Hydrogel bioelectronic device and preparation method thereof

Abstract

The invention discloses a hydrogel bioelectronic device and a preparation method thereof, and belongs to the technical field of high polymer materials. The preparation method of the polyacrylate anti-swelling hydrogel comprises the following steps: mixing a hydrophilic acrylate monomer, a hydrophobic or amphiphilic acrylate monomer and water to obtain a micelle solution; or mixing an amphiphilic acrylate monomer with water to obtain a micelle solution; adding a photoinitiator into the micelle solution, and uniformly dispersing to obtain a hydrogel precursor solution; the hydrogel precursor solution is subjected to ultraviolet light curing firstly, then dialysis is conducted, and finally the polyacrylate anti-swelling hydrogel is obtained. The hydrogel disclosed by the invention has good anti-swelling performance, high flexibility, high stretchability and good biocompatibility, and a bioelectronic device prepared based on the anti-swelling hydrogel can be implanted in a living body for a long time without causing immune response.

Description

Technical Field

[0001] The present invention belongs to the technical field of polymer materials, and in particular relates to a hydrogel bioelectronic device and a preparation method thereof. Background Art

[0002] Bioelectronic devices, a new type of electronic device capable of conducting and exchanging physiological electrical signals on the surface of living organisms, break through the limitations of traditional electronic devices, which are large, rigid, and bioincompatible, with their unique miniaturization, flexibility, and certain biocompatibility. They build a bridge for deep interaction and communication between organisms and machines. In recent years, with the rapid advancement of materials science and flexible electronics manufacturing technology, hydrogel-based bioelectronic devices have been applied in many emerging biomedical fields, such as brain-computer interfaces, flexible electrodes, and medical implants. Hydrogel materials have natural biocompatibility, low toxicity, high water content, and mechanical properties similar to those of biological tissues, showing excellent development prospects.

[0003] However, most hydrogel materials are in a non-equilibrium state when they are prepared. When placed in a liquid environment, the hydrogels in a non-equilibrium state will continue to absorb water and swell until equilibrium. During the swelling process, water molecules enter the hydrogel network and combine with the hydrophilic segments in the hydrogel, while weakening the intermolecular forces in the hydrogel, resulting in a significant decrease in the mechanical properties of the hydrogel material itself. When used as a substrate for bioelectronic devices, the humid environment in the body will cause the hydrogel substrate to swell in the body, making it difficult for the device to maintain its initial mechanical properties. In addition, changes in the volume of the hydrogel will also cause compression on the tissues or nerves around the implant environment, leading to unpredictable side effects.

[0004] Currently, the preparation method of anti-swelling hydrogels is still in the early stages of development. The methods for preparing anti-swelling hydrogels reported in the existing literature include introducing a high degree of chemical crosslinking, designing multiple physical and chemical crosslinking systems, phase separation design, and introducing a large amount of surfactants. However, based on the above methods, a certain amount of chemical crosslinking must be introduced into the hydrogel, making it difficult to prepare anti-swelling hydrogels with high flexibility (low Young's modulus) and high stretchability. In addition, the anti-swelling hydrogels prepared by the above-mentioned reported methods are generally difficult to maintain transparent properties. For example, the method of introducing multiple physical crosslinks involves the addition of high-valent metal ions (such as iron ions), thereby giving the hydrogel the color of metal ions; for example, the anti-swelling of the hydrogel achieved by phase separation design usually causes the hydrogel to lose transparency. Although the introduction of a large amount of surfactants into the hydrogel can make the hydrogel have anti-swelling properties, the surfactants are prone to seepage after long-term use, which can cause certain biological toxicity and limit its application in the biological field. In short, existing hydrogels are difficult to combine high flexibility, high stretchability and anti-swelling properties. They are prone to inflammatory reactions after long-term implantation in the body and have poor biocompatibility.

[0005] Therefore, there is an urgent need to provide a hydrogel bioelectronic device with excellent performance and a preparation method thereof. Summary of the Invention

[0006] The main purpose of the present invention is to provide a hydrogel bioelectronic device and a preparation method thereof, so as to solve the technical problem that existing hydrogels cannot take into account both anti-swelling properties and high flexibility and high stretchability, making it difficult to prepare hydrogel bioelectronic devices with good performance.

