Hydrogel-based flexible liquid-state metal electrode for inducing controlled release of medicine as well as preparation method and application of hydrogel-based flexible liquid-state metal electrode

Abstract

The invention provides a hydrogel-based flexible liquid metal electrode capable of inducing controlled release of drugs and a preparation method and application of the hydrogel-based flexible liquid metal electrode. The hydrogel-based flexible liquid metal electrode is characterized in that conductive amyloid fibers loaded with drug particles are doped in a hydrogel film substrate; and a patterned stretchable flexible interdigital electrode based on liquid metal ink is embedded. The hydrogel-based flexible liquid metal electrode provides a novel method for inducing controlled release of drugs, the conductive amyloid fibers are driven by a high-frequency alternating electric field to vibrate at high frequency so as to realize accurate release of loaded drugs, and by means of ion vibration induced by the high-frequency alternating electric field in hydrogel and a heat effect generated by friction, the drug release of the conductive amyloid fibers is realized. The hydrogel can be used for promoting release and diffusion of drugs in the hydrogel, can intelligently regulate and control the drug release rate according to personalized use requirements, is suitable for a plurality of use scenes such as pain relief, wound management, beauty and skin care and the like, and overcomes the limitations of single function and incapability of precise regulation and control according to requirements in the prior art.

Description

Technical Field

[0001] The present invention belongs to the technical field of flexible electronic materials, and particularly relates to a hydrogel-based flexible liquid metal electrode for inducing drug controlled release, a preparation method thereof, and an application thereof. Background Art

[0002] Hydrogels are regarded as ideal drug delivery carriers due to their good biocompatibility, adjustable physical and chemical properties, and biomimetic three-dimensional network structure. Their high water content can simulate the natural extracellular matrix environment and provide a stable loading space for pharmacological functional factors. At the same time, by introducing physical or chemical stimulus-responsive groups such as temperature, light, and pH, hydrogels can achieve environment-triggered drug release behavior, showing great application potential in biomedical fields such as chronic disease treatment and wound repair. However, most current drug controlled release systems based on stimulus-responsive hydrogels rely on the passive interaction between the material and the environment, and the release behavior is limited by the random fluctuations of local physiological conditions, making it difficult to achieve precise on-demand regulation.

[0003] The Chinese invention patent with the publication number CN112370567A discloses a hydrogel active dressing with antibacterial and anti-inflammatory functions, and uses the thermosensitivity of poly(N-isopropylacrylamide) to prepare thermosensitive poly(N-isopropylacrylamide) hydrogel microspheres. However, due to its phase transition hysteresis near body temperature, it is easy to cause burst release of drugs. The Chinese invention patent with the publication number CN116444818A discloses a pH-responsive hydrogel with shape memory function, a preparation method thereof, and an application thereof. However, the selectivity of pH-responsive hydrogels in complex body fluid environments is insufficient, which may cause non-targeted release. These limitations seriously restrict the application of hydrogels as drug delivery carriers in precision medicine.

[0004] The rapid development of flexible electronic technology provides the possibility for the realization of intelligent drug controlled release systems. Integrating hydrogels with electronic circuits and directionally inputting external energies such as electricity, light, and magnetism, which are further converted into changes in the local microenvironment within the hydrogel, dynamically regulates the diffusion rate of drug molecules, thereby achieving precise drug controlled release. This active control strategy based on external energy not only avoids the hysteresis problem of traditional stimulus-responsive hydrogels but also provides higher spatio-temporal precision and repeatability for drug release. However, problems such as the incompatibility of the interface between hydrogels and flexible electronics and functional integration pose challenges to the realization of actively regulated and on-demand released drug delivery systems. Summary of the Invention

[0005] In view of this, the present invention aims to provide a hydrogel-based flexible liquid metal electrode for inducing drug controlled release, a preparation method thereof, and an application thereof, which can intelligently regulate the drug release rate according to personalized usage requirements, overcoming the limitations of traditional drug controlled release methods that cannot achieve precise on-demand regulation.

