4d printed polyurethane-based hydrogel material, preparation method therefor and use thereof

Abstract

Provided are a 4D printed polyurethane-based hydrogel material, a preparation method therefor and the use thereof. The 4D printed polyurethane-based hydrogel material comprises a combination of a first dynamic cross-linked polyurethane and a second dynamic cross-linked polyurethane, wherein the swelling degree of the first dynamic cross-linked polyurethane is less than the swelling degree of the second dynamic cross-linked polyurethane, and the chain extenders in the first dynamic cross-linked polyurethane and the second dynamic cross-linked polyurethane are each independently a diol constructed on the basis of the Diels-Alder reaction. By means of designing and compounding dynamic cross-linked polyurethane having different swelling degrees, the 4D printed polyurethane-based hydrogel material has a swelling mismatch structure and a water-triggered enhancement property, shows good mechanical properties and biocompatibility, can transform from a one-dimensional shape to a three-dimensional shape by virtue of its own temperature-sensitive and water-responsive properties, and is expected to be used in filling tissue defects by means of minimally invasive surgeries.

Description

A 4D printing polyurethane-based hydrogel material and its preparation method and application Technical Field

[0001] The present invention belongs to the technical field of biomedical materials, and specifically relates to a 4D printing polyurethane-based hydrogel material and a preparation method and application thereof. Background Art

[0002] With the continuous development and progress of science and technology, the concept of "minimally invasive" has gradually become a goal that medical workers are constantly pursuing with its advantages of small wounds, less bleeding, less pain, and faster recovery, representing an inevitable trend in surgical operations. Thanks to the development of precision medical devices, minimally invasive surgery has developed rapidly in the fields of urology, neurosurgery, interventional cardiology, etc. in recent years. For tissue defects and loss of function caused by diseases and accidents, transplantation surgery is still the most commonly used treatment method in clinical medicine, but it is limited by donor shortages, tissue compatibility, and lifelong immunosuppression. Therefore, how to repair critical-sized tissue defects in a minimally invasive manner still faces many challenges. As an extracellular matrix-like material, polymer hydrogel has physical and chemical properties similar to those of living tissue and is expected to be used in the construction of tissue defect repair scaffolds. For example, CN116271219A discloses the application of silk fibroin porous hydrogel in the preparation of bone defect repair scaffolds, utilizing the self-solidification properties of silk fibroin porous hydrogel, combined with its injectability, to mimic bone cement materials for vertebroplasty. However, the monolithic hydrogels produced by traditional mold-forming methods suffer from a single structure, slow nutrient transport, and difficulty forming vascularized structures, making them unfavorable for tissue regeneration. The advent of 3D printing technology has enabled the construction of heterogeneous, personalized tissue engineering scaffolds, and has shown promising applications in the repair and treatment of tissue defects in skin, heart, bone, and cartilage. For example, in the 3D-printed hydrogel bone repair scaffold disclosed in CN116407680A, a printing slurry is prepared using 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, sodium citrate, polyethylene glycol diacrylate, short-chain chitosan, and water. After 3D printing, the slurry is cured under ultraviolet light and then sequentially immersed in a mixed ion solution of sodium citrate and sodium tripolyphosphate and a tris(hydroxymethyl)aminomethane buffer to obtain an ion-crosslinked chitosan-based hydrogel. The slurry is then alternately immersed in a dipotassium hydrogen phosphate solution and a calcium chloride solution for multiple cycles to deposit amorphous calcium phosphate on the ion-crosslinked chitosan-based hydrogel. The slurry is then immersed in a calcium chloride solution to incubate the amorphous calcium phosphate into hydroxyapatite, thereby obtaining a 3D-printed hydrogel bone repair scaffold. In the 3D-printed antibacterial hydrogel repair scaffold disclosed in CN106983912A, a modified sodium hyaluronate / modified oxidized sodium alginate hydrogel precursor is prepared through photocuring 3D printing to form a composite hydrogel scaffold. The antimicrobial peptide LL-37 is then modified on the surface to create the antibacterial hydrogel repair scaffold. However, implantation of the in vitro-formed scaffold requires invasive surgery, which can cause new damage to human tissue. Furthermore, the complex surgical procedure can be dangerous and uncomfortable for the patient. Technical issues

[0003] Since its first proposal by Skylar Tibbits of MIT in 2013, 4D printing technology has rapidly garnered widespread attention across numerous research fields. A comprehensive definition of 4D printing is that 3D-printed structures can spontaneously change shape and function over time under pre-defined stimuli (sound, light, heat, electricity, etc.). Compared to 3D printing, 4D printing enhances the ability of printed structures to change over time, potentially enabling minimally invasive delivery of complex scaffolds. However, conventional 4D-printed hydrogel scaffolds suffer from poor mechanical properties and difficulties in minimally invasive delivery, limiting their practical application. Consequently, developing 4D-printed hydrogel scaffolds with superior mechanical properties and the ability to achieve minimally invasive delivery is a pressing challenge in this field. Technical Solutions

[0004] In response to the shortcomings of the existing technology, the purpose of the present invention is to provide a 4D printed polyurethane-based hydrogel material, a preparation method and application thereof. By designing and compounding dynamically cross-linked polyurethanes with different swelling degrees, the 4D printed polyurethane-based hydrogel material has a swelling mismatch structure and water-triggered enhancement properties, exhibiting good mechanical properties and biocompatibility. It can also utilize its own temperature-sensitive and water-responsive properties to achieve shape transformation from one dimension to three dimensions, and is expected to be used for filling tissue defects in a minimally invasive surgical manner.

[0005] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0006] In a first aspect, the present invention provides a 4D printing polyurethane-based hydrogel material, comprising a combination of a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane, wherein the swelling degree of the first dynamically cross-linked polyurethane is less than the swelling degree of the second dynamically cross-linked polyurethane; the raw materials for preparing the first dynamically cross-linked polyurethane include a combination of a first polyester polyol, a first chain extender, a first polyisocyanate, and optionally a first hydrophilic polyether polyol; the raw materials for preparing the second dynamically cross-linked polyurethane include a combination of a second polyester polyol, a second hydrophilic polyether polyol, a second chain extender, and a second polyisocyanate; the first chain extender and the second chain extender are each independently a diol constructed based on a Diels-Alder reaction.

[0007] The 4D printable polyurethane-based hydrogel material provided by the present invention comprises a combination of a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane with different swelling degrees. The dynamically cross-linked polyurethane comprises a temperature-sensitive soft segment composed of a polyol (a first polyester polyol and optionally a first hydrophilic polyether polyol, a second polyester polyol, and a second hydrophilic polyether polyol), a polyisocyanate (a first polyisocyanate, a second polyisocyanate) as a hard segment, and a diol constructed based on the Diels-Alder reaction as a chain extender. The chain extender is designed to contain structural units constructed based on the Diels-Alder reaction in the 4D printable polyurethane-based hydrogel material, thereby forming a dynamically cross-linked structure. In the present invention, the soft segment with a lower melting point imparts temperature sensitivity to the 4D printable polyurethane-based hydrogel material, helping it to be fixed in a temporary one-dimensional shape as a scaffold and to transform from one dimension to three dimensions in response to stimuli (temperature, water). Furthermore, the 4D-printable polyurethane-based hydrogel material contains both hydrophilic and hydrophobic segments. The hydrophilic polyether polyol (a second hydrophilic polyether polyol, optionally a first hydrophilic polyether polyol) serves as the sole hydrophilic segment. Its mobility in water facilitates aggregation of the hydrophilic segments, which swell upon contact with water, thereby forming a phase-separated structure. This improves the modulus and mechanical properties of the 4D-printable polyurethane-based hydrogel material, endowing it with water-triggered enhancement capabilities. Furthermore, two dynamically cross-linked polyurethanes with different swelling degrees are combined: the second dynamically cross-linked polyurethane with a higher swelling degree and the first dynamically cross-linked polyurethane with a lower swelling degree jointly create a swelling-mismatched structure, endowing the 4D-printable polyurethane-based hydrogel material with excellent water responsiveness.

