TWI624492B - Use of sugar-soluble material for 3d printing and 3d printing method using the same - Google Patents

Abstract

The invention provides a sugar-dissolvable 3D printing material and a 3D printing method using the printing material, the method comprising the steps of: providing or forming a base layer; forming the sugar-soluble printing material on the base layer a support layer; a cover layer is formed, the support layer is coated therein to produce a print formed body comprising the base layer, the support layer and the cover layer; the print body is immersed in In the sugar solution, the support layer is dissolved therein, and a space having the support structure configuration is formed between the cover layer and the base layer; wherein the sugar-soluble printing material comprises water glue. The water gel can be formed by the reaction of polyethylene glycol diacrylate, dithiothreitol and borax.

Description

The use of the sugar-soluble printing material in 3D printing and the 3D printing method using the same

The present invention relates to a 3D printing material and a 3D printing method, and more particularly to a printing material capable of dissolving in a sugar solution, and a 3D printing method using the printing material.

The principle of 3D printing mainly includes photopolymerization, laser sintering and thermoplastic, etc., and its printing method generally adopts the so-called lamination principle (incremental manufacturing). Under the control of computer, the printing materials are printed layer by layer. After stacking out three-dimensional objects. Since the structure is extended from the bottom to the top in a lamination manner, when the inner space or the overhanging structure is printed, it is necessary to design a corresponding supporting structure so as to be gradually formed upwardly. Due to this limitation, it is necessary to accurately calculate the distribution of the design support material when printing a more complicated structure, or to separately print the components and then assemble them, which inevitably increases the manufacturing cost, the post-press processing cost or even the column. Print structure restrictions.

Especially in the field of 3D biological printing, the printed products will be used in animals or on the body. In order to conform to the body structure or special biochemical reactions and physiological operations, the configuration design may be more complicated. In general, for example, rigid bone prints, which can be printed to produce the desired space or pipe via a suitably designed support structure, but for soft colloidal printing, the support material must be sufficient in addition to itself. In addition to the strength, it can not damage or affect the structure of the main body, and if it can be removed after the main structure is formed, it will create more diversity of the internal space of the colloid and increase the applicable range of the colloid.

In addition, since most of the printed 3D biomaterials are used in the body, whether the printed components and the supporting materials are acceptable to the body, no repulsion, and The presence of toxicity is an important consideration when choosing. Therefore, if a printing material and supporting materials that do not cause toxicity to cells and tissues can be found, it will be more beneficial to the development of 3D biological printing, and more expand the feasibility of adapting to human tissues or even organs in the future.

One of the objects of the present invention is to provide a sugar-soluble printing support material which can be used as a sacrificial material to form a complicated inner space or a cantilever structure by utilizing the material to be removed in a dissolved manner after printing. Can be widely used in physiological tissues.

Another object of the present invention is to provide a print support material that is easily removed, so that the support material is removed without affecting the structure of the remaining body portions due to physical or chemical effects.

A further object of the present invention is to provide a non-cytotoxic printing support material which does not cause toxicity to cells or tissues even if the support material is not completely removed after printing.

In addition, the further object of the present invention is to provide a printing support material capable of easily adjusting the strength, so that adjustment can be made according to requirements to produce a desired supporting effect.

In order to achieve the foregoing object, the present invention provides a sugar-soluble printing material as a sacrificial material and applies it to 3D printing, wherein the printing material is a hydrogel which is composed of a hydrogel. It is formed by the reaction of a diacrylate compound, a disulfide compound, and an acid, and the printing material is dissolved therein when the printing material is placed in a sugar solution.

In an embodiment of the invention, the diacrylate compound may be poly(ethylene glycol) diacrylate or poly(ethylene glycol) dipropylene decylamine (poly(ethylene). Glycol) (diacrylamide) or methacrylate gelatin (such as gelatin methacrylate) with a carbon-carbon double bond at the end; the disulfide compound can be dithiothreitol, 2,3-bis (hydrogen sulfide) a thiol group at the end, such as 2-(3-bis(sulfanyl)propan-1-ol) or 2-mercaptoethanol, with A compound of a hydroxyl group (-OH). Thereby, the diacrylate compound and the disulfide compound can undergo a thiol-ene reaction to form a chain structure. Further by acid, for example: borax (borax), Phenylboronic acid or borate, cross-linking with a hydroxyl group on a disulfide compound to produce a colloidal polymer structure.

In an embodiment of the invention, the sugar-soluble printing support material, wherein the water gel system dissolves polyethylene glycol diacrylate and dithiothreitol in a phosphate (PBS) buffer solution. After that, borax is added to catalyze the polymerization reaction.

