A pH-responsive 3D-printed hydrogel dressing, its preparation method and application

Abstract

This invention belongs to the field of biomedical materials and discloses a pH-responsive 3D-printed hydrogel dressing, its preparation method, and its application. The hydrogel dressing is obtained by assembling a color-changing unit, an exudate-trapping module, a hydrogel layer, and a transparent dressing patch. The color-changing unit is prepared by extracting anthocyanins and staining with anthocyanins. The exudate-trapping module is prepared in one step using polyether polyol, water, catalyst, and foam stabilizer as the main raw materials. The hydrogel layer is obtained by 3D printing using gelatin, methacrylic anhydride, sodium alginate, growth factors, and photoinitiators as the main raw materials, followed by cross-linking with anhydrous calcium chloride solution and soaking in a metal cation aqueous solution. The hydrogel dressing prepared by this invention using 3D printing technology can perform CAD modeling according to the depth of the wound, and the printed hydrogel layer can fully contact the wound, better meeting the actual needs of different patients in clinical use.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials, and in particular to a pH-responsive 3D-printed hydrogel dressing, its preparation method, and its application. Background Technology

[0002] The skin is an important organ of the human body, composed of the epidermis and dermis, and plays a vital role in providing physical, chemical, and biological barriers. When the skin is injured due to trauma, burns, abscesses, or ulceration, medical dressings, which are alternatives to skin dressings, are usually used to protect the wound and achieve purposes such as stopping bleeding, providing protection, preventing infection, and promoting wound healing.

[0003] Traditional dressings primarily refer to medical absorbent cotton gauze, which can protect and cover wounds. They are simple to make and inexpensive, but their exudate absorption capacity is limited, failing to keep the wound moist. Dressing fibers are prone to shedding, causing foreign body reactions and hindering healing. Granulation tissue can easily grow into the dressing mesh, further damaging newly formed epithelial tissue and causing bleeding, resulting in secondary trauma to the wound and increasing pain after dressing changes. Most importantly, traditional dressings cannot provide real-time wound information, such as pH, temperature, and tissue oxygen content. When clinicians require immediate information on wound healing and monitoring of changes in the wound microenvironment for timely intervention, traditional dressings cannot provide this information.

[0004] The treatment of chronic wounds is one of the most pressing medical challenges. Chronic wounds are characterized by their long duration and slow healing, posing a significant clinical obstacle. Wound pH plays a crucial role in the healing process; angiogenesis, changes in protease activity, and bacterial infection all contribute to variations in wound pH. Therefore, real-time monitoring of wound pH is essential for wound recovery.

[0005] While existing smart dressing technologies can monitor the pH of the wound microenvironment to some extent, the continuity and sensitivity of the monitoring response are not high. They also cannot effectively inhibit bacterial infection and scar tissue growth, and cannot be matched according to the size and depth of the wound, resulting in an unsatisfactory fit between the dressing and the wound. Summary of the Invention

[0006] Therefore, the purpose of this invention is to address the shortcomings of existing technologies by providing a method for preparing a pH-responsive 3D printed hydrogel dressing.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] This invention provides a method for preparing a pH-responsive 3D-printed hydrogel dressing, characterized by comprising the following steps:

[0009] S1 prepares the color-changing unit

[0010] (1) Extraction of anthocyanins: The anthocyanin raw material is washed with deionized water, dried and pulverized to obtain anthocyanin raw material powder. Add 50%-70% (mass fraction) of ethanol (extraction solution) to the anthocyanin raw material powder. The material-to-liquid ratio of anthocyanin raw material powder to ethanol is 1:10-1:30 (the unit of the material-to-liquid ratio of anthocyanin raw material powder to ethanol is g / mL). Place the mixture formed by the anthocyanin raw material powder and ethanol solution in an ultrasonic cleaner with a temperature of 30-60℃ and a power of 300W. The extraction time is 25-40min. Adjust the pH of the extraction solution to 2.0-6.0.

[0011] (2) Anthocyanin dyeing: Soak the fabric to be dyed in a container with purified water for 30-40 minutes, then take it out and place it in anthocyanin extract. The bath ratio of the fabric to be dyed to the anthocyanin extract is 1:30-1:50 (the bath ratio of the fabric to the anthocyanin extract is by mass). The ultrasonic cleaner has a power of 300W, the dyeing temperature is 40-80℃, the dyeing time is 30-40 minutes, the dyeing pH is 3.0-9.0, and mordant with a mass fraction of 1%-5% is added. The mordant accounts for 2%-5% of the weight of the fabric to be dyed. After dyeing, wash off the floating color with a mass fraction of 20% sodium chloride solution for 20-30 minutes, wash with deionized water, and then air dry in the dark.

[0012] S2 preparation of seepage traction module

[0013] One-step preparation of the permeation traction module: Polyether polyol, water, catalyst, and foam stabilizer are poured into a reaction vessel in sequence and stirred evenly. Isocyanate is added at a speed of 2800-3200 r / min and stirred for 9-13 seconds. When the mixture turns milky white, stirring is stopped. The mixture is poured into a mold and foamed for 4-8 minutes. Finally, the sample is placed in an 80℃ oven for constant temperature curing for 1.5-2 hours to obtain the permeation traction module.

