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] The present invention belongs to the technical field of electrochemical monitoring, and particularly relates to an implantable cardiac flexible sensor for integrated physiological and biochemical diagnosis and treatment. Background Art

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

[0003] Currently, many studies focus on single-functional sensors. Wearable electrophysiological devices are mainly used to monitor the physiological signals of the heart, such as flexible ECG electrodes, intelligent stethoscopes, wireless pressure sensors, etc. Relevant references are as follows: Cell Rep. Phys. Sci., 2 (2021), 100541; IEEE Sens. J. 22 (2022), 18045–18055; J. Clin. Med. 2024, 13(4), 1033. Most fiber optic and electrochemical sensor devices are extracorporeal devices, mainly monitoring the biochemical signals of the heart. Among them, fiber optic sensors use optical signals to detect biomarkers (such as cardiac troponin), and electrochemical sensors detect markers through antigen-antibody reactions or enzyme catalysis, with the advantages of fast response and low cost. Relevant references are as follows: Bioelectron. 210 (2022), 114328; Molecules 2021, 26(14), 4252; ACS Omega, 5 (2020), 3924–3931.

[0004] Although certain achievements have been made in the field of cardiac sensors, there are still many challenges to achieve 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 usually requires different hardware and software systems, which are prone to conflicts in working principles, signal processing, or energy requirements. For example, monitoring physiological signals relies on highly sensitive electrodes and precise signal amplification circuits, while the working voltage and current characteristics of the electrical stimulation system during treatment are vastly different, easily leading to conflicts and causing the device to malfunction. In addition, cardiac sensors usually need to be miniaturized to fit for human implantation or wear, but integrating multiple functions will increase the size and complexity of the device, affecting its applicability and wearing comfort.

[0006] Signal interference also restricts the development of sensors. The electrical stimulation during treatment will generate electromagnetic interference, which will mix into the circuits used to monitor cardiac physiological signals, causing problems such as distortion of physiological signals and increased noise, seriously affecting the accuracy and stability of physiological signal monitoring, and leading to misjudgment of the cardiac state. At the same time, the drugs or energy released during the treatment process will change the local biochemical environment, interfering with the monitoring of cardiac biochemical indicators by biochemical signal sensors, and thus unable to truly reflect the biochemical state of the heart.

[0007] In addition, energy supply is also a major challenge. When running physiological and biochemical signal monitoring and therapeutic functions simultaneously, the energy consumption of the device increases significantly. The energy density of conventional batteries is difficult to meet the long-term working requirements of cardiac sensors. In the in-vivo environment, the efficiency of wireless energy transmission is low, unable to ensure the stable operation of the device.

[0008] The issues of materials and biocompatibility cannot be ignored either. The materials required for monitoring and therapeutic functions may have differences in biocompatibility, durability, and chemical stability, and are prone to interact with each other in the same device, affecting the device performance. In the in-vivo environment, body fluids will cause material corrosion and degradation, and at the same time, the formation of biofilms will also cover the material surface, affecting its performance. These changes in materials will cause the device to gradually fail and unable to achieve the integration of physiological and biochemical diagnosis and treatment stably in the long term.

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

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

[0011] To achieve the above purpose, the present invention adopts the following technical solutions:

[0012] A physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor, comprising an insulating substrate and a counter electrode, a working electrode, a reference electrode and two electrocardiogram electrodes printed on the insulating substrate at the same time. 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.

[0013] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor of the present invention can realize the three-in-one collaborative function of physiological signal monitoring, biochemical signal monitoring and treatment function. Among them, the electrocardiogram electrodes can collect cardiac physiological signals (i.e., electrical signals), and can capture key electrophysiological parameters such as P wave, QRS complex, T wave of animal electrocardiogram in real time; the working electrode of the graphene aerogel loaded with the monitoring substance can monitor specific cardiac biochemical signals, such as reactive oxygen species (including hydrogen peroxide, superoxide anion), cardiac troponin I (cTnI), brain natriuretic peptide (BNP), etc.; the graphene aerogel with high electrical conductivity can reconstruct the cardiac electrical conduction pathway and treat cardiac electrical conduction disorders, such as myocardial infarction, arrhythmia.

[0014] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor of the present invention has the advantages of high signal-to-noise ratio, dynamic adaptability, long-term stability, etc. when monitoring physiological signals. The principle of the electrocardiogram electrodes collecting cardiac physiological signals is based on the synergistic effect of cardiac electrophysiological activities and electrochemical conversion at the electrode-tissue interface. The two electrocardiogram electrodes are printed with carbon ink, and the carbon ink has high electrical conductivity. The ionic current generated by cardiac electrical activities undergoes an electrochemical reaction (such as oxidation-reduction reaction) on the electrode surface and is converted into a measurable electronic current. The double-layer capacitance characteristic of the carbon ink helps to buffer low-frequency signal fluctuations and ensure signal quality, so that the sensor of the present invention has a high signal-to-noise ratio when monitoring signals; the insulating substrate uses a flexible material, which can ensure the dynamic fit of the electrodes and cardiac tissue, reduce motion artifacts, and can capture key electrophysiological parameters such as P wave, QRS complex, T wave of animal electrocardiogram in real time, so that the sensor of the present invention has dynamic adaptability when monitoring signals; both the electrocardiogram electrodes and the flexible insulating substrate material have good corrosion resistance and biocompatibility, and can be monitored in vivo for a long time, so that the sensor of the present invention has long-term stability when monitoring signals.

