Physiological and biochemical diagnosis and treatment integrated implantable heart flexible sensor

Abstract

The invention belongs to the technical field of electrochemical monitoring, and particularly relates to a physiological and biochemical diagnosis and treatment integrated implantable heart flexible sensor which comprises an insulating substrate, a counter electrode, a working electrode, a reference electrode and two electrocardiogram electrodes, graphene aerogel loaded with a monitoring substance is adhered to the working end of the working electrode, and the monitoring substance is a substance for monitoring biochemical signals. The implantable heart flexible sensor provided by the invention can realize trinity collaborative operation of physiological signal monitoring, biochemical signal monitoring and treatment functions. In the aspect of monitoring physiological signals, the system has the advantages of high signal-to-noise ratio, dynamic adaptability, long-term stability and the like; in the aspect of monitoring biochemical signals, the sensor has the advantages of high sensitivity and high stability; in the aspect of treatment, the device has the characteristics of promoting electrical signal conduction, being flexibly attached to the heart, providing three-dimensional structure support regeneration and being stable for a long time.

Description

Technical Field

[0001] This invention belongs to the field of electrochemical monitoring technology, specifically relating to an implantable flexible cardiac sensor that integrates physiological and biochemical diagnosis and treatment. Background Technology

[0002] As a key medical device, cardiac sensors can accurately capture a variety of heart-related information, providing crucial data support for the monitoring, diagnosis, and treatment of heart diseases. Key physiological signals of the heart include electrocardiogram (ECG), phonocardiogram (PCG), pulse wave velocity (PWV), and blood pressure. Key biomolecular markers of the heart include reactive oxygen species (ROS), troponin (cTnI / cTnT), myoglobin, C-reactive protein (CRP), and B-type natriuretic peptide (BNP), which can be used to detect diseases such as myocardial infarction and heart failure.

[0003] Currently, much research focuses on single-function sensors. Wearable electrophysiological devices are mainly used to monitor physiological signals of the heart, such as flexible ECG electrodes, smart stethoscopes, and wireless pressure sensors. Relevant references include: CellRep.Phys.Sci.,2(2021),100541; IEEE Sens.J.22(2022),18045–18055; J.Clin.Med.2024,13(4),1033. In contrast, fiber optic and electrochemical sensor devices are mostly external devices, primarily monitoring biochemical signals of the heart. Among them, fiber optic sensors use light signals to detect biomarkers (such as troponin), while electrochemical sensors detect biomarkers through antigen-antibody reactions or enzyme catalysis. They have the advantages of rapid response and low cost. Relevant references include: Bioelectron. 210(2022), 114328; Molecules 2021, 26(14), 4252; ACS Omega, 5(2020), 3924–3931.

[0004] Despite the progress made in the field of cardiac sensors, there are still many challenges to achieving integrated physiological and biochemical diagnosis and treatment.

[0005] The complexity of integrated design is one of the major obstacles. Monitoring physiological signals, biochemical signals, and therapeutic functions often require different hardware and software systems, which are prone to conflict in their operating principles, signal processing, or energy requirements. For example, monitoring physiological signals relies on highly sensitive electrodes and sophisticated signal amplification circuits, while the operating voltage and current characteristics of the electrical stimulation system used in therapy differ greatly, easily causing conflicts that can lead to unstable device operation. Furthermore, cardiac sensors typically need to be miniaturized to fit implantation or wearability in the human body, but integrating multiple functions increases the size and complexity of the device, affecting its applicability and wearing comfort.

[0006] Signal interference also hinders the development of sensors. Electrical stimulation during treatment generates electromagnetic interference, which can seep into the circuitry used to monitor cardiac physiological signals, causing distortion and increased noise. This severely affects the accuracy and stability of physiological signal monitoring, leading to misjudgments of the heart's condition. Simultaneously, drugs or energy released during treatment alter the local biochemical environment, interfering with biochemical signal sensors' monitoring of cardiac biochemical indicators, thus failing to accurately reflect the heart's biochemical state.

[0007] Furthermore, energy supply is also a major challenge. Simultaneously operating physiological and biochemical signal monitoring and therapeutic functions significantly increases the device's energy consumption. The energy density of conventional batteries is insufficient to meet the long-term operational needs of the cardiac sensors. In the in vivo environment, wireless power transmission efficiency is low, making it impossible to guarantee stable device operation.

[0008] Materials and biocompatibility issues cannot be ignored. Materials required for monitoring and treatment functions may differ in biocompatibility, durability, and chemical stability, and can easily interact within the same device, affecting its performance. In the body environment, bodily fluids can cause material corrosion and degradation, while biofilm formation can also cover the material surface, affecting its performance. These changes in materials can lead to gradual device failure, making it impossible to achieve long-term, stable integration of physiological and biochemical diagnostics and treatment.

[0009] In conclusion, although cardiac sensor technology has made some progress, existing sensors still cannot meet the needs of integrated physiological and biochemical diagnosis and treatment. Summary of the Invention

[0010] The purpose of this invention is to solve the problems in the prior art and to propose an implantable flexible cardiac sensor that integrates physiological and biochemical diagnosis and treatment.

[0011] To achieve the above objectives, the present invention adopts the following technical solution:

[0012] An implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment includes an insulating substrate and a counter electrode, a working electrode, a reference electrode, and two electrocardiogram electrodes printed on the insulating substrate. The working end of the working electrode is attached with a graphene aerogel loaded with a monitoring substance, which is a substance used to monitor biochemical signals.

[0013] The implantable flexible cardiac sensor of this invention, integrating physiological and biochemical diagnostic and therapeutic functions, achieves a three-in-one synergistic function of physiological signal monitoring, biochemical signal monitoring, and treatment. Specifically, the electrocardiogram electrode can collect cardiac physiological signals (i.e., electrical signals), capturing key electrophysiological parameters such as the P wave, QRS complex, and T wave in animal electrocardiograms in real time; the working electrode, loaded with monitoring substances, is composed of graphene aerogel that can monitor specific cardiac biochemical signals, such as reactive oxygen species (including hydrogen peroxide and superoxide anion), cardiac troponin I (cTnI), and brain natriuretic peptide (BNP); and the high conductivity of the graphene aerogel can reconstruct cardiac electrical conduction pathways, treating cardiac electrical conduction abnormalities such as myocardial infarction and arrhythmias.

[0014] The implantable flexible cardiac sensor of this invention, integrating physiological and biochemical diagnostics, offers advantages such as high signal-to-noise ratio, dynamic adaptability, and long-term stability when monitoring physiological signals. The principle of the electrocardiogram (ECG) electrodes acquiring cardiac physiological signals is based on the synergistic effect of cardiac electrophysiological activity and electrochemical conversion at the electrode-tissue interface. The two ECG electrodes are printed with carbon ink, which has high conductivity. The ionic current generated by cardiac electrical activity undergoes an electrochemical reaction (such as a redox reaction) on the electrode surface, converting it into a measurable electronic current. The double-layer capacitance of carbon ink helps buffer low-frequency signal fluctuations, ensuring signal quality and giving the sensor a high signal-to-noise ratio. The insulating substrate is made of a flexible material, ensuring dynamic adhesion between the electrodes and cardiac tissue, reducing motion artifacts, and enabling real-time capture of key electrophysiological parameters such as the P wave, QRS complex, and T wave in animal ECGs, thus giving the sensor dynamic adaptability. Both the ECG electrodes and the flexible insulating substrate material have good corrosion resistance and biocompatibility, allowing for long-term monitoring in vivo, thus ensuring long-term stability of the sensor.

[0015] The implantable flexible cardiac sensor for physiological and biochemical diagnosis of the present invention has the advantages of high sensitivity and high stability when monitoring biochemical signals. Graphene aerogel, as the loading substrate for the monitored substance, has a high conductivity (5-15 S / cm), which significantly improves the sensor's sensitivity to changes in electron current. This is because the three-dimensional continuous conductive network of graphene aerogel can greatly reduce the internal resistance of electron transport, accelerate the transfer efficiency of reaction electrons, and according to Ohm's law (V=IR), low resistance (R) reduces voltage drop (V), thereby amplifying the signal-to-noise ratio of the current signal (I), making minute concentration changes easier to detect. Secondly, the highly conductive substrate can suppress the double-layer capacitance effect and background noise, reduce interfacial contact impedance, and enhance the distinction between Faraday current and background signals. Furthermore, the synergistic effect of the three-dimensional continuous conductive network and the monitored substance can optimize the electronic structure of catalytic active sites, reduce the activation energy of the reduction reaction of the monitored substance, and accelerate reaction kinetics. Therefore, the sensor of the present invention has high sensitivity when monitoring biochemical signals.

[0016] The three-dimensional continuous conductive network of graphene aerogel possesses a high specific surface area, providing numerous uniform loading sites for the monitored substance, thereby significantly improving sensor stability. Furthermore, the continuous conductive network of graphene aerogel not only provides a low-resistance electron transport path, but its porous structure also promotes electrolyte permeation and ion diffusion, ensuring continuous and efficient operation of the reaction interface and reducing performance degradation caused by polarization or limited mass transfer. The three-dimensional structure of graphene aerogel also buffers against direct impacts from external environments (such as temperature changes, humidity variations, or chemical corrosion). Simultaneously, the highly conductive substrate suppresses side reactions (such as oxidative decomposition) through rapid electron transfer, further extending sensor lifespan. This physicochemical synergy enables graphene aerogel to stably load the monitored substance, thus ensuring reliable sensor performance in long-term use and complex environments.

