Electrical stimulation targeted drug delivery and closed-loop control method for sepsis immunoregulation

Abstract

The invention provides an electrical stimulation targeted drug delivery and closed-loop control method for sepsis immune regulation and control, and belongs to the technical field of automatic control systems.The electrical stimulation targeted drug delivery and closed-loop control method comprises the steps that immune index data of a patient is monitored in real time, abnormal analysis is conducted on the immune index data, and an inflammation unbalance coefficient is determined; outputting a corresponding electrical stimulation signal according to the inflammation imbalance coefficient; a micro-needle array sensor is adopted to detect local tissue impedance of a drug targeted delivery area, and the optimal administration dosage and administration frequency are generated; based on the optimal administration dosage and the administration frequency, controlling an electric control micropump to execute targeted administration, collecting real-time immune feedback data after administration, calculating an immune adjustment error, and adaptively adjusting electrical stimulation parameters to form closed-loop control; and repeating the above steps until the inflammation imbalance coefficient and the real-time immune feedback data reach a dynamic termination condition, and executing a regulation and control termination program to complete sepsis immune regulation and control. The regulation and control efficiency and safety of sepsis immune imbalance are obviously improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of automatic control system, and particularly relates to an electric stimulation targeted drug delivery and closed-loop control method for immune regulation of sepsis. BACKGROUND

[0002] Sepsis is a fatal systemic inflammatory response caused by the disorder of the host immune system. The existing treatment methods (such as antibiotics and immunosuppressants) often lead to excessive suppression of inflammation or fail to block the inflammatory storm due to the lack of real-time feedback regulation, and the mortality rate remains high.

[0003] The current mainstream technology adopts open-loop drug delivery (such as fixed-dose glucocorticoids) or single signal regulation (such as relying only on serum inflammatory factor levels to adjust treatment), and some schemes attempt to regulate inflammation through electric stimulation (such as vagus nerve stimulation), but have the following limitations: static regulation: unable to dynamically adjust the intervention intensity in combination with multi-dimensional immune indicators (pro-inflammatory / anti-inflammatory factors, white blood cell count); drug efficacy lag: traditional drug delivery methods are difficult to accurately control local drug concentration, which easily leads to systemic side effects; lack of closed-loop feedback: treatment termination relies on subjective clinical judgment, and no automatic decision-making mechanism based on real-time data has been established.

[0004] Therefore, the present application provides an electric stimulation targeted drug delivery and closed-loop control method for immune regulation of sepsis. SUMMARY

[0005] The present application provides an electric stimulation targeted drug delivery and closed-loop control method for immune regulation of sepsis, which realizes dynamic and accurate regulation of the immune state of sepsis through the synergistic closed-loop control of electric stimulation and targeted drug delivery. The inflammation imbalance coefficient is calculated in combination with multi-dimensional immune indicators (pro-inflammatory / anti-inflammatory factors, white blood cell count) to optimize electric stimulation parameters and drug dosage; local delivery is accurately controlled using a microneedle impedance sensor, and the intervention intensity is automatically adjusted based on real-time feedback to avoid excessive / insufficient treatment, thereby significantly improving the regulation efficiency and safety of sepsis immune imbalance.

[0006] The present application provides an electric stimulation targeted drug delivery and closed-loop control method for immune regulation of sepsis, comprising: Step 1: Real-time monitoring of immune indicator data of a patient, wherein the immune indicator data includes pro-inflammatory factor levels, anti-inflammatory factor levels, and white blood cell count, abnormal analysis of the immune indicator data is performed to determine an inflammation imbalance coefficient; Step 2: Dynamically adjusting electric stimulation parameters according to the inflammation imbalance coefficient, and outputting a corresponding electric stimulation signal; Step 3: Detecting the local tissue impedance of the drug targeted delivery area using a microneedle array sensor, and generating an optimal drug dosage and drug frequency in combination with the electric stimulation signal; Step 4: Based on the optimal dosage and frequency of administration, the electrically controlled micropump is controlled to perform targeted administration, while real-time immune feedback data after administration is collected, immune regulation error is calculated based on the real-time immune feedback data, and the electric stimulation parameters are self-adaptively adjusted to form a closed-loop control; Step 5: Repeat steps 1 to 4 until the inflammation imbalance coefficient and the real-time immune feedback data reach the dynamic termination condition to execute the regulation termination program, and the sepsis immune regulation is completed.