[0015] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor of the present invention has the advantages of high sensitivity and high stability when monitoring biochemical signals. Graphene aerogel is used as the loading substrate of the monitoring substance, and its high conductivity (5-15 S / cm) can significantly improve the sensitivity of the sensor to changes in electronic current, because the three-dimensional continuous conductive network of graphene aerogel can greatly reduce the internal resistance of electron transmission and accelerate the transfer efficiency of reaction electrons. According to Ohm's law (V = IR), low resistance (R) can reduce the voltage drop (V), thereby amplifying the signal-to-noise ratio of the current signal (I), making it easier to detect small concentration changes; secondly, the high conductive substrate can suppress the double-layer capacitance effect and background noise, reduce the interface contact impedance, and enhance the distinction between the Faraday current and the background signal; in addition, the synergistic effect of the three-dimensional continuous conductive network and the monitoring substance can optimize the electronic structure of the catalytic active site, reduce the activation energy of the reduction reaction of the monitored substance, and accelerate the 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 has a high specific surface area and can provide a large number of uniform loading sites for monitoring substances, thereby significantly improving the stability of the sensor. In addition, the continuous conductive network of graphene aerogel can not only provide a low-resistance electron transmission path, but its porous structure can also promote the penetration of electrolytes and ion diffusion, ensuring that the reaction interface continues to operate efficiently and reduce performance degradation caused by polarization or mass transfer limitations. The three-dimensional structure of graphene aerogel can also buffer direct impacts from the external environment (such as temperature changes, humidity changes, or chemical corrosion). At the same time, the highly conductive substrate can inhibit side reactions (such as oxidative decomposition) through rapid electron transfer, further extending the life of the sensor. This physical-chemical synergy enables graphene aerogel to stably load monitoring substances, thereby ensuring the reliable performance of the sensor in long-term use and complex environments.

[0017] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor of the present invention has the advantages of promoting electrical signal conduction, flexible fit to the heart, three-dimensional structural support regeneration and long-term stability during treatment. After the sensor is implanted in the myocardial infarction or fibrosis area, the three-dimensional conductive network of graphene aerogel can cross the non-conductive scar tissue to form an "artificial electrical bypass", restore the synchronization of electrical signals and inhibit arrhythmias; the flexible porous structure matches the myocardial mechanics and can deform dynamically with the heart to reduce mechanical damage; the three-dimensional network simulates the extracellular matrix, promotes myocardial cell regeneration, stem cell differentiation and angiogenesis through the regulation of the electroactive microenvironment, and inhibits fibrosis; the biocompatibility can ensure its long-term safety on the heart.

[0018] As the preferred technical solution:

[0019] A physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor as shown above, with the insulating substrate made of polyimide (PI), which has good chemical stability and electrical insulation, a thickness of 20 - 60 μm, and is flexible, making it easier to fit on the heart.

[0020] A physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor as shown above, where the working electrode is printed with gold ink or carbon ink, the counter electrode is printed with gold ink or carbon ink, the reference electrode is printed with silver / silver chloride ink, and the electrocardiogram electrode is printed with gold ink or carbon ink.

[0021] A physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor as shown above, an insulating layer is coated on the areas of the counter electrode, working electrode, reference electrode, and electrocardiogram electrode except for the working ends to isolate the interference of other biological signals and prevent short - circuits.

[0022] The process of printing the counter electrode, working electrode, reference electrode, and two electrocardiogram electrodes on the insulating substrate for a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor as shown above is as follows: Place the screen on the insulating substrate, and evenly squeeze the conductive ink corresponding to each electrode through the screen with a squeegee to ensure that it is precisely printed at the predetermined position, and then dry or cure it. Among them, the design of the screen should be determined according to the requirements such as the shape, size, and conductivity of the electrode. Before placing the screen on the insulating substrate, the insulating substrate needs to be cleaned. Common methods include ultrasonic cleaning, deionized water washing, drying, etc., to ensure that there are no impurities such as oil stains and dust, so as to improve the printing quality.

[0023] A physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor as shown above, the graphene aerogel loaded with the monitoring substance completely covers the working end of the working electrode, and their shapes and sizes are the same.

[0024] The process of pasting the graphene aerogel loaded with the monitoring substance on the working end of the working electrode for a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor as shown above is as follows: After bonding the graphene aerogel loaded with the monitoring substance to the working end of the working electrode with conductive silver paste, dry it at 80 - 100 °C for 10 - 20 min.

[0025] A physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor as shown above, the thickness of the graphene aerogel is 500 - 1000 mm, the specific surface area is 1000 - 1200 m 2 / g, the porosity is 95 - 99%, the pore size is 5 - 20 mm, 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%.

[0026] A physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor as shown above further includes an electrochemical device and a Bluetooth electrocardiogram device. The non-working ends of the counter electrode, the working electrode and the reference electrode are simultaneously connected to the electrochemical device, and the non-working ends of the two electrocardiogram electrodes are simultaneously connected to the Bluetooth electrocardiogram device.

[0027] For a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor as shown above, when the biochemical signal is hydrogen peroxide and the monitored substance is Prussian blue nanoparticles, the sensitivity of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor for monitoring the biochemical signal is 500 - 600 μA / (mM×cm 2 ), the monitoring lower limit is 1 - 5 μM, the linear range is (1 - 5) - (800 - 1000) μM, and the response time is 0.5 - 2 s; after continuously performing 500 detections, the detection current change rate is 1 - 5%; after continuously performing detections for 20 days, the detection current change rate is 2 - 7%; during the detection process, after adding a bioactive substance to the detection object, the detection current change rate is 1 - 3%, and the bioactive substance is one or more of ascorbic acid, glucose, dopamine, urea, and uric acid;

[0028] In the prior art, the substrate materials for loading Prussian blue in the sensors for monitoring hydrogen peroxide are mainly divided into metal materials and carbon materials. When using metal materials as the substrate, the sensor has relatively high sensitivity but poor stability. For example, in the literature (S. Electroanalysis, (2013), 25: 2211 - 2220.), a novel Prussian blue / copper-gold bimetallic nanoparticle hybrid film modified electrode (PB / Cu-AuNPs / GCE) was prepared on a glassy carbon electrode by electrochemical deposition. Since the sensor did not integrate the working electrode and the counter electrode, the three-electrode system of an electrochemical instrument was used to evaluate the performance of the sensor. 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, selectivity in complex samples, and the complexity of the preparation process of the sensor are still the directions that need further research and improvement in the literature. When using carbon materials as the substrate, the stability of the sensor is improved, but the sensitivity is lower. For example, in the literature (Electrochimica Acta 89 (2013): 454 - 460.), a reduced graphene oxide (RGO) suspension was dropped on the surface of a glassy carbon electrode (GC), and after drying, an electrode with RGO as the substrate was formed. Prussian blue (PB) was deposited on the RGO electrode by electrochemical deposition to form a GC / RGO / PB electrode. Since the sensor did not integrate the working electrode and the counter electrode, the three-electrode system of an electrochemical instrument was used to evaluate the performance of the sensor, but the highest sensitivity shown by the electrode was only 420 uA / (mM*cm2 )。Therefore, sensors in the prior art cannot simultaneously possess the advantages of high sensitivity and high stability when monitoring hydrogen peroxide. By optimizing the substrate material (three-dimensional graphene aerogel), the present invention can improve the sensitivity and stability of the sensor, overcoming the limitations of poor stability of traditional metal substrates or insufficient sensitivity of carbon substrates.