In an embodiment of the invention, the molar ratio of the polyethylene glycol diacrylate, the dithiothreitol to the borax in the water gel may be between about 1:1:0.1 and 0.4. In one aspect of the present invention, the composition of the water gel may include: 0.1 to 0.4 mM of polyethylene glycol diacrylate, 0.1 to 0.4 mM of dithiothreitol, and 0.01 to 0.04 mM of borax. Jia can be 0.14 mM polyethylene glycol diacrylate, 0.14 mM dithiothreitol and 0.02 mM borax (polyethylene glycol diacrylate: dithiothreitol: borax molar ratio is about 1:1:0.36). The foregoing component ratios are merely exemplified, and a colloidal structure can be formed by combining the reactions in an appropriate ratio, which is a feasible range.

In an embodiment of the present invention, the sugar-soluble printing support material, wherein the sugar solution may be a solution of glucose, fructose, galactose, maltose, lactose and sucrose, which is not particularly limited, only It must be a saccharide solution, because after the addition of the saccharide, it will undergo a misalignment with the acid, destroying the crosslinked structure produced by the reaction of the original thiol-ene, and thereby disintegrating the water gel. In one aspect of the invention, the sugar solution is a glucose solution and may have a concentration of from about 1 to 5 g/L, preferably from 2.5 to 4.8 g/L, more preferably 4.5 g/L. As the concentration of sugar is higher, the rate of dissolution of the water gel will be faster.

In another aspect, the present invention also provides a 3D printing method using a sugar soluble printing material, comprising the steps of: providing or forming a base layer; forming a support layer on the base layer by using the sugar soluble printing material; Forming a cover layer, coating the support structure layer therein to produce a print formed body comprising the base layer, the support structure layer and the cover layer; soaking the print formed body in a sugar solution, so that Wherein the support structure layer is dissolved, and a space having the support structure layer structure is formed between the cover layer and the base layer; wherein the sugar-dissolvable print material comprises water glue, and the water glue system is composed of two It is produced by reacting a diacrylate compound, a disulfide compound, and an acid.

In one embodiment, the diacrylate compound may be poly(ethylene glycol). Poly(ethylene glycol) diacrylate, poly(ethylene glycol) diacrylamide or gelatin methacrylate with carbon-carbon double bonds at the end a compound; the disulfide compound may be dithiothreitol, 2,3-bis(sulfanyl)propan-1-ol or 2 a compound having a thiol group at the end and a hydroxyl group (-OH) at the same time as 2-mercaptoethanol. The acid may be borax, phenylboronic acid or borate.

Similarly, in an embodiment of the invention, the 3D printing method using a sugar soluble printing material, wherein the water gel system dissolves polyethylene glycol diacrylate and dithiothreitol in phosphoric acid After the salt (PBS) buffer solution is added, borax is added to catalyze the polymerization.

In an embodiment of the invention, the molar ratio of the polyethylene glycol diacrylate, the dithiothreitol to the borax in the water gel may be between about 1:1:0.1 and 0.4. In one aspect of the present invention, the composition of the water gel may include: 0.1 to 0.4 mM of polyethylene glycol diacrylate, 0.1 to 0.4 mM of dithiothreitol, and 0.01 to 0.04 mM of borax. Jia can be 0.14 mM polyethylene glycol diacrylate, 0.14 mM dithiothreitol and 0.02 mM borax (polyethylene glycol diacrylate: dithiothreitol: borax molar ratio is about 1:1:0.36). The foregoing component ratios are merely exemplified, and a colloidal structure can be formed by combining the reactions in an appropriate ratio, which is a feasible range.

In an embodiment of the present invention, the 3D printing method using a sugar-soluble printing material, wherein the sugar solution may be a solution of glucose, fructose, galactose, maltose, lactose and sucrose, which is not particularly The restriction is only required for the sugar solution. In one aspect of the invention, the sugar solution is a glucose solution and may have a concentration of from about 1 to 5 g/L, preferably from 2.5 to 4.8 g/L, more preferably 4.5 g/L.

In another embodiment of the present invention, the base layer may be fibrin or chitosan water gel, but is not limited thereto.

The sugar-dissolvable support material of the present invention can be used for 3D printing, and can be easily removed after being printed by a sugar solution, and the support material is not toxic to cells, so it can be widely applied to 3D biological printing. In the field.

Embodiments of the present invention will be further described below, the examples listed below The present invention is not intended to limit the scope of the present invention, and those skilled in the art can make some modifications and retouchings without departing from the spirit and scope of the present invention. The scope defined in the patent application is subject to change.

