for 4h, removing ice, continuing reaction for 24h after the reaction is finished, adding anhydrous 4-mercaptobutyric acid and a catalyst N, N-diisopropyl ethyl acetate EA, wherein the molar ratio of 4-DIP to PEG20000 for reaction, adding a large amount of sodium sulfate and stirring until the saturated sodium sulfate is 20 h, adding a large amount of sodium sulfate, drying, and carrying out vacuum distillation for 24h, wherein the saturated sodium sulfate precipitation is 20 h, the yield of the saturated sodium sulfate is calculated as the yield of the saturated sodium sulfate after the absolute sodium sulfate is obtained, the absolute precipitation of the absolute sodium sulfate precipitation under normal temperature, the average molecular weight of the saturated sodium sulfate is 24h, the saturated sodium sulfate is calculated as 24h, the absolute yield of the absolute precipitation of the absolute sodium sulfate of the saturated sodium sulfate of the absolute sodium sulfate after the absolute sodium sulfate is calculated as 24h, the absolute precipitation of the absolute sodium sulfate is obtained after the absolute precipitation of the absolute sodium sulfate is obtained after the absolute precipitation under.

III, under the same argon atmosphere, adding thioester-containing polyethylene glycol 2e in the step II into a 250m L eggplant-shaped bottle, adding 4- (2-hydroxyethyl) benzaldehyde, wherein the molar ratio of 4- (2-hydroxyethyl) benzaldehyde to thioester-containing polyethylene glycol 2e is 8.8: 1, and 40m L anhydrous dichloromethane, adding a magnet, stirring until the mixture is completely dissolved, weighing 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC as a dehydrating agent and 4-dimethylaminopyridine DMAP as a catalyst, wherein the molar ratio of EDC to thioester-containing polyethylene glycol 2e is 9.6: 1, the molar ratio of DMAP to thioester-containing polyethylene glycol 2e is 2.4: 1, adding 10m L anhydrous dichloromethane, dissolving, slowly adding the mixture into the reaction system through a micro injection pump, reacting in an ice water bath for 4 hours, removing the ice water bath, continuing to react for 48 hours, filtering after the reaction is finished, adding a large amount of dichloromethane, extracting anhydrous sodium sulfate, adding saturated salt, drying for 12 hours, removing a large amount of thioester modification solvent, performing rotary evaporation, pouring a large amount of formaldehyde-containing solvent for 24 hours, and drying at normal temperature to obtain a supernatant containing ether-containing yield, wherein the aldehyde-containing supernatant is represented by a temperature calculation.

Example 6

III, under the same nitrogen atmosphere, adding thioester-containing polyethylene glycol 2b in the step II into a 250m L eggplant-shaped bottle, then adding p-hydroxymethylbenzaldehyde, wherein the molar ratio of the p-hydroxymethylbenzaldehyde to the thioester-containing polyethylene glycol 2b is 4.4: 1, and 40m L anhydrous dichloromethane, adding a magnet, stirring until the p-hydroxymethylbenzaldehyde is completely dissolved, weighing a dehydrating agent N, N-Dicyclohexylcarbodiimide (DCC), a catalyst 4-Dimethylaminopyridine (DMAP), wherein the molar ratio of the DCC to the thioester-containing polyethylene glycol 2b is 4.8: 1, the molar ratio of the DMAP to the thioester-containing polyethylene glycol 2b is 1.2: 1, adding 10m L anhydrous dichloromethane, slowly adding the mixture into the reaction system through a micro-injection pump, carrying out an ice water bath reaction for 4 hours, then removing the ice water bath, continuing the reaction for 48 hours at normal temperature, adding a few drops of deionized water after the reaction is finished, converting excessive DCC in the reaction system into insoluble Dicyclohexylurea (DCU) salt, filtering, removing most of the thioester solvent, steaming, carrying out a large amount of modification on the dichloromethane, adding 24 hours, carrying out vacuum sedimentation, and carrying out vacuum drying on the supernatant to obtain a supernatant containing 24 hours, wherein the yield of the aldehyde group is calculated as the yield of the aldehyde group of 24 hours.