[0029] In addition to hydrogen peroxide, the biochemical signal of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor of the present invention can also be other signals, and at this time, the monitored substance needs to change adaptively.

[0030] In the prior art, there are also cases where aerogels are used in sensors. However, it mainly relies on the deformation of the aerogel itself to trigger changes in electrical signals to achieve the monitoring function, and is mainly used for detecting motion signals. The detection principle is as follows: when the aerogel is subjected to external stimuli such as pressure, tension, or compression, it will deform, causing a change in its internal conductive network, and then resulting in changes in electrical signals such as resistance, capacitance, or current. By measuring these changes in electrical signals, the intensity or type of external stimuli can be indirectly reflected.

[0031] Different from the prior art, the present invention utilizes the synergistic effect of the efficient three-dimensional continuous conductive network of graphene aerogel and the electrocatalytic properties of the monitored substance to achieve the detection function, and is used to detect biochemical molecule (such as hydrogen peroxide) signals. The detection principle is: when the sensor contacts a sample containing hydrogen peroxide (H2O2), the monitored substance catalyzes its reduction reaction (H2O2 + 2H + +2e - → 2H2O), and the generated electrons are rapidly transmitted 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 electrical conductivity (5 - 15 S / cm) of graphene aerogel can significantly reduce the electron transfer resistance. Its porous structure can load more monitored substances due to its high specific surface area, and the catalytic site stability is enhanced by physical confinement and chemical bonding; at the same time, the combination of the highly selective catalysis of the monitored substance and the anti-interference characteristics of graphene aerogel effectively inhibits the interference of other electroactive substances. Compared with traditional sensors relying on physical deformation, the present invention realizes highly sensitive and highly specific detection of biochemical molecules through the synergistic effect of a highly conductive substrate - electrochemical activity, expanding the application potential of graphene aerogel in the fields of biomedicine and environmental monitoring.

[0032] The electrical signal acquisition module of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor of the present invention adopts the same module as the medical-grade electrocardiograph (the gold standard for monitoring), that is, the BM101 module. This module has low system noise and controllable gain, and can effectively monitor biological signals in the mV to mV range; the sampling frequency is 512 Hz, and it can accurately monitor most experimental organisms with a heart rate below this frequency.

[0033] The implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment of the present invention has an electrocardiogram treatment effect. After the graphene aerogel loaded with the monitoring substance contacts the diseased part of the animal heart 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%.

[0034] The implantable flexible cardiac sensor integrating physiological and biochemical diagnosis and treatment of the present invention has a biochemical treatment effect. After the graphene aerogel loaded with the monitoring substance contacts the diseased part of the animal heart for 10-30 minutes, the reactive oxygen species generated after myocardial infarction completely disappear, and the number of apoptotic cells decreases.

[0035] Beneficial effects

[0036] The implantable flexible cardiac sensor of the present invention can realize the three-in-one coordinated operation of physiological signal monitoring, biochemical signal monitoring and treatment functions. It has the advantages of high signal-to-noise ratio, dynamic adaptability and long-term stability in monitoring physiological signals; it has the advantages of high sensitivity and strong stability in monitoring biochemical signals; in terms of treatment, it has the characteristics of promoting electrical signal conduction, being able to flexibly fit the heart, providing three-dimensional structural support for regeneration and long-term stability. Description of the drawings

[0037] Figure 1 It is a schematic diagram of the positional relationship of each electrode in the sensor of the present invention.

[0038] Among them, 1-negative electrode of the electrocardiogram electrode, 2-positive electrode of the electrocardiogram electrode, 3-counter electrode, 4-working electrode, 5-reference electrode, 6-insulating layer. Detailed implementation manners

[0039] The present invention will be further described below in conjunction with specific implementation manners. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0040] The detection methods of relevant indicators in the embodiments are as follows:

[0041] The loading area of the monitoring substance (prussian blue nanoparticles) on the surface of the graphene aerogel and the loading area of the monitoring substance (prussian blue nanoparticles) in the pores of the graphene aerogel are obtained by acquiring the scanning electron microscope images (SEM) of the surface and pores of the graphene aerogel loaded with the monitoring substance and calculated by Image J software.

[0042] The test steps of the sensitivity are as follows:

[0043] (1) Connect the three electrodes of the sensor to an electrochemical workstation (Autolab), immerse it in a 0.1 M HCl / KCl solution, and use the cyclic voltammetry program with the following parameter settings: scanning voltage range -0.1 to 0.4 V, scanning rate 0.01 - 0.08 V / s, and cycle 10 - 30 times to stabilize the Prussian blue nanoparticles;

[0044] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution of 1X PBS containing 0.1 M KCl, and use the chronoamperometry program with the monitoring voltage set at -0.1 to -0.5 V; before adding hydrogen peroxide, activate the sensor for 60 - 100 min; add hydrogen peroxide to the solution for the first time until the hydrogen peroxide concentration in the monitoring solution reaches 10 mM. After the current stabilizes, repeat the addition operation of adding an equimolar amount of hydrogen peroxide 3 - 5 times; obtain the current difference each time after adding hydrogen peroxide, and 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)". Take the average value of all sensitivities as the sensitivity of the sensor.

