Photoacoustic multimodal neuromodulation detection device

Abstract

The present application relates to a kind of photoacoustic multimodal nerve regulation detection device, the device includes: at least one flexible integrated patch and the external control circuit module of electric connection with flexible integrated patch;Flexible integrated patch includes: flexible substrate, optical module for emitting light signal, focusing ultrasound module for emitting focused ultrasound signal, and the flexible packaging module integrated with them;Focusing ultrasound module and optical module are prepared on the flexible substrate, and are encapsulated by flexible packaging module;External control circuit module is electrically connected with the optical module in flexible packaging module and the focusing ultrasound module by flexible flexible flat cable, for providing driving signal and electric energy to optical module and focusing ultrasound module, to regulate and repair nervous system function, or to enhance the sensitivity of pathogenic protein signal detection.The photoacoustic synergistic regulation device of the present application can break the pathological cascade amplification process in early stage of disease, and greatly improve the treatment effect.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and in particular to a photoacoustic multimodal neural modulation detection device. Background Technology

[0002] Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease are typically characterized by insidious onset, slow progression, complex pathological processes, and difficulty in early identification. Taking Alzheimer's disease as an example, its development is often associated with multiple factors, including abnormal brain metabolism, neuroinflammation, abnormal aggregation of amyloid-β (Aβ), and neural network dysfunction. For these diseases, clinical and research fields need to develop non-invasive, long-term, and reusable neuromodulation techniques, and also improve the sensitivity of relevant biomarker detection to support early screening, disease progression assessment, and evaluation of the effectiveness of neuromodulation.

[0003] Currently, non-invasive neuromodulation technology and biomarker sample pretreatment technology have been extensively studied. Among them, the technology that relies on light and acoustic physical fields to achieve brain modulation and sample pretreatment has application potential due to its advantages of no surgical trauma and high biosafety. However, existing light and acoustic devices generally have problems such as large size and unsuitability for long-term wear.

[0004] Meanwhile, existing sample pretreatment methods for detecting Aβ protein biomarkers related to Alzheimer's disease have significant limitations: large-scale protein aggregation structures can obscure antigen recognition sites, significantly weakening the immune detection response signal; existing processing methods cannot simultaneously meet the requirements of mild biological samples, batch processing repeatability, and detection signal enhancement, which is not conducive to the high-sensitivity detection of trace amounts of early biological samples. Summary of the Invention

[0005] To address or partially address the problems existing in related technologies, this invention provides a photoacoustic multimodal neural modulation detection device.

[0006] This invention provides a photoacoustic multimodal neural modulation detection device, comprising: at least one flexible integrated patch and an external control circuit module electrically connected to the flexible integrated patch; the flexible integrated patch comprises: a flexible substrate, an optical module for emitting light signals, a focused ultrasound module for emitting focused ultrasound signals, and a flexible encapsulation module; the focused ultrasound module and the optical module are disposed on the flexible substrate and encapsulated by the flexible encapsulation module; the external control circuit module is electrically connected to the optical module and the focused ultrasound module within the flexible encapsulation module via a flexible flat cable, for providing driving signals and electrical energy to the optical module and the focused ultrasound module, so that the optical module and the focused ultrasound module work independently or collaboratively according to a preset timing sequence, to regulate and repair the function of the nervous system, or to enhance the sensitivity of pathogenic protein signal detection.

[0007] Furthermore, in the aforementioned photoacoustic multimodal neural modulation detection device, the optical module is composed of multiple light-emitting diode patches arranged in an array; the focused ultrasound module is composed of multiple piezoelectric ceramic sheets arranged in an array.

[0008] Furthermore, in the aforementioned photoacoustic multimodal neural modulation detection device, the piezoelectric ceramic sheets of the focused ultrasound module are arranged in a ring matrix; the light-emitting diode patches of the optical module are arranged in a ring matrix; and the ring diameter of the focused ultrasound module is larger than the ring diameter of the optical module, and the two ring matrices are arranged in concentric circles.

[0009] Furthermore, in the aforementioned photoacoustic multimodal neuromodulation detection device, the annular matrix of the focused ultrasound module and the annular matrix of the optical module are arranged in a staggered manner along the circumference to reduce the mutual occlusion of the piezoelectric ceramic sheet and the light-emitting diode patch in the projection direction, thereby achieving spatial complementarity of the treatment area.

[0010] Furthermore, in the aforementioned photoacoustic multimodal neural modulation detection device, a biocompatible material layer is provided between the optical module and the focused ultrasound module. The biocompatible material layer is used to achieve physical isolation and electrical insulation between the focused ultrasound module and the optical module, and to achieve layered integration between the optical module and the focused ultrasound module.

[0011] Furthermore, in the aforementioned photoacoustic multimodal neural modulation detection device, the optical module and the focused ultrasound module are electrically connected to the flexible flat cable via flexible electrodes; the flexible electrodes are disposed inside the flexible packaging module to adapt to the bending and deformation of the flexible integrated patch.

[0012] Furthermore, in the aforementioned photoacoustic multimodal neural modulation detection device, the optical module is an infrared optical module.

[0013] Furthermore, in the aforementioned photoacoustic multimodal neuromodulation detection device, the focused ultrasound module is composed of multiple independently controlled piezoelectric ceramic sheets; the external control circuit module independently controls the phase and amplitude of each piezoelectric ceramic sheet to achieve focused ultrasound emission at different depths and deflection angles, which is used to non-invasively penetrate the skull and precisely target deep brain regions.

[0014] Furthermore, in the aforementioned photoacoustic multimodal neural modulation detection device, the light-emitting diode is a light-emitting diode patch; the operating wavelength of the light-emitting diode patch is 900nm~1300nm.

[0015] Furthermore, in the aforementioned photoacoustic multimodal neural modulation detection device, the external control circuit module includes a control unit, and a piezoelectric ceramic driving circuit, a light-emitting diode driving circuit, and a power management circuit, which are electrically connected to the control unit respectively; the control unit is used to control the light-emitting diode driving circuit and the piezoelectric ceramic driving circuit to operate in a light-only working mode, an ultrasound-only working mode, or a photoacoustic combined working mode, and in the photoacoustic combined working mode, to control the optical module and the focused ultrasound module to operate in a synchronous output, delayed output, or time-division output mode.

[0016] The present invention has the following beneficial effects: First, this invention integrates an optical module and a focused ultrasound module onto a flexible substrate and fabricates a patch using a flexible encapsulation module, achieving spatiotemporal coupling of two physical fields in the same target area. From a biological perspective, focused ultrasound targets and disaggregates pathogenic protein aggregates at a physical level, while light waves improve microenvironment metabolism at a biochemical level. The combination of the two, i.e., photoacoustic synergistic regulation, can work together in the early stages of disease to interrupt the pathological cascade amplification process, thereby significantly improving the therapeutic effect.

[0017] Secondly, the optical module and the focused ultrasound module are integrated together in a flexible substrate and a flexible packaging module, which can maintain a stable correspondence in spatial position, avoiding the problem of difficulty in aligning the light field and the sound field.

[0018] Third, in this invention, the external control circuit module is externally mounted via a flexible flat cable, which allows the flexible integrated patch to remain thin, soft, and conformable. Therefore, it is not only beneficial for the attachment to the curved surface of the head, long-term use, and stable positioning during sample processing, but also reduces the weight and volume of the wearable component. At the same time, it avoids the risk of thermal damage to the scalp caused by the heat generated by the external control circuit module.

[0019] Fourth, this invention, through ultrasound combined with optical targeting of the right prefrontal AF4 neuromodulation, can significantly reshape the high-frequency rhythm of the occipital lobe of the brain, enhance the excitability of the prefrontal brain region, optimize EEG indicators related to visual working memory, and effectively improve cognitive processing ability.

[0020] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and are not intended to limit the invention. Attached Figure Description

[0021] The above and other objects, features and advantages of the present invention will become more apparent from the more detailed description of exemplary embodiments of the invention in conjunction with the accompanying drawings, wherein the same reference numerals generally represent the same parts in the exemplary embodiments of the invention.

