Bio-macromolecular hydrogel, preparation method thereof and application of bio-macromolecular hydrogel in tissue-adaptive in-situ forming bioelectronic interface

Abstract

The invention discloses a biomacromolecular hydrogel, a preparation method thereof and an application of the biomacromolecular hydrogel in a tissue-adaptive in-situ forming bioelectronic interface, and the method comprises the following steps: taking gallic acid modified fish skin gelatin, gallic acid modified epsilon-poly-L-lysine and pigskin gelatin as main raw materials; and preparing the in-situ coating formed biomacromolecular hydrogel by adopting a sol-gel method. The biomacromolecule hydrogel is heated and melted into a viscous liquid state, then the viscous liquid state is coated on a target tissue and is connected with a metal wire, and the self-adaptive bioelectronic interface is obtained after the viscous liquid state is cooled and solidified into gel. The method is simple in preparation process, and the cost can be reduced; the prepared biomacromolecular hydrogel is used for preparing a tissue-adaptive in-situ forming bioelectronic interface, and the prepared bioelectronic interface has the advantages of excellent biological adaptability, high mechanical compliance, high signal-to-noise ratio and the like, and can be widely applied to the fields of motion monitoring, electronic skin and the like; and the practical application performance of the flexible bioelectronic device is effectively expanded.

Description

Technical Field

[0001] The present invention relates to the technical field of biomaterials, and in particular to a biomacromolecule hydrogel and a preparation method thereof, and an application thereof in tissue-adaptive in-situ forming bioelectronic interface. Background Art

[0002] Adaptive bioelectronics can achieve instantaneous compensation and re-driving of interface electromechanical coupling by reconstructing bidirectional bioelectrical conduction at tissue defects, effectively alleviate local motor and sensory dysfunction, and promote early functional recovery of patients. Bioelectronic interfaces can also use endogenous electrical conduction to capture low-noise electrophysiological signals, apply low-threshold exogenous electrical stimulation therapy, and promote accurate diagnosis and effective intervention treatment of related diseases. At present, bioelectronic interface active materials with electrical function replacement capabilities are still in the early stages of exploration. The incompatibility and modulus mismatch between existing electroactive materials and soft tissues can cause tissue inflammation and electrical insulation scar formation, resulting in inefficient bioelectrical signal transduction and interaction. Therefore, there is an urgent need to develop new electroactive materials to eliminate the differences in modulus, shape and size with soft tissues and establish standardized tissue electronic interfaces.

[0003] Electroactive hydrogels are considered to be ideal materials for bioelectronic interfaces due to their high conductivity, tissue-matching adhesion and mechanical softness. However, patch-type hydrogels currently on the market will inevitably form huge gaps when facing narrow, tiny and irregular tissue surfaces, resulting in serious motion artifacts and ineffective bioelectric transduction, reducing their application value. Patch-type hydrogel bioelectrodes generally have problems such as poor flexibility, poor biocompatibility, difficulty in in vivo degradation and easy failure of wet interface adhesion. Tissue-adaptive in situ coated hydrogels can easily achieve conformal, stable and biocompatible tissue-electronic interface adaptation through chemical bonds or physical topological effects, and quickly establish dynamically compliant bioelectronic interfaces with various tissues (epithelial, muscle and neural tissues) for early emergency treatment and later rehabilitation of tissue injuries. Therefore, constructing tissue-adaptive in situ formed hydrogel electroactive materials is an effective solution for constructing highly mechanically compliant bioelectronic interfaces. Summary of the invention

[0004] The purpose of the present invention is to provide a biomacromolecule hydrogel and a preparation method thereof and an application in a tissue-adaptive in situ formed bioelectronic interface. The method has a simple preparation process and can reduce costs. The prepared biomacromolecule hydrogel is used to prepare a tissue-adaptive in situ formed bioelectronic interface. The prepared bioelectronic interface has the advantages of excellent biocompatibility, high mechanical compliance and high signal-to-noise ratio, and can be widely used in the fields of motion monitoring, electronic skin, etc., effectively broadening the practical application performance of flexible bioelectronic devices.