[0014] The contents of each component are as follows: 80-100 parts of polyether polyol, 3-5 parts of water, 0.1-0.5 parts of catalyst, 0.6-1.2 parts of foam stabilizer, and 30-50 parts of isocyanate;

[0015] S3 Preparation of Hydrogel Layer

[0016] (1) Weigh 10 parts of gelatin and dissolve it in 100 parts of PBS buffer. Heat until completely dissolved. Add 1 part of methacrylic anhydride (MA) and react for 2 hours. Then add 500 parts of PBS buffer to terminate the reaction and obtain solution one. Solution one is dialyzed (to remove unreacted MA and small molecule impurities), frozen, dried and dissolved to obtain solution two.

[0017] (2) Add a 3%-5% sodium alginate solution to solution two. The mass ratio of sodium alginate solution to solution two is 1:1. After dissolving and mixing, solution three is obtained.

[0018] (3) Add growth factor lyophilized powder to solution three. The proportion of growth factor lyophilized powder to solution three is 0.01%-0.05%. Mix well to obtain solution four.

[0019] (4) Add photoinitiator to solution four. The proportion of photoinitiator in solution four is 0.2%-0.3%. After mixing thoroughly, solution five is obtained. Use a syringe to draw 5 ml of solution five and place it in a refrigerator at 4°C for 20-30 min in the dark.

[0020] (5) After attaching the needle to the syringe, place it into the printer cartridge and print according to the printing parameters (Table 1) to obtain the first layer of the hydrogel with a mesh structure.

[0021] Table 1

[0022]

[0023] (6) Immerse hydrogel layer one in an anhydrous calcium chloride solution with a mass fraction of 0.3%-0.5% to crosslink it, and you will get hydrogel layer two with a mesh structure.

[0024] (7) The second hydrogel layer is immersed in an aqueous solution of metal cations to obtain the third hydrogel layer containing a metal cation grid structure.

[0025] S4 Assembly

[0026] Prepare a transparent dressing patch. Assemble the color-changing unit prepared in S1, the exudate traction module prepared in S2, and the hydrogel layer prepared in S3 with the transparent dressing patch. The assembly order from contact with the wound to away from the wound is as follows: hydrogel layer, exudate traction module, color-changing unit, and transparent dressing patch, thus obtaining a pH-responsive 3D-printed hydrogel dressing. The length of the hydrogel in the pH-responsive 3D-printed hydrogel dressing is 1-5cm, the width is 0.5-4.5cm, and the thickness is 0.2-0.4cm; the length, width, and thickness of the exudate traction module are 0.3-0.4mm, and the thickness is 0.3-0.4mm; the length and width of the color-changing unit are 0.3-0.4mm. Exudate traction modules are evenly distributed on the hydrogel layer, and the number of exudate traction modules is ≥1. The number and position of the color-changing units correspond one-to-one with the exudate traction modules.

[0027] As a further improvement of the present invention, the anthocyanins are derived from one or more of the following: dragon fruit peel, hibiscus, grape seeds, and mulberry.

[0028] As a further improvement of the present invention, the fabric to be dyed includes any one or more of cotton, silk, linen, and non-woven fabric.

[0029] As a further improvement of the present invention, the mordant includes any one or more of alum, magnesium sulfate, aluminum sulfate, and ferrous sulfate.

[0030] As a further improvement of the present invention, the polyether polyol has any one or more of the following properties: hydroxyl value of 54-58 mg KOH / g, viscosity of 400-600 mPa·S, acid value of 0.05 mg KOH / g, and pH of 5-7.

[0031] As a further improvement of the present invention, the catalyst includes one or more of amine catalysts and tin catalysts. The amine catalysts include FOCAT-8002, amine catalyst A1, and triethylenediamine (amine catalyst A33), and the tin catalysts include stannous octoate (tin catalyst T9).

[0032] As a further improvement of the present invention, the foam stabilizer includes any one or more of polyether modified silicone oil (DC-190), foam-smoothing silicone oil (DC-191), NiaL-20, silicone oil (L-540), and silicone oil (L-580).

[0033] As a further improvement of the present invention, the isocyanate index includes 1.0-1.2, and the isocyanate includes any one or more of toluene diisocyanate (TDI) and diphenylmethane diisocyanate (MDI).

[0034] As a further improvement of the present invention, the photoinitiator includes any one of phenyl-2,4,6-trimethylbenzoyl lithium phosphite (LAP) and 2-hydroxy-4-(2-hydroxyethoxy)-2-methylphenylacetone (I2959).

[0035] As a further improvement of the present invention, the metal ions include Cu. 2+ Zn 2+ Ag + Any one or more of the following, the corresponding aqueous solution of the metal cation is Cu 2+ Zn 2+ Ag + One or more aqueous solutions of salts, with a concentration of 0.03-0.6 mol / L.

[0036] As a further improvement of the present invention, the cutting size of the fabric to be dyed is (0.3mm-0.4mm)×(0.3mm-0.4mm), and the cutting size of the seepage traction module is (0.3mm-0.4mm)×(0.3mm-0.4mm)×(0.3mm-0.4mm).

[0037] This invention also provides an application of a pH-responsive 3D-printed hydrogel dressing in wound healing.

[0038] The beneficial effects of this invention are:

[0039] 1. The hydrogel dressing prepared by this invention has good biocompatibility and hydrophilicity in its hydrogel layer, and the growth factors contained therein can promote epidermal growth, wound healing, and reduce scar formation.

[0040] 2. The metal ions in the hydrogel layer of the hydrogel dressing prepared by this invention have antibacterial properties, inhibiting bacterial growth and reducing the occurrence of wound infection.