[0045] The test steps for the lower detection limit are as follows:

[0046] (1) Connect the three electrodes of the sensor to an electrochemical workstation (Autolab), immerse it in a 0.1 M HCl / KCl solution, and use the cyclic voltammetry program with the following parameter settings: scanning voltage range -0.1 to 0.4 V, scanning rate 0.01 - 0.08 V / s, and cycle 10 - 30 times to stabilize the Prussian blue nanoparticles;

[0047] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution of 1X PBS containing 0.1 M KCl, and use the chronoamperometry program with the monitoring voltage set at -0.1 to -0.5 V; before adding hydrogen peroxide, activate the sensor for 60 - 100 min; add hydrogen peroxide to the solution for the first time until the hydrogen peroxide concentration in the monitoring solution reaches 10 mM. After the current stabilizes, add an equimolar amount of hydrogen peroxide to the solution in the same steps until the hydrogen peroxide concentrations in the monitoring solution are 10 mM, 10 mM, 20 mM, 50 mM, 100 mM, 200 mM, 200 mM, 200 mM, 200 mM respectively. Obtain the current difference each time after reaching the target hydrogen peroxide concentration;

[0048] (3) Plot the standard curve of hydrogen peroxide concentration - current difference in the monitoring solution and calculate the slope S through linear fitting. The final limit of detection (LOD) is obtained from the formula "LOD = 3.3s / S"; s can be measured by two methods: 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 s; the other is the residual standard deviation of the standard curve or the standard deviation of the intercept, which is s.

[0049] The test steps for the linear range are as follows:

[0050] (1) Connect the three electrodes of the sensor to an electrochemical workstation (Autolab), immerse it in a 0.1 M HCl / KCl solution, and use the cyclic voltammetry program with the following parameter settings: scanning voltage range -0.1 to 0.4 V, scanning rate 0.01 - 0.08 V / s, and cycle 10 - 30 times to stabilize the Prussian blue nanoparticles;

[0051] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution of 1X PBS containing 0.1 M KCl, and use the chronoamperometry program with the monitoring voltage set at -0.1 to -0.5 V; before adding hydrogen peroxide, activate the sensor for 60 - 100 min first; add hydrogen peroxide to the solution for the first time until the hydrogen peroxide concentration in the monitoring solution reaches 10 mM. After the current stabilizes, repeat adding equimolar amounts of hydrogen peroxide to the solution in the same steps 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 hydrogen peroxide concentration in the monitoring solution is the upper limit of the linear range. The linear range is composed of the lower limit of detection to this upper limit concentration. The method for obtaining the lower limit of detection has been described above.

[0052] The test steps for the response time are as follows:

[0053] (1) Connect the three electrodes of the sensor to an electrochemical workstation (Autolab), immerse it in a 0.1 M HCl / KCl solution, and use the cyclic voltammetry program with the following parameter settings: scanning voltage range -0.1 to 0.4 V, scanning rate 0.01 - 0.08 V / s, and cycle 10 - 30 times to stabilize the Prussian blue nanoparticles; (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution of 1X PBS containing 0.1 M KCl, and use the chronoamperometry program with the monitoring voltage set at -0.1 to -0.5 V; before adding hydrogen peroxide, activate the sensor for 60 - 100 min first;

[0054] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution of 1X PBS containing 0.1 M KCl. Using a chronoamperometry procedure, set the monitoring voltage to -0.1 to -0.5 V. Before adding hydrogen peroxide, activate the sensor for 60 - 100 min. First, add hydrogen peroxide to the solution until the hydrogen peroxide concentration in the monitoring solution reaches 100 mM. After the current stabilizes, calculate the time difference from the start of the current change to its stabilization. Repeat the operation of adding equimolar amounts of hydrogen peroxide until the hydrogen peroxide concentration in the monitoring solution reaches 100 mM and calculate the time difference. Take the average value of each time difference as the sensor response time.

[0055] The test procedure for monitoring the current change rate is as follows:

[0056] (1) Connect the three electrodes of the sensor to an electrochemical workstation (Autolab), immerse it in a 0.1 M HCl / KCl solution, and use a cyclic voltammetry procedure with the following parameter settings: scanning voltage range -0.1 to 0.4 V, scanning rate 0.01 - 0.08 V / s, and cycle 10 - 30 times to stabilize the Prussian blue nanoparticles;

[0057] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution of 1X PBS containing 0.1 M KCl. Using a chronoamperometry procedure, set the monitoring voltage to -0.1 to -0.5 V. Before adding hydrogen peroxide, activate the sensor for 60 - 100 min. First, add hydrogen peroxide to the solution until the hydrogen peroxide concentration in the monitoring solution reaches 100 mM. After the current stabilizes, record the current difference at this time as the initial current difference of the sensor. Subsequently, continuously monitor the current difference 2 - 500 times or for 2 - 20 days (perform the operation once a day, and repeat the same operation on the same sensor the next day) using the same procedure. Calculate the stability monitoring current change rate according to the formula "stability monitoring current change rate = 100% × |current difference at the nth time or on the nth day - initial current difference| / initial current difference".

[0058] The test procedure for monitoring the current change rate (after adding bioactive substances) is as follows:

[0059] (1) Connect the three electrodes of the sensor to an electrochemical workstation (Autolab), immerse it in a 0.1 M HCl / KCl solution, and use a cyclic voltammetry procedure with the following parameter settings: scanning voltage range -0.1 to 0.4 V, scanning rate 0.01 - 0.08 V / s, and cycle 10 - 30 times to stabilize the Prussian blue nanoparticles;

[0060] (2) After rinsing the sensor three times with deionized water, transfer it to a monitoring solution of 1X PBS containing 0.1 M KCl. Using a chronoamperometry procedure, set the monitoring voltage to -0.1 to -0.5 V. Before adding hydrogen peroxide, activate the sensor for 60 - 100 min. First, add hydrogen peroxide to the solution until the hydrogen peroxide concentration in the monitoring solution reaches 100 mM. After the current stabilizes, record the current value at this time as the initial current value of the sensor. Subsequently, add the bioactive substance to the solution until the bioactive substance concentration in the monitoring solution reaches 100 mM. After the current stabilizes, record the current value at this time as the monitoring current value of the sensor for the bioactive substance. According to the formula "monitoring current change rate = 100% × |monitoring current value of bioactive substance - initial current value| / initial current value", calculate the monitoring current change rate.