[0006] To achieve the above object, the technical solution of the present invention is realized as follows:

[0007] In a first aspect, the present invention provides a method for preparing a hydrogel-based flexible liquid metal electrode for inducing drug controlled release, and the preparation method includes the following steps:

[0008] (1) Prepare a liquid metal ink, print the liquid metal ink onto an electrospun membrane to obtain an electrode to be activated, freeze the electrode to be activated and then activate it under pressure to obtain a flexible liquid metal electrode;

[0009] (2) Prepare an amyloid fiber solution, stir and dissolve the amyloid fiber solution with a conductive material, drug particles, salt powder, and polyvinyl alcohol (PVA), and let it stand to defoam to obtain a pre-gel solution;

[0010] (3) Cover the flexible liquid metal electrode with the pre-gel solution through a film-forming process and infiltrate it into the pores of the electrospun membrane, and repeat freezing and thawing to obtain a hydrogel-based flexible liquid metal electrode.

[0011] Further, the method for preparing the liquid metal ink includes the following steps: fully mix and dissolve polyvinylpyrrolidone and n-hexanol to obtain a polyvinylpyrrolidone / n-hexanol solution, add liquid metal and then perform ultrasonic treatment to obtain the liquid metal ink;

[0012] Preferably, the liquid metal is selected from one or more of gallium, eutectic gallium-indium alloy, and gallium-indium-tin alloy;

[0013] Preferably, the concentration of polyvinylpyrrolidone in the polyvinylpyrrolidone / n-hexanol solution is 3% - 7%;

[0014] More preferably, the mass ratio of the liquid metal to the polyvinylpyrrolidone / n-hexanol solution is 1 - 5:1;

[0015] Further, the instrument used for the ultrasonic treatment is a cell disruptor.

[0016] Further, the liquid metal ink is printed onto the electrospun membrane by screen printing, and the printed shape of the liquid metal ink is interdigitated. By changing the structural parameters (finger width, finger spacing, finger length) of the interdigitated electrode, or adjusting the high-frequency alternating electric field frequency, electric field strength, etc., the release and diffusion rates of the drug particles can be changed.

[0017] Further, the method for preparing the electrospun membrane includes the following steps: fully mix and dissolve an elastomer and an organic solvent to obtain an electrospinning solution, and perform electrospinning on the electrospinning solution to obtain the electrospun membrane;

[0018] Preferably, the elastomer is selected from one or more of thermoplastic polyurethane (TPU), styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, and poly(styrene-block-butadiene-block-styrene) copolymer;

[0019] Preferably, the organic solvent is selected from one or two of N,N-dimethylformamide and tetrahydrofuran;

[0020] Preferably, the concentration of the elastomer in the electrospinning solution is 15-25 wt%;

[0021] Preferably, the thickness of the electrospun membrane is 20-400 μm.

[0022] Furthermore, in step (1), the freezing temperature is -20 to -80 °C, the instrument used for pressure activation is a tablet press, and the pressure of the tablet press is 5-80 MPa.

[0023] Furthermore, the method for preparing the amyloid fiber solution includes the following steps: fully mixing and dissolving the protein powder with deionized water to obtain a protein powder solution, adjusting the pH of the protein powder solution to acidic, and heating and stirring in a water bath to obtain the amyloid fiber solution;

[0024] Preferably, the protein powder is selected from one or more of soy protein powder, pea protein powder, oat protein powder, chickpea protein powder, mung bean protein powder, rice protein powder, whey protein isolate, and ovalbumin;

[0025] Preferably, the pH of the protein powder solution is adjusted to 2-3;

[0026] Preferably, the water bath heating temperature is 80-95 °C, and the heating time is 10-24 h.

[0027] Furthermore, the salt powder is selected from one or more of sodium chloride, calcium chloride, zinc chloride, magnesium chloride, potassium chloride, etc.

[0028] Furthermore, the conductive material is selected from one or more of polypyrrole, gold nanoparticles, silver nanoparticles, and carbon nanotubes.

[0029] Furthermore, the film-forming process in step (3) includes but is not limited to spin coating, dip coating, mold method, etc.