[0005] To achieve the above object, the present invention provides a method for preparing a biomacromolecule hydrogel, comprising the following steps:

[0006] S1. Slowly add gallic acid and ε-poly-L-lysine to a 2-morpholineethanesulfonic acid buffer solution, and stir to dissolve under a nitrogen atmosphere to obtain a mixed solution; then, under a nitrogen atmosphere, sequentially add N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride to the mixed solution, stir for 1 to 5 hours, dialyze for 3 to 5 days, and freeze-dry to obtain gallic acid-modified ε-poly-L-lysine powder;

[0007] S2, gallic acid and fish skin gelatin aqueous solution are slowly added in 2-morpholineethanesulfonic acid buffer solution, stirring and dissolving under nitrogen atmosphere protection obtains mixed solution; Then under nitrogen protection, N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride are added successively in the mixed solution, stirred for 1~5h, and after dialysis for 3~8 days, concentrated into viscous gallic acid modified fish skin gelatin solution;

[0008] S3, ultrasonically dispersing sodium citrate and the gallic acid-modified ε-poly-L-lysine prepared in step S1 in a conductive polymer aqueous solution to obtain a mixture A; then adding the gallic acid-modified fish skin gelatin solution prepared in step S2 and glycerol to the mixture A, stirring to obtain a mixture B;

[0009] S4. Add pigskin gelatin to the mixture B obtained in step S3, blow nitrogen to remove oxygen and seal, heat at 60° C. to 80° C. for 3 to 12 hours to obtain a uniform viscous liquid, transfer to a mold and cool to obtain a biomacromolecule hydrogel that is degradable, tissue-adaptive, and in-situ coated.

[0010] Preferably, in step S1, the mass ratio of the 2-morpholineethanesulfonic acid buffer solution to ε-poly-L-lysine is 50:1-200:1, preferably 80:1-150:1; the molar ratio of gallic acid to ε-poly-L-lysine is 2:1-6:1, preferably 3:1-5:1; the molar ratio of N-hydroxysuccinimide to ε-poly-L-lysine is 1:3-3:1, preferably 1:2-2:1; the molar ratio of N-hydroxysuccinimide to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:1-5:1, preferably 1:1-3:1; the pH value of the 2-morpholineethanesulfonic acid buffer solution is 5.5; and the stirring speed is 200-800rpm.

[0011] Preferably, in step S1, the mass ratio of the 2-morpholineethanesulfonic acid buffer solution to ε-poly-L-lysine is 90:1 to 100:1; the molar ratio of the gallic acid to ε-poly-L-lysine is 3.8:1 to 4:1; the molar ratio of the N-hydroxysuccinimide to ε-poly-L-lysine is 1:2 to 1:1; the molar ratio of the N-hydroxysuccinimide to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:1 to 2:1.

[0012] Preferably, in step S2, the mass ratio of the 2-morpholineethanesulfonic acid buffer solution to gallic acid is 40:1-300:1, preferably 80:1-150:1; the fish skin gelatin aqueous solution is prepared by adding fish skin gelatin powder to ultrapure water and stirring and mixing, and the mass concentration of the fish skin gelatin aqueous solution is 25%-70%; the mass ratio of the 2-morpholineethanesulfonic acid buffer solution to the fish skin gelatin aqueous solution is 3:1-20:1, preferably 4:1-10:1; the mass ratio of the N-hydroxysuccinimide to the fish skin gelatin aqueous solution is 1:40-1:100; the molar ratio of the N-hydroxysuccinimide to 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is 1:1-5:1, preferably 1:1-3:1; the pH value of the 2-morpholineethanesulfonic acid buffer solution is 5.5; and the stirring speed is 500-1000rpm.

[0013] Preferably, in step S2, the mass ratio of the 2-morpholineethanesulfonic acid buffer solution to gallic acid is 80:1 to 100:1; the mass concentration of the fish skin gelatin aqueous solution is 30% to 50%; the mass ratio of the 2-morpholineethanesulfonic acid buffer solution to the fish skin gelatin aqueous solution is 4:1 to 5:1; the mass ratio of N-hydroxysuccinimide to the fish skin gelatin aqueous solution is 1:50 to 1:70; the molar ratio of N-hydroxysuccinimide to 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is 1:1 to 2:1.