[0007] In a first aspect, the present invention provides a hydrogel bioelectronic device comprising a matrix containing a polyacrylate hydrogel and a conductive hydrogel material within the matrix, wherein the conductive hydrogel material comprises a polyacrylate hydrogel and metal microsheets, and a method for preparing the polyacrylate hydrogel comprises:

[0008] Mixing a hydrophilic acrylate monomer with a hydrophobic or amphiphilic acrylate monomer and water to obtain a micellar solution; or mixing an amphiphilic acrylate monomer with water to obtain a micellar solution;

[0009] Adding a photoinitiator to the micelle solution and dispersing the solution evenly to obtain a hydrogel precursor solution;

[0010] The hydrogel precursor solution is first subjected to UV curing and then dialyzed to finally obtain the polyacrylate anti-swelling hydrogel;

[0011] The hydrophilic acrylate monomer is selected from one or more of acrylic acid, methacrylic acid, acrylamide, methacrylamide, 2-hydroxyethyl acrylate, 2-acrylamide-2-methylpropanesulfonic acid, and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl)ammonium hydroxide;

[0012] The hydrophobic acrylic acid ester monomer is selected from one or more of ethyl acrylate, n-butyl acrylate, isobutyl acrylate, and isooctyl acrylate;

[0013] The amphiphilic acrylate monomer is selected from one or more of 2-hydroxyethyl methacrylate and 2-methoxyethyl 2-acrylate.

[0014] Furthermore, the mass ratio of the hydrophilic acrylate monomer to the hydrophobic acrylate monomer is 2 to 3:1, the mass ratio of the hydrophilic acrylate monomer to the amphiphilic acrylate monomer is less than 1:2, and the monomers account for 40% to 75% of the precursor solution mass.

[0015] Furthermore, the photoinitiator is a hydrophilic photoinitiator, selected from at least one of α-ketoglutaric acid, Irgacure 2959, and phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt.

[0016] Furthermore, the photoinitiator accounts for 0.1 to 2% of the total mass of the monomers.

[0017] Furthermore, the intensity of the ultraviolet light is 2 to 5 mW / cm 2 The solidification time is 1 to 2 hours, and the dialysis time is at least 1 day.

[0018] Furthermore, the bioelectronic device is a brain-computer interface or a wireless radio stimulator.

[0019] In a second aspect, the present invention provides a method for preparing the hydrogel bioelectronic device, which comprises: using embedded 3D printing technology to print a conductive hydrogel material along a planned path in a matrix to form a circuit with a three-dimensional structure, and preparing the hydrogel bioelectronic device after curing.

[0020] Furthermore, the preparation method of the matrix includes:

[0021] The prepared polyacrylate hydrogel is ground into micron-sized hydrogel particles, which are then swelled in a mixture of a certain amount of monomer and water to equilibrium, and a photoinitiator and a thermal initiator are added after grinding.

[0022] Furthermore, the conductive hydrogel material is prepared by mixing a matrix and metal microsheets in a mass ratio of 1:0.6 to 2.5.

[0023] Further, the preparation method further comprises: placing the printed hydrogel electronic device into distilled water for dialysis for 1-3 days until the unreacted monomers and unreacted photoinitiator and thermal initiator are removed.

[0024] Further, the mass ratio of the micron-sized hydrogel particles to the monomer-water mixture is 1:3-10, the mass ratio of the monomer to water in the monomer-water mixture is 1-2.5:1, the addition amount of the photoinitiator is 0.2%-1% of the mass of the ground substrate, and the addition amount of the thermal initiator is 0.1%-0.5% of the mass of the ground substrate.

[0025] Further, the photoinitiator is a hydrophilic photoinitiator selected from at least one of alpha-ketoglutaric acid, Irgacure 2959, and lithium phenyl (2,4,6-trimethylbenzoyl) phosphate salt; and the thermal initiator is a hydrophilic thermal initiator selected from at least one of ammonium persulfate and potassium persulfate.

[0026] Further, the light curing time after the photoinitiator and the thermal initiator are added is 20-60 minutes, and the thermal curing time is 30-120 minutes.

[0027] Invention principle: a certain amount of proportion of hydrophilic and hydrophobic acrylate monomers or amphiphilic acrylate monomers is reacted in water, the hydrophilic and hydrophobic monomers are self-assembled to form a transparent and stable micellar solution by using the hydrophilic and hydrophobic properties, and then the micellar solution is gelled by in-situ photopolymerization technology. By controlling the mass ratio of the total mass of the hydrophilic and hydrophobic monomers to water, the secondary aggregation of the micellar solution during the gelation process can be adjusted, and the preparation of the anti-swelling hydrogel from opaque to transparent can be realized. In addition, the preparation process of the anti-swelling hydrogel of the present application does not need to add a crosslinking agent, and the anti-swelling hydrogel prepared can achieve extremely low Young's modulus and excellent tensile properties, and can be implanted in the body for a long time without causing immune response.