[0008] Based on the design and compounding of a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane with different swelling degrees, the 4D-printed polyurethane-based hydrogel material provided by the present invention has excellent mechanical properties, biocompatibility, and water-triggered enhancement properties, making it suitable for use as a support scaffold in the body. Furthermore, the 4D-printed polyurethane-based hydrogel material utilizes its inherent temperature sensitivity and water-responsiveness to achieve a shape transition from one dimension to three dimensions, providing a reliable pathway for minimally invasive delivery and promising potential for use in filling tissue defects through minimally invasive surgery.

[0009] The following are preferred technical solutions of the present invention, but are not intended to limit the technical solutions provided by the present invention. Through the following preferred technical solutions, the objectives and beneficial effects of the present invention can be better achieved and realized.

[0010] Preferably, the first polyester polyol and the second polyester polyol each independently include any one of polycaprolactone triol and polycaprolactone diol, or a combination of at least two of them, and polycaprolactone triol is more preferred.

[0011] Preferably, the first hydrophilic polyether polyol and the second hydrophilic polyether polyol each independently include any one of polyethylene glycol and polytetramethylene ether glycol or a combination of at least two thereof, and polyethylene glycol is more preferred.

[0012] As a preferred technical solution of the present invention, the first hydrophilic polyether polyol and the second hydrophilic polyether polyol are polyethylene glycol, which construct the hydrophilic segments of the first dynamically cross-linked polyurethane and the second dynamically cross-linked polyurethane. After absorbing water, the hydrophilic segments of the polyethylene glycol undergo obvious phase separation from other hydrophobic segments, and the phase separation structure helps to improve the mechanical properties.

[0013] Preferably, the molecular weight of the first polyester polyol and the second polyester polyol is independently 500-5000 Da, for example, 800 Da, 1000 Da, 1200 Da, 1500 Da, 1800 Da, 2000 Da, 2500 Da, 3000 Da, 3500 Da, 4000 Da or 4500 Da, as well as specific values ​​between the above values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific values ​​included in the range, and 550-2000 Da is further preferred.

[0014] Preferably, the molecular weight of the first hydrophilic polyether polyol and the second hydrophilic polyether polyol is independently 500-10000 Da, for example, 1000 Da, 2000 Da, 3000 Da, 4000 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da or 9000 Da, as well as specific values ​​between the above values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific values ​​included in the range, and 1000-6000 Da is further preferred.

[0015] As a preferred technical solution of the present invention, the molecular weight of the first polyester polyol and the second polyester polyol is 500-5000 Da (Dalton); the molecular weight of the first hydrophilic polyether polyol and the second hydrophilic polyether polyol is 500-10000 Da; the first polyester polyol and the second polyester polyol (preferably polycaprolactone triol) and the first hydrophilic polyether polyol and the second hydrophilic polyether polyol (preferably polyethylene glycol) with different molecular weights are helpful to adjust the swelling degree, body temperature sensitivity and water-triggered enhancement ability of 4D printing polyurethane-based hydrogel materials.

[0016] Preferably, the molar ratio of the first polyester polyol to the first hydrophilic polyether polyol is 1:(0-1.2), for example, it can be 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1 or 1:1.1, and more preferably 1:(0.1-0.5).

[0017] Preferably, the molar ratio of the second polyester polyol to the second hydrophilic polyether polyol is 1:(0.1-1.2), for example, it can be 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1 or 1:1.1, and more preferably 1:(0.25-1).

[0018] Preferably, the first polyisocyanate and the second polyisocyanate are each independently an aliphatic polyisocyanate and / or an alicyclic polyisocyanate.

[0019] Preferably, the first polyisocyanate and the second polyisocyanate independently include any one or a combination of at least two of isophorone diisocyanate, hexamethylene diisocyanate, pentamethylene diisocyanate, and cyclohexyl diisocyanate, and isophorone diisocyanate is more preferred.

[0020] Preferably, the molar ratio of the first polyisocyanate to the first polyester polyol is (2-6):1, for example, it can be 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, 4:1, 4.2:1, 4.5:1, 4.8:1, 5:1, 5.3:1, 5.5:1 or 5.8:1, and more preferably (3-4.3):1.

[0021] Preferably, the molar ratio of the second polyisocyanate to the second polyester polyol is (2-6):1, for example, it can be 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, 4:1, 4.2:1, 4.5:1, 4.8:1, 5:1, 5.3:1, 5.5:1 or 5.8:1, and more preferably (3-5.3):1.

[0022] Preferably, the molar ratio of the first chain extender to the first polyester polyol is (1.3-2.8):1, for example, it can be 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1 or 2.7:1, and more preferably (1.4-2.5):1.

[0023] Preferably, the molar ratio of the second chain extender to the second polyester polyol is (1.3-2.8):1, for example, it can be 1.5:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1 or 2.7:1, and more preferably (1.6-2.5):1.

[0024] As a preferred technical solution of the present invention, in the first dynamically cross-linked polyurethane, the molar ratio of the first polyester polyol, the first hydrophilic polyether polyol, the first chain extender, and the first polyisocyanate is 1:(0-1.2):(1.3-2.8):(2-6); in the second dynamically cross-linked polyurethane, the molar ratio of the second polyester polyol, the second hydrophilic polyether polyol, the second chain extender, and the second polyisocyanate is 1:(0.1-1.2):(1.3-2.8):(2-6); by designing the molar ratio of each material, the first dynamically cross-linked polyurethane and the second dynamically cross-linked polyurethane can exhibit a series of adjustable mechanical properties ranging from hard and brittle to soft and tough. The wide range of mechanical properties is conducive to the application of the 4D printed polyurethane-based hydrogel material as a scaffold in tissues of different strengths.

[0025] Preferably, the diol constructed based on the Diels-Alder reaction is obtained by reacting bismaleimide with a hydroxyl-containing furan compound.

[0026] As a preferred technical solution of the present invention, the Diels-Alder reaction is a diene synthesis reaction between bismaleimide and a hydroxyl-containing furan compound, and the diene synthesis reaction can undergo a reverse reaction at 100-150°C. As a result, the Diels-Alder reaction-based structural units in the first and second chain extenders become the basis of the dynamic crosslinking structures in the first and second dynamically crosslinked polyurethanes.

[0027] Preferably, the bismaleimide includes any one of N,N'-(4,4'-methylenediphenyl)bismaleimide, N,N'-(1,4-phenylene)bismaleimide, and N,N'-(1,3-phenylene)bismaleimide, or a combination of at least two thereof, and N,N'-(4,4'-methylenediphenyl)bismaleimide (BMI) is further preferred.

[0028] Preferably, the hydroxyl-containing furan compound includes furfuryl alcohol.

[0029] As a preferred technical solution of the present invention, the first chain extender and the second chain extender are obtained by reacting N,N'-(4,4'-methylenediphenyl)bismaleimide with furfuryl alcohol, and the reaction formula is as follows:

[0030]

[0031] Preferably, the molar ratio of the maleimide group in the bismaleimide to the furan group in the hydroxyl-containing furan compound is 1:(1-5), for example, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4 or 1:4.5.

[0032] Preferably, the reaction of the bismaleimide and the hydroxyl-containing furan compound is carried out in the presence of a solvent.

[0033] Preferably, the solvent includes any one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetone, and tetrahydrofuran, or a combination of at least two thereof.