[0017] The implantable flexible cardiac sensor of this invention, integrating physiological and biochemical diagnostics and therapy, offers advantages such as promoting electrical signal conduction, flexible fit to the heart, three-dimensional structural support for regeneration, and long-term stability during treatment. After implantation into the myocardial infarction or fibrosis area, the three-dimensional conductive network of graphene aerogel can cross non-conductive scar tissue, forming an "artificial electrical bypass," restoring electrical signal synchronicity and suppressing arrhythmias. Its flexible porous structure is mechanically matched to the myocardium, allowing it to dynamically deform with the heart and reduce mechanical damage. The three-dimensional network simulates the extracellular matrix, promoting cardiomyocyte regeneration, stem cell differentiation, and angiogenesis through electroactive microenvironment regulation, while simultaneously inhibiting fibrosis. Its biocompatibility ensures long-term safety in the heart.

[0018] As a preferred technical solution:

[0019] The above-described implantable flexible cardiac sensor, which integrates physiological and biochemical diagnostics, uses polyimide (PI) as its insulating substrate. PI has good chemical stability and electrical insulation properties, and its thickness is 20-60 μm. It is flexible and easier to fit onto the heart.

[0020] As shown above, an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment has a working electrode printed with gold ink or carbon ink, a counter electrode printed with gold ink or carbon ink, a reference electrode printed with silver / silver chloride ink, and an electrocardiogram electrode printed with gold ink or carbon ink.

[0021] As shown above, an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment has an insulating layer coated on the areas of the counter electrode, working electrode, reference electrode, and electrocardiogram electrode, except for the working end, to isolate interference from other biological signals and prevent short circuits.

[0022] As shown above, an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment involves printing counter electrodes, working electrodes, reference electrodes, and two electrocardiogram electrodes on an insulating substrate. The process is as follows: a screen is placed on the insulating substrate, and conductive ink corresponding to each electrode is evenly squeezed through the screen using a squeegee to ensure precise printing in the predetermined positions. After this, the screen is dried or cured. The design of the screen must be determined according to the shape, size, conductivity, and other requirements of the electrodes. Before placing the screen on the insulating substrate, the substrate must be cleaned. Common methods include ultrasonic cleaning, deionized water washing, and drying to ensure the absence of oil, dust, and other impurities, thereby improving printing quality.

[0023] As shown above, an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment is used. The graphene aerogel loaded with the monitoring material completely covers the working end of the working electrode, and the two have the same shape and size.

[0024] As shown above, the process of attaching graphene aerogel carrying the monitoring substance to the working end of the working electrode of a physiological and biochemical diagnostic and therapeutic implantable flexible cardiac sensor is as follows: After attaching the graphene aerogel carrying the monitoring substance to the working end of the working electrode with conductive silver paste, it is dried at 80-100℃ for 10-20 minutes.

[0025] The above-described implantable flexible cardiac sensor, integrating physiological and biochemical diagnostics, uses graphene aerogel with a thickness of 500-1000 μm and a specific surface area of ​​1000-1200 m². 2 / g, porosity 95-99%, pore size 5-20μm, electrical conductivity 5-15S / cm; particle size of the monitored substance 40-100nm; loading area of ​​the monitored substance on the surface of the graphene aerogel 99-100%; loading area of ​​the monitored substance in the pores of the graphene aerogel 90-99%.

[0026] Heart tissue is a complex, electroexcitable three-dimensional (3D) structure, requiring repair materials to simultaneously meet multiple needs, including structural support, electrical signal conduction, nutrient transport, and cell interaction. Therefore, this invention utilizes the synergistic effect of graphene aerogel's thickness, specific surface area, porosity, pore size, and conductivity to enable it to function as a structurally matched, electrophysiologically active, nutrient-permeable, and cell-friendly 3D scaffold, effectively treating cardiac injuries. Deviation from any of these parameters can lead to functional failure.

[0027] The graphene aerogel of this invention has a thickness of 500-1000 μm, ensuring that it can span most of the damaged area and provide a sufficiently thick, low-resistance pathway for the current. This allows the electrical pulse to bypass scar tissue and simultaneously activate the underlying and surrounding myocardial cells, preventing arrhythmias. It also provides adequate mechanical strength to support myocardial contraction, preventing ventricular wall thinning and aneurysm formation. When the thickness is too small (less than 500 μm), it cannot effectively transmit electrical signals, has no therapeutic effect from electrical conduction, and may even lead to insufficient support, causing the heart to gradually enlarge. When the thickness is too large (greater than 1000 μm), it can also hinder the heart's own beating, causing myocardial tissue to stiffen and the heart to become increasingly enlarged.

[0028] The graphene aerogel of this invention has a specific surface area of ​​1000-1200 m². 2 / g, such a high specific surface area can provide a huge space for the adhesion, migration and proliferation of a large number of cardiomyocytes, fibroblasts and endothelial cells to mimic the natural extracellular matrix (ECM).

[0029] The graphene aerogel of this invention has a pore size of 5-20 μm, which ensures that cardiomyocytes with a diameter of 10-20 μm can easily migrate into the aerogel and extend and connect within it to form a three-dimensional functional network. If the pore size is too small (e.g., <5 μm), it will physically block cell entry, while if the pore size is too large (e.g., >20 μm), it will reduce the specific surface area, which is not conducive to cell adhesion, and the mechanical strength will decrease.

[0030] The graphene aerogel of this invention has a porosity of 95-99%, which ensures that nutrients such as oxygen, glucose, and growth factors can freely diffuse into the depths of the material, while metabolic waste can also be smoothly discharged. This is crucial for long-term cell survival and functionalization; if the porosity is below 95%, cell necrosis may occur in the central region of the material. Furthermore, the larger porous network provides channels and space for the ingrowth of new blood vessels, which is essential for the long-term survival and functional integration of the transplanted material.

[0031] The graphene aerogel of this invention has an electrical conductivity of 5-15 S / cm, which is much higher than that of natural myocardial tissue. It can form a rapid conductive pathway, quickly and uniformly conduct bioelectrical signals, effectively bridging scar areas and resynchronizing the beating heart. If the conductivity is too low, it is no different from insulating scar tissue and cannot improve electrical conduction.

[0032] As shown above, an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment also includes an electrochemical device and a Bluetooth ECG device. The non-working ends of the counter electrode, working electrode, and reference electrode are simultaneously connected to the electrochemical device, and the non-working ends of the two ECG electrodes are simultaneously connected to the Bluetooth ECG device.

[0033] As shown above, an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment, when the biochemical signal is hydrogen peroxide and the monitoring substance is Prussian blue nanoparticles, exhibits a sensitivity of 500-600 μA / (mM×cm) for monitoring biochemical signals. 2 The detection limit is 1-5 μM, the linear range is (1-5)-(800-1000) μM, and the response time is 0.5-2 s. After 500 continuous tests, the detection current change rate is 1-5%. After 20 days of continuous testing, the detection current change rate is 2-7%. During the testing process, when bioactive substances are added to the test subject, the detection current change rate is 1-3%. The bioactive substances are one or more of ascorbic acid, glucose, dopamine, urea, and uric acid.

[0034] In existing technologies, the substrate materials used for loading Prussian blue in sensors for monitoring hydrogen peroxide are mainly divided into metallic materials and carbon materials. When using metallic materials as substrates, the sensor has relatively high sensitivity but poor stability. For example, the literature (S. Electroanalysis, (2013), 25:2211-2220.) prepared a novel Prussian blue / copper-gold bimetallic nanoparticle hybrid film modified electrode (PB / Cu-AuNPs / GCE) on a glassy carbon electrode by electrochemical deposition. Because the sensor does not integrate the working electrode and the counter electrode, a three-electrode system of electrochemical instruments was used to evaluate the sensor's performance. Compared with a single Prussian blue modified electrode (PB / GCE), this sensor showed significantly better electrocatalytic activity in the hydrogen peroxide reduction reaction. However, the long-term stability of the sensor, the selectivity in complex samples, and the complexity of the preparation process are still directions that require further research and improvement as mentioned in the literature. When using carbon materials as substrates, the sensor's stability is improved, but the sensitivity is lower. For example, the literature (Electrochimica Acta 89(2013):454-460.) describes the application of reduced graphene oxide (RGO) suspension droplets onto the surface of a glassy carbon electrode (GC). After drying, an RGO-based electrode is formed. Prussian blue (PB) is then deposited onto the RGO electrode via electrochemical deposition, forming a GC / RGO / PB electrode. Because the sensor does not integrate a working electrode and a counter electrode, a three-electrode system of an electrochemical instrument is used to evaluate the sensor's performance. However, the highest sensitivity exhibited by the electrode is only 420 μA / (mM*cm). 2 Therefore, existing sensors for monitoring hydrogen peroxide cannot simultaneously possess the advantages of high sensitivity and high stability. This invention improves the sensitivity and stability of the sensor by optimizing the substrate material (three-dimensional graphene aerogel), overcoming the limitations of poor stability of traditional metal substrates or insufficient sensitivity of carbon substrates.