[0014] Furthermore, in step S3, the conductive polymer aqueous solution is prepared by adding a conductive polymer to ultrapure water and stirring and mixing; the mass concentration of the conductive polymer aqueous solution is 0.25% to 1%, preferably 0.5%; the conductive polymer is one of PEDOT:PSS, polyacetylene, polypyrrole, polyaniline, polyphenylene, polyphenylene ethylene, polydiacetylene, and polyfluorene.

[0015] Preferably, in step S3, the mass ratio of the conductive polymer aqueous solution to sodium citrate is 1:1-10:1, preferably 4:1-8:1; the mass ratio of the conductive polymer aqueous solution to gallic acid-modified ε-poly-L-lysine is 10:1-50:1, preferably 15:1-30:1; the mass ratio of the conductive polymer aqueous solution to gallic acid-modified fish skin gelatin solution is 1:1-10:1, preferably 4:1-8:1; the mass ratio of the conductive polymer aqueous solution to glycerol is 1:1-5:1, preferably 1:1-3:1; in step S4, the mass ratio of the mixture B to pig skin gelatin is 1:1-5:1, preferably 1:1-4:1.

[0016] Preferably, in step S3, the mass ratio of the conductive polymer aqueous solution to sodium citrate is 5:1 to 6:1; the mass ratio of the conductive polymer aqueous solution to gallic acid-modified ε-poly-L-lysine is 18:1 to 25:1; the mass ratio of the conductive polymer aqueous solution to gallic acid-modified fish skin gelatin solution is 2:1 to 1:1; the mass ratio of the conductive polymer aqueous solution to glycerol is 1:1 to 2:1; in step S4, the mass ratio of the mixture B to pig skin gelatin is 1:1 to 5:1.

[0017] To achieve the above object, the present invention also provides a biomacromolecule hydrogel prepared by the above preparation method.

[0018] To achieve the above objectives, the present invention also provides the use of the above-mentioned biomacromolecule hydrogel in tissue-adaptive in situ forming bioelectronic interface. The specific application process is: after the biomacromolecule hydrogel described in claim 9 is heated and melted into a viscous liquid state, it is coated on the target tissue and connected to a metal wire, and then cooled and solidified into a gel to obtain an adaptive bioelectronic interface.

[0019] The present invention aims at the common problems of poor flexibility, poor biocompatibility, difficult in vivo degradation and easy failure of wet interface adhesion in current patch-type hydrogel bioelectrodes, and proposes a coatable, shape-adaptive electroactive hydrogel, which effectively overcomes the size and shape limitations of patch-type hydrogels. The bioelectronic interface based on tissue-adaptive in-situ formed hydrogel obtained by the present invention can be further applied to electrocardiographic signal monitoring, electromyographic signal monitoring and neural regulation. The bioelectronic interface based on tissue-adaptive in-situ formed hydrogel can be used in the treatment and rehabilitation of acute tissue damage, especially in the application of bioelectronic interfaces in many fields such as electrophysiological signal acquisition, transient tissue function reconstruction and electrical stimulation tissue repair.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The present invention uses 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide to catalyze the grafting of gallic acid onto fish skin gelatin and ε-poly-L-lysine rich in lysine residues to achieve wet tissue adhesion. Benefiting from the reversible fluid-gel transition characteristics of biomacromolecules, the in-situ coated hydrogel can quickly establish a robust bioelectronic interface with various tissues (epithelial, muscle and neural tissue) through chemical bonds and physical topological effects. The large number of exposed adhesive groups (catechol groups, amino groups, carboxyl groups) in the hydrogel can form a strong interface interaction with the target tissue, ensuring conformal contact and dynamic compliance with soft tissue. The hydrogel with complete non-covalent cross-linking (hydrogen bonds, ionic interactions and triple helical entanglement of gelatin chains) also exhibits excellent biodegradation characteristics. Through ionic interactions, sodium citrate forms a local amine-carboxylate electrostatic domain with pig skin gelatin, which significantly increases the phase transition temperature by increasing the cross-linking density, can be precisely destroyed under physiological conditions, and accelerates the degradation rate in vivo. Moreover, the conductive polymers with dual conductivity (electronic and ionic) endow the hydrogels with excellent flexibility and electrical properties (high conductivity, low interfacial impedance, and high charge injection / storage capabilities). BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The stress-strain curves of the biomacromolecule hydrogels prepared with different PEDOT:PSS dosages in Examples 1-4;

