CN107875444B - Preparation method of biodegradable hydrogel scaffold material for cardiac repair - Google Patents
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- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
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- A61L2430/00—Materials or treatment for tissue regeneration
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Abstract
The invention relates to the technical field of biomedical materials, in particular to a preparation method of a biodegradable hydrogel stent material for heart repair. So as to solve the problems of immunological rejection caused by the treatment of heart disease by the traditional allotransplantation method, serious shortage of donor organs and the like. The preparation method adopted by the technical scheme of the invention comprises the following steps: 1) preparing PVL-PEG-PVL; 2) modification; 3) preparing the hydrogel scaffold material.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a preparation method of a biodegradable hydrogel stent material for heart repair.
Background
Heart disease has a high morbidity and mortality rate in clinical medicine, accounting for 12% of the worldwide mortality rate. Therefore, the life health of people in the world is seriously threatened, and the life of people is seriously influenced. The method of using ventricular assist devices and the method of allogeneic heart transplantation have been used for the treatment of damaged cardiac areas for many years, but the method of using ventricular assist devices has problems of large size, complex structure and control, high device failure rate, and the like. Although the method of allogeneic heart transplantation can effectively treat patients in middle and late stages, the method also has the problems of potential immunological rejection, insufficient donor organs and the like. The rise of cardiac tissue engineering provides a new approach to solve the above-mentioned problems.
Cardiac tissue engineering is a new research field developed in recent years, and is a novel interdiscipline combining molecular biology, cell biology, materials science and molecular mechanics, and the principles of engineering and life science are applied to develop biomaterials capable of growing, repairing or improving the functions of damaged tissues and organs. The method mainly comprises the contents of seed cells, biological scaffold materials, tissue construction and the like. The scaffold material is an adhesion supporting substance for the growth and proliferation of seed cells, so the scaffold material must have certain biocompatibility, degradability, cell adhesion and good binding property with growth factors. Cells can adhere to the scaffold material and differentiate to form new tissue regions to replace the original damaged regions. The characteristics of the scaffold material can play a crucial role in whether or not an engineered tissue can ultimately be formed. The development of multifunctional (tissue generation and degradation) scaffold materials for cardiac tissue engineering is one of the most critical issues in the development of the current field of tissue engineering.
The medical implant hydrogel material has reliable biological safety and good biocompatibility, the higher water content of the medical implant hydrogel material is very similar to the environment of a human cell matrix, and small molecules such as growth factors and the like can freely enter and exit from 'cavities' in the gel. The high liquid content makes it suitable for cell seeding and encapsulation. In addition, they are also strongly recommended for tissue implantation and other biomedical applications due to their biocompatibility and excellent diffusion properties. And since it can also support the adhesion and growth of cells, hydrogels are widely used in cardiac tissue engineering. In recent years, medical implant hydrogel materials of polyesters prepared by taking PEG as a raw material are mostly prepared by adding substances such as a cross-linking agent, and thus, the cross-linking agent harmful to organisms is introduced into a gel system to cause cells to be diseased. And its curing to form a gel cannot be performed at room temperature. Such as hilbon, d.a.o.a. etc. (macromolecules, 2006,39 (5)) utilize a click reaction to prepare a hydrogel, but a metal catalyst and an initiator are introduced in the preparation process, and the substances can cause harm to human health, and meanwhile, some inevitable byproducts are generated in the gelation process, so that the gel strength is greatly reduced. Yu, L et al (Polymer chemistry,2007,45 (60)) prepared temperature-sensitive hydrogels of PEG-based triblock copolymers by in situ injection molding. However, the hydrogel is mainly formed by crosslinking through physical interaction (such as hydrogen bonds) between molecular chains, so that the crosslinking degree and strength are far from enough.
