CN114702695A - PHA hydrogel and preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of medicines, and discloses PHA hydrogel and a preparation method and application thereof. The PHA hydrogel comprises the following raw material components: PHA, hyaluronic acid, gelatin and a photoinitiator. According to the invention, the main raw materials of the gel are formed by the action of hyaluronic acid, gelatin and PHA, the hydrogel is formed under the action of photoinitiator and ultraviolet light, and by controlling the dosage of each raw material, stable hydrogel can be formed under mild conditions, the breaking of molecular chains in PHA is not caused, and the molecular weight is stable and controllable; in addition, PHA in the hydrogel can be degraded to generate 3-hydroxybutyrate, so that the hydrogel is favorable for diminishing inflammation, easing pain, promoting cell growth and angiogenesis, and has strong wound healing capability.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to PHA hydrogel and a preparation method and application thereof.
Background
Hydrogels are widely used as drug carriers, and currently, polymer hydrogels dominate the hydrogel market. However, the residue of the polymer hydrogel also brings certain limitations to the application due to its non-degradability and toxicity, such as the commonly used polyacrylamide. Therefore, natural polymer hydrogels have attracted a wide range of attention.
Polyhydroxyalkanoate (PHA) is a degradable biopolymer material, which degrades in vivo to release 3-hydroxybutyrate (3HB) to promote tissue repair, and a large number of documents indicate that PHA has good biocompatibility. The PHA microspheres carrying exosomes are also shown in documents to be used for treating chronic wounds, so that inflammatory reaction can be well relieved; the PHA microspheres are used for carrying the mesenchymal stem cell exosomes, so that the angiogenesis can be promoted in vitro.
The hydrogel prepared from Polyhydroxyalkanoate (PHA) can be used for external application of trauma (such as burn). The hydrogel containing polyhydroxyalkanoate is externally applied, and the degradation product 3HB of PHA can provide a nutrient source for burn patients. However, in the current hydrogel containing polyhydroxyalkanoate, high temperature is adopted in the preparation process to break molecules of polyhydroxyalkanoate, so that the molecular weight of PHA in the prepared hydrogel is uncontrollable, and a good wound healing effect cannot be achieved.
Therefore, there is a need to provide a PHA hydrogel, which has no PHA molecule breakage, stable and controllable molecular weight, and good wound healing effect.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides the PHA hydrogel, PHA molecules in the hydrogel are not broken, the molecular weight is stable and controllable, and the PHA hydrogel has a good wound healing effect.
In a first aspect, the present invention provides a PHA hydrogel.
Specifically, the PHA hydrogel comprises the following raw material components: PHA, hyaluronic acid, gelatin and a photoinitiator.
Preferably, the PHA is selected from at least one of poly- β -hydroxybutyrate, 3-hydroxybutyrate, and 3-hydroxyvalerate copolymer (PHBV), 3-hydroxybutyrate copolyester with 3-hydroxyhexanoate (PHBHHx), or poly (3-hydroxybutyrate-co-4-hydroxybutyrate) (P34 HB).
Preferably, the PHA may be in any form, such as pure PHA powder or PHA microspheres, and the like. The PHA can be in any dosage form, such as a solid powder or a liquid, and the like.
Preferably, the preparation method of the PHA microspheres is as follows: dissolving PHA in a solvent, mixing with a polymer, and removing the solvent to obtain the PHA composite material; then dissolving the PHA composite material in a solvent to obtain an oil phase; dissolving polyvinyl alcohol or hyaluronic acid in water to prepare a water phase; mixing the oil phase and the water phase to obtain a mixture, emulsifying the mixture, and solidifying to obtain PHA microspheres; the polymer is one of polyethylene glycol, collagen, hyaluronic acid or polylysine.
Preferably, the PHA microspheres may be coated with drugs or coated with cells, such as anti-inflammatory drugs, mesenchymal stem cells, neural stem cells, hematopoietic stem cells, and the like. After being applied, the slow-release agent is slowly released to wound tissues or attached to wounds to help the wounds heal.
Preferably, the hyaluronic acid is a modified hyaluronic acid.
Further preferably, the modified hyaluronic acid is at least one selected from the group consisting of aminoethyl methacrylate hyaluronic acid, cinnamic acid modified hyaluronic acid, coumarin derivative modified hyaluronic acid, and a graft of hyaluronic acid and dopamine.
Preferably, the gelatin is a modified gelatin.