[0041] 3. The exudate traction module in the hydrogel dressing prepared by this invention is prepared in one step, which is simple and easy to operate. The pore size of the exudate traction module is very uniform and the pores are interconnected, providing a good channel for wound exudate inside and having a good traction effect on the exudate.

[0042] 4. The color-changing unit in the hydrogel dressing prepared by this invention can sensitively monitor changes in the pH value of the wound in real time. It appears red under acidic conditions, purple under neutral conditions, and blue under alkaline conditions. Monitoring the pH value of the wound helps medical staff to accurately administer medication to the wound and accelerate wound healing. It has a promising application prospect in wound dressings.

[0043] 5. The pH-responsive 3D-printed hydrogel dressing prepared by this invention has a response time between 60-75 seconds, and the response is sensitive and rapid.

[0044] 6. The hydrogel dressing prepared by the present invention using 3D printing technology can be CAD modeled according to the depth of the wound, and the printed hydrogel layer can fully contact the wound, which better meets the actual needs of different patients in clinical use. Attached Figure Description

[0045] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0046] Appendix Figure 1 This is a schematic diagram of the pH-responsive 3D-printed hydrogel dressing prepared according to the present invention.

[0047] Appendix Figure 2 This is a flowchart illustrating the preparation process of the seepage traction module in Example 6.

[0048] Appendix Figure 3 This is a scanning electron microscope image of the aperture of the seepage traction module in Example 6.

[0049] Appendix Figure 4 This is a scanning electron microscope image of a single aperture of the seepage traction module in Example 6.

[0050] Appendix Figure 5 This is a test diagram of the contact angle of the seepage traction module in Example 6.

[0051] Appendix Figure 6 The response diagram is shown for the pH-responsive 3D-printed hydrogel dressing prepared in Example 6.

[0052] Appendix Figure 7 The image shows the hydrogel layer of the pH-responsive 3D-printed hydrogel dressing prepared in Example 7.

[0053] Appendix Figure 8 The image shows the antibacterial performance test results of the hydrogel layer of the pH-responsive 3D-printed hydrogel dressing prepared in Example 1.

[0054] Appendix Figure 9 The antibacterial performance test diagram of the hydrogel layer of the pH-responsive 3D printed hydrogel dressing prepared for Comparative Example 1. Implementation

[0055] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0056] The first step in this invention is to prepare buffer solutions with different pH values ​​to test and verify the hydrogel dressing prepared in this invention.

[0057] The following steps were taken to prepare a phosphate buffer solution with a pH of 6: 7.6 g of NaH₂PO₄·H₂O was weighed, dissolved in deionized water, and the volume was adjusted to 1000 mL to obtain solution one; 3.6 g of Na₂HPO₄·7H₂O was weighed, dissolved in deionized water, and the volume was adjusted to 1000 mL to obtain solution two; 87.7 mL of solution one and 12.3 mL of solution two were measured using a graduated cylinder, mixed, shaken well, and stored at 4°C for later use.

[0058] The following steps were taken to prepare a phosphate buffer solution with a pH of 7: 7.6 g of NaH2PO4·H2O was weighed, dissolved in deionized water, and the volume was adjusted to 1000 mL to obtain solution one; 3.6 g of Na2HPO4·7H2O was weighed, dissolved in deionized water, and the volume was adjusted to 1000 mL to obtain solution two; 39.0 mL of solution one and 61.0 mL of solution two were measured using a graduated cylinder, mixed, shaken well, and stored at 4°C for later use.

[0059] The following steps were taken to prepare a phosphate buffer solution with a pH of 9: Weigh 27.6 g of NaH2PO4, dissolve it in deionized water, and bring the volume to 1000 mL to obtain solution one; weigh 25.6 g of Na2HPO4, dissolve it in deionized water, and bring the volume to 1000 mL to obtain solution two; measure 33 mL of solution one and 50.4 mL of solution two using a graduated cylinder, mix them, shake well, and store at 4°C for later use. Example 1

[0060] S1 prepares the color-changing unit

[0061] (1) Extraction of pigment from dragon fruit peel: Take 4 portions of dragon fruit peel, wash with deionized water, dry and crush to obtain dragon fruit peel raw material powder. Add 50% ethanol to the dragon fruit peel raw material powder. The ratio of dragon fruit peel raw material powder to ethanol is 1:10. Place the mixture of dragon fruit peel raw material powder and ethanol solution in an ultrasonic cleaner with a temperature of 30℃ and a power of 300W. The extraction time is 25min. Adjust the pH of the extract to 6.0.

[0062] (2) Dyeing with dragon fruit peel pigment: Soak two pieces of cotton cloth in purified water in a container for 30 minutes and then take them out and place them in the dragon fruit peel pigment extract. The bath ratio of the cotton cloth to be dyed to the dragon fruit peel pigment extract is 1:30. The ultrasonic cleaner power is 300W, the dyeing temperature is 40℃, the dyeing time is 30 minutes, the dyeing pH is 6.0, and 2% alum is added. The alum accounts for 2% of the weight of the cotton cloth to be dyed. After dyeing, wash off the floating color with 20% sodium chloride solution for 30 minutes, wash with deionized water and then air dry in the dark.

[0063] S2 preparation of seepage traction module

[0064] A one-step method for preparing a permeation traction module: 95 parts of polyether polyol, 3 parts of water, 0.1 parts of amine catalyst A1, 0.3 parts of tin catalyst T9, and 0.9 parts of foam stabilizer L-580 were sequentially poured into a reaction vessel and stirred evenly. Then, 48 parts of TDI were added at 3000 r / min and stirred for 10 seconds. When the mixture turned milky white, stirring was stopped. The mixture was poured into a foaming mold and foamed for 5 minutes. Finally, the foamed sample was placed in an 80℃ oven for constant temperature curing for 1.5 hours to obtain the permeation traction module.