[0034] Preferably, the temperature for the reaction of the bismaleimide with the hydroxyl furan compound is 50-80°C, for example, it can be 52°C, 55°C, 58°C, 60°C, 62°C, 65°C, 68°C, 70°C or 75°C, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0035] Preferably, the reaction time of the bismaleimide and the hydroxyl-containing furan compound is 2-12 h, for example, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h or 11 h, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0036] Preferably, the diol constructed based on the Diels-Alder reaction is obtained by reacting bismaleimide with a hydroxyl-containing furan compound. The specific method includes: mixing bismaleimide with a solvent, heating at 50-80°C for 5-60 minutes, adding furfuryl alcohol, and carrying out a Diels-Alder reaction at 50-80°C under stirring for 2-12 hours to obtain a reaction solution; the reaction solution is post-treated to obtain the diol.

[0037] Preferably, the post-treatment method comprises: purifying the reaction solution by precipitation with cold diethyl ether, and subjecting the obtained solid to primary drying, washing, and secondary drying to obtain the diol.

[0038] Preferably, the washing agent used in the washing comprises diethyl ether.

[0039] Preferably, the number of washings is 1-5 times, such as 2 times, 3 times or 4 times.

[0040] Preferably, the temperature of the primary drying and the secondary drying are each independently 50-80°C, for example, 52°C, 55°C, 58°C, 60°C, 62°C, 65°C, 68°C, 70°C or 75°C, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0041] Preferably, the time for the primary drying and the secondary drying are each independently 6-24 h, for example, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h or 22 h, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range; further preferably, the time for the primary drying is 8-24 h, and the time for the secondary drying is 12-24 h.

[0042] Preferably, the first dynamically cross-linked polyurethane is prepared by the following method, which includes: conducting a first prepolymerization reaction of a first polyester polyol, optionally a first hydrophilic polyether polyol and a first polyisocyanate to obtain a first prepolymer; and conducting a first chain extension reaction of the first prepolymer and a first chain extender to obtain the first dynamically cross-linked polyurethane.

[0043] Preferably, the first polyester polyol, optionally the first hydrophilic polyether polyol, is subjected to a dehydration treatment, and the dehydration treatment method comprises: vacuum filtering the first polyester polyol, optionally the first hydrophilic polyether polyol, at 100-125° C. (for example, 105° C., 110° C., 115° C., 120° C., etc.) for 0-2 h (for example, 0.2 h, 0.5 h, 0.8 h, 1 h, 1.2 h, 1.5 h, 1.8 h, etc.).

[0044] Preferably, the first prepolymerization reaction is carried out in the presence of a first solvent and a first catalyst.

[0045] Preferably, the first solvent includes any one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and tetrahydrofuran, or a combination of at least two thereof, and more preferably a combination of N,N-dimethylformamide and tetrahydrofuran.

[0046] Preferably, the volume ratio of N,N-dimethylformamide to tetrahydrofuran in the first solvent is 1:(2-8), for example, it can be 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7 or 1:7.5, etc.

[0047] Preferably, based on the mass of the first polyester polyol as 1 g, the amount of the first solvent used is 10-50 mL, for example, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL or 45 mL, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0048] Preferably, the first catalyst comprises an organotin catalyst.

[0049] Preferably, the first catalyst comprises any one of dibutyltin dilaurate, stannous octoate, and dibutyltin diacetate, or a combination of at least two thereof, with dibutyltin dilaurate being more preferred.

[0050] Preferably, based on the mass of the first polyester polyol being 1 g, the amount of the first catalyst used is 10-40 μL, for example, 15 μL, 20 μL, 25 μL, 30 μL or 35 μL, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0051] Preferably, the temperature of the first prepolymerization reaction is 50-70°C, for example, it can be 52°C, 55°C, 58°C, 60°C, 62°C, 65°C or 68°C, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0052] Preferably, the time of the first prepolymerization reaction is 2-8 h, for example, it can be 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h or 7.5 h, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0053] Preferably, the temperature of the first chain extension reaction is 50-70°C, for example, 52°C, 55°C, 58°C, 60°C, 62°C, 65°C or 68°C, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0054] Preferably, the time of the first chain extension reaction is 4-8 h, for example, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h or 7.5 h, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0055] Preferably, the process further comprises a solvent removal step after the first chain extension reaction is completed.

[0056] Preferably, the solvent removal method is high-temperature drying, the temperature is 50-70°C, for example, 52°C, 55°C, 58°C, 60°C, 62°C, 65°C or 68°C, etc.; the time is 18-72 h, for example, 20 h, 22 h, 24 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, 44 h, 48 h, 52 h, 56 h, 60 h, 64 h, 68 h, etc.

[0057] Preferably, the second dynamically cross-linked polyurethane is prepared by the following method, which includes: conducting a second prepolymerization reaction on a second polyester polyol, a second hydrophilic polyether polyol and a second polyisocyanate to obtain a second prepolymer; and conducting a second chain extension reaction on the second prepolymer and a second chain extender to obtain the second dynamically cross-linked polyurethane.

[0058] Preferably, the second polyester polyol and the second hydrophilic polyether polyol are dehydrated, and the dehydration method comprises: vacuum filtering the second polyester polyol and the second hydrophilic polyether polyol at 100-125° C. (for example, 105° C., 110° C., 115° C., 120° C., etc.) for 0-2 h (for example, 0.2 h, 0.5 h, 0.8 h, 1 h, 1.2 h, 1.5 h, 1.8 h, etc.).

[0059] Preferably, the second prepolymerization reaction is carried out in the presence of a second solvent and a second catalyst.

[0060] Preferably, the second solvent includes any one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and tetrahydrofuran, or a combination of at least two thereof, and more preferably a combination of N,N-dimethylformamide and tetrahydrofuran.

[0061] Preferably, the volume ratio of N,N-dimethylformamide to tetrahydrofuran in the second solvent is 1:(2-8), for example, it can be 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7 or 1:7.5, etc.

[0062] Preferably, based on the mass of the second polyester polyol as 1 g, the amount of the second solvent used is 10-50 mL, for example, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL or 45 mL, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0063] Preferably, the second catalyst comprises an organotin catalyst.

[0064] Preferably, the second catalyst comprises any one of dibutyltin dilaurate, stannous octoate, and dibutyltin diacetate, or a combination of at least two thereof, with dibutyltin dilaurate being more preferred.

[0065] Preferably, based on the mass of the second polyester polyol being 1 g, the amount of the second catalyst used is 10-40 μL, for example, 15 μL, 20 μL, 25 μL, 30 μL or 35 μL, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0066] Preferably, the temperature of the second prepolymerization reaction is 50-70°C, for example, it can be 52°C, 55°C, 58°C, 60°C, 62°C, 65°C or 68°C, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0067] Preferably, the time of the second prepolymerization reaction is 2-8 h, for example, it can be 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h or 7.5 h, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0068] Preferably, the temperature of the second chain extension reaction is 50-70°C, for example, 52°C, 55°C, 58°C, 60°C, 62°C, 65°C or 68°C, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0069] Preferably, the time of the second chain extension reaction is 4-8 h, for example, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h or 7.5 h, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0070] Preferably, the step of removing the solvent is further included after the second chain extension reaction is completed.

[0071] Preferably, the solvent removal method is high-temperature drying, the temperature is 50-70°C, for example, 52°C, 55°C, 58°C, 60°C, 62°C, 65°C or 68°C, etc.; the time is 18-72 h, for example, 20 h, 22 h, 24 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, 44 h, 48 h, 52 h, 56 h, 60 h, 64 h, 68 h, etc.

[0072] In the present invention, the mass ratio of the first dynamically cross-linked polyurethane to the second dynamically cross-linked polyurethane is not particularly limited and can be adjusted according to different application scenarios and application requirements to obtain 4D printing polyurethane-based hydrogel materials with different mechanical properties, water-triggered enhancement properties, temperature sensitivity and water responsiveness, and shape transformation properties.