[0023] Figure 2 The conductivity curves of the biomacromolecule hydrogels prepared with different PEDOT:PSS dosages in Examples 1-4;

[0024] Figure 3 The 100% stress stretching-recovery cycle curve of the biomacromolecule hydrogel prepared in Example 1;

[0025] Figure 4 Schematic diagram of the adhesion test results of the biomacromolecule hydrogel prepared in Example 1;

[0026] Figure 5 Schematic diagram of impedance test results of the biomacromolecule hydrogel prepared in Example 1 and a commercial electrode;

[0027] Figure 6 Schematic diagram of the stretch sensitivity factor of the biomacromolecule hydrogel prepared in Example 1;

[0028] Figure 7 The monitoring diagram of the biomacromolecule hydrogel bioelectronic interface and the commercial electrode prepared in Example 1 on the ECG signal, (a) is the ECG signal diagram, and (b) is the ECG signal-to-noise ratio;

[0029] Figure 8This is a monitoring diagram of myoelectric signals by the biomacromolecule hydrogel bioelectronic interface prepared in Example 1;

[0030] Fig. 9 This is a curve diagram of the regulation of the sciatic nerve by the biomacromolecule hydrogel bioelectronic interface prepared in Example 1. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0032] The raw materials and reagents used in the following examples, unless otherwise specified, are all commercially available.

[0033] Example 1

[0034] A method for preparing a biomacromolecule hydrogel comprises the following steps:

[0035] S1. Slowly add 1.36 g of gallic acid and 0.26 g of ε-poly-L-lysine to 30 mL of 2-morpholineethanesulfonic acid buffer solution (pH=5.5), and stir and dissolve under nitrogen atmosphere to obtain a mixed solution; then, add 0.23 g of N-hydroxysuccinimide and 0.31 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride to the mixed solution in sequence under nitrogen protection, vigorously stir at 500 rpm for 1 to 5 h, dialyze for 3 to 5 days, and freeze-dry to obtain gallic acid-modified ε-poly-L-lysine powder.

[0036] S2, 0.17g gallic acid and 7g fish skin gelatin aqueous solution (50wt%) are slowly added in 20mL 2-morpholineethanesulfonic acid buffer solution (pH=5.5), and stirring and dissolving obtains mixed solution under nitrogen atmosphere protection; Then under nitrogen protection, 0.115g N-hydroxysuccinimide and 0.155g 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride are added successively in the mixed solution, and vigorously stirred for 1~5h at 800rpm rotating speed, and after dialysis for 3~8 days, it is concentrated into viscous gallic acid modified fish skin gelatin (GA-FG) solution.

[0037] S3, 0.4g sodium citrate and 0.08g gallic acid modified ε-poly-L-lysine are ultrasonically dispersed in 2mL (mass is 2.0-2.1g) conductive polymer (poly 3,4-ethylenedioxythiophene: polystyrene sulfonate) PEDOT:PSS aqueous solution (0.5wt%: i.e., the mass of PEDOT:PSS is 0.5% of the mass of ultrapure water) to obtain mixture A; then 2g gallic acid modified fish skin gelatin solution and 1.5g glycerol are added to mixture A, and vigorously stirred at a rotating speed of 800rpm to obtain mixture B.

[0038] S4. Add 1.6 g of pigskin gelatin to the 6 g mixture B obtained in step S3, and blow nitrogen into the mixture for 10 minutes. Remove oxygen from the mixture and seal it, then heat it at 60° C. to 80° C. for 3 to 12 hours to obtain a uniform viscous liquid, transfer it to a mold, and cool it to obtain a degradable, tissue-adaptive, in-situ coated biomacromolecule hydrogel.