[0065] The polyether polyol has a hydroxyl value of 55 mg KOH / g, a viscosity of 600 mPa•S, an acid value of 0.05 mg KOH / g, and a pH of 6; the TDI index is 1.1.

[0066] S3 Preparation of Hydrogel Layer

[0067] (1) Weigh 10 parts of gelatin and dissolve it in 100 parts of PBS buffer. Heat until completely dissolved. Add 1 part of methacrylic anhydride (MA) and react for 2 hours. Then add 500 parts of PBS buffer to terminate the reaction and obtain solution one. Solution one is dialyzed, frozen, dried and dissolved to obtain solution two.

[0068] (2) Add a 5% sodium alginate solution to solution two. The mass ratio of sodium alginate solution to solution two is 1:1. After dissolving and mixing, solution three is obtained.

[0069] (3) Add fibroblast growth factor to solution three, the proportion of fibroblast growth factor in solution three is 0.04%, and mix well to obtain solution four;

[0070] (4) Add the photoinitiator phenyl-2,4,6-trimethylbenzoyl lithium phosphite (LAP) to solution four. The proportion of the photoinitiator phenyl-2,4,6-trimethylbenzoyl lithium phosphite (LAP) in solution four is 0.25%. After thorough mixing, solution five is obtained. Use a syringe to draw 5 ml of solution five and place it in a refrigerator at 4°C for 20 min in the dark.

[0071] (5) After attaching the needle to the syringe, place it into the printer cartridge and print according to the printing parameters (Table 2) to obtain the first layer of the hydrogel with a mesh structure.

[0072] Table 2

[0073]

[0074] (6) Immerse hydrogel layer one in an anhydrous calcium chloride solution with a mass fraction of 0.5% to crosslink it, and then obtain hydrogel layer two with a mesh structure.

[0075] (7) The hydrogel layer 2 is immersed in an aqueous solution of metal cation CuSO4, wherein Cu 2+ At a concentration of 0.1 mol / L, a metal cation containing Cu was obtained. 2+ The third layer is a hydrogel with a mesh-like structure.

[0076] S4 Assembly

[0077] Prepare a transparent dressing patch, and assemble the color-changing unit prepared in S1, the exudate traction module prepared in S2, and the hydrogel layer prepared in S3 with the transparent dressing patch to obtain a pH-responsive 3D printed hydrogel dressing.

[0078] The hydrogel dressing prepared in this embodiment was tested and verified using a phosphate buffer solution with a pH of 6. Example 2

[0079] S1 prepares the color-changing unit

[0080] (1) Extraction of hibiscus pigment: Take 3 portions of hibiscus, wash with deionized water, dry and crush to obtain hibiscus raw material powder. Add 70% ethanol to the hibiscus raw material powder. The ratio of hibiscus raw material powder to ethanol is 1:20. Place the mixture of hibiscus raw material powder and ethanol solution in an ultrasonic cleaner with a temperature of 50℃ and a power of 300W. The extraction time is 40min. Adjust the pH of the extract to 2.0.

[0081] (2) Roselle pigment dyeing: Soak 2.5 parts of silk in a container with purified water for 30 minutes and then take it out and place it in roselle pigment extract. The bath ratio of the silk to be dyed to the roselle pigment extract is 1:50. The ultrasonic cleaner power is 300W, the dyeing temperature is 50℃, the dyeing time is 40 minutes, the dyeing pH is 7.0, and 3% magnesium sulfate is added. The magnesium sulfate accounts for 3% of the weight of the silk to be dyed. After dyeing, wash off the floating color with 20% sodium chloride solution for 30 minutes, wash with deionized water and then air dry in the dark.

[0082] S2 preparation of seepage traction module

[0083] A one-step method for preparing a permeation traction module: 95 parts of polyether polyol, 3 parts of water, 0.1 parts of amine catalyst A1, 0.3 parts of tin catalyst T9, and 0.9 parts of foam stabilizer L-580 were sequentially poured into a reaction vessel and stirred evenly. Then, 48 parts of MDI were added at 3000 r / min and stirred for 10 seconds. When the mixture turned milky white, stirring was stopped. The mixture was poured into a foaming mold and foamed for 5 minutes. Finally, the foamed sample was placed in an 80℃ oven for constant temperature curing for 1.5 hours to obtain the permeation traction module.

[0084] The polyether polyol has a hydroxyl value of 55 mg KOH / g, a viscosity of 600 mPa•S, an acid value of 0.05 mg KOH / g, and a pH of 6; the MDI index is 1.2.

[0085] S3 Preparation of Hydrogel Layer

[0086] (1) Weigh 10 parts of gelatin and dissolve it in 100 parts of PBS buffer. Heat until completely dissolved, add 1 part of methacrylic anhydride (MA) and react for 2 hours. Then add 500 parts of PBS buffer to terminate the reaction and obtain solution one. Solution one is dialyzed, frozen, dried and dissolved to obtain solution two.

[0087] (2) Add a 5% sodium alginate solution to solution two. The mass ratio of sodium alginate solution to solution two is 1:1. After dissolving and mixing, solution three is obtained.