[0035] In addition to hydrogen peroxide, the biochemical signal of the implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment of the present invention can also be other signals, in which case the monitored substance needs to adapt to changes.

[0036] Existing technologies also utilize aerogels in sensors, primarily relying on the deformation of the aerogel itself to induce changes in electrical signals, thereby achieving monitoring functions, and mainly for detecting motion signals. The detection principle is as follows: when the aerogel is subjected to external stimuli, such as pressure, stretching, or compression, it deforms, causing changes in its internal conductive network, which in turn leads to changes in electrical signals such as resistance, capacitance, or current. By measuring these changes in electrical signals, the intensity or type of external stimulus can be indirectly reflected.

[0037] Unlike existing technologies, this invention utilizes the synergistic effect of the highly efficient three-dimensional continuous conductive network of graphene aerogel and the electrocatalytic properties of the monitored substance to achieve detection functionality. It is used to detect biochemical molecules (such as hydrogen peroxide) signals. The detection principle is as follows: when the sensor comes into contact with a sample containing hydrogen peroxide (H2O2), the monitored substance catalyzes its reduction reaction (H2O2 + 2H+). + +2e - →2H₂O), the generated electrons are rapidly transferred to the electrode through the three-dimensional continuous conductive network of the aerogel, forming a current signal positively correlated with the H₂O₂ concentration. The high conductivity (5-15 S / cm) of graphene aerogel can significantly reduce electron transport resistance. Its porous structure, due to its high specific surface area, can load more monitoring substances, and the stability of catalytic sites is enhanced by physical confinement and chemical bonding. At the same time, the high selective catalysis of the monitoring substances combined with the anti-interference properties of graphene aerogel effectively suppresses interference from other electroactive substances. Compared with traditional sensors that rely on physical deformation, this invention achieves highly sensitive and specific detection of biochemical molecules through the synergistic effect of a highly conductive substrate and electrochemical activity, expanding the application potential of graphene aerogel in the fields of biomedicine and environmental monitoring.

[0038] The electrical signal acquisition module of the implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment of the present invention adopts the same module (i.e., the BM101 module) as the medical-grade electrocardiograph (the gold standard for monitoring). This module has low system noise and controllable gain, and can effectively monitor biological signals in the range of μV to mV; the sampling frequency is 512Hz, which can accurately monitor most experimental organisms with heart rates below this frequency.

[0039] The implantable flexible cardiac sensor of the present invention, which integrates physiological and biochemical diagnosis and treatment, has the effect of electrocardiogram therapy. After the graphene aerogel loaded with the monitoring material is in contact with the heart lesion site of an animal for 10 minutes, the QRS interval is reduced by 50%-60%, the QT interval is reduced by 60%-70%, and the QTc interval is reduced by 60%-70%.

[0040] The implantable flexible cardiac sensor of the present invention, which integrates physiological and biochemical diagnosis and treatment, has a biochemical therapeutic effect. After the graphene aerogel loaded with the monitoring substance comes into contact with the heart lesion site of an animal for 10-30 minutes, the reactive oxygen species generated after myocardial infarction completely disappears, and the number of apoptotic cells is reduced.

[0041] Beneficial effects

[0042] The implantable flexible cardiac sensor of this invention enables the integrated operation of physiological signal monitoring, biochemical signal monitoring, and therapeutic functions. In monitoring physiological signals, it boasts advantages such as high signal-to-noise ratio, dynamic adaptability, and long-term stability; in monitoring biochemical signals, it exhibits high sensitivity and strong stability; and in therapeutic applications, it promotes electrical signal conduction, flexibly conforms to the heart, provides three-dimensional structural support for regeneration, and offers long-term stability. Attached Figure Description

[0043] Figure 1 This is a schematic diagram showing the positional relationship of each electrode in the implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment of the present invention.

[0044] Figure 2 This is an electrocardiogram of an animal after the implantable flexible cardiac sensor, which integrates physiological and biochemical diagnosis and treatment, was implanted in the heart of an animal in Comparative Example 1 of the present invention.

[0045] Figure 3 This is an echocardiogram of the implantable flexible cardiac sensor for physiological and biochemical diagnosis and treatment in Comparative Example 2 of the present invention after being implanted into the heart of an animal.

[0046] Figure 4 This is a schematic diagram of myocardial fluorescence staining after the implantable flexible cardiac sensor for physiological and biochemical diagnosis and treatment was implanted into the heart of an animal in Comparative Example 3 of the present invention; in the figure, the myocardial fluorescence staining sections of CD31 (green) and α-SMA (red) represent new angiogenesis;

[0047] Figure 5 This is a schematic diagram of myocardial fluorescence staining after the implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment was implanted into the heart of an animal in Embodiment 1 of the present invention.

[0048] Figure 6 The electrocardiogram of the implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment in Comparative Example 4 of the present invention after being implanted in the heart of an animal.

[0049] Figure 7 This is an electrocardiogram of an animal after the implantable flexible cardiac sensor, which integrates physiological and biochemical diagnosis and treatment, was implanted into the heart in Embodiment 1 of the present invention.

[0050] Figure 8This is an echocardiogram of an animal after the implantable flexible cardiac sensor, which integrates physiological and biochemical diagnosis and treatment, was implanted into the heart in Embodiment 1 of the present invention.

[0051] Figure 9 This is a schematic diagram showing the dimensions of the implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment according to the present invention.

[0052] Among them, 1-negative electrode of electrocardiogram, 2-positive electrode of electrocardiogram, 3-counter electrode, 4-working electrode, 5-reference electrode, and 6-insulating layer. Detailed Implementation

[0053] The present invention will be further described below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0054] The detection methods for the relevant indicators in this embodiment are as follows:

[0055] The loading area of ​​the monitoring material (Prussian blue nanoparticles) on the surface of the graphene aerogel and the loading area of ​​the monitoring material (Prussian blue nanoparticles) in the pores of the graphene aerogel were obtained by scanning electron microscopy (SEM) images of the surface and pores of the graphene aerogel loaded with the monitoring material and calculated using ImageJ software.

[0056] The sensitivity testing steps are as follows:

[0057] (1) Connect the three electrodes of the sensor to the electrochemical workstation (Autolab), immerse them in a solution containing 0.1M HCl / KCl, and use a cyclic voltammetry program with the following parameters: scan voltage range -0.1 to 0.4V, scan rate 0.01 to 0.08V / s, and 10 to 30 cycles to stabilize the Prussian blue nanoparticles.

[0058] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution containing 0.1M KCl in 1X PBS. Use a time-current program and set the monitoring voltage to -0.1 to -0.5V. Before adding hydrogen peroxide, activate the sensor for 60-100 minutes. Add hydrogen peroxide to the solution for the first time until the concentration of hydrogen peroxide in the monitoring solution is 10μM. After the current stabilizes, repeat the addition of an equal amount of hydrogen peroxide 3-5 times. After each addition of hydrogen peroxide, obtain the current difference. Calculate the sensitivity each time using the formula "Sensitivity = Current Difference / (Initial value of hydrogen peroxide concentration in the monitoring solution after each addition of hydrogen peroxide × Electrode Surface Area)". Use the average value of all the sensitivities as the sensitivity of the sensor.

[0059] The testing steps for the monitoring lower limit are as follows:

[0060] (1) Connect the three electrodes of the sensor to the electrochemical workstation (Autolab), immerse them in a solution containing 0.1M HCl / KCl, and use a cyclic voltammetry program with the following parameters: scan voltage range -0.1 to 0.4V, scan rate 0.01 to 0.08V / s, and 10 to 30 cycles to stabilize the Prussian blue nanoparticles.

[0061] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution containing 0.1M KCl in 1X PBS. Use a time-current program and set the monitoring voltage to -0.1 to -0.5V. Before adding hydrogen peroxide, activate the sensor for 60-100 minutes. Add hydrogen peroxide to the solution for the first time until the concentration of hydrogen peroxide in the monitoring solution is 10μM. After the current stabilizes, add an equal amount of hydrogen peroxide to the solution in the same way until the concentration of hydrogen peroxide in the monitoring solution is 10μM, 10μM, 20μM, 50μM, 100μM, 200μM, 200μM, 200μM, 200μM, 200μM, 200μM, 200μM, and 200μM respectively. Obtain the current difference after each time the target hydrogen peroxide concentration is reached.

[0062] (3) Plot the standard curve of hydrogen peroxide concentration-current difference in the monitoring solution and calculate the slope S by linear fitting. The final monitoring limit (LOD) is obtained by the formula "LOD=3.3σ / S". σ can be measured in two ways: one is to measure the blank value, that is, the standard deviation of the sensor current when the hydrogen peroxide concentration in the monitoring solution is zero, which is σ; the other is the standard deviation of the residual standard deviation or the standard deviation of the intercept of the standard curve.