In addition, ultraviolet light initiated polymerization has the advantages of energy saving, no pollution, no need of using a crosslinking reagent, convenient operation and the like, so the ultraviolet light initiated polymerization is often used for preparing medical hydrogel materials. However, the existing hydrogel prepared by photocuring has a long curing time, and cannot prepare a gel with a large volume and uniform crosslinking due to the limitation of light penetration capability, and the gel material is often deformed due to an excessively large curing shrinkage rate of the gel. So that the hydrogel material does not degrade at a uniform rate with cell growth after implantation into the human body. For example, Sawhney et al (macromolecules, 1993,26, 58) have prepared PEG-based hydrogels by ultraviolet light initiation, but the intensity of light gradually decreases in the vertical direction inside the gel during curing, so that hydrogel materials with large volume, uniform cross-linking and complex shape cannot be prepared.
Disclosure of Invention
The invention provides a preparation method of a biodegradable hydrogel scaffold for heart repair, which aims to solve the problems of immunological rejection and serious deficiency of donor organs caused by the treatment of heart diseases by a traditional allotransplantation method.
In order to solve the problems in the prior art, the technical scheme of the invention is as follows: a preparation method of a biodegradable hydrogel scaffold material for heart repair is characterized by comprising the following steps: the preparation method comprises the following steps:
1) preparation of PVL-PEG-PVL
a. Weighing 2g of polyethylene glycol PEG and 4mL of anhydrous-valerolactone, adding into a test tube, uniformly stirring, and then adding a catalyst stannous octoate according to 2-5 wt% of the polyethylene glycol, and uniformly stirring;
b. vacuumizing the reaction system for 10min to remove water and oxygen in the reaction system, and reacting the sealing body at the temperature of 110-140 ℃ for 12-16 h;
c. dissolving the product obtained by the reaction in dichloromethane DCM, removing bubbles in the solution by ultrasonic wave, moving the solution into a mould to remove the dichloromethane DCM, and preparing the product into PVL-PEG-PVL triblock copolymer for later use;
2) modification of
a. Dissolving the synthesized PVL-PEG-PVL triblock copolymer in anhydrous tetrahydrofuran THF under the protection of nitrogen, cooling to 0 ℃, then adding anhydrous triethylamine 4 times of the polymer, slowly dropwise adding a tetrahydrofuran solution of acryloyl chloride by using a constant-pressure dropping funnel, stirring the reaction mixture at 0 ℃ for 4 hours, reacting overnight at room temperature, centrifuging at 5000r/min for half an hour, removing generated triethylamine hydrochloride, pouring out the supernatant, adding 5 times of excessive n-hexane at-4 ℃, fully stirring, standing, pouring out the supernatant to obtain a macromonomer, further using tetrahydrofuran and n-hexane as a good solvent and a poor solvent, dissolving, precipitating, performing suction filtration repeatedly twice, and finally performing vacuum drying at 40 ℃ for 24 hours to obtain a gel precursor, freezing and sealing for preservation in dark;
3) preparation of hydrogel scaffold Material
a. Phosphate buffered saline PBS with pH 7.4 was prepared
Dissolving 0.5g of PVL-PEG-PVL gel precursor modified by acryloyl chloride in phosphate buffer solution to form 0.05g/mL solution, and heating the solution on magnetic stirring to fully dissolve the PVL-PEG-PVL gel precursor;
b. and (b) adding a photoinitiator 2, 2-dimethoxy-2-phenylacetophenone DMPA into the solution obtained in the step a according to 0.5wt% of the amount of the monomer, stirring and dissolving uniformly, and forming the hydrogel material in 5min under 365nm ultraviolet light.
The volume ratio of the acryloyl chloride to the tetrahydrofuran solution in the step 2) is 1: 10.
The dropping speed of the constant pressure dropping funnel is 2 s/drop.
Compared with the prior art, the invention has the following advantages:
the whole preparation process has the advantages of mild conditions (ultraviolet photocurrent of 15A), energy conservation, no pollution, high speed (curing speed within 5 min), high precision (molding shrinkage of about 4% when no filler is added), convenient operation and the like, and most importantly, the preparation process has no toxic cross-linking agent and has high biological safety;
the hydrogel scaffold material prepared by the invention can effectively solve the problems of immunological rejection of heart implantation and serious insufficiency of donor organs;
the hydrogel scaffold material prepared by the invention is composed of a poly valerolactone-polyethylene glycol-poly valerolactone (PVL-PEG-PVL) triblock copolymer modified by Acryloyl Chloride (AC); as an aliphatic polyester material, the aliphatic polyester material has good degradation performance besides good biocompatibility, can not stay in a human body for a long time, can be used for ultraviolet curing 3D printing, namely, the material can be individually designed and customized by adopting a 3D printing technology, has low curing shrinkage and high strength due to the structural characteristics of the material, is high in printing precision and speed, and can meet the requirements of future clinical application by printing multiple layers of hydrogel according to requirements.