[0028] Compared with the prior art, the present application has the following beneficial effects:

[0029] (1) The hydrogel has good anti-swelling performance; the swelling rate of the polyacrylate anti-swelling hydrogel prepared by the present application in water is less than 20%;

[0030] (2) The hydrogel realizes high flexibility and high tensile property; the preparation process of the anti-swelling hydrogel of the present application does not need to add a crosslinking agent, and can realize extremely low Young's modulus (the lowest can reach about 20kPa) and extremely high tensile property (the maximum can reach 35 times);

[0031] (3) good biocompatibility; the bioelectronic device prepared based on the anti-swelling hydrogel has high softness, high stretchability and anti-swelling property, and can be implanted in a living body for a long time without causing an immune response;

[0032] (4) the conductivity of the hydrogel ranges from 20 S / cm to 5000 S / cm after reaching equilibrium in a solution, and wireless sensing can be achieved. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 is an atomic force microscope image of the transparent anti-swelling polyacrylate hydrogel prepared in Example 3;

[0034] Figure 2 is a transparency diagram of the anti-swelling hydrogel prepared in Examples 1-3 before and after swelling;

[0035] Figure 3 is a swelling rate column chart of the polyacrylate anti-swelling hydrogel prepared in Examples 1-3;

[0036] Figure 4 is a stress-strain curve of the polyacrylate anti-swelling hydrogel prepared in Examples 1-3;

[0037] Figure 5 is a real object diagram of the transparent high-stretchability anti-swelling hydrogel prepared in Example 3;

[0038] Figure 6 is a transparency diagram of the anti-swelling hydrogel prepared in Examples 4-6 before and after swelling;

[0039] Figure 7 is a swelling rate column chart of the poly(2-hydroxyethyl methacrylate) hydrogel prepared in Examples 4-6;

[0040] Figure 8 is a stress-strain curve of the poly(2-hydroxyethyl methacrylate) hydrogel prepared in Examples 4-6;

[0041] Figure 9 is a transparency diagram of the anti-swelling hydrogel prepared in Examples 7-9 before and after swelling;

[0042] Figure 10 is a swelling rate column chart of the poly(2-hydroxyethyl methacrylate) hydrogel prepared in Examples 7-9;

[0043] Figure 11 is a stress-strain curve of the poly(2-hydroxyethyl methacrylate) hydrogel prepared in Examples 7-9;

[0044] Figure 12 is a schematic diagram of the transparency of the anti-swelling hydrogel before and after swelling prepared in Examples 10-12;

[0045] Figure 13 is a bar chart of the swelling ratio of the poly(acrylic acid-acrylamide-ethyl acrylate) hydrogel prepared in Examples 10-12;

[0046] Figure 14 is a stress-strain curve of the poly(acrylic acid-acrylamide-ethyl acrylate) hydrogel prepared in Examples 10-12;

[0047] Figure 15 is an anti-swelling hydrogel microparticle prepared by cryogenic ball milling;

[0048] Figure 16 is a hydrogel matrix configured by swelling the anti-swelling hydrogel microparticle in a monomer and water mixed solution and adding a photothermal initiator;

[0049] Figure 17 is a conductive paste formed by mixing the hydrogel matrix with silver microparticles;

[0050] Figure 18 is a brain-computer interface based on the anti-swelling hydrogel;

[0051] Figure 19 is a schematic diagram and a physical diagram of a radio stimulator based on the anti-swelling hydrogel;

[0052] Figure 20 is a brain electrical signal collected one week after implanting the anti-swelling hydrogel brain-computer interface into the cerebral cortex of a rat in a resting state and under the condition of applying electrical stimulation to the left leg of the rat;

[0053] Figure 21 is an impedance diagram of the rat after implanting the anti-swelling hydrogel-based brain-computer interface into the rat;

[0054] Figure 22 is a physiological electrical signal diagram of the rat after implanting the anti-swelling hydrogel-based brain-computer interface into the rat;

[0055] Figure 23 is a bar chart of the relationship between the swing angle of the rat's leg and the applied voltage of the sciatic nerve under electrical stimulation when the rat's sciatic nerve receives electrical stimulation when a radio signal is applied externally one week after implanting the anti-swelling hydrogel radio stimulator into the rat;

[0056] Figure 24 is an HE staining diagram of the sciatic nerve of the control group and the sciatic nerve after implanting the hydrogel radio stimulator one month later. DETAILED DESCRIPTION

[0057] To make the purpose, technical solutions, and advantages of the embodiments of the present invention more clear, 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, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making creative efforts shall fall within the scope of protection of the present invention.

