CN110124105B - Preparation method of biological 3D printing ink capable of regulating and controlling gel-sol phase transition temperature - Google Patents
Preparation method of biological 3D printing ink capable of regulating and controlling gel-sol phase transition temperature Download PDFInfo
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Abstract
The invention discloses a preparation method of biological 3D printing ink capable of regulating and controlling gel-sol phase transition temperature. Then, the cell 3D printing technology is utilized to print the cartilage scaffold with high resolution, so that the printability and the biocompatibility of the hydrogel material are improved. The mechanical property of the cartilage scaffold can be improved by adding the inorganic nano particles into the basic hydrogel system, so that the technical problems that the printing and forming temperature is not matched with the cell growth temperature and the mechanical property of a hydrogel material is poor are solved.
Description
Technical Field
The invention relates to the technical field of material preparation for preparing an artificial cartilage scaffold by biological 3D printing, in particular to a preparation method for preparing a cartilage scaffold capable of regulating and controlling a sol-gel transition temperature and printing ink on the basis of sodium alginate/gelatin.
Background
The number of patients with cartilage defects caused by obesity, exercise, age or disease is increasing, and the cartilage defects become a killer for human health. At present, cartilage repair remains a major problem in clinical medicine. In recent years, the development of cell 3D printing technology has facilitated the application of additive manufacturing technology in the field of tissue engineering. The cell 3D printing technology not only controls the microstructure, shape and composition of the tissue scaffold with high precision, thereby regulating and controlling the mechanical property of the scaffold, but also has certain influence on the number and distribution of cells.
Polysaccharide matrixes such as gelatin, sodium alginate and chitosan are derived from natural tissues, are main components of extracellular matrixes and have good biocompatibility, so that the polysaccharide matrixes are often used as biological printing ink for biological 3D printing. The sol-gel state transformation of the printing ink system based on gelatin/sodium alginate is reversible, and the printing ink can generate the sol-gel state transformation at a certain temperature, so that the support can be printed and molded. Therefore, the gelatin/sodium alginate biological ink has higher requirement on printing temperature. Meanwhile, the cells are sensitive to the temperature of the living environment, so that the requirement on the printing temperature is extremely high. However, the sol-gel transition temperature suitable for stent printing is not necessarily compatible with the temperature range suitable for cell growth. If the two are not matched, the printability of the printing ink using the mixed cells will be affected, and the activity of the cells encapsulated in the printing ink will be adversely affected. The application of 3D printed cartilage scaffolds to repair damaged cartilage is limited. The development of bioprinting inks suitable for 3D printing of cells for the preparation of cartilage scaffolds is a challenge. Therefore, the invention provides gelatin/sodium alginate-based printing ink with adjustable sol-gel phase transition temperature, which is a technical problem to be solved urgently in the field.
Disclosure of Invention
The invention aims to prepare a gelatin/sodium alginate system with adjustable sol-gel phase transition temperature and improve the printing precision of mixed cell printing slurry. The invention can regulate and control the sol-gel phase transition temperature of the gelatin/sodium alginate 3D printing hydrogel system and control the temperature in the temperature range most suitable for cell growth. Then, the cell 3D printing technology is utilized to print the cartilage scaffold with high resolution, so that the printability and the biocompatibility of the hydrogel material are improved. The mechanical property of the cartilage scaffold can be improved by adding the inorganic nano particles into the basic hydrogel system, so that the technical problems that the printing and forming temperature is not matched with the cell growth temperature and the mechanical property of a hydrogel material is poor are solved.
The technical scheme of the invention is realized as follows:
the invention provides a method for regulating and controlling the sol-gel conversion temperature of a temperature-sensitive hydrogel system of printing ink based on gelatin/sodium alginate, which comprises the following steps:
dissolving or dispersing gelatin powder in deionized water, heating in a water bath at 65-90 ℃, stirring at a rotation speed of 10-30 r/min, and heating and stirring for 20-45 min to prepare a gelatin solution.
And (2) dissolving or dispersing sodium alginate in a gelatin solution, heating in a water bath at 65-90 ℃, stirring at the rotating speed of 10-30 r/min, and heating and stirring for 80-150 min to prepare a sodium alginate/gelatin solution mixed hydrogel solution.
Step (3), mixing the sodium alginate/gelatin solution with the hydrogel solution, and naturally cooling to 20-28 ℃ in a water bath kettle; obtaining sodium alginate/gelatin mixed hydrogel;
heating and cooling the sodium alginate/gelatin solution mixed hydrogel solution for multiple times; heating and cooling for different times; obtaining the sodium alginate/gelatin mixed hydrogel with different phase transition temperatures, namely obtaining the biological 3D printing ink with different phase transition temperatures.