[0030] In a second aspect, the present invention provides a hydrogel-based flexible liquid metal electrode for inducing drug controlled release prepared by the preparation method according to the first aspect.

[0031] In a third aspect, the present invention provides an induced drug particle controlled release system, which includes a high-frequency alternating electric field generator and the hydrogel-based flexible liquid metal electrode as described in the second aspect. The high-frequency alternating electric field generator is used to apply a high-frequency alternating electric field to the hydrogel-based flexible liquid metal electrode. Preferably, the high-frequency alternating electric field generator is a radiofrequency ablation instrument.

[0032] In a fourth aspect, the present invention provides an induced drug particle controlled release method, which includes the step of applying a high-frequency alternating electric field to the hydrogel-based flexible liquid metal electrode as described in the second aspect. Further, the application includes the following steps: connecting the hydrogel-based flexible liquid metal electrode to a radiofrequency ablation instrument through a wire, conformally attaching the hydrogel-based flexible liquid metal electrode to the action site, adjusting the parameters of the radiofrequency ablation instrument to control the temperature, and regulating the drug particle release rate through the temperature.

[0033] Compared with the prior art, the hydrogel-based flexible liquid metal electrode for induced drug controlled release and its preparation method and application according to the present invention have the following advantages:

[0034] (1) The hydrogel-based flexible liquid metal electrode of the present invention provides a new method for induced drug controlled release. The high-frequency vibration of conductive amyloid fibers is driven by a high-frequency alternating electric field to achieve precise release of the loaded drug. With the ion vibration induced by the high-frequency alternating electric field in the hydrogel and the thermal effect generated by friction, the release and diffusion of the drug in the hydrogel are promoted. The drug release rate can be intelligently regulated according to personalized usage requirements, and it is applicable to multiple usage scenarios such as pain relief, wound management, and beauty skin care, overcoming the limitations of single function and inability to accurately regulate as needed in the prior art.

[0035] (2) The method of activating the liquid metal electrode by applying pressure after freezing for the hydrogel-based flexible liquid metal electrode of the present invention can not only ensure the original precision of the electrode pattern with better consistency, but also the obtained electrode has high conductivity and stability and can work normally under deformations such as bending and stretching.

[0036] (3) The hydrogel-based flexible liquid metal electrode of the present invention doped with amyloid fibers in the hydrogel improves the mechanical properties of the hydrogel. With the electrospun membrane as the skeleton structure, on the one hand, the mechanical strength of the flexible substrate is enhanced, and on the other hand, it is convenient to introduce a patterned liquid metal electrode, obtaining a hydrogel-based flexible liquid metal electrode that takes into account biocompatibility, mechanical properties, and functionality, overcoming the problems of large surface tension of liquid metal and poor wettability on the hydrogel surface.

[0037] (4) The hydrogel-based flexible liquid metal electrode of the present invention uses hydrogel as a drug delivery carrier, taking into account biocompatibility, mechanical properties, and functionality, and can conformally attach to the action site, solving the problems of poor conformability and lack of comfort of traditional drug-loaded patches. Brief Description of the Drawings

[0038] The drawings forming a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation to the present invention. In the drawings:

[0039] Figure 1 is a schematic structural diagram of the hydrogel-based flexible liquid metal electrode of the present invention;

[0040] Figure 2 is a transmission electron microscope image of the whey protein isolate amyloid fibrils (WPIF) prepared in Example 1;

[0041] Figure 3 is a graph of the elongation at break and Young's modulus of the PVA hydrogel film doped with WPIF, the TPU nanofiber film, and the ionic TPU-PVA hydrogel composite film prepared in Example 1;

[0042] Figure 4 is a physical image and a scanning electron microscope image of the patterned stretchable flexible electrode based on liquid metal ink before and after activation prepared in Example 1;

[0043] Figure 5 is a physical image, a scanning electron microscope image, and a conductivity graph of the patterned stretchable flexible electrode based on liquid metal ink activated by a conventional mechanical sintering method, where a) is the physical image and the scanning electron microscope image of the flexible electrode, and b) is the conductivity graph of the physical image and the scanning electron microscope image of the flexible electrode;