[0058] As described in the background of the present invention, the preparation method of anti-swelling hydrogels is still in the early stages of development. The methods for preparing anti-swelling hydrogels reported in the existing literature include the introduction of a high degree of chemical crosslinking, the design of multiple physical and chemical crosslinking systems, phase separation design, and the introduction of a large amount of surfactants. However, all of the above methods require the introduction of a certain amount of chemical crosslinking into the hydrogel, making it difficult to prepare anti-swelling hydrogels with high flexibility (low Young's modulus) and high stretchability. In addition, the anti-swelling hydrogels prepared by the above-mentioned reported methods are generally difficult to maintain transparent properties. For example, the method of introducing multiple physical crosslinking involves the addition of high-valent metal ions (such as iron ions), thereby giving the hydrogel the color of metal ions; for example, the anti-swelling of the hydrogel achieved by phase separation design usually causes the hydrogel to lose transparency. Although the introduction of a large amount of surfactants into the hydrogel can make the hydrogel have anti-swelling properties, the surfactants are prone to seepage after long-term use, which can cause certain biological toxicity. In short, existing hydrogels are difficult to combine high softness, high stretchability and anti-swelling properties. They are prone to induce inflammatory reactions after long-term implantation in the body, have poor biocompatibility, and are difficult to apply to bioelectronic devices.

[0059] In a first aspect, the present invention provides a hydrogel bioelectronic device comprising a matrix containing a polyacrylate hydrogel and a conductive hydrogel material within the matrix, wherein the conductive hydrogel material comprises a polyacrylate hydrogel and metal microsheets, and a method for preparing the polyacrylate hydrogel comprises:

[0060] Mixing a hydrophilic acrylate monomer with a hydrophobic or amphiphilic acrylate monomer and water to obtain a micellar solution; or mixing an amphiphilic acrylate monomer with water to obtain a micellar solution;

[0061] Adding a photoinitiator to the micelle solution and dispersing the solution evenly to obtain a hydrogel precursor solution;

[0062] The hydrogel precursor solution is first subjected to UV curing and then dialyzed to finally obtain the polyacrylate anti-swelling hydrogel;

[0063] the hydrophilic acrylate monomer is selected from one or more of acrylic acid, methacrylic acid, acrylamide, methacrylamide, 2-hydroxyethyl acrylate, 2-acrylamido-2-methylpropanesulfonic acid, [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide;

[0064] the hydrophobic acrylate monomer is selected from one or more of ethyl acrylate, n-butyl acrylate, isobutyl acrylate, isooctyl acrylate;

[0065] the amphiphilic acrylate monomer is selected from one or more of 2-hydroxyethyl methacrylate, 2-methoxyethyl acrylate.

[0066] In some specific embodiments, the mass ratio of the hydrophilic acrylate monomer to the hydrophobic acrylate monomer is 2-3:1, the mass ratio of the hydrophilic acrylate monomer to the amphiphilic acrylate monomer is less than 1:2, and the monomers account for 40%-75% of the mass of the precursor solution.

[0067] In some specific embodiments, the photoinitiator is a hydrophilic photoinitiator selected from at least one of α-ketoglutaric acid, Irgacure 2959, and lithium phenyl(2,4,6-trimethylbenzoyl)phosphinate.

[0068] In some specific embodiments, the photoinitiator accounts for 0.1-2% of the total mass of the monomers.

[0069] In some specific embodiments, the intensity of the ultraviolet light is 2-5 mW / cm 2 , the curing time is 1-2 hours, and the dialysis time is at least 1 day.

[0070] In some specific embodiments, the bioelectronic device is a brain-computer interface or a radio stimulator.

[0071] In a second aspect, the present application provides a method for preparing the hydrogel bioelectronic device, which comprises: printing a conductive hydrogel material along a planned path in a matrix by using an embedded 3D printing technology to form a circuit with a three-dimensional structure, and obtaining the hydrogel bioelectronic device after curing.