Further preferably, the modified gelatin is selected from at least one of methacrylamido gelatin, methacrylated gelatin, o-carboxylated gelatin, quaternized gelatin, or acid-aminated gelatin.
Preferably, the modified hyaluronic acid is aminoethyl methacrylate hyaluronic acid, and the modified gelatin is methacrylamido gelatin. Experiments show that the selection of the aminoethyl methacrylate hyaluronic acid and the methacrylamide gelatin is beneficial to forming uniform and stable gel under the ultraviolet light by the PHA, can reduce the irradiation time of the ultraviolet light, avoids the breakage of molecular chains in the PHA and keeps the molecular weight of the PHA unchanged.
Preferably, the photoinitiator is lithium phenyl-2, 4, 6-trimethylbenzoylphosphonate.
Preferably, the raw material components of the PHA hydrogel further comprise water.
Preferably, the PHA hydrogel comprises the following raw material components in parts by weight:
further preferably, the PHA hydrogel comprises the following raw material components in parts by weight:
more preferably, the PHA hydrogel comprises the following raw material components in parts by weight:
preferably, the raw material components of the PHA hydrogel further comprise at least one of alginate, chitin, chitosan or carboxymethyl chitosan.
Preferably, the raw material components of the PHA hydrogel further include at least one of glycopeptides, liposomes, nanosilver, dopamine, or antimicrobial polypeptides.
In a second aspect, the invention provides a method for preparing a PHA hydrogel.
Specifically, the preparation method of the PHA hydrogel comprises the following steps:
mixing the PHA, the hyaluronic acid, the gelatin, and the photoinitiator with water; then reacting under ultraviolet light to prepare the PHA hydrogel.
Preferably, the reaction temperature is 10-40 ℃, and the reaction time is 10-40 min; further preferably, the reaction temperature is 15-35 ℃, and the reaction time is 10-30 min.
More specifically, a method for preparing PHA hydrogel, comprising the following steps:
mixing the PHA, the aminoethyl methacrylate hyaluronic acid, the methacrylated gelatin, and the photoinitiator with water; then reacting under ultraviolet light to prepare the PHA hydrogel.
Preferably, the method for preparing the aminoethyl methacrylate hyaluronic acid is as follows: dissolving hyaluronic acid in water, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide and N- (2-aminoethyl) methacrylamide hydrochloride, reacting at 10-40 ℃, dialyzing after reaction, and freeze-drying to obtain the aminoethyl methacrylate hyaluronic acid.
Preferably, the dialysis uses a cellulose dialysis bag with a molecular weight cut-off of 800-.
Preferably, the preparation method of the methacrylated gelatin is as follows: dissolving gelatin in water, adding methyl methacrylate, reacting at 40-60 deg.C, dialyzing, and lyophilizing to obtain the final product.
Preferably, the dialysis uses a cellulose dialysis bag with a molecular weight cut-off of 800-1200 kDa.
In a third aspect, the invention provides a use of a PHA hydrogel.
Specifically, the PHA hydrogel is applied to the preparation of wound external materials or medicines; the wound surface external material or the drug has at least one of the following functions (1) to (4):
(1) relieving pain;
(2) diminishing inflammation;
(3) hemostasis is carried out;
(4) promoting tissue healing.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, the main raw materials of the gel are formed by the action of hyaluronic acid, gelatin and PHA, the hydrogel is formed under the action of photoinitiator and ultraviolet light, and by controlling the dosage of each raw material, stable hydrogel can be formed under mild conditions, the breaking of molecular chains in PHA is not caused, and the molecular weight is stable and controllable; in addition, PHA in the hydrogel can be degraded to generate 3-hydroxybutyrate, so that the hydrogel is favorable for diminishing inflammation, easing pain, promoting cell growth and angiogenesis, and has strong wound healing capability.
Drawings
FIG. 1 is a micrograph of a PHA hydrogel prepared in example 1;
FIG. 2 is a micrograph of the PHA hydrogel prepared in comparative example 1.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.
The starting materials, reagents or apparatuses used in the following examples are conventionally commercially available or can be obtained by conventionally known methods, unless otherwise specified.
Example 1
A PHA composite hydrogel comprises the following raw material components in percentage by mass: 12.5 wt% of aminoethyl methacrylate hyaluronic acid, 10 wt% of methacrylated gelatin, 0.5 wt% of PHA microspheres, 0.1 wt% of phenyl-2, 4, 6-trimethylbenzoyllithium phosphonate and the balance of water.