[0073] In the present invention, the modulus of the 4D printing polyurethane-based hydrogel material has a strong temperature dependence, and can be changed in shape by an external force at a first temperature to obtain a temporary shape; the temporary shape can be fixed at a second temperature; when placed in an environment of the first temperature again, the temporary shape can spontaneously recover to the initial shape within a time of ≤5 min (for example, 0.5 min, 1 min, 2 min, 3 min, 4 min, etc.); wherein, the first temperature is 20-40°C, for example, 22°C, 25°C, 28°C, 30°C, 32°C, 35°C, 37°C, 39°C, etc., preferably 36-37°C (body temperature); the second temperature is ≤5°C, for example, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, etc.

[0074] In a second aspect, the present invention provides a method for preparing a 4D printing polyurethane-based hydrogel material as described in the first aspect, the preparation method comprising: placing a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane in different barrels of a 3D printer, respectively, extruding and performing 3D printing to obtain the 4D printing polyurethane-based hydrogel material.

[0075] Preferably, the 3D printing method is multi-nozzle fused deposition modeling.

[0076] As a preferred technical solution of the present invention, the method for preparing a 4D-printable polyurethane-based hydrogel material uses polyols (a first polyester polyol and optionally a first hydrophilic polyether polyol, a second polyester polyol, and a second hydrophilic polyether polyol) as temperature-sensitive soft segments and polyisocyanates (a first polyisocyanate and a second polyisocyanate) as hard segments. Prepolymerization is then performed, followed by chain extension using a diol constructed via a Diels-Alder reaction, to produce a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane. The 4D-printable polyurethane-based hydrogel material is then constructed using multi-nozzle fused deposition modeling technology. This simple preparation method produces a water-triggered, reinforced 4D-printable polyurethane-based hydrogel material with excellent mechanical properties, biocompatibility, and water-triggered reinforcement properties, promising broad application prospects.

[0077] Preferably, the heating temperature of the barrel is 110-130°C, for example, it can be 112°C, 115°C, 118°C, 120°C, 122°C, 125°C or 128°C, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0078] Preferably, the extrusion pressure is 100-750 kPa, for example, it can be 150 kPa, 200 kPa, 250 kPa, 300 kPa, 350 kPa, 400 kPa, 450 kPa, 500 kPa, 550 kPa, 600 kPa, 650 kPa or 700 kPa, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0079] Preferably, the printing speed of the 3D printing is 10-500 mm / min, for example, it can be 50 mm / min, 100 mm / min, 150 mm / min, 200 mm / min, 250 mm / min, 300 mm / min, 350 mm / min, 400 mm / min or 450 mm / min, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0080] Preferably, the caliber of the printing needle of the 3D printing is 200-1000 μm, for example, it can be 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm or 900 μm, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0081] In the present invention, the 3D printing path and method, parameters such as line spacing, the arrangement of the first dynamically cross-linked polyurethane and the second dynamically cross-linked polyurethane, etc. can be determined according to actual needs so that the structure of the 4D printed polyurethane-based hydrogel material meets its deformation requirements.

[0082] Exemplarily, the 3D printing is performed according to a preset pattern, preferably using a layer-by-layer printing method to form a 4D printed polyurethane-based hydrogel material with a multi-layer (at least two-layer) structure.

[0083] Preferably, at least one cross-section of the 4D printed polyurethane-based hydrogel material comprises a first dynamically cross-linked polyurethane layer and a second dynamically cross-linked polyurethane layer stacked on top of each other.

[0084] In a third aspect, the present invention provides an application of the 4D printing polyurethane-based hydrogel material as described in the first aspect, wherein the 4D printing polyurethane-based hydrogel material is used to prepare a biological scaffold.

[0085] Preferably, the 4D printed polyurethane-based hydrogel material is used to prepare a minimally invasive support scaffold or a tissue defect repair scaffold.

[0086] In the present invention, the 4D printed polyurethane-based hydrogel material serves as a scaffold, which can be curled into a one-dimensional long cylindrical structure under the action of external force at 20-40°C (preferably 37°C). The one-dimensional long cylindrical structure can be fixed at low temperature (≤5°C, preferably 4°C); the fixed one-dimensional long cylindrical structure can be delivered into the body through a microcatheter and spontaneously complete the deformation from one dimension to three dimensions in the body temperature and body fluid environment to complete the filling of the defect. Beneficial effects

[0087] (1) In the 4D printing polyurethane-based hydrogel material provided by the present invention, polyol is used as the soft segment of the dynamically cross-linked polyurethane. The low melting point of the soft segment gives the 4D printing polyurethane-based hydrogel material a temperature / body temperature sensitive property. This temperature / body temperature sensitive property helps it to be fixed into a temporary one-dimensional shape as a scaffold and realize a multi-dimensional shape transition from one dimension to three dimensions under the stimulation of temperature and / or water.

[0088] (2) The 4D printed polyurethane-based hydrogel material contains both hydrophilic segments and hydrophobic segments. After swelling in water, the hydrophilic segments aggregate to form a phase-separated structure, which can improve the modulus of the hydrogel material and exhibit excellent water-triggered enhancement properties. This water-triggered enhancement property helps it to better play a supporting role as a scaffold in the humid environment in the body.

[0089] (3) Based on the design and compounding of the first dynamically cross-linked polyurethane and the second dynamically cross-linked polyurethane with different swelling degrees, the 4D printed polyurethane-based hydrogel material has a swelling mismatch structure and exhibits the characteristics of spontaneous deformation into a preset three-dimensional shape after contacting water. The endogenous stimulus responsiveness (water response and temperature response) is safer and suitable for application in the biomedical field.

[0090] (4) The 4D printed polyurethane-based hydrogel material has both temperature response and water response. As a scaffold, it can be fixed into a one-dimensional shape in vitro, which is convenient for minimally invasive delivery. After being implanted into the body, it restores its original shape under body temperature stimulation and then deforms into a preset three-dimensional shape under body fluid stimulation, completing the filling of the defect and playing a certain supporting role. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] FIG1 is a hydrogen NMR spectrum of the diol DA-diol prepared by the Diels-Alder reaction according to Preparation Example 1;

[0092] FIG2 is a Fourier transform infrared spectrum of the second dynamically cross-linked polyurethane in Example 1;

[0093] FIG3 is a tensile stress-strain test diagram of the first dynamically cross-linked polyurethane in Example 1;

[0094] FIG4 is a storage modulus test graph of the first dynamically cross-linked polyurethane and the second dynamically cross-linked polyurethane in Example 1;

[0095] FIG5 is a swelling test diagram of the first dynamically cross-linked polyurethane and the second dynamically cross-linked polyurethane in Example 1;

[0096] FIG6 is a shape transformation test diagram of the 4D printed polyurethane-based hydrogel material provided in Example 1;

[0097] FIG7 is a shape transformation test diagram of the polyurethane-based hydrogel material provided in Comparative Example 1. Best Mode for Carrying Out the Invention

[0098] The technical solution of the present invention is further illustrated below by specific embodiments. Those skilled in the art should understand that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention. The terms "comprise", "include", "have", "contain" or any other variations thereof used herein are intended to cover non-exclusive inclusions. For example, a composition, step, method, product or device comprising the listed elements is not necessarily limited to those elements, but may also include other elements not explicitly listed or elements inherent to such a composition, step, method, product or device. "Optionally", "optionally" or "any one" means that the matter or event described thereafter may occur or not, and the description includes situations in which the event occurs and situations in which the event does not occur. In the present invention, the features defined as "first" or "second" may explicitly or implicitly include one or more of the features, and are used to distinguish and describe features, without distinction of order or importance. In the description of the present invention, unless otherwise indicated, the meaning of "multiple" is two or more.