Example 7

I. under argon atmosphere, adding four-arm polyethylene glycol PEG4000 and phthalic anhydride with a molar ratio of 1: 6 into a 250m L eggplant-shaped bottle, adding 40m L of anhydrous dichloromethane, stirring magnetons until the magnetons are completely dissolved, then weighing a catalyst 4-dimethylaminopyridine DMAP with a molar ratio of 4: 1 of DMAP and PEG4000, dissolving the DMAP and PEG4000 into 10m L of anhydrous dichloromethane, slowly injecting the mixture into the reaction system through a micro-injection pump, reacting in an ice-water bath for 4 hours, removing the ice-water bath, continuing to react for 24 hours at normal temperature, performing rotary evaporation to remove most of dichloromethane, adding 150m L of deionized water, stirring uniformly, adjusting the pH to be about 3 with hydrochloric acid, adding a large amount of dichloromethane for extraction, washing with saturated saline, drying with anhydrous sodium sulfate for 12 hours, then performing rotary evaporation to remove most of dichloromethane, adding a large amount of anhydrous ether, settling for 24 hours at-20 ℃, pouring supernatant and performing vacuum drying for 24 hours to obtain polyethylene glycol 1b with a carboxyl group modified end group with a yield of about 97%.

Example 8

A chemical crosslinking hydrogel containing thioester bond and aldehyde group capable of being rapidly dissolved is prepared by adding polyethylene glycol 3a containing thioester and aldehyde group, namely a linear polyethylene glycol crosslinking agent in example 1 into PBS buffer solution (pH is 7.4), preparing a sample with the weight percentage concentration of 50 wt%, and dissolving the polymer by magnetic stirring to prepare a corresponding aqueous solution; adding a PBS (phosphate buffer solution) (pH 7.4) into the G2 dendrimer PAMAM to prepare a sample with the weight percentage concentration of 10 wt%, and magnetically stirring to obtain a corresponding aqueous solution; the two PBS solutions were mixed in equal volumes to give a 25 wt% PEG2000(thioester) -CHO/5 wt% PAMAM chemically crosslinked hydrogel.

Example 9

A chemical crosslinking hydrogel containing thioester bonds and capable of being rapidly dissolved is prepared by adding polyethylene glycol 3b containing thioester and aldehyde groups, namely a four-arm polyethylene glycol crosslinking agent in example 2 into a PBS (pH 7.4) buffer solution to prepare a sample with the weight percentage concentration of 50 wt%, and dissolving a polymer by magnetic stirring to prepare a corresponding aqueous solution; adding a PBS (phosphate buffer solution) (pH 7.4) into the G4 dendrimer PAMAM to prepare a sample with the weight percentage concentration of 6 wt%, and magnetically stirring to obtain a corresponding aqueous solution; after mixing the two PBS solutions in equal volumes, 25 wt% 4-armPEG (thioester) -CHO/3 wt% PAMAM chemically crosslinked hydrogel was obtained.

Example 10

A chemical crosslinking hydrogel containing thioester bonds and capable of being rapidly dissolved is prepared by adding polyethylene glycol 3c containing thioester and aldehyde groups, namely a six-arm polyethylene glycol crosslinking agent in example 3 into a PBS (pH 7.4) buffer solution to prepare a sample with the weight percentage concentration of 50 wt%, and dissolving a polymer by magnetic stirring to prepare a corresponding aqueous solution; adding a PBS (PBS buffer solution (pH 7.4)) into polyethyleneimine PEI (molecular weight 10000) to prepare a sample with the weight percentage concentration of 12 wt%, and magnetically stirring to obtain a corresponding aqueous solution; the two PBS solutions were mixed in equal volumes to give a 25 wt% 6-armPEG (thioester) -CHO/6 wt% PEI chemically crosslinked hydrogel.

Example 11

A chemical crosslinking hydrogel containing thioester bonds and capable of being rapidly dissolved is prepared by adding polyethylene glycol 3d containing thioester and aldehyde groups, namely an eight-arm polyethylene glycol crosslinking agent in example 4 into a PBS buffer solution (pH is 7.4), preparing a sample with the weight percentage concentration of 30 wt%, and dissolving a polymer by magnetic stirring to prepare a corresponding aqueous solution; adding a PBS (PBS buffer solution (pH 7.4)) into polyethyleneimine PEI (molecular weight 20000) to prepare a sample with the weight percentage concentration of 10 wt%, and magnetically stirring to obtain a corresponding aqueous solution; the two PBS solutions were mixed in equal volumes to give a 15 wt% 8-armPEG (thioester) -CHO/5 wt% PEI chemically crosslinked hydrogel.

Example 12

A chemical cross-linking hydrogel containing thioester bonds and capable of being rapidly dissolved is prepared by adding polyethylene glycol 3e containing thioester and aldehyde groups, namely an eight-arm polyethylene glycol cross-linking agent in example 5 into a PBS buffer solution (pH 7.4) to prepare a sample with the weight percentage concentration of 40 wt%, dissolving a polymer by magnetic stirring to prepare a corresponding aqueous solution, adding the PBS buffer solution (pH 7.4) into polylysine P LL (molecular weight 34000) to prepare a sample with the weight percentage concentration of 8 wt%, magnetically stirring to obtain a corresponding aqueous solution, and mixing the two PBS solutions in equal volumes to obtain 20 wt% 8-armPEG (thioester) -CHO/4 wt% P LL chemical cross-linking hydrogel.