A preparation method of PHA composite hydrogel comprises the following steps:
(1) preparation of aminoethyl methacrylate hyaluronic acid: weighing 1g of hyaluronic acid, dissolving the hyaluronic acid in 100mL of distilled water, adding 0.25g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.125g N-hydroxysuccinimide and 0.125g N- (2-aminoethyl) methacrylamide hydrochloride after the hyaluronic acid is completely dissolved, reacting for 24 hours at room temperature (25 ℃), dialyzing by using a cellulose dialysis bag with the molecular weight cutoff of 1000kDa, and freeze-drying at-80 ℃ to obtain the aminoethyl methacrylate hyaluronic acid (HA-AEMA).
(2) Preparation of methacrylated gelatin: weighing 10g of gelatin, dissolving, adding into 100mL of distilled water, dissolving at 50 ℃, adding 15g of methyl methacrylate, reacting at 50 ℃ for 4h, dialyzing by using a cellulose dialysis bag with the molecular weight cutoff of 1000kDa, and freeze-drying at-80 ℃ to obtain the methacrylic acid gelatin (GelMA).
(3) Preparing PHA microspheres: preparing a solution of P34HB (poly (3-hydroxybutyrate-co-4-hydroxybutyrate) with the weight-average molecular weight of 3-6W) with the concentration of 20mg/mL by taking dichloromethane as a solvent; then taking 400mL of P34HB solution, adding 8g of PEG4000, stirring for dissolving, putting the solution into a 1L rotary evaporation bottle, carrying out rotary evaporation for 20h at the oil bath temperature of 45 ℃, and recovering the solvent by adopting condensed water at the temperature of-10 ℃; and freeze-drying the paste after rotary evaporation at-40 ℃ to obtain the PHA composite material. Adopting dichloromethane as a solvent, and preparing the PHA composite material prepared by the method into PHA composite material solution with the mass concentration of 30mg/mL to obtain an oil phase; dissolving polyvinyl alcohol (PVA) in 280mL of water to prepare a water phase with PVA mass concentration of 1.5%; mixing 40mL of the oil phase prepared in the step (2) with the water phase to obtain a mixed solution; adding the mixed solution into a conventional membrane emulsifier of Zhongkesen glow, setting the buffer pressure to be 0.015MPa, and checking the air tightness: 0.03MPa, 6.1 mu m and no air bubble; then a 6.1-micron membrane tube is used for carrying, the debugging emulsification pressure is 0.012MPa, the emulsification stirring rotating speed is 220r/min, and the emulsification is carried out for 60 min; after the emulsification is finished, adding 280mL of water, stirring for 40h at the rotating speed of 120r/min, and naturally volatilizing the organic solvent; and finally, freeze-drying for 31h to prepare the PHA microspheres.
(4) Adding 0.25g of aminoethyl methacrylate hyaluronic acid, 0.2g of methacrylated gelatin, 10mg of PHA microspheres and 2mg of phenyl-2, 4, 6-trimethylbenzoyllithium phosphonate into 2mL of deionized water, and uniformly stirring; then irradiating for 20min under ultraviolet light to obtain PHA hydrogel. FIG. 1 is a micrograph of PHA hydrogel, and it can be seen from FIG. 1 that the hydrogel had a uniform texture, no impurities, and good integrity.
Example 2
A PHA composite hydrogel comprises the following raw material components in percentage by mass: 12.5 wt% of aminoethyl methacrylate hyaluronic acid, 10 wt% of methacrylated gelatin, 0.5 wt% of PHA, 0.1 wt% of phenyl-2, 4, 6-trimethylbenzoyllithium phosphonate and the balance of water.
A preparation method of PHA composite hydrogel comprises the following steps:
(1) preparation of aminoethyl methacrylate hyaluronic acid: weighing 1g of hyaluronic acid, dissolving the hyaluronic acid in 100mL of distilled water, adding 0.25g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.125g N-hydroxysuccinimide and 0.125g N- (2-aminoethyl) methacrylamide hydrochloride after the hyaluronic acid is completely dissolved, reacting for 24 hours at room temperature (25 ℃), dialyzing by using a cellulose dialysis bag with the molecular weight cutoff of 1000kDa, and freeze-drying at-80 ℃ to obtain the aminoethyl methacrylate hyaluronic acid (HA-AEMA).
(2) Preparation of methacrylated gelatin: weighing 10g of gelatin, dissolving, adding into 100mL of distilled water, dissolving at 50 ℃, adding 15g of methyl methacrylate, reacting at 50 ℃ for 4h, dialyzing by using a cellulose dialysis bag with the molecular weight cutoff of 1000kDa, and freeze-drying at-80 ℃ to obtain the methacrylic acid gelatin (GelMA).