[0022] Figure 1 This is a structural block diagram of the photoacoustic multimodal neural modulation detection device shown in an embodiment of the present invention; Figure 2 This is a line graph illustrating the LED continuous output stability test of the photoacoustic multimodal neural modulation detection device shown in an embodiment of the present invention; Figure 3 This is a test diagram of the ultrasonic stimulation output stability of the photoacoustic multimodal neural modulation detection device shown in an embodiment of the present invention; Figure 4 This is a test diagram of the photoacoustic combined continuous operation stability of the photoacoustic multimodal neural modulation detection device shown in an embodiment of the present invention; Figure 5 These are transmission electron microscope images showing the changes in the morphology of Aβ aggregates before and after photoacoustic combined stimulation of the device shown in the embodiments of the present invention; Figure 6 This is a box plot of ThT detection data of the device shown in the embodiment of the present invention; Figure 7 This is a curve showing the relationship between Aβ42 concentration and OD value under different treatment conditions, as illustrated in the embodiments of the present invention. Figure 8 These are transmission electron microscope images of the morphology of four groups of Aβ aggregates in the device shown in the embodiments of the present invention; Figure 9 This is a comparison of BSA protein electrophoresis bands before and after photoacoustic combined stimulation treatment using the device shown in this embodiment of the invention; Figure 10 This is a schematic diagram of an LED driving circuit shown in an embodiment of the present invention; Figure 11 This is a schematic diagram of the ultrasonic driving circuit shown in an embodiment of the present invention; Figure 12 This is a schematic diagram of the BUCK step-down circuit shown in an embodiment of the present invention; Figure 13 This is a ranking diagram of the importance of EEG features in distinguishing between EEG signals before and after modulation, according to an embodiment of the present invention. Figure 14 This is a diagram showing the changes in brain network functional connectivity using the right frontal AF4 electrode as a seed point in an embodiment of the present invention. Figure 15 This is a graph showing the change in static EEG indicators of visual working memory ability before and after photoacoustic combined modulation according to an embodiment of the present invention.

[0023] Figure 16 This is a graph showing the change in static EEG indicators of visual working memory ability before and after infrared light modulation according to an embodiment of the present invention.

[0024] Figure 17 This is a static EEG graph showing the changes in visual working memory ability before and after ultrasound modulation according to an embodiment of the present invention. Detailed Implementation

[0025] Embodiments of the invention will now be described in more detail with reference to the accompanying drawings. While embodiments of the invention are shown in the drawings, it should be understood that the invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that the invention will be more thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0026] It should be understood that although the terms "first," "second," "third," etc., may be used in this invention to describe various information, this information should not be limited to these terms. These terms are only used to distinguish information of the same type from one another. For example, without departing from the scope of this invention, first information may also be referred to as second information, and similarly, second information may also be referred to as first information. Thus, features defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0027] In the description of this invention, it should be understood that the terms "length", "width", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this invention.

[0028] Unless otherwise explicitly specified and limited, the terms "installation," "connection," "linking," and "fixing," etc., should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral part; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; they can refer to the internal communication of two components or the interaction between two components. Those skilled in the art can understand the specific meaning of the above terms in this invention according to the specific circumstances.

[0029] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The singular forms “a,” “the,” and “the” used in this invention and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term “and / or” as used herein refers to and includes any or all possible combinations of one or more of the associated listed items.

[0030] See Figure 1 This invention provides a photoacoustic multimodal neural modulation detection device.

[0031] The device includes at least one flexible integrated patch 10 and an external control circuit module 20 electrically connected to each flexible integrated patch. The flexible integrated patch 10 serves as the actuator for attaching to or acting on a target area, and the external control circuit module serves as the power supply and signal control terminal.

[0032] In this embodiment, the flexible integrated patch 10 can be attached to the surface of the patient's head for non-invasive neuromodulation; it can also be positioned toward the biological sample to be processed, serving as the photoacoustic preprocessing execution end for Alzheimer's disease-related biomarker protein samples.

[0033] The flexible integrated patch 10 may include a flexible substrate 11, an optical module 12, a focused ultrasound module 13, and a flexible encapsulation module 14. The focused ultrasound module 13 and the optical module 12 are disposed on the flexible substrate 11 and encapsulated by the flexible encapsulation module 14. The optical module 12 is used to emit optical wavelength signals towards the target tissue or sample, and the focused ultrasound module 13 is used to emit ultrasound signals that can form a focal point at a predetermined location. The flexible encapsulation module 14 is used to integrate the flexible substrate 11, the optical module 12, and the focused ultrasound module 13, and the flexible encapsulation module 14 can be in patch shape to facilitate adhesion to the surface of the patient's head.

[0034] In this embodiment, the flexible substrate 11 is used to support various functional units, such as the optical module 12 and the focused ultrasound module 13. Specifically, the flexible substrate 11 can be made of polyimide film, polyurethane film, parylene film, or other polymer materials with flexibility and biocompatibility. The optical module 12 and the focused ultrasound module 13 are disposed on the flexible substrate 11 and are encapsulated by the flexible packaging module 14, thereby forming a thin, flexible, and attachable flexible execution structure. The optical module 12 and the focused ultrasound module 13 can be located in different areas of the same flexible substrate 11, or they can be layered together by an intermediate flexible insulating layer and supported by the flexible substrate 11.

[0035] The flexible packaging module 14 encapsulates the optical module 12, the focused ultrasound module 13, and their electrical connection structures, forming an integral flexible patch structure at the actuator. The flexible packaging module 14 can be formed by hot pressing, bonding, or laminating two layers of biocompatible polymer films to reduce the impact of external liquids, sweat, or sample solutions on the device.

[0036] In specific implementation, the flexible packaging module 14 can be fully encapsulated with a double-layer medical thermoplastic polyurethane (TPU) film, and the flexible packaging module can be achieved by polyimide (PI) composite polyurethane. Alternatively, it can be encapsulated by parylene coating and TPU film composite. Of course, other methods known to those skilled in the art can also be used to achieve flexible packaging, and this embodiment does not limit them in any way.

[0037] The external control circuit module 20 is electrically connected to the optical module 12 and the focused ultrasound module 13 inside the flexible packaging module 14 via a flexible flat cable. It is used to provide drive signals and electrical energy to the optical module 12 and the focused ultrasound module 13 so that the optical module 12 and the focused ultrasound module 13 can work independently or collaboratively according to a preset timing sequence to regulate and repair the function of the nervous system, or to enhance the sensitivity of pathogenic protein signal detection.

[0038] In a preferred embodiment, the optical module 12 in this invention can be an infrared optical module, specifically composed of multiple light-emitting diode patches arranged in an array. This infrared optical module can utilize the second near-infrared window band, with a working wavelength range of 900nm to 1300nm, preferably 1050nm. Infrared light in this band has good scalp and skull penetration, effectively penetrating human brain tissue. On one hand, it can regulate and repair damaged nerve function through photobiological modulation, improving nervous system function; on the other hand, it can precisely excite photoacoustic signals of pathogenic proteins in the brain, significantly improving the sensitivity of pathogenic protein signal detection.

[0039] In one embodiment, the infrared optical module operates at a wavelength of 900 nm; in another embodiment, the infrared optical module operates at a wavelength of 1300 nm; and in yet another embodiment, the infrared optical module operates at a wavelength of 1050 nm.

[0040] In other alternative embodiments, the optical module 12 may also be a non-infrared optical module. Specifically, depending on the different requirements of the detection target, neural modulation intensity, and detection depth, other medical optical emission modules such as visible light optical modules, short-wavelength optical modules, multi-band light source modules, laser scanning modules, or broadband light emission modules may be selected. As long as it can emit light signals for modulation, detection, repair, or auxiliary modulation to the target area, it can be regarded as an equivalent implementation of the optical module 12 in the embodiments of the present invention.

[0041] The optical module 12 is used to emit light signals, and the focused ultrasound module 13 is used to emit ultrasound signals that can form a focal point at a predetermined location. The external control circuit module 20 is connected to the optical module 12 and the focused ultrasound module 13 inside the flexible packaging module 14 via a flexible flat cable, providing drive signals and power to the optical module 12 and the focused ultrasound module 13. This external design allows the flexible integrated patch 10 to maintain a low thickness and weight, while moving the relatively heat-concentrated control and power supply components outside the patch, thereby reducing heat accumulation at the wear end.

[0042] In this embodiment, the flexible flat cable can maintain stable conduction when the flexible integrated patch 10 bends, while the large and heavy drive circuit is arranged outside the flexible integrated patch 10, reducing the load on the attachment end of the flexible integrated patch 10. The external control circuit module 20 can provide constant current or pulse current to the optical module 12, and can also provide drive signals with predetermined frequency, phase and amplitude to the focused ultrasound module 13.

[0043] In this embodiment, the external control circuit module 20 can control the optical module 12 and the focused ultrasound module 13 to operate in a light-only working mode (i.e., only control the optical module 12 to work), an ultrasound-only working mode (i.e., only control the focused ultrasound module 13 to work), or a photoacoustic combined working mode (i.e., control the optical module 12 and the focused ultrasound module 13 to work simultaneously). In the photoacoustic combined working mode, timing control can also be performed in the form of synchronous output, delayed output, or time-division output to adapt to different neural modulation or protein sample processing needs.

[0044] The working principle of this embodiment is as follows: When working in the neuromodulation scenario, the optical module 12 outputs infrared light to the target tissue, and the focused ultrasound module 13 outputs focused ultrasound signals to the deep brain region. The two are coupled in time and space, thereby forming photoacoustic multi-physics field synergistic stimulation in the same target area. When the device works in the sample detection pretreatment scenario, the optical module 12 and the focused ultrasound module 13 synergistically process the protein sample to be tested to change the aggregation state of abnormal aggregated proteins or the degree of exposure of antigen epitopes, thereby enhancing the subsequent immune detection response signal.

