Degradable flexible electronic device, preparation method and monitoring device

Abstract

The invention provides a degradable flexible electronic device which is applied to tumor postoperative monitoring and comprises a substrate layer, an electrode layer, an electrode modification layer and a packaging layer. The electrode layer is formed on the substrate layer in a patterned structure and forms a plurality of groups of electrode arrays, and a working electrode is configured in each group of electrode array; the electrode modification layers are located on all the working electrodes, aptamers are assembled in the electrode modification layers, and the electrode modification layers are used for being in targeted combination with tumor target markers in the to-be-monitored area after the tumor operation and reacting, changing the interface impedance of the working electrodes and transmitting interface impedance signals of the working electrodes to an external receiving device; the external receiving device monitors the interface impedance signal state based on the interface impedance signal of the working electrode so as to obtain information about whether tumor recurrence and / or metastasis exist in the to-be-monitored area after the tumor operation; the substrate layer, the electrode layer and the packaging layer are all made of degradable materials. The invention further provides a preparation method of the degradable flexible electronic device and a monitoring system.

Description

Technical Field

[0001] This disclosure relates to the field of tumor postoperative monitoring technology, specifically to a biodegradable flexible electronic device, its preparation method, and a monitoring device. Background Technology

[0002] Current cancer treatments primarily focus on surgery, radiotherapy, and chemotherapy. After surgery or radiotherapy / chemotherapy, residual cancer cells or micrometastases may remain dormant for months or even years, making them difficult to detect with routine imaging. These residual cells may spread through the bloodstream or lymphatic system, becoming a source of tumor recurrence or metastasis. Furthermore, some cancer stem cells with self-renewal capabilities can tolerate radiotherapy and chemotherapy, proliferating again after treatment and leading to tumor recurrence. Therefore, it is essential for cancer patients to undergo regular monitoring for tumor cell recurrence and metastasis after surgery or treatment, especially for ovarian cancer, which has extremely high recurrence and metastasis rates.

[0003] Currently, the assessment of postoperative tumor recurrence and metastasis mainly relies on regular imaging examinations (ultrasound, MRI, etc.) and / or blood tests (tumor markers, etc.). These methods have certain limitations due to their lag and cannot meet the needs of real-time monitoring. In addition, subsequent pathological examinations for diagnosis usually require minimally invasive surgery, which carries the risk of infection and tumor spread. Summary of the Invention

[0004] In view of the above problems, this disclosure provides a biodegradable flexible electronic device, a preparation method, and a monitoring device.

[0005] According to a first aspect of this disclosure, a biodegradable flexible electronic device is provided for post-tumor monitoring, comprising a base layer, an electrode layer, an electrode modification layer, and an encapsulation layer. Specifically, the base layer provides support and is fixed to the post-tumor monitoring area by a biocompatible hydrogel; the electrode layer is formed on the base layer with a patterned structure, forming multiple electrode arrays, each array containing a working electrode; the electrode modification layer is located on each working electrode, and an aptamer is fitted in the electrode modification layer for targeted binding and reaction with tumor target markers in the post-tumor monitoring area to change the interfacial impedance of the working electrode, transmitting the interfacial impedance signal of the working electrode to an external receiving device, so that the external receiving device can monitor the state of the interfacial impedance signal based on the interfacial impedance signal of the working electrode to obtain information on whether the tumor has recurred and / or metastasized in the post-tumor monitoring area; the encapsulation layer is formed on the electrode layer and covers each electrode array, exposing each electrode modification layer; wherein the base layer, electrode layer, and encapsulation layer are all made of biodegradable materials.

[0006] According to embodiments of this disclosure, in the above-mentioned biodegradable flexible electronic device, the aptamers in the electrode modification layer on each group of electrode arrays are of different types, and each type of aptamer is used to target and bind to its corresponding tumor target marker and react accordingly.

[0007] According to embodiments of this disclosure, in the aforementioned biodegradable flexible electronic device, each electrode array is further configured with a counter electrode, a reference electrode, and an electrical connection structure for connecting the working electrode, the counter electrode, and the reference electrode. An encapsulation layer covers the electrical connection structure in each electrode array. The counter electrode and the working electrode form a closed loop to balance the charge transfer generated after the aptamer on the working electrode targets and binds to the tumor target biomarker, ensuring the continuous reaction between the aptamer and the tumor target biomarker. The reference electrode provides a predetermined potential reference to reduce interference from environmental fluctuations in the monitored area after tumor surgery on the interface impedance of the working electrode.

[0008] According to embodiments of this disclosure, in the above-mentioned biodegradable flexible electronic device, the thickness of the substrate layer is 1µm to 100µm, the thickness of the electrode layer is 100nm to 10µm, and the thickness of the encapsulation layer is 1µm to 100µm. The degradation rates of the substrate layer, electrode layer, and encapsulation layer in the monitored area after tumor surgery are different from each other.