1‧‧‧Printed molded body

10‧‧‧ grassroots

20‧‧‧Support structure

21‧‧‧ cavity

30‧‧‧ Coverage

G‧‧‧glucose solution

1 is a schematic diagram showing the reaction formula of PEGDA, DTT and borax in the examples of the present invention.

2 is a graph showing the test results of sugar dissolution of the support material in the embodiment of the present invention; the left side is a relationship diagram of the reaction time and the remaining volume, and the right side is a dissolution state diagram observed when the water gel is respectively at 10 to 50 hours.

Figure 3 is a graph showing the test results of the rigidity of the support material of the embodiment of the present invention.

4 is a graph showing the results of elastic modulus scanning of a support material in a strain amplitude according to an embodiment of the present invention.

Fig. 5 is a graph showing the test results of the self-healing properties of the support material of the embodiment of the present invention.

Fig. 6 is a schematic flow chart showing a 3D printing method using a sugar-dissolvable supporting material in Example 4 of the present invention; the lower left corner is a formed sheet in which sugar is dissolved.

Example 1 Preparation of Printed Support Material

First, 100 mg of polyethylene glycol diacrylate (PEGDA) and 22 mg of dithiothreitol (DTT) were dissolved in 0.5 ml of phosphate (PBS) buffer solution, followed by 0.1 M. The borax solution is stirred vigorously and stirred for a few minutes to obtain a gelatinous water gel. Please also refer to Figure 1. In the gelation process, borax is used as a catalytic initiator to produce a thiol-acrylate Michael polyaddition, which is crosslinked with DTT to form a borate. The bond thus makes the formed water gel self-healing and reactive to glucose.

In addition, the hardness of the water gel can be adjusted by the concentration change of the polymer, wherein the molar ratio of the polyethylene glycol diacrylate, the dithiothreitol to the borax can be about 1:1:0.1~0.4. Preferably, the mixture may include: 0.1 to 0.4 mM of polyethylene glycol diacrylate, 0.1 to 0.4 mM of dithiothreitol, and 0.01 to 0.04 mM of borax. In the present embodiment, a preferred reactant concentration is 0.14 mM polyethylene glycol diacrylate, 0.14 mM dithiothreitol, and 0.02 mM borax (polyethylene glycol diacrylate: dithiothreose). Alcohol: The molar ratio of borax is about 1:1:0.36).

Example 2 Sugar Solubility Test

The water gel prepared in the foregoing Example 1 can be firstly immersed in phosphate buffered saline (PBS) because the phosphate buffered physiological saline does not cause dissolution of the water gel. For the sugar solubility test, 0.5 ml of the water gel prepared in the above Example 1 was taken, and 0.5 ml of a culture solution containing 2.25 mg of glucose (including an amino acid such as L-glutamine, L-cystine, etc.) was added. , vitamins such as vitamin B group, inorganic salts such as sodium bicarbonate, calcium chloride, potassium chloride, sodium chloride, sodium phosphate, etc., and glucose, phenol red), and record the reaction time and remaining The volume, the result is shown in Figure 2.

From the results of Fig. 2, as the reaction time increases, the volume of the water gel becomes smaller and smaller, and it dissolves completely at about 60 minutes. Therefore, the water gel of the embodiment of the present invention is soluble in the glucose solution. Since the sugar solution can react with boric acid to cause dissolution of the water gel, other sugar solutions such as fructose, galactose, maltose, lactose and sucrose solutions can also be used.

Example 3 Testing of mechanical properties

For the mechanical property test, the PEGDA and DTT solutions as in Example 1 were first placed on a flat plate, and then a borax solution was added to carry out a polymerization reaction to form a water gel. The mechanical properties were then measured with a rheometer (HR2, TA Instruments) at a frequency of 1 Hz and 1% strain with a cone/plate clamp with an angle of 2° and a diameter of 40 mm. The temperature was adjusted to 25 ° C and 37 ° C during the measurement, and the results of the rigidity (toughness) are shown in FIG. The water gel of the embodiment of the present invention has a modulus of elasticity (G') of about 10,000 Pa at 25 °C. In addition, analysis by strain amplitude scanning (1 to 500% strain) revealed that the elastic modulus (G') gradually decreased as the strain increased (see Figure 4).

In addition, the self-healing properties were evaluated by rheological analysis. At the time of measurement, the strain-induced water gel was subjected to structural damage and recovery by alternating with an oscillation strain of 1% and 150% at a frequency of 1.0 Hz. Structural failure by applying 150% strain for 2 minutes, then strain reduction The structure recovery was evaluated by applying as little as 1% for 2 minutes, and the results are shown in Fig. 5.

