Hydrogel-based flexible liquid metal electrode for inducing drug controlled release and preparation method and application thereof

Abstract

This invention provides a hydrogel-based flexible liquid metal electrode for inducing controlled drug release, its preparation method, and its applications. The hydrogel-based flexible liquid metal electrode incorporates conductive amyloid fibers loaded with drug particles doped into a hydrogel film substrate, and embeds patterned, stretchable, flexible interdigital electrodes based on liquid metal ink. This invention provides a novel method for inducing controlled drug release. It achieves precise drug release by driving the conductive amyloid fibers to vibrate at high frequency using a high-frequency alternating electric field. Furthermore, the release and diffusion of the drug are promoted by the ion vibrations induced by the high-frequency alternating electric field in the hydrogel and the thermal effect generated by friction. The drug release rate can be intelligently controlled according to individual usage needs, making it suitable for multiple application scenarios such as pain relief, wound management, and cosmetic skincare. This overcomes the limitations of existing technologies, which are characterized by single functionality and inability to precisely control the release on demand.

Description

Technical Field

[0001] This invention belongs to the field of flexible electronic materials technology, and in particular relates to a hydrogel-based flexible liquid metal electrode for inducing controlled drug release, its preparation method, and its application. Background Technology

[0002] Hydrogels are considered ideal drug delivery carriers due to their excellent biocompatibility, tunable physicochemical properties, and biomimetic three-dimensional network structure. Their high water content can mimic the natural extracellular matrix environment, providing a stable loading space for pharmacological functional factors. Furthermore, by introducing responsive groups to physical or chemical stimuli such as temperature, light, and pH, hydrogels can achieve environment-triggered drug release, demonstrating great application potential in biomedical fields such as chronic disease treatment and wound repair. However, most current drug control release systems based on stimulus-responsive hydrogels rely on passive interactions between the material and the environment, with release behavior limited by random fluctuations in local physiological conditions, making precise on-demand control difficult.

[0003] Chinese invention patent CN112370567A discloses a hydrogel active dressing with antibacterial and anti-inflammatory functions. It utilizes the thermosensitive nature of poly(N-isopropylacrylamide) to prepare thermosensitive poly(N-isopropylacrylamide) hydrogel microspheres. However, due to its phase transition hysteresis near body temperature, it is prone to causing burst drug release. Chinese invention patent CN116444818A discloses a pH-responsive hydrogel with shape memory function, its preparation method, and its application. However, pH-responsive hydrogels lack selectivity in complex body fluid environments, potentially leading to non-targeted release. These limitations severely restrict the application of hydrogels as drug delivery carriers in precision medicine.

[0004] The rapid development of flexible electronics technology has made intelligent drug delivery systems possible. Integrating hydrogels with electronic circuits and directionally inputting external energy such as electricity, light, and magnetism further transforms this energy into changes in the local microenvironment within the hydrogel, dynamically regulating the diffusion rate of drug molecules and thus achieving precise drug release. This active control strategy based on external energy not only avoids the hysteresis problem of traditional stimulus-responsive hydrogels but also provides higher spatiotemporal precision and repeatability for drug release. However, the incompatibility of the hydrogel-flexible electronics interface and issues related to functional integration pose challenges to the realization of actively regulated, on-demand drug delivery systems. Summary of the Invention

[0005] In view of this, the present invention aims to propose a hydrogel-based flexible liquid metal electrode for inducing drug release, its preparation method and application, which can intelligently control the drug release rate according to personalized usage needs, overcoming the limitation of traditional drug release methods that cannot be precisely controlled as needed.

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

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

[0008] (1) Prepare liquid metal ink, print the liquid metal ink onto an electrospinning film to obtain an electrode to be activated, freeze the electrode to be activated and then pressurize it to obtain a flexible liquid metal electrode;

[0009] (2) Prepare amyloid cellulose solution by stirring and dissolving the amyloid cellulose solution with conductive material, drug particles, salt powder and polyvinyl alcohol (PVA), and allowing it to stand to defoam, thus obtaining a pregel solution;

[0010] (3) The pregel liquid is covered with the flexible liquid metal electrode by a film forming process and penetrated into the pores of the electrospinning membrane. The freeze-thaw process is repeated to obtain the hydrogel-based flexible liquid metal electrode.