[0099] Preparation Example 1

[0100] A diol (DA-diol) constructed based on the Diels-Alder reaction is obtained by reacting N,N'-(4,4'-methylenediphenyl)bismaleimide (BMI) with furfuryl alcohol (FA). The reaction formula is as follows:

[0101]

[0102] The specific preparation method is as follows: 17.92 g of BMI is dissolved in 15 mL of N,N-dimethylformamide, heated at 60°C for 10 min, and then 13 mL of FA is added. The Diels-Alder reaction (DA reaction) is carried out at 60°C under magnetic stirring for 3 h to obtain a reaction solution; the reaction solution is added dropwise to 500 mL of cold ether, the precipitated product is collected and placed in a vacuum drying oven at 60°C for 12 h, the dried product is washed three times with excess ether, and the washed product is placed in a vacuum drying oven at 60°C for 24 h to obtain a diol (DA-diol) constructed based on the Diels-Alder reaction.

[0103] The diol DA-diol provided in this preparation example was dissolved in deuterated dimethyl sulfoxide and characterized by a proton spectrum on a 400 MHz Bruker ARX 400 NMR spectrometer. The solution was then heated at 120°C for 20 minutes and again characterized by a proton spectrum on a 400 MHz Bruker ARX 400 NMR spectrometer. The resulting proton NMR spectrum is shown in Figure 1. As can be seen from Figure 1, the target diol DA-diol was successfully synthesized, and the Diels-Alder reaction (DA reaction) undergoes a reverse reaction (Retro-DA) at 120°C. Modes for Carrying Out the Invention

[0104] Example 1

[0105] A 4D printing polyurethane-based hydrogel material and a preparation method thereof. The 4D printing polyurethane-based hydrogel material comprises a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane. The raw materials for the preparation thereof include polycaprolactone triol (molecular weight 550 Da), polyethylene glycol (molecular weight 4000 Da), diol DA-diol (Preparation Example 1), and isophorone diisocyanate. The preparation method is specifically as follows:

[0106] (1) Preparation of dynamically cross-linked polyurethane:

[0107] Preparation of the first dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 2 g of polyethylene glycol with a molecular weight of 4000 Da were added to a No. 1 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added. After mechanical stirring, 1.556 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 1.942 g of diol DA-diol was added to the No. 1 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the first dynamically cross-linked polyurethane.

[0108] Preparation of the second dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 4 g of polyethylene glycol with a molecular weight of 4000 Da were added to a No. 2 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added thereto. After mechanical stirring, 1.778 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 2.24 g of diol DA-diol was added to the No. 2 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the second dynamically cross-linked polyurethane.

[0109] (2) Preparation of 4D printing polyurethane-based hydrogel materials:

[0110] The two dynamically cross-linked polyurethanes obtained in step (1) were added to two high-temperature barrels of an extrusion 3D printer, respectively, and equipped with a nozzle with an inner diameter of 300 μm. The two high-temperature barrels were heated to 130°C, the extrusion pressure of the two high-temperature barrels was set to 200 kPa, and the printing speed was set to 500 mm / min. The specific method of 3D printing is as follows: a 3 cm × 0.6 cm rectangle is designed and divided into five equal 0.6 cm × 0.6 cm squares, which are named 1, 2, 3, 4, and 5 in sequence; the first layer is printed in a serpentine manner along the long axis in regions 1, 2, 3, and 5 using the first dynamically cross-linked polyurethane, with a line spacing of 1 mm; the second layer is printed in a serpentine manner along the long axis in region 4 using the second dynamically cross-linked polyurethane, with a line spacing of 1 mm; the second layer is printed in a serpentine manner above the first layer (regions 1, 2, 3, 4, and 5) along the short axis using the first dynamically cross-linked polyurethane, with a line spacing of 1 mm; the third layer is printed in a serpentine manner along the long axis in regions 1, 3, 4, and 5 using the first dynamically cross-linked polyurethane, with a line spacing of 1 mm; the second dynamically cross-linked polyurethane is printed in a serpentine manner along the long axis in region 2 with a line spacing of 1 mm; the above printing is performed alternately through two high-temperature barrels to obtain the 4D printed polyurethane-based hydrogel material.

[0111] The first dynamically cross-linked polyurethane, the second dynamically cross-linked polyurethane, and the 4D printing polyurethane-based hydrogel material in this embodiment were tested as follows:

[0112] 1. Structural Characterization

[0113] The structures of the first dynamically cross-linked polyurethane and the second dynamically cross-linked polyurethane were characterized by Fourier transform infrared spectrometry. The Fourier transform infrared spectrum of the second dynamically cross-linked polyurethane is shown in Figure 2. As can be seen from Figure 2, the second dynamically cross-linked polyurethane contains characteristic peaks of soft segment polycaprolactone triol, polyethylene glycol, and chain extender diol DA-diol, indicating the successful synthesis of the second dynamically cross-linked polyurethane.

[0114] 2. Tensile stress and strain test

[0115] The tensile stress-strain test of the first and second dynamically cross-linked polyurethanes was conducted using an in-situ mechanical observation instrument. The specific method is as follows: the first and second dynamically cross-linked polyurethanes were cut into IV dumbbell-shaped specimens that meet the GB / T 528-2009 standard using a cutter, and the tensile rate parameter was set to 50 mm·min -1 At least three replicates were prepared for each sample group and tested at room temperature (25°C). Young's modulus was calculated from the initial linear region within a strain of 10%. The tensile stress-strain test graph of the first dynamically cross-linked polyurethane is shown in Figure 3. As can be seen from Figure 3, the Young's modulus of the dry first dynamically cross-linked polyurethane is 38.55 MPa, which is lower than the Young's modulus (81.98 MPa) exhibited after swelling in water (swelling equilibrium, i.e., after immersion in 25°C water for 72 hours), indicating that the first dynamically cross-linked polyurethane exhibits water-triggered reinforcement. The second dynamically cross-linked polyurethane was tested using the same method and also exhibited water-triggered reinforcement.

[0116] 3. Dynamic Thermodynamic Analysis

[0117] Dynamic thermomechanical analysis of the first and second dynamically cross-linked polyurethanes was performed using a Q800 dynamic thermomechanical analyzer. Specifically, the dry first and second dynamically cross-linked polyurethanes were cut into rectangular specimens with a length of 12 mm, a width of 4 mm, and a thickness of 0.5 mm using a cutter. These specimens were then tested using a tensile fixture. Test parameters were set as follows: preload 0.01 N, tensile frequency 1 Hz, strain 0.1%, and heating rate 5°C min. -1The test temperature range is -80℃ to 100℃. The storage modulus, loss modulus and loss factor of the dynamically cross-linked polyurethane are recorded as a function of temperature. Among them, the storage modulus of the first dynamically cross-linked polyurethane and the second dynamically cross-linked polyurethane as a function of temperature is shown in Figure 4. As can be seen from Figure 4, the storage modulus of the first dynamically cross-linked polyurethane at 10℃, 20℃, 30℃, 40℃ and 50℃ are 1167 MPa, 799 MPa, 452 MPa, 177 MPa and 48 MPa respectively, and the storage modulus of the second dynamically cross-linked polyurethane at 10℃, 20℃, 30℃, 40℃ and 50℃ are 184 MPa, 55 MPa, 15 MPa, 5 MPa and 2 MPa respectively. Its storage modulus gradually decreases with the increase of the test temperature, indicating that the dynamically cross-linked polyurethane has temperature-sensitive characteristics.

[0118] 4. Swelling test

[0119] The swelling degree of the first and second dynamically cross-linked polyurethanes was tested using 37°C deionized water. The specific method was as follows: first, the dry first and second dynamically cross-linked polyurethanes were weighed and placed in deionized water. The first and second dynamically cross-linked polyurethanes were removed at regular intervals, excess surface water was removed, and then weighed. The swelling degree was calculated using the following formula:

[0120] Swelling degree=100%×(wet weight-dry weight) / dry weight;

[0121] The dry weight represents the initial mass of the dried dynamically cross-linked polyurethane to be tested, and the wet weight represents the mass of the dynamically cross-linked polyurethane to be tested at different times in deionized water at 37°C.