The heating method comprises the following steps: heating the mixed sodium alginate/gelatin solution and hydrogel solution in water bath at 65-90 deg.c and at 10-30 r/min for 50-120 min;
the cooling method comprises the following steps: the sodium alginate/gelatin solution mixed with the hydrogel solution is naturally cooled to 20-28 ℃ in a water bath kettle.
Preferably, the temperature of the water bath in the step (1) is 78 ℃;
preferably, the rotating speed in the step (1) is 20 r/min;
preferably, the total heating and stirring time of the step (1) and the step (2) is 110-130 min;
preferably, the stirring is stopped and the temperature is naturally reduced in the cooling process;
preferably, the mass ratio of the gelatin to the sodium alginate is 4:1, and the concentrations of the gelatin and the sodium alginate in the remixed solution are respectively 8-8.8% and 2.0-2.2%.
Preferably, in the cooling process of the sodium alginate/gelatin solution mixed hydrogel solution, the nanoparticles are uniformly and ultrasonically dispersed into deionized water at room temperature, and after the heating and stirring of the sodium alginate/gelatin solution mixed hydrogel solution are stopped, and the temperature is reduced to 50 ℃, then the uniform nanoparticle suspension is added into the sodium alginate/gelatin solution mixed hydrogel solution and heated and stirred at 50 ℃ for 60 min.
The prepared gelatin/sodium alginate mixed printing ink containing the inorganic nano-particles is printed into a 3D cartilage scaffold by using a cell assembling machine at normal temperature, and the composite hydrogel 3D porous cartilage scaffold with higher bioactivity and biocompatibility and certain precision can be obtained by using a calcium chloride solution for ion crosslinking.
The gelatin, the sodium alginate and the inorganic nano particles are commercially available, and the deionized water is prepared by equipment.
Compared with the prior art, the invention has the following advantages:
1) the invention can regulate and control the sol-gel conversion temperature and the viscosity of the temperature-sensitive hydrogel material taking gelatin/sodium alginate as the bio-printing slurry.
2) Various inorganic nanoparticles can be added into a hydrogel system of printing paste based on gelatin/sodium alginate, the mechanical property of the hydrogel can be enhanced, and the cell adhesion has influence.
3) The invention has simple process method and low cost, is convenient for being suitable for industrial production and can be widely applied to the field of biological medical treatment.
4) Compared with the gelatin/sodium alginate hydrogel system prepared by the common method, the method can balance the 3D printing precision, the scaffold activity and the cell compatibility, and can prepare a fine cartilage scaffold with good mechanical property for cartilage repair.
Drawings
FIG. 1 is a graph showing the variation of storage modulus and loss modulus with temperature at a transition temperature of 31.6 ℃;
FIG. 2 is a graph showing the variation of storage modulus and loss modulus with temperature at a transition temperature of 30.5 ℃;
FIG. 3 is a graph showing the variation of storage modulus and loss modulus with temperature at a transition temperature of 29.2 ℃;
FIG. 4 is a graph of viscosity as a function of temperature for a base printing paste for different processing methods;
FIG. 5 is a graph of phase change temperatures of base print pastes for different processing methods;
FIGS. 6(a), (b) are structural diagrams printed under a condition of 21 ℃ after heating and cooling cycles are performed three times;
FIG. 7 is a structural diagram printed at 25 ℃ after a heating and cooling cycle is performed three times;
FIG. 8 is a block diagram of a print at 25 deg.C after two heating and cooling cycles have been performed;
fig. 9 is a structural view printed under a 25 c condition after a heating and cooling cycle is performed once.
Detailed Description
The technical solutions and effects of the present invention will be described in detail with reference to the following examples, but the present invention should not be construed as being limited to the applicable scope thereof.
In the following examples, gelatin, sodium alginate, nano-hydroxyapatite, nanocellulose are all materials commonly used in the art and are available in a commercially available range.
Several specific examples are provided below to aid in the understanding of the present invention.