[0011] Furthermore, the method for preparing the liquid metal ink includes the following steps: fully mixing and dissolving polyvinylpyrrolidone and n-hexanol to obtain a polyvinylpyrrolidone / n-hexanol solution, adding liquid metal, and then ultrasonically treating to obtain 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% to 7%;

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

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

[0016] Furthermore, liquid metal ink is printed onto an electrospun film using screen printing. The printed shape of the liquid metal ink is interdigitated. By changing the structural parameters of the interdigitated electrodes (interdigitation width, interdigitation spacing, interdigitation length), or adjusting the frequency and intensity of the high-frequency alternating electric field, the release and diffusion rate of drug particles can be changed.

[0017] Furthermore, the method for preparing the electrospun membrane includes the following steps: thoroughly mixing and dissolving the elastomer with an organic solvent to obtain an electrospun solution, and electrospinning the electrospun solution to obtain an 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 elastomer in the electrospinning solution is 15-25 wt%.

[0021] Preferably, the thickness of the electrospun film is 20–400 μm.

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

[0023] Furthermore, the method for preparing the amyloid cellulose solution includes the following steps: thoroughly mixing and dissolving 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 cellulose solution;

[0024] Preferably, the protein powder is selected from one or more of the following: 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.

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

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

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

[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, step coating, and mold coating.

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

[0031] Thirdly, the present invention provides an induced drug particle controlled release system, the system comprising a high-frequency alternating electric field generator and a hydrogel-based flexible liquid metal electrode as described in the second aspect, wherein 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 device.

[0032] Fourthly, the present invention provides a method for inducing controlled release of drug particles, the method comprising the step of applying a high-frequency alternating electric field to a hydrogel-based flexible liquid metal electrode as described in the second aspect; further, the application comprises the following steps: connecting the hydrogel-based flexible liquid metal electrode to a radiofrequency ablation device via a wire, conformally attaching the hydrogel-based flexible liquid metal electrode to the site of action, adjusting the parameters of the radiofrequency ablation device to control the temperature, and regulating the drug particle release rate by means of the temperature.

[0033] Compared with existing technologies, the hydrogel-based flexible liquid metal electrode for inducing controlled drug release, its preparation method, and its application described in this invention have the following advantages:

[0034] (1) The hydrogel-based flexible liquid metal electrode of the present invention provides a novel method for inducing controlled drug release. It achieves precise release of the loaded drug by driving the high-frequency vibration of conductive amyloid fibers through a high-frequency alternating electric field. It also promotes the release and diffusion of the drug in the hydrogel by means of the ion vibration induced by the high-frequency alternating electric field and the heat effect generated by friction. The drug release rate can be intelligently controlled according to individual usage needs. It is suitable for multiple usage scenarios such as pain relief, wound management, and beauty skin care, and overcomes the limitations of the existing technology that has a single function and cannot be precisely controlled as needed.

[0035] (2) The hydrogel-based flexible liquid metal electrode of the present invention can ensure the original precision of the electrode pattern and better consistency by freezing and then pressurizing to activate the liquid metal electrode. The resulting electrode also has high conductivity and stability and can work normally under bending, stretching and other deformations.

[0036] (3) The hydrogel-based flexible liquid metal electrode of the present invention is doped with amyloid fibers in the hydrogel, which improves the mechanical properties of the hydrogel. The electrospun film is used as the skeleton structure, which enhances the mechanical strength of the flexible substrate on the one hand, and facilitates the introduction of patterned liquid metal electrodes on the other hand. This results in a hydrogel-based flexible liquid metal electrode that takes into account biocompatibility, mechanical properties and functionality, and overcomes the problems of high surface tension and poor wettability of liquid metal on the surface of hydrogel.

[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 be conformally attached to the site of action, solving the problems of poor conformability and lack of comfort of traditional drug-loaded patches. Attached Figure Description

[0038] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

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

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

[0041] Figure 3 The diagram shows the elongation at break and Young's modulus of the WPIF-doped PVA hydrogel film, the TPU nanofiber film, and the ion-modulated TPU-PVA hydrogel composite film prepared in Example 1.

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

[0043] Figure 5 The images show physical images, scanning electron microscope images, and conductivity diagrams of patterned stretchable flexible electrodes based on liquid metal ink activated by conventional mechanical sintering methods, where a) is the physical image and scanning electron microscope image of the flexible electrode, and b) is the physical image and scanning electron microscope image of the flexible electrode and its conductivity diagram.

[0044] Figure 6 The figure shows the performance test results of the ionic TPU-PVA composite hydrogel with patterned stretchable flexible interdigitated electrodes based on liquid metal ink prepared in Example 2. In the figure, a) and b) are the drug release at different radio frequency heating temperatures; c) is the infrared thermal imaging at different time points after applying a high frequency alternating electric field; and d) is the temperature change curve of different temperature measurement points over time. Detailed Implementation

[0045] It should be noted that, unless otherwise specified, the embodiments and features described in the present invention can be combined with each other.

