CN109280129B - A salt-responsive injectable hydrogel polymer and its preparation method under physiological conditions - Google Patents

Abstract

A salt-responsive injectable hydrogel polymer under physiological conditions and a preparation method thereof are prepared by grafting a salt-responsive functional segment on a biocompatible matrix material. The matrix material provides the polymer with good water solubility and biocompatibility, and the salt-responsive functional unit can enable the polymer to generate hydrophobic association due to electrostatic shielding under the action of the electrolyte, and build physical cross-linking points between macromolecules, so that the The polymer undergoes a sol-gel transition to form a hydrogel. By rationally designing the molecular structure of the polymer, the copolymer is a sol in pure water at room temperature and is injectable. After entering the body, it undergoes gelation transformation under the action of electrolytes to form a hydrogel. This salt-responsive polymer for injectable hydrogels under physiological conditions is used in the field of biotherapeutics.

Description

A salt-responsive injectable hydrogel polymer and its preparation under physiological conditions backup method

technical field

The present invention relates to the technical field of polymers, in particular to a salt-responsive injectable gel polymer and a preparation method thereof under physiological conditions.

Background technique

Tissue engineering has been widely used in the field of biotherapy in recent decades, especially for the treatment of defects. However, its clinical application is very limited, because traditional tissue regeneration methods, such as the formation of hydrogel scaffolds, need to face the problems of wound trauma, infection, and incompatibility to the defect site leading to scaffold failure. Therefore, it is necessary to seek new gel materials with good biocompatibility, minimally invasive injection, and repair of deep tissue damage without destroying the blood supply to the repaired area.

At present, the polymers with good biocompatibility are mainly polysaccharides and polyvinyl alcohol. Polysaccharide is a kind of natural macromolecule, which widely exists in the body of animals and plants, so it has a wide range of sources, and it also has the characteristics of biodegradation, non-toxic metabolites, and can be completely absorbed by organisms; polyvinyl alcohol is also a kind of applied It has been proven to be a very safe and biocompatible synthetic polymer material for biotherapy. However, these two types of polymer materials are generally difficult to form hydrogels, so many scholars propose to modify them, by introducing other components into the solution or directly modifying the polymer, so that the polymer solution can be modified. Injectability and Physiological Responsiveness. At present, most of the research is on thermosensitive hydrogels, such as chitosan/sodium glycerophosphate injectable gel, which is an aqueous solution at room temperature. When the temperature reaches around 37 °C, chitosan is hydrophobic through proton transfer. enhanced to form a gel. However, this multi-component system has problems such as long phase transition time, easy diffusion and transfer of β-glycerophosphate small molecules, resulting in uneven concentration, certain side effects and insufficient gel strength when the content is high, which limits its application. .

In view of the above-mentioned problems, the present invention provides a salt-responsive water-soluble polymer, which is a hydrophilic macromolecule with good biocompatibility by introducing salt-responsive functional structural units. Under the electrostatic shielding effect of the electrolyte, the hydrophobic association between polymers can be enhanced and the polymers can be gelled. By rationally designing the molecular structure, the polymer can be made into a sol in pure water, which is injectable, and can form a hydrogel under the action of sodium ions under physiological conditions. Secondly, according to actual needs, the molecular structure can be adjusted to change the size of the intermolecular interaction, and the properties such as gel strength and gelation speed can be adjusted to broaden its application range. In addition, compared with the general thermosensitive system, the system does not contain small molecules, and there is no diffusion and transfer, so the concentration is more uniform, the response is more sensitive, and there are no side effects. It can repair deep tissues without damaging the blood supply to the repaired area.

SUMMARY OF THE INVENTION

The purpose of the present invention is to overcome the deficiencies of the prior art and provide a polymer for injectable hydrogel based on salt response under physiological conditions.

A salt-responsive injectable hydrogel polymer under physiological conditions is prepared by grafting salt-responsive functional macromolecules on a biocompatible matrix material.

Wherein, the biocompatible matrix material is selected from chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, hemicellulose, xanthan gum, starch, polyethylene One or more of alcohols; monomers with salt-responsive functional segments are selected from acrylamide, sodium acrylate, alkyl acrylate, N-alkyl acrylamide, styrene sulfonate, acrylamide alkyl One or more of sulfonates; the polymer is a sol in pure water, is injectable, and transforms into a hydrogel under physiological conditions based on its salt-responsive energy.

The polymer contains at least one ionic functional monomer unit and at least one functional monomer unit with an alkyl chain.