[0044] Figure 6 is a graph of the performance test results of the ionic TPU-PVA composite hydrogel embedded with the patterned stretchable flexible interdigital electrode based on liquid metal ink prepared in Example 2, where a) and b) are graphs of the drug release at different radio frequency heating temperatures; c) is an infrared thermal imaging graph at different time nodes after applying a high-frequency alternating electric field; d) is a curve of the temperature change with time at different temperature measurement points. Detailed Description of the Embodiments

[0045] It should be noted that, without conflict, the embodiments in the present invention and the features in the embodiments can be combined with each other.

[0046] The present invention will be described in detail below with reference to the drawings and in combination with the embodiments.

[0047] Example 1

[0048] This example provides a preparation method for an ionic TPU-PVA composite hydrogel embedded with a patterned stretchable flexible interdigital electrode based on liquid metal ink, including the following steps:

[0049] 1) Mix tetrahydrofuran and N,N-dimethylformamide in a volume ratio of 1:1, add TPU with a concentration of 20 wt%, heat and stir until dissolved to obtain an electrospinning solution, and prepare a TPU nanofiber membrane using electrospinning technology.

[0050] 2) Dissolve polyvinylpyrrolidone in n-hexanol with a concentration of 3 wt%. Mix 3 g of EGaIn (75.5 wt% Ga and 24.5 wt% In) with 1 g of the polyvinylpyrrolidone-n-hexanol solution, and perform ultrasonic treatment using a cell disruptor. The diameter of the horn is 6 mm, the ultrasonic power is 300 W, it is turned on for 2 s and off for 2 s, and the actual working time is 1 min to obtain a liquid metal ink.

[0051] 3) Print the liquid metal ink on the TPU nanofiber membrane using screen printing technology to obtain an electrode to be activated. Place the electrode to be activated in the refrigerator for freezing, and apply pressure to the frozen electrode using a tablet press with a pressure of 20 MPa. The liquid metal is activated to form a conductive path, and a patterned stretchable flexible electrode based on the liquid metal ink is obtained.

[0052] 4) Dissolve whey protein isolate powder in deionized water with a concentration of 2 wt%, adjust the pH of the solution to 2.0, magnetically stir in a water bath at 80 °C for 24 h, and keep it in an ice-water bath for 20 min to terminate fibrillation to obtain a WPIF solution. Its transmission electron microscopy image is as Figure 2 shown.

[0053] 5) Adjust the pH of the WPIF solution to 7.4, add sodium chloride (0.9 wt%) and PVA (10 wt%), heat and stir until fully dissolved, and then let it stand to defoam to obtain a uniform pre-gel solution.

[0054] 6) Use the spin coating method to cover the electrode part with the pre-gel solution and infiltrate it into the pores of the TPU nanofibers. The rotation speed of the spin coater is 300 rpm and the time is 30 s.

[0055] 7) Freeze the electrode obtained in step 6) at -20 °C for 10 h, then thaw it at room temperature for 2 h, and repeat the freeze-thaw process 3 times to obtain an ionic TPU-PVA composite hydrogel embedded with a patterned stretchable flexible electrode based on the liquid metal ink.

[0056] 8) To detect the mechanical properties of the flexible substrate in the prepared hydrogel-based flexible liquid metal electrode, the pre-gel solution prepared in step 5) was directly spin-coated on a glass plate, frozen at -20 °C for 10 h, and then thawed at room temperature for 2 h. The freeze-thaw process was repeated 3 times to obtain a PVA hydrogel film doped with WPIF. The pre-gel solution prepared in step 5) was spin-coated on a TPU nanofiber membrane, and the freeze-thaw process was repeated 3 times to obtain an ionic TPU-PVA composite hydrogel film.

[0057] Mechanical property tests were respectively carried out on the PVA hydrogel film doped with WPIF, the TPU nanofiber membrane, and the ionic TPU-PVA composite hydrogel film prepared in Example 1, and the test results are as Figure 3 shown. Adding a TPU nanofiber membrane as a supporting skeleton in the PVA hydrogel film improved the elongation at break and Young's modulus of the ionic TPU-PVA composite hydrogel film.