[0088] (3) Add epidermal growth factor to solution three, the proportion of epidermal growth factor in solution three is 0.04%, and mix well to obtain solution four;

[0089] (4) Add the photoinitiator phenyl-2,4,6-trimethylbenzoyl lithium phosphite (LAP) to solution four. The proportion of the photoinitiator phenyl-2,4,6-trimethylbenzoyl lithium phosphite (LAP) in solution four is 0.25%. After thorough mixing, solution five is obtained. Use a syringe to draw 5 ml of solution five and place it in a refrigerator at 4°C for 20 min in the dark.

[0090] (5) After attaching the needle to the syringe, place it into the printer cartridge and print according to the printing parameters (Table 3) to obtain the first layer of the hydrogel with a mesh structure.

[0091] Table 3

[0092]

[0093] (6) Immerse hydrogel layer one in an anhydrous calcium chloride solution with a mass fraction of 0.5% to crosslink it, and then obtain hydrogel layer two with a mesh structure.

[0094] (7) The hydrogel layer 2 is immersed in an aqueous solution of metal cation CuSO4, wherein Cu 2+ At a concentration of 0.1 mol / L, a metal cation containing Cu was obtained. 2+ The third layer is a hydrogel with a mesh-like structure.

[0095] S4 Assembly

[0096] Prepare a transparent dressing patch, and assemble the color-changing unit prepared in S1, the exudate traction module prepared in S2, and the hydrogel layer prepared in S3 with the transparent dressing patch to obtain a pH-responsive 3D printed hydrogel dressing.

[0097] The hydrogel dressing prepared in this embodiment was tested and verified using a phosphate buffer solution with a pH of 7.

[0098] Example 3

[0099] The difference between this embodiment and the preparation of the color-changing unit in S1 of Example 2 is that grape seed pigment is extracted in this embodiment. The difference between this embodiment and steps 3, 5, and 7 in the preparation of the hydrogel layer in S3 of Example 3 is that nerve growth factor is added in step 3; the printing parameters for step 5 are shown in Table 4; and the difference for step 7 is that the hydrogel layer is immersed in an aqueous solution of the metal cation ZnSO4, wherein Zn... 2+ At a concentration of 0.6 mol / L, a metal cation Zn was obtained. 2+ The third layer is a hydrogel with a mesh-like structure. The steps for extracting grape seed pigment and staining are shown below; the remaining steps are the same as in Example 3.

[0100] S1 prepares the color-changing unit

[0101] (1) Extraction of grape seed pigment: Take 5 portions of grape seed pigment, wash with deionized water, dry and pulverize to obtain grape seed raw material powder. Add 60% ethanol by mass to the grape seed raw material powder. The ratio of grape seed raw material powder to ethanol is 1:30. Place the mixture of grape seed raw material powder and ethanol solution in an ultrasonic cleaner with a temperature of 45℃ and a power of 300W. The extraction time is 30min. Adjust the pH of the extract to 4.0.

[0102] (2) Grape seed pigment dyeing: Soak and wash 3 portions of linen in purified water in a container for 40 minutes, then take them out and place them in grape seed pigment extract. The bath ratio of the linen to be dyed to the grape seed pigment extract is 1:40. The ultrasonic cleaner power is 300W, the dyeing temperature is 80℃, the dyeing time is 40 minutes, the dyeing pH is 3.0, and 5% ferrous sulfate is added. The ferrous sulfate accounts for 5% of the weight of the linen to be dyed. After dyeing, wash off the floating color with 20% sodium chloride solution for 30 minutes, wash with deionized water and then air dry in the dark.

[0103] Table 4

[0104]

[0105] The hydrogel dressing prepared in this embodiment was tested and verified using a phosphate buffer solution with a pH of 9.

[0106] Example 4

[0107] The difference between this embodiment and the preparation of the color-changing unit in S1 of Example 2 is that the pigment extracted in this embodiment is mulberry pigment. The difference between this embodiment and steps 3, 5, and 7 in the preparation of the hydrogel layer in S3 of Example 3 is that connective tissue growth factor is added in step 3; the printing parameters for step 5 are shown in Table 5; and the difference in step 7 is that the second layer of the mesh-structured hydrogel is immersed in an aqueous solution of the metal cation AgNO3, wherein Ag... + At a concentration of 0.2 mol / L, a metal cation Ag was obtained. + The third layer is a hydrogel with a mesh-like structure. The steps for extracting mulberry pigment and staining are shown below; the remaining steps are the same as in Example 3.

[0108] S1 prepares the color-changing unit

[0109] (1) Extraction of mulberry pigment: Take 2 portions of mulberry pigment, wash with deionized water, dry and pulverize to obtain mulberry raw material powder. Add 70% ethanol to the mulberry raw material powder. The ratio of mulberry raw material powder to ethanol is 1:10. Place the mixture of mulberry raw material powder and ethanol solution in an ultrasonic cleaner with a temperature of 60℃ and a power of 300W. The extraction time is 20min. Adjust the pH of the extract to 3.0.

[0110] (2) Mulberry pigment dyeing: Soak two portions of non-woven fabric in purified water in a container for 30 minutes and then take them out and place them in mulberry pigment extract. The bath ratio of the non-woven fabric to be dyed to the mulberry pigment extract is 1:30. The ultrasonic cleaner power is 300W, the dyeing temperature is 80℃, the dyeing time is 40 minutes, the dyeing pH is 9.0, and 4% aluminum sulfate is added. The aluminum sulfate accounts for 2% of the weight of the non-woven fabric to be dyed. After dyeing, wash off the floating color with 20% sodium chloride solution for 30 minutes, wash with deionized water and then air dry in the dark.

