Time-space acoustic metamaterial patch and preparation method and application thereof

Abstract

The invention discloses a time-space acoustic metamaterial patch as well as a preparation method and application thereof. The time-space acoustic metamaterial patch comprises a piezoelectric substrate, a focused acoustic wave transducer and an acoustic impedance matching layer which are sequentially arranged from bottom to top, the focused acoustic wave transducer comprises more than two interdigital electrode pairs, and each interdigital electrode pair can be activated through an alternating frequency signal and generate a focused acoustic field; the acoustic impedance matching layer is a micrometer scale conical structure array which is photocrosslinked layer by layer through photoetching printing, and impedance matching of the acoustic sensor and the tissue can be achieved. The multiple interdigital electrodes have the function of focusing ultrasonic energy in a time-space mode, and the acoustic impedance matching layer can better transmit sound wave energy and load active substances with various treatment functions, so that multiple management of heat, inflammation and healing of low-temperature wounds is achieved. The patch based on the acoustic metamaterial has the advantages of multiple functions, digitalization, controllability, accurate treatment, convenience, reliability and the like.

Description

Technical Field

[0001] The present invention belongs to the field of ultrasonic bioelectronics, and particularly relates to acoustic metamaterial patches and their applications. In particular, it relates to a spatio-temporal acoustic metamaterial patch and its preparation method. This patch can be applied to technologies and clinical fields such as precise spatio-temporal temperature regulation, efficient painless transdermal drug delivery, and skin wound microenvironment regulation and treatment. Background Art

[0002] Wound healing is a dynamic multi-stage process involving inflammation, proliferation, and remodeling, presenting a multi-factorial therapeutic challenge. A large variety of patches have been used to promote wound healing because of their ease of use and reduced risk of infection. However, traditional wound patches mainly focus on delivering bioactive agents but often fail to adapt to the dynamic wound microenvironment or effectively affect deep tissues. As a pressure wave, ultrasound can also have a physical impact on tissues, enabling a series of therapeutic applications. Compared with traditional patches, ultrasound patches have unique advantages, such as non-invasively regulating cellular processes, enhancing drug delivery to deep tissue sites, and accelerating wound healing.

[0003] Ultrasound has also been used for mechanical removal of kidney stones, direct regulation of neuronal and immune activities, etc. Despite some progress, each ultrasound-mediated patch requires a unique shape, configuration, and ultrasound energy intensity to achieve the desired effect, making it difficult to standardize different ultrasound patches. In addition, existing ultrasound patches usually lack versatility and are insufficient to meet the complex requirements of multi-factorial treatment. Therefore, the application of ultrasound patches with high-resolution energy control and multiple therapeutic capabilities in the management of complex diseases (such as wound healing) has rarely been explored.

[0004] As a promising tool, acoustic metamaterials are artificial engineering structures that can precisely guide sound waves. Acoustic metamaterials with specified resonators or patterned surfaces can significantly enhance the capabilities of ultrasound patches in terms of ultrasound energy control and multifunctionality. Therefore, the introduction of acoustic metamaterials is expected to endow ultrasound patches with more functions and therapeutic capabilities, enabling advanced wound treatment. Summary of the Invention

[0005] Object of the Invention: The technical problem to be solved by the present invention is to provide an ultrasound patch with multiple therapeutic functions and controllability, which can be used for the management of deep-infected wounds, aiming at the disadvantages of traditional ultrasound patches such as difficult sound field control and few functions.

[0006] To achieve the above object of the invention, the technical solutions adopted by the present invention are as follows: A spatio-temporal acoustic metamaterial patch, comprising a piezoelectric substrate, a focused acoustic wave transducer, and an acoustic impedance matching layer arranged in sequence from bottom to top; the focused acoustic wave transducer is two or more pairs of interdigital electrode pairs, and each interdigital electrode pair can be activated by a cross-frequency signal respectively to generate a focused sound field; the acoustic impedance matching layer is an array of micron-scale conical structures cross-linked layer by layer through photolithographic printing, which can achieve impedance matching between the acoustic sensor and the tissue.

[0007] Further, the interdigital electrode pairs are multiple independent structures, and the wavelengths of each interdigital electrode pair can be independently adjusted, and the wavelength is 80 microns - 2 millimeters. By increasing or decreasing the number of activated interdigital electrode pairs, the height of the focused sound field will be correspondingly increased and decreased.