[0058] The liquid metal activation method adopted in Example 1 was compared with the conventional mechanical sintering method, and the results are as Figure 4 、 Figure 5 shown. The liquid metal electrodes obtained by conventional mechanical sintering processes such as scraping, stretching, and pressing have poor consistency and limited pattern resolution; the liquid metal activation method described in the present invention can not only ensure the original precision of the electrode pattern, but also the obtained electrodes have high conductivity and consistency.

[0059] Example 2

[0060] This example demonstrates the intelligent drug controlled release effect of an ionic TPU-PVA composite hydrogel embedded with a patterned stretchable flexible interdigitated electrode based on liquid metal ink as a drug delivery patch.

[0061] The preparation method of the ionic TPU-PVA composite hydrogel in this example is basically the same as that in Example 1, except that the electrode pattern is interdigitated, the number of interdigits is 11, the width of the interdigits is 1.4 mm, and the spacing between the interdigits is 2.0 mm. After the electrode was activated, leads were pasted at the pins. After obtaining the pre-gel solution in step 5), 0.3 wt% of rhodamine B was added as a model drug, and after mixing evenly, it was injected into a mold with a thickness of 1.3 mm, so that the pre-gel solution covered the electrode part and penetrated into the pores of the TPU nanofiber membrane, and the freeze-thaw cycle was carried out according to step 7) of Example 1 to obtain an ionic TPU-PVA composite hydrogel embedded with a patterned stretchable flexible interdigitated electrode based on liquid metal ink.

[0062] Prepare a 1.5 wt% agar solution, inject it into the mold, and let it stand and cool at room temperature until the gel is formed to obtain an agar gel simulating human tissue.

[0063] Connect the radiofrequency ablation instrument through a wire to apply a high-frequency alternating electric field. Conformally attach the ionic TPU-PVA composite hydrogel to the agar surface. Set the instrument to the temperature control mode and adjust the temperature to 45 °C and 50 °C respectively. The control group does not apply a high-frequency alternating electric field, and the test is carried out at room temperature. Photograph the release of the model drug from the drug-loaded patch at different time points, and process the images with software Image J to calculate the fluorescence intensity. The results are as Figure 6 a), Figure 6 shown in b). As the temperature increases, the fluorescence intensity increases and the drug release increases, proving that the drug release rate can be controlled by adjusting the temperature.

[0064] Set the instrument to the power mode and use an infrared thermal imager to photograph the heating effect of the ionic TPU-PVA composite hydrogel. The results are as Figure 6 shown in c). After connecting a conventional resistive heating patch to a DC power supply, Joule heat is generated at the electrodes, and then the heat is transferred to the non-electrode part of the patch through heat conduction. The heating efficiency is low, the uniformity is poor, and there is a risk of local scalding. The heating effect of the present invention is caused by the vibration, collision and frictional heat generation of ions in the ionic TPU-PVA composite hydrogel between the interdigitated electrodes. Within 10 s after applying a high-frequency alternating electric field, a uniform heating effect can be achieved. As can be seen from Figure 6 d), the two selected temperature measurement points simultaneously increase in temperature after applying a high-frequency alternating electric field, proving that the heating patch of the present invention has an overall heating effect, higher heating efficiency and more uniform heating.

[0065] The structure of the ionic TPU-PVA composite hydrogel prepared in the present invention embedded with a patterned stretchable flexible electrode based on liquid metal ink is as Figure 1 shown. By applying a high-frequency alternating electric field, the high-frequency vibration of the conductive amyloid fibers is driven to achieve the precise release of the loaded drug. With the help of the thermal effect generated by the ion vibration and friction induced by the high-frequency alternating electric field in the composite hydrogel, the release and diffusion of the drug in the composite hydrogel are promoted. Compared with the traditional stimulus-responsive hydrogel, the release speed is faster, and by changing the structural parameters of the interdigitated electrodes, or adjusting the high-frequency alternating electric field frequency, electric field intensity, etc., on-demand precise regulation can be achieved.