[0007] Preferably, the immune index data of the patient is monitored in real time, wherein the immune index data includes pro-inflammatory factor level, anti-inflammatory factor level and white blood cell count, including: Periodically collecting blood samples of the patient; Measuring the blood samples by an electrochemical sensor to obtain the pro-inflammatory factor level and the anti-inflammatory factor level, and measuring the blood samples by an optical sensor to obtain the white blood cell count, the electrochemical sensor measurement and the optical sensor measurement are both based on the blood samples collected at the same time point.

[0008] Preferably, the immune index data is analyzed for abnormalities to determine the inflammation imbalance coefficient, including: According to the immune index data, the total effect value of the pro-inflammatory factor and the total effect value of the anti-inflammatory factor are calculated respectively. Wherein, is the concentration of the ith pro-inflammatory factor, is the concentration of the jth anti-inflammatory factor, n is the number of pro-inflammatory factor types, and m is the number of anti-inflammatory factor types, is the weight corresponding to the jth anti-inflammatory factor, is the weight corresponding to the ith pro-inflammatory factor, and are the clinical calibration coefficients of the pro-inflammatory factor and the anti-inflammatory factor respectively, and a and b are the nonlinear regulation indexes corresponding to the total effect value of the pro-inflammatory factor and the total effect value of the anti-inflammatory factor respectively; The white blood cell count abnormal correction term is determined based on the immune index data: Wherein, ΔW is the white blood cell abnormal correction factor, is the current white blood cell count, is the baseline white blood cell count of the patient, wherein σ is the white blood cell fluctuation threshold: Wherein, σ0 is a preset white blood cell fluctuation coefficient. Based on the total effect value of pro-inflammatory factors , the total effect value of anti-inflammatory factors , and the abnormal correction term of white blood cell count, the inflammation imbalance coefficient is determined: wherein, is the inflammation imbalance coefficient, and ε is a zero-division prevention constant.

[0009] Preferably, according to the inflammation imbalance coefficient, the electrical stimulation parameters are dynamically adjusted, and the corresponding electrical stimulation signal is output, including: If the inflammation imbalance coefficient is higher than a first preset threshold, the electrical stimulation intensity is increased; If the inflammation imbalance coefficient is lower than a second preset threshold but higher than a preset immune imbalance boundary threshold, the current electrical stimulation intensity is maintained; If the inflammation imbalance coefficient is lower than the preset immune imbalance boundary threshold, the electrical stimulation intensity is reduced or the electrical stimulation is turned off.

[0010] Preferably, the local tissue impedance of the drug targeted delivery area is detected by a microneedle array sensor, and the optimal drug dosage and drug frequency are generated in combination with the electrical stimulation signal, including: The local tissue impedance change value of the drug targeted delivery area is monitored in real time by the microneedle array sensor, and the tissue ischemia degree grade is generated according to the impedance change value; Based on the inflammation imbalance coefficient and the tissue ischemia degree grade, the initial drug dosage is determined; The initial drug dosage is corrected based on the current electrical stimulation signal intensity to obtain the optimal drug dosage; Based on the optimal drug dosage and the tissue ischemia degree grade, the final drug frequency is determined.

[0011] Preferably, based on the optimal drug dosage and drug frequency, the electrically controlled micropump is controlled to perform targeted drug delivery, and real-time immune feedback data after drug delivery is collected, the immune regulation error is calculated based on the real-time immune feedback data, and the electrical stimulation parameters are adjusted adaptively, including: The electrically controlled micropump performs targeted drug delivery according to the optimal drug dosage and the final drug frequency; After each drug delivery cycle is completed, the updated pro-inflammatory factor level, anti-inflammatory factor level, and white blood cell count are synchronously collected by the electrochemical sensor and the optical sensor as real-time immune feedback data; The immune regulation deviation degree is calculated according to the real-time immune feedback data, wherein the immune regulation deviation degree is obtained by comparing the relative deviation degree of the current inflammation imbalance coefficient and the target threshold interval; When the immune regulation deviation exceeds the set allowable range, the electric stimulation parameters are adjusted in a stepwise manner according to the deviation direction and amplitude, until the real-time immune feedback data indicates that the inflammation imbalance coefficient is continuously and stably in the target threshold interval, and the closed-loop regulation of immune homeostasis is completed.