[0008] Preferably, the interdigital electrode pairs are 5 pairs of interdigital electrode pairs that can be excited respectively, and the wavelength is 1000 microns.

[0009] Preferably, the focused acoustic wave transducer is disc-shaped, and the power output part angle of a single interdigital electrode of the transducer is 60 - 180 degrees. This angle will affect the size and distribution uniformity of the focused energy.

[0010] Preferably, the acoustic impedance matching layer is an array of quadrangular conical structures, made of a photocurable material; the height of the quadrangular conical structure is 1 / 4 of the wavelength of the interdigital electrode pair, that is, 250 µm; the bottom width of the quadrangular conical structure is 1 / 20 - 1 / 4 of the wavelength of the interdigital electrode pair; preferably 100 µm. The spacing between each conical structure is the same as the base width. It can achieve an impedance matching mode without interference in the sound field.

[0011] Further, the present invention also provides a preparation method for the above spatio-temporal acoustic metamaterial patch, comprising the following steps: (1) Construct a mask plate for a multiple independently activatable focused acoustic wave transducer, use standard soft lithography and lift-off processes to manufacture a multiple independently activatable reconfigurable acoustic metamaterial substrate, then use electron beam evaporation method to deposit a metal conductive layer including a chromium layer and a gold layer on the piezoelectric substrate, and finally wash away the excess metal layer with acetone to obtain a focused acoustic wave transducer with two or more pairs of interdigital electrode pairs; (2) Construct a quadrangular cone structure model, then use slicing software to perform height and horizontal slicing on the quadrangular cone structure model, and import it into a 3D maskless printer; stick the reconfigurable focused acoustic wave transducer obtained in step (1) on the printing platform, and perform alignment operations in the printer to in-situ layer-by-layer print a conical array on the transducer, thereby obtaining the acoustic impedance matching layer.

[0012] Specifically, in step (1), the piezoelectric substrate is a lithium niobate crystal, and the thickness is 0.3 - 2 mm.

[0013] Preferably, in step (1), there are 5 pairs of interdigital electrode pairs, each of which can be independently activated, and the wavelength is 1000 microns.

[0014] Preferably, in step (2), the material of the square pyramid structure in the acoustic impedance matching layer is any one or a mixture of two or more of epoxy acrylate, polyurethane acrylate resin, polyester acrylate resin, amino acrylate resin, polyethylene glycol diacrylate, and methacrylate gelatin.

[0015] Preferably, the size of the square pyramid structure array is 2×2 cm, and the center of the array is located at the center of the interdigital electrode.

[0016] Furthermore, the present invention also claims the application of the above-mentioned spatio-temporal acoustic metamaterial patch in the preparation of a transdermal drug delivery patch, and drugs are carried outside the conical array of the acoustic impedance matching layer. Beneficial effects

[0017] (1) The present invention mainly uses acoustic metamaterials to prepare a patch, which has the advantages of simple method, convenient operation, high repeatability, and can accurately control the sound field structure. The multiple interdigital electrodes have the function of focusing ultrasonic energy in space and time, and the acoustic impedance matching layer can better transmit acoustic wave energy and load active substances with various therapeutic functions, so as to realize the multiple management of heat, inflammation, and healing of low-temperature wounds. This patch based on acoustic metamaterials has the advantages of multi-function, digital controllability, precise treatment, convenience and reliability.

[0018] (2) The present invention designs an ultrasonic patch with an acoustic impedance matching layer, which is wearable and easy to attach to the skin, can reduce the acoustic impedance mismatch between the hard transducer and soft tissue, and realizes the efficient conduction of sound waves.

[0019] (3) The conical array of the acoustic impedance matching layer prepared by the present invention can carry drugs for transdermal drug delivery, and can realize painless, safe, fast, and autonomous drug delivery, with strong practicability. Description of the drawings

[0020] The following further specifically describes the present invention in conjunction with the drawings and specific embodiments, and the above and / or other advantages of the present invention will become clearer.

[0021] Figure 1 Schematic diagram of the preparation process of the acoustic metamaterial patch.

[0022] Figure 2 It is the design and preparation process of the reconfigurable focused acoustic wave transducer.