[0061] QRS interval:

[0062] (1) QRS interval test after animal myocardial infarction modeling

[0063] Animal electrocardiogram measurement is performed using lead II, that is, the negative electrode of the needle electrode is connected to the right upper limb of the animal, and the positive electrode is connected to the left lower limb of the animal. Connect the computer to record the animal electrocardiogram through a Bluetooth electrocardiogram acquisition device. The acquisition time is 60 - 200 s. Calculate all QRS intervals during the acquisition time and take their average value as the QRS interval value during animal myocardial infarction.

[0064] (2) QRS interval test after sensor treatment

[0065] First, place the sensor parallel to the long axis of the heart and closely attach it to the outer wall of the left ventricle of the heart. After 10 min of treatment, measure the animal electrocardiogram. The electrocardiogram measurement also uses lead II, that is, the negative electrode of the sensor electrocardiogram electrode is on top and the positive electrode is at the bottom. Connect the computer to record the animal electrocardiogram through a Bluetooth electrocardiogram acquisition device. The acquisition time is 60 - 200 s. Calculate all QRS intervals during the acquisition time and take their average value as the QRS interval value after sensor treatment.

[0066] Compare with the QRS interval value during animal myocardial infarction to interpret the change in the QRS interval value after sensor treatment.

[0067] QT interval change:

[0068] (1) QT interval test after animal myocardial infarction modeling

[0069] Animal electrocardiogram measurement is performed using lead II, that is, the negative electrode of the needle electrode is connected to the right upper limb of the animal, and the positive electrode is connected to the left lower limb of the animal. Connect the computer to record the animal electrocardiogram through a Bluetooth electrocardiogram acquisition device. The acquisition time is 60 - 200 s. Calculate all QT intervals during the acquisition time and take their average value as the QT interval value during animal myocardial infarction.

[0070] (2)QT interval test after sensor treatment

[0071] First, place the sensor parallel to the long axis of the heart and closely attach it to the outer wall of the left ventricle of the heart. After 10 minutes of treatment, measure the electrocardiogram of the animal. The electrocardiogram is also measured in lead II mode, that is, the negative electrode of the sensor electrocardiogram electrode is on top and the positive electrode is at the bottom. Connect the computer through a Bluetooth electrocardiogram acquisition device to record the electrocardiogram of the animal. The acquisition time is 60 - 200 s, calculate all QT intervals within the acquisition time, and take their average value as the QT interval value after sensor treatment;

[0072] Compare with the QT interval value during animal myocardial infarction to judge the change of the QT interval value after sensor treatment.

[0073] Example 1

[0074] A preparation method of a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is as follows:

[0075] (1)As shown in Figure 1 , print the counter electrode 3, working electrode 4, reference electrode 5 and 2 electrocardiogram electrodes (electrocardiogram electrode negative electrode 1 and electrocardiogram electrode positive electrode 2) on the insulating substrate:

[0076] Place the silk screen on a 20 - μm - thick polyimide insulating substrate, and evenly squeeze the conductive ink corresponding to each electrode through the silk screen with a squeegee. After ensuring that it is accurately printed in the predetermined position, dry or cure it;

[0077] Among them, the working electrode 4 uses carbon ink (manufacturer: Shenzhen Tengyu High - tech Materials Co., Ltd., grade: Field - 808), the counter electrode 3 uses carbon ink (manufacturer: Shenzhen Tengyu High - tech Materials Co., Ltd., grade: Field - 808), the reference electrode 5 uses silver / silver chloride ink (manufacturer: Creative Materials Company, USA, model: 119 - 10), and the electrocardiogram electrode uses carbon ink (manufacturer: Shenzhen Tengyu High - tech Materials Co., Ltd., grade: Field - 808);

[0078] (2)Paste the graphene aerogel loaded with the monitoring substance on the working end of the working electrode 4:

[0079] Bond the graphene aerogel loaded with the monitoring substance to the working end of the working electrode 4 with conductive silver paste (the graphene aerogel loaded with the monitoring substance completely covers the working end of the working electrode 4, and their shapes and sizes are the same), and dry it at 80 °C for 20 minutes;

[0080] Among them, the average thickness of the graphene aerogel is 800 mm, and the specific surface area is 1100 m 2 / g, with a porosity of 99%, an average pore size of 13 mm, and a conductivity of 11 S / cm; the average particle size of the monitored substance is 86 nm; the loading area of the monitored substance on the surface of the graphene aerogel is 99%; the loading area of the monitored substance in the pores of the graphene aerogel is 96%;

[0081] (3)Coat the areas of the counter electrode 3, working electrode 4, reference electrode 5 and electrocardiogram electrode other than the working ends with an insulating layer 6;

[0082] (4)Simultaneously connect the non-working ends of the counter electrode 3, working electrode 4 and reference electrode 5 to the electrochemical device, and simultaneously connect the non-working ends of the two electrocardiogram electrodes to the Bluetooth electrocardiogram device, thus obtaining a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor.

[0083] When the biochemical signal of the finally obtained physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is hydrogen peroxide and the monitored substance is Prussian blue nanoparticles, the sensitivity of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor for monitoring the biochemical signal is 550 μA / (mM×cm 2 ), the detection lower limit is 3 μM, the linear range is 3 - 800 μM, and the response time is 1 s; after continuously performing 500 detections, the monitoring current change rate is 2%; after continuously performing 20-day detections, the monitoring current change rate is 2%; during the detection process, after adding a bioactive substance (any one of ascorbic acid, glucose, dopamine, urea) to the detection object, the monitoring current change rate is less than 3%;

[0084] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has an electrocardiogram treatment effect. After the graphene aerogel loaded with the monitored substance contacts the animal heart lesion site for 10 min, the QRS interval decreases by 60%, the QT interval decreases by 70%, and the QTc interval decreases by 69%;

[0085] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has a biochemical treatment effect. After the graphene aerogel loaded with the monitored substance contacts the animal heart lesion site for 10 - 30 min, the reactive oxygen species generated after myocardial infarction completely disappear, and the number of apoptotic cells decreases.