[0063] The testing steps for linear intervals are as follows:

[0064] (1) Connect the three electrodes of the sensor to the electrochemical workstation (Autolab), immerse them in a solution containing 0.1M HCl / KCl, and use a cyclic voltammetry program with the following parameters: scan voltage range -0.1 to 0.4V, scan rate 0.01 to 0.08V / s, and 10 to 30 cycles to stabilize the Prussian blue nanoparticles.

[0065] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution containing 0.1M KCl in 1X PBS. Use a time-current program and set the monitoring voltage to -0.1 to -0.5V. Before adding hydrogen peroxide, activate the sensor for 60-100 minutes. Add hydrogen peroxide to the solution for the first time until the concentration of hydrogen peroxide in the monitoring solution is 10μM. After the current stabilizes, repeat the same steps to add an equal amount of hydrogen peroxide to the solution until the monitoring current starts to rise. This indicates that the sensor has reached the upper limit of hydrogen peroxide monitoring. At this time, the total concentration of hydrogen peroxide in the monitoring solution is the upper limit of the linear interval. The linear interval range is composed of the lower limit of monitoring to the upper limit concentration. The method for obtaining the lower limit of monitoring has been described above.

[0066] The steps for testing response time are as follows:

[0067] (1) Connect the three electrodes of the sensor to the electrochemical workstation (Autolab), immerse them in a solution containing 0.1M HCl / KCl, and use a cyclic voltammetry program with the following parameters: scan voltage range -0.1 to 0.4V, scan rate 0.01 to 0.08V / s, and 10 to 30 cycles to stabilize the Prussian blue nanoparticles.

[0068] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution containing 0.1M KCl in 1X PBS. Use a time-current program and set the monitoring voltage to -0.1 to -0.5V. Before adding hydrogen peroxide, activate the sensor for 60-100 minutes. Add hydrogen peroxide to the solution for the first time until the concentration of hydrogen peroxide in the monitoring solution is 100μM. After the current stabilizes, calculate the time difference from the start of the change to the stabilization. Repeat the operation of adding an equal amount of hydrogen peroxide until the concentration of hydrogen peroxide in the monitoring solution is 100μM and calculating the time difference. Take the average value of each time difference as the sensor response time.

[0069] The test steps for monitoring the rate of change of current are as follows:

[0070] (1) Connect the three electrodes of the sensor to the electrochemical workstation (Autolab), immerse them in a solution containing 0.1M HCl / KCl, and use a cyclic voltammetry program with the following parameters: scan voltage range -0.1 to 0.4V, scan rate 0.01 to 0.08V / s, and 10 to 30 cycles to stabilize the Prussian blue nanoparticles.

[0071] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution containing 0.1M KCl in 1X PBS. Use a timed current program and set the monitoring voltage to -0.1 to -0.5V. Before adding hydrogen peroxide, activate the sensor for 60-100 minutes. Add hydrogen peroxide to the solution for the first time until the concentration of hydrogen peroxide in the monitoring solution is 100μM. After the current stabilizes, record the current difference at this time as the initial current difference of the sensor. Then, use the same steps to continuously monitor the current difference for 2-500 times or for 2-20 days (perform the operation once a day, and perform the same operation on the same sensor again the next day). Calculate the stability monitoring current change rate according to the formula "Stability monitoring current change rate = 100% × |current difference of n times or n days - initial current difference| / initial current difference".

[0072] The test procedure for monitoring the rate of change of current (with the addition of bioactive substances) is as follows:

[0073] (1) Connect the three electrodes of the sensor to the electrochemical workstation (Autolab), immerse them in a solution containing 0.1M HCl / KCl, and use a cyclic voltammetry program with the following parameters: scan voltage range -0.1 to 0.4V, scan rate 0.01 to 0.08V / s, and 10 to 30 cycles to stabilize the Prussian blue nanoparticles.

[0074] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution containing 0.1M KCl in 1X PBS. Use a time-current program and set the monitoring voltage to -0.1 to -0.5V. Activate the sensor for 60-100 minutes before adding hydrogen peroxide. Add hydrogen peroxide to the solution for the first time until the concentration of hydrogen peroxide in the monitoring solution is 100μM. After the current stabilizes, record the current value as the initial current value of the sensor. Then add bioactive substances to the solution until the concentration of bioactive substances in the monitoring solution is 100μM. After the current stabilizes, record the current value as the monitoring current value of the sensor for the bioactive substances. Calculate the monitoring current change rate according to the formula "Monitoring current change rate = 100% × |Monitoring current value of bioactive substances - Initial current value| / Initial current value".

[0075] QRS interval:

[0076] (1) QRS interval testing after animal myocardial infarction modeling

[0077] Animal electrocardiograms were measured using a lead II configuration, with the negative electrode of a needle connected to the animal's right upper limb and the positive electrode connected to the animal's left lower limb. The electrocardiogram was recorded by connecting to a computer via a Bluetooth electrocardiogram acquisition device. The acquisition time was 60-200 seconds. All QRS intervals within the acquisition time were calculated, and the average value was taken as the QRS interval value during myocardial infarction in the animal.

[0078] (2) QRS interval testing after sensor treatment

[0079] First, the sensor was placed parallel to the long axis of the heart and attached tightly to the outer wall of the left ventricle. After 10 minutes of treatment, the animal's electrocardiogram (ECG) was measured. The ECG measurement was also performed using the II lead method, with the negative electrode of the sensor's ECG electrode on top and the positive electrode on the bottom. The animal's ECG was recorded by connecting to a computer via a Bluetooth ECG acquisition device. The acquisition time was 60-200 seconds. All QRS intervals during the acquisition time were calculated, and the average value was taken as the QRS interval value after sensor treatment.

[0080] By comparing the QRS interval values ​​with those of animals during myocardial infarction, the changes in QRS interval values ​​after sensor treatment were interpreted.

[0081] QT interval changes:

[0082] (1) QT interval testing after animal myocardial infarction modeling

[0083] Animal electrocardiograms were measured using a lead II configuration, with the negative electrode of a needle connected to the animal's right upper limb and the positive electrode connected to the animal's left lower limb. The animal's electrocardiogram was recorded via a Bluetooth electrocardiogram acquisition device connected to a computer. The acquisition time was 60-200 seconds. All QT intervals within the acquisition time were calculated, and the average value was taken as the QT interval value during myocardial infarction in the animal.

[0084] (2) QT interval testing after sensor therapy

[0085] First, the sensor was placed parallel to the long axis of the heart and attached tightly to the outer wall of the left ventricle. After 10 minutes of treatment, the animal's electrocardiogram (ECG) was measured. The ECG measurement was also performed using the II lead method, with the negative electrode of the sensor's ECG electrode on top and the positive electrode on the bottom. The animal's ECG was recorded by connecting to a computer via a Bluetooth ECG acquisition device. The acquisition time was 60-200 seconds. All QT intervals during the acquisition time were calculated, and the average value was taken as the QT interval value after sensor treatment.

[0086] By comparing the QT interval values ​​with those of animals during myocardial infarction, the changes in QT interval values ​​after sensor treatment were interpreted.

[0087] QTc interval changes:

[0088] (1) QTc interval testing after animal myocardial infarction modeling

[0089] Animal electrocardiograms (ECGs) were measured using a lead II configuration, with the negative electrode of a needle connected to the animal's right upper limb and the positive electrode connected to the left lower limb. The ECG was recorded via a Bluetooth-connected computer. The acquisition time was 60-200 seconds. All QTc intervals were calculated within the acquisition time using Bazett's formula: QTc = QT / RR. 0.5Calculate the QTc value (RR is the time interval between two adjacent R waves), and use the average value as the QTc interval value during myocardial infarction in animals;

[0090] (2) QTc interval testing after sensor therapy

[0091] First, the sensor was placed parallel to the long axis of the heart and firmly attached to the ventricular wall of the left ventricle. After 10 minutes of treatment, the animal's electrocardiogram (ECG) was measured. The ECG measurement was also performed using lead II, with the negative electrode of the sensor's ECG electrode at the top and the positive electrode at the bottom. The animal's ECG was recorded via a Bluetooth ECG acquisition device connected to a computer. All QTc intervals were calculated during the acquisition time. According to Bazett's formula, QTc = QT / RR, the intervals were calculated. 0.5 Calculate the QTc value (RR is the time interval between two adjacent R waves), and use the average value as the QTc interval value after sensor treatment;

[0092] By comparing the QTc interval values ​​with those of animals during myocardial infarction, the changes in QTc interval values ​​after sensor treatment were interpreted.

[0093] Example 1

[0094] A method for preparing an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment, the specific steps of which are as follows:

[0095] (1) As Figure 1 As shown, counter electrode 3, working electrode 4, reference electrode 5, and two electrocardiogram (ECG) electrodes (ECG electrode negative 1 and ECG electrode positive 2) are printed on an insulating substrate:

[0096] The screen is placed on a 20μm thick polyimide insulating substrate. The conductive ink corresponding to each electrode is evenly squeezed through the screen using a squeegee to ensure that it is accurately printed in the predetermined position. Then, it is dried or cured.