[0045] This embodiment has the following beneficial effects: First, in this embodiment, the optical module 12 and the focused ultrasound module 13 are integrated together on the flexible substrate 11 and fabricated into a patch using the flexible encapsulation module 14, achieving spatiotemporal coupling of two physical fields in the same target area. Focused ultrasound targets and depolymerizes pathogenic protein aggregates at the physical level, while infrared light improves microenvironment metabolism at the biochemical level. The combination of the two, i.e., photoacoustic synergistic regulation, can work together in the early stages of disease to interrupt the pathological cascade amplification process, thereby significantly improving the treatment effect.

[0046] Secondly, the optical module 12 and the focused ultrasound module 13 are integrated together in the flexible substrate 11 and the flexible packaging module 14. The two can maintain a stable correspondence in spatial position, avoiding the problem of the light field and sound field being difficult to align.

[0047] Third, in this embodiment, the external control circuit module 20 is externally mounted via a flexible flat cable, which allows the flexible integrated patch 10 to remain thin, soft, and fit well. Therefore, it is not only beneficial for the attachment to the curved surface of the head, long-term use, and stable positioning during sample processing, but also reduces the weight and volume of the wearable component. At the same time, it avoids the risk of thermal damage to the scalp caused by the heat generated by the external control circuit module 20.

[0048] Fourth, the embodiments of the present invention can not only be used for neural modulation and repair, but also for preprocessing of pathogenic protein detection, enhancing the sensitivity of pathogenic protein signal detection, thus possessing dual application potential for treatment and detection; in addition, the embodiments of the present invention, through ultrasound combined with infrared targeted right prefrontal AF4 neural modulation, can also significantly reshape the high-frequency rhythm of the occipital lobe of the EEG, enhance the excitability of the prefrontal brain region, optimize EEG indicators related to visual working memory, and effectively improve cognitive processing ability.

[0049] In some embodiments, the optical module 12 is composed of an array of multiple light-emitting diodes, and the focused ultrasound module 13 is composed of an array of multiple piezoelectric ceramic sheets.

[0050] In this embodiment, the optical module 12 does not use a single light-emitting point, but rather an array of multiple light-emitting diodes (LEDs). These LEDs can be arranged in a ring, rectangle, arc, or other suitable surface-mount configuration. Each LED can be a miniature LED or a surface-mount LED, connected to the external control circuit module 20 via flexible electrodes. This array arrangement allows for a more uniform or controllable distribution of light energy within the target area.

[0051] The focused ultrasound module 13 is composed of multiple piezoelectric ceramic sheets, each of which can serve as an independent or semi-independent ultrasound transmitting unit. In this embodiment, the coherent superposition of multiple piezoelectric ceramic sheets provides a basis for focused control, thus moving beyond the limitations of single-point, wide-beam, or uncontrollable ultrasound output.

[0052] In practical implementation, the piezoelectric ceramic sheet can be a micro-piezoelectric ceramic sheet, or PZT piezoelectric ceramic, i.e., lead zirconate titanate piezoelectric ceramic, such as PZT-5H material. Other piezoelectric materials and sizes can also be selected according to the actual acoustic output requirements. After multiple piezoelectric ceramic sheets are arranged in an array, by controlling their excitation timing, amplitude, or phase, the sound waves emitted by each piezoelectric ceramic sheet can be superimposed at the target position to form a focused sound field.

[0053] In a preferred embodiment, the optical module 12 may include six infrared LED patches, and the focused ultrasound module 13 includes six piezoelectric ceramic sheets. The six infrared LED patches may be mounted in the inner ring region of the flexible substrate 11, and the six piezoelectric ceramic sheets may be mounted in the outer ring region, and connected to a flexible flat cable via flexible electrodes.

[0054] More preferably, the infrared light-emitting diode can be a 1050 nm surface-mount LED, and the piezoelectric ceramic sheet can be a PZT-5H piezoelectric transducer, with an operating frequency preferably of 1 MHz. Each piezoelectric ceramic sheet can serve as an independent or group-controllable ultrasonic transmitting unit, so that its phase and amplitude can be controlled subsequently by an external control circuit module 20.

[0055] In this embodiment, multiple light-emitting diode patches and multiple piezoelectric ceramic sheets together constitute an arrayed photoacoustic actuator. The array structure not only increases the degree of freedom in adjusting the parameters, but also provides a basis for adapting to different brain region depths, sample volumes, or processing areas.

[0056] In this embodiment, since both the optical module 12 and the focused ultrasound module 13 adopt an array structure, stimulation no longer relies on a single light source or a single piezoelectric ceramic sheet. The arrayed light-emitting diodes can improve the illumination coverage and light power distribution, while the arrayed piezoelectric ceramic sheets can provide multiple acoustic degrees of freedom for focusing control. Therefore, this structure improves the adjustability and spatial controllability of photoacoustic stimulation parameters, which is beneficial for adapting to different brain regions, different sample sizes, or different processing requirements. It can improve the coverage of the target area without significantly increasing the volume of the wearable end, and provides a basis for ultrasound focusing, illumination distribution optimization, and photoacoustic synergistic coupling. Therefore, it is beneficial for improving the targeting of neuromodulation and the consistency of sample processing.

[0057] In some embodiments, the piezoelectric ceramic sheets of the focused ultrasound module 13 can be arranged in a ring matrix; the light-emitting diodes of the optical module 12 are arranged in a ring matrix, and the ring diameter of the focused ultrasound module 13 is larger than the ring diameter of the optical module 12 and the two ring matrices are arranged in concentric circles.

[0058] In this embodiment, the focused ultrasound module 13 includes multiple piezoelectric ceramic sheets, which are arranged uniformly or nearly uniformly along a ring path to form an outer ring ultrasound emission array. The optical module 12 includes multiple light-emitting diodes, which are also arranged along a ring path to form an inner ring light-emitting array. The ring diameter of the focused ultrasound module 13 is larger than that of the optical module 12, and the two ring matrices share the same center point, forming a concentric circle layout.

[0059] For example, in one specific embodiment, the optical module 12 may include six 1050 nm light-emitting diode patches uniformly distributed along the inner ring; the focusing ultrasound module 13 may include six PZT piezoelectric ceramic sheets with an operating frequency of 1 MHz uniformly distributed along the outer ring. Insulation spacing and wiring space can be reserved between the inner and outer rings to accommodate flexible electrodes and encapsulation materials. The outer ring ultrasound array is arranged around the inner ring light source, ensuring that both the light and sound fields are output around the same geometric center. The equivalent aperture of the outer ring ultrasound array is larger than that of the inner ring optical array, thereby enabling stronger focusing capability of the focused ultrasound output around the same geometric center, while the infrared light output is located in the central region, closer to the target control center.

[0060] It should be noted that, in specific implementation, the operating wavelength of the light-emitting diode can be determined according to the actual situation, and this embodiment does not impose any limitation on it.

[0061] The concentric layout in this embodiment also lies in the design of the photoacoustic coupling relationship: since the ultrasonic array is located in the outer ring, its equivalent aperture is increased, which is beneficial to improving the directivity of the sound beam and the ability to form a focal point; since the optical array is located in the inner ring, its output area has a good spatial correspondence with the ultrasonic focusing center, so the two can form a synergistic effect around the same center of action.

[0062] In this embodiment, the larger diameter of the focused ultrasound module 13 increases its equivalent acoustic aperture, which is beneficial for improving the beam focusing ability and sound field directivity. Since the optical module 12 is located in the smaller diameter inner ring, the light output area and the ultrasound focusing center have a good spatial correspondence. With the two ring matrices arranged concentrically, the light stimulation area and the ultrasound stimulation area can form a synergistic coupling around the same center of action. This not only improves the spatial consistency during deep brain region modulation but also enhances the photoacoustic coupling effect within the same region of action in sample pretreatment scenarios, thereby improving the targeting and synergy of the device.

[0063] In some embodiments, the annular matrix of the focused ultrasound module 13 and the annular matrix of the optical module 12 are staggered in the circumferential direction to reduce the mutual occlusion of the piezoelectric ceramic sheet and the light-emitting diode patch in the projection direction, so as to achieve spatial complementarity of the treatment area.

[0064] In this embodiment, although the focused ultrasound module 13 and the optical module 12 adopt a concentric ring layout as a whole, they are preferably not completely overlapped in the circumferential position, but are arranged in an angularly staggered manner. That is, the piezoelectric ceramic sheet of the outer ring and the light-emitting diode patch of the inner ring do not form a completely corresponding overlapping position in the projection direction (for example, the projection surface can be parallel to the plane where the concentric ring is located).