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

[0047] Example 1

[0048] This embodiment provides a method for preparing an ionic TPU-PVA composite hydrogel embedded with patterned, stretchable, flexible interdigitated electrodes based on liquid metal ink, comprising the following steps:

[0049] 1) Tetrahydrofuran and N,N-dimethylformamide were mixed at a volume ratio of 1:1, and TPU was added, wherein the concentration of TPU was 20wt%. The mixture was heated and stirred until dissolved to obtain an electrospinning solution. TPU nanofiber membranes were prepared by electrospinning technology.

[0050] 2) Dissolve polyvinylpyrrolidone in n-hexanol with a polyvinylpyrrolidone concentration of 3wt%. Mix 3g of EGaIn (75.5wt% Ga and 24.5wt% In) with 1g of polyvinylpyrrolidone-n-hexanol solution and sonicate using a cell disruptor with an amplitude transformer diameter of 6mm, an ultrasonic power of 300W, a 2s on and 2s off cycle, and an actual working time of 1min to obtain liquid metal ink.

[0051] 3) Liquid metal ink is printed onto a TPU nanofiber membrane using screen printing technology to obtain an electrode to be activated. The electrode to be activated is placed in a refrigerator to freeze, and pressure of 20 MPa is applied to the frozen electrode using a tablet press. The liquid metal is activated to form a conductive path, thus obtaining a patterned stretchable flexible electrode based on liquid metal ink.

[0052] 4) Dissolve whey protein isolate powder in deionized water to a concentration of 2 wt%, adjust the pH of the solution to 2.0, and magnetically stir in an 80℃ water bath for 24 h. Then, stop the fibrillation process by maintaining the solution in an ice-water bath for 20 min to obtain the WPIF solution. Its transmission electron microscopy image is shown below. Figure 2 As shown.

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

[0054] 6) Use spin coating to cover the electrode part with the pregel liquid and penetrate into the pores of TPU nanofibers. The spin coating speed 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. Repeat the freeze-thaw process 3 times to obtain an ionic TPU-PVA composite hydrogel with a patterned stretchable flexible electrode based on liquid metal ink embedded in it.

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

[0057] The mechanical properties of the WPIF-doped PVA hydrogel film, TPU nanofiber film, and ionomer-modified TPU-PVA composite hydrogel film prepared in Example 1 were tested respectively. The test results are as follows: Figure 3 As shown, adding TPU nanofiber membranes as a supporting framework to PVA hydrogel membranes improves the elongation at break and Young's modulus of ionotropic TPU-PVA composite hydrogel membranes.

[0058] The liquid metal activation method used in Example 1 was compared with the conventional mechanical sintering method, and the results are as follows: Figure 4 , Figure 5 As shown. 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 this invention can ensure the original precision of the electrode pattern, and the resulting electrode also has high conductivity and consistency.

[0059] Example 2

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

[0061] The preparation method of the ionic TPU-PVA composite hydrogel in this embodiment is basically the same as that in Example 1, except that the electrode pattern is interdigitated, with an interdigitation quantity of 11, an interdigitation width of 1.4 mm, and an interdigitation spacing of 2.0 mm. After the electrode is activated, leads are attached to the pins. After obtaining the pregel solution in step 5), 0.3 wt% of Rhodamine B is added as a model drug, mixed evenly, and then injected into a mold with a thickness of 1.3 mm, so that the pregel solution covers the electrode part and penetrates into the pores of the TPU nanofiber membrane. The freeze-thaw cycle is performed according to step 7) of Example 1 to obtain the ionic TPU-PVA composite hydrogel embedded with patterned stretchable flexible interdigitated electrodes based on liquid metal ink.

[0062] Prepare a 1.5 wt% agar solution, pour it into a mold, and let it stand and cool at room temperature until the gel forms to obtain an agar gel that simulates human tissue.

[0063] A radiofrequency ablation instrument was connected via wires to apply a high-frequency alternating electric field. Ionic TPU-PVA composite hydrogel was conformally attached to the agar surface. The instrument was set to temperature control mode, with temperatures adjusted to 45℃ and 50℃ respectively. No high-frequency alternating electric field was applied to the control group. Tests were conducted at room temperature. The drug release from the drug-loaded patch was captured on images at different time points, and the images were processed using ImageJ software to calculate fluorescence intensity. The results are shown below. Figure 6 a) Figure 6 As shown in b), the fluorescence intensity increases with increasing temperature, indicating that drug release increases, demonstrating that the drug release rate can be controlled by adjusting the temperature.