Example 13

A chemical crosslinking hydrogel containing thioester bond and capable of being rapidly dissolved is prepared by adding polyethylene glycol 3b containing thioester and aldehyde group, namely a four-arm polyethylene glycol crosslinking agent in example 6 into a PBS buffer solution (pH is 7.4), preparing a sample with the weight percentage concentration of 50 wt%, and dissolving a polymer by magnetic stirring to prepare a corresponding aqueous solution; adding a PBS (phosphate buffer solution) (pH 7.4) into the G3 dendrimer PAMAM to prepare a sample with the weight percentage concentration of 4 wt%, and magnetically stirring to obtain a corresponding aqueous solution; after mixing the two PBS solutions in equal volumes, 25 wt% 4-armPEG (thioester) -CHO/2 wt% PAMAM chemically crosslinked hydrogel was obtained.

Example 14

A chemical crosslinking hydrogel containing thioester bond and capable of being rapidly dissolved is prepared by adding polyethylene glycol 3b containing thioester and aldehyde group, namely a four-arm polyethylene glycol crosslinking agent in example 7 into a PBS buffer solution (pH is 7.4), preparing a sample with the weight percentage concentration of 40 wt%, and dissolving a polymer by magnetic stirring to prepare a corresponding aqueous solution; adding a PBS (phosphate buffer solution) (pH 7.4) into the G4 dendrimer PAMAM to prepare a sample with the weight percentage concentration of 3 wt%, and magnetically stirring to obtain a corresponding aqueous solution; the two PBS solutions were mixed in equal volumes to give a 20 wt% 4-armPEG (thioester) -CHO/1.5 wt% PAMAM chemically crosslinked hydrogel.

In order to further prove the beneficial effects of the present invention and to better understand the present invention, the following determination tests further illustrate the properties and application properties of the chemically crosslinked hydrogel containing thio ester bond capable of being rapidly dissolved, but should not be construed as limiting the present invention, and the properties of the product obtained by other determination tests and the applications based on the above properties, which are performed by those skilled in the art according to the above summary of the invention, are also considered to fall within the protection scope of the present invention.

Experimental example 1

Testing of elastic and viscous moduli of gel samples:

a25 wt% 4-armPEG (thioester) -CHO/3 wt% PAMAM chemically crosslinked hydrogel of example 9 was formed into a shape of 9mm in diameter and 3mm in thickness by dynamic rheometer measurement, and the rheological test was conducted after stabilization for one hour. The changes of the elastic modulus and the viscous modulus of the hydrogel before swelling and after swelling (soaking in PBS solution) with time are measured to obtain the change graphs of the elastic modulus and the viscous modulus of the gel sample with time, and the elastic modulus before swelling, 24h after swelling and 48h after swelling is kept at 130000Pa, which is about 2000-one, as shown in FIG. 4.

Experimental example 2

Testing of elastic and viscous moduli of gel samples:

a25 wt% 4-armPEG (thioester) -CHO/2 wt% PAMAM chemically crosslinked hydrogel of example 13 was formed into a shape of 9mm in diameter and 3mm in thickness by dynamic rheometer measurement, and the rheology test was conducted after stabilization for one hour. And measuring the changes of the elastic modulus and the viscous modulus of the hydrogel before swelling and after swelling (soaking in a PBS solution) along with time to obtain a change chart of the elastic modulus and the viscous modulus of the gel sample along with time, wherein the elastic modulus is kept at about 1000-50000Pa before swelling, 24h after swelling and 48h after swelling.

Experimental example 3

Testing of elastic and viscous moduli of gel samples:

a25 wt% 6-armPEG (thioester) -CHO/6 wt% PEI chemically crosslinked hydrogel of example 10 was formed into a shape of 9mm in diameter and 3mm in thickness by dynamic rheometer measurement, and the rheology test was conducted after stabilization for one hour. The change of the elastic modulus and the viscous modulus of the hydrogel with time is obtained, and the change of the elastic modulus and the viscous modulus of the gel sample with time is shown, and the elastic modulus is kept at about 1000-150000 Pa.

Experimental example 4

The dissolution behavior of the gel samples was determined:

the dissolution behavior of 25 wt% 4-armPEG (thioester) -CHO/3 wt% PAMAM chemically crosslinked hydrogel of example 9 was investigated, and the chemically crosslinked hydrogel after swelling for 48 hours in PBS was placed in 2m L of 1 mol/L aqueous cysteine methyl ester solution (pH8.6) and completely dissolved at 10 minutes.