[0066] The embodiments described above are only a part of the embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative efforts shall fall within the scope of protection of the present invention.

Claims

1. A preparation method of a hydrogel-based flexible liquid metal electrode for inducing drug controlled release, characterized in that, The preparation method includes the following steps: (1) Prepare a liquid metal ink, print the liquid metal ink onto an electrospun membrane to obtain an electrode to be activated, freeze the electrode to be activated and then activate it under pressure to obtain a flexible liquid metal electrode; (2) Prepare an amyloid fiber solution, stir and dissolve the amyloid fiber solution with a conductive material, drug particles, salt powder, and polyvinyl alcohol to obtain a pre-gel solution; (3) Cover the flexible liquid metal electrode with the pre-gel solution through a film-forming process, and repeat the freeze-thaw process to obtain a hydrogel-based flexible liquid metal electrode.

2. The preparation method according to claim 1, characterized in that, The method for preparing the liquid metal ink includes the following steps: fully mix and dissolve polyvinylpyrrolidone and n-hexanol to obtain a polyvinylpyrrolidone / n-hexanol solution, add liquid metal and then perform ultrasonic treatment to obtain the liquid metal ink; Preferably, the liquid metal is selected from one or more of gallium, eutectic gallium-indium alloy, and gallium-indium-tin alloy; preferably, the concentration of polyvinylpyrrolidone in the polyvinylpyrrolidone / n-hexanol solution is 3% - 7%; further preferably, the mass ratio of the liquid metal to the polyvinylpyrrolidone / n-hexanol solution is 1 - 5:

1.

3. The preparation method according to claim 1, characterized in that, The method for preparing the electrospun membrane includes the following steps: fully mix and dissolve an elastomer with an organic solvent to obtain an electrospinning solution, and perform electrospinning on the electrospinning solution to obtain the electrospun membrane; Preferably, the elastomer is selected from one or more of thermoplastic polyurethane, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, and poly(styrene-block-butadiene-block-styrene) copolymer; Preferably, the organic solvent is selected from one or two of N,N-dimethylformamide and tetrahydrofuran; preferably, the concentration of the elastomer in the electrospinning solution is 15 - 25 wt%; Preferably, the thickness of the electrospun membrane is 20 - 400 μm.

4. The preparation method according to claim 1, wherein: In step (1), the freezing temperature is -20 to -80 °C, and the pressure for activation under pressure is 5 - 80 MPa.

5. The preparation method according to claim 1, characterized in that, The method for preparing the amyloid fiber solution includes the following steps: fully mix and dissolve a protein powder with deionized water to obtain a protein powder solution, adjust the pH of the protein powder solution to acidic, and perform water bath heating and stirring to obtain the amyloid fiber solution; Preferably, the protein powder is selected from one or more of soy protein powder, pea protein powder, oat protein powder, chickpea protein powder, mung bean protein powder, rice protein powder, whey protein isolate, and egg white protein powder; Preferably, the pH of the protein powder solution is adjusted to 2 - 3; Preferably, the water bath heating temperature is 80 - 95 °C, and the heating time is 10 - 24 h.

6. The preparation method according to claim 1, characterized in that: The salt powder is selected from one or more of sodium chloride, calcium chloride, zinc chloride, magnesium chloride, potassium chloride, etc.

7. According to the preparation method described in claim 1, characterized in that: The conductive material is selected from one or more of polypyrrole, gold nanoparticles, silver nanoparticles, and carbon nanotubes.

8. A hydrogel-based flexible liquid metal electrode for inducing drug controlled release prepared by the preparation method according to any one of claims 1 - 7.

9. An induced drug particle controlled release system, characterized in that, The system includes a high-frequency alternating electric field generator and the hydrogel-based flexible liquid metal electrode according to claim 8.

10. A method for inducing controlled release of drug particles, characterized in that: The method includes the step of applying a high-frequency alternating electric field to the hydrogel-based flexible liquid metal electrode as described in claim 8.

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