[0023] Figure 3 It is the design and preparation process of the acoustic impedance matching layer.

[0024] Figure 4 Experimental application effect of the acoustic metamaterial patch prepared in Example 3. Specific implementation manners

[0025] The present invention can be better understood according to the following embodiments.

[0026] See Figure 1 , which is a schematic diagram of the preparation process of the spatio-temporal acoustic metamaterial patch of the present invention, specifically including the following steps: (1) Construct a mask plate of a multi-layer independently activatable focused acoustic wave transducer, manufacture a reconfigurable acoustic metamaterial substrate by using standard soft lithography and lift-off processes, then deposit a metal conductive layer including a chromium layer and a gold layer on a piezoelectric substrate by using an electron beam evaporation method, and finally elute the excess metal layer with acetone to obtain a focused acoustic wave transducer having two or more pairs of interdigital electrode pairs.

[0027] (2) Construct a quadrangular pyramid structure model, then perform height-horizontal slicing on the quadrangular pyramid structure model by using slicing software, and import it into a 3D maskless printer; attach the reconfigurable focused acoustic wave transducer in step (1) to the printing platform, and perform an alignment operation in the printer to in-situ layer-by-layer print a conical array on the transducer, thereby obtaining an acoustic impedance matching layer.

[0028] As Figure 1 shown, wherein, A is a schematic diagram of the components of the acoustic metamaterial patch; B is a maskless lithography acoustic impedance matching layer on the in-situ transducer substrate; C is a finished product display of the layer-by-layer lithography steps and the patch, the scale bar is 4 mm; D is a scanning electron microscope characterization of the cross-sectional structure of the acoustic metamaterial patch, including the transducer substrate and the quadrangular pyramid structure, the scale bar is 100 μm. E is a scanning electron microscope picture of the acoustic impedance matching layer based on the conical array, the scale bar is 250 μm. Example 1

[0029] Preparation of the acoustic metamaterial patch: (1) Preparation of the reconfigurable focused acoustic wave transducer Design a reconfigurable focused acoustic wave transducer in AutoCAD software, and design the angle of the power output part of a single interdigital electrode of the transducer to be 60 degrees. After standard soft lithography steps: spin coating (600 r / min for 20 seconds and 4000 r / min for 40 seconds), pre-baking (100 °C for 5 minutes), exposure (9.1 mJ, 6.3 seconds), development (45 seconds). Then use an electron beam evaporator to deposit a 5-nm-thick chromium layer and a 50-nm gold layer on the lithographed lithium niobate substrate. Finally, elute the excess metal layer with acetone to obtain a reconfigurable focused acoustic wave transducer.

[0030] (2) Preparation of the conical array acoustic impedance matching layer: Use 3D software to model a square pyramid structure with a height of 250 microns and a base width of 100 microns. Then use slicing software to slice the structure horizontally in the height direction and import it into a 3D maskless printer. At the same time, the reconfigurable focused acoustic wave transducer is attached to the printing platform, and alignment operations are performed inside the printer to layer-print a resin-derived conical array in-situ on the transducer, thereby obtaining an acoustic impedance matching layer. Example 2

[0031] Preparation of the acoustic metamaterial patch: (1) Preparation of the reconfigurable focused acoustic wave transducer Design the reconfigurable focused acoustic wave transducer in AutoCAD software, and design the angle of the power output part of a single interdigital electrode of the transducer to be 120 degrees. After standard soft lithography steps: spin coating (600 r / min for 20 seconds and 4000 r / min for 40 seconds), pre-baking (100 degrees Celsius for 5 minutes), exposure (9.1 mJ, 6.3 seconds), development (45 seconds). Then use an electron beam evaporator to deposit a 5-nanometer-thick chromium layer and a 50-nanometer-thick gold layer on the lithographed lithium niobate substrate. Finally, use acetone to wash away the excess metal layer to obtain the reconfigurable focused acoustic wave transducer.