[0012] Preferably, the dynamic termination condition includes: the continuous preset number of monitoring results of the inflammation imbalance coefficient are lower than the preset immune imbalance threshold; and the dynamic balance rate of the concentrations of pro-inflammatory factors and anti-inflammatory factors is maintained in the preset safe interval; and the fluctuation amplitude of the white blood cell count does not exceed the preset allowable deviation range of the baseline value.

[0013] Preferably, the execution of the control termination procedure includes: decreasing the electric stimulation intensity in stages until it is completely turned off; gradually reducing the administration frequency according to a preset decay curve to a maintenance dose; maintaining the microneedle array sensor for continuous monitoring, and if the indicators rebound, restarting the closed-loop regulation of steps 1 to 4.

[0014] Compared with the prior art, the beneficial effects of the present application are as follows: Through the synergistic closed-loop control of electric stimulation and targeted drug delivery, dynamic and accurate regulation of the immune state of sepsis is achieved. The inflammation imbalance coefficient is calculated by combining multi-dimensional immune indicators (pro-inflammatory / anti-inflammatory factors, white blood cell count), and the electric stimulation parameters and drug dose are optimized; the local delivery is precisely controlled by using the microneedle impedance sensor, and the intervention intensity is automatically adjusted based on real-time feedback to avoid excessive / insufficient treatment. This method significantly improves the regulation efficiency and safety of sepsis immune imbalance. BRIEF DESCRIPTION OF DRAWINGS

[0015] In order to more clearly illustrate the technical solutions in the present application or prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0016] Figure 1 is a flowchart of the electric stimulation and targeted drug delivery and closed-loop control method for sepsis immune regulation provided by the embodiments of the present application. DETAILED DESCRIPTION

[0017] In order to make the purposes, technical solutions and advantages of the present application clearer, the technical solutions in the present application will be clearly and completely described below in combination with the drawings in the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0018] Embodiment 1 The embodiment of the present application provides a sepsis immune regulation electric stimulation targeted drug delivery and closed-loop control method, as shown in formula (I), which comprises the following steps: Figure 1 Step 1: Real-time monitoring of immune index data of the patient, wherein the immune index data comprises pro-inflammatory factor level, anti-inflammatory factor level and white blood cell count, abnormal analysis is performed on the immune index data, and an inflammation imbalance coefficient is determined; Step 2: Dynamically adjusting the electric stimulation parameters according to the inflammation imbalance coefficient, and outputting the corresponding electric stimulation signal; Step 3: Detecting the local tissue impedance of the drug targeted delivery area by using a microneedle array sensor, and combining the electric stimulation signal to generate an optimal drug delivery dose and drug delivery frequency; Step 4: Controlling the electrically controlled micropump to execute targeted drug delivery based on the optimal drug delivery dose and drug delivery frequency, simultaneously collecting real-time immune feedback data after drug delivery, calculating an immune regulation error based on the real-time immune feedback data and self-adaptively adjusting the electric stimulation parameters to form a closed-loop control; Step 5: Repeating the above steps 1 to 4 until the inflammation imbalance coefficient and the real-time immune feedback data reach a dynamic termination condition to execute a regulation termination program, and completing the sepsis immune regulation.

[0019] In this embodiment, the real-time monitoring of the immune index data: the immune-related physiological indicators of the patient are dynamically and continuously collected by using a biological sensor or a blood analysis device, including pro-inflammatory factors, anti-inflammatory factors and white blood cell count, etc., reflecting the change of the inflammation state of the patient. The pro-inflammatory factors (such as TNF-α, IL-6): abnormal increase in the level usually indicates that the inflammation cascade reaction is excessive, examples: the serum IL-6 concentration of a sepsis patient may exceed 100 pg / mL (normal value <7 pg / mL); the anti-inflammatory factors (such as IL-10, TGF-β): excessive expression may lead to inhibitory imbalance of the immune system, examples: when the IL-10 level exceeds 20 pg / mL, the immunoparalysis phenomenon may occur; the white blood cell count (WBC): significant deviation from the normal range (such as >12×10 9 / L or <4×10 9 / L) may indicate immune disorder, examples: the white blood cell of a sepsis patient often abnormally fluctuates.