[0039] The biomacromolecule hydrogel prepared in this embodiment is heated and melted into a viscous liquid state, coated on the target tissue and connected with a metal wire, and then cooled and solidified into a gel to obtain an adaptive bioelectronic interface.

[0040] The stress-strain curve of the biomacromolecule hydrogel prepared in this example is shown in Figure 1 , conductivity see Figure 2 .

[0041] from Figure 3 It can be seen that the biomacromolecule hydrogel prepared in this example can maintain stable mechanical properties during more than 10,000 loading-release cycles.

[0042] from Figure 4 It can be seen that the biomacromolecule hydrogel prepared in this example can be tightly bonded to biological substrates such as liver, nerves, heart, skin, and kidneys, and has high bonding strength.

[0043] from Figure 5 It can be seen that the impedance of the biomacromolecule hydrogel prepared in this embodiment is significantly lower than that of the commercial hydrogel electrode.

[0044] from Figure 6 It can be seen from the figure that the biomacromolecule hydrogel prepared in this embodiment has almost no change in relative resistance even within a large strain range, showing excellent strain resistance.

[0045] from Figure 7 It can be seen that compared with commercial electrodes, the ECG signals monitored by the biomacromolecule hydrogel prepared in this embodiment show a higher signal-to-noise ratio.

[0046] from Figure 8 It can be seen that the biomacromolecule hydrogel prepared in this embodiment is used to prepare a bioelectronic interface, and the bioelectronic interface can accurately recognize gestures.

[0047] from Fig. 9 It can be seen that the biomacromolecule hydrogel prepared in this example is used to prepare a bioelectronic interface, and the bioelectronic interface can more efficiently regulate the sciatic nerve of rats.

[0048] Example 2

[0049] Except for step S3 in this embodiment which is different from embodiment 1, other steps in this embodiment are consistent with embodiment 1.

[0050] Step S3, ultrasonically dispersing 0.4 g of sodium citrate and 0.08 g of gallic acid-modified ε-poly-L-lysine in 2 mL of a conductive polymer PEDOT:PSS aqueous solution (0.25 wt%) to obtain a mixture A; then adding 2 g of a gallic acid-modified fish skin gelatin solution and 1.5 g of glycerol to the mixture A, and vigorously stirring at a rotation speed of 800 rpm to obtain a mixture B.

[0051] The stress-strain curve of the biomacromolecule hydrogel prepared in this example is shown in Figure 1 , conductivity see Figure 2 .

[0052] Example 3

[0053] Except for step S3 in this embodiment which is different from embodiment 1, other steps in this embodiment are consistent with embodiment 1.

[0054] Step S3, ultrasonically dispersing 0.4 g sodium citrate and 0.08 g gallic acid-modified ε-poly-L-lysine in 2 mL of a conductive polymer PEDOT:PSS aqueous solution (0.75 wt%) to obtain a mixture A; then adding 2 g gallic acid-modified fish skin gelatin solution and 1.5 g glycerol to the mixture A, and vigorously stirring at a rotation speed of 800 rpm to obtain a mixture B.

[0055] The stress-strain curve of the biomacromolecule hydrogel prepared in this example is shown in Figure 1 , conductivity see Figure 2 .

[0056] Example 4

[0057] Except for step S3 in this embodiment which is different from embodiment 1, other steps in this embodiment are consistent with embodiment 1.

[0058] Step S3, ultrasonically dispersing 0.4 g sodium citrate and 0.08 g gallic acid-modified ε-poly-L-lysine in 2 mL of a conductive polymer PEDOT:PSS aqueous solution (1.0 wt%) to obtain a mixture A; then adding 2 g gallic acid-modified fish skin gelatin solution and 1.5 g glycerol to the mixture A, and vigorously stirring at a rotation speed of 800 rpm to obtain a mixture B.

[0059] The stress-strain curve of the biomacromolecule hydrogel prepared in this example is shown in Figure 1 , conductivity see Figure 2 .