[0009] According to embodiments of this disclosure, in the above-mentioned degradable flexible electronic device, the substrate layer material includes a degradable biosafety polymer, which includes any one of the following: polylactic acid-glycolic acid copolymer, polylactic acid, silk fibroin, and cellulose; the electrode layer material includes a degradable metal material, which includes any one of the following: magnesium, zinc, iron, molybdenum, and tungsten; the encapsulation layer material includes a degradable biocompatible material, which includes polylactic acid-glycolic acid copolymer, gelatin, or chitosan.

[0010] A second aspect of this disclosure provides a method for fabricating a biodegradable flexible electronic device, comprising: dissolving a biodegradable biosafety polymer in a solvent and forming a substrate thin film by solution casting or spin coating; patterning and depositing a biodegradable metal material on the substrate thin film to form an electrode layer having multiple electrode arrays, each electrode array having a working electrode; forming an electrode modification layer on the surface of each working electrode, the electrode modification layer being fitted with an aptamer; and encapsulating each electrode array and exposing the electrode modification layer to form an encapsulation layer.

[0011] According to embodiments of this disclosure, in the above method, a degradable metal material is patterned and deposited on a substrate thin film to form an electrode layer with multiple electrode arrays, including the preparation of a mixed ink of a degradable metal material and a polylactic acid-glycolic acid copolymer adhesive, and the formation of the electrode array using screen printing or inkjet printing technology.

[0012] According to embodiments of this disclosure, the above method involves patterning and depositing a biodegradable metal material on a substrate thin film to form an electrode layer with multiple electrode arrays. It also includes forming the structure of the electrode array using ultraviolet laser direct writing technology, preparing an electrolyte containing the biodegradable metal material, and electrodepositing to form the electrode array.

[0013] According to embodiments of this disclosure, in the above method, an electrode modification layer is formed on the surface of each working electrode, and an aptamer is assembled in the electrode modification layer. The method further includes encapsulating the aptamer by drop-coating a polymer onto the surface of the aptamer.

[0014] A third aspect of this disclosure provides a biodegradable flexible electronic monitoring device, comprising a power supply device, a transmission device, an external receiving device, and the aforementioned biodegradable flexible electronic device. The power supply device and the transmission device are electrically connected to an electrode layer on the biodegradable flexible electronic device and are disposed on the biodegradable flexible electronic device. The power supply device is used to provide electrical energy to the electrode layer; the transmission device is used to transmit the interface impedance signal from the working electrode on the electrode layer to the external receiving device; the external receiving device is disposed outside the area to be monitored after tumor surgery and is used to monitor the state of the interface impedance signal based on the interface impedance signal of the working electrode; wherein the power supply device and the transmission device are both made of biodegradable materials.

[0015] According to embodiments of this disclosure, a biodegradable flexible electronic device for post-tumor monitoring is provided. The device, fixed to the area to be monitored after tumor surgery, comprises a biodegradable base layer, an electrode layer, an encapsulation layer, and an electrode modification layer fitted with aptamers corresponding to tumor target biomarkers. The aptamers in the electrode modification layer target and bind to the tumor target biomarkers appearing in the post-tumor monitoring area, causing a change in the interfacial impedance of the working electrode. An external receiving device monitors this change in interfacial impedance based on the received interfacial impedance signal, thereby acquiring information on tumor recurrence and / or metastasis in the post-tumor monitoring area. This method overcomes the bottleneck of the lag in traditional monitoring methods, fulfills the need for real-time monitoring, and avoids the safety issues of existing minimally invasive pathological examinations. Attached Figure Description

[0016] The foregoing contents, as well as other objects, features, and advantages of this disclosure, will become clearer from the following description of embodiments with reference to the accompanying drawings, in which:

[0017] Figure 1 This schematic diagram illustrates a layered structure of a biodegradable flexible electronic device according to an embodiment of the present disclosure.

[0018] Figure 2 This diagram illustrates the distribution of ovarian tumor cells before ovarian cancer surgery.

[0019] Figure 3 This schematic diagram illustrates the distribution of the biodegradable flexible electronic devices in the monitoring area after ovarian cancer surgery, according to embodiments of the present disclosure.

[0020] Figure 4 A flowchart illustrating a method for fabricating a biodegradable flexible electronic device according to an embodiment of the present disclosure is shown.

[0021] In the accompanying drawings of this disclosure, the reference numerals have the following meanings:

[0022] 1-Degradable flexible electronic device; 11-Base layer; 12-Electrode layer; 21-Working electrode; 22-Counter electrode; 23-Reference electrode; 24-Electrical connection structure; 13-Electrode modification layer; 31-Adaptor; 14-Encapsulation layer; 3-Ovary; 4-Ovary tumor cell. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of this disclosure clearer, the following detailed description is provided in conjunction with specific embodiments and the accompanying drawings.