[0111] Table 5

[0112]

[0113] The hydrogel dressing prepared in this embodiment was tested and verified using a phosphate buffer solution with a pH of 6.

[0114] Example 5

[0115] The preparation conditions for the seepage traction module in this embodiment differ from those in Example 1 (S2), but the remaining operational steps are the same as in Example 1. The steps for preparing the seepage traction module in S2 are as follows:

[0116] A one-step method for preparing a permeation traction module: 80 parts of polyether polyol, 5 parts of water, 0.2 parts of amine catalyst A33, 0.2 parts of tin catalyst T9, 0.3 parts of foam stabilizers DC-190 and DC-191 were sequentially poured into a reaction vessel and stirred evenly. Then, 20 parts of TDI and 10 parts of MDI were added at 2800 r / min. After stirring for 9 seconds, the mixture turned milky white and stirring was stopped. The mixture was poured into a foaming mold and foamed for 4 minutes. Finally, the foamed sample was placed in an 80℃ oven for constant temperature curing for 2 hours to obtain the permeation traction module.

[0117] The polyether polyol has a hydroxyl value of 58 mg KOH / g, a viscosity of 500 mPa•S, an acid value of 0.05 mg KOH / g, and a pH of 6.5; the indices of TDI and MDI are 1.0.

[0118] The hydrogel dressing prepared in this embodiment was tested and verified using a phosphate buffer solution with a pH of 6.

[0119] Example 6

[0120] The preparation conditions for the seepage traction module in this embodiment differ from those in Example 1 (S2), but the remaining operational steps are the same as in Example 1. The steps for preparing the seepage traction module in S2 are as follows:

[0121] One-step preparation of the permeation traction module: 100 parts of polyether polyol, 4 parts of water, 0.5 parts of FOCAT-8002, 0.6 parts of foam stabilizer NiaL-20, and 0.6 parts of L-540 were successively poured into a reaction vessel and stirred evenly. Then, 50 parts of TDI were added at 3200 r / min and stirred for 13 seconds. When the mixture turned milky white, stirring was stopped. The mixture was poured into a foaming mold and foamed for 8 minutes. Finally, the foamed sample was placed in an 80℃ oven for constant temperature curing for 1.8 hours to obtain the permeation traction module.

[0122] The polyether polyol has a hydroxyl value of 54 mgKOH / g, a viscosity of 400 mPa•S, an acid value of 0.05 mgKOH / g, and a pH of 7; the TDI index is 1.0.

[0123] The hydrogel dressing prepared in this embodiment was tested and verified using a phosphate buffer solution with a pH of 6.

[0124] Example 7

[0125] The difference between this embodiment and step 6 in S3 of Example 1 for preparing the hydrogel layer is that step 2 uses a 3% sodium alginate solution and step 6 uses a 0.3% anhydrous calcium chloride solution. All other steps are the same as in Example 1.

[0126] The hydrogel dressing prepared in this embodiment was tested and verified using a phosphate buffer solution with a pH of 6.

[0127] Example 8

[0128] The difference between this embodiment and step 6 in S3 of Example 1 for preparing the hydrogel layer is that step 2 uses a 4% sodium alginate solution and step 6 uses a 0.4% anhydrous calcium chloride solution. All other steps are the same as in Example 1.

[0129] The hydrogel dressing prepared in this embodiment was tested and verified using a phosphate buffer solution with a pH of 6.

[0130] Comparative Example 1

[0131] The difference between this comparative example and Example 1 is that the hydrogel layer does not contain Cu. 2+ To verify whether its hydrogel layer inhibits bacterial growth, Staphylococcus aureus, a commonly used bacterium, was used for plate testing. The results showed that it contained Cu. 2+ The hydrogel layer has a distinct antibacterial ring around it, i.e., it contains Cu. 2+ The hydrogel layer inhibits the growth of Staphylococcus aureus, such as Figure 8 As shown; does not contain Cu 2+ The hydrogel layer does not affect the normal growth of Staphylococcus aureus, i.e., it does not contain Cu. 2+ The hydrogel layer does not have the property of inhibiting bacterial growth, such as Figure 9 As shown.

[0132] Comparative Example 2

[0133] The difference between this comparative example and Example 1 is that it does not contain a color-changing unit. This is because the dressing prepared in Example 1 contains Cu. 2+ When in contact with wound exudate, the weakly acidic environment induces the hydrogel to release Cu. 2+ However, it is not possible for medical staff to visually observe the healing status of the wound through color changes.

[0134] Comparative Example 3

[0135] The difference between this comparative example and Example 3 is that it does not include the exudate traction module. Since the grape seed-dyed silk is in direct contact with the hydrogel layer, it is first moistened by the water in the hydrogel before absorbing wound exudate, which will directly affect the accuracy of the wound pH result.

[0136] Comparative Example 4

[0137] The difference between this comparative example and Example 6 is that the curing time in the preparation of the seepage traction module in S2 is 30 hours. Due to the excessively long curing time, the seepage traction module core burned, rendering it unable to perform its seepage traction function.