Experimental example 5

The dissolution behavior of the gel samples was determined:

the dissolution behavior of the 25 wt% 4-armPEG (thioester) -CHO/2 wt% PAMAM chemically crosslinked hydrogel of example 13 was studied, as shown in FIG. 5. the chemically crosslinked hydrogel after swelling for 48h in PBS was placed in 2m L of 0.3 mol/L aqueous solution of methyl cysteine ester (pH8.6) (left vial in FIG. 5) and the hydrogel was substantially completely dissolved at 20 minutes, 2m L of 0.5 mol/L aqueous solution of methyl cysteine ester (pH8.6) (left vial in FIG. 5) and the hydrogel was substantially completely dissolved at 10 minutes, 2m L of 0.5 mol/L aqueous solution of α -chymotrypsin (pH7.5) (right vial in FIG. 5) and the hydrogel was substantially disintegrated at 20 minutes.

Experimental example 6

The dissolution behavior of the gel samples was determined:

the dissolution behavior of the 25 wt% 6-armPEG (thioester) -CHO/6 wt% PEI chemically crosslinked hydrogel of example 10 was investigated, and the chemically crosslinked hydrogel after swelling for 48 hours in PBS was placed in a 2m L aqueous solution of chymotrypsin (pH8.6) at 0.5 mol/L, and the hydrogel was substantially completely dissolved at 20 minutes.

Experimental example 7

The dissolution behavior of the gel samples was determined:

the dissolution behavior of the 15 wt% 8-armPEG (thioester) -CHO/5 wt% PEI chemically crosslinked hydrogel of example 11 was investigated, and the chemically crosslinked hydrogel after swelling for 48 hours in PBS was placed in 2m L of 1 mol/L aqueous chymotrypsin solution (pH8.6) and was substantially completely dissolved in 10 minutes.

Experimental example 8

The dissolution behavior of the gel samples was determined:

the dissolution behavior of the 20 wt% 8-armPEG (thioester) -CHO/4 wt% P LL chemically crosslinked hydrogel of example 12 was investigated, and the chemically crosslinked hydrogel after swelling for 48 hours in PBS was placed in 2m L of 0.5 mol/L chymotrypsin and 0.5 mol/L cysteine aqueous solution (pH8.6) and was substantially completely dissolved at 10 minutes.

Experimental example 9

The adhesion of the chemically crosslinked hydrogel was determined:

the adhesion behavior of the hydrogel on the skin surface of nude mice was tested by mixing 25 wt% 4-armPEG (thioester) -CHO/2 wt% PAMAM chemically crosslinked hydrogel of example 13 on the skin tissue surface of nude mice, applying a twisting force to the sample after sufficient gelling, and examining the adhesion ability of the hydrogel on the skin surface, and it was found that the hydrogel adhered well to the skin surface of nude mice, as shown in FIG. 6.

Experimental example 10

The application prospect of the hydrogel system as the liquid band-aid is determined as follows:

an SD rat is used as an animal model for carrying out an experiment, a wound model with the longitudinal length of 1cm is constructed on the surface of the skin of the SD rat, a control group adopts a Bundy waterproof woundplast to treat a wound, 25 wt% of 4-armPEG (thioester) -CHO/2 wt% PAMAM chemical crosslinking hydrogel in the embodiment 13 is applied to the wound of the skin of the SD rat, and after 24 hours, the control group directly tears the woundplast to carry out secondary injury on the skin wound; while the test group applied gauze impregnated with the cysteine methyl ester solution to the hydrogel surface, the hydrogel was easily removed in half a hour, as shown in fig. 7.

Experimental example 11

The application prospect of the emergency hemostatic material of the hydrogel system is determined as follows:

a SD rat femoral artery model was constructed, the femoral artery was punctured with a needle to cause massive hemorrhage, and 25 wt% 4-armPEG (thioester) -CHO/2 wt% PAMAM chemically crosslinked hydrogel of example 13 was applied to the femoral artery massive hemorrhage, and hemostasis was achieved after 1 minute, as shown in FIG. 8.