[0072] In some specific embodiments, the method for preparing the matrix comprises:

[0073] The prepared polyacrylate hydrogel is ground into micron-sized hydrogel particles, which are then swelled to equilibrium in a mixed solution of a certain amount of monomers and water, and the photoinitiator and thermal initiator are added after grinding.

[0074] In some specific embodiments, the conductive hydrogel material is prepared by mixing a matrix and metal microsheets in a mass ratio of 1:0.6 to 2.5.

[0075] In some specific embodiments, the preparation method further comprises: placing the printed hydrogel electronic device in distilled water for 1-3 days for dialysis until unreacted monomers and unreacted photoinitiators and thermal initiators are removed.

[0076] In some specific embodiments, the mass ratio of the micron-sized hydrogel particles to the monomer-water mixture is 1:3-10, the mass ratio of the monomer to water in the monomer-water mixture is 1:1-2.5:1, the added amount of the photoinitiator is 0.2%-1% of the mass of the ground matrix, and the added amount of the thermal initiator is 0.1%-0.5% of the mass of the ground matrix.

[0077] In some specific embodiments, the photoinitiator is a hydrophilic photoinitiator selected from at least one of α-ketoglutaric acid, Irgacure2959, and phenyl (2,4,6-trimethylbenzoyl) lithium phosphate; the thermal initiator is a hydrophilic thermal initiator selected from at least one of ammonium persulfate and potassium persulfate.

[0078] In some specific embodiments, the light curing time after adding the photoinitiator and the thermal initiator is 20 to 60 minutes, and the thermal curing time is 30 to 120 minutes.

[0079] Example 1

[0080] The preparation method of the polyacrylate anti-swelling hydrogel is as follows:

[0081] 2.2g of hydrophilic 2-hydroxyethyl acrylate monomer (HEA) was mixed with 0.93g of hydrophobic ethyl acrylate (EA) and 2g of water to form a transparent micellar solution. A photoinitiator (α-ketoglutaric acid) with a monomer mass fraction of 1% was added to the micellar solution and ultrasonically dissolved to form a hydrogel precursor solution. The precursor solution was injected into a Teflon mold and covered with a glass sheet to isolate the air. Then, a 2-5mW / cm 2 The hydrogel was then cured under 365 nm ultraviolet light for 1 hour. The hydrogel was then taken out and dialyzed in deionized water for 1 day to prepare an anti-swelling hydrogel based on poly (2-hydroxyethyl acrylate-ethyl acrylate).

[0082] Example 2

[0083] The only difference from Example 1 is that the added amount of 2-hydroxyethyl acrylate monomer is 2.8 g, and the added amount of ethyl acrylate is 1.2 g.

[0084] Example 3

[0085] The only difference from Example 1 is that the amount of 2-hydroxyethyl acrylate monomer added is 4g and the amount of ethyl acrylate added is 1.73g. The atomic force microscope image of the transparent anti-swelling polyacrylate hydrogel prepared is as follows: Figure 1 shown.

[0086] like Figure 2 As shown, the anti-swelling hydrogels prepared in Examples 1-3 gradually become completely transparent as the monomer ratio increases; Figure 3 As shown, the swelling ratio (swelling ratio = (mass of hydrogel after swelling - initial mass of hydrogel) / initial mass of hydrogel × 100%) of the anti-swelling hydrogels prepared in Examples 1-3 did not exceed 10%, and the anti-swelling effect was far superior to that of the swellable hydrogel used as a control (the preparation of the swellable hydrogel was the same as that in reference: Sun, JY., Zhao, X., Illeperuma, W. et al. Highly stretchable and tough hydrogels. Nature 489, 133–136 (2012).); Figure 4 As shown, all anti-swelling hydrogels exhibited excellent stretchability and extremely low Young's modulus. The hydrogels prepared in Examples 1-3 could be stretched to ∼3500%, ∼3300% and ∼2450%, respectively, and the Young's modulus were ∼65 kPa, ∼95 kPa and ∼150 kPa, respectively.

[0087] Example 4

[0088] 2.1g of amphiphilic 2-hydroxyethyl methacrylate monomer (HEMA) was mixed with 2g of water to form a transparent micellar solution. A photoinitiator (α-ketoglutaric acid) with a monomer mass fraction of 1% was added to the micellar solution and ultrasonically dissolved to form a hydrogel precursor solution. The precursor solution was injected into a Teflon mold and covered with a glass sheet to isolate it from the air. Then, a 2mW / cm 2 The hydrogel was cured under 365 nm ultraviolet light for 1 hour. The hydrogel was then taken out and dialyzed in deionized water for 1 day to prepare an anti-swelling hydrogel based on poly(2-hydroxyethyl methacrylate).