[0024] The endpoints and any values ​​of the ranges disclosed in this disclosure are not limited to the precise ranges or values, and such ranges or values ​​should be understood to include values ​​close to such ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be regarded as specifically disclosed in this disclosure.

[0025] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit this disclosure. The terms “comprising,” “including,” etc., as used herein indicate the presence of the stated features, steps, operations, and / or components, but do not exclude the presence or addition of one or more other features, steps, operations, or components.

[0026] All terms used herein (including technical and scientific terms) have the meanings commonly understood by those skilled in the art, unless otherwise defined. It should be noted that the terms used herein are to be interpreted in a manner consistent with the context of this specification, and not in an idealized or overly rigid way.

[0027] In the description of this disclosure, it should be understood that the terms "longitudinal", "length", "circumferential", "front", "rear", "left", "right", "top", "bottom", "inner", "outer", etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, and are only for the convenience of describing this disclosure and simplifying the description, and do not indicate or imply that the subsystem or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of this disclosure.

[0028] Similarly, to simplify this disclosure and aid in understanding one or more of the various aspects of the disclosure, in the above description of exemplary embodiments of the present disclosure, various features of the present disclosure are sometimes grouped together in a single embodiment, figure, or description thereof. The use of terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refers to a specific feature, structure, material, or characteristic described in connection with that embodiment or example, which is included in at least one embodiment or example of the present disclosure. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0029] Following tumor surgery or radiotherapy / chemotherapy, residual cancer cells, micrometastases, and tumor stem cells resistant to radiotherapy / chemotherapy may become the source of tumor recurrence or metastasis. Therefore, it is essential for cancer patients to regularly monitor tumor cell recurrence and metastasis after surgery or treatment, especially for ovarian cancer, which has extremely high recurrence and metastasis rates. Currently, the assessment of postoperative tumor recurrence and metastasis relies primarily on regular imaging examinations (ultrasound, MRI, etc.) and / or blood tests (tumor markers, etc.). However, these methods have certain limitations due to their lag and cannot meet the needs of real-time postoperative tumor monitoring. Furthermore, subsequent pathological examinations for definitive diagnosis often require minimally invasive surgery, which carries risks of infection and tumor spread.

[0030] In view of this, embodiments of the present disclosure provide a biodegradable flexible electronic device, a fabrication method, and a monitoring device. This device, fixed to the post-tumor surgery monitoring area, comprises a biodegradable base layer, an electrode layer, an encapsulation layer, and an electrode modification layer equipped with aptamers corresponding to tumor target biomarkers. The aptamers in the electrode modification layer target and bind to the tumor target biomarkers appearing in the post-tumor surgery monitoring area, undergoing a chemical reaction that causes a change in the interfacial impedance of the working electrode. An external receiving device monitors the change in interfacial impedance based on the received interfacial impedance signal, thereby obtaining information on tumor recurrence and / or metastasis in the post-tumor surgery monitoring area. This method overcomes the bottleneck of the lag in traditional monitoring methods, fulfills the need for real-time monitoring, and avoids the safety issues of existing minimally invasive pathological examinations. Furthermore, by assembling different aptamers corresponding to different tumor target biomarkers on multiple electrode arrays, in-situ synchronous detection of multiple tumor target biomarkers is achieved, improving the comprehensiveness and accuracy of monitoring.

[0031] The biodegradable flexible electronic device of this disclosure can be applied to postoperative monitoring of various types of tumors. The application scope of this embodiment is taken as postoperative monitoring of ovarian cancer, but it is not limited thereto.

[0032] Figure 1 A schematic diagram illustrating the layered structure of a biodegradable flexible electronic device according to an embodiment of the present disclosure is provided. It should be noted that... Figure 1 The layered structure diagram in the image is an exploded view showing the layers along the vertical direction.

[0033] like Figure 1 As shown, the biodegradable flexible electronic device 1 of this disclosure includes a substrate layer 11, an electrode layer 12, an electrode modification layer 13, and an encapsulation layer 14. Specifically, the substrate layer 11 provides support and is fixed to the post-tumor monitoring area by a biocompatible hydrogel. The electrode layer 12 is formed on the substrate layer in a patterned structure, forming multiple electrode arrays, each array containing a working electrode 21. The electrode modification layer 13 is located on each working electrode 21, and an aptamer 31 is assembled therein for targeted binding and reaction with tumor markers in the post-tumor monitoring area to change the interfacial impedance of the working electrode 21. This alters the interfacial impedance signal of the working electrode and transmits it to an external receiving device, allowing the external receiving device to monitor the state of the interfacial impedance signal based on the signal, thereby obtaining information on whether the tumor has recurred and / or metastasized in the post-tumor monitoring area. The encapsulation layer 14 is formed on the electrode layer 12 and encapsulates each electrode array, exposing each electrode modification layer 13. The substrate layer 11, electrode layer 12 and encapsulation layer 14 are all made of biodegradable materials.