[0065] In this embodiment, although the focused ultrasound module 13 and the optical module 12 can be arranged in a concentric ring, the two types of array units do not completely overlap in the angular direction. For example, if the piezoelectric ceramic sheet in the focused ultrasound module 13 is positioned at 0°, 60°, 120°, 180°, 240°, and 300°, then the light-emitting diode in the optical module 12 can be positioned at 30°, 90°, 150°, 210°, 270°, and 330°, so that the two are staggered in the circumferential direction. This staggered arrangement can also be adjusted according to the device size, wiring requirements, and the shape of the working area.

[0066] This spatially staggered arrangement also prevents the LED and piezoelectric ceramic sheet from completely overlapping in the vertical projection direction, thereby reducing device thickness accumulation and localized rigidity concentration. For flexible patches, the staggered structure can also provide more reasonable routing paths for flexible electrodes, reducing the risk of crossovers and short circuits.

[0067] This misaligned structure can reduce the occlusion and local thickness superposition of the LED patch and piezoelectric ceramic sheet in the vertical projection direction. On the other hand, it also provides space for flexible electrode wiring, pad arrangement and uniform encapsulation layer thickness, which is conducive to the overall thinning and reliable manufacturing of flexible patches.

[0068] At the functional level, the circumferential misalignment also allows the light output area and the sound output area to form a complementary coverage on the target plane, rather than completely overlapping at a few fixed points, thereby avoiding excessive concentration of local energy.

[0069] In this embodiment, the optical signal emitting unit and the ultrasonic emitting unit are spatially misaligned, allowing the optical and acoustic action areas to form complementary coverage on the target surface, rather than simply overlapping at a limited number of points. This avoids excessive local energy concentration and expands the effective processing area. Simultaneously, the misaligned arrangement provides space for device packaging and electrical connections, contributing to improved flexibility, reliability, and manufacturability of the surface mount.

[0070] In one specific embodiment, the light-emitting diodes (LEDs) in the optical module 12 are surface-mount LEDs, and the operating wavelength of the LED surface-mounts can be 1050 nm. The surface-mount structure facilitates fixation to the flexible substrate 11 or the intermediate encapsulation layer by surface mounting, conductive adhesive bonding, or low-temperature soldering. Each LED surface-mount emits light at a wavelength of 1050 nm, which is in the infrared band. Multiple 1050 nm LED surface-mounts can be connected in series, parallel, or a combination of series and parallel, and a constant current output is provided by the LED driving circuit in the external control circuit module 20.

[0071] In one specific embodiment, the external control circuit module 20 drives the 1050 nm LED patch with a drive current of approximately 60 mA, enabling it to output infrared light in continuous or pulsed operation modes. The flexible packaging module 14 can use an infrared-transmitting polymer material on the light-emitting side of the LED to reduce light loss. If used for sample processing, the LED array can be oriented towards the sample cavity or sample surface; if used for neural modulation, the LED array can be oriented towards the skin or head adhesion surface.

[0072] The light-emitting diodes are in a patch form, and the optical module 12 can be miniaturized, thinned, and integrated in an array, making it suitable for flexible patch structures. 1050 nm infrared light has good tissue penetration potential and biocompatibility, enabling it to form a multi-physics field combined stimulation with the focused ultrasound module. This structure, while maintaining the patch's thinness, provides a stable light source for cell metabolism regulation, sample photoacoustic processing, and detection signal enhancement.

[0073] In some embodiments, a biocompatible material layer is provided between the optical module 12 and the focused ultrasound module 13. The biocompatible material layer is used to achieve physical isolation and electrical insulation between the focused ultrasound module 13 and the optical module 12, and to achieve layered integration of the optical module 12 and the focused ultrasound module 13 in the vertical direction (i.e., the direction perpendicular to the contact surface between the flexible integrated patch 10 and the patient's head).

[0074] In this embodiment, the optical module 12 and the focused ultrasound module 13 are not simply exposed and mounted on the same plane, but rather a biocompatible material layer is disposed between them. Specifically, this biocompatible material layer can be a polyurethane film, a polyimide film, a parylene film, or other insulating polymer films. The biocompatible material layer can be formed by lamination, spin coating, deposition, hot pressing, or bonding.

[0075] Specifically, one functional module (e.g., optical module 12) and its flexible electrodes can be first set on the flexible substrate 11, and then covered with a biocompatible insulating film; subsequently, another functional module (e.g., focused ultrasound module 13) can be set on the insulating film, and electrical connection can be achieved through reserved pads, vias, or flexible interconnect ports. The optical module 12 and the focused ultrasound module 13 can form a vertically layered structure, rather than occupying the same planar space completely. The layered structure retains the concentric or staggered spatial design while providing electrical isolation between the two functional modules.

[0076] In this embodiment, a biocompatible material layer is disposed between the optical module 12 and the focused ultrasound module 13. The driving current of the optical module 12 will not directly interfere with the high-frequency driving signal of the focused ultrasound module 13, and the voltage excitation of the focused ultrasound module 13 is less likely to cause a short circuit or breakdown risk to the optical module 12. Because this material layer is both flexible and biocompatible, the device is safer and more comfortable when attached to the human body or in contact with biological samples. In addition, layered integration can increase the device integration density per unit area, allowing the patch to maintain a compact structure.

[0077] In some embodiments, the optical module 12 and the focused ultrasound module 13 are electrically connected to a flexible flat cable via flexible electrodes; the flexible electrodes are disposed inside the flexible encapsulation module 14 to accommodate the bending and deformation of the flexible integrated patch 10.

[0078] In this embodiment, the electrical connection between the optical module 12 and the focused ultrasound module 13 is not a direct connection using rigid wires, but rather a flexible electrode disposed inside the flexible encapsulation module 14. One end of the flexible electrode is connected to an infrared light-emitting diode and a piezoelectric ceramic sheet, respectively, while the other end converges to the flexible flat cable connection area. The flexible flat cable is then plugged, soldered, or crimped to the external control circuit module 20.

[0079] In practical implementation, the flexible electrode can be made of copper, gold, silver, metal composite layers, or conductive polymer materials, and its shape can be serpentine, wavy, arc-shaped, or grid-shaped. The flexible electrode is encapsulated inside the flexible packaging module 14, which protects the flexible electrode from external mechanical friction and liquid corrosion, and allows it to deform synchronously with the packaging layer when the patch is bent. For devices with high local rigidity, such as piezoelectric ceramic sheets, the flexible electrode can also form a strain buffer zone between rigid components.

[0080] The flexible electrode preferably employs a serpentine, wavy, arc-shaped, or grid-shaped conductive pattern to absorb strain when the flexible integrated patch 10 is bent, attached to a curved surface, or subjected to minor stretching, thereby reducing the risk of wire breakage. Since the flexible electrode is encapsulated inside the flexible packaging module 14, it can avoid the direct effects of external liquids, sweat, biological sample fluids, or mechanical friction.

[0081] In one specific embodiment, the flexible electrode can be fabricated using processes well known to those skilled in the art. For example, a serpentine stretchable copper electrode can be fabricated using laser cutting and substrate transfer processes. During fabrication, a copper conductive layer can first be formed on a temporary support substrate or copper foil composite film, and then the copper conductive layer can be processed into a serpentine pattern using laser cutting. The serpentine pattern includes multiple continuous bending segments, each of which can absorb external strain through unfolding, rotation, or micro-deformation when the patch is stretched or bent. Subsequently, the serpentine copper electrode is transferred to a predetermined position on the flexible substrate or encapsulation layer using a substrate transfer process, and then connected to an infrared light-emitting diode, a piezoelectric ceramic sheet, and flexible flatbed cable pads.

[0082] In practical implementation, the linewidth, spacing, bending radius, and copper layer thickness of the serpentine copper electrodes can be designed according to the current carrying capacity, ultrasonic driving voltage, and patch bending radius. For optical module 12, the serpentine copper electrodes can handle constant current driving current; for focused ultrasound module 13, the serpentine copper electrodes can handle high-frequency driving signal transmission.

[0083] In this embodiment, the flexible electrode is located inside the packaging module and connected to a flexible flat cable, allowing the optical module 12 and the focused ultrasound module 13 to maintain electrical conductivity when the patch is bent, stretched, or adhered to curved surfaces. Compared to straight, rigid wires, the flexible electrode can distribute stress, reducing the probability of solder joint detachment, circuit breakage, and poor contact. Therefore, this structure improves the wearability and long-term operational reliability of the device.

[0084] Furthermore, copper, with its low electrical resistance and good conductivity, meets the energy transmission requirements of the optical module 12 and the focused ultrasound module 13. The flexible electrode, fabricated into a serpentine structure, is less prone to stress concentration under bending or stretching conditions. Laser cutting facilitates the formation of fine, repeatable electrode patterns, while substrate transfer facilitates the bonding of the metal electrode to the flexible polymer substrate. Therefore, this technical solution balances conductivity, flexibility, and the feasibility of mass production.