Drawings
FIG. 1 is a Fourier transform infrared spectrum of a synthetic PVL-PEG-PVL;
FIG. 2 is a tensile curve of a hydrogel;
in FIG. 3, a and b are SEM images of the hydrogel at different magnifications;
FIG. 4 is a graph showing the degradation curve of a hydrogel at 37 ℃.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The first embodiment is as follows:
the preparation method of the biodegradable hydrogel scaffold material for heart repair comprises the following steps:
1) preparation of Polyvalerolactone-polyethylene glycol-Polyvalerolactone (PVL-PEG-PVL)
a. Weighing 2g of polyethylene glycol (PEG) (except water) and 4mL of valerolactone (-VL) (except water) and adding into a test tube to be uniformly stirred, and then adding 0.138g of catalyst stannous octoate to be uniformly stirred;
b. vacuumizing the reaction system for 10min to remove water and oxygen in the reaction system, and reacting the sealed system at the temperature of 120 ℃ for 14 h;
c. dissolving the product obtained by the reaction in Dichloromethane (DCM), removing air bubbles in the solution by ultrasound, moving the solution into a mold to remove the Dichloromethane (DCM), and preparing the product into a film (PVL-PEG-PVL triblock copolymer) for later use.
2) Modification of
a. Dissolving 1.2g of the synthesized PVL-PEG-PVL triblock copolymer in 20mL of anhydrous Tetrahydrofuran (THF) under the protection of nitrogen, cooling to 0 ℃, adding anhydrous triethylamine 4 times of the polymer, slowly dripping (2 s/drop) 20mL of an acryloyl chloride tetrahydrofuran solution (volume ratio is 1: 10) by using a constant-pressure dropping funnel, stirring the reaction mixture at 0 ℃ for 4 hours, reacting at room temperature overnight, centrifuging at 5000r/min for half an hour, removing triethylamine hydrochloride generated, pouring out the supernatant, adding 5 times of excessive n-hexane at-4 ℃, fully stirring, standing, pouring out the supernatant to obtain a macromonomer, further using Tetrahydrofuran (THF) and n-hexane as a good solvent and a poor solvent, dissolving, repeatedly carrying out suction filtration twice, finally, vacuum drying for 24h at 40 ℃ to obtain a gel precursor, and freezing and sealing for storage in a dark place.
3) Preparation of hydrogel scaffold Material
(1) Phosphate Buffered Saline (PBS) with pH 7.4 was prepared
Taking 0.5g of Acryloyl Chloride (AC) modified PVL-PEG-PVL gel precursor, dissolving the precursor in 10mL of phosphate buffer solution (PBS, PH = 7.4) to form a homogeneous solution with the concentration of 0.05g/mL, and heating the solution on a magnetic stirring way to fully dissolve the precursor;
(2) and (b) adding 0.025g of photoinitiator 2, 2-dimethoxy-2-phenylacetophenone (DMPA) into the solution obtained in the step a, stirring and dissolving uniformly, and forming a hydrogel material in 5min under ultraviolet light (365 nm).
Example 2:
the preparation method of the biodegradable hydrogel scaffold material for heart repair comprises the following steps:
1) preparation of Polyvalerolactone-polyethylene glycol-Polyvalerolactone (PVL-PEG-PVL)
a. Weighing 2g of PEG (PEG) (water removal) and 4mL of valerolactone (-VL) (water removal) and adding into a test tube to be uniformly stirred, and then adding 0.021g of catalyst stannous octoate to be uniformly stirred;
b. vacuumizing the reaction system for 10min to remove water and oxygen in the reaction system, and reacting the sealed system at the temperature of 130 ℃ for 15 hours;
c. dissolving the product obtained by the reaction in Dichloromethane (DCM), removing air bubbles in the solution by ultrasound, moving the solution into a mold to remove the Dichloromethane (DCM), and preparing the product into a film (PVL-PEG-PVL triblock copolymer) for later use.