Preferably, the number of carbon atoms in the alkyl chain of the alkyl acrylate, N-alkylacrylamide, and acrylamide alkylsulfonate is each independently 3-12.

Preferably, the functional monomer is selected from acrylamide, sodium acrylate, ethyl acrylate, butyl acrylate, heptyl acrylate, nonyl acrylate, N-tert-butyl acrylamide, N-octyl acrylamide, styrene sulfonate one or more of acid salts, acrylamide butyl sulfonate, acrylamide hexyl sulfonate, acrylamide octyl sulfonate, acrylamide decyl sulfonate, acrylamide dodecyl sulfonate .

Preferably, the biocompatible matrix material is selected from one or more of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, starch and polyvinyl alcohol kind.

The graft ratio of the polymer is 30% to 300%. The calculation method of the graft ratio: the mass of the purified graft copolymer is m ₁ , and the mass of the base material before grafting is m ₂ ; then the graft ratio G%=[(m ₁ -m ₂ )/m ₂ ]× 100%.

The present invention also provides the preparation method of polymer:

The polymers are prepared by homogeneous grafting or heterogeneous graft copolymerization.

The preparation method of the polymer is as follows: the macromolecules with biocompatibility are prepared into a mixed system with a concentration of 0.1wt% to 5wt% with deionized water or 1% acetic acid, a certain proportion of functional monomers are added, and the temperature is room temperature. Argon gas was introduced into the solution for 30 min, the initiation temperature was controlled between 40 °C and 70 °C, an initiator was added, and the reaction was carried out for 2 h to 6 h. The obtained copolymer was separated from the solution, purified and dried to obtain a graft copolymer.

The biocompatible matrix material is selected from chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, hemicellulose, xanthan gum, starch, polyvinyl alcohol one or more of;

The monomer of the functional segment is selected from one or more of acrylamide, sodium acrylate, alkyl acrylate, N-alkylacrylamide, styrene sulfonate, and acrylamide alkyl sulfonate;

The polymer contains at least one ionic functional monomer unit and at least one functional monomer unit with an alkyl chain;

The graft ratio of the polymer is 30% to 300%. The calculation method of the graft ratio: the mass of the purified graft copolymer is m ₁ , and the mass of the base material before grafting is m ₂ ; then the graft ratio G%=[(m ₁ -m ₂ )/m ₂ ]× 100%;

Described initiator can be the initiator well known to those skilled in the art, and there is no special limitation;

The present invention also provides the application of the polymer in the field of biotherapy.

The present invention has the following beneficial effects:

The present invention provides a salt-responsive polymer for injectable hydrogels under physiological conditions and a preparation method thereof. The polymer has a salt-responsive functional structure by grafting a biocompatible matrix material. The polymer has the following beneficial effects: 1. The matrix polymer has good hydrophilicity and biocompatibility; 2. Its salt responsiveness is based on the electrostatic shielding effect of electrolytes rather than ions under physiological conditions. Cross-linking, when the ionic groups on the functional units are electrostatically shielded, the hydrophilicity of the polymer decreases, resulting in hydrophobic association, building physical cross-linking points between macromolecules, and causing the polymer to undergo a sol-gel transition To form a hydrogel, there is no need to introduce other cross-linking agent components; 3. By rationally designing the molecular structure, the polymer can be made into a sol in pure water, which is injectable. Under physiological conditions, it can be affected by sodium ions. form a hydrogel. In addition, properties such as gel strength and gelation speed can also be adjusted according to actual needs, and the application range is wide. 4. Wide source of raw materials, mild synthesis conditions and easy industrialization.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

The present invention provides a salt-responsive injectable hydrogel polymer under physiological conditions, which is prepared by grafting salt-responsive functional macromolecules on a biocompatible matrix material.

Wherein, the biocompatible matrix material is selected from chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, hemicellulose, xanthan gum, starch, polyethylene One or more of alcohols; monomers with salt-responsive functional segments are selected from acrylamide, sodium acrylate, alkyl acrylate, N-alkyl acrylamide, styrene sulfonate, acrylamide alkyl One or more of sulfonates; the polymer is a sol in pure water, is injectable, and transforms into a hydrogel under physiological conditions based on its salt-responsive energy.

The polymer contains at least one ionic functional monomer unit and at least one functional monomer unit with an alkyl chain.

The number of carbon atoms of the alkyl chain in the alkyl acrylate, N-alkylacrylamide, and acrylamide alkyl sulfonate is each independently 3-12, preferably 4-10, more preferably 6-9, Most preferably 8.