[0085] In some embodiments, the focused ultrasound module 13 is composed of multiple independently controlled piezoelectric ceramic sheets; the external control circuit module 20 independently controls the phase and amplitude of each piezoelectric ceramic sheet to achieve focused ultrasound emission at different depths and deflection angles, which is used to non-invasively penetrate the skull and precisely target deep brain regions.

[0086] Each piezoelectric ceramic element in the focused ultrasound module 13 has an independent or group-controllable drive channel. The external control circuit module 20 can generate multiple synchronous reference signals via a control unit, and apply them to each piezoelectric ceramic element after phase delay, waveform shaping, power amplification, and impedance matching. The control unit can calculate the acoustic path difference of each piezoelectric ceramic element relative to the focal point based on the target focal point, and set the phase compensation amount accordingly. For piezoelectric ceramic elements operating at 1 MHz, the phase delay between adjacent channels can be achieved using a timer, a DDS signal source, a programmable logic device, or a multi-channel drive chip.

[0087] The amplitude of each piezoelectric ceramic element can also be adjusted independently. For example, when the sound attenuation in a certain direction is large, the driving amplitude of the corresponding piezoelectric ceramic element can be appropriately increased; when it is necessary to reduce local sound energy, the amplitude of the corresponding channel can be reduced or some channels can be turned off. By changing the phase combination, the ultrasonic waves emitted by multiple piezoelectric ceramic elements can form coherent superposition at different depths or different spatial positions, thereby achieving adjustable focus.

[0088] In a preferred embodiment, the focused ultrasound module 13 employs six PZT-5H piezoelectric ceramic plates with an operating frequency of 1MHz. The MCU in the external control circuit module 20 outputs a 1MHz control signal, which, after logic shaping, is amplified by a half-bridge driver stage and a power output stage, and then applied to each piezoelectric ceramic plate. By controlling the phase delay and drive amplitude of each channel, focal points at different depths can be formed.

[0089] When used for transcranial nerve modulation, the focused ultrasound output can non-invasively penetrate the skull and target deep brain regions; when used for protein sample processing, it can apply focused acoustic energy to local areas of the sample to affect the aggregation structure of pathogenic proteins.

[0090] In this embodiment, the multiple piezoelectric ceramic plates of the focused ultrasound module 13 can be independently controlled, not limited to a mechanical structure with a fixed focal depth, but the sound field distribution can be changed through electronic control. Phase control determines whether the ultrasound waves are superimposed in phase at the target location, and amplitude control determines the sound energy in each direction. Therefore, focused ultrasound emission at different depths and deflection angles can be achieved without changing the physical structure of the patches, improving adaptability to different patient head structures, different brain region depths, or different sample thicknesses.

[0091] In some embodiments of the present invention, the optical module 12 preferably uses a surface-mount LED as the light-emitting unit. Surface-mount LEDs are easy to fix onto the flexible substrate 11 or intermediate layer by surface mounting, conductive adhesive bonding, or low-temperature soldering, which facilitates the miniaturization and arraying of the device.

[0092] The preferred operating wavelength of the LED patch is 1050 nm, which falls within the infrared band. This wavelength has good tissue penetration potential and biocompatibility, making it suitable for forming multi-physics field synergistic stimulation with the focused ultrasound module 13.

[0093] In a preferred embodiment, six 1050 nm LED patches are driven by a constant current LED driving circuit in the external control circuit module 20. During testing, the input voltage can be 5.00 V and the driving current can be 60 mA. Under these conditions, after the 1050 nm LEDs operate continuously for 60 min, the optical power decreases from 12.80 mW to 11.84 mW, while the normalized light output remains at 92.50%, indicating that the optical module 12 has good continuous output stability.

[0094] In the above embodiments, the external control circuit module includes a control unit, and a piezoelectric ceramic driving circuit, a light-emitting diode driving circuit, and a power management circuit that are electrically connected to the control unit respectively; the control unit is used to control the light-emitting diode driving circuit and the piezoelectric ceramic driving circuit to operate in a light-only working mode, an ultrasound-only working mode, or a photoacoustic combined working mode, and in the photoacoustic combined working mode, control the optical module and the focused ultrasound module to operate in a synchronous output, delayed output, or time-division output mode.

[0095] The external control circuit module 20 can be integrated on a printed circuit board, and the control unit can be an MCU, FPGA, or other programmable controller. In specific implementations, the control unit can be an STM32 series microcontroller, used to generate switching control signals for the optical module, brightness adjustment signals, frequency signals and phase control signals for the ultrasonic module, and photoacoustic joint timing control signals, etc.

[0096] The piezoelectric ceramic drive circuit is electrically connected to the control unit and may include a logic shaping circuit, a half-bridge or full-bridge drive circuit, a power amplifier circuit, and a matching network, used to convert the low-voltage control signal output by the control unit into a high-frequency drive signal that can drive the piezoelectric ceramic sheet to work.

[0097] Specifically, see Figure 11 The piezoelectric ceramic drive circuit preferably adopts a half-bridge drive topology. The 1 MHz square wave signal output by the STM32 is first logic shaped, and then the UCC27211, together with the bootstrap capacitor, drives the upper and lower bridge arms of the MOSFET, forming a high-frequency voltage at the midpoint of the half-bridge to excite the piezoelectric ceramic chip. A 5 Ω resistor can be connected in series with the gates of the upper and lower bridges to suppress switching overshoot and improve drive stability.

[0098] The LED driving circuit is electrically connected to the control unit and may include a constant current driving chip, a switching dimming circuit, and a protection circuit to provide a stable current for the 1050 nm LED patch. The external control circuit module may also include a DC-DC power supply circuit to convert the input power supply into a piezoelectric ceramic driving voltage and an LED driving voltage.

[0099] Specifically, see Figure 10 The LED driving circuit preferably uses the TLC5940 constant current driver chip. This chip can provide constant current output for a 1050 nm LED array and supports 12-bit grayscale PWM adjustment to suppress the impact of power supply fluctuations on the stability of light output. With this driving method, the optical module 12 can operate stably in either continuous output mode or pulse output mode.

[0100] See Figure 12 The power management circuit preferably uses an MP2225GJ to construct a 12V to 5V buck converter circuit. This circuit provides a stable operating voltage for the control unit and LED driver section through feedback voltage division closed-loop regulation, and can also work with other power supply branches to provide the required energy support for the ultrasonic drive section.

[0101] The control unit can control the device to operate in the following modes: light-only mode: only drive the optical module 12 to output infrared light; ultrasound-only mode: only drive the focused ultrasound module 13 to output focused ultrasound; photoacoustic combined mode: drive the optical module 12 and the focused ultrasound module 13 to work simultaneously.

[0102] In the combined photoacoustic and optical operating mode, further control is possible as follows: Synchronous output mode: Optical module 12 and focused ultrasound module 13 start and output simultaneously; Delayed output mode: One of the optical module 12 and the focused ultrasound module 13 is started first, and the other is started after a preset delay time; Time-sharing output mode: Optical module 12 and focused ultrasound module 13 work alternately according to different time slices.

[0103] This multi-mode, programmable timing control structure can adapt to both neural modulation and sample processing applications. For example, in neural modulation, synchronization or delay parameters can be set according to the response window of the target brain region to photoacoustic stimulation; in sample processing scenarios, the time-sharing mode can be set according to the pre-processing requirements.

[0104] In this embodiment, the control unit can be set to a single light stimulation mode, a single ultrasound stimulation mode, and a combined photoacoustic mode. In the combined photoacoustic mode, the control unit can control the optical module to continuously output or pulse output according to a preset program, while simultaneously controlling the focused ultrasound module to output ultrasound signals with set frequency, phase, and amplitude. Different modes can be switched via buttons, host computer communication, or preset programs.

[0105] In this embodiment, the infrared light output and focused ultrasound output can operate synchronously, alternately, or independently under a unified control architecture. The control unit is responsible for timing coordination, the piezoelectric ceramic driving circuit is responsible for acoustic energy output, and the light-emitting diode driving circuit is responsible for optical energy output. Therefore, the device can obtain repeatable and adjustable photoacoustic combined stimulation conditions, avoiding the problem of synchronization difficulties between multiple discrete devices. This not only improves the device's integration and ease of use, but also ensures good consistency of stimulation output dose and stability of long-term continuous operation through integrated timing coordination control.