[0122] The swelling degree test graph obtained by the aforementioned method is shown in Figure 5. Combining Figure 5 and the preparation method, it can be seen that the second dynamically cross-linked polyurethane has a higher proportion of hydrophilic polyethylene glycol segments and therefore has a higher swelling degree of 118% after swelling equilibrium. The first dynamically cross-linked polyurethane has a lower proportion of polyethylene glycol segments and a swelling degree of 68%, indicating that two dynamically cross-linked polyurethanes with different swelling degrees can be used to construct a swelling-mismatched structure.

[0123] 5. Shape Transformation Test

[0124] The 4D printed polyurethane-based hydrogel material provided in this embodiment was tested for one-dimensional to three-dimensional shape transformation. As shown in Figure 6, the 4D printed polyurethane-based hydrogel material with an initial sheet shape was rolled into a one-dimensional cylinder by external force in a 37°C environment and fixed in a 4°C environment. The water-triggered enhanced 4D printed polyurethane-based hydrogel scaffold with a temporary cylindrical shape was placed in a 37°C water environment. The one-dimensional cylinder was first stimulated by temperature and restored to its initial sheet structure, and then gradually swelled by absorbing water. Due to the swelling mismatch structure, it spontaneously folded into a three-dimensional "S" shape, indicating that the water-triggered enhanced 4D printed polyurethane-based hydrogel material can use its own temperature-sensitive and water-responsive properties to achieve shape transformation from one dimension to three dimensions, and is expected to be used for filling tissue defects in a minimally invasive surgical manner.

[0125] Example 2

[0126] A 4D printing polyurethane-based hydrogel material and a preparation method thereof. The 4D printing polyurethane-based hydrogel material comprises a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane. The raw materials for the preparation thereof include polycaprolactone triol (molecular weight 550 Da), polyethylene glycol (molecular weight 2000 Da), diol DA-diol (Preparation Example 1), and isophorone diisocyanate. The preparation method is specifically as follows:

[0127] (1) Preparation of dynamically cross-linked polyurethane:

[0128] Preparation of the first dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 1 g of polyethylene glycol with a molecular weight of 2000 Da were added to a No. 1 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added thereto. After mechanical stirring, 1.556 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 1.942 g of diol DA-diol was added to the No. 1 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the first dynamically cross-linked polyurethane.

[0129] Preparation of the second dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 2 g of polyethylene glycol with a molecular weight of 2000 Da were added to a No. 2 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added thereto. After mechanical stirring, 1.778 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 2.24 g of diol DA-diol was added to the No. 2 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the second dynamically cross-linked polyurethane.

[0130] (2) Preparation of 4D printing polyurethane-based hydrogel materials:

[0131] The two dynamically cross-linked polyurethanes obtained in step (1) were added to two high-temperature barrels of an extrusion-type 3D printer, respectively, and equipped with a nozzle with an inner diameter of 300 μm. The two high-temperature barrels were heated to 130°C, the extrusion pressure of the two high-temperature barrels was set to 500 kPa, and the printing speed was 200 mm / min. The specific method of 3D printing is as follows: the first layer is printed in a serpentine shape along the long axis within a range of 2 cm×1 cm using the first dynamically cross-linked polyurethane, with a line spacing of 1 mm; the second layer is printed in a serpentine shape along the short axis above the first layer using the second dynamically cross-linked polyurethane, with a line spacing of 2 mm; the two high-temperature barrels are alternately printed to obtain the 4D printed polyurethane-based hydrogel material.

[0132] The 4D printing polyurethane-based hydrogel material provided in Example 2 was tested for performance using the same method as in Example 1. The swelling equilibrium of the first dynamically cross-linked polyurethane was 22%, the Young's modulus in the dry state was 201.9 MPa, the Young's modulus in the wet state was 465.28 MPa, the storage modulus at 30°C was 1614 MPa, and the storage modulus at 10°C was 1958 MPa; the swelling equilibrium of the second dynamically cross-linked polyurethane was 56%, the Young's modulus in the dry state was 85.89 MPa, the Young's modulus in the wet state (immersed in water at 25°C for 72 h) was 113.78 MPa, the storage modulus at 30°C was 880 MPa, and the storage modulus at 10°C was 1397 MPa; the above results indicate that the swelling degree of the first dynamically cross-linked polyurethane is less than the swelling degree of the second dynamically cross-linked polyurethane, and a swelling mismatch structure can be formed, and the material has water-triggered enhancement properties, excellent temperature response, and water responsiveness.

[0133] Example 3

[0134] A 4D printing polyurethane-based hydrogel material and a preparation method thereof. The 4D printing polyurethane-based hydrogel material comprises a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane. The raw materials for the preparation thereof include polycaprolactone triol (molecular weight 550 Da), polyethylene glycol (molecular weight 1000 Da), diol DA-diol (Preparation Example 1), and isophorone diisocyanate. The preparation method is specifically as follows:

[0135] (1) Preparation of dynamically cross-linked polyurethane:

[0136] Preparation of the first dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 0.5 g of polyethylene glycol with a molecular weight of 1000 Da were added to a No. 1 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added. After mechanical stirring, 1.556 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 1.942 g of diol DA-diol was added to the No. 1 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the first dynamically cross-linked polyurethane.

[0137] Preparation of the second dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 1 g of polyethylene glycol with a molecular weight of 1000 Da were added to a No. 2 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added thereto. After mechanical stirring, 1.778 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 2.24 g of diol DA-diol was added to the No. 2 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the second dynamically cross-linked polyurethane.

[0138] (2) Preparation of 4D printing polyurethane-based hydrogel materials:

[0139] The two dynamically cross-linked polyurethanes obtained in step (1) were added to two high-temperature barrels of an extrusion-type 3D printer, respectively, and equipped with a nozzle with an inner diameter of 300 μm. The two high-temperature barrels were heated to 130°C, the extrusion pressure of the two high-temperature barrels was set to 700 kPa, and the printing speed was 100 mm / min. The specific method of 3D printing is as follows: the first layer is printed in a serpentine shape along the short axis within a range of 2 cm×1 cm using the first dynamically cross-linked polyurethane, with a line spacing of 1 mm; the second layer is printed in a serpentine shape along the long axis above the first layer using the second dynamically cross-linked polyurethane, with a line spacing of 2 mm; the two high-temperature barrels are alternately printed to obtain the 4D printed polyurethane-based hydrogel material.

[0140] The performance test of the 4D printing polyurethane-based hydrogel material provided in Example 3 was carried out using the same method as in Example 1. The swelling degree of the first dynamically cross-linked polyurethane at swelling equilibrium was 11%, the storage modulus at 30°C was 2011 MPa, and the storage modulus at 10°C was 2170 MPa; the swelling degree of the second dynamically cross-linked polyurethane at swelling equilibrium was 14%, the storage modulus at 30°C was 1905 MPa, and the storage modulus at 10°C was 2106 MPa; the above results indicate that the swelling degree of the first dynamically cross-linked polyurethane is less than the swelling degree of the second dynamically cross-linked polyurethane, and a swelling mismatch structure can be formed with excellent temperature response and water responsiveness; due to the small molecular weight of the hydrophilic segment polyethylene glycol in Example 3, its water-triggered enhancement properties are not obvious.

[0141] Example 4

[0142] A 4D printing polyurethane-based hydrogel material and a preparation method thereof. The 4D printing polyurethane-based hydrogel material comprises a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane. The raw materials for the preparation thereof comprise polycaprolactone triol (molecular weight 2000 Da), polyethylene glycol (molecular weight 4000 Da), diol DA-diol (Preparation Example 1), and isophorone diisocyanate. The preparation method is specifically as follows:

[0143] (1) Preparation of dynamically cross-linked polyurethane:

[0144] Preparation of the first dynamically cross-linked polyurethane: 4 g of polycaprolactone triol with a molecular weight of 2000 Da and 0.8 g of polyethylene glycol with a molecular weight of 4000 Da were added to a No. 1 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added. After mechanical stirring, 1.423 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 1.776 g of diol DA-diol was added to the No. 1 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and placed in a 60°C oven to dry for 48 h to obtain the first dynamically cross-linked polyurethane.

[0145] Preparation of the second dynamically cross-linked polyurethane: 4 g of polycaprolactone triol with a molecular weight of 2000 Da and 8 g of polyethylene glycol with a molecular weight of 4000 Da were added to a No. 2 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added thereto. After mechanical stirring, 2.223 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 2.774 g of diol DA-diol was added to the No. 2 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the second dynamically cross-linked polyurethane.

[0146] (2) Preparation of 4D printing polyurethane-based hydrogel materials:

[0147] The two dynamically cross-linked polyurethanes obtained in step (1) were added to two high-temperature barrels of an extrusion-type 3D printer, respectively, and equipped with a nozzle with an inner diameter of 300 μm. The two high-temperature barrels were heated to 130°C, the extrusion pressure of the two high-temperature barrels was set to 700 kPa, and the printing speed was 100 mm / min. The specific method of 3D printing is as follows: the first layer is printed in a serpentine shape along the short axis within a range of 2 cm×1 cm using the first dynamically cross-linked polyurethane, with a line spacing of 1 mm; the second layer is printed in a serpentine shape along the long axis above the first layer using the second dynamically cross-linked polyurethane, with a line spacing of 2 mm; the two high-temperature barrels are alternately printed to obtain the 4D printed polyurethane-based hydrogel material.

[0148] Example 5

[0149] A 4D printing polyurethane-based hydrogel material and a preparation method thereof. The 4D printing polyurethane-based hydrogel material comprises a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane. The raw materials for the preparation thereof include polycaprolactone triol (molecular weight 550 Da), polyethylene glycol (molecular weight 4000 Da), diol DA-diol (Preparation Example 1), and isophorone diisocyanate. The preparation method is specifically as follows:

[0150] (1) Preparation of dynamically cross-linked polyurethane:

[0151] Preparation of the first dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 1.6 g of polyethylene glycol with a molecular weight of 4000 Da were added to a No. 1 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added. After mechanical stirring, 1.512 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 1.887 g of diol DA-diol was added to the No. 1 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the first dynamically cross-linked polyurethane.

[0152] Preparation of the second dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 6.4 g of polyethylene glycol with a molecular weight of 4000 Da were added to a No. 2 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added thereto. After mechanical stirring, 2.045 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 2.552 g of diol DA-diol was added to the No. 2 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the second dynamically cross-linked polyurethane.

[0153] (2) Preparation of 4D printing polyurethane-based hydrogel materials:

[0154] The two dynamically cross-linked polyurethanes obtained in step (1) were added to two high-temperature barrels of an extrusion-type 3D printer, respectively, and equipped with a nozzle with an inner diameter of 300 μm. The two high-temperature barrels were heated to 130°C, the extrusion pressure of the two high-temperature barrels was set to 700 kPa, and the printing speed was 100 mm / min. The specific method of 3D printing is as follows: the first layer is printed in a serpentine shape along the short axis within a range of 2 cm×1 cm using the first dynamically cross-linked polyurethane, with a line spacing of 1 mm; the second layer is printed in a serpentine shape along the long axis above the first layer using the second dynamically cross-linked polyurethane, with a line spacing of 2 mm; the two high-temperature barrels are alternately printed to obtain the 4D printed polyurethane-based hydrogel material.

[0155] Example 6

[0156] A 4D printing polyurethane-based hydrogel material and a preparation method thereof. The 4D printing polyurethane-based hydrogel material comprises a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane. The raw materials for the preparation thereof include polycaprolactone triol (molecular weight 550 Da), polyethylene glycol (molecular weights 2000 Da and 4000 Da, respectively), diol DA-diol (Preparation Example 1), and isophorone diisocyanate. The preparation method is specifically as follows:

[0157] (1) Preparation of dynamically cross-linked polyurethane:

[0158] Preparation of the first dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 2 g of polyethylene glycol with a molecular weight of 2000 Da were added to a No. 1 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added thereto. After mechanical stirring, 1.778 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 2.24 g of diol DA-diol was added to the No. 1 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the first dynamically cross-linked polyurethane.

[0159] Preparation of the second dynamically cross-linked polyurethane: 1.1 g of polycaprolactone triol with a molecular weight of 550 Da and 4 g of polyethylene glycol with a molecular weight of 4000 Da were added to a No. 2 three-necked flask, heated to 120°C and vacuum filtered for 2 h. After the temperature dropped to 60°C, 4 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran were added thereto. After mechanical stirring, 1.778 mL of isophorone diisocyanate and 20 μL of dibutyltin dilaurate were added, and a prepolymerization reaction was carried out at 60°C for 3 h. Subsequently, 2.24 g of diol DA-diol was added to the No. 2 three-necked flask, and a chain extension reaction was carried out at 60°C for 5 h. The reaction solution was poured into a polytetrafluoroethylene mold and dried in an oven at 60°C for 48 h to obtain the second dynamically cross-linked polyurethane.

[0160] (2) Preparation of 4D printing polyurethane-based hydrogel materials:

[0161] The two dynamically cross-linked polyurethanes obtained in step (1) were added to two high-temperature barrels of an extrusion-type 3D printer, respectively, and equipped with a nozzle with an inner diameter of 300 μm. The two high-temperature barrels were heated to 130°C, the extrusion pressure of the two high-temperature barrels was set to 700 kPa, and the printing speed was set to 100 mm / min. The specific method of 3D printing is as follows: the first layer is printed in a serpentine pattern along the short axis within a range of 2 cm × 1 cm using the first dynamically cross-linked polyurethane, with a line spacing of 1 mm; the second layer is printed in a serpentine pattern along the long axis above the first layer using the second dynamically cross-linked polyurethane, with a line spacing of 2 mm. After alternating printing with the two high-temperature barrels, the 4D printed polyurethane-based hydrogel material is obtained.

[0162] The same method as in Example 1 was used to perform performance tests on the dynamically cross-linked polyurethane and 4D printing polyurethane-based hydrogel materials of Examples 2-6. The test results are shown in Table 1:

[0163] Table 1

[0164]

[0165] It can be seen that the 4D printing polyurethane-based hydrogel materials provided in Examples 1-6 of the present invention all have a swelling mismatch structure and water-triggered enhancement properties, and have excellent temperature response and water responsiveness. Industrial Applicability

[0166] Comparative Example 1

[0167] A polyurethane-based hydrogel material and a preparation method thereof, which is made of a first dynamically cross-linked polyurethane (the same as the first dynamically cross-linked polyurethane in Example 1), the specific method is as follows:

[0168] (1) Using the same method as step (1) of Example 1, a first dynamically cross-linked polyurethane was prepared;

[0169] (2) The first dynamically cross-linked polyurethane was added to the high-temperature barrel of an extrusion 3D printer and equipped with a nozzle with an inner diameter of 300 μm. The high-temperature barrel was heated to 130°C, the extrusion pressure of the high-temperature barrel was set to 200 kPa, and the printing speed was 500 mm / min. A 3 cm × 0.6 cm rectangle was designed as in Example 1. The first layer was printed in a serpentine pattern along the long axis using the first dynamically cross-linked polyurethane with a line spacing of 1 mm. The second layer was printed in a serpentine pattern above the first layer along the short axis using the first dynamically cross-linked polyurethane with a line spacing of 1 mm. The third layer was printed in a serpentine pattern above the second layer along the long axis using the first dynamically cross-linked polyurethane with a line spacing of 1 mm, and finally a polyurethane-based hydrogel material printed with a single material was obtained.

[0170] The polyurethane-based hydrogel material provided in Comparative Example 1 was used as a scaffold to perform a one-dimensional to three-dimensional shape transformation test. As shown in Figure 7, the 3D-printed polyurethane-based hydrogel scaffold with an initial sheet shape was rolled into a one-dimensional cylinder by external force in a 37°C environment and fixed in a 4°C environment. The 3D-printed scaffold with a temporary cylindrical shape was placed in a 37°C water environment. The one-dimensional cylinder was first stimulated by temperature and restored to its initial sheet structure, and then gradually swelled by absorbing water. Since there was no swelling mismatch structure in the polyurethane-based hydrogel scaffold printed with only the first dynamically cross-linked polyurethane, the two-dimensional sheet structure only expanded in volume in water and could not complete the transformation to a three-dimensional shape, indicating the necessity of using two polyurethanes with different swelling degrees to construct a swelling mismatch structure.

[0171] The applicant states that while the above-described embodiments illustrate the present invention's 4D printing polyurethane-based hydrogel material, its preparation method, and its application, the present invention is not limited to the aforementioned process steps, nor does it necessarily rely on the aforementioned process steps for implementation. Persons skilled in the art should understand that any improvements to the present invention, equivalent substitutions for the raw materials used, addition of auxiliary components, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

Claims

1. A 4D printing polyurethane-based hydrogel material, characterized in that: The 4D printing polyurethane-based hydrogel material comprises a combination of a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane, wherein the swelling degree of the first dynamically cross-linked polyurethane is less than the swelling degree of the second dynamically cross-linked polyurethane; The raw materials for preparing the first dynamically cross-linked polyurethane include a combination of a first polyester polyol, a first chain extender, a first polyisocyanate and optionally a first hydrophilic polyether polyol; The raw materials for preparing the second dynamically cross-linked polyurethane include a combination of a second polyester polyol, a second hydrophilic polyether polyol, a second chain extender, and a second polyisocyanate; The first chain extender and the second chain extender are each independently a diol constructed based on a Diels-Alder reaction.

2. The 4D printing polyurethane-based hydrogel material according to claim 1, characterized in that: The first polyester polyol and the second polyester polyol each independently include any one of polycaprolactone triol and polycaprolactone diol or a combination of at least two thereof, preferably polycaprolactone triol; Preferably, the molecular weight of the first polyester polyol and the second polyester polyol are each independently 500-5000 Da; Preferably, the first hydrophilic polyether polyol and the second hydrophilic polyether polyol each independently include any one of polyethylene glycol and polytetramethylene ether glycol or a combination of at least two thereof, and polyethylene glycol is further preferred; Preferably, the molecular weights of the first hydrophilic polyether polyol and the second hydrophilic polyether polyol are independently 500-10000 Da; Preferably, the molar ratio of the first polyester polyol to the first hydrophilic polyether polyol is 1:(0-1.2), more preferably 1:(0.1-0.5); Preferably, the molar ratio of the second polyester polyol to the second hydrophilic polyether polyol is 1:(0.1-1.2), and more preferably 1:(0.25-1).

3. The 4D printing polyurethane-based hydrogel material according to claim 1 or 2, characterized in that: The first polyisocyanate and the second polyisocyanate are each independently an aliphatic polyisocyanate and / or an alicyclic polyisocyanate; Preferably, the first polyisocyanate and the second polyisocyanate each independently include any one or a combination of at least two of isophorone diisocyanate, hexamethylene diisocyanate, pentamethylene diisocyanate, and cyclohexyl diisocyanate; Preferably, the molar ratio of the first polyisocyanate to the first polyester polyol is (2-6):1; Preferably, the molar ratio of the second polyisocyanate to the second polyester polyol is (2-6):

1.

4. The 4D printing polyurethane-based hydrogel material according to any one of claims 1 to 3, characterized in that: The molar ratio of the first chain extender to the first polyester polyol is (1.3-2.8):1, preferably (1.4-2.5):1; Preferably, the molar ratio of the second chain extender to the second polyester polyol is (1.3-2.8):1, more preferably (1.6-2.5):

1.

5. The 4D printing polyurethane-based hydrogel material according to any one of claims 1 to 4, characterized in that: The diol constructed based on the Diels-Alder reaction is obtained by reacting bismaleimide with a hydroxyl-containing furan compound; Preferably, the bismaleimide includes any one of N,N'-(4,4'-methylenediphenyl)bismaleimide, N,N'-(1,4-phenylene)bismaleimide, and N,N'-(1,3-phenylene)bismaleimide, or a combination of at least two thereof, and N,N'-(4,4'-methylenediphenyl)bismaleimide is further preferred; Preferably, the hydroxyl-containing furan compound comprises furfuryl alcohol; Preferably, the molar ratio of the maleimide group in the bismaleimide to the furan group in the hydroxyl-containing furan compound is 1:(1-5); Preferably, the reaction temperature of the bismaleimide and the hydroxyl-containing furan compound is 50-80° C. and the reaction time is 2-12 h.

6. The 4D printing polyurethane-based hydrogel material according to any one of claims 1 to 5, characterized in that: The first dynamically cross-linked polyurethane is prepared by the following method, which includes: performing a first prepolymerization reaction on a first polyester polyol, optionally a first hydrophilic polyether polyol and a first polyisocyanate to obtain a first prepolymer; performing a first chain extension reaction on the first prepolymer and a first chain extender to obtain the first dynamically cross-linked polyurethane; Preferably, the first prepolymerization reaction is carried out in the presence of a first solvent and a first catalyst; Preferably, the temperature of the first prepolymerization reaction is 50-70°C and the time is 2-8 h; Preferably, the temperature of the first chain extension reaction is 50-70° C. and the time is 4-8 h.

7. The 4D printing polyurethane-based hydrogel material according to any one of claims 1 to 6, characterized in that: The second dynamically cross-linked polyurethane is prepared by the following method, which includes: performing a second prepolymerization reaction on a second polyester polyol, a second hydrophilic polyether polyol and a second polyisocyanate to obtain a second prepolymer; performing a second chain extension reaction on the second prepolymer and a second chain extender to obtain the second dynamically cross-linked polyurethane; Preferably, the second prepolymerization reaction is carried out in the presence of a second solvent and a second catalyst; Preferably, the temperature of the second prepolymerization reaction is 50-70°C and the time is 2-8 h; Preferably, the temperature of the second chain extension reaction is 50-70° C. and the time is 4-8 h.

8. A method for preparing a 4D printing polyurethane-based hydrogel material according to any one of claims 1 to 7, characterized in that: The preparation method comprises: placing a first dynamically cross-linked polyurethane and a second dynamically cross-linked polyurethane in different barrels of a 3D printer respectively, extruding and performing 3D printing to obtain the 4D printed polyurethane-based hydrogel material.

9. The preparation method according to claim 8, characterized in that: The 3D printing method is multi-nozzle fused deposition modeling; Preferably, the heating temperature of the barrel is 110-130°C; Preferably, the extrusion pressure is 100-750 kPa; Preferably, the printing speed of the 3D printing is 10-500 mm / min; Preferably, the caliber of the printing needle for 3D printing is 200-1000 μm.

10. An application of a 4D printing polyurethane-based hydrogel material as claimed in any one of claims 1 to 7, characterized in that: The 4D printed polyurethane-based hydrogel material is used to prepare a biological scaffold; Preferably, the 4D printed polyurethane-based hydrogel material is used to prepare a minimally invasive support scaffold or a tissue defect repair scaffold.

Images