[0060] Depend on Figure 1It can be seen that different contents of PEDOT:PSS have a certain influence on the mechanical properties of the hydrogel. When the mass concentration of the conductive polymer aqueous solution is 0.25% to 0.5%, the elongation at break and the fracture strength of the hydrogel increase, showing excellent flexibility and adjustable mechanical properties. Figure 2 It can be seen that different contents of PEDOT:PSS have a great influence on the conductivity of the hydrogel; especially when the mass concentration of the conductive polymer aqueous solution is 0.5%, the balance between the flexibility and conductivity of the hydrogel reaches the optimal level.

[0061] Example 5

[0062] Except for step S3 in this embodiment which is different from embodiment 1, other steps in this embodiment are consistent with embodiment 1.

[0063] Step S3, ultrasonically dispersing 0.4 g sodium citrate and 0.08 g gallic acid-modified ε-poly-L-lysine in 2 mL of a conductive polymer polyphenylene aqueous solution (0.5 wt %) to obtain a mixture A; then adding 2 g gallic acid-modified fish skin gelatin solution and 1.5 g glycerol to the mixture A, and vigorously stirring at a rotation speed of 800 rpm to obtain a mixture B.

[0064] The performance evaluation method of the biomacromolecule hydrogel and hydrogel bioelectronic interface prepared in this example is consistent with that in the example, and both can obtain performance similar to that in Example 1.

[0065] Example 6

[0066] Except for step S3 in this embodiment which is different from embodiment 1, other steps in this embodiment are consistent with embodiment 1.

[0067] Step S3, ultrasonically dispersing 0.4 g sodium citrate and 0.08 g gallic acid-modified ε-poly-L-lysine in 2 mL of a conductive polymer polypyrrole aqueous solution (0.5 wt %) to obtain a mixture A; then adding 2 g gallic acid-modified fish skin gelatin solution and 1.5 g glycerol to the mixture A, and vigorously stirring at a rotation speed of 800 rpm to obtain a mixture B.

[0068] The performance evaluation method of the biomacromolecule hydrogel and hydrogel bioelectronic interface prepared in this example is consistent with that in the example, and both can obtain performance similar to that in Example 1.

[0069] Example 7

[0070] Except for step S3 in this embodiment which is different from embodiment 1, other steps in this embodiment are consistent with embodiment 1.

[0071] Step S3, ultrasonically dispersing 0.4 g sodium citrate and 0.08 g gallic acid-modified ε-poly-L-lysine in 2 mL of a conductive polymer polyaniline aqueous solution (0.5 wt%) to obtain a mixture A; then adding 2 mL of a gallic acid-modified fish skin gelatin solution and 1.5 g of glycerol to the mixture A, and vigorously stirring at a rotation speed of 800 rpm to obtain a mixture B.

[0072] The performance evaluation method of the biomacromolecule hydrogel and hydrogel bioelectronic interface prepared in this example is consistent with that in the example, and both can obtain performance similar to that in Example 1.

[0073] Example 8

[0074] In this embodiment, except step S4 which is different from embodiment 1, other steps are consistent with embodiment 1.

[0075] S4. Add 2.5 g of pig skin gelatin to 6 g of mixture B, and blow nitrogen into the mixture for 10 minutes. After removing oxygen from the mixture and sealing it, heat it at 60°C to 80°C for 3 to 12 hours to obtain a uniform viscous liquid. Transfer it to a mold and cool it to obtain a degradable, tissue-adaptive, in-situ coated biomacromolecule hydrogel.

[0076] The performance evaluation method of the biomacromolecule hydrogel and hydrogel bioelectronic interface prepared in this example is consistent with that in the example, and both can obtain performance similar to that in Example 1.

[0077] Example 9

[0078] Except for step S3 in this embodiment which is different from embodiment 1, other steps in this embodiment are consistent with embodiment 1.

[0079] S3, 0.4g sodium citrate and 0.08g gallic acid modified ε-poly-L-lysine were ultrasonically dispersed in 2mL conductive polymer (poly 3,4-ethylenedioxythiophene: polystyrene sulfonate) PEDOT:PSS aqueous solution (0.5wt%: i.e., the mass of PEDOT:PSS is 0.5% of the mass of ultrapure water)) to obtain mixture A; then 1.5g gallic acid modified fish skin gelatin solution and 2g glycerol were added to mixture A, and the mixture was vigorously stirred at a rotating speed of 800rpm to obtain mixture B.