Example 1: swelling 4g gelatin powder in a beaker containing 20ml deionized water for 30min, placing the secondary beaker in a water bath magnetic stirrer with water temperature of 78 deg.C, heating at 20r/min and stirring for 30min to obtain gelatin water solution with concentration of 20.0% (W/V), dissolving gelatin in waterAdding 1g of sodium alginate powder and 25ml of deionized water into a beaker of the solution, keeping the heating temperature of a magnetic stirrer unchanged, adjusting the rotating speed to 10r/min, and heating and stirring for 80min to finally obtain a sodium alginate and gelatin composite solution with the concentration of about 2.2% (W/V) and about 8.8% (W/V); the heating temperature of the magnetic stirrer is adjusted to 28 ℃, the temperature of the composite solution is gradually reduced to 20 ℃ along with the water temperature, and the composite solution is taken out for low-temperature refrigeration and standby. The 3D cartilage hydrogel scaffolds were printed at room temperature using a cell controlled assembly machine. Placing the printed stent in 4% CaCl2Crosslinking in solution by removing the scaffold from CaCl2And taking out the hydrogel scaffold from the solution, and washing the scaffold for 3 times by using deionized water to obtain the hydrogel scaffold with better mechanical property.
Example 2: swelling 4g of gelatin powder in a beaker filled with 20ml of deionized water for 30min, putting the beaker into a water bath magnetic stirrer with the water temperature of 78 ℃, heating and stirring at the speed of 20r/min for 30min to prepare a gelatin aqueous solution with the concentration of 20.0 percent (W/V), adding 1g of sodium alginate powder and 25ml of deionized water into the beaker filled with the gelatin aqueous solution, keeping the heating temperature of the magnetic stirrer unchanged, adjusting the rotating speed to 14r/min, heating and stirring for 90min, and finally obtaining a sodium alginate with the concentration of about 2.2 percent (W/V) and gelatin composite solution with the concentration of about 8.8 percent (W/V); adjusting the heating temperature of the magnetic stirrer to 28 ℃, setting the rotating speed to be 0r/min, and gradually reducing the temperature of the composite solution to 28 ℃ along with the water temperature; and setting the heating temperature to 78 ℃ again, setting the rotating speed to 14r/min, heating and stirring for 60min, then cooling again, taking out and refrigerating at low temperature for later use. After being taken out and heated to room temperature, a part of the material is taken out for rheological property test, and the change of the loss modulus and the storage modulus along with the temperature is shown in figure 2. The 3D cartilage hydrogel scaffolds were printed at room temperature using a cell controlled assembly machine. Placing the printed stent in 4% CaCl2Crosslinking in solution for 10min, and removing the stent from CaCl2And taking out the hydrogel scaffold from the solution, and washing the scaffold for 3 times by using deionized water to obtain the hydrogel scaffold with better mechanical property.
Example 3: swelling 4g gelatin powder in a beaker containing 20ml deionized water for 30min, placing the secondary beaker in a water bath magnetic stirrer with water temperature of 78 deg.C, heating at a speed of 20r/min, and stirring for 30minObtaining a gelatin aqueous solution with the concentration of 20.0 percent (W/V), adding 1g of sodium alginate powder and 25ml of deionized water into a beaker filled with the gelatin aqueous solution, keeping the heating temperature of a magnetic stirrer unchanged, adjusting the rotating speed to 14r/min, heating and stirring for 90min, and finally obtaining a compound solution of the sodium alginate with the concentration of about 2.2 percent (W/V) and the gelatin with the concentration of about 8.8 percent (W/V); adjusting the heating temperature of the magnetic stirrer to 28 ℃, setting the rotating speed to be 0r/min, and gradually reducing the temperature of the composite solution to 28 ℃ along with the water temperature; setting the heating temperature to 78 ℃ again, setting the rotating speed to 14r/min, heating and stirring for 60min, and then cooling again; repeating the heating and cooling treatment, taking out and refrigerating at low temperature for later use. After being taken out and heated to room temperature, a part of the material is taken out for rheological property test, and the change of the loss modulus and the storage modulus along with the temperature is shown in figure 3. The 3D cartilage hydrogel scaffolds were printed at room temperature using a cell controlled assembly machine. Placing the printed stent in 4% CaCl2Crosslinking in solution for 10min, and removing the stent from CaCl2And taking out the hydrogel scaffold from the solution, and washing the scaffold for 3 times by using deionized water to obtain the hydrogel scaffold with better mechanical property.