[0034] According to embodiments of this disclosure, a flexible electronic device refers to an electronic device that integrates functional materials on a substrate using flexible electronics technology, and can be fixedly attached to the complex curved surface of soft tissue using biocompatible hydrogel. The area to be monitored after tumor surgery may include the post-operative location of the tumor, related post-operative locations, and areas of tumor cell spread. The biodegradable flexible electronic device 1 can be fixed at one or more points in the post-operative monitoring area. Taking ovarian cancer as an example, the monitoring area of ​​the biodegradable flexible electronic device in this disclosure embodiment may include the location of the removed unilateral ovary, the area above the healthy ovary, the pelvic region, and the abdominal region.

[0035] In some embodiments, the aptamer 31 in the electrode modification layer 13 and the tumor target marker are specifically bound by non-covalent interactions such as hydrogen bonds, van der Waals forces and π-π stacking. The aptamer 31 can capture the tumor target marker corresponding to the aptamer 31 to form a complex. The formation of the complex hinders electrons from approaching the surface of the working electrode 21 and inhibits the polarization response of ions on the surface of the working electrode 21, thereby causing a change in the interfacial impedance of the working electrode 21.

[0036] Figure 2 This diagram schematically illustrates the distribution of ovarian tumor cells before ovarian cancer surgery. (For example...) Figure 2 In the example shown, ovarian cancer cells 4 were found in one ovary 3. Ovarian cancer surgery can remove the ovary where ovarian cancer cells 4 were found, and a biodegradable flexible electronic device can be implanted after surgery to monitor tumor recurrence and / or metastasis.

[0037] Figure 3 This illustration schematically shows the distribution of biodegradable flexible electronic devices according to embodiments of the present disclosure in the area to be monitored after ovarian cancer surgery. For example... Figure 3 As shown, after ovarian cancer surgery to remove unilateral ovary 3 where ovarian tumor cells 4 were found, the biodegradable flexible electronic device of this embodiment can be fixed at one or more points in the postoperative monitoring area of ​​ovarian cancer, such as on the other ovary, on the uterine wall, on the abdominal wall, etc.

[0038] In a specific embodiment, an aptamer 31 is assembled in the electrode modification layer 13. The aptamer 31 can specifically bind to the target tumor marker. The target tumor marker can react on the surface of the working electrode 21, causing a change in the interfacial impedance of the working electrode 21.

[0039] According to embodiments of this disclosure, a biodegradable flexible electronic device 1, fixed to the post-tumor monitoring area, comprises a biodegradable base layer 11, an electrode layer 12, an encapsulation layer 14, and an electrode modification layer 13 equipped with aptamers 31 corresponding to tumor target markers. The aptamers 13 in the electrode modification layer 13 target and bind to the tumor target markers appearing in the post-tumor monitoring area, causing a change in the interfacial impedance of the working electrode 21. An external receiving device monitors this change in interfacial impedance based on the received interfacial impedance signal, thereby obtaining information on tumor recurrence and / or metastasis in the post-tumor monitoring area. This method overcomes the bottleneck of the lag in traditional monitoring methods, fulfills the need for real-time monitoring, and avoids the safety issues of existing minimally invasive pathological examinations.

[0040] According to embodiments of this disclosure, in the above-mentioned biodegradable flexible electronic device 1, the aptamers 31 in the electrode modification layer 13 on each group of electrode arrays are of different types, and each type of aptamer 13 is used to target and bind to its corresponding tumor target marker and undergo a chemical reaction.

[0041] In specific embodiments, different types of tumors may include multiple target tumor markers. Taking ovarian cancer as an example, target tumor markers for ovarian cancer may include carbohydrate antigen-125, human epididymal protein-4, alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen-199, etc. Each target tumor marker has its own corresponding aptamer, used to monitor tumor recurrence and / or metastasis after surgery.

[0042] According to embodiments of this disclosure, by assembling different types of aptamers 31 in the electrode modification layer 13 on each group of electrode arrays, multiple target tumor markers can be monitored at multiple locations in the abdominal cavity, achieving simultaneous monitoring of multiple tumor markers. Compared with single indicator monitoring, this improves the comprehensiveness and accuracy of monitoring, providing a more reliable basis for postoperative management decisions.