[0089] Example 5

[0090] The only difference from Example 4 is that the added amount of 2-hydroxyethyl methacrylate monomer is 2.6 g.

[0091] Example 6

[0092] The only difference from Example 4 is that the added amount of 2-hydroxyethyl methacrylate monomer is 3.64 g.

[0093] like Figure 6As shown, the anti-swelling hydrogels prepared in Examples 4-6 gradually became completely transparent as the monomer ratio increased; Figure 7 As shown, the swelling ratio of the anti-swelling hydrogels prepared in Examples 4-6 does not exceed 15%; Figure 8 As shown, all anti-swelling hydrogels exhibited excellent stretchability and extremely low Young's modulus. The hydrogels prepared in Examples 4-6 could be stretched to ∼590%, ∼540% and ∼490%, respectively, and the Young's modulus were ∼185 kPa, ∼210 kPa and ∼270 kPa, respectively.

[0094] Example 7

[0095] 0.6g of hydrophilic 2-hydroxyethyl acrylate monomer (HEA) was mixed with 1.56g of amphiphilic 2-methoxyethyl acrylate (MEA) and 2g of water to form a transparent micellar solution. A photoinitiator (α-ketoglutaric acid) containing 1% by mass of the monomer was added to the micellar solution and ultrasonically dissolved to form a hydrogel precursor solution. The precursor solution was injected into a Teflon mold and covered with a glass sheet to isolate the air. Then, a 2-5W / cm 2 The hydrogel was then cured under 365 nm ultraviolet light for 1 hour. The hydrogel was then taken out and dialyzed in deionized water for 1 day to prepare an anti-swelling hydrogel based on poly (2-hydroxyethyl acrylate-2-methoxyethyl acrylate).

[0096] Example 8

[0097] The only difference from Example 7 is that the added amount of 2-hydroxyethyl acrylate monomer is 0.9 g, and the added amount of 2-methoxyethyl 2-acrylate is 2.34 g.

[0098] Example 9

[0099] The only difference from Example 7 is that the added amount of 2-hydroxyethyl acrylate monomer is 0.14 g, and the added amount of 2-methoxyethyl 2-acrylate is 3.64 g.

[0100] like Figure 9 As shown, the anti-swelling hydrogels prepared in Examples 7-9 gradually became completely transparent as the monomer ratio increased; Figure 10 As shown, the swelling ratio of the anti-swelling hydrogels prepared in Examples 7-9 does not exceed 20%; Figure 11 As shown, all anti-swelling hydrogels exhibited excellent stretchability and extremely low Young's modulus. The hydrogels prepared in Examples 7-9 could be stretched to ∼1280%, ∼880% and ∼680%, respectively, and the Young's modulus were ∼27 kPa, ∼48 kPa and 52 kPa, respectively.

[0101] Example 10

[0102] 1.3g hydrophilic acrylic acid monomer (AA), 0.64g hydrophilic acrylamide monomer (AM), 0.9g hydrophobic ethyl acrylate (EA) monomer and 2g water were mixed to form a transparent micellar solution. A photoinitiator (α-ketoglutaric acid) containing 1% by mass of monomers was added to the micellar solution and ultrasonically dissolved to form a hydrogel precursor solution. The precursor solution was injected into a Teflon mold and covered with a glass sheet to isolate the air. Then, 2-5W / cm 2 The hydrogel was cured under 365 nm ultraviolet light for 1 hour. The hydrogel was then taken out and dialyzed in deionized water for 1 day to prepare a poly(2-hydroxyethyl methacrylate)-based anti-swelling hydrogel.

[0103] Example 11

[0104] The only difference from Example 10 is that the added amount of acrylic acid monomer is 1.58 g, the added amount of acrylamide monomer is 0.78 g, and the added amount of ethyl acrylate is 1.1 g.

[0105] Example 12

[0106] The only difference from Example 10 is that the added amount of acrylic acid monomer is 2.16 g, the added amount of acrylamide monomer is 1.06 g, and the added amount of ethyl acrylate is 1.5 g.