[0032] (2) Preparation of the acoustic impedance matching layer of the conical array: Use 3D software to model a square pyramid structure with a height of 500 microns and a base width of 250 microns. Then use slicing software to slice the structure horizontally in the height direction and import it into a 3D maskless printer. At the same time, the reconfigurable focused acoustic wave transducer is attached to the printing platform, and alignment operations are performed inside the printer to layer-print a resin-derived conical array in-situ on the transducer, thereby obtaining an acoustic impedance matching layer. Example 3

[0033] Preparation of the acoustic metamaterial patch: (1) Preparation of the reconfigurable focused acoustic wave transducer Design the reconfigurable focused acoustic wave transducer in AutoCAD software, and design the angle of the power output part of a single interdigital electrode of the transducer to be 180 degrees. After standard soft lithography steps: spin coating (600 r / min for 20 seconds and 4000 r / min for 40 seconds), pre-baking (100 degrees Celsius for 5 minutes), exposure (9.1 mJ, 6.3 seconds), development (45 seconds). Then use an electron beam evaporator to deposit a 5-nanometer-thick chromium layer and a 50-nanometer-thick gold layer on the lithographed lithium niobate substrate. Finally, use acetone to wash away the excess metal layer to obtain the reconfigurable focused acoustic wave transducer.

[0034] (2) Preparation of the acoustic impedance matching layer of the conical array: A square pyramid structure with a height of 1000 microns and a base width of 500 microns was constructed using 3D software modeling. Then, the structure was sliced horizontally in the height direction using slicing software and imported into a 3D maskless printer. At the same time, a reconfigurable focused acoustic wave transducer was attached to the printing platform, and alignment operations were performed inside the printer to layer-print a resin-derived cone array in situ on the transducer, thereby obtaining an acoustic impedance matching layer.

[0035] Combined with Figure 2 As shown in the figure, in the figure, A are the design parameters of the reconfigurable focused acoustic wave transducer, B are the standard soft lithography and metal layer deposition steps, and C are examples of reconfigurable focused acoustic wave transducers at different angles. The digital electrode design and the use of soft lithography in the present invention can standardize and mass-produce the preparation of commercial ultrasonic transducers; it can also make the sound field of the ultrasonic transducer more accurate and dynamically controllable; it can also bring more possibilities, including the function of focusing the sound field energy.

[0036] Combined with Figure 3 As shown in the figure, in the figure, A are the design parameters of the acoustic impedance matching layer, B is a schematic diagram of the maskless lithography process, C are examples of acoustic impedance matching layers of different sizes, and the scale bar is 5 mm. The maskless lithography in the present invention directly prepares an acoustic impedance matching layer on the ultrasonic transducer, which has high-precision controllability, convenience, and design multi-dimensionality. Example 4

[0037] Taking the acoustic metamaterial patch in Example 3 as an example, a 180-degree reconfigurable focused acoustic wave transducer and an acoustic impedance matching layer with a height of 250 microns were used to conduct an application effect characterization experiment, such as Figure 4 As shown in the figure, in the figure, the scale bar of A is 4 mm; B are the ultrasonic parameters; C is the spatially controllable heating characterization; D is the application in wound healing, including drug management.

[0038] It can be seen that Figure 4 By analyzing the gradient impedance distribution of the stepped cone structure along the height direction in B, the applicability of the stepped cone structure as an acoustic impedance transformer was demonstrated for the first time. As shown in Figure 4 In B (upper left), the impedance gradually decreases from 30 MRayl to 1.5 MRayl, effectively reducing the energy loss between the hard piezoelectric substrate and the soft biological tissue. The integration of the gradient impedance matching layer significantly improves the ultrasonic transmission in the wide frequency range ( Figure 4 lower left in B). In particular, at 4 MHz, the transmission coefficient increases by about 15 dB, while in the absence of a matching layer, the transmission efficiency is still very low (-22.4 dB).

[0039] In addition, numerical simulations confirm that the cone array design with a height much smaller than λ minimizes the sound field distortion ( Figure 4 right).

[0040] FromFigure 4 C It can be seen that by adjusting the input voltage and duty cycle, the temperature can be precisely adjusted within a range of 10 °C ( Figure 4 C left). Programmable heating can be achieved through digital signal control ( Figure 4 right).

