CN106008850A - Modified hydrogel material used for 3D printing and application of same to drug loading - Google Patents

Abstract

The invention discloses a modified hydrogel material used for 3D printing and application of the same to drug loading, belonging to the technical field of 3D printing materials. The modified hydrogel material is prepared through the following steps: adding a hydrogel material, acryloyl chloride and triethylamine into a solvent, carrying out a reaction in an ice bath for 12 h and then carrying out a reaction at normal temperature for 12 h; and washing a reaction product with a saturated sodium bicarbonate solution and then carrying out rotary evaporation so as to obtain the modified hydrogel material. The modified hydrogel is of a long-chain structure and has an active chemical group at its tail end; and as a photopolymerization initiator is added into the aqueous solution of the modified hydrogel, a crosslinking reaction occurs under the illumination of light with a wavelength of 365 nm, so rapid shaping of the material is realized. The modified hydrogel material prepared by using 3D printing technology and used for drug loading can be subjected to injection and printing at normal temperature without extra high-temperature apparatuses, low-temperature apparatuses or the like; and the material is easy to shape, fast in gelating speed, excellent in mechanical properties and beneficial for loading and effective release of different medicine molecules.

Description

A modified hydrogel material for 3D printing and its application in drug loading

technical field

The invention belongs to the technical field of three-dimensional printing materials, and in particular relates to a modified hydrogel material for 3D printing and its application in drug loading.

Background technique

In the traditional processing industry, object molding is mainly divided into subtractive molding, pressure molding, additive molding, and growth molding. . 3D printing technology is a combination of computer data model and rapid automatic prototyping system, which processes and superimposes liquid, powder, sheet and other materials layer by layer without additional molds, and finally prints into the desired shape. In the past few decades, 3D printing technology has been successfully applied in clinical fields, including neurosurgery, orthopedics, and stomatology. At present, the main application of 3D printing is in auxiliary medical treatment, such as 3D printing patient models, 3D printing personalized surgical guides and other medical tools.

With the continuous development of living cell culture technology and the continuous exposure of existing 3D printing materials in practical applications, such as harsh molding conditions, heating, laser lights, softness and mechanical properties are not well compatible, and mechanical properties Relatively simple, printing biomaterials has gradually become a research hotspot in recent years. At present, foreign research teams have combined engineering principles and biology to apply hydrogels to robot structures to achieve detailed robot operations. The Australian Research Council Center of Excellence in Electronic Materials Science has succeeded in 3D printing tough fiber-reinforced hydrogels to mimic the softness and strength of human cartilage. Texas Tech University and Texas A&M University introduced calcium ions by immersing the 3D printed alginate structure in a calcium chloride solution, and the two formed cross-links, making their tensile strength close to that of natural human cartilage. But the types of materials used in 3D printing are still in short supply.

Contents of the invention

In order to overcome the shortcomings and deficiencies of the above-mentioned prior art, the primary purpose of the present invention is to provide a modified hydrogel material for 3D printing.

Another object of the present invention is to provide the application of the above-mentioned modified hydrogel material for 3D printing on drug loading.

The object of the present invention is achieved through the following solutions:

A modified hydrogel material for 3D printing, mainly prepared by the following method:

Add the hydrogel material, acryloyl chloride, and triethylamine into the solvent, react in an ice bath for 12 hours, and then react for 12 hours at room temperature, then wash the reaction product with a saturated solution of sodium bicarbonate, and then rotary evaporate to obtain a modified hydrogel Material.

The hydrogel material is at least one of Pluronic series and polyethylene glycol series.

Preferably, the hydrogel material is at least one of PO-EO block copolymer, EO-PO block copolymer, PEG-2000, PEG-4000, and PEG-6000.

The solvent is at least one of dichloromethane, chloroform, methanol, toluene and acetone.

The amount of hydrogel material used is 0.6-13g of hydrogel material per 100mL of solvent; the amount of acryloyl chloride used is 3-6mL of acryloyl chloride per 100mL of solvent; the amount of triethylamine used is per 100mL As a solvent, 3-6 mL of triethylamine was used.

Application of the above-mentioned modified hydrogel materials for 3D printing in drug loading.

The application of the modified hydrogel material for 3D printing on drug loading is mainly realized by the following methods:

Dissolve the modified hydrogel material in water, mix it with drug molecules, and then add a photopolymerization initiator to make a printing solution; inject the printing solution into a 3D printer, and perform 3D printing under ultraviolet light to obtain 3D printing drug-loaded hydrogel materials.