It can be seen from Fig. 5 that at a higher strain (150%), the elastic modulus (G') of the water gel is reduced from about 10,000 Pa to about 2000 Pa, and is lower than G", which means that the hydrogel generating solution after the large strain induction. After the strain is lowered (1%), G' quickly returns to the original initial value, and the solution state is converted back to the gel state. These results show that the water gel of the embodiment of the present invention can be subjected to a larger The strain is restored and its original structure is restored.

Embodiment 4 3D printing method using the supporting material

Please refer to FIG. 6. FIG. 6 is a 3D printing method using a sugar-dissolvable support material according to an embodiment of the present invention. First, a base layer 10 is prepared, or a base layer 10 is printed. The base layer 10 may be a polyglycosyl sugar type water gel, such as fibrin or chitosan water gel which is not soluble in a glucose solution. . The support layer 20 is then printed on the base layer 10 using the water gel prepared in Example 1 as a support material or as a template for the desired structure. Thereafter, the cover layer 30 is printed again, and the support profile layer 20 is coated therein to form a column of the stamped body 1. The print molded body 1 is immersed in the glucose-containing solution G to dissolve the support material, so that a space similar to that of the support structure layer 20 is formed between the base layer 10 and the cover layer 30 (cavity 21). . Thereby, when used in 3D biological printing, a plurality of structures such as a tubular network or a cavity can be manufactured, and the dilemma that the 3D biological printing is difficult to prepare due to complicated structure is overcome.

Claims (12)

The use of a sugar-soluble printing material for 3D printing, wherein the printing material is a water gel, which is formed by reacting a diacrylate compound, a disulfide compound and an acid, and the The print material is soluble in the sugar solution as a sacrificial material in 3D printing. The use of the first aspect of the invention, wherein the diacrylate compound is poly(ethylene glycol) diacrylate, poly(ethylene glycol) dipropylene decylamine (poly(poly(ethylene glycol) diacrylate) Ethylene glycol)diacrylamide) or gelatin methacrylate; the disulfide compound is dithiothreitol, 2,3-bis(hydrothio)-1-propanol (2,3- Bis (sulfanyl) propan-1-ol) or 2-mercaptoethanol; and the acid borax, phenylboronic acid or borate. The use according to claim 2, wherein the water gel is prepared by dissolving polyethylene glycol diacrylate and dithiothreitol in a phosphate buffer solution by adding borax to a catalytic polymerization reaction. The use according to claim 2, wherein the molar ratio of polyethylene glycol diacrylate, dithiothreitol to borax in the water gel is about 1:1:0.1 to 0.4. The use of claim 1, wherein the sugar solution is selected from the group consisting of fructose, galactose, maltose, lactose and sucrose solutions. The use according to claim 5, wherein the sugar solution is a glucose solution, and the concentration thereof is 1 to 5 g/L. A 3D printing method using a sugar-soluble printing material, comprising the steps of: providing or forming a base layer; forming a support layer on the base layer by dissolving a printing material; forming a cover layer, Forming a support layer thereon to produce a printed body comprising the base layer, the support layer and the cover layer; Soaking the printed body in a sugar solution to dissolve the support layer therein, and forming a space having a structure of the support layer between the cover layer and the base layer; wherein the sugar-soluble solution The printing material includes a water gel which is formed by a diacrylate compound, a disulfide compound, and an acid reaction. The 3D printing method according to claim 7, wherein the diacrylate compound is poly(ethylene glycol) diacrylate, poly(ethylene glycol) dipropylene decylamine. (poly(ethylene glycol) diacrylamide) or gelatin methacrylate; the disulfide compound is dithiothreitol, 2,3-bis(hydrothio)-1-propanol (2 , 3-bis(sulfanyl)propan-1-ol) or 2-mercaptoethanol; and the acid borax, Phenylboronic acid or borate. The 3D printing method according to claim 8, wherein the water gel is prepared by dissolving polyethylene glycol diacrylate and dithiothreitol in a phosphate buffer solution, and adding borax to the catalytic polymerization reaction. . The 3D printing method according to claim 8 or 9, wherein the molar ratio of polyethylene glycol diacrylate, dithiothreitol to borax in the water gel is about 1:1:0.1. ~0.4. The 3D printing method of claim 7, wherein the sugar solution is selected from the group consisting of fructose, galactose, maltose, lactose and sucrose solutions. The 3D printing method according to claim 11, wherein the sugar solution is a glucose solution, and the concentration thereof is 1 to 5 g/L.