2) Modification of
a. Dissolving 1.2g of the synthesized PVL-PEG-PVL triblock copolymer in 20mL of anhydrous Tetrahydrofuran (THF) under the protection of nitrogen, cooling to 0 ℃, adding anhydrous triethylamine 4 times of the polymer, slowly dropwise adding (2 s/drop) 20mL of an acryloyl chloride tetrahydrofuran solution (volume ratio is 1: 10) by using a constant-pressure dropping funnel, stirring the reaction mixture at 0 ℃ for 4 hours, reacting overnight at room temperature, centrifuging (5000 r/min) for half an hour, removing triethylamine hydrochloride generated, pouring out the supernatant, adding n-hexane (-4) 5 times of the excessive amount, fully stirring, standing, pouring out the supernatant to obtain a macromonomer, further using Tetrahydrofuran (THF) and the n-hexane as a good solvent and a poor solvent, dissolving, precipitating, suction-filtering, dissolving, Repeating twice, drying at 40 deg.C for 24 hr, and freezing and sealing in dark to obtain gel precursor.
3) Preparation of hydrogel scaffold Material
(1) Phosphate Buffered Saline (PBS) at pH 7.4 was prepared.
Dissolving 0.5g of PVL-PEG-PVL gel precursor modified with Acryloyl Chloride (AC) in 10mL of phosphate buffer (PBS, pH = 7.4) to form a homogeneous solution with a concentration of 0.05g/mL, and heating the solution under magnetic stirring to fully dissolve the precursor;
(2) and (b) adding 0.025g of photoinitiator 2, 2-dimethoxy-2-phenylacetophenone (DMPA) into the solution obtained in the step a, stirring and dissolving uniformly, and forming a hydrogel material in 5min under ultraviolet light (365 nm).
In the above examples, example 2 was the best example, and the results of the tests were as follows:
the PEG hydrogel selected in the step 1) has good biocompatibility, does not generate immune rejection reaction after being implanted into a human body, but has poor adhesion performance of cells and growth factors due to the inertia of the surface. The block copolymer PVL-PEG-PVL copolymer obtained by the reaction of valerolactone (-VL) and PEG can provide certain cell viscosity for the copolymer, and improve the degradation rate and the mechanical strength of the copolymer.
From FIG. 1, it can be seen that the absorption peak caused by the shear vibration of the 1395cm-1 six-membered ring originally belonging to-VL and the absorption peak caused by the six-membered ring conjugation effect at 1466cm-1 have disappeared, which proves that-VL has been ring-opening polymerized, and the result proves that PVL-PEG-PVL block copolymer has been successfully synthesized by comparing the infrared spectrograms of the monomers and the synthesized block copolymer and analyzing these special vibration bands;
the modified product in the step 2) has certain photocuring performance, the curing speed is high (within 5 min), the shape of the product is kept from collapsing due to enough strength during layer-by-layer printing, and the shrinkage rate of gel is low in the curing process due to enough long molecular chains, namely the printing precision is high. Therefore, the method is very suitable for preparing hydrogel scaffolds for cardiac tissue repair by rapid 3D printing.
The viscosity of the gel precursor solution in the step 3) is 1-300mPa/s, the tensile strength of the prepared scaffold material is not less than 50KPa, and the modulus is not less than 22.7 KPa.
From FIG. 2, it can be seen that the hydrogel has a modulus (E) of 56KPa, a strength of 332KPa, and a strain of 358.791%, (natural myocardial tissue modulus of 22.7KPa, strength of 50KPa, and strain of 15-22%);
FIG. 3 shows the porous cross-linked structure inside the gel and can be concluded that the degree of cross-linking between macromolecular chains inside the hydrogel is high and the network is dense;
from fig. 4, it can be seen that the overall degradation rate of the gel is relatively uniform and can be degraded to 93.2% of the original mass within 14 days.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention.