[0097] Among them, the working electrode 4 uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808), the counter electrode 3 uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808), the reference electrode 5 uses silver / silver chloride ink (manufacturer: Creative Materials, Inc., USA, model name: 119-10), and the electrocardiogram electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808).

[0098] (2) Graphene aerogel loaded with monitoring material is attached to the working end of the working electrode 4:

[0099] (2.1) A macroscopic material graphene oxide film, which is assembled by stacking graphene oxide sheets, is placed in a polar solution containing a foaming agent for plasticization and foaming. After the foaming agent solution is replaced, it is directly dried under normal pressure to obtain graphene aerogel. The foaming agent is hydrazine hydrate and the polar solution is water.

[0100] The prepared graphene aerogel had an average thickness of 800 μm and a specific surface area of ​​1100 m². 2 / g, porosity 99%, average pore size 13μm, electrical conductivity 11S / cm;

[0101] (2.2) The graphene aerogel loaded with the monitoring material is bonded to the working end of the working electrode 4 with conductive silver paste (the graphene aerogel loaded with the monitoring material completely covers the working end of the working electrode 4, and the two have the same shape and size), and dried at 80°C for 20 min.

[0102] The average particle size of the monitored material is 86 nm; the loading area of ​​the monitored material on the surface of the graphene aerogel is 99%; and the loading area of ​​the monitored material in the pores of the graphene aerogel is 96%.

[0103] (3) Apply an insulating layer 6 to the areas of the counter electrode 3, working electrode 4, reference electrode 5 and electrocardiogram electrode except for the working end;

[0104] (4) Connect the non-working ends of the counter electrode 3, working electrode 4 and reference electrode 5 to the electrochemical device at the same time, and connect the non-working ends of the two electrocardiogram electrodes to the Bluetooth electrocardiogram device at the same time to obtain an implantable flexible cardiac sensor that integrates physiological and biochemical diagnosis and treatment.

[0105] The final implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment uses hydrogen peroxide as its biochemical signal. When the monitored substance is Prussian blue nanoparticles, the sensitivity of the sensor for monitoring biochemical signals is 550 μA / (mM×cm). 2 The detection limit is 3 μM, the linear range is 3-800 μM, and the response time is 1 s. After 500 continuous detections, the monitoring current change rate is 2%. After 20 days of continuous detection, the monitoring current change rate is 2%. During the detection process, when a bioactive substance (any one of ascorbic acid, glucose, dopamine, or urea) is added to the test subject, the monitoring current change rate is less than 3%.

[0106] An implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment has an electrocardiogram therapy effect. After the graphene aerogel loaded with the monitoring material is in contact with the heart lesion site of an animal for 10 minutes, the QRS interval is reduced by 60%, the QT interval is reduced by 70%, and the QTc interval is reduced by 69%.

[0107] The implantable flexible cardiac sensor that integrates physiological and biochemical diagnosis and treatment has a biochemical therapeutic effect. After the graphene aerogel loaded with the monitoring substance comes into contact with the heart lesion site of an animal for 10-30 minutes, the reactive oxygen species generated after myocardial infarction completely disappears, and the number of apoptotic cells is reduced.

[0108] The hearts of animals treated with the implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment prepared in this embodiment were subjected to electrocardiogram and echocardiogram tests, and the results are as follows: Figure 7 , Figure 8 As shown, by Figure 7 It can be seen that the QRS complex narrows, and the electrocardiogram characteristics change to those of a healthy electrocardiogram, indicating that myocardial electrical signal conduction is well restored and approaches normal levels; from Figure 8 It can be seen that the heart size is no different from that of a healthy heart, the left ventricular wall can contract and beat normally, and the cardiac ejection fraction can be increased to 96%, reaching a healthy level.

[0109] Comparative Example 1

[0110] The preparation method of an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment is basically the same as that in Example 1, except that the average thickness of the graphene aerogel obtained in step (2.1) is 400 μm.

[0111] The final implantable flexible cardiac sensor for physiological and biochemical diagnosis and treatment is basically the same as in Example 1, except that: after the graphene aerogel loaded with the monitoring material was in contact with the heart lesion site of the animal for 10 minutes, the QRS interval, QT interval and QTc interval did not decrease.

[0112] The implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment does not have biochemical therapeutic effects.

[0113] Electrocardiogram (ECG) tests were performed on the hearts of animals treated with the implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment, which was prepared in this comparative model. The results are as follows: Figure 2 As shown in the figure, when the thickness is small, the electrocardiogram characteristics are still those of myocardial infarction, without effective transmission of electrical signals and without the therapeutic effect of electrical conduction.

[0114] A comparison of Comparative Example 1 and Example 1 reveals that the implantable flexible cardiac sensor integrating physiological and biochemical diagnostics and therapy prepared in Comparative Example 1 does not exhibit good cardiac electrophysiological and biochemical therapeutic effects. This is because the graphene aerogel in Comparative Example 1 is too thin, failing to provide effective mechanical support and electrical bridging. The electrical signal may only be conducted on the surface, making deep integration difficult. In contrast, the aerogel prepared in this invention has a moderate thickness, perfectly matching the physiological dimensions of the ventricular wall and providing stable three-dimensional structural support for damaged myocardium, preventing pathological remodeling of the ventricle. Furthermore, it acts as a highly efficient "electronic bridge," guiding electrical signals to penetrate the originally insulating scar tissue and achieve electrophysiological synchronization with surviving myocardial cells at a deeper level, significantly improving the overall contractile coordination of the heart and inhibiting arrhythmias. In addition, the excellent physiological therapeutic effect achieved by the aerogel of this invention is the fundamental prerequisite for its subsequent biochemical therapeutic effect. Moreover, the improvement in electrophysiology also promotes the recovery of local microcirculation and cellular energy metabolism, thereby curbing the excessive generation of reactive oxygen species (ROS), significantly reducing oxidative stress levels, reducing myocardial cell apoptosis, and increasing survival rates.

[0115] Comparative Example 2

[0116] The preparation method of an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment is basically the same as that in Example 1, except that the average thickness of the graphene aerogel obtained in step (2.1) is 1200 μm.

[0117] The final implantable flexible cardiac sensor for physiological and biochemical diagnosis and treatment is basically the same as in Example 1, except that: after the graphene aerogel loaded with the monitoring material was in contact with the heart lesion site of the animal for 10 minutes, the QRS interval, QT interval and QTc interval did not decrease.

[0118] The implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment does not have biochemical therapeutic effects.

[0119] Echocardiography was performed on the hearts of animals treated with the implantable flexible cardiac sensor for physiological and biochemical diagnosis and treatment developed in this comparative study. The results are as follows: Figure 3 As shown in the figure, when the thickness is large, the echocardiogram shows that the left ventricle is larger, there is no pulsating wave on the outer wall of the left ventricle, and the cardiac ejection fraction is only 41% (the ejection fraction of a healthy heart is over 90%).

[0120] A comparison of Comparative Example 2 and Example 1 reveals that the implantable flexible cardiac sensor for physiological and biochemical diagnosis and treatment prepared in Comparative Example 2 does not exhibit good cardiac electrophysiological and biochemical therapeutic effects. This is because the excessive thickness of the graphene aerogel in Comparative Example 2 creates a physical barrier, hindering normal intercellular communication and material exchange. Its large volume excessively compresses the surrounding surviving myocardial tissue, failing to provide effective mechanical support and instead restricting the heart's diastolic and systolic functions, exacerbating ventricular wall stiffness and mechanical asynchrony, and directly impairing the heart's pumping ability. Secondly, at the electrophysiological level, the excessively thick material significantly prolongs the electrical signal conduction path. Although the material itself has high conductivity, the signal generates additional impedance when passing through the ultra-thick stent, leading to conduction delay. More importantly, the electrical signal cannot be accurately integrated spatiotemporally with the deep host myocardium. Effective electrical synchronization is difficult to achieve, and conduction delays may even create new lesions that induce reentrant arrhythmias. However, the aerogel in Example 1 has a moderate thickness, which not only perfectly matches the physiological scale of the ventricular wall, providing stable three-dimensional structural support for damaged myocardium and preventing pathological remodeling of the ventricle, but also acts as a highly efficient "electronic bridge," guiding electrical signals to penetrate the originally insulating scar tissue and achieve electrophysiological synchronization with surviving cardiomyocytes deep within the tissue. This significantly improves the overall contractile coordination of the heart and inhibits arrhythmias. More importantly, the excellent physiological therapeutic effect achieved by the aerogel of this invention is the fundamental prerequisite for its subsequent biochemical therapeutic effect. The improvement in electrophysiology promotes the recovery of local microcirculation and cellular energy metabolism, thereby curbing the excessive generation of reactive oxygen species (ROS), significantly reducing oxidative stress levels, reducing cardiomyocyte apoptosis, and increasing survival rate.

[0121] Comparative Example 3

[0122] A method for preparing an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment is basically the same as in Example 1, except that the specific surface area of ​​the graphene aerogel obtained in step (2.1) is 800 m². 2 / g, with a porosity of 85% and an average pore size of 4μm;

[0123] The final implantable flexible cardiac sensor for physiological and biochemical diagnosis and treatment is basically the same as in Example 1, except that: after the graphene aerogel loaded with the monitoring material was in contact with the heart lesion site of the animal for 10 minutes, the QRS interval, QT interval and QTc interval did not decrease.