In the described printing solution, the mass fraction of each component is as follows:

The drug molecules include but not limited to drugs for treating tumors, anti-inflammatory drugs for treating skin wounds, hemostatic drugs, antibacterial drugs and preparations for accelerating wound healing.

Preferably, the drug for treating tumors is 5-FU or camptothecin.

Preferably, the preparation for accelerating wound healing is nitrofurazone.

The photopolymerization initiator is 2,2-dimethoxy-2-phenylethanone.

The ultraviolet light refers to the ultraviolet light with a wavelength of 365nm and an energy of 5-100W.

Said mixing refers to stirring at room temperature for 24 hours.

Replacing drug molecules with other biomaterials, such as disulfides, diselenides, etc., can prepare more diverse hydrogels that can be used for 3D printing.

Mechanism of the present invention is:

The modified hydrogel has a long-chain structure with active chemical groups at the end of the long chain. A photopolymerization initiator is added to the aqueous solution of the modified hydrogel material. The initiator can produce Free radicals, thus triggering chain segment reactions, the stronger the light irradiance, the stronger the speed and concentration of free radicals, which enhances the degree of crosslinking reaction, accelerates the gelation speed of materials, and realizes rapid prototyping of materials.

On this basis, the present invention applies 3D printing technology, that is, cumulative manufacturing technology, which is a machine of rapid prototyping technology. Based on the digital model file, a layer of extremely thin mixed printing liquid is sprayed and printed on the tray through the printer nozzle , and at the same time irradiate with ultraviolet light, and then the tray is lowered for a very small distance, and the next layer of printing liquid is sprayed and formed.

Compared with the prior art, the present invention has the following advantages and beneficial effects:

The 3D printing hydrogel material of the present invention can be injected and printed at room temperature, without additional high temperature, low temperature and other devices, easy to form, and has a fast gelation speed and excellent mechanical properties. It can be used to prepare various complex structures, which is beneficial to Load different drug molecules and release them effectively.

The 3D printing hydrogel material of the present invention can be mixed with other materials, has good biocompatibility, improves the loading rate of chemical preparations and diversifies the content of the load, and at the same time improves the mechanical properties of printing materials, etc., which is conducive to expanding printing Material use range.

Description of drawings

Fig. 1 is a diagram of the elastic modulus of the mixed printing liquid prepared in Examples 1-4 under different ultraviolet light irradiation times.

Fig. 2 is the elastic modulus graph of the cube model of the hydrogel material loaded with drugs printed in Examples 1-4 at different scanning frequencies.

FIG. 3 is a comparison chart of drug sustained release of the drug-loaded hydrogel materials prepared in Example 8 and Comparative Example 1. FIG.

detailed description

The present invention will be further described in detail below with reference to the examples and drawings, but the implementation of the present invention is not limited thereto.

The reagents used in the examples of the present invention can be purchased from the market, and the main raw material information is as follows:

Pluronic F-127 (EO100-PO65-EO100): purchased from Sigma-Aldrich company

Acryloyl chloride: purchased from Schuchardt Company

Triethylamine, dichloromethane, acetone, sodium bicarbonate: all purchased from Damao Chemical Reagent Factory, Tianjin, China

2,2-dimethoxy-2-phenylethanone: purchased from Acros

5-FU: purchased from Aladdin

Camptothecin: purchased from Aladdin

Example 1: Preparation of 3D printed drug-loaded hydrogel material

(1) Preparation of modified hydrogel material: 12.6g of Pluronic F-127 was dissolved in 100mL of a mixed solution with a volume ratio of dichloromethane: acetone = 1:1, and 3mL of acryloyl chloride and 3mL of Tris were added dropwise in an ice bath. Ethylamine, react in ice bath for 12h, and react at room temperature for 12h. After the reaction, washed with saturated sodium bicarbonate solution, rotary evaporated and vacuum dried at 40° C. for 24 hours to obtain modified F-127 (12 g).

(2) Preparation of drug-loaded hydrogel material for 3D printing: Dissolve 11 g of modified F-127 in 100 mL of pure water, add 1 g of camptothecin, stir at room temperature for 24 hours, then add 0.5 g of 2,2-di Methoxy-2-phenylethanone was mixed uniformly to obtain a printing liquid.