[0041] Figure 4 D Fluorescence imaging was used to characterize the release behavior of the rhodamine RhB dye. The patch loaded with RhB was inserted into an agar gel (length: 1 cm; width: 1 cm; height: 5 mm), and then ultrasonic stimulation (600 mVpp, 4.0 MHz) was performed for 30 minutes. We recorded the release of the RhB fluorescent dye under a fluorescence microscope. The released RhB fluorescence was analyzed by ImageJ software. Quantitative analysis confirmed that the dye release efficiency was significantly improved when the matching layer was present.

[0042] The present invention provides an idea and method for a spatio-temporal acoustic metamaterial patch, its preparation method and application. There are many methods and ways to specifically implement this technical solution. The above description is only a preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention. Each component not clearly defined in this embodiment can be implemented by existing technologies.

Claims

1. A spatio-temporal acoustic metamaterial patch, characterized in that It includes a piezoelectric substrate, a focused acoustic wave transducer, and an acoustic impedance matching layer arranged successively from bottom to top; the focused acoustic wave transducer is two or more pairs of interdigital electrode pairs, and each interdigital electrode pair can be activated separately by an alternating frequency signal to generate a focused sound field; the acoustic impedance matching layer is an array of micron-scale conical structures formed by layer-by-layer photocrosslinking through photolithographic printing, which can achieve impedance matching between the acoustic sensor and the tissue.

2. The spatio-temporal acoustic metamaterial patch according to claim 1, wherein The interdigital electrode pairs are multiple independent structures, and the wavelength of each interdigital electrode pair can be independently adjusted, with the wavelength ranging from 80 microns to 2 millimeters.

3. The spatio-temporal acoustic metamaterial patch according to claim 2, wherein The interdigital electrode pairs are 5 pairs of interdigital electrode pairs that can be excited separately, and the wavelength of each is 1000 microns.

4. The spatio-temporal acoustic metamaterial patch according to claim 1, characterized in that, The focused acoustic wave transducer is disc-shaped, and the angle of the power output part of a single interdigital electrode of the transducer is 60 - 180 degrees.

5. The spatio-temporal acoustic metamaterial patch according to claim 1, wherein The acoustic impedance matching layer is an array of quadrangular conical structures, made of a photocurable material; the height of the quadrangular conical structure is 1 / 4 of the wavelength of the interdigital electrode pair, and the bottom width of the quadrangular conical structure is 1 / 20 - 1 / 4 of the wavelength of the interdigital electrode pair.

6. The preparation method of the spatio-temporal acoustic metamaterial patch according to claim 1, characterized in that, It includes the following steps: (1) Construct a mask plate of a multiple independently activatable focused acoustic wave transducer, use standard soft lithography and lift-off processes to fabricate a multiple independently activatable reconfigurable acoustic metamaterial substrate, then use electron beam evaporation method to deposit a metal conductive layer including a chromium layer and a gold layer on the piezoelectric substrate, and finally elute the excess metal layer with acetone to obtain a focused acoustic wave transducer with two or more pairs of interdigital electrode pairs; (2) Construct a quadrangular cone structure model, then use slicing software to slice the quadrangular cone structure model in the height horizontal direction and import it into a 3D maskless printer; attach the reconfigurable focused acoustic wave transducer obtained in step (1) to the printing platform, and perform alignment operations in the printer to in-situ layer-by-layer print a conical array on the transducer, thereby obtaining the acoustic impedance matching layer.

7. The preparation method of the spatio-temporal acoustic metamaterial patch according to claim 6, characterized in that, In step (1), the piezoelectric substrate is a lithium niobate crystal with a thickness of 0.3 - 2 mm.

8. The preparation method of the spatio-temporal acoustic metamaterial patch according to claim 6, characterized in that, In step (1), the interdigital electrode pairs are 5 pairs, and each interdigital electrode pair can be independently activated, with a wavelength of 1000 microns for each.

9. The preparation method of the spatio-temporal acoustic metamaterial patch according to claim 6, characterized in that, In step (2), the material of the quadrangular cone structure in the acoustic impedance matching layer is any one or a mixture of two or more of epoxy acrylate, polyurethane acrylate resin, polyester acrylate resin, amino acrylate resin, polyethylene glycol diacrylate, and methacrylate gelatin.

10. Use of the spatio-temporal acoustic metamaterial patch according to claim 1 in the preparation of a drug-loaded transdermal patch, characterized in that, Drugs are carried on the outside of the conical array of the acoustic impedance matching layer.

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