[0138] The pH-responsive 3D-printed hydrogel dressings prepared in Examples 1-8 and Comparative Examples 1-4 were tested, and the results are detailed in Table 6:

[0139] Table 6

[0140]

[0141] Table 6 shows the test results for the anthocyanin source of Examples 1-8 and Comparative Examples 1-4, the contact angle of the exudate traction module prepared in S2, the cytotoxicity of the hydrogel layer prepared in S3, whether it inhibits bacterial growth, and the response time and response color of the pH-responsive 3D-printed hydrogel dressing after treatment with different pH phosphate buffer solutions. The cut size of the fabric to be dyed was (0.3mm-0.4mm) × (0.3mm-0.4mm), and the cut size of the exudate traction module was (0.3mm-0.4mm) × (0.3mm-0.4mm). As can be seen from Table 6:

[0142] In the pH-responsive 3D-printed hydrogel dressings prepared in Examples 1-8 and Comparative Examples 1-2, the contact angle of the exudate traction module prepared by S2 was less than 90°, indicating that the exudate traction module has good hydrophilicity and meets the requirements for traction of wound exudate. The difference between Comparative Example 1 and Example 1 is that the hydrogel layer does not contain Cu. 2+ To verify whether its hydrogel layer inhibits bacterial growth, Staphylococcus aureus, a commonly used bacterium, was used for plate testing. The results showed that it contained Cu. 2+ The hydrogel layer has a distinct antibacterial ring around it, i.e., it contains Cu. 2+ The hydrogel layer inhibits the growth of Staphylococcus aureus, such as Figure 8 As shown; does not contain Cu 2+ The hydrogel layer does not affect the normal growth of Staphylococcus aureus, i.e., it does not contain Cu. 2+ The hydrogel layer does not have the property of inhibiting bacterial growth, such as Figure 9 As shown. The difference between Comparative Example 2 and Example 1 is that Comparative Example 2 does not contain a color-changing unit, while the dressing prepared in Example 1 contains Cu. 2+ When in contact with wound exudate, the weakly acidic environment induces the hydrogel layer to release Cu. 2+However, this method does not allow medical staff to visually observe the wound healing status through color changes. Comparative Example 3 lacks an exudate traction module, causing the color-changing unit to directly contact the hydrogel layer. Before absorbing wound exudate, the unit is first moistened by the water in the hydrogel layer, directly affecting the accuracy of medical staff's judgment of wound pH results. The exudate traction module prepared in Comparative Example 4 underwent a curing time of 30 hours. Due to the excessive curing time, the core of the exudate traction module burned, rendering it unable to perform its exudate traction function.

[0143] In Examples 1-8 and Comparative Examples 1-4, the S3-prepared hydrogel layer of the pH-responsive 3D-printed hydrogel dressings was prepared according to standard ISO 10993-12, and the cytotoxicity test was performed according to ISO 10993-5. The cytotoxicity results were all greater than 70%, indicating that the S3-prepared hydrogel layers were non-cytotoxic. Using buffer solutions of different pH values ​​to simulate the acid-base environment of wound exudate, it can be seen that when the pH is 6, the response color of the pH-responsive 3D-printed hydrogel dressing is red; when the pH is 7, the response color is purple; and when the pH is 9, the response color is blue. However, Comparative Example 3 did not contain an exudate traction module, and the color-changing unit directly contacted the hydrogel layer. Before absorbing wound exudate, it absorbed water from the hydrogel layer. As shown in Table 6, it only took 2 seconds to absorb water from the hydrogel layer, presenting the original light brownish-red color of the color-changing unit. The pH-responsive 3D-printed hydrogel dressings prepared in Examples 1-8 had a response time between 60 and 75 seconds, exhibiting a sensitive and rapid response.

[0144] Example 6 is the preferred embodiment of the present invention, and the following description is based on Example 6: The preparation process of the seepage traction module in Example 6 is as follows: Figure 2 As shown; Scanning electron microscope image of the aperture of the seepage traction module, as follows. Figure 3 As shown, the scanning electron microscope images of individual apertures of the seepage traction module are as follows: Figure 4 As shown in the figure, the pore size of the exudate traction module is very uniform, and the pores are interconnected, providing a good channel for wound exudate. Contact angle testing of the exudate traction module showed a contact angle of 18.709°, indicating that the prepared hydrogel dressing has good hydrophilicity. Figure 5 As shown. When a buffer solution with pH 6 is used to simulate the acidic environment of wound exudate, the response time is 60 seconds, and the response color is red, as shown. Figure 6 As shown.

[0145] The pH-responsive 3D-printed hydrogel dressing prepared by this invention can help medical staff to accurately administer medication to wounds by monitoring the pH value of the wound, thereby accelerating wound healing and showing great promise for application in wound dressings.

[0146] Finally, it should be noted that in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0147] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0148] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

[0149] The above are preferred embodiments of the present application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the embodiments of the present application, and these improvements and modifications are also considered to be within the scope of protection of the present application.

Claims

1. A method for preparing a pH-responsive 3D-printed hydrogel dressing, characterized in that, Includes the following steps: S1 prepares the color-changing unit S1-1 Anthocyanin Extraction: Add 50%-70% ethanol by mass to the anthocyanin raw material powder at a material-to-liquid ratio of 1:10-1:30, and obtain anthocyanins after treatment. S1-2 Anthocyanin Dyeing: Place the cleaned fabric piece to be dyed in anthocyanin extract solution at a bath ratio of 1:30-1:50, set an appropriate dyeing process, and complete the dyeing process; S2 preparation of seepage traction module Polyether polyol, water, catalyst, and foam stabilizer are sequentially poured into a reaction vessel and stirred evenly. Isocyanate is then added to prepare the permeation traction module in one step. The contents of each component include: 80-100 parts of polyether polyol, 3-5 parts of water, 0.1-0.5 parts of catalyst, 0.6-1.2 parts of foam stabilizer, and 30-50 parts of isocyanate. The permeation traction module has uniform pore size and interconnected pores. S3 Preparation of Hydrogel Layer S3-1 3D Printing Preparation of Hydrogel Layer The hydrogel layer comprises a mesh-like structure prepared by 3D printing using gelatin, methacrylic anhydride, sodium alginate, growth factors, and photoinitiators as the main raw materials. S3-2 Preparation of Hydrogel Layer II The first hydrogel layer was immersed in anhydrous calcium chloride solution for cross-linking to obtain the second hydrogel layer with a mesh structure. S3-3 Preparation of Hydrogel Layer Three The second hydrogel layer was immersed in an aqueous solution of metal cations to obtain the third hydrogel layer containing a metal cation mesh structure. S4 Assembly Prepare a transparent dressing patch, and assemble the color-changing unit prepared in S1, the exudate traction module prepared in S2, and the hydrogel layer prepared in S3 with the transparent dressing patch to obtain a pH-responsive 3D printed hydrogel dressing.