(3) 3D printing: Use CAD to design a cube with a size of 20*20*2mm (length, width and height) and load it into the printing software, inject the mixed printing liquid into the injection head of the 3D printer, start the instrument, and the injection head will spray out layer by layer. Print the liquid, print the model under ultraviolet light, and test the elastic modulus under different ultraviolet light irradiation times. The results are shown in Figure 1, corresponding to 10% F-127 in Figure 1.

Example 2: Preparation of 3D printed drug-loaded hydrogel materials

In Example 1, "dissolve 12 g of modified F-127 in 100 mL of water" is changed to "dissolve 5.3 g of modified F-127 in 100 mL of water", and the rest are the same as in Example 1. At this time, the mass fraction of modified F-127 in the printed hydrogel material is 5%. The elastic modulus was tested under different ultraviolet light irradiation times, and the results are shown in Figure 1, corresponding to 5% F-127 in Figure 1.

Example 3: Preparation of 3D printed drug-loaded hydrogel material

In Example 1, "dissolve 12g of modified F-127 in 100mL of water" is changed to "dissolve 18g of modified F-127 in 100mL of water", and the rest are the same as in Example 1, and the printed The mass fraction of modified F-127 in the hydrogel material is 15%. The elastic modulus was tested under different ultraviolet light irradiation times, and the results are shown in Figure 1, corresponding to 15% F-127 in Figure 1.

Example 4: Preparation of 3D printed drug-loaded hydrogel material

In Example 1, "dissolve 12 g of modified F-127 in 100 mL of water" is changed to "dissolve 25 g of modified F-127 in 100 mL of water", and the rest are the same as in Example 1. At this time, the mass fraction of modified F-127 in the printed hydrogel material is 20%. The elastic modulus was tested under different ultraviolet light irradiation times, and the results are shown in Figure 1, corresponding to 20% F-127 in Figure 1.

It can be seen from Figure 1 that the mixed printing liquid can be formed in only 4-10 seconds, which shows that the gelation speed of the hydrogel material of the present invention is very fast.

Example 5: Preparation of 3D printed drug-loaded hydrogel material

In the step (2) of Example 1, "add 1 g of camptothecin" is replaced with "add 2 g of 5-FU", and the rest of the operations are the same as in Example 1.

Example 6: Testing of the elastic properties of 3D printed drug-loaded hydrogel materials

The elastic properties of the cube models of the 3D-printed drug-loading hydrogel materials in Examples 1 to 4 were tested, and the results are shown in Figure 2. It can be seen from Figure 2 that the elastic modulus is greater than 10 ³ Pa, excellent mechanical properties, the printed model is not easy to break.

Example 7: Drug loading detection of 3D printed drug-loaded hydrogel materials

The cube model of the 3D-printed drug-loaded hydrogel material in Examples 1 and 5 was tested for drug loading under an ultraviolet spectrophotometer, and it can be seen that the drug loading of modified F-127 to camptothecin Up to 100μg/mg, the drug loading of 5-FU up to 250μg/mg. It shows that the hydrogel material of the present invention is beneficial to load different drug molecules.

Example 8: Drug sustained release of 3D printed drug-loaded hydrogel materials

Drawing of standard curve: configure camptothecin as 0.1μL/mL, 1μL/mL, 10μL/mL, 20μL/mL, 30μL/mL, 40μL/mL, 60μL/mL, 70μL/mL, 80μL/mL, 90μL /mL, 100μL/mL, 120μL/mL, 150μL/mL, put the sample into the UV spectrophotometer, get the absorbance value, use the camptothecin concentration and its corresponding absorbance value to plot, and get the standard curve y=0.032x +0.1211 (where x is camptothecin concentration and y is absorbance).

3D print the camptothecin-loaded modified hydrogel obtained in step (2) of Example 1 into a cube of 2cm*2cm*0.5cm, print 5 samples, and place the samples in 10mL of PBS with pH=7.4 In the solution, take samples at the following time (15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 18h, 20h, 24h, 36h, 48h) and use a UV spectrophotometer to measure the UV absorption intensity at 350nm. The average value of each sample is substituted into the standard curve to obtain the camptothecin concentration in the buffer solution at different times, and the volume of the PBS solution is known, so the slow-release efficiency=camptothecin concentration/put into the PBS solution in the PBS solution The total concentration of camptothecin after the sample is completely dissolved can be obtained by measuring the absorbance value of camptothecin at different times and the solution after the sample is completely dissolved. The drug sustained release efficiency graph of the gel material at different times is shown in Figure 3.