[0080] The performance evaluation method of the biomacromolecule hydrogel and hydrogel bioelectronic interface prepared in this example is consistent with that in the example, and both can obtain performance similar to that in Example 1.

[0081] Example 10

[0082] Except for step S1 in this embodiment which is different from embodiment 1, other steps in this embodiment are consistent with embodiment 1.

[0083] S1. 1.36 g of gallic acid and 0.26 g of ε-poly-L-lysine were slowly added to 30 mL of 2-morpholineethanesulfonic acid buffer solution (pH=5.5), and stirred to dissolve under nitrogen atmosphere to obtain a mixed solution; then, 0.46 g of N-hydroxysuccinimide and 0.62 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to the mixed solution in sequence under nitrogen protection, and the mixture was vigorously stirred at a speed of 500 rpm for 1 to 5 h, dialyzed for 3 to 5 days, and freeze-dried to obtain gallic acid-modified ε-poly-L-lysine powder.

[0084] The performance evaluation method of the biomacromolecule hydrogel and hydrogel bioelectronic interface prepared in this example is consistent with that in the example, and both can obtain performance similar to that in Example 1.

Claims

1. A method for preparing a biomacromolecule hydrogel, characterized in that: The following steps are involved: S1. Slowly add gallic acid and ε-poly-L-lysine to a 2-morpholineethanesulfonic acid buffer solution, and stir to dissolve under a nitrogen atmosphere to obtain a mixed solution; then, under a nitrogen atmosphere, sequentially add N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride to the mixed solution, stir for 1 to 5 hours, dialyze for 3 to 5 days, and freeze-dry to obtain gallic acid-modified ε-poly-L-lysine powder; S2, gallic acid and fish skin gelatin aqueous solution are slowly added in 2-morpholineethanesulfonic acid buffer solution, stirring and dissolving under nitrogen atmosphere protection obtains mixed solution; Then under nitrogen protection, N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride are added successively in the mixed solution, stirred for 1~5h, and after dialysis for 3~8 days, concentrated into viscous gallic acid modified fish skin gelatin solution; S3, ultrasonically dispersing sodium citrate and the gallic acid-modified ε-poly-L-lysine prepared in step S1 in a conductive polymer aqueous solution to obtain a mixture A; then adding the gallic acid-modified fish skin gelatin solution prepared in step S2 and glycerol to the mixture A, stirring to obtain a mixture B; S4. Add pigskin gelatin to the mixture B obtained in step S3, blow nitrogen to remove oxygen and seal, heat at 60° C. to 80° C. for 3 to 12 hours to obtain a uniform viscous liquid, transfer to a mold and cool to obtain a biomacromolecule hydrogel that is degradable, tissue-adaptive, and in-situ coated.

2. The method for preparing a biomacromolecule hydrogel according to claim 1, characterized in that: In step S1, The mass ratio between the 2-morpholineethanesulfonic acid buffer solution and ε-poly-L-lysine is 50:1 to 200:1, preferably 80:1 to 150:1; The molar ratio between gallic acid and ε-poly-L-lysine is 2:1 to 6:1, preferably 3:1 to 5:1; The molar ratio between the N-hydroxysuccinimide and ε-poly-L-lysine is 1:3 to 3:1, preferably 1:2 to 2:1; The molar ratio between the N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:1 to 5:1, preferably 1:1 to 3:1; The pH value of the 2-morpholineethanesulfonic acid buffer solution is 5.5; the stirring speed is 200-800 rpm.

3. The method for preparing a biomacromolecule hydrogel according to claim 2, characterized in that: In step S1, The mass ratio between the 2-morpholineethanesulfonic acid buffer solution and ε-poly-L-lysine is 90:1 to 100:1; The molar ratio between gallic acid and ε-poly-L-lysine is 3.8:1 to 4:1; The molar ratio between the N-hydroxysuccinimide and the ε-poly-L-lysine is 1:2 to 1:1; The molar ratio between the N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:1 to 2:

1.