[0043] According to embodiments of this disclosure, in the aforementioned biodegradable flexible electronic device 1, each electrode array may further be configured with a counter electrode 22, a reference electrode 23, and an electrical connection structure 24 for connecting the working electrode, the counter electrode, and the reference electrode. An encapsulation layer 14 is used to cover the electrical connection structure 24 in each electrode array. The counter electrode 22 forms a closed loop with the working electrode 21 to balance the charge transfer generated after the aptamer 31 on the working electrode 21 targets and binds to the tumor target marker, thus ensuring the continuous reaction between the aptamer 31 and the tumor target marker. The reference electrode 23 is used to provide a predetermined potential reference to reduce the interference of environmental fluctuations in the monitored area after tumor surgery on the interface impedance of the working electrode 21.

[0044] In some specific embodiments, the working electrode 21, as the core electrode in the electrode array, targets and binds to the target tumor marker via a surface-mounted aptamer 31, reacting with the target tumor marker and causing a change in the interfacial impedance of the working electrode 21. The counter electrode 22 does not participate in the chemical reaction with the target tumor marker, balancing the charge transfer of the working electrode 21. The reference electrode 23 does not participate in the chemical reaction with the target tumor marker, is independent of the current loop, and eliminates interference from environmental fluctuations.

[0045] According to embodiments of this disclosure, in the three-electrode array of working electrode 21, counter electrode 22, and reference electrode 23, the counter electrode 22 can carry a high current density to ensure the stability of the current loop; the reference electrode 23 is isolated from the current loop to reduce the interference of changes in the composition and / or concentration of tissue fluid in the area to be monitored after tumor surgery on the monitoring of target tumor markers, thereby improving the accuracy and anti-interference ability of monitoring.

[0046] According to embodiments of this disclosure, in the aforementioned biodegradable flexible electronic device 1, the material of the substrate layer 11 may include biodegradable biosafety polymers, such as polylactic acid-glycolic acid copolymer, polylactic acid, silk fibroin, cellulose, etc. The material of the electrode layer 12 may include biodegradable metallic materials, such as magnesium, zinc, iron, molybdenum, tungsten, etc. The material of the encapsulation layer 14 may include biodegradable biocompatible materials, such as polylactic acid-glycolic acid copolymer, gelatin, chitosan, etc.

[0047] In some specific embodiments, the materials of the substrate layer, electrode layer and encapsulation layer can be any material with biocompatibility and degradation properties. The biodegradable biosafety polymers, biodegradable metal materials and biodegradable biocompatible materials in the above embodiments are only examples and are not limited thereto.

[0048] According to embodiments of this disclosure, in the aforementioned biodegradable flexible electronic device 1, the thickness of the substrate layer 11 is 1µm to 100µm, for example, it can be 1µm, 10µm, 20µm, 30µm, 40µm, 50µm, 60µm, 70µm, 80µm, 90µm, 100µm, etc.; the thickness of the electrode layer 12 is 100nm to 10µm, for example, it can be 100nm, 500nm, 1µm, 2µm, 5µm, 10µm, etc.; the thickness of the encapsulation layer 14 is 1µm to 100µm, for example, it can be 1µm, 10µm, 20µm, 30µm, 40µm, 50µm, 60µm, 70µm, 80µm, 90µm, 100µm, etc. The degradation rates of the substrate layer, electrode layer, and encapsulation layer in the monitored area after tumor surgery are different from each other.

[0049] In the embodiments of this disclosure, the degradation rate of the substrate layer 11, electrode layer 12 and encapsulation layer 14 is determined by the thickness and material composition of the substrate layer 11, electrode layer 12 and encapsulation layer 14. By regulating the degradation rate of the flexible electronic device 1 in the area to be monitored, the degradation time is regulated. After the monitoring cycle is completed, the materials of each layer of the device are gradually degraded and discharged from the body, thereby realizing long-term real-time monitoring after tumor surgery.

[0050] According to embodiments of this disclosure, a biodegradable flexible electronic monitoring device includes a power supply device, a transmission device, an external receiving device, and the aforementioned biodegradable flexible electronic device 1. The power supply device and the transmission device are electrically connected to the electrode layer 12 on the biodegradable flexible electronic device 1 and are disposed on the biodegradable flexible electronic device 1. The power supply device provides electrical energy to the electrode layer 12; the transmission device transmits the interface impedance signal from the working electrode 21 on the electrode layer 12 to the external receiving device; the external receiving device is disposed outside the area to be monitored after tumor surgery and is used to monitor the state of the interface impedance signal based on the interface impedance signal of the working electrode 21. Both the power supply device and the transmission device are made of biodegradable materials.

[0051] In embodiments of this disclosure, the power supply device can utilize near-field communication or bio-environmental energy harvesting to achieve wireless power supply, such as power supply through biochemical reactions. The transmission device can transmit data signals in real time using radio frequency or Bluetooth Low Energy technology, such as the interface impedance signal of the working electrode 21. When the aptamer 13 specifically binds to the target biomarker, the interface impedance signal of the working electrode 21 is transmitted through the transmission device to an external receiving device, which monitors the changes in the interface impedance of the working electrode 21. This enables remote and real-time monitoring of multiple target tumor biomarkers in the area to be monitored after tumor surgery, thereby meeting the need for long-term and dynamic evaluation after tumor surgery.