[0106] As can be seen, this embodiment integrates a focused ultrasound module and an infrared light module at high density on an ultrathin flexible substrate, achieving heterogeneous integration of acoustic, optical, and electrical multi-material components. Targeting the cascade evolution of neurodegenerative diseases—"metabolic imbalance-neuroinflammation-protein deposition-network disconnection"—the focused ultrasound module is used for precise targeted depolymerization of pathogenic proteins in deep brain regions, while the optical module is used to improve mitochondrial function and brain metabolic homeostasis. Through photoacoustic synergy, both modules simultaneously achieve metabolic microenvironment regulation and deep pathological targeted regulation. Furthermore, the combined photoacoustic detection enhances signal contrast, thereby improving the detection sensitivity of pathogenic biomarkers, interrupting the pathological cascade amplification process in the early stages of the disease, and improving early diagnostic accuracy. Compared to invasive deep brain stimulation and non-invasive single-modal modulation schemes, this embodiment features a compact structure, good biocompatibility, and comfortable wear, providing an efficient, portable, and highly targeted solution for early prevention and long-term intelligent home-based regulation.

[0107] The performance testing of the present invention will be described below with reference to a preferred embodiment.

[0108] The flexible integrated patch comprises six 1050 nm LED patches and six PZT piezoelectric ceramic sheets. The six LED patches form an inner ring array, and the six PZT piezoelectric ceramic sheets form an outer ring array, both concentrically and angularly staggered. The flexible integrated patch 10 is encapsulated by two layers of polyurethane film, with a biocompatible material layer in between to provide electrical insulation between the infrared optical module and the focused ultrasound module. A serpentine, stretchable copper electrode connects each functional unit and converges to a flexible flat cable. The flexible flat cable connects to an external control circuit module, which includes an MCU, DC-DC circuitry, piezoelectric ceramic drive circuitry, and LED drive circuitry.

[0109] The LED driver module uses a TLC5940 constant current chip to achieve constant current output and 12-bit grayscale PWM adjustment for a 1050 nm infrared LED. The ultrasonic stimulation driver module adopts a half-bridge topology; the 1 MHz square wave output from the STM32 is logic-shaped and then driven by a UCC27211 and a bootstrap capacitor to drive the MOSFET, achieving high-frequency excitation of the piezoelectric transducer. The power management module uses an MP2225GJ to form a 12 V to 5 V buck circuit, forming a closed-loop voltage regulator through feedback voltage division. The overall control system supports light-only, ultrasound-only, and combined modes, and in the combined mode, it supports synchronous, delayed, and time-division output. Through heterogeneous integration technology, the miniature infrared module and the focused ultrasound module are integrated in a high-density conformal manner on an ultra-thin flexible substrate.

[0110] In use, the flexible integrated patch can be attached to the target site (e.g., a patient's head) or positioned with its active surface facing the biological sample to be processed. The control unit activates the infrared module 12 and the focused ultrasound module 13 according to a pre-set program. The infrared optical module outputs 1050 nm infrared light in a constant-current manner; the focused ultrasound module 13 drives multiple piezoelectric ceramic plates at a frequency of approximately 1 MHz and forms a focused sound field at a predetermined position through phase and amplitude control. For neuromodulation applications, photoacoustic combined stimulation can be used for multimodal physical modulation of target brain regions; for detection applications, photoacoustic combined processing can be used to alter the aggregation state of proteins such as Aβ or increase the exposure of antigen epitopes, thereby enhancing immune detection signals.

[0111] The following performance tests were performed on the device in this embodiment: 1) The stability of the infrared light output was tested, and the test data is shown in Table 1 below: Table 1. Continuous Output Stability Test Data for 1050 nm LED

[0112] The line graph of the continuous output stability test of 1050 nm LED is shown below. Figure 2 As shown. Figure 2 The horizontal axis represents time in minutes, and the vertical axis represents optical power in milliwatts and surface temperature in degrees Celsius. The red curve represents the optical power change curve, and the blue curve represents the surface temperature change curve. Under the conditions of an input voltage of 5.00 V and a driving current of 60 mA, the optical power of the 1050 nm LED gradually decreased from the initial 12.80 mW to 11.84 mW after 60 min of continuous operation, while the normalized light output remained at 92.50%, indicating that the infrared module has good light output stability during continuous operation.

[0113] 2) The output stability of the focused ultrasound module 13 was tested, and the test data are shown in Table 2 below: Table 2. Test data on the stability of ultrasound stimulation output

[0114] Test results are as follows Figure 3 As shown, Figure 3 This is a graph showing the stability of the ultrasonic stimulation output. In the graph, the horizontal axis represents time in minutes, the left vertical axis represents the received voltage in millivolts, and the right vertical axis represents the response value in percent. The red curve represents the change in received voltage, the blue curve represents the normalized acoustic response curve, and the green curve represents the relative ultrasonic output intensity curve. It can be seen that under 1 MHz and 12 V driving conditions, after 60 minutes of continuous operation, the output voltage of the ultrasonic receiver drops from 486 mV to 449 mV, while the normalized acoustic response remains at 92.39%, indicating that the focused ultrasound module 13 can maintain a relatively stable ultrasonic output under the set driving conditions.

[0115] 3) The test data under the combined photoacoustic and optical operating mode is shown in Table 3 below: Table 3: Stability Test Data of Photoacoustic Combined Continuous Operation

[0116] The test results are shown in Table 4 below. Figure 4 As shown. Figure 4 The horizontal axis represents time in minutes, the left vertical axis represents the normalized output value in %, and the right vertical axis represents temperature in degrees Celsius. The red curve represents the normalized light output curve, the blue curve represents the normalized acoustic response curve, the green curve represents the LED temperature change curve, and the purple curve represents the piezoelectric element temperature change curve.

[0117] Table 4: Repeatability Test Results of the Photoacoustic Combined Stimulation Device

[0118] In the combined photoacoustic and optical operating mode, after 60 minutes of continuous operation, the light output of the infrared optical module remained at 91.88%, and the normalized acoustic response of the focused ultrasonic module 13 remained at 90.74%. Repeatability test results showed that the coefficients of variation for optical power and ultrasonic receiver output voltage were 0.24% and 0.33%, respectively, indicating that the device exhibits good output consistency and repeatability when operating in both photoacoustic and optical modes synchronously. Simultaneously, the LED temperature rose from 25.4℃ to 40.1℃, and the piezoelectric element temperature rose from 25.8℃ to 41.6℃, with the overall temperature rise remaining within a controllable range.

[0119] Based on the performance test results above, this embodiment not only possesses the structural advantages of flexible attachment and external control, but also exhibits good stability and repeatability in infrared output, ultrasonic output, and combined output modes. This indicates that this embodiment has the hardware foundation to serve as a neural modulation execution end, providing stable, uniform, and repeatable stimulation conditions for subsequent biological experimental verification.

[0120] The following section verifies the application effect of this embodiment in the in vitro regulation of Aβ protein aggregation.

[0121] Based on the in vitro aggregation model of Aβ protein, the effects were characterized using transmission electron microscopy, ThT fluorescence detection, and quantitative detection by double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). Under the set driving conditions, the 1050nm LED infrared optical module maintained a relatively stable continuous output; the focused ultrasound module 13 exhibited good electrical and relative acoustic output stability under 1MHz and 12V driving conditions; in the photoacoustic synergistic working mode, the device operated stably overall, and both optical and acoustic outputs showed good repeatability and consistency, meeting the requirements of uniformity, continuity, and reproducibility of stimulation conditions in in vitro protein experiments.

[0122] Transmission electron microscopy characterization results are as follows Figure 5 , Figure 8 As shown in Tables 5 and 6.

[0123] Table 5: Statistical results of aggregate area ratio in TEM images of the control group and the photoacoustic combined stimulation group.

[0124] Table 6: Statistical results of average particle area in TEM images of the control group and the photoacoustic combined stimulation group.

[0125] Depend on Figure 5It can be seen that the control group Aβ protein samples contained relatively large-scale dense aggregates, with continuous and concentrated aggregate structures. After photoacoustic stimulation, the large aggregate structures in the samples were significantly reduced, and the Aβ aggregates as a whole showed a trend of dispersion and fragmentation. Further, combined with the semi-quantitative statistical results in Table 5, the area ratio of Aβ aggregates in the control group was 49.60%, 38.57%, and 35.11%, with an average of 41.09%; the area ratio of aggregates in the photoacoustic stimulation group was 3.55%, 2.37%, and 3.02%, with an average value decreasing to 2.98%. Meanwhile, as shown in Table 6, the average particle area in the control group was 141.24 pixel², 114.59 pixel², and 58.90 pixel², with an average of 104.91 pixel²; the average particle area in the photoacoustic stimulation group was 16.68 pixel², 14.82 pixel², and 14.61 pixel², with an average value decreasing to 15.37 pixel². The above results indicate that photoacoustic stimulation can significantly reduce the area ratio and particle size of Aβ aggregates, causing them to transform from a large-scale dense aggregated state to a small-scale dispersed state.

[0126] To verify the non-specific effect of this embodiment on proteins, bovine serum albumin (BSA) was selected as a non-amyloid model protein control sample. Under the same stimulation parameters, a non-stimulated control group and a photoacoustic combined stimulation group were set up. After the regulation was completed, polyacrylamide gel electrophoresis (SDS-PAGE) was used for detection. The results are as follows: Figure 9 The electrophoretic spectra of the two groups of samples showed that the main protein bands were in the same position, with clear band morphology and no obvious changes in migration rate. Simultaneously, no new low-molecular-weight degradation bands or high-molecular-weight aggregation bands appeared in the stimulation group, and the staining depth and width of the main bands were only slightly different from the control group. These results indicate that the photoacoustic modulation conditions used in this invention do not cause significant degradation, breakage, or large-scale cross-linking aggregation in ordinary protein samples, and have no obvious non-specific destructive effect on the primary structure and electrophoretic migration behavior of proteins. Combined with the results showing that the aggregation state of Aβ protein was significantly affected by photoacoustics in this experiment, the regulatory effect of the photoacoustic signal on Aβ aggregation in this invention does not stem from general damage to protein molecules, but is closely related to the unique β-sheet amyloid structure of Aβ protein and the sensitivity of its aggregation state to external physical stimuli. This confirms that the photoacoustic combined device of this invention has selective action on target amyloid proteins, while exhibiting good biocompatibility and safety for non-target proteins.

[0127] The following will verify the effect of this embodiment on regulating and improving the detection sensitivity of AD biomarker proteins.

[0128] In this embodiment, a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) was used to quantitatively detect Aβ42 samples before and after photoacoustic stimulation treatment to evaluate the effect of this stimulation on the immune recognition signal of AD marker proteins. The two groups of samples were diluted to a series of theoretical concentration gradients, and the absorbance (OD value) at 450 nm was measured and concentration-response curves were plotted. The test data are shown in Table 7 below. Table 7:

[0129] In the table above, Aβ42 Concentration is the concentration of β-amyloid protein 42, NIR-LIFU(+) is the infrared low-frequency focused ultrasound treatment group, and NIR-LIFU(-) is the infrared low-frequency ultrasound blank control group.

[0130] The results are as follows Figure 7 As shown in the figure, the vertical axis represents the optical density value at 450 nm, and the horizontal axis represents the β-amyloid protein concentration at 42 picograms / mL. NIR-LIFU (+) represents the experimental group treated with infrared low-frequency focused ultrasound, and NIR-LIFU (-) represents the control group without infrared low-frequency focused ultrasound. P < 0.01 indicates a highly statistically significant difference. Both groups showed a good concentration-dependent increase in OD values ​​with increasing theoretical concentration. The linear fitting coefficients of determination (R²) were both high, indicating good linearity and reliable results. Two-way statistical analysis showed a significant interaction between the treatment factor and the concentration. p =0.003), and comparisons at various concentration points revealed that the OD values ​​of the two groups were similar in the low concentration range, while the OD value of the photoacoustic treatment group was significantly higher than that of the untreated group in the medium-to-high concentration range. This result indicates that, at the same theoretical protein concentration, photoacoustic combined stimulation did not increase the absolute content of Aβ42, but rather altered its aggregation state or the degree of antigenic epitope exposure, allowing more epitopes to be recognized by the detection antibody, thus exhibiting an enhanced immune detection signal in the ELISA system. Meanwhile, ThT fluorescence detection results (see...) Figure 6 In the figure, the vertical axis represents fluorescence intensity, and the Control Group represents the control group, while the Experimental Group represents the experimental group. The figure shows that the average fluorescence intensity of the photoacoustic stimulation group was approximately 10.30% lower than that of the control group, a statistically significant difference. p =0.020), indicating a significant reduction in the β-sheet amyloid aggregation structure of Aβ protein. Transmission electron microscopy further confirmed from a microscopic morphology perspective that the aggregate structure exhibited a trend of transformation from large-scale, dense aggregation to a small-scale, dispersed state. The above-mentioned ELISA, ThT fluorescence, and electron microscopy results corroborate each other from the three levels of immune recognition signal, aggregation degree, and microscopic morphology, respectively. The overall trend of change is highly consistent, jointly confirming that the photoacoustic combined stimulation of this invention can effectively regulate the abnormal aggregation behavior of Aβ protein and significantly enhance its immune recognition response. In summary, the photoacoustic multimodal regulation method provided by this invention is not only suitable for the highly sensitive immunoassay pretreatment of the AD marker protein Aβ42, effectively improving the sensitivity in detection systems such as ELISA; at the same time, the device has been verified by in vitro protein experiments to be stable and have significant regulatory effects, providing solid experimental evidence and technical support for the application of photoacoustic physical stimulation in the research of protein aggregation behavior related to neurodegenerative diseases and in the field of rehabilitation treatment.

[0131] As can be seen, this embodiment completed a full-process study on the effect of photoacoustic combined stimulation on Aβ aggregation characteristics, from device design and integration to protein-level experimental verification. The constructed photoacoustic combined stimulation device can operate stably and significantly affect the abnormal aggregation behavior of Aβ protein in in vitro protein experiments. These results provide important experimental evidence for in-depth research on the aggregation behavior of AD-related Aβ protein by photoacoustic combined stimulation, and also lay an important technical foundation for the application of multimodal physical stimulation devices in the rehabilitation treatment of neurodegenerative diseases.

[0132] In the verification experiments, the 1050 nm light-emitting diode maintained relatively stable light output during continuous operation; the focused ultrasound module maintained relatively stable acoustic response under the set driving conditions; and both light and acoustic outputs showed good repeatability when working in photoacoustic combination. After photoacoustic combined treatment of Aβ protein samples, transmission electron microscopy revealed a reduction in large-scale aggregates and an enhanced tendency for particle dispersion; ThT fluorescence detection and ELISA results also showed changes in aggregation state and immune recognition signals. This demonstrates that the device in this embodiment can not only stably output infrared light and focused ultrasound, but also provide a feasible hardware foundation for preprocessing in neural modulation and biomarker detection.

[0133] The following verifies the effect of ultrasound combined with infrared neuromodulation on the right prefrontal lobe in this embodiment.

[0134] In this embodiment, ultrasound combined with infrared neuromodulation was performed on the right prefrontal lobe. By collecting and comparing resting-state electroencephalogram (EEG) signals before and after modulation, the modulation effect was systematically analyzed from multiple dimensions, including feature importance screening, statistical permutation test, scalp power topology distribution, target time-frequency dynamics, brain functional connectivity, and visual working memory-related EEG indicators.

[0135] 1) Key feature selection and classification verification

[0136] The results of the feature importance selection based on machine learning are as follows: Figure 13 As shown, the top 10 EEG features distinguishing the states before and after modulation were concentrated in the β (13–30 Hz) and γ (30–45 Hz) frequency bands of the O1, O2, Oz, PO3, and PO4 electrodes in the occipital lobe (standard occipital region electrode locations on EEG, in order: left occipital, middle occipital, right occipital, left posterior occipital, right posterior occipital, and mid-posterior occipital line). Among them, the γ band oscillation of the PO3 electrode had the highest contribution, suggesting that high-frequency rhythm reconstruction in the occipital visual cortex is the core biomarker for distinguishing the EEG patterns before and after modulation. The permutation test results showed that the random forest classifier achieved an average accuracy of 87.3% under strict time block cross-validation. In 500 permutation tests, the accuracy of all randomly shuffled labels was far lower than the true value (P < 0.0001), confirming that the EEG differences induced by modulation were statistically significant, rather than random signal fluctuations.

[0137] Figure 13 In this context, beta represents beta brainwaves, gamma represents gamma brainwaves, and Top 10 Feature Importances (EEG only) refers to the top 10 EEG features.

[0138] 2) Target temporal and frequency characteristics and local excitability changes

[0139] Topological mapping of scalp power difference showed a significant increase in gamma-band power in the frontal and midline brain regions after modulation. Time-frequency analysis of the stimulation target AF4 in the right frontal lobe indicated that the power of this electrode was generally enhanced across the entire frequency band after modulation, and the difference thermogram visually presented the upregulation of local excitability at the target point.

[0140] 3) Functional connection reorganization mode

[0141] The results of the whole-brain functional connectivity analysis using AF4 as the seed point are as follows: Figure 14 As shown, the results indicate that functional connectivity between the target site and other brain regions is generally weakened in the α band; while extensive connectivity between the prefrontal-central-parietal-occipital region is significantly enhanced in the β and γ bands, with the most prominent increase in coupling strength between the Fp2 electrode and AF4 in the midfrontal region. This reorganization pattern of cross-band connectivity suggests that right prefrontal stimulation may reshape the prefrontal-visual cortex functional network through long-range synchronization and enhance the efficiency of information exchange within the prefrontal cognitive network.

[0142] Figure 14 In the first image, alpha band connectivity change (seed AF4) represents the change in the connectivity strength of the alpha band brain network (seed electrode: AF4).

[0143] In the second image, beta band connectivity change (seed AF4) represents the change in the strength of beta band brain network connectivity (seed electrode: AF4).

[0144] In the third image, gamma band connectivity change (seed AF4) represents the change in the strength of gamma band brain network connectivity (seed electrode: AF4).

[0145] In the diagram: C1: Left paracentral midline electrode; FC1: Left paracentral midline electrode; FT7: Left frontotemporal electrode; F5: Left lateral frontal electrode; FC5: Left frontotemporal electrode; F7: Left frontal electrode; C3: Left central electrode. F3: Left frontal lobe electrode; AF7: Left prefrontal electrode; FC3: Left central frontal electrode; FC4: Right central frontal electrode; FC2: Right paracentral frontal electrode; Fp1: Left frontal electrode; F2: Right paracentral frontal electrode; Fp2: Right frontal electrode; Fpz: Frontal midline electrode; F1: Left paracentral frontal electrode; AF3: Left prefrontal electrode; F8: Right frontotemporal electrode; F6: Right frontal electrode; AF8: Right prefrontal electrode. F4: Right frontal lobe electrode.

[0146] 4) Changes in EEG markers related to visual working memory

[0147] The results of changes in EEG indicators related to visual working memory before and after photoacoustic co-modulation are as follows: Figure 15 As shown in the figure, Pre-stim represents the period before stimulation, Post-stim represents the period after stimulation, IAF (Individual Alpha Frequency) represents the individual alpha oscillation frequency (in Hertz), Alpha Power represents the alpha band EEG power, Theta Power represents the theta band EEG power, Theta / Beta represents the theta / β power ratio, and Alpha PLV (Phase Locking Value) represents the alpha band phase locking value. The vertical axis Value represents the numerical values ​​of the above parameters. After modulation, the individual alpha peak frequency, posterior alpha power, and frontal theta power all increased compared to the baseline level, the theta / β ratio decreased, and the frontoparietal alpha phase synchronization (PLV) slightly increased. These results indicate that right prefrontal targeted neural modulation can optimize the EEG characteristics corresponding to visual working memory, providing electrophysiological evidence that this modulation scheme has a positive regulatory effect on cognitive processing ability.

[0148] The results of changes in visual working memory-related EEG indicators before and after near-infrared light modulation are as follows: Figure 16As shown, after modulation, the individual α peak frequency increased compared to the baseline level, the θ / β ratio decreased, and the posterior α power, frontal θ power, and frontoparietal α phase synchronization (PLV) all slightly increased. These results indicate that single infrared light stimulation has a certain optimizing effect on EEG features related to visual working memory, but the overall modulating amplitude is limited.

[0149] Changes in visual working memory-related EEG indicators before and after ultrasound modulation are as follows: Figure 17 As shown, after modulation, the frontal θ power increased compared to the baseline level, the α peak frequency did not change significantly, the posterior α power decreased slightly, the θ / β ratio increased, and the frontoparietal α phase synchronization increased slightly. These results indicate that the modulatory effect of single ultrasound stimulation on visual working memory-related EEG features is uneven and fails to effectively optimize the α band and θ / β ratio.

[0150] Comprehensive comparison Figure 15 , Figure 16 , Figure 17 It is evident that photoacoustic combined stimulation, compared to single infrared light stimulation and single ultrasound stimulation, exhibits superior regulatory effects in increasing alpha peak frequency, enhancing posterior alpha power, and reducing the θ / β ratio. Single ultrasound stimulation even resulted in a decrease in posterior alpha power and an increase in the θ / β ratio. These results fully demonstrate that right prefrontal targeted photoacoustic combined neuromodulation can more comprehensively optimize the EEG characteristics corresponding to visual working memory, and its synergistic effect is superior to single physical factor stimulation. This further corroborates from an electrophysiological perspective that this combined regulatory approach has a more significant positive regulatory effect on cognitive processing ability.

[0151] Figure 15 , Figure 16 , Figure 17 In the diagram, Resting-state EEG markers of visual WM capacity represent characteristic indicators of visual working memory capacity reflected by resting-state EEG. Pre-stim indicates the period before stimulation, and Post-stim indicates the period after stimulation. The vertical axis represents the numerical value of the indicator, and the horizontal axis represents IAF (Individual Alpha Frequency, the individual's unique baseline alpha wave frequency, in Hertz), Alpha Power, Theta Power, Theta / Beta, and Alpha PLV.

[0152] It is evident that the reorganization of high-frequency occipital rhythms is likely the terminal manifestation of the long-range network effect triggered by right prefrontal stimulation, while the overall remodeling of the prefrontal-visual cortex network is the core neural mechanism of the regulatory effect.

[0153] In summary, this embodiment utilizes focused ultrasound to achieve precise targeted depolymerization of pathogenic proteins in deep brain regions. Simultaneously, it combines this with infrared light of specific wavelengths to improve mitochondrial function and brain metabolic homeostasis. Through photoacoustic synergy, it simultaneously regulates the metabolic microenvironment and targets deep pathological conditions, effectively interrupting the cascade amplification of pathological processes in the early stages of disease. Compared to existing technologies, this device offers advantages such as compact structure, good biocompatibility, and comfortable wear. It overcomes the drawbacks of invasive deep brain stimulation surgery (high risk) and non-invasive single-modality modulation (discretionary function), providing an efficient, portable, and highly targeted solution for early prevention and long-term intelligent home-based regulation.

[0154] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or improvement of the technology in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A photoacoustic multimodal neural modulation detection device, characterized in that, include: At least one flexible integrated patch and an external control circuit module electrically connected to the flexible integrated patch; The flexible integrated patch includes: a flexible substrate, an optical module for emitting optical signals, a focused ultrasound module for emitting focused ultrasound signals, and a flexible packaging module. The focused ultrasound module and the optical module are disposed on the flexible substrate and encapsulated by the flexible packaging module; The external control circuit module is electrically connected to the optical module and the focused ultrasound module within the flexible packaging module via a flexible flat cable. It is used to provide drive signals and electrical energy to the optical module and the focused ultrasound module so that the optical module and the focused ultrasound module can work independently or collaboratively according to a preset timing sequence to regulate and repair the function of the nervous system, or to enhance the sensitivity of pathogenic protein signal detection.

2. The photoacoustic multimodal neural modulation detection device according to claim 1, characterized in that... , The optical module is composed of multiple light-emitting diode patches arranged in an array; The focused ultrasound module is composed of multiple piezoelectric ceramic sheets arranged in an array.

3. The photoacoustic multimodal neural modulation detection device according to claim 2, characterized in that, The piezoelectric ceramic sheets of the focused ultrasound module are arranged in a ring matrix. The light-emitting diode patches of the optical module are arranged in a ring matrix; and... The annular diameter of the focused ultrasound module is larger than that of the optical module, and the two annular matrices are arranged in concentric circles.

4. The photoacoustic multimodal neural modulation detection device according to claim 2, characterized in that, The ring matrix of the focused ultrasound module and the ring matrix of the optical module are staggered circumferentially to reduce the mutual occlusion of the piezoelectric ceramic sheet and the light-emitting diode patch in the projection direction, so as to achieve spatial complementarity of the treatment area.

5. The photoacoustic multimodal neural modulation detection device according to claim 4, characterized in that, A biocompatible material layer is provided between the optical module and the focused ultrasound module. The biocompatible material layer is used to achieve physical isolation and electrical insulation between the focused ultrasound module and the optical module, and to achieve layered integration of the optical module and the focused ultrasound module.

6. The photoacoustic multimodal neural modulation detection device according to claim 5, characterized in that, The optical module and the focused ultrasound module are electrically connected to the flexible flat cable via flexible electrodes. The flexible electrode is disposed inside the flexible packaging module to accommodate the bending and deformation of the flexible integrated patch.

7. The photoacoustic multimodal neural modulation detection device according to claim 6, characterized in that, The optical module is an infrared optical module.

8. The photoacoustic multimodal neural modulation detection device according to claim 1, characterized in that, The focused ultrasound module is composed of multiple independently controlled piezoelectric ceramic sheets; The external control circuit module independently controls the phase and amplitude of each piezoelectric ceramic sheet to achieve focused ultrasound emission at different depths and deflection angles, which is used for non-invasive penetration of the skull and precise targeting of deep brain regions.

9. The photoacoustic multimodal neural modulation detection device according to claim 7, characterized in that, The light-emitting diode is a surface-mount light-emitting diode; The operating wavelength of the light-emitting diode patch is 900nm to 1300nm.

10. The photoacoustic multimodal neural modulation detection device according to any one of claims 1 to 9, characterized in that, The external control circuit module includes a control unit, and a piezoelectric ceramic driving circuit, a light-emitting diode driving circuit, and a power management circuit that are electrically connected to the control unit. The control unit is used to control the light-emitting diode driving circuit and the piezoelectric ceramic driving circuit to operate in light-only mode, ultrasonic-only mode or photoacoustic combined mode, and in the photoacoustic combined mode, to control the optical module and the focused ultrasonic module to operate in synchronous output, delayed output or time-division output mode.

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