2. The method for preparing the hydrogel dressing according to claim 1, characterized in that, The mixture of anthocyanin raw material powder and ethanol solution in S1-1 is placed in an ultrasonic cleaner with a temperature of 30-60℃ and a power of 300W, and the extraction time is 25-40 minutes. The pH of the extract is adjusted to 2.0-6.

0.

3. The method for preparing the hydrogel dressing according to claim 1, characterized in that, The dyeing process in S1-2 is as follows: the ultrasonic cleaner has a power of 300W, the dyeing temperature is 40-80℃, the dyeing time is 30-40min, the dyeing pH is 3.0-9.0, mordant with a mass fraction of 1%-5% is added, the mordant accounts for 2%-5% of the weight of the fabric to be dyed, after dyeing, the floating color is washed away with a 20% sodium chloride solution for 20-30min, and then washed with deionized water and dried in the dark.

4. The method for preparing the hydrogel dressing according to claim 3, characterized in that, The mordant includes any one or more of alum, magnesium sulfate, aluminum sulfate, and ferrous sulfate.

5. The method for preparing the hydrogel dressing according to claim 1, characterized in that, The rotation speed for adding isocyanate in S2 is 2800-3200 r / min, and the prepared permeation traction module is placed in an 80℃ oven for constant temperature curing for 1.5-2 h.

6. The method for preparing the hydrogel dressing according to claim 1, characterized in that, The 3D printing parameters include a printing speed of 5-10 mm / s, a nozzle temperature of 20-25℃, a light intensity of 100%, a light exposure time of 10-20 s, a light exposure distance of 20 mm, a light wavelength of 365 nm or 405 nm, a light exposure layer number of 1-3, and a line spacing of 1-2 mm.

7. The method for preparing the hydrogel dressing according to claim 1, characterized in that, The metal cation includes Cu. 2 + Zn 2+ Ag + The concentration of the aqueous solution of the metal cation is 0.03-0.6 mol / L, which is any one or more of the following:

8. The pH-responsive 3D-printed hydrogel dressing prepared by any one of the preparation methods according to claims 1 to 7, characterized in that, The response time is between 60-75 seconds. The device comprises, sequentially, a hydrogel layer (from contact with the wound to distance from the wound), an exudate traction module, a color-changing unit, and a transparent dressing patch. Specifically: the hydrogel has a length of 1-5 cm, a width of 0.5-4.5 cm, and a thickness of 0.2-0.4 cm; the exudate traction module has a length of 0.3-0.4 mm, a width of 0.3-0.4 mm, and a thickness of 0.3-0.4 mm; the color-changing unit has a length of 0.3-0.4 mm and a width of 0.3-0.4 mm. Exudate traction modules are uniformly distributed on the hydrogel layer, with a quantity ≥ 1. The number and position of the color-changing units correspond one-to-one with the exudate traction modules. The color-changing unit comprises a fabric patch dyed primarily with anthocyanin extract. The exudate traction module is prepared primarily with polyether polyol, isocyanate, catalyst, and foam stabilizer.

9. The hydrogel dressing according to claim 8, characterized in that, The anthocyanins are derived from one or more of the following: dragon fruit peel, hibiscus, grape seeds, and mulberry; the dyed fabric includes one or more of the following: cotton, silk, linen, and non-woven fabric.

10. The hydrogel dressing according to claim 8, characterized in that, The polyether polyol has one or more of the following properties: hydroxyl value of 54-58 mg KOH / g, viscosity of 400-600 mPa•S, acid value of 0.05 mg KOH / g, and pH of 5-7; the catalyst includes one or more of amine catalysts and tin catalysts, with amine catalysts including FOCAT-8002 and triethylenediamine, and tin catalysts including stannous octoate; the foam stabilizer includes one or more of polyether-modified silicone oil DC-190, foam-regulating silicone oil DC-191, silicone oil L-540, and silicone oil L-580; the isocyanate index is 1.0-1.2, and the isocyanate includes one or more of toluene diisocyanate and diphenylmethane diisocyanate.

11. The hydrogel dressing according to claim 8, characterized in that, The growth factors include one or more of fibroblast growth factor, epidermal growth factor, nerve growth factor, and connective tissue growth factor.

12. The hydrogel dressing according to claim 8, characterized in that, The photoinitiator includes any one of phenyl-2,4,6-trimethylbenzoyl lithium phosphite and 2-hydroxy-4-(2-hydroxyethoxy)-2-methylphenylacetone.

13. The application of any of the pH-responsive 3D-printed hydrogel dressings according to claims 9-12 in the preparation of wound healing materials.

Images