Preferably, the functional monomer is selected from acrylamide, sodium acrylate, ethyl acrylate, butyl acrylate, heptyl acrylate, nonyl acrylate, N-tert-butyl acrylamide, N-octyl acrylamide, styrene sulfonate Acrylamide butyl sulfonate, acrylamide hexyl sulfonate, acrylamide octyl sulfonate, acrylamide decyl sulfonate, acrylamide dodecyl sulfonate.

Preferably, the biocompatible matrix material is selected from one of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, starch, and polyvinyl alcohol.

The graft ratio of the polymer is 30%-300%, preferably 50%-300%, more preferably 80%-250%, most preferably 100%-200%. The calculation method of the graft ratio: the mass of the purified graft copolymer is m ₁ , and the mass of the base material before grafting is m ₂ ; then the graft ratio G%=[(m ₁ -m ₂ )/m ₂ ]× 100%.

The polymers can undergo a sol-gel transition based on electrostatic shielding and hydrophobic association under physiological conditions.

The present invention relates to a salt-responsive polymer for injectable hydrogels, which is prepared by grafting salt-responsive functional structural units on a biocompatible matrix material, and thus has good The hydrophilicity and biocompatibility of the polymer; its salt responsiveness is based on the electrostatic shielding effect of the electrolyte rather than the ionic crosslinking effect. When the ionic groups on the functional units are electrostatically shielded, the hydrophilicity of the polymer decreases, resulting in The hydrophobic association creates physical cross-linking points between macromolecules, so that the polymer undergoes a sol-gel transition, and hydrogels can be formed without introducing other cross-linking agents. By rationally designing the molecular structure, the polymer can be made into a sol in pure water, which is injectable, and can form a hydrogel under the action of sodium ions under physiological conditions. In addition, properties such as gel strength and gelation speed can also be adjusted according to actual needs, and the application range is wide. The raw materials for the preparation of polymers are widely sourced, the synthesis conditions are mild, and the industrialization is easy.

The present invention also provides a method for preparing a salt-responsive injectable polymer for hydrogel.

The polymers are prepared by homogeneous grafting or heterogeneous graft copolymerization. The specific preparation method is as follows: preparing a biocompatible macromolecule with deionized water or 1% acetic acid into a mixed system with a concentration of 0.1wt% to 5wt%, adding a certain proportion of functional monomers, and passing argon at room temperature Incubate for 30min, control the initiation temperature between 40℃～70℃, add the initiator, react for 2h～6h, separate the obtained copolymer from the solution, purify and dry to obtain the graft copolymer.

The raw materials and proportions are the same as above, and are not repeated here. The initiator may be an initiator well known to those skilled in the art, and there is no special limitation. The graft ratio of the polymer is 30% to 300%, preferably 50% to 300%, more preferably 80% to 250%, and most preferably 100% to 200%.

The following examples will further illustrate the salt-responsive-based injectable hydrogel polymers and preparation methods of the present invention.

The reagents used in the following examples are all commercially available.

Example 1

Homogeneous graft copolymerization: dissolve 2 g of polyvinyl alcohol in 100 g of deionized water to prepare a solution with a mass concentration of 2%, add 2 g of functional monomer sodium acrylamide octyl sulfonate, and pass argon gas at room temperature for 30 minutes to control the initiation temperature At 40°C, the initiator ceric ammonium nitrate was added to make the concentration 0.2 mol/L, and the reaction was carried out for 4 h. The obtained copolymer was separated from the solution, purified and dried to obtain 3.6 g of the graft copolymer. Calculation of graft ratio: the mass of the purified graft copolymer is m ₁ , and the mass of the base material before grafting is m ₂ ; then the graft ratio G%=[(m ₁ -m ₂ )/m ₂ ]×100 %. The graft ratio of the copolymer was calculated as 80% in the above manner.

Example 2

Heterogeneous graft copolymerization: Dissolve 1 g of chitosan in 100 g of deionized water to form a mixed system with a mass concentration of 1%, add 2 g of functional monomer sodium acrylamide decyl sulfonate, pass argon at room temperature for 30 minutes, control The initiation temperature was 40°C, the initiator ceric ammonium nitrate was added to make the concentration 0.2mol/L, and the reaction was carried out for 2h. The obtained copolymer was separated from the solution, purified and dried to obtain 1.35g of graft copolymer. The graft ratio of the copolymer was calculated as in Example 1 to be 35%.