Example 4: swelling 4g of gelatin powder in a beaker filled with 20ml of deionized water for 30min, putting a secondary beaker into a water bath magnetic stirrer with the water temperature of 78 ℃, heating and stirring at the speed of 20r/min for 20min to prepare a gelatin aqueous solution with the concentration of 20.0 percent (W/V), adding 1g of sodium alginate powder and 25ml of deionized water into the beaker filled with the gelatin aqueous solution, keeping the heating temperature of the magnetic stirrer unchanged, adjusting the rotating speed to 14r/min, heating and stirring for 90min, and finally obtaining a sodium alginate with the concentration of about 2.2 percent (W/V) and gelatin composite solution with the concentration of about 8.8 percent (W/V); adjusting the heating temperature of the magnetic stirrer to 28 ℃, setting the rotating speed to be 20r/min, and gradually reducing the temperature of the composite solution to 28 ℃ along with the water temperature; and setting the heating temperature to 78 ℃ again, setting the rotating speed to 14r/min, heating and stirring for 60min, then cooling again, taking out and refrigerating at low temperature for later use. Taking out the gelatin/sodium alginate basic composite hydrogel printing slurry, heating to 50 ℃ in a water bath, adding 0.55g of nano-hydroxyapatite until the basic hydrogel system is heated and stirred for 1 h. Cooling to room temperature at normal temperature, and refrigerating the gelatin/sodium alginate hydrogel containing nano-hydroxyapatiteAnd storing for later use. The 3D cartilage scaffold was printed at room temperature using a cell controlled assembly machine. Placing the printed stent in 4% CaCl2Crosslinking in solution for 10min, and removing the stent from CaCl2And taking out the hydrogel scaffold from the solution, and washing the scaffold for 3 times by using deionized water to obtain the hydrogel scaffold with better mechanical property.
Example 5: swelling 4g of gelatin powder in a beaker filled with 23ml of deionized water for 30min, putting a secondary beaker into a water bath magnetic stirrer with the water temperature of 65 ℃, heating and stirring for 30min at the speed of 10r/min to prepare a gelatin aqueous solution with the concentration of 20.0 percent (W/V), adding 1g of sodium alginate powder and 25ml of deionized water into the beaker filled with the gelatin aqueous solution, keeping the heating temperature of the magnetic stirrer unchanged, adjusting the rotating speed to 10r/min, heating and stirring for 80min, and finally obtaining a sodium alginate with the concentration of about 2.2 percent (W/V) and gelatin composite solution with the concentration of about 8.8 percent (W/V); adjusting the heating temperature of the magnetic stirrer to 20 ℃, setting the rotating speed to 10r/min, and gradually reducing the temperature of the composite solution to 20 ℃ along with the water temperature; and setting the heating temperature to 65 ℃ again, setting the rotating speed to 10r/min, heating and stirring for 50min, then cooling again, taking out and refrigerating at low temperature for later use. The 3D cartilage scaffold was printed at room temperature using a cell controlled assembly machine. Placing the printed stent in 4% CaCl2Crosslinking in solution by removing the scaffold from CaCl2Taking out the solution, and washing the bracket for 3 times by using deionized water to obtain the gelatin/sodium alginate hydrogel bracket.
Example 6: swelling 4g of gelatin powder in a beaker filled with 25ml of deionized water for 30min, putting a secondary beaker into a water bath magnetic stirrer with the water temperature of 90 ℃, heating and stirring for 45min at the speed of 30r/min to prepare a gelatin aqueous solution with the concentration of 20.0 percent (W/V), adding 1g of sodium alginate powder and 25ml of deionized water into the beaker filled with the gelatin aqueous solution, keeping the heating temperature of the magnetic stirrer unchanged, adjusting the rotating speed to 30r/min, heating and stirring for 150min, and finally obtaining a sodium alginate with the concentration of about 2.2 percent (W/V) and gelatin composite solution with the concentration of about 8.8 percent (W/V); adjusting the heating temperature of the magnetic stirrer to 28 ℃, setting the rotating speed to be 30r/min, and gradually reducing the temperature of the composite solution to 28 ℃ along with the water temperature; heating again at 90 deg.C and rotation speed of 30r/min, heating and stirring for 120minAnd cooling again, taking out and refrigerating at low temperature for later use. The 3D cartilage scaffold was printed at room temperature using a cell controlled assembly machine. Placing the printed stent in 4% CaCl2Crosslinking in solution by removing the scaffold from CaCl2Taking out the solution, and washing the bracket for 3 times by using deionized water to obtain the gelatin/sodium alginate hydrogel bracket.
As can be seen from fig. 4, the viscosity of the gelatin-sodium alginate mixed hydrogel is reduced significantly by increasing the heating and cooling times of the gelatin-sodium alginate mixed hydrogel solution.
As can be seen from FIG. 5, the sol-gel transition temperature of the gelatin-sodium alginate mixed hydrogel solution is reduced significantly by increasing the heating and cooling times.
In FIGS. 5 and 6, A is treatment once B, and C is treatment twice and three times.