[0124] The implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment does not have biochemical therapeutic effects.

[0125] The myocardial tissue of animals treated with the implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment prepared in this comparative example and Example 1 was subjected to fluorescent staining. The results are as follows: Figure 4, Figure 5 As shown in the comparison, it can be seen that there is no fluorescence in the graphene aerogel of the treated animal heart in this comparative example, which means that there are no living cells in the material and no blood vessels are generated. In contrast, a large amount of fluorescence expression was found in the graphene aerogel of the treated animal heart in Example 1, which means that a large number of cells survive in the pores of the aerogel and new blood vessels are generated.

[0126] A comparison of Comparative Example 3 and Example 1 reveals that the implantable flexible cardiac sensor integrating physiological and biochemical diagnostics and therapy prepared in Comparative Example 3 does not exhibit good cardiac electrophysiological and biochemical therapeutic effects. This is because the material in Comparative Example 3, due to its excessively low specific surface area, excessively low porosity, and excessively small pore size, suffers from structural defects that severely hinder cell migration, nutrient exchange, and angiogenesis. Ultimately, this leads to cell death and angiogenesis within the material, resulting in complete therapeutic failure. It is precisely this structural failure that prevents Comparative Example 3 from achieving either electrocardiogram (electrophysiological) therapeutic effects or ROS (biochemical) therapeutic effects. The absence of surviving cells within the material makes it unsuitable as an electronic bridge for [treatment / conversion / etc.]. While improving cardiac function by stimulating electrophysiological signals, the exacerbated ischemic and hypoxic microenvironment not only fails to alleviate symptoms but may also promote ROS outbreaks, completely negating the biochemical therapeutic effect. In Example 1, by precisely controlling these key parameters, a microenvironment suitable for cell habitation and growth was created, successfully achieving deep regeneration and vascularization of myocardial tissue. The large number of surviving myocardial cells inside the material and the graphene network form a functional electrical integration, thereby achieving excellent electrophysiological therapeutic effects (ECG improvement). At the same time, the newly formed blood vessels effectively improve local metabolism, fundamentally reducing oxidative stress levels and achieving biochemical therapeutic effects (ROS clearance and anti-apoptosis).

[0127] Comparative Example 4

[0128] A method for preparing an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment is basically the same as in Example 1, except that the conductivity of the graphene aerogel obtained in step (2.1) is 4 S / cm.

[0129] The final implantable flexible cardiac sensor for physiological and biochemical diagnosis and treatment is basically the same as in Example 1, except that: after the graphene aerogel loaded with the monitoring material was in contact with the heart lesion site of the animal for 10 minutes, the QRS interval, QT interval and QTc interval did not decrease.

[0130] The implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment does not have biochemical therapeutic effects.

[0131] Electrocardiogram (ECG) tests were performed on the hearts of animals treated with the implantable flexible cardiac sensor for physiological and biochemical diagnosis and treatment developed in this comparative study. The results are as follows: Figure 6As shown in the figure, the QRS wave is still relatively wide, and the image shape is still a characteristic electrocardiogram of myocardial infarction. There is no electrical conduction therapy, and the electrocardiogram has not recovered to a healthy electrocardiogram.

[0132] A comparison of Comparative Example 4 and Example 1 reveals that the implantable flexible cardiac sensor integrating physiological and biochemical diagnostics and therapy prepared in Comparative Example 4 does not exhibit good cardiac electrophysiological and biochemical therapeutic effects. This is because the low-conductivity material in Comparative Example 4 has excessively high resistance, making it unable to efficiently conduct bioelectrical signals. Implanting it is equivalent to adding another layer of electrical insulation barrier to the damaged insulating scar area. Electrical pulses still cannot bypass or penetrate this area, resulting in a continuous widening of the QRS complex. The problem of asynchronous cardiac electrical conduction remains unresolved, and the asynchronous ECG signals indicate that the electrical activity of myocardial cells and calcium ion circulation remain disordered. This electrophysiological... The desynchronization at the surface directly hinders the effective recovery of local microcirculation. However, the graphene aerogel in Example 1 has a moderate conductivity, which is much higher than that of natural myocardial tissue. It can instantly bridge the scar area and quickly and evenly conduct the electrical pulses generated by the upstream myocardium, thereby synchronizing the separated myocardial areas and restoring the electrocardiogram to normal. At the same time, it is this pioneering electrophysiological synchronization that drives the coordination of the heartbeat, improves the pumping efficiency of the heart, and promotes the blood perfusion and microcirculation recovery of the scar area. Furthermore, the improvement of local oxygen supply and energy metabolism fundamentally reverses the vicious cycle of oxidative stress, resulting in a significant reduction in ROS levels.

[0133] Example 2

[0134] A method for preparing an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment, the specific steps of which are as follows:

[0135] (1) Print the counter electrode, working electrode, reference electrode, and two electrocardiogram electrodes on an insulating substrate:

[0136] The screen is placed on a 30μm thick polyimide insulating substrate. The conductive ink corresponding to each electrode is evenly squeezed through the screen using a squeegee to ensure that it is accurately printed in the predetermined position. Then, it is dried or cured.

[0137] The working electrode uses gold ink (manufacturer: Huizhou Jinfuqi Industrial Co., Ltd., grade LV53-121), the counter electrode uses gold ink (manufacturer: Huizhou Jinfuqi Industrial Co., Ltd., grade LV53-121), the reference electrode uses silver / silver chloride ink (manufacturer: Creative Materials, USA, model 119-10), and the electrocardiogram electrode uses gold ink (manufacturer: Huizhou Jinfuqi Industrial Co., Ltd., grade LV53-121).

[0138] (2) Graphene aerogel loaded with the monitoring material is attached to the working end of the working electrode:

[0139] (2.1) A macroscopic material graphene oxide film, which is assembled by stacking graphene oxide sheets, is placed in a polar solution containing a foaming agent for plasticization and foaming. After the foaming agent solution is replaced, it is directly dried under normal pressure to obtain graphene aerogel. The foaming agent is hydrazine hydrate and the polar solution is water.

[0140] The prepared graphene aerogel had an average thickness of 600 μm and a specific surface area of ​​1030 m². 2 / g, porosity 97%, average pore size 8μm, electrical conductivity 15S / cm;

[0141] (2.2) The graphene aerogel of the load monitoring material is bonded to the working end of the working electrode with conductive silver paste (the graphene aerogel of the load monitoring material completely covers the working end of the working electrode, and the two have the same shape and size), and dried at 90°C for 15 min.

[0142] The average particle size of the monitored material is 70 nm; the loading area of ​​the monitored material on the surface of the graphene aerogel is 100%; and the loading area of ​​the monitored material in the pores of the graphene aerogel is 98%.

[0143] (3) Apply an insulating layer to the areas of the counter electrode, working electrode, reference electrode and electrocardiogram electrode except for the working end;

[0144] (4) Connect the non-working ends of the counter electrode, working electrode and reference electrode to the electrochemical device at the same time, and connect the non-working ends of the two electrocardiogram electrodes to the Bluetooth electrocardiogram device at the same time to obtain an implantable flexible cardiac sensor that integrates physiological and biochemical diagnosis and treatment.

[0145] The final implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment uses hydrogen peroxide as its biochemical signal. When the monitored substance is Prussian blue nanoparticles, the sensitivity of the sensor for monitoring biochemical signals is 600 μA / (mM×cm). 2 The detection limit is 5 μM, the linear range is 5-1000 μM, and the response time is 2 s. After 500 continuous detections, the monitoring current change rate is 5%. After 20 days of continuous detection, the monitoring current change rate is 2%. During the detection process, when a bioactive substance (any one of ascorbic acid, glucose, or dopamine) is added to the test subject, the monitoring current change rate is less than 1%.

[0146] An implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment has an electrocardiogram therapy effect. After the graphene aerogel loaded with the monitoring material came into contact with the heart lesion site of an animal for 10 minutes, the QRS interval decreased by 58%, the QT interval decreased by 65%, and the QTc interval decreased by 65%.

[0147] The implantable flexible cardiac sensor, which integrates physiological and biochemical diagnosis and treatment, has a biochemical therapeutic effect. After the graphene aerogel loaded with the monitoring substance comes into contact with the heart lesion site of an animal for 10-30 minutes, the reactive oxygen species generated after myocardial infarction completely disappears, and the number of apoptotic cells is reduced.

[0148] Example 3

[0149] A method for preparing an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment, the specific steps of which are as follows:

[0150] (1) Print the counter electrode, working electrode, reference electrode, and two electrocardiogram electrodes on an insulating substrate:

[0151] The screen is placed on a 60μm thick polyimide insulating substrate. The conductive ink corresponding to each electrode is evenly squeezed through the screen using a squeegee to ensure that it is accurately printed in the predetermined position. Then, it is dried or cured.

[0152] The working electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808), the counter electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808), the reference electrode uses silver / silver chloride ink (manufacturer: Creative Materials, Inc., USA, model name: 119-10), and the electrocardiogram electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808).