[0107] like Figure 12 As shown, the anti-swelling hydrogels prepared in Examples 10-12 gradually became completely transparent as the monomer ratio increased; Figure 13 As shown, the swelling ratio of the anti-swelling hydrogels prepared in Examples 10-12 does not exceed 15%; Figure 14 As shown, all anti-swelling hydrogels exhibited excellent stretchability and extremely low Young's modulus. The hydrogels prepared in Examples 10-12 could be stretched to ∼1490%, ∼1600% and ∼890%, respectively, and the Young's modulus were ∼255 kPa, ∼290 kPa and ∼340 kPa, respectively.

[0108] Example 13

[0109] The anti-swelling hydrogel prepared in Example 9 was ground into micron-sized particles (such as Figure 15 As shown), 1 g of micron-sized anti-swelling hydrogel particles was then swollen in a mixture of 4.03 g of monomer and 1.47 g of water for 2 days to equilibrium, thereby forming a viscoelastic matrix ink having non-Newtonian fluid properties.

[0110] The anti-swelling hydrogel matrix was ground twice with a freezing ball mill and then filtered with a 10 μm filter to obtain a uniform anti-swelling hydrogel matrix. A photoinitiator with a weight fraction of 1% of the matrix and a thermal initiator with a weight fraction of 0.3% of the matrix (such as Figure 16As shown), a curable anti-swelling hydrogel matrix was prepared.

[0111] The above matrix was mixed with micron silver flakes, with the amount of micron silver flakes added being 2.2 times the mass of the ink, to prepare a conductive hydrogel material (such as Figure 17 shown).

[0112] The above-mentioned matrix ink is filled into the mold, and the conductive hydrogel material is printed in the matrix ink using embedded 3D printing technology to form a circuit with a three-dimensional structure. The printed hydrogel electronic device is allowed to stand for 30 minutes, first cured with 365nm ultraviolet light for 40 minutes, and then transferred to a hot plate for heat curing for 100 minutes to obtain an anti-swelling hydrogel bioelectronic device. The prepared device is then placed in deionized water for dialysis for 1 day until unreacted monomers and unreacted photothermal initiators are dialyzed away. Finally, a hydrogel brain-computer interface based on anti-swelling hydrogel (such as Figure 18 As shown), implantable wireless hydrogel electrical stimulator (as Figure 19 shown).

[0113] The anti-swelling hydrogel brain-computer interface was implanted into the motor center area of ​​the rat's cerebral cortex surface, which can be used to detect changes in EEG signals under electrical stimulation ( Figure 20 Since the hydrogel brain-computer interface prepared based on anti-swelling hydrogel has extremely low impedance, the impedance is ~640 ohms after 28 days of implantation (e.g. Figure 21 As shown) and extremely low foreign body reaction, it is conducive to obtaining high-quality physiological electrical signals for a long time ( Figure 22 shown).

[0114] The electrode end of the anti-swelling hydrogel wireless stimulator was wrapped around the sciatic nerve of the rat, and the wireless coil end was placed under the skin. After the wound was sutured, the sciatic nerve of the rat was stimulated by wireless transmission of electrical signals. Figure 23 As shown, one week after implantation, almost consistent motion feedback can be obtained under the same voltage stimulation, indicating that the performance of the device can be maintained and the electrode part of the device is in good contact with the sciatic nerve.

[0115] like Figure 24 As shown, the non-swelling hydrogel-based bioelectronic device showed extremely low foreign body reaction after 32 weeks of long-term implantation, while the foreign body reaction of the control group (silicone-based wireless radio stimulator) was obvious.

[0116] Comparative Example

[0117] On the basis of Example 9, only HEA monomer and 0.3% of the monomer weight of cross-linking agent were added when preparing the hydrogel precursor solution, and the remaining steps were the same.

[0118] The resulting swellable hydrogel electronic device, after being placed in water to reach equilibrium, swells violently, causing the circuit part to almost lose its conductivity, and the device subsequently fails.

[0119] Although the embodiments of the present invention have been described with reference to the accompanying drawings, those skilled in the art may make various modifications and variations without departing from the spirit and scope of the present invention, and such modifications and variations are all within the scope defined by the present invention.