[0064] The instrument was set to power mode, and the heating effect of the ionic TPU-PVA composite hydrogel was captured using a thermal imager. The results are as follows: Figure 6 As shown in c). Conventional resistive heating pads, when connected to a DC power supply, generate Joule heat at the electrodes, which is then transferred to the non-electrode parts of the pad via thermal conduction. This results in low heating efficiency, poor uniformity, and a risk of localized burns. In contrast, the heating effect of this invention is due to the vibration and collision of ions in the ionic TPU-PVA composite hydrogel between the interdigital electrodes, generating heat through friction. A uniform heating effect can be achieved within 10 seconds after applying a high-frequency alternating electric field. Figure 6 d) It can be seen that the temperature of the two selected temperature measuring points rises simultaneously after a high-frequency alternating electric field is applied, proving that the heating patch of the present invention has the effect of overall heating, with higher heating efficiency and more uniform heating.

[0065] The ionotropic TPU-PVA composite hydrogel structure prepared by this invention, which incorporates patterned, stretchable, flexible electrodes based on liquid metal ink, is as follows: Figure 1 As shown, by applying a high-frequency alternating electric field, the conductive amyloid fibers are driven to vibrate at high frequency to achieve precise release of the loaded drug. The release and diffusion of the drug in the composite hydrogel are promoted by the ion vibration induced by the high-frequency alternating electric field and the thermal effect generated by friction. Compared with the traditional stimulus-responsive hydrogel, the release rate is faster. Furthermore, by changing the structural parameters of the interdigitated electrodes or adjusting the frequency and intensity of the high-frequency alternating electric field, precise control can be achieved as needed.

[0066] The embodiments described above are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

Claims

1. A method for preparing a hydrogel-based flexible liquid metal electrode for inducing drug controlled release, characterized in that, The preparation method includes the following steps: (1) Prepare liquid metal ink, print the liquid metal ink onto an electrospinning film to obtain an electrode to be activated, freeze the electrode to be activated and then pressurize it to obtain a flexible liquid metal electrode. The preparation method of 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 sonicate to obtain liquid metal ink. The liquid metal is a eutectic gallium indium alloy. The preparation method of the electrospinning film includes the following steps: fully mix and dissolve an elastomer and an organic solvent to obtain an electrospinning solution, electrospin the electrospinning solution to obtain an electrospinning film. The elastomer is thermoplastic polyurethane. (2) Prepare amyloid cellulose solution by stirring and dissolving the amyloid cellulose solution with conductive material, drug particles, salt powder and polyvinyl alcohol to obtain a pregel solution. The preparation method of the amyloid cellulose solution includes the following steps: mixing and dissolving 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 an amyloid cellulose solution. The protein powder is whey protein isolate powder and the salt powder is sodium chloride. (3) The pregel liquid is coated onto the flexible liquid metal electrode by spin coating and the freeze-thaw cycle is repeated to obtain the hydrogel-based flexible liquid metal electrode.

2. The production method according to claim 1, characterized by, The concentration of polyvinylpyrrolidone in the polyvinylpyrrolidone / n-hexanol solution is 3%~7%.

3. The production method according to claim 1, characterized by, The mass ratio of liquid metal to polyvinylpyrrolidone / n-hexanol solution is 1-5:

1.

4. The method of claim 1, wherein, The organic solvent is selected from one or two of N,N-dimethylformamide and tetrahydrofuran.

5. The preparation method according to claim 4, characterized in that, The concentration of elastomer in the electrospinning solution is 15~25 wt%.

6. The preparation method according to claim 4, characterized in that, The thickness of the electrospun film is 20~400 μm.

7. The method of claim 1, wherein: In step (1), the freezing temperature is -20~-80℃ and the pressure for activation is 5-80 MPa.

8. The preparation method according to claim 1, characterized in that, Adjust the pH of the protein powder solution to 2-3.

9. The preparation method according to claim 1, characterized in that, The water bath heating temperature is 80~95℃, and the heating time is 10-24 h.

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

11. A hydrogel-based flexible liquid metal electrode for inducing controlled drug release, prepared by any one of claims 1-10.

12. A controlled-release system for induced drug particles, characterized in that, The system includes a high-frequency alternating electric field generator and a hydrogel-based flexible liquid metal electrode as described in claim 11.

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