4. The method for preparing a biomacromolecule hydrogel according to claim 1 or 2, characterized in that: In step S2, The mass ratio between the 2-morpholineethanesulfonic acid buffer solution and gallic acid is 40:1 to 300:1, preferably 80:1 to 150:1; The fish skin gelatin aqueous solution is prepared by adding fish skin gelatin powder into ultrapure water and stirring and mixing; the mass concentration of the fish skin gelatin aqueous solution is 25% to 70%; The mass ratio between the 2-morpholineethanesulfonic acid buffer solution and the fish skin gelatin aqueous solution is 3:1 to 20:1, preferably 4:1 to 10:1; The mass ratio of the N-hydroxysuccinimide to the fish skin gelatin aqueous solution is 1:40 to 1:100; The molar ratio between the N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:1 to 5:1, preferably 1:1 to 3:1; The pH value of the 2-morpholineethanesulfonic acid buffer solution is 5.5; the stirring speed is 500-1000 rpm.

5. The method for preparing a biomacromolecule hydrogel according to claim 4, characterized in that: In step S2, The mass ratio between the 2-morpholineethanesulfonic acid buffer solution and gallic acid is 80:1 to 100:1; The mass concentration of the fish skin gelatin aqueous solution is 30% to 50%; The mass ratio between the 2-morpholineethanesulfonic acid buffer solution and the fish skin gelatin aqueous solution is 4:1 to 5:1; The mass ratio between the N-hydroxysuccinimide and the fish skin gelatin aqueous solution is 1:50 to 1:70; The molar ratio between the N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:1 to 2:

1.

6. The method for preparing a biomacromolecule hydrogel according to claim 1 or 2, characterized in that: In step S3, the conductive polymer aqueous solution is prepared by adding a conductive polymer to ultrapure water and stirring and mixing; the mass concentration of the conductive polymer aqueous solution is 0.25% to 1%, preferably 0.5%; the conductive polymer is one of PEDOT:PSS, polyacetylene, polypyrrole, polyaniline, polyphenylene, polyphenylene ethylene, polydiacetylene, and polyfluorene.

7. The method for preparing a biomacromolecule hydrogel according to claim 1 or 2, characterized in that: In step S3, the mass ratio between the conductive polymer aqueous solution and sodium citrate is 1:1 to 10:1, preferably 4:1 to 8:1; The mass ratio between the conductive polymer aqueous solution and the gallic acid-modified ε-poly-L-lysine is 10:1 to 50:1, preferably 15:1 to 30:1; The mass ratio between the conductive polymer aqueous solution and the gallic acid modified fish skin gelatin solution is 1:1 to 10:1, preferably 4:1 to 8:1; The mass ratio between the conductive polymer aqueous solution and glycerol is 1:1 to 5:1, preferably 1:1 to 3:1; In step S4, the mass ratio between the mixture B and the pig skin gelatin is 1:1 to 5:1, preferably 1:1 to 4:

1.

8. The method for preparing a biomacromolecule hydrogel according to claim 7, characterized in that: In step S3, the mass ratio between the conductive polymer aqueous solution and sodium citrate is 5:1 to 6:1; The mass ratio between the conductive polymer aqueous solution and the gallic acid-modified ε-poly-L-lysine is 18:1 to 25:1; The mass ratio between the conductive polymer aqueous solution and the gallic acid modified fish skin gelatin solution is 2:1 to 1:1; The mass ratio between the conductive polymer aqueous solution and glycerol is 1:1 to 2:1; In step S4, the mass ratio between the mixture B and the pig skin gelatin is 1:1 to 5:

1.

9. A biomacromolecule hydrogel prepared by the preparation method according to any one of claims 1 to 8.

10. The application of the biomacromolecule hydrogel as claimed in claim 9 in the tissue-adaptive in situ forming bioelectronic interface, the specific application process is: after heating and melting the biomacromolecule hydrogel as claimed in claim 9 into a viscous liquid state, coating it on the target tissue and connecting it with a metal wire, and cooling and solidifying it into a gel to obtain an adaptive bioelectronic interface.

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