Claims

1. A hydrogel bioelectronic device, characterized in that: The invention comprises a matrix containing polyacrylate hydrogel and a conductive hydrogel material inside the matrix, wherein the conductive hydrogel material comprises polyacrylate hydrogel and metal microsheets, and the preparation method of the polyacrylate hydrogel comprises: Mixing a hydrophilic acrylate monomer with a hydrophobic or amphiphilic acrylate monomer and water to obtain a micellar solution; or mixing an amphiphilic acrylate monomer with water to obtain a micellar solution; Adding a photoinitiator to the micelle solution and dispersing the solution evenly to obtain a hydrogel precursor solution; The hydrogel precursor solution is first subjected to UV curing and then dialyzed to finally obtain the polyacrylate anti-swelling hydrogel; The hydrophilic acrylate monomer is selected from one or more of acrylic acid, methacrylic acid, acrylamide, methacrylamide, 2-hydroxyethyl acrylate, 2-acrylamide-2-methylpropanesulfonic acid, and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfonic acid propyl)ammonium hydroxide; The hydrophobic acrylic acid ester monomer is selected from one or more of ethyl acrylate, n-butyl acrylate, isobutyl acrylate, and isooctyl acrylate; The amphiphilic acrylate monomer is selected from one or more of 2-hydroxyethyl methacrylate and 2-methoxyethyl 2-acrylate.

2. The hydrogel bioelectronic device according to claim 1, characterized in that The mass ratio of the hydrophilic acrylic ester monomer to the hydrophobic acrylic ester monomer is 2 to 3:1, and the mass ratio of the hydrophilic acrylic ester monomer to the amphiphilic acrylic ester monomer is less than 1:

2.

3. The hydrogel bioelectronic device according to claim 1, characterized in that The monomer accounts for 40% to 75% of the mass of the precursor solution.

4. The hydrogel bioelectronic device according to claim 1, characterized in that The photoinitiator is a hydrophilic photoinitiator, and is selected from at least one of α-ketoglutaric acid, Irgacure 2959, and phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt.

5. The hydrogel bioelectronic device according to claim 1, characterized in that The photoinitiator accounts for 0.1-2% of the total mass of the monomers.

6. The hydrogel bioelectronic device according to claim 1, characterized in that The ultraviolet light intensity is 2-5 mW / cm 2 The solidification time is 1 to 2 hours, and the dialysis time is at least 1 day.

7. The hydrogel bioelectronic device according to claim 1, characterized in that The bioelectronic device is a brain-computer interface or a wireless radio stimulator.

8. A method for preparing a hydrogel bioelectronic device according to any one of claims 1 to 7, characterized in that: Embedded 3D printing technology is used to print conductive hydrogel materials along a planned path in a matrix to form a circuit with a three-dimensional structure, and the hydrogel bioelectronic device is prepared after curing.

9. The method for preparing a hydrogel bioelectronic device according to claim 8, characterized in that: The preparation method of the matrix comprises: The prepared polyacrylate hydrogel is ground into micron-sized hydrogel particles, which are then swelled in a mixture of a certain amount of monomer and water to equilibrium, and a photoinitiator and a thermal initiator are added after grinding.

10. The method for preparing a hydrogel bioelectronic device according to claim 8, characterized in that: The conductive hydrogel material is prepared by mixing a matrix and metal microsheets in a mass ratio of 1:0.6 to 2.

5.

11. The method for preparing a hydrogel bioelectronic device according to claim 8, characterized in that: The preparation method further comprises: placing the printed hydrogel electronic device in distilled water for dialysis for 1-3 days until unreacted monomers and unreacted photoinitiators and thermal initiators are removed.

12. The method for preparing a hydrogel bioelectronic device according to claim 8, characterized in that: The mass ratio of the micron-sized hydrogel particles to the monomer-water mixture is 1:3-10, the mass ratio of the monomer to water in the monomer-water mixture is 1-2.5:1, the added amount of the photoinitiator is 0.2%-1% of the mass of the ground matrix, and the added amount of the thermal initiator is 0.1%-0.5% of the mass of the ground matrix.

13. The method for preparing a hydrogel bioelectronic device according to claim 8, wherein: The photoinitiator is a hydrophilic photoinitiator selected from at least one of α-ketoglutaric acid, Irgacure 2959, and phenyl (2,4,6-trimethylbenzoyl) lithium phosphate; the thermal initiator is a hydrophilic thermal initiator selected from at least one of ammonium persulfate and potassium persulfate.

14. The method for preparing a hydrogel bioelectronic device according to claim 8, characterized in that: The light curing time after adding the light initiator and the heat initiator is 20 to 60 minutes, and the heat curing time is 30 to 120 minutes.

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