[0086] Example 2

[0087] A preparation method of a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor, the specific steps are as follows:

[0088] (1)Print a counter electrode, a working electrode, a reference electrode and two electrocardiogram electrodes on an insulating substrate:

[0089] Place the silk screen on a polyimide insulating substrate with a thickness of 30 μm. Use a squeegee to evenly squeeze the conductive ink corresponding to each electrode through the silk screen. After ensuring that it is accurately printed at the predetermined position, perform drying or curing;

[0090] Among them, 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);

[0091] (2) Paste the graphene aerogel loaded with the monitoring substance at the working end of the working electrode:

[0092] Bond the graphene aerogel loaded with the monitoring substance to the working end of the working electrode with conductive silver paste (the graphene aerogel loaded with the monitoring substance completely covers the working end of the working electrode, and their shapes and sizes are the same), and dry it at 90 °C for 15 min;

[0093] Among them, the average thickness of the graphene aerogel is 600 mm, the specific surface area is 1030 m 2 / g, the porosity is 97%, the average pore diameter is 8 mm, and the conductivity is 15 S / cm; the average particle size of the monitoring substance is 70 nm; the loading area of the monitoring substance on the surface of the graphene aerogel is 100%; the loading area of the monitoring substance in the pores of the graphene aerogel is 98%;

[0094] (3) Coat the insulating layer on the areas of the counter electrode, working electrode, reference electrode, and electrocardiogram electrode except for the working end;

[0095] (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 2 electrocardiogram electrodes to the Bluetooth electrocardiogram device at the same time, then the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is obtained.

[0096] When the biochemical signal of the finally obtained physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is hydrogen peroxide and the monitoring substance is Prussian blue nanoparticles, the sensitivity of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor to monitor the biochemical signal is 600 μA / (mM×cm 2) The lower detection limit is 5 μM, the linear range is 5 - 1000 μM, and the response time is 2 s; after 500 consecutive detections, the monitoring current change rate is 5%; after 20 consecutive days of detection, the monitoring current change rate is 2%; during the detection process, after adding a bioactive substance (any one of ascorbic acid, glucose, and dopamine) to the detection object, the monitoring current change rate is less than 1%;

[0097] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has an electrocardiogram treatment effect. After the graphene aerogel loaded with the monitoring substance contacts the animal's heart lesion site for 10 min, the QRS interval decreases by 58%, the QT interval decreases by 65%, and the QTc interval decreases by 65%;

[0098] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has a biochemical treatment effect. After the graphene aerogel loaded with the monitoring substance contacts the animal's heart lesion site for 10 - 30 min, the reactive oxygen species generated after myocardial infarction completely disappear, and the number of apoptotic cells decreases.

[0099] Example 3

[0100] A preparation method of a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is as follows;

[0101] (1) Print a counter electrode, a working electrode, a reference electrode, and two electrocardiogram electrodes on an insulating substrate:

[0102] Place the silk screen on a 60 - μm - thick polyimide insulating substrate, and evenly squeeze the conductive ink corresponding to each electrode through the silk screen with a squeegee. After ensuring that it is accurately printed in the predetermined position, dry or cure it;

[0103] Among them, the working electrode uses carbon ink (manufacturer: Shenzhen Tengyu High - tech Materials Co., Ltd., brand: Field - 808), the counter electrode uses carbon ink (manufacturer: Shenzhen Tengyu High - tech Materials Co., Ltd., brand: Field - 808), the reference electrode uses silver / silver chloride ink (manufacturer: Creative Materials Company, USA, model: 119 - 10), and the electrocardiogram electrode uses carbon ink (manufacturer: Shenzhen Tengyu High - tech Materials Co., Ltd., brand: Field - 808);

[0104] (2) Paste the graphene aerogel loaded with the monitoring substance on the working end of the working electrode:

[0105] Bond the graphene aerogel loaded with the monitoring substance to the working end of the working electrode with conductive silver paste (the graphene aerogel loaded with the monitoring substance completely covers the working end of the working electrode, and their shapes and sizes are the same), and dry it at 100 °C for 10 min;

[0106] Among them, the average thickness of the graphene aerogel is 1000 mm, the specific surface area is 1200 m 2 / g, the porosity is 99%, the average pore size is 20 mm, and the conductivity is 5 S / cm; the average particle size of the monitored substance is 100 nm; the loading area of the monitored substance on the surface of the graphene aerogel is 100%; the loading area of the monitored substance in the pores of the graphene aerogel is 97%;

[0107] (3) Coat the insulating layer on the regions of the counter electrode, working electrode, reference electrode and electrocardiogram electrode except for the working ends;

[0108] (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, then the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is obtained.

[0109] When the biochemical signal of the finally prepared physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is hydrogen peroxide and the monitored substance is Prussian blue nanoparticles, the sensitivity of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor for monitoring the biochemical signal is 500 μA / (mM×cm 2 ), the monitoring lower limit is 4 μM, the linear range is 4 - 1000 μM, and the response time is 1 s; after continuously performing 500 detections, the monitoring current change rate is 2%; after continuously performing 20-day detections, the monitoring current change rate is 7%; during the detection process, after adding a bioactive substance (any one of ascorbic acid, glucose, dopamine, urea and uric acid) to the detection object, the monitoring current change rate is less than 1%;

[0110] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has an electrocardiogram treatment effect. After the graphene aerogel loaded with the monitored substance contacts the animal heart lesion site for 10 min, the QRS interval decreases by 60%, the QT interval decreases by 68%, and the QTc interval decreases by 68%;

[0111] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has a biochemical treatment effect. After the graphene aerogel loaded with the monitored substance contacts the animal heart lesion site for 10 - 30 min, the reactive oxygen species generated after myocardial infarction completely disappear, and the number of apoptotic cells decreases.