[0153] (2) Graphene aerogel loaded with the monitoring material is attached to the working end of the working electrode:

[0154] (2.1) A macroscopic material graphene oxide film, which is assembled by stacking graphene oxide sheets, is placed in a polar solution containing a foaming agent for plasticization and foaming. After the foaming agent solution is replaced, it is directly dried under normal pressure to obtain graphene aerogel. The foaming agent is hydrazine hydrate and the polar solution is water.

[0155] The prepared graphene aerogel had an average thickness of 1000 μm and a specific surface area of ​​1200 m². 2 / g, porosity 99%, average pore size 20μm, electrical conductivity 5S / cm;

[0156] (2.2) The graphene aerogel loaded with the monitoring material was bonded to the working end of the working electrode with conductive silver paste (the graphene aerogel loaded with the monitoring material completely covered the working end of the working electrode, and the two had the same shape and size), and dried at 100°C for 10 min.

[0157] The average particle size of the monitored material is 100 nm; the loading area of ​​the monitored material on the surface of the graphene aerogel is 100%; and the loading area of ​​the monitored material in the pores of the graphene aerogel is 97%.

[0158] (3) Apply an insulating layer to the areas of the counter electrode, working electrode, reference electrode and electrocardiogram electrode except for the working end;

[0159] (4) Connect the non-working ends of the counter electrode, working electrode and reference electrode to the electrochemical device at the same time, and connect the non-working ends of the two electrocardiogram electrodes to the Bluetooth electrocardiogram device at the same time to obtain an implantable flexible cardiac sensor that integrates physiological and biochemical diagnosis and treatment.

[0160] The final implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment uses hydrogen peroxide as its biochemical signal. When the monitored substance is Prussian blue nanoparticles, the sensitivity of the sensor for monitoring biochemical signals is 500 μA / (mM×cm). 2 The detection limit is 4 μM, the linear range is 4-1000 μM, and the response time is 1 s. After 500 continuous tests, the monitoring current change rate is 2%. After 20 days of continuous testing, the monitoring current change rate is 7%. During the testing process, when a bioactive substance (any one of ascorbic acid, glucose, dopamine, urea, and uric acid) is added to the test subject, the monitoring current change rate is less than 1%.

[0161] An implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment has an electrocardiogram therapy effect. After the graphene aerogel loaded with the monitoring material is in contact with the heart lesion site of an animal for 10 minutes, the QRS interval is reduced by 60%, the QT interval is reduced by 68%, and the QTc interval is reduced by 68%.

[0162] The implantable flexible cardiac sensor, which integrates physiological and biochemical diagnosis and treatment, has a biochemical therapeutic effect. After the graphene aerogel loaded with the monitoring substance comes into contact with the heart lesion site of an animal for 10-30 minutes, the reactive oxygen species generated after myocardial infarction completely disappears, and the number of apoptotic cells is reduced.

[0163] Example 4

[0164] A method for preparing an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment, the specific steps of which are as follows:

[0165] (1) Print the counter electrode, working electrode, reference electrode, and two electrocardiogram electrodes on an insulating substrate:

[0166] The screen is placed on a 30μm thick polyimide insulating substrate. The conductive ink corresponding to each electrode is evenly squeezed through the screen using a squeegee to ensure that it is accurately printed in the predetermined position. Then, it is dried or cured.

[0167] The working electrode uses gold ink (manufacturer: Huizhou Jinfuqi Industrial Co., Ltd., grade: LV53-121), the counter electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-tech Materials Co., Ltd., grade: Field-808), the reference electrode uses silver / silver chloride ink (manufacturer: Creative Materials, USA, model: 119-10), and the electrocardiogram electrode uses gold ink (manufacturer: Huizhou Jinfuqi Industrial Co., Ltd., grade: LV53-121).

[0168] (2) Graphene aerogel loaded with the monitoring material is attached to the working end of the working electrode:

[0169] (2.1) A macroscopic material graphene oxide film, which is assembled by stacking graphene oxide sheets, is placed in a polar solution containing a foaming agent for plasticization and foaming. After the foaming agent solution is replaced, it is directly dried under normal pressure to obtain graphene aerogel. The foaming agent is hydrazine hydrate and the polar solution is water.

[0170] The prepared graphene aerogel had an average thickness of 700 μm and a specific surface area of ​​1080 m². 2 / g, porosity 97%, average pore size 11μm, electrical conductivity 14S / cm;

[0171] (2.2) The graphene aerogel of the load monitoring material is bonded to the working end of the working electrode with conductive silver paste (the graphene aerogel of the load monitoring material completely covers the working end of the working electrode, and the two have the same shape and size), and dried at 90°C for 15 min.

[0172] The average particle size of the monitored material is 50 nm; the loading area of ​​the monitored material on the surface of the graphene aerogel is 100%; and the loading area of ​​the monitored material in the pores of the graphene aerogel is 99%.

[0173] (3) Apply an insulating layer to the areas of the counter electrode, working electrode, reference electrode and electrocardiogram electrode except for the working end;

[0174] (4) Connect the non-working ends of the counter electrode, working electrode and reference electrode to the electrochemical device at the same time, and connect the non-working ends of the two electrocardiogram electrodes to the Bluetooth electrocardiogram device at the same time to obtain an implantable flexible cardiac sensor that integrates physiological and biochemical diagnosis and treatment.

[0175] The final implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment uses hydrogen peroxide as its biochemical signal. When the monitored substance is Prussian blue nanoparticles, the sensitivity of the sensor for monitoring biochemical signals is 580 μA / (mM×cm). 2 The detection limit was 4 μM, the linear range was 4-1000 μM, and the response time was 0.5 s. After 500 continuous tests, the monitoring current change rate was 4%. After 20 days of continuous testing, the monitoring current change rate was 5%. During the testing process, when a bioactive substance (any one of glucose, dopamine, urea, and uric acid) was added to the test subject, the monitoring current change rate was less than 3%.

[0176] An implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment has an electrocardiogram therapy effect. After the graphene aerogel loaded with the monitoring material is in contact with the heart lesion site of an animal for 10 minutes, the QRS interval is reduced by 50%, the QT interval is reduced by 60%, and the QTc interval is reduced by 62%.

[0177] The implantable flexible cardiac sensor, which integrates physiological and biochemical diagnosis and treatment, has a biochemical therapeutic effect. After the graphene aerogel loaded with the monitoring substance comes into contact with the heart lesion site of an animal for 10-30 minutes, the reactive oxygen species generated after myocardial infarction completely disappears, and the number of apoptotic cells is reduced.

[0178] Example 5

[0179] A method for preparing an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment, the specific steps of which are as follows:

[0180] (1) Print the counter electrode, working electrode, reference electrode, and two electrocardiogram electrodes on an insulating substrate:

[0181] The screen is placed on a 40μm thick polyimide insulating substrate. The conductive ink corresponding to each electrode is evenly squeezed through the screen using a squeegee to ensure that it is accurately printed in the predetermined position. Then, it is dried or cured.

[0182] The working electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808), the counter electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808), the reference electrode uses silver / silver chloride ink (manufacturer: Creative Materials, Inc., USA, model name: 119-10), and the electrocardiogram electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808).

[0183] (2) Graphene aerogel loaded with the monitoring material is attached to the working end of the working electrode:

[0184] (2.1) A macroscopic material graphene oxide film, which is assembled by stacking graphene oxide sheets, is placed in a polar solution containing a foaming agent for plasticization and foaming. After the foaming agent solution is replaced, it is directly dried under normal pressure to obtain graphene aerogel. The foaming agent is hydrazine hydrate and the polar solution is water.

[0185] The prepared graphene aerogel had an average thickness of 500 μm and a specific surface area of ​​1000 m². 2 / g, porosity 95%, average pore size 5μm, electrical conductivity 15S / cm;

[0186] (2.2) The graphene aerogel loaded with the monitoring material was bonded to the working end of the working electrode with conductive silver paste (the graphene aerogel loaded with the monitoring material completely covered the working end of the working electrode, and the two had the same shape and size), and dried at 80°C for 20 min.

[0187] The average particle size of the monitored material is 40 nm; the loading area of ​​the monitored material on the surface of the graphene aerogel is 99%; and the loading area of ​​the monitored material in the pores of the graphene aerogel is 90%.

[0188] (3) Apply an insulating layer to the areas of the counter electrode, working electrode, reference electrode and electrocardiogram electrode except for the working end;

[0189] (4) Connect the non-working ends of the counter electrode, working electrode and reference electrode to the electrochemical device at the same time, and connect the non-working ends of the two electrocardiogram electrodes to the Bluetooth electrocardiogram device at the same time to obtain an implantable flexible cardiac sensor that integrates physiological and biochemical diagnosis and treatment.

[0190] The final implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment uses hydrogen peroxide as its biochemical signal. When the monitored substance is Prussian blue nanoparticles, the sensitivity of the sensor for monitoring biochemical signals is 590 μA / (mM×cm). 2 The detection limit was 1 μM, the linear range was 1-1000 μM, and the response time was 1.5 s. After 500 continuous tests, the monitoring current change rate was 1%. After 20 days of continuous testing, the monitoring current change rate was 3%. During the testing process, when a bioactive substance (any one of ascorbic acid, dopamine, urea, and uric acid) was added to the test subject, the monitoring current change rate was less than 2%.