Comparative Example 1: Sustained drug release of commonly printed drug-loaded hydrogel materials

Place the camptothecin-loaded printing liquid prepared in step (2) of Example 1 in a 2cm*2cm*0.5cm plastic mold printed with FDM 3D in advance, irradiate with ultraviolet light, take it out after curing and molding, and take out the molded The samples were placed in 10mL of PBS solution with pH=7.4, and the samples were taken at the following times (15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 18h, 20h, 24h, 36h, 48h) and used for UV spectrophotometry Measure the ultraviolet absorption intensity at 350nm, take the average value, and substitute it into the standard curve to obtain the concentration of camptothecin in the buffer solution at different times. By measuring the absorbance value of camptothecin at different times and the concentration after the sample is completely dissolved The absorbance value of the solution can be used to obtain the drug sustained release efficiency graph of the commonly printed drug-loaded hydrogel material in Comparative Example 1 at different times.

Fig. 3 is the drug sustained-release comparison chart of the drug-loaded hydrogel material prepared in Example 8 and Comparative Example 1. It can be seen from Fig. 3 that the amount of drug released by 3D printing is more than that prepared by ordinary molds. Moreover, the variance of the drug release amount of the 3D printed sample is smaller and more average than that of the common mold sample, indicating that the drug sustained release efficiency of the 3D printed drug-loaded hydrogel material of the present invention is higher and more stable.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.

Claims (10)

1. the hydrogel material printed for 3D, it is characterised in that prepared by following methods:

Hydrogel material, acryloyl chloride, triethylamine are joined in solvent, reaction 12h under ice bath, more often Reacting 12h under temperature, then with saturated solution of sodium bicarbonate washing reaction product, then rotary evaporation i.e. obtains modified Hydrogel material.

The hydrogel material printed for 3D the most according to claim 1, it is characterised in that:

Described hydrogel material is at least one in Pluronic series and Polyethylene Glycol series；

Described solvent is at least one in dichloromethane, chloroform, methanol, toluene and acetone.

The hydrogel material printed for 3D the most according to claim 1, it is characterised in that:

Described hydrogel material is PO-EO block copolymer, EO-PO block copolymer, PEG-2000, At least one in PEG-4000, PEG-6000.

The hydrogel material printed for 3D the most according to claim 1, it is characterised in that:

The consumption of hydrogel material used is the hydrogel material that every 100mL solvent uses 0.6～13g； The consumption of acryloyl chloride used is the acryloyl chloride that every 100mL solvent uses 3～6mL；Three second used The consumption of amine is the triethylamine that every 100mL solvent uses 3～6mL.

5. according to the modified water gel rubber material for 3D printing described in any one of Claims 1 to 4 at medicine Application in thing load.

The modified water gel rubber material printed for 3D the most according to claim 5 is at drug loading Application, it is characterised in that realized by following methods:

Modified water gel rubber material is dissolved in water, then mixes with drug molecule, add Photoepolymerizationinitiater initiater, Make printing solution；Solution will be printed and inject in three-dimensional printer, under ultraviolet light irradiates, carry out 3D printing, Obtain the hydrogel material of the carrying medicament that 3D prints.

The modified water gel rubber material printed for 3D the most according to claim 6 is at drug loading Application, it is characterised in that:

In described printing solution, the mass fraction of each component is as follows:

The modified water gel rubber material printed for 3D the most according to claim 6 is at drug loading Application, it is characterised in that:

Described drug molecule is treatment tumor class medicine, the anti-inflammatory drugs for the treatment of skin wounds, hemostasis class Medicine, antimicrobial DP finish or acceleration wound healing formulation；

Described Photoepolymerizationinitiater initiater is 2,2-dimethoxy-2-Phenyl ethyl ketone.

The modified water gel rubber material printed for 3D the most according to claim 8 is at drug loading Application, it is characterised in that:

Described treatment tumor class medicine is 5-FU or camptothecine；

Described acceleration wound healing formulation is nitrofural.

The modified water gel rubber material printed for 3D the most according to claim 6 is at drug loading Application, it is characterised in that:

Described ultraviolet light refers to that wavelength is 365nm, and energy is the ultraviolet light of 5～100W；

Described mixing refers to stir under room temperature 24h.