The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. The polyethylene glycol polymer containing thioester and aldehyde group is characterized in that the average molecular weight of the polyethylene glycol polymer is 2000-40000, and the polyethylene glycol polymer is a linear structure polyethylene glycol polymer or a multi-arm structure polyethylene glycol polymer;

the linear polyethylene glycol polymer has a structural formula:

wherein R is₁Is composed of

R₂Is composed of

R₃Is composed of

the number of arms of the multi-arm polyethylene glycol polymer is 3-8, and the structural formula is as follows:

wherein R is₁Is composed of

R₂Is composed of

R₃Is composed of

2. The method for preparing the thioester and aldehyde group-containing polyethylene glycol polymer according to claim 1, comprising the steps of:

I. preparation of carboxyl-terminated polyethylene glycol polymer: adding a polyethylene glycol macromonomer into an anhydrous dichloromethane solvent, adding a micromolecular monomer, adding a catalyst after complete dissolution for esterification reaction, extracting, drying, rotary steaming, settling and drying in vacuum after the reaction is finished to obtain a carboxyl-terminated polyethylene glycol polymer;

II. Preparation of thioester-containing polyethylene glycol polymer: dissolving the carboxyl-terminated polyethylene glycol polymer obtained in the step I, 4-dimethylaminopyridine and a dehydrating agent in an anhydrous dichloromethane solvent, adding an activated carboxyl-terminated micromolecule monomer for reaction, adding a sulfydryl donor micromolecule monomer and N, N-diisopropylethylamine for reaction after the reaction is finished, and filtering, extracting, drying, rotary steaming, settling and vacuum drying after the reaction is finished to obtain a polyethylene glycol polymer containing thioester;

3. The method for preparing a polyethylene glycol polymer containing thioester and aldehyde groups according to claim 2, wherein the small molecule monomer in step I comprises succinic anhydride, glutaric anhydride, phthalic anhydride, maleic anhydride, 1-cyclopentene-1, 2-dicarboxylic anhydride, 3-fluorophthalic anhydride, 4-fluorophthalic anhydride, methyl-5-norbornene-2, 3-dicarboxylic anhydride, bicyclo [2,2,1] hept-5-ene-2, 3-dicarboxylic anhydride or 3- (tert-butyldimethylsilyloxy) glutaric anhydride; the catalyst comprises 4-dimethylaminopyridine, N-hydroxysuccinimide or N-hydroxythiosuccinimide.

4. The method for preparing a polyethylene glycol polymer containing thioester and aldehyde groups according to claim 2, wherein the dehydrating agent in step II is N, N-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; the activated carboxyl-terminated small molecule monomer comprises N-hydroxysuccinimide or N-hydroxythiosuccinimide; the sulfhydryl donor micromolecule monomer comprises thioglycolic acid, mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptobutyric acid or 4-mercaptobutyric acid.

5. The method for preparing the polyethylene glycol polymer containing thioester and aldehyde group according to claim 2, wherein the catalyst in the step III is 4-dimethylaminopyridine, N-hydroxysuccinimide or N-hydroxythiosuccinimide, the dehydrating agent is N, N-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the aldehyde donor small molecule monomer is p-hydroxymethylbenzaldehyde, 2-hydroxy-5- (hydroxymethyl) benzaldehyde, 4-hydroxy-3-hydroxymethylbenzaldehyde or 4- (2-hydroxyethyl) benzaldehyde.

6. A chemically crosslinked hydrogel containing a thioester group that dissolves rapidly, comprising: 10-40 wt% of the polyethylene glycol polymer according to claim 1, 2-20 wt% of the primary amino group-containing high molecular polymer, and the balance of the vehicle.

7. The rapidly dissolvable chemical cross-linked hydrogel having a sulfide bond as claimed in claim 6, wherein said primary amino group-containing high molecular weight polymer comprises 2-4 th generation polyethylene diamine dendrimer PAMAM, polyethyleneimine PEI having an average molecular weight of 1800-70000 or polylysine P LL having an average molecular weight of 3000-70000.

8. The rapidly dissolvable chemical cross-linked hydrogel having a sulfide bond according to claim 6, wherein said vehicle comprises one or more of purified water, water for injection, physiological saline, buffer solution, body fluid of animal, plant or human body, tissue culture fluid, and cell culture fluid.

9. Use of a chemically cross-linked hydrogel containing thioester linkages capable of rapid dissolution according to any of claims 6 to 8 as or in the preparation of a drug loaded material, a tissue engineering scaffold, a medical sponge, a hemostatic sealant, a surface coating for medical implants, a topical hemostatic sealant coating, a coating for burn treatment or a material for preventing tissue adhesions.

10. The use of the chemical crosslinked hydrogel containing a thioester group capable of being rapidly dissolved according to claim 9, wherein the hydrogel is degraded in a body fluid environment or rapidly dissolved in a wash solution, and the wash solution comprises one or more of a methyl cysteine ester aqueous solution, a cysteine aqueous solution, and a chymotrypsin aqueous solution.