The 3D printing environment temperature of fig. 6 is 21 ℃, and due to the relatively high phase transition temperature of the bio-ink with the relatively low processing frequency, the broken filaments are accumulated during printing at a relatively low temperature, as shown in the two left brackets of fig. 6; the stent after being heated for 3 times has relatively low conversion temperature, high printing and forming precision under the condition of 21 ℃, and no wire breakage.
And processing the gelatin/sodium alginate hydrogel solution by using different processing methods to obtain the 3D printing biological ink with different phase transition temperatures. Printing at room temperature of 25 ℃, as can be seen from fig. 7, the extruded silk threads of the biological 3D printing ink treated three times are not easy to solidify, resulting in easy collapse of the scaffold, since the biological ink obtained by treating three times has a lower sol-gel transition temperature; as can be seen from fig. 9, the biological 3D printing ink processed once is prone to filament breakage and has poor forming effect, because the biological 3D printing ink processed less times has a higher conversion temperature; as can be seen from fig. 8, the 3D printing bio-ink with the best molding effect is processed twice. Therefore, at a certain temperature, the phase transition temperature of the hydrogel material can be regulated so that the forming effect is optimal at the temperature.
Claims (6)
1. The preparation method of the biological 3D printing ink capable of regulating and controlling the gel-sol phase transition temperature is characterized by comprising the following steps:
dissolving or dispersing gelatin powder in deionized water, heating in a water bath at 65-90 ℃ and stirring at the rotating speed of 10-30 r/min, and heating and stirring for 20-45 min to prepare a gelatin solution;
dissolving or dispersing sodium alginate in a gelatin solution, heating in a water bath at 65-90 ℃, stirring at a rotation speed of 10-30 r/min, and heating and stirring for 80-150 min to prepare a sodium alginate/gelatin solution mixed hydrogel solution;
step (3) mixing the sodium alginate/gelatin solution with the hydrogel solution, stopping stirring in a water bath kettle, and naturally cooling to 20-28 ℃; obtaining sodium alginate/gelatin mixed hydrogel;
heating and cooling the sodium alginate/gelatin solution mixed hydrogel solution for multiple times; heating and cooling for different times; obtaining sodium alginate/gelatin mixed hydrogel with different phase transition temperatures, namely obtaining biological 3D printing ink with different phase transition temperatures;
the heating method comprises the following steps: heating the mixed sodium alginate/gelatin solution and hydrogel solution in water bath at 65-90 deg.c and at 10-30 r/min for 80-150 min;
the cooling method comprises the following steps: the sodium alginate/gelatin solution mixed hydrogel solution is stopped stirring in a water bath kettle and is naturally cooled to 20-28 ℃.
2. The method for preparing biological 3D printing ink capable of regulating and controlling gel-sol phase transition temperature according to claim 1, wherein the method comprises the following steps: the heating temperature of the water bath in the step (1) is 78 ℃.
3. The method for preparing biological 3D printing ink capable of regulating and controlling gel-sol phase transition temperature according to claim 1, wherein the method comprises the following steps: the rotating speed in the step (1) is 20 r/min.
4. The method for preparing biological 3D printing ink capable of regulating and controlling gel-sol phase transition temperature according to claim 1, wherein the method comprises the following steps: the total heating and stirring time of the step (1) and the step (2) is 110-.
5. The method for preparing biological 3D printing ink capable of regulating and controlling gel-sol phase transition temperature according to claim 1, wherein the method comprises the following steps: in the process of cooling the sodium alginate/gelatin solution mixed hydrogel solution, firstly, uniformly and ultrasonically dispersing nanoparticles into deionized water at room temperature, after the heating and stirring of the sodium alginate/gelatin solution mixed hydrogel solution are stopped, and when the temperature is reduced to 50 ℃, then, uniformly suspending the nanoparticles into the sodium alginate/gelatin solution mixed hydrogel solution, and heating and stirring the suspension at 50 ℃ for 60 min.
6. The method for preparing biological 3D printing ink capable of regulating and controlling gel-sol phase transition temperature according to claim 1, wherein the method comprises the following steps: the mass ratio of the gelatin to the sodium alginate is 4:1, and the mass concentrations of the gelatin and the sodium alginate in the mixed solution are respectively 8-8.8% and 2.0-2.2%.
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| CN114681675A (en) * | 2022-04-08 | 2022-07-01 | 张楷乐 | Preparation method of 3D printing hydrogel urethral stent |
| CN114796617B (en) * | 2022-05-25 | 2023-05-23 | 中山大学 | Composite 3D printing ink and application thereof |
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