[0112] Example 4

[0113] A preparation method of a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor, the specific steps are as follows:

[0114] (1) Print the counter electrode, working electrode, reference electrode and two electrocardiogram electrodes on the insulating substrate:

[0115] Place the silk screen on a polyimide insulating substrate with a thickness of 30 μm. Use a squeegee to evenly squeeze the conductive ink corresponding to each electrode through the silk screen. After ensuring that it is accurately printed at the predetermined position, perform drying or curing;

[0116] Among them, the working electrode uses gold ink (manufacturer: Huizhou Jinfuqi Industrial Co., Ltd., brand: LV53-121), the counter electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand: Field-808), the reference electrode uses silver / silver chloride ink (manufacturer: Creative Materials Corporation, USA, model: 119-10), and the electrocardiogram electrode uses gold ink (manufacturer: Huizhou Jinfuqi Industrial Co., Ltd., brand: LV53-121);

[0117] (2) Paste the graphene aerogel loaded with the monitoring substance at the working end of the working electrode:

[0118] Bond the graphene aerogel loaded with the monitoring substance to the working end of the working electrode with conductive silver paste (the graphene aerogel loaded with the monitoring substance completely covers the working end of the working electrode, and their shapes and sizes are the same), and dry it at 90 °C for 15 min;

[0119] Among them, the average thickness of the graphene aerogel is 700 mm, the specific surface area is 1080 m 2 / g, the porosity is 97%, the average pore diameter is 11 mm, and the conductivity is 14 S / cm; the average particle size of the monitoring substance is 50 nm; the loading area of the monitoring substance on the surface of the graphene aerogel is 100%; the loading area of the monitoring substance in the pores of the graphene aerogel is 99%;

[0120] (3) Coat the insulating layer on the areas of the counter electrode, working electrode, reference electrode, and electrocardiogram electrode except for the working end;

[0121] (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 2 electrocardiogram electrodes to the Bluetooth electrocardiogram device at the same time, then the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is obtained.

[0122] When the biochemical signal of the finally prepared physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is hydrogen peroxide and the monitoring substance is Prussian blue nanoparticles, the sensitivity of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor for monitoring biochemical signals is 580 μA / (mM×cm 2) The lower detection limit is 4 μM, the linear range is 4 - 1000 μM, and the response time is 0.5 s; after 500 consecutive detections, the change rate of the monitored current is 4%; after 20 consecutive days of detection, the change rate of the monitored current is 5%; during the detection process, when a bioactive substance (any one of glucose, dopamine, urea, and uric acid) is added to the detection object, the change rate of the monitored current is less than 3%;

[0123] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has an electrocardiogram treatment effect. After the graphene aerogel loaded with the monitoring substance contacts the diseased part of the animal heart for 10 min, the QRS interval decreases by 50%, the QT interval decreases by 60%, and the QTc interval decreases by 62%;

[0124] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has a biochemical treatment effect. After the graphene aerogel loaded with the monitoring substance contacts the diseased part of the animal heart for 10 - 30 min, the reactive oxygen species generated after myocardial infarction completely disappear, and the number of apoptotic cells decreases.

[0125] Example 5

[0126] A preparation method of a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is as follows:

[0127] (1) Print a counter electrode, a working electrode, a reference electrode, and 2 electrocardiogram electrodes on an insulating substrate:

[0128] Place the silk screen on a 40-μm-thick polyimide insulating substrate, and evenly squeeze the conductive ink corresponding to each electrode through the silk screen with a squeegee. After ensuring that it is accurately printed at the predetermined position, dry or cure it;

[0129] Among them, the working electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand: Field-808), the counter electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand: Field-808), the reference electrode uses silver / silver chloride ink (manufacturer: Creative Materials Company, USA, model: 119-10), and the electrocardiogram electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., brand: Field-808);

[0130] (2) Paste the graphene aerogel loaded with the monitoring substance at the working end of the working electrode:

[0131] Bond the graphene aerogel loaded with the monitoring substance to the working end of the working electrode with conductive silver paste (the graphene aerogel loaded with the monitoring substance completely covers the working end of the working electrode, and their shapes and sizes are the same), and dry it at 80 °C for 20 min;

[0132] Among them, the average thickness of the graphene aerogel is 500 mm, the specific surface area is 1000 m 2 / g, the porosity is 95%, the average pore size is 5 mm, and the conductivity is 15 S / cm; the average particle size of the monitored substance is 40 nm; the loading area of the monitored substance on the surface of the graphene aerogel is 99%; the loading area of the monitored substance in the pores of the graphene aerogel is 90%;

[0133] (3)Coat the areas of the counter electrode, working electrode, reference electrode and electrocardiogram electrode except the working ends with an insulating layer;

[0134] (4)Simultaneously connect the non-working ends of the counter electrode, working electrode and reference electrode to the electrochemical device, and simultaneously connect the non-working ends of the two electrocardiogram electrodes to the Bluetooth electrocardiogram device, thus obtaining a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor.

[0135] When the biochemical signal of the finally obtained physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is hydrogen peroxide and the monitored substance is Prussian blue nanoparticles, the sensitivity of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor for monitoring the biochemical signal is 590 μA / (mM×cm 2 ), the monitoring lower limit is 1 μM, the linear range is 1 - 1000 μM, and the response time is 1.5 s; after continuously performing 500 detections, the monitoring current change rate is 1%; after continuously performing detections for 20 days, the monitoring current change rate is 3%; during the detection process, after adding a bioactive substance (any one of ascorbic acid, dopamine, urea and uric acid) to the detection object, the monitoring current change rate is less than 2%;

[0136] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has an electrocardiogram treatment effect. After the graphene aerogel loaded with the monitored substance contacts the diseased part of the animal heart for 10 min, the QRS interval is reduced by 55%, the QT interval is reduced by 70%, and the QTc interval is reduced by 70%;

[0137] The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor has a biochemical treatment effect. After the graphene aerogel loaded with the monitored substance contacts the diseased part of the animal heart for 10 - 30 min, the reactive oxygen species generated after myocardial infarction completely disappear, and the number of apoptotic cells decreases.

[0138] Example 6

[0139] A preparation method of a physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor, the specific steps are as follows:

[0140] (1)Print a counter electrode, a working electrode, a reference electrode and two electrocardiogram electrodes on an insulating substrate:

[0141] Place the silk screen on a polyimide insulating substrate with a thickness of 50 μm. Use a squeegee to evenly squeeze the conductive ink corresponding to each electrode through the silk screen. After ensuring that it is precisely printed at the predetermined position, perform drying or curing.