[0052] Figure 4 A flowchart illustrating a method for fabricating a biodegradable flexible electronic device according to an embodiment of the present disclosure is shown.

[0053] like Figure 4 As shown, the method for fabricating a biodegradable flexible electronic device may include operations S410 to S440.

[0054] In operation S410, a biodegradable biosafe polymer is dissolved in a solvent and a base layer film is formed by solution casting or spin coating.

[0055] In operation S420, a degradable metallic material is patterned and deposited on a substrate thin film to form an electrode layer with multiple electrode arrays, each array containing a working electrode.

[0056] In operation S430, an electrode modification layer is formed on the surface of each working electrode, and an adapter is assembled in the electrode modification layer.

[0057] In operation S440, each group of electrode arrays is encapsulated and the electrode modification layer is exposed to form an encapsulation layer.

[0058] In a specific embodiment, the solvent may include a liquid that dissolves the biodegradable biosafety polymer, such as water and an organic solvent, which may include chloroform. After solution casting or spin coating, drying and curing are performed to remove the solvent, forming the substrate layer 11 film. During the formation of the substrate layer 11 film, the drying temperature may be 70°C to 90°C, for example, 70°C, 75°C, 80°C, 85°C, 90°C, etc.

[0059] In a specific embodiment, a biodegradable metal material is patterned and deposited on a substrate layer 11 film to form an electrode layer 12 with multiple electrode arrays. This includes formulating a mixed ink of the biodegradable metal material and a polylactic acid-glycolic acid copolymer (PLA) binder, and forming the electrode array using screen printing or inkjet printing technology. The working electrode can be printed using a mixed ink of zinc powder and PLA binder, where the zinc powder particle size can be 0.5 μm to 3 μm, for example, 0.5 μm, 1 μm, 2 μm, 3 μm, etc., and the ratio of zinc powder to PLA binder can be 7:3 w / w. The counter electrode can be printed using a mixed ink of iron powder and PLA binder, where the iron powder particle size can be 1 μm to 3 μm, for example, 1 μm, 2 μm, 3 μm, etc., and the ratio of iron powder to PLA binder can be 13:7 w / w. The reference electrode can be printed using a mixed ink of zinc and zinc oxide, where the ratio of zinc to zinc oxide can be 1:1 w / w to 1:2 w / w.

[0060] In a specific embodiment, after forming an electrode array using screen printing or inkjet printing technology, the electrode array can be sintered to increase the conductivity of the electrodes. Cyclic voltammetry scanning of the electrodes in phosphate buffer solution is performed to form a porous structure to increase the specific surface area of ​​the electrodes. In the sintering process, the sintering temperature can be 100℃~200℃, such as 100℃, 110℃, 120℃, 130℃, 140℃, 150℃, 160℃, 170℃, 180℃, 190℃, 200℃, etc.; the sintering time can be 20min~40min, such as 20min, 25min, 30min, 35min, 40min, etc.; the sintering atmosphere can include a nitrogen atmosphere; the phosphate buffer concentration is 0.05M~0.15M, such as 0.05M, 0.1M, 0.15M, etc.; the potential window of the cyclic voltammetry scan can be -1.5V~0.5V; the number of cycles can be 8~12 cycles, such as 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles.

[0061] In a specific embodiment, a biodegradable metal material is patterned and deposited on the substrate layer 11 thin film to form an electrode layer 12 with multiple electrode arrays. The process also includes forming the electrode array structure using ultraviolet laser direct writing technology, preparing an electrolyte containing the biodegradable metal material, and electrodepositing to form the electrode array. The electrolyte containing the biodegradable metal material can be a mixed solution containing magnesium nitrate, nitric acid, and citric acid. During the preparation of the electrolyte, the concentration of magnesium nitrate can be 0.05M to 0.15M, for example, 0.05M, 0.1M, 0.015M, etc.; the concentration of nitric acid can be 0.005M to 0.015M, for example, 0.005M, 0.01M, 0.015M, etc.; and the concentration of citric acid can be 4mM to 6mM, for example, 4 mM, 5mM, 6 mM, etc.

[0062] In a specific embodiment, after electrode array is formed by electrodeposition, metal nanoparticles can be assembled on the surface of the working electrode 21 to increase the specific surface area of ​​the working electrode 21. The metal nanoparticles may include gold nanoparticles.

[0063] In a specific embodiment, the assembly of the aptamer 31 is performed using molecular self-assembly technology or covalent coupling. After assembling the aptamer 31 on the surface of each working electrode 21, the method further includes drop-coating an ion-selective polymer onto the surface of the aptamer 31 to encapsulate the aptamer 31. The ion-selective polymer may include, but is not limited to, perfluorosulfonic acid-based polymers.