[0020] ​In this embodiment, the microneedle array sensor: a non-invasive sensing device composed of multiple micron-sized needle-shaped electrodes, can penetrate the skin surface, real-time collect the impedance or metabolite concentration in the tissue, for monitoring local inflammation or drug efficacy feedback, implanting the microneedle array into the drug action target (such as the inflammation site), and continuously monitoring the local tissue impedance; impedance reduction usually indicates edema or increased tissue exudation, which can indicate worsening of inflammation.

[0021] In this embodiment, the electrically controlled micropump realizes targeted drug delivery by using an electrically controllable micropump device (such as a piezoelectric or electroosmotic micropump), which can accurately deliver drugs to the target tissue, realize quantitative, targeted therapy, and the example process is as follows: anti-inflammatory drugs (such as hydrocortisone) are delivered to the spleen or the vicinity of the infection source through a catheter; if the microneedle detects a decrease in local impedance (indicating that inflammation is worsening), the system automatically adjusts the micropump output rate from 0.1 mL / h to 0.15 mL / h, realizing dynamic response control.

[0022] The beneficial effects of the above technical solutions are: through the synergistic closed-loop control of electric stimulation and targeted drug delivery, the dynamic and accurate regulation of sepsis immune state is realized. The inflammation imbalance coefficient is calculated by combining multi-dimensional immune indicators (pro-inflammatory / anti-inflammatory factors, white blood cell count), and the electric stimulation parameters and drug dosage are optimized; the local delivery precision control is realized by using the microneedle impedance sensor, and the intervention intensity is automatically adjusted based on real-time feedback to avoid excessive / insufficient treatment. This method significantly improves the regulation efficiency and safety of sepsis immune imbalance.

[0023] Embodiment 2: The embodiment of the present application provides an electric stimulation and targeted drug delivery and closed-loop control method for sepsis immune regulation, which realizes real-time monitoring of immune indicator data of a patient, wherein the immune indicator data includes pro-inflammatory factor level, anti-inflammatory factor level and white blood cell count, and includes: Periodically collecting blood samples of the patient; Measuring the blood samples by an electrochemical sensor to obtain the pro-inflammatory factor level and the anti-inflammatory factor level, and measuring the blood samples by an optical sensor to obtain the white blood cell count, wherein the electrochemical sensor measurement and the optical sensor measurement are both based on the blood samples collected at the same time point.

[0024] The beneficial effects of the above technical solutions are: through synchronous collection of blood samples and the use of electrochemical sensors and optical sensors, the accurate and synchronous detection of pro-inflammatory / anti-inflammatory factor level and white blood cell count is realized, avoiding the time efficiency error of traditional step-by-step detection. This scheme improves the real-time and consistency of immune indicator data, provides a reliable data basis for subsequent inflammation imbalance analysis, and significantly optimizes the closed-loop response efficiency of sepsis immune regulation.

[0025] Embodiment 3: The embodiment of the present application provides a sepsis immune regulation electric stimulation targeted administration and closed-loop control method, abnormal analysis is performed on the immune index data, an inflammatory imbalance coefficient is determined, and the method comprises the following steps: According to the immune index data, total effect values of proinflammatory factors and total effect values of anti-inflammatory factors are respectively calculated Among them, is the concentration of the ith proinflammatory factor, is the concentration of the jth anti-inflammatory factor, n is the number of proinflammatory factor types, m is the number of anti-inflammatory factor types, is the weight corresponding to the jth anti-inflammatory factor, is the weight corresponding to the ith proinflammatory factor, and are clinical calibration coefficients of the proinflammatory factors and the anti-inflammatory factors respectively, and a and b are nonlinear regulation indexes corresponding to the total effect values of the proