Shape memory effect enhanced injectable hydrogel as well as preparation method and application thereof

Abstract

The invention provides a preparation method of shape memory effect enhanced injectable hydrogel, which comprises the following steps: S1, preparing electrostatic spinning nanofibers by using a lactide-caprolactone copolymer and polyoxyethylene, and carrying out temporary deformation treatment on the electrostatic spinning nanofibers to obtain a deformed nanofiber membrane, the deformed nanofiber membrane is cut into pieces and homogenized, and shape memory short fibers are obtained; and S2, mixing the shape memory short fibers with the injectable hydrogel precursor solution, initiating the injectable hydrogel precursor solution to generate a cross-linking reaction, and exciting the shape memory effect of the shape memory short fibers to obtain the shape memory effect enhanced injectable hydrogel. The method provided by the invention is helpful for improving the Young modulus of the hydrogel, balancing the relationship between the hydrogel rigidity and the biocompatibility and injectability, and providing a solution thought for taking the hydrogel as a drug delivery carrier and a bone defect minimally invasive injection filling material.

Description

Technical Field

[0001] The present invention relates to the technical field of biomaterials, and particularly relates to a shape memory effect-enhanced injectable hydrogel, a preparation method thereof, and an application thereof. Background Art

[0002] Hydrogel is a kind of hot biomaterial with adjustable composition and stiffness, which is used to construct the composition, structure, and mechanical microenvironment of a biomimetic natural extracellular matrix. Hydrogel can effectively adjust its stiffness according to the selection of polymers, the adjustment of polymer and crosslinker concentrations, and the addition of organic / inorganic fillers. This kind of hydrogel with adjustable stiffness can be used as an in vitro mechanical regulation cell behavior research platform, and can also promote in situ tissue regeneration and repair by minimally invasive injection of cells or direct implantation into the body. However, most of the current methods for adjusting the stiffness of hydrogels rely on increasing the crosslinking degree of hydrogels or adding some rigid fillers, etc. As the concentrations of crosslinkers and fillers increase, problems such as poor biocompatibility and decreased injectability of hydrogels occur. Therefore, how to balance the stiffness, biocompatibility, and injectability of hydrogels is one of the technical problems that those skilled in the art urgently need to solve. Summary of the Invention

[0003] The present invention provides a shape memory effect-enhanced injectable hydrogel, a preparation method thereof, and an application thereof.

[0004] In the first aspect of the present invention, a preparation method of a shape memory effect-enhanced injectable hydrogel is provided, including:

[0005] S1. Electrospun nanofibers are prepared using a lactide-caprolactone copolymer and polyethylene oxide, and the electrospun nanofibers are subjected to temporary deformation treatment to obtain a deformed nanofiber membrane, and then the deformed nanofiber membrane is cut into pieces and homogenized to obtain shape memory short fibers; the length of the shape memory short fibers is 200 - 1000 μm;

[0006] S2. The shape memory short fibers are mixed with an injectable hydrogel precursor solution, the injectable hydrogel precursor solution is induced to undergo a crosslinking reaction, and a shape memory effect-enhanced injectable hydrogel is obtained by activating the shape memory effect of the shape memory short fibers;

[0007] Wherein, the injectable hydrogel precursor solution at least includes an aldehyde-group-modified first polymer, a methacryloyl-group-modified second polymer, a crosslinker, and a photoinitiator.

[0008] Further, S1 specifically includes:

[0009] S11. Dissolve the lactide-caprolactone copolymer and polyethylene oxide in a solvent to prepare a polymer mixture solution, and perform electrospinning on the polymer mixture solution to obtain electrospun nanofibers;

[0010] S12. Shape the electrospun nanofibers at a temperature within 20 °C below the glass transition temperature and fix the temporary deformation at a temperature of at least 0 °C below the glass transition temperature to obtain a deformed nanofiber membrane;

[0011] S13. Cut the deformed nanofiber membrane into pieces and disperse and shear it using a homogenizer to obtain shape memory short fibers.

[0012] Further, the lactide-caprolactone copolymer is polymerized from lactide (LA) and ε-caprolactone (CL), and the molar ratio of lactide (LA) to ε-caprolactone (CL) is 90:10.

[0013] Further, in the polymer mixture solution, the mass fraction of the lactide-caprolactone copolymer is 5% - 15%, and the mass fraction of polyethylene oxide is 1% - 5%.

[0014] Further, in S11, the process parameters of the electrospinning are: the diameter of the syringe needle is 18 - 22G, the flow rate of the polymer mixture solution is 0.1 - 10 mL / h, the voltage is 1 - 50 kV, the distance between the syringe needle and the roller is 5 - 100 cm, the rotation speed of the receiving roller is 1 - 10000 rpm, the ambient temperature is 0 - 60 °C, and the ambient relative humidity is 20% - 100%.

[0015] Further, the shape memory effect enhanced injectable hydrogel has biocompatibility.

[0016] Further, the mass of the shape memory short fibers is 0.5% - 3.0% of the mass of the injectable hydrogel precursor solution.

[0017] Further, the Young's modulus of the shape memory effect enhanced injectable hydrogel is 27.83 ± 1.68 kPa.

[0018] Further, the first polymer is selected from at least one of hyaluronic acid, sodium alginate, dextran, chitosan, cellulose, and starch;

[0019] And / or, the second polymer is selected from at least one of polyvinyl alcohol, polyethylene oxide, gelatin, hyaluronic acid, sodium alginate, chitosan, cellulose, dextran, polylysine, and polyglutamic acid;

[0020] And / or, the crosslinking agent is selected from at least one of adipic dihydrazide, polyethylene glycol diamine, polyethylene glycol diacrylate, and polyethylene glycol dimercapto;

[0021] And / or, the photoinitiator is selected from at least one of 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone and lithium phenyl(2,4,6-trimethylbenzoyl)phosphate.

[0022] Furthermore, the first polymer is sodium alginate, and aldehyde-functionalized sodium alginate can be obtained by reacting sodium alginate with sodium periodate. The second polymer is gelatin, and methacrylated gelatin can be obtained by reacting gelatin with methacrylic anhydride.

[0023] The second aspect of the present invention provides a shape memory effect-enhanced injectable hydrogel prepared according to the above method.

[0024] The third aspect of the present invention provides the application of any of the above-mentioned methods or the above-mentioned shape memory effect-enhanced injectable hydrogel in the preparation of a drug delivery carrier or a minimally invasive injection filling material for bone defects.

[0025] Furthermore, when using the shape memory effect-enhanced injectable hydrogel as a drug delivery carrier, the molecular structure of the drug may contain an amino group. A compound with an amino group in its molecular structure is used as the drug to be delivered. The amino group can react with the aldehyde group in the aldehyde-functionalized sodium alginate to cause the shape memory effect-enhanced injectable hydrogel to have the effect of pH-responsive drug release.

[0026] The present invention provides a shape memory effect-enhanced injectable hydrogel. Shape memory short fibers are prepared using a lactide-caprolactone copolymer and polyethylene oxide, and the shape memory short fibers are added to the hydrogel precursor liquid system. By initiating the crosslinking reaction of the hydrogel precursor liquid and activating the shape memory effect of the shape memory short fibers, it helps to improve the Young's modulus of the hydrogel and balance the relationship between the hydrogel stiffness and biocompatibility and injectability, providing a solution idea for the hydrogel as a drug delivery carrier and a minimally invasive injection filling material for bone defects. Description of the Drawings

[0027] Figure 1 XRD patterns of the PLCL fiber membrane, after 100% shaping and shape recovery;

[0028] Figure 2 Maximum shape recovery force of the PLCL and PLGA shape memory fiber membranes;

[0029] Figure 3 SEM images of the shape memory short fibers (SMSFs) of PLCL and PLGA and after shape recovery;

[0030] Figure 4 Compressive stress-strain and Young's modulus (C) of hydrogels enhanced for PLCL SMSFs (A) and PLGA SMSFs (B);

[0031] Figure 5 Drug release behavior of hydrogels with different contents of PLCL SMSFs under different pH conditions;

[0032] Figure 6 Compressive stress-strain curves (A) and Young's modulus (B) of hydrogels with different contents of PLCL SMSFs;

[0033] Figure 7 Curve of the change of injection force of hydrogel precursor solution with different contents of PLCL SMSFs over time;

[0034] Figure 8 Injectable schematic diagram (A) and physical diagram (B) of PLCL SMSFs-enhanced hydrogels for bone defects;

[0035] Figure 9 Live / dead staining (A) and cell survival rate (B) of PLCL SMSFs-enhanced hydrogels. Detailed implementation mode

[0036] To make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0037] Example 1. Preparation of shape memory short fibers

[0038] Step 1. Preparation of PLCL electrospun fibers

[0039] Dissolve 0.6 g of lactide-caprolactone copolymer (PLCL, LA:CL = 90:10 moL:moL) (purchased from DaiGang Biotechnology Co., Ltd., Jinan, China, IV 3.4 dl / g) and 0.025 g of polyethylene oxide (PEO) (purchased from Alfa Aesar, UK, Mw≈5000 kDa) in 5 mL of hexafluoroisopropanol and stir overnight. Load the uniformly stirred polymer mixture into a 10 mL syringe. The stable electrospinning conditions are as follows: the needle diameter is 18G, the flow rate is 0.5 mL / h, the voltage is 5 - 10 kV, the distance between the syringe needle and the roller is 10 - 15 cm, the rotation speed of the receiving roller is 1000 rpm, at room temperature and 40 - 60% humidity to obtain a nanofiber membrane, named PLCL. Use the XRD method to test the crystallinity of the PLCL nanofiber membrane. The test results are as Figure 1 shown. It can be seen that its crystallinity is 25.09%.

[0040] Step 2. Shaping of the PLCL nanofiber membrane

[0041] Cut the prepared PLCL nanofiber membrane into a rectangle of 1 cm×3 cm, clamp it on a shaping fixture, and perform 100% deformation shaping at a temperature about 11 °C below T g (the glass transition temperature (T g ) of the PLCL fiber membrane is 51 °C, that is, about 40 °C), and then quickly fix the fiber membrane at 0 °C to obtain a PLCL 100% fiber membrane with shape memory performance. Use the same method to test the crystallinity. The results are as Figure 1 shown. The crystallinity of this fiber membrane increases to 43.27%. Heat it to 40 °C again, that is, PLCL recovery. Its shape recovery rate reaches 34.17%, and the crystallinity drops to 31.47% (as Figure 1 ), and a shape recovery force of 2.00 ± 0.33 MPa is generated (as Figure 2 ).

[0042] Step 3. Preparation of PLCL shape memory short fibers

[0043] Cut the PLCL 100% fiber membrane obtained in Step 2 into fiber fragments, place them in ice water at 0 °C, and disperse them under high-speed (25000 rpm) shearing in a homogenizer for 10 - 30 min to obtain shape memory short fibers PLCL SMSFs with a length of 620.76 ± 130.60 μm. Heat the PLCL SMSFs to 40 °C again, and the short fibers will undergo shape recovery (as Figure 3) After shape recovery, its length is 380.19 ± 43.01 μm, and its shape recovery rate reaches 37.72%, which is similar to the shape recovery rate of the macroscopic PLCL 100% fiber membrane. Therefore, the PLCL SMSFs can also generate a shape recovery force of about 2.00 MPa.

[0044] Comparative Example 1: Preparation of non-shape memory PLCL short fibers

[0045] The unshaped PLCL fiber membrane prepared in Step 1 of Example 1 was directly subjected to Step 3, that is, it was cut into fiber fragments, placed in ice water at 0 °C, and dispersed under high-speed (25,000 rpm) shearing in a homogenizer for 10 - 30 min to obtain non-shape memory PLCL short fibers, named P0.

[0046] Example 2: Preparation of shape memory effect enhanced hydrogel

[0047] 1. Synthesis of raw materials for preparing hydrogel:

[0048] Aldehyde-functionalized sodium alginate (SA-CHO): Dissolve 2 g of sodium alginate in 100 mL of deionized water and dissolve evenly. Dissolve 1.08 g of sodium periodate in 20 mL of deionized water, add it to the sodium alginate solution under light-shielding conditions, stir at room temperature for 2 h, then add 1.6 mL of ethylene glycol to terminate the reaction, and stir for 1 h. Finally, dialyze the reaction solution with a dialysis bag with a molecular weight of 0.8 - 1.2 kDa for 3 days and freeze-dry for 3 days to obtain SA-CHO.

[0049] Methacrylated gelatin (GelMA): Dissolve 4 g of gelatin in 30 mL of carbonate buffer (0.075 M Na 2 CO 3 and 0.175 M NaHCO 3 ), heat to 60 °C to completely dissolve, then add 0.2 mL of methacrylic anhydride, react at 50 °C for 3 h, finally add 150 mL of deionized water to terminate the reaction, and dialyze with a dialysis bag with a molecular weight of 0.8 - 1.2 kDa for 3 days and freeze-dry for 3 days to obtain GelMA.

[0050] 2. Weigh 0.1 g of the PLCL SMSFs prepared in Example 1, add 0.6 g of SA-CHO, 0.3 g of GelMA, 0.3 mL of polyethylene glycol diacrylate (PEGDA), and 0.02 g of lithium phenyl(2,4,6-trimethylbenzoyl)phosphate (LAP) photoinitiator dissolved in 10 mL of PBS (pH = 7.4). Stir the mixed solution evenly to form Solution 1, add 1 mL of Solution 2 (4 wt% adipic dihydrazide), stir further evenly, and Schiff base crosslinking occurs in 5 min. Then irradiate with blue light for 1 min. Finally, heat the hydrogel in a water bath to 40 °C and maintain it for 10 min to stimulate the shape memory effect of the shape memory short fibers in the hydrogel, and obtain a hydrogel with enhanced shape memory effect.

[0051] In this example, the hydrogel reinforced with PLCL SMSFs after shape recovery (27.83 ± 1.68 kPa), compared with the hydrogel reinforced with short fibers without activating the shape memory behavior (14.76 ± 0.73 kPa), the compressive Young's modulus is enhanced by about 1.89 times (as Figure 4 ).

[0052] Example 3. Application of the hydrogel with enhanced shape memory effect in preparing a drug delivery carrier

[0053] According to Example 2, add 0.027 g of alendronate sodium (ALN) to Solution 1 in Step 2 of Example 2, stir well and maintain for 10 - 60 min to allow ALN to react with SA-CHO to form a Schiff base reaction. Then add adipic dihydrazide and stir evenly, let it stand for 5 min to occur Schiff base crosslinking, irradiate with blue light for 1 min to prepare a drug-loaded hydrogel. Finally, heat the hydrogel in a water bath to 40 °C and maintain it for 10 min to stimulate the shape memory effect of the shape memory short fibers in the hydrogel, and obtain a drug-loaded hydrogel with enhanced shape memory effect, named N3.

[0054] The Schiff base bond between the aldehyde group of SA-CHO and the amino group of ALN in the hydrogel has the function of pH-responsive drug release. Therefore, the release of ALN is faster under low pH (5.4) conditions than under neutral conditions, and the shape memory enhanced hydrogel shows a stronger sustained release effect (as Figure 5 ).

[0055] Figure 5Among them, N2 is a hydrogel without shape memory effect. That is, 0.6 g of SA-CHO, 0.3 g of GelMA, 0.5 mL of PEGDA, 0.02 g of LAP photoinitiator, and 0.027 g of ALN are dissolved in 10 mL of PBS (pH = 7.4). The mixed solution is stirred evenly to form Solution 1. Then 1 mL of Solution 2 (4 wt% adipic dihydrazide) is added and stirred evenly further. Schiff base crosslinking occurs in 5 min, and then it is irradiated with blue light for 1 min to prepare a drug-loaded hydrogel, named N2. P0-N3 is a drug-loaded hydrogel prepared using the nanofiber P0 without shape memory effect provided in Comparative Example 1. According to Figure 5 It can be seen that compared with N2, N3 has a better sustained release effect.

[0056] Example 4. Mechanical property analysis of shape memory effect enhanced hydrogel

[0057] Weigh 0.05 g, 0.1 g, and 0.5 g of the PLCL SMSFs prepared in Example 1 respectively, and the corresponding mass of the P0 short fibers provided in Comparative Example 1, and 0.6 g of SA-CHO, 0.3 g of GelMA, 0.5 mL of PEGDA, and 0.02 g of LAP photoinitiator provided in Example 2 are dissolved in 10 mL of PBS (pH = 7.4). The mixed solution is stirred evenly to form Solution 1. Then 1 mL of Solution 2 (4 wt% adipic dihydrazide) is added and stirred evenly further. Schiff base crosslinking occurs in 5 min, and then it is irradiated with blue light for 1 min. Finally, the hydrogel is heated in a water bath to 40 °C and maintained for 10 min to obtain a shape memory effect enhanced hydrogel, named 0.5%-N3, 1%-N3, 1.5%-N3, 0.5%-P0-N3, 1%-P0-N3, and 1.5%-P0-N3.

[0058] In this example, the stiffness of the 0.5%-N3, 1%-N3, and 1.5%-N3 hydrogels containing SMSFs are (47.81 ± 0.35 kPa, 55.38 ± 2.38 kPa, 78.05 ± 3.88 kPa) respectively. Compared with the 0.5%-P0-N3, 1%-P0-N3, and 1.5%-P0-N3 hydrogels (36.62 ± 1.30 kPa, 37.38 ± 1.02 kPa, 45.86 ± 0.83 kPa), the mechanical properties are significantly improved (such as Figure 6 ).

[0059] Example 5. Injectability analysis of shape memory effect enhanced hydrogel

[0060] Weigh 0.05 g, 0.1 g, and 0.5 g of the PLCL SMSFs prepared in Example 1 respectively, mix them with 0.6 g of SA-CHO, 0.3 g of GelMA, 0.5 mL of PEGDA, and 0.02 g of LAP photoinitiator, dissolve them in 10 mL of PBS (pH = 7.4), and load them into a syringe, named 0.5%-N3*, 1%-N3*, and 1.5%-N3*. Test the force-time curve with a universal testing machine.

[0061] In this example, the injection forces of the 0.5%-N3, 1%-N3, and 1.5%-N3 hydrogels containing SMSFs all have good injectability (<20 N) at 0.5 - 2 N, but the injectability of 1.5%-N3 is slightly poor (as Figure 7 ).

[0062] Example 6. Application of shape memory effect enhanced hydrogel in in-situ bone tissue material filling

[0063] According to Example 2, load the solution 1 prepared in Example 2 into one syringe, then load the adipic dihydrazide solution into another syringe, mix them through a two-way valve and push them into the bone, and let it stand for 5 min to undergo Schiff base crosslinking to obtain an in-situ injectable N3 hydrogel ( Figure 8 ).

[0064] Example 7. Biosafety of shape memory short fiber reinforced hydrogel

[0065] Soak 6% w / v SA-CHO and 3% w / v GelMA in 90% v / v alcohol for 6 h and dry them in a sterile workbench. Dissolve 5% v / v PEGDA, 0.21% w / v ALN, and 0.2% w / v LAP in PBS, dissolve 4% w / v adipic dihydrazide in deionized water, and then sterilize the two solutions separately by filtering through a 0.22 μm filter membrane. Dissolve the dried and sterile SA-CHO and GelMA in the sterilized PEGDA / LAP solution. Sterilize the PLCL SMSFs under ultraviolet light for 12 h. According to the preparation method described in Example 2, after adding adipic dihydrazide, sequentially induce crosslinking and shape memory effect in a 24-well plate to form hydrogels with different stiffnesses. Before cell seeding, pre-incubate all hydrogels with DMEM / F12 mixed medium. Harvest cells with a confluence of 90% and seed them on the hydrogels.

[0066] Seed BMSCs on different hydrogels in a 24-well plate at a density of 1×10 4 cells / well. After culturing for 24 h, use a solution containing 0.5×10 -6 M calcein-AM and 4.0×10 -6The viability of cells was determined using a live / dead cell staining kit for propidium iodide (PI) (Invitrogen, USA), and the cells were incubated for 15 minutes. Finally, the stained cells were observed using an inverted fluorescence microscope. The number of live and dead cells was quantified using ImageJ software. The results showed that the shape memory short fiber-reinforced hydrogel was non-cytotoxic ( Figure 9 ).

[0067] Comparative Example 1

[0068] Shape memory short fibers were prepared from an amorphous copolymer of lactic acid and glycolic acid (PLGA, LA:GA = 50:50 mol:mol) in this comparative example, including the following steps:

[0069] (1) Preparation of PLGA electrospun fiber membrane

[0070] Weigh 0.32 g of PLGA and 0.08 g of PEO and dissolve them in 5 mL of hexafluoroisopropanol, and stir overnight. Load the well-stirred spinning solution into a 10 ml syringe. The stable jet spinning conditions are as follows: the needle diameter is 20G, the flow rate is 0.5 mL / h, the voltage is 3 - 10 kV, the distance between the syringe needle and the roller is 10 - 15 cm, the rotational speed of the receiving roller is 1000 rpm, at room temperature and 40 - 60% humidity, to obtain a PLGA fiber membrane with a crystallinity of 4.43% (as Figure 1 ).

[0071] (2) Shaping of the PLGA fiber membrane

[0072] Cut the prepared PLGA fiber membrane into a rectangle of 1 cm × 3 cm, clamp it on a shaping fixture, and perform 100% deformation shaping at T g (the glass transition temperature (T g ) of the PLGA fiber membrane is 40 °C, that is, about 40 °C), and then quickly fix the fiber membrane at 0 °C to obtain a PLGA 100% fiber membrane with shape memory performance. The crystallinity of this fiber membrane increased to 29.52%. When heated to 40 °C again, its shape recovery rate reached 66.67%, the crystallinity increased to 30.05%, and a shape recovery force of 0.73 ± 0.14 MPa was generated (as Figure 2 ).

[0073] (3) Preparation of PLGA shape memory short fibers

[0074] The PLGA 100% fiber membrane obtained in step (2) was cut into fiber fragments and placed in ice water at 0 °C. It was dispersed for 10 - 30 min under high-speed shearing (25000 rpm) by a homogenizer to obtain shape memory short fiber PLGA SMSFs with a length of 563.17 ± 88.42 μm. The PLGA SMSFs were heated to 40 °C again, and the short fibers would undergo shape recovery (as shown in Figure 3 ). After recovery, their length was 151.36 ± 16.09 μm. The shape recovery rate reached 72.90%, which was similar to that of the macroscopic PLGA 100% fiber membrane. Therefore, the PLGA SMSFs could generate a shape recovery force of about 0.7 MPa.

[0075] (4) 0.1 g of the shape memory short fibers, 0.6 g of SA-CHO, 0.3 g of GelMA, 0.3 mL of PEGDA, and 0.02 g of LAP photoinitiator in (3) were dissolved in 10 mL of PBS (pH = 7.4). The mixed solution was stirred evenly, 0.04 g of adipic dihydrazide was added and stirred evenly again. Schiff base crosslinking occurred in 5 min, then it was irradiated with blue light for 1 min, and finally the hydrogel was heated in a water bath to 40 °C and maintained for 10 min to obtain a hydrogel with enhanced shape memory effect.

[0076] In this comparative example, the hydrogel reinforced with short fibers after shape recovery (7.95 ± 0.644 kPa), compared with the hydrogel reinforced with short fibers without activating the shape memory behavior (26.68 ± 1.58 kPa), the compressive Young's modulus decreased by about 3.35 times (as shown in Figure 4 ).

[0077] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing an injectable hydrogel with enhanced shape memory effect, characterized in that: include: S1. Electrospun nanofibers are prepared using lactide-caprolactone copolymer and polyethylene oxide, and the electrospun nanofibers are temporarily deformed to obtain deformed nanofiber membranes, and the deformed nanofiber membranes are cut into pieces and homogenized to obtain shape memory short fibers; the length of the shape memory short fibers is 200-1000 μm; S2, mixing the shape memory short fibers with an injectable hydrogel precursor solution to induce a cross-linking reaction in the injectable hydrogel precursor solution, and obtaining an injectable hydrogel with enhanced shape memory effect by stimulating the shape memory effect of the shape memory short fibers; The injectable hydrogel precursor solution at least comprises a aldehyde-modified first polymer, a methacrylylated second polymer, a cross-linking agent and a photoinitiator.

2. The method according to claim 1, characterized in that S1 specifically includes: S11, dissolving lactide-caprolactone copolymer and polyethylene oxide in a solvent to prepare a polymer mixture, and electrospinning the polymer mixture to prepare electrospun nanofibers; S12, shaping the electrospun nanofibers at a temperature less than 20° C. below the glass transition temperature, and temporarily deforming and fixing the nanofibers at a temperature at least 0° C. below the glass transition temperature to obtain a deformed nanofiber membrane; S13, cutting the deformed nanofiber membrane into pieces and using a homogenizer to disperse and shear the pieces to obtain shape memory short fibers.

3. The method according to claim 2, characterized in that In S11, the process parameters of the electrospinning are: the diameter of the syringe needle is 18-22G, the flow rate of the polymer mixture is 0.1-10mL / h, the voltage is 1-50kV, the distance between the syringe needle and the roller is 5-100cm, the rotation speed of the receiving roller is 1-10000rpm, the ambient temperature is 0-60℃, and the relative humidity of the environment is 20%-100%.

4. The method according to any one of claims 1 to 3, characterized in that: The shape memory effect enhanced injectable hydrogel has biocompatibility.

5. The method according to any one of claims 1 to 4, characterized in that: The mass of the shape memory short fibers is 0.5%-3.0% of the mass of the injectable hydrogel precursor solution.

6. The method according to any one of claims 1 to 5, characterized in that: The Young's modulus of the shape memory effect enhanced injectable hydrogel is 27.83±1.68 kPa.

7. The method according to any one of claims 1 to 6, characterized in that: The first polymer is selected from at least one of hyaluronic acid, sodium alginate, dextran, chitosan, cellulose, and starch; and / or, the second polymer is selected from at least one of polyvinyl alcohol, polyethylene oxide, gelatin, hyaluronic acid, sodium alginate, chitosan, cellulose, dextran, polylysine, and polyglutamic acid; And / or, the cross-linking agent is at least one selected from adipic acid dihydrazide, polyethylene glycol diamine, polyethylene glycol diacrylate, and bis-mercapto polyethylene glycol; And / or, the photoinitiator is selected from at least one of 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone and phenyl (2,4,6-trimethylbenzoyl) lithium phosphate.

8. The shape memory effect enhanced injectable hydrogel prepared according to the method according to any one of claims 1 to 7.

9. Use of the method according to any one of claims 1 to 7 or the shape memory effect enhanced injectable hydrogel according to claim 8 in the preparation of a drug delivery carrier or a minimally invasive injection filling material for bone defects.

10. The use according to claim 9, characterized in that: When the shape memory effect enhanced injectable hydrogel is used as a drug delivery carrier, the drug contains an amino group in its molecular structure.

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