[0064] According to embodiments of this disclosure, a monitoring system based on degradable flexible electronic devices overcomes the bottleneck of the lag in traditional monitoring methods, fulfills the need for real-time monitoring, and has significant timeliness advantages. Long-term monitoring can be completed with a single implantation after tumor surgery, and the system degrades after monitoring, avoiding the risks of infection and tumor spread from repeated minimally invasive examinations and the need for reoperation for removal. Furthermore, by assembling different aptamers corresponding to different tumor target biomarkers on multiple electrode arrays, in-situ synchronous detection of multiple tumor target biomarkers is achieved, improving the comprehensiveness and accuracy of monitoring and providing a more reliable basis for postoperative management decisions.

[0065] The technical solutions of this disclosure will be described in detail below through preferred embodiments. It should be noted that the specific embodiments in the following text are for illustrative purposes only and are not intended to limit this disclosure.

[0066] Example 1:

[0067] Step 1: Dissolve the polylactic acid-glycolic acid copolymer in chloroform solution to prepare a 15% w / v polylactic acid-glycolic acid copolymer chloroform solution. Use spin coating to form a 10µm thick polylactic acid-glycolic acid copolymer flexible film on a PET substrate. Vacuum dry at 80°C to remove the solvent and remove the PET substrate.

[0068] Step 2: A three-electrode array is fabricated on the polylactic acid-glycolic acid copolymer flexible film obtained in Step 1 using screen printing technology, with a minimum linewidth of 100 μm. The working electrode is printed using ink obtained by mixing zinc powder with a particle size of 0.5 μm and a polylactic acid-glycolic acid copolymer binder, with a zinc powder to polylactic acid-glycolic acid copolymer binder ratio of 7:3 w / w. The counter electrode is printed using ink obtained by mixing iron powder with a particle size of 1 μm and a polylactic acid-glycolic acid copolymer binder, with an iron powder to polylactic acid-glycolic acid copolymer binder ratio of 13:7 w / w. The reference electrode is printed using ink obtained by mixing Zn and ZnO in a 1:1 w / w ratio.

[0069] Step 3: The device obtained in Step 2 was sintered at 150°C for 30 min under a nitrogen atmosphere to enhance the conductivity of the electrode. Cyclic voltammetry was performed in 0.1 M phosphate buffer solution for 10 cycles with a potential window of -1.5 V to 0.5 V to form a porous electrode structure and improve the specific surface area of ​​the electrode.

[0070] Step 4: Assemble the aptamer of ovarian cancer tumor marker carbohydrate antigen-125 on the surface of the working electrode, and encapsulate the aptamer by drop-coating a perfluorosulfonic acid polymer.

[0071] Step 5: Coat the electrical connection structure of the three-electrode array with polylactic acid-glycolic acid copolymer.

[0072] Example 2:

[0073] Step 1: Dissolve silk fibroin in water to prepare a 6-8% w / v silk fibroin aqueous solution. Add 0.1% v / v glycerol solution to the silk fibroin aqueous solution and form a 100µm thick flexible silk fibroin film using a casting process.

[0074] Step 2: A three-electrode array is fabricated on the flexible silk fibroin film obtained in Step 1 using ultraviolet laser direct writing technology. An electrolyte consisting of 0.1M magnesium nitrate, 0.01M nitric acid, and 5mM citric acid is prepared, and magnesium electrodes are formed by electrodeposition. The surface of the working electrodes is then modified using gold nanoparticles.

[0075] Step 3: Assemble the aptamer of human epididymal protein-4, an ovarian cancer tumor marker, on the surface of the working electrode, and encapsulate the aptamer by drop-coating a perfluorosulfonic acid-based polymer.

[0076] Step 4: Coat the electrical connection structure of the three-electrode array with chitosan.

[0077] Those skilled in the art will understand that the features described in the various embodiments of this disclosure can be combined and / or combined in various ways, even if such combinations or combinations are not explicitly described in this disclosure. In particular, the features described in the various embodiments of this disclosure can be combined and / or combined in various ways without departing from the spirit and teachings of this disclosure. All such combinations and / or combinations fall within the scope of this disclosure.

[0078] The embodiments of this disclosure have been described above. However, these embodiments are for illustrative purposes only and are not intended to limit the scope of this disclosure. Although various embodiments have been described above, this does not mean that the measures in the various embodiments cannot be used advantageously in combination. Various substitutions and modifications can be made by those skilled in the art without departing from the scope of this disclosure, and all such substitutions and modifications should fall within the scope of this disclosure.