[0142] Among them, the working electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., grade: Field-808), 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 Company, USA, model: 119-10), and the electrocardiogram electrode uses carbon ink (manufacturer: Shenzhen Tengyu High-Tech Materials Co., Ltd., grade: Field-808);

[0143] (2) Paste the graphene aerogel loaded with the monitoring substance at the working end of the working electrode:

[0144] Bond the graphene aerogel loaded with the monitoring substance to the working end of the working electrode with conductive silver paste (the graphene aerogel loaded with the monitoring substance completely covers the working end of the working electrode, and their shapes and sizes are the same), and dry it at 80 °C for 20 min;

[0145] Among them, the average thickness of the graphene aerogel is 900 mm, the specific surface area is 1150 m 2 / g, the porosity is 98%, the average pore diameter is 15 mm, and the conductivity is 7 S / cm; the average particle size of the monitoring substance is 90 nm; the loading area of the monitoring substance on the surface of the graphene aerogel is 99%; the loading area of the monitoring substance in the pores of the graphene aerogel is 99%;

[0146] (3) Coat the insulating layer on the areas of the counter electrode, working electrode, reference electrode, and electrocardiogram electrode except for the working end;

[0147] (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 2 electrocardiogram electrodes to the Bluetooth electrocardiogram device at the same time, then the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is obtained.

[0148] When the biochemical signal of the finally obtained physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor is hydrogen peroxide and the monitoring substance is Prussian blue nanoparticles, the sensitivity of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor to monitor the biochemical signal is 590 μA / (mM×cm 2), the lower detection limit is 4 μM, the linear range is 4 - 1000 μM, and the response time is 1 s; after 500 consecutive detections, the monitoring current change rate is 3%; after 20 consecutive days of detection, the monitoring current change rate is 3%; during the detection process, after adding a bioactive substance (any one of urea and uric acid) to the detection object, the monitoring current change rate is less than 1%;

[0149] The integrated physiological and biochemical diagnosis and treatment implantable cardiac flexible sensor has an electrocardiogram treatment effect. After the graphene aerogel loaded with the monitoring substance contacts the diseased part of the animal heart for 10 min, the QRS interval decreases by 60%, the QT interval decreases by 68%, and the QTc interval decreases by 69%;

[0150] The integrated physiological and biochemical diagnosis and treatment implantable cardiac flexible sensor has a biochemical treatment effect. After the graphene aerogel loaded with the monitoring substance contacts the diseased part of the animal heart for 10 - 30 min, the reactive oxygen species generated after myocardial infarction completely disappear, and the number of apoptotic cells decreases.

Claims

1. An implantable cardiac flexible sensor integrating physiological and biochemical diagnosis and treatment, characterized in that, It includes an insulating substrate, and a counter electrode, a working electrode, a reference electrode, and two electrocardiogram electrodes printed on the insulating substrate simultaneously. 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 integrated physiological and biochemical diagnosis and treatment implantable cardiac flexible sensor according to claim 1, characterized in that, The insulating substrate is made of polyimide with a thickness of 20 - 60 μm.

3. The implantable cardiac flexible sensor for integrated physiological and biochemical diagnosis and treatment according to claim 1, wherein The working electrode is printed with gold ink or carbon ink, the counter electrode is printed with gold ink or carbon ink, the reference electrode is printed with silver / silver chloride ink, and the electrocardiogram electrode is printed with gold ink or carbon ink.

4. The integrated physiological and biochemical diagnosis and treatment implantable cardiac flexible sensor according to claim 3, characterized in that, An insulating layer is coated on the regions of the counter electrode, the working electrode, the reference electrode, and the electrocardiogram electrode except for the working ends.

5. The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor according to 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: Place the screen on the insulating substrate, and evenly squeeze the conductive ink corresponding to each electrode through the screen with a squeegee. After ensuring that it is accurately printed at the predetermined position, perform drying or curing.

6. The implantable cardiac flexible sensor for integrated physiological and biochemical diagnosis and treatment according to claim 1, wherein The graphene aerogel loaded with the monitoring substance completely covers the working end of the working electrode, and their shapes and sizes are the same.

7. The integrated physiological and biochemical diagnosis and treatment implantable cardiac flexible sensor according to 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: Bond the graphene aerogel loaded with the monitoring substance to the working end of the working electrode with conductive silver paste, and then dry it at 80 - 100 °C for 10 - 20 min.

8. The integrated physiological and biochemical diagnosis and treatment implantable cardiac flexible sensor according to claim 1, characterized in that The thickness of the graphene aerogel is 500 - 1000 mm, the specific surface area is 1000 - 1200 m 2 / g, the porosity is 95 - 99%, the pore size is 5 - 20 mm, and the conductivity is 5 - 15 S / cm; the particle size of the monitored substance is 40 - 100 nm; the loading area of the monitored substance on the surface of the graphene aerogel is 99 - 100%; the loading area of the monitored substance in the pores of the graphene aerogel is 90 - 99%.

9. The physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor according to claim 1, characterized in that, It also includes an electrochemical device and a Bluetooth electrocardiogram device. The non - working ends of the counter electrode, the working electrode, and the reference electrode are simultaneously connected to the electrochemical device, and the non - working ends of the two electrocardiogram electrodes are simultaneously connected to the Bluetooth electrocardiogram device.

10. The implantable cardiac flexible sensor for integrated physiological and biochemical diagnosis and treatment according to claim 1, characterized in that, When the biochemical signal is hydrogen peroxide and the monitored substance is Prussian blue nanoparticles, the sensitivity of the physiological and biochemical diagnosis and treatment integrated implantable cardiac flexible sensor for monitoring the biochemical signal is 500 - 600 μA / (mM×cm 2 ), the lower 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 consecutive detections, the detection current change rate is 1 - 5%; after 20 consecutive days of detection, the detection current change rate is 2 - 7%; during the detection process, after adding a bioactive substance to the detection object, the detection current change rate is 1 - 3%, and the bioactive substance is one or more of ascorbic acid, glucose, dopamine, urea, and uric acid.

Images