(3) Adding 0.25g of aminoethyl methacrylate hyaluronic acid, 0.2g of methacrylated gelatin, 10mg of PHA and 2mg of phenyl-2, 4, 6-trimethylbenzoyllithium phosphonate into 2mL of deionized water, and uniformly stirring; then irradiating for 20min under ultraviolet light to obtain PHA hydrogel.
The experimental invention shows that when the aminoethyl methacrylate hyaluronic acid is replaced by other modified hyaluronic acid or the methacrylated gelatin is replaced by other gelatin, hydrogel with uniform texture and good integrity is formed, and the ultraviolet irradiation is required for 40-60 min.
Comparative example 1
A PHA hydrogel, comprising the following raw material components in percentage by mass: 12.5 wt% of aminoethyl methacrylate hyaluronic acid prepared in example 1, 10 wt% of methacrylated gelatin prepared in example 1, 5 wt% of PHA microspheres prepared in example 1, 0.1 wt% of photoinitiator, and the balance of water.
A method for preparing a PHA hydrogel comprising the steps of:
adding 0.25g of aminoethyl methacrylate hyaluronic acid, 0.2g of methacrylated gelatin, 100mg of PHA microspheres and 2mg of phenyl-2, 4, 6-trimethylbenzoyl lithium phosphonate into 2mL of deionized water, and uniformly stirring; then irradiating for 20min under ultraviolet light to obtain PHA hydrogel. FIG. 2 is a micrograph of PHA hydrogel, and it can be seen from FIG. 2 that the hydrogel has a non-uniform texture and a non-uniform transparent state, and PHA microspheres are not well dispersed in other components, and thus have poor stability and uncontrollable effect in practical applications.
Comparative example 2
The PHA hydrogel comprises the following raw material components in percentage by mass: 12.5 wt% of aminoethyl methacrylate hyaluronic acid prepared in example 1, 10 wt% of methacrylated gelatin prepared in example 1, 0.001 wt% of PHA microspheres prepared in example 1, 0.1 wt% of photoinitiator, and the balance of water.
A method for preparing a PHA hydrogel comprising the steps of:
adding 0.25g of aminoethyl methacrylate hyaluronic acid, 0.2g of methacrylated gelatin, 20 mu g of PHA microspheres and 2mg of phenyl-2, 4, 6-trimethylbenzoyllithium phosphonate into 2mL of deionized water, and uniformly stirring; then irradiating for 20min under ultraviolet light to obtain PHA hydrogel.
The analysis of the prepared PHA hydrogel shows that the hydrogel prepared by the comparative example is in a non-uniform and transparent state, and the PHA microspheres are too few to be well dispersed, so that the effect of the hydrogel in practical application is weak.
Comparative example 3
A PHA complex, the complex comprising the following raw material components in percentage by mass: 22.5 wt% of methacrylated gelatin prepared in example 1, 0.5 wt% of PHA microspheres prepared in example 1, 0.1 wt% of photoinitiator, and the balance of water.
A method for preparing a PHA hydrogel comprising the steps of:
adding 0.45g of methacrylated gelatin, 10mg of PHA and 2mg of lithium phenyl-2, 4, 6-trimethylbenzoyl phosphonate into 2mL of deionized water, and uniformly stirring; then irradiating for 20min under ultraviolet light to obtain PHA compound.
It was found that the product prepared in this comparative example was a very hard, lumpy solid, not in the form of a hydrogel. Thus, hyaluronic acid is indispensable for the production of PHA hydrogels.
Comparative example 4
The PHA hydrogel comprises the following raw material components in percentage by mass: 22.5 wt% of aminoethyl methacrylate hyaluronic acid prepared in example 1, 0.5 wt% of PHA microspheres prepared in example 1, 0.1 wt% of photoinitiator, and the balance of water.
A method for preparing a PHA hydrogel comprising the steps of:
adding 0.45g of aminoethyl methacrylate hyaluronic acid, 10mg of PHA microspheres and 2mg of phenyl-2, 4, 6-trimethylbenzoyllithium phosphonate (0.1 wt%) into 2mL of deionized water, and uniformly stirring; then irradiating for 20min under ultraviolet light to obtain PHA hydrogel.
It was found that the product prepared in this comparative example was liquid in state and did not gel. Thus, it can be seen that gelatin and hyaluronic acid are indispensable for the preparation of PHA hydrogels.