[0191] An implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment has an electrocardiogram therapy effect. After the graphene aerogel loaded with the monitoring material is in contact with the heart lesion site of an animal for 10 minutes, the QRS interval is reduced by 55%, the QT interval is reduced by 70%, and the QTc interval is reduced by 70%.

[0192] The implantable flexible cardiac sensor, which integrates physiological and biochemical diagnosis and treatment, has a biochemical therapeutic effect. After the graphene aerogel loaded with the monitoring substance comes into contact with the heart lesion site of an animal for 10-30 minutes, the reactive oxygen species generated after myocardial infarction completely disappears, and the number of apoptotic cells is reduced.

[0193] Example 6

[0194] A method for preparing an implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment, the specific steps of which are as follows:

[0195] (1) Print the counter electrode, working electrode, reference electrode, and two electrocardiogram electrodes on an insulating substrate:

[0196] The screen is placed on a 50μm thick polyimide insulating substrate. The conductive ink corresponding to each electrode is evenly squeezed through the screen using a squeegee to ensure that it is accurately printed in the predetermined position. Then, it is dried or cured.

[0197] The working electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808), the counter electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808), the reference electrode uses silver / silver chloride ink (manufacturer: Creative Materials, Inc., USA, model name: 119-10), and the electrocardiogram electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand name: Field-808).

[0198] (2) Graphene aerogel loaded with the monitoring material is attached to the working end of the working electrode:

[0199] (2.1) A macroscopic material graphene oxide film, which is assembled by stacking graphene oxide sheets, is placed in a polar solution containing a foaming agent for plasticization and foaming. After the foaming agent solution is replaced, it is directly dried under normal pressure to obtain graphene aerogel. The foaming agent is hydrazine hydrate and the polar solution is water.

[0200] The prepared graphene aerogel had an average thickness of 900 μm and a specific surface area of ​​1150 m². 2 / g, porosity 98%, average pore size 15μm, electrical conductivity 7S / cm;

[0201] (2.2) The graphene aerogel loaded with the monitoring material was bonded to the working end of the working electrode with conductive silver paste (the graphene aerogel loaded with the monitoring material completely covered the working end of the working electrode, and the two had the same shape and size), and dried at 80°C for 20 min.

[0202] The average particle size of the monitored material is 90 nm; the loading area of ​​the monitored material on the surface of the graphene aerogel is 99%; and the loading area of ​​the monitored material in the pores of the graphene aerogel is 99%.

[0203] (3) Apply an insulating layer to the areas of the counter electrode, working electrode, reference electrode and electrocardiogram electrode except for the working end;

[0204] (4) Connect the non-working ends of the counter electrode, working electrode and reference electrode to the electrochemical device at the same time, and connect the non-working ends of the two electrocardiogram electrodes to the Bluetooth electrocardiogram device at the same time to obtain an implantable flexible cardiac sensor that integrates physiological and biochemical diagnosis and treatment.

[0205] The final implantable flexible cardiac sensor for integrated physiological and biochemical diagnosis and treatment uses hydrogen peroxide as its biochemical signal. When the monitored substance is Prussian blue nanoparticles, the sensitivity of the sensor for monitoring biochemical signals is 590 μA / (mM×cm). 2 The detection limit is 4 μM, the linear range is 4-1000 μM, and the response time is 1 s. After 500 continuous tests, the monitoring current change rate is 3%. After 20 days of continuous testing, the monitoring current change rate is 3%. During the testing process, when a bioactive substance (either urea or uric acid) is added to the test subject, the monitoring current change rate is less than 1%.

[0206] An implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment has an electrocardiogram therapy effect. After the graphene aerogel loaded with the monitoring material came into contact with the heart lesion site of an animal for 10 minutes, the QRS interval decreased by 60%, the QT interval decreased by 68%, and the QTc interval decreased by 69%.

[0207] The implantable flexible cardiac sensor, which integrates physiological and biochemical diagnosis and treatment, has a biochemical therapeutic effect. After the graphene aerogel loaded with the monitoring substance comes into contact with the heart lesion site of an animal for 10-30 minutes, the reactive oxygen species generated after myocardial infarction completely disappears, and the number of apoptotic cells is reduced.

[0208] The dimensions of the implantable flexible cardiac sensor integrating physiological and biochemical diagnostics and therapy prepared in Examples 1-6 are all as follows: Figure 9The dimensions shown are as follows: insulating substrate width 20-25mm, length 60-70mm; insulating coating width 20-25mm, length 40-50mm; wire width 0.8-1.2mm; wire spacing 3.5-4mm; ECG electrode is a square with sides of 0.5-0.6mm; sensor electrochemical three-electrode spacing 0.8-1mm; counter and reference electrode width 2-3mm; working electrode is a circle with a diameter of 7-9mm. These dimensions ensure a perfect fit between the flexible sensor and the curved surface of the heart, providing sufficient working area without affecting the heart's diastolic and systolic movements. Miniature... The electrocardiogram electrodes achieve high spatial resolution electrical signal mapping, enabling precise localization of abnormal cardiac electrical activity, while the rational lead layout effectively prevents signal crosstalk. Simultaneously, the sufficiently large working electrode area and the compact arrangement of the three electrodes (1mm spacing) significantly improve the sensitivity and response speed of electrochemical detection of biochemical molecules such as ROS, laying the foundation for real-time monitoring of changes in the biochemical microenvironment. Ultimately, this integrated size layout successfully integrates electrophysiological and biochemical sensing functions onto a single interface, achieving synchronous and correlated acquisition of cardiac physiological and biochemical signals at the same time and location, providing a novel technological means for the precise diagnosis and treatment of heart disease.

Claims

1. A physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor, characterized in that, The electrode device comprises an insulating substrate and a counter electrode, a working electrode, a reference electrode and two electrocardiogram electrodes printed on the insulating substrate simultaneously, and a graphene aerogel loaded with a monitoring substance is pasted on the working end of the working electrode, and the monitoring substance is a substance for monitoring biochemical signals. 2.The physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor according to claim 1, wherein, The insulating substrate is polyimide, and the thickness is 20-60 microns. 3.The physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor according to claim 1, characterized in that, The working electrode is printed by gold ink or carbon ink, the counter electrode is printed by gold ink or carbon ink, the reference electrode is printed by silver / silver chloride ink, and the electrocardiogram electrode is printed by gold ink or carbon ink. 4.The physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor of claim 3, wherein, The counter electrode, the working electrode, the reference electrode and the electrocardiogram electrode are coated with an insulating layer on the area other than the working end. 5.The physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor of claim 3, wherein, The process of printing the counter electrode, the working electrode, the reference electrode and the two electrocardiogram electrodes on the insulating substrate is as follows: placing a silk screen on the insulating substrate, uniformly extruding the conductive ink corresponding to each electrode through the silk screen by a doctor blade, ensuring that it is accurately printed on the predetermined position, and then drying or curing. 6.The physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor of claim 1, wherein, The graphene aerogel loaded with the monitoring substance completely covers the working end of the working electrode, and the shape and size of the two are the same. 7.The physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor of claim 6, wherein, The process of pasting the graphene aerogel loaded with the monitoring substance on the working end of the working electrode is as follows: after the graphene aerogel loaded with the monitoring substance is adhered to the working end of the working electrode with conductive silver paste, it is dried at 80-100 DEG C for 10-20 min. 8.The physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor of claim 1, wherein, The thickness of the graphene aerogel is 500-1000 μm, the specific surface area is 1000-1200 m 2 / g, the porosity is 95-99%, the pore size is 5-20 μm, the conductivity is 5-15 S / cm; the particle size of the monitoring substance is 40-100 nm; the loading area of the monitoring substance on the surface of the graphene aerogel is 99-100%; the loading area of the monitoring substance in the pores of the graphene aerogel is 90-99%. 9.The physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor of claim 1, wherein, It also comprises an electrochemical device and a Bluetooth electrocardiogram device, and the non-working end of the counter electrode, the working electrode and the reference electrode is connected to the electrochemical device simultaneously, and the non-working end of the two electrocardiogram electrodes is connected to the Bluetooth electrocardiogram device simultaneously. 10.The physiological and biochemical diagnosis and treatment integrated implantable flexible cardiac sensor of claim 1, wherein, The sensitivity of the physiological and biochemical diagnosis and treatment integrated implantable flexible sensor for monitoring the biochemical signal is 500-600 μA / (mM×cm 2 ) when the biochemical signal is hydrogen peroxide and the monitoring substance is Prussian blue nanoparticles, the lower limit of monitoring is 1-5 μM, the linear interval is (1-5)-(800-1000) μM, the response time is 0.5-2 s; the change rate of detection current is 1-5% after 500 detections; the change rate of detection current is 2-7% after 20 days of detection; the change rate of detection current is 1-3% after adding a biological active substance to the detection object during the detection process, the biological active substance is one or more of ascorbic acid, glucose, dopamine, urea and uric acid.

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