Claims (1)
1. A preparation method of a biodegradable hydrogel scaffold material for heart repair is characterized by comprising the following steps: the preparation method comprises the following steps:
1) preparation of PVL-PEG-PVL
a. Weighing 2g of polyethylene glycol PEG and 4mL of anhydrous-valerolactone, adding into a test tube, uniformly stirring, and then adding a catalyst stannous octoate according to 2-5 wt% of the polyethylene glycol, and uniformly stirring;
b. vacuumizing the reaction system for 10min to remove water and oxygen in the reaction system, and reacting the sealing body at the temperature of 110-140 ℃ for 12-16 h;
c. dissolving the product obtained by the reaction in dichloromethane DCM, removing bubbles in the solution by ultrasonic wave, moving the solution into a mould to remove the dichloromethane DCM, and preparing the product into PVL-PEG-PVL triblock copolymer for later use;
2) modification of
a. Dissolving the synthesized PVL-PEG-PVL triblock copolymer in anhydrous tetrahydrofuran THF under the protection of nitrogen, cooling to 0 ℃, then adding anhydrous triethylamine 4 times of the polymer, slowly dropwise adding a tetrahydrofuran solution of acryloyl chloride by using a constant-pressure dropping funnel, stirring the reaction mixture at 0 ℃ for 4 hours, reacting overnight at room temperature, centrifuging at 5000r/min for half an hour, removing generated triethylamine hydrochloride, pouring out the supernatant, adding 5 times of excessive n-hexane at-4 ℃, fully stirring, standing, pouring out the supernatant to obtain a macromonomer, further using tetrahydrofuran and n-hexane as a good solvent and a poor solvent, dissolving, precipitating, performing suction filtration repeatedly twice, and finally performing vacuum drying at 40 ℃ for 24 hours to obtain a gel precursor, freezing and sealing for preservation in dark;
3) preparation of hydrogel scaffold Material
a. Phosphate buffered saline PBS formulation p H at 7.4
Dissolving 0.5g of PVL-PEG-PVL gel precursor modified by acryloyl chloride in phosphate buffer solution to form 0.05g/mL solution, and heating the solution on magnetic stirring to fully dissolve the PVL-PEG-PVL gel precursor;
b. b, adding a photoinitiator 2, 2-dimethoxy-2-phenylacetophenone DMPA into the solution obtained in the step a according to 0.5wt% of the amount of the monomer, stirring and dissolving uniformly, and forming a hydrogel material in 5min under 365nm ultraviolet light;
the volume ratio of the acryloyl chloride to the tetrahydrofuran solution in the step 2) is 1: 10;
the dropping speed of the constant pressure dropping funnel is 2 s/drop.
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| CN101864069A (en) * | 2010-06-10 | 2010-10-20 | 武汉大学 | Biodegradable hydrogel and synthesis method thereof |
| CN102068719A (en) * | 2011-01-18 | 2011-05-25 | 复旦大学 | Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof |
| CN102309779A (en) * | 2010-06-30 | 2012-01-11 | 财团法人工业技术研究院 | Thermal responsive composition for treating bone diseases |
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| CN104877087A (en) * | 2015-04-29 | 2015-09-02 | 武汉理工大学 | Temperature-sensitive hydrogel having bioactivity and preparation method of temperature-sensitive hydrogel |
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| CN101864069A (en) * | 2010-06-10 | 2010-10-20 | 武汉大学 | Biodegradable hydrogel and synthesis method thereof |
| CN102309779A (en) * | 2010-06-30 | 2012-01-11 | 财团法人工业技术研究院 | Thermal responsive composition for treating bone diseases |
| CN102068719A (en) * | 2011-01-18 | 2011-05-25 | 复旦大学 | Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof |
| CN104592727A (en) * | 2015-01-19 | 2015-05-06 | 浙江大学 | Biodegradable physical hydrogel capable of being rapidly gelatinized in situ and preparation method of biodegradable physical hydrogel |
| CN104877087A (en) * | 2015-04-29 | 2015-09-02 | 武汉理工大学 | Temperature-sensitive hydrogel having bioactivity and preparation method of temperature-sensitive hydrogel |
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