Product effectiveness testing
(1) Clinical test of PHA-containing hydrogel for treating superficial second-degree and deep second-degree burn wounds
In clinical tests, 15 patients with superficial second-degree and deep second-degree burn wounds are selected respectively, hydrogel is locally used, the wounds of an experimental group are smeared with 2g of hydrogel dressing containing the hydrogel dressings of example 1, example 2 and comparative example 1, the thickness of the hydrogel dressing is 2 mm, and the outer layer of the wound dressing is wrapped with common gauze; the wound surface of the control group wound is coated with sulfadiazine silver ointment, single-layer vaseline oil is coated on the wound surface, 2g of the vaseline oil is 2 mm thick, and the wound surface of the control group wound is bound with common gauze. The days for wound healing (average days) were counted for each group, and the test results are shown in table 1.
TABLE 1
Clinical test results prove that the hydrogel containing PHA has the obvious effect of promoting wound healing.
2. Analgesia experiment
In the tail shearing experiment of the mice, the tails of the mice are sheared, 12 cases are respectively used, hydrogel is locally used, the wound surfaces of experimental groups are smeared with 2g of the hydrogel dressing containing the hydrogel dressing of the example 1, the thickness of the wound surfaces is 2 mm, and the wound surfaces of the experimental groups are bound by common gauze; the wound surface of the control group wound is coated with sulfadiazine silver ointment, a single layer of vaseline oil is coated on the wound surface, the thickness of the vaseline oil is 2g, the vaseline oil is coated on the wound surface, the wound surface is covered by gauze, and multiple layers of sterile gauze are additionally arranged for bandaging. The number of writhing (average number of writhing) occurred after the mice had suffered from pain was measured, and the results of the experiment are shown in Table 2.
TABLE 2
| Group of | Number of animals | Number of wriggling of mouse |
| Control group | 12 | 40.2 |
| Example 1 | 12 | 29.5 |
Experiments show that the PHA hydrogel prepared by the invention has good analgesic effect.
Claims (10)
1. The PHA hydrogel is characterized by comprising the following raw material components: PHA, hyaluronic acid, gelatin and a photoinitiator.
2. The PHA hydrogel of claim 1, wherein the hyaluronic acid is a modified hyaluronic acid; preferably, the modified hyaluronic acid is selected from at least one of aminoethyl methacrylate hyaluronic acid, cinnamic acid modified hyaluronic acid, coumarin derivative modified hyaluronic acid or a graft of hyaluronic acid and dopamine.
3. The PHA hydrogel of claim 1, wherein the gelatin is a modified gelatin; preferably, the modified gelatin is selected from at least one of methacrylamido gelatin, methacrylated gelatin, o-carboxylated, phthalylated gelatin, quaternized gelatin, or acid aminated gelatin.
4. The PHA hydrogel of claim 2 or 3, wherein the modified hyaluronic acid is an aminoethylmethacrylate hyaluronic acid and the modified gelatin is a methacrylamido gelatin.
5. The PHA hydrogel of any one of claims 1 to 3, wherein the raw material components of the PHA hydrogel further comprise water; the PHA hydrogel comprises the following raw material components in parts by weight:
6. the PHA hydrogel of claim 5, wherein the PHA hydrogel comprises the following raw material components:
7. the PHA hydrogel of claim 6, wherein the raw material components of the PHA hydrogel further comprise at least one of glycopeptides, liposomes, nanosilver, dopamine, or antimicrobial polypeptides.
8. The process for the preparation of PHA hydrogels of any one of claims 1 to 7, comprising the following steps:
mixing the PHA, the hyaluronic acid, the gelatin, and the photoinitiator with water; then reacting under ultraviolet light to prepare the PHA hydrogel.
9. The method according to claim 8, wherein the reaction temperature is 10 to 40 ℃ and the reaction time is 10 to 40 min.
10. Use of the PHA hydrogel of any one of claims 1 to 7 in the preparation of a wound-healing topical material or medicament; the wound surface external material or the drug has at least one of the following functions (1) to (4):
(1) relieving pain;
(2) diminishing inflammation;
(3) hemostasis is carried out;
(4) promoting tissue healing.
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| CN115417980A (en) * | 2022-10-08 | 2022-12-02 | 万华化学集团股份有限公司 | High-adhesion polyester polyol and preparation method thereof |
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| CN115417980A (en) * | 2022-10-08 | 2022-12-02 | 万华化学集团股份有限公司 | High-adhesion polyester polyol and preparation method thereof |
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