Example 3

5 g of chitosan oligosaccharide was dissolved in 100 g of deionized water to prepare a solution with a mass concentration of 5%, 0.8 g of functional monomer sodium acrylate and 2 g of heptyl acrylate were added respectively, and argon gas was introduced for 30 min at room temperature, and the initiation temperature was controlled to 65 ° C. The initiator ceric ammonium nitrate was added to make the concentration of 0.2 mol/L, and the reaction was carried out for 6 h. The obtained copolymer was separated from the solution, purified and dried to obtain 6.7 g of the graft copolymer. The graft ratio of the copolymer was calculated as in Example 1 to be 34%. Dissolve 1.6 g of the graft copolymer in 10 g of pure water, prepare a solution with a mass concentration of 16%, slowly add it to 10 g of a sodium chloride solution with a mass concentration of 1.8%, stir for 3 minutes and put it in a water bath at 37°C , the solution gradually changed from sol to gel.

Example 4

Dissolve 1 g of chitosan in 100 g of 1% acetic acid solution to prepare a solution with a mass concentration of 1%, add 2 g of functional monomer sodium styrene sulfonate and 2 g of N-octyl acrylamide respectively, and pass argon at room temperature for 30 min , control the initiation temperature to 50°C, add the initiator ceric ammonium nitrate to make the concentration 0.2mol/L, react for 4h, separate, purify and dry the obtained copolymer from the solution to obtain 3.2g of graft copolymer. The graft ratio of the copolymer was calculated as in Example 1 to be 220%. Dissolve 1 g of the graft copolymer in 10 g of pure water, prepare a solution with a mass concentration of 10%, slowly add it to 10 g of a sodium chloride solution with a mass concentration of 1.8%, stir for 5 minutes and put it in a 37 ° C water bath, The solution quickly changed from a sol to a gel.

Example 5

To illustrate the importance of molecular design, different monomers were used to synthesize polymers with different graft ratios. The states of the copolymers under pure water at room temperature and physiological conditions (0.9% sodium chloride solution, 37°C) are shown in Table 1 below. :

Table 2

Claims (7)

1. An injectable hydrogel polymer based on salt response under physiological conditions, which is prepared by grafting functional macromolecules with salt response on a biocompatible matrix material; wherein the biocompatible matrix material is selected from one or more of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, hemicellulose, xanthan gum, starch and polyvinyl alcohol; the monomer with the salt-responsive functional chain segment is selected from one or more of acrylamide, sodium acrylate, alkyl acrylate, N-alkyl acrylamide, styrene sulfonate and acrylamide alkyl sulfonate; the polymer is sol in pure water, has injectability and can be converted into hydrogel under physiological conditions based on salt induction energy; the polymer at least contains one ionic monomer unit with a functional chain segment with salt responsiveness, and at least contains one monomer unit with an alkyl chain with a functional chain segment with salt responsiveness.

2. The polymer according to claim 1, wherein the number of carbon atoms in the alkyl chain of the alkyl acrylate, the N-alkylacrylamide, or the acrylamide alkylsulfonate is 3 to 12, independently of each other.

3. The polymer of claim 1, wherein the monomer having a functional segment with salt responsiveness is selected from one or more of acrylamide, sodium acrylate, ethyl acrylate, butyl acrylate, heptyl acrylate, nonyl acrylate, N-t-butylacrylamide, N-octylacrylamide, styrene sulfonate, acrylamide butyl sulfonate, acrylamide hexyl sulfonate, acrylamide octyl sulfonate, acrylamide decyl sulfonate, and acrylamide dodecyl sulfonate.

4. The polymer of claim 1, wherein the biocompatible matrix material is selected from one or more of chitosan, chitosan oligosaccharide, carboxylated chitosan, alkylated chitosan, cellulose, starch, polyvinyl alcohol.

5. The polymer of claim 1, wherein the polymer has a grafting yield of 30% to 300%.

6. The polymer of claim 1, wherein the polymer is prepared by a homogeneous graft or heterogeneous graft copolymerization process.

7. The polymer of claim 1, wherein the polymer is prepared by the following steps: preparing a mixed system with the concentration of 0.1 wt% -5 wt% by using deionized water or 1% acetic acid for macromolecules with biocompatibility, adding a certain proportion of monomers with functional chain segments with salt responsiveness, introducing argon gas for 30min at room temperature, controlling the initiation temperature to be between 40 ℃ and 70 ℃, adding an initiator, reacting for 2 h-6 h, and separating, purifying and drying the obtained copolymer from a solution to obtain the graft copolymer.