Claims

1. A biodegradable flexible electronic device for postoperative tumor monitoring, characterized in that, include: The basal layer, which provides support, is fixed to the area to be monitored after tumor surgery using a biocompatible hydrogel; An electrode layer is formed on the substrate layer in a patterned structure and forms multiple sets of electrode arrays, each set of electrode arrays being configured with a working electrode; An electrode modification layer is located on each of the working electrodes. An aptamer is assembled in the electrode modification layer for targeted binding and reaction with tumor target markers in the tumor monitoring area after tumor surgery, thereby changing the interface impedance of the working electrode and transmitting the interface impedance signal of the working electrode to an external receiving device. The external receiving device monitors the state of the interface impedance signal based on the interface impedance signal of the working electrode to obtain information on whether the tumor has recurred and / or metastasized in the tumor monitoring area after tumor surgery. as well as An encapsulation layer is formed on the electrode layer and covers each group of electrode arrays, while exposing each of the electrode modification layers; The substrate layer, the electrode layer, and the encapsulation layer are all made of biodegradable materials.

2. The biodegradable flexible electronic device according to claim 1, characterized in that, The aptamers in the electrode modification layer on each electrode array are of different types, and each type of aptamer is used to target and bind to its corresponding tumor marker and react accordingly.

3. The biodegradable flexible electronic device according to claim 2, characterized in that, Each electrode array is further configured with a counter electrode, a reference electrode, and an electrical connection structure for connecting the working electrode, the counter electrode, and the reference electrode. The encapsulation layer is used to cover the electrical connection structure in each electrode array. The counter electrode and the working electrode form a closed loop to balance the charge transfer generated after the aptamer and the tumor target marker target bind to each other on the working electrode and react, so that the reaction between the aptamer and the tumor target marker continues. The reference electrode is used to provide a predetermined potential reference to reduce the interference of environmental fluctuations in the monitored area after tumor surgery on the interface impedance of the working electrode.

4. The biodegradable flexible electronic device according to any one of claims 1 to 3, characterized in that, The thickness of the substrate layer is 1µm to 100µm; The thickness of the electrode layer is 100 nm to 10 μm; The thickness of the encapsulation layer is 1µm to 100µm; The degradation rates of the base layer, the electrode layer, and the encapsulation layer in the post-tumor monitoring area differ from each other.

5. The biodegradable flexible electronic device according to claim 4, characterized in that, The base layer material includes a biodegradable biosafe polymer, which includes any one of the following: polylactic acid-glycolic acid copolymer, polylactic acid, silk fibroin, and cellulose; The electrode layer is made of a biodegradable metallic material, which includes any one of the following: magnesium, zinc, iron, molybdenum, and tungsten; The encapsulation layer is made of biodegradable biocompatible materials, including polylactic acid-glycolic acid copolymer, gelatin, or chitosan.

6. A method for preparing a biodegradable flexible electronic device, characterized in that, include: Degradable biosafe polymers are dissolved in a solvent and then formed into a base layer film through solution casting or spin coating processes. A degradable metallic material is patterned and deposited on the substrate thin film to form an electrode layer with multiple sets of electrode arrays, each set of electrode arrays being configured with a working electrode; An electrode modification layer is formed on the surface of each working electrode, and an adapter is assembled in the electrode modification layer; as well as Each electrode array is encapsulated and the electrode modification layer is exposed to form an encapsulation layer.

7. The preparation method according to claim 6, characterized in that, The process of patterning and depositing a degradable metal material on the substrate film to form an electrode layer with multiple electrode arrays includes: preparing a mixed ink of the degradable metal material and a polylactic acid-glycolic acid copolymer adhesive, and forming the electrode array using screen printing or inkjet printing technology.

8. The preparation method according to claim 6, characterized in that, The step of patterning and depositing a biodegradable metal material on the substrate thin film to form an electrode layer with multiple electrode arrays further includes: forming the structure of the electrode array using ultraviolet laser direct writing technology, preparing an electrolyte containing the biodegradable metal material, and electrodepositing to form the electrode array.

9. The preparation method according to any one of claims 6 to 8, characterized in that, The method further includes forming an electrode modification layer on the surface of each working electrode, wherein an aptamer is assembled in the electrode modification layer, and encapsulating the aptamer by drop-coating a polymer onto the surface of the aptamer.

10. A biodegradable flexible electronic monitoring device, characterized in that, The device includes a power supply device, a transmission device, an external receiving device, and a biodegradable flexible electronic device as described in any one of claims 1 to 5. The power supply device and the transmission device are electrically connected to an electrode layer on the biodegradable flexible electronic device and are disposed on the biodegradable flexible electronic device. A power supply device for providing electrical energy to the electrode layer; A transmission device for transmitting the interface impedance signal from the working electrode on the electrode layer to an external receiving device; and An external receiving device is disposed outside the area to be monitored after tumor surgery, and is used to monitor the state of the interface impedance signal based on the interface impedance signal of the working electrode; The power supply device and the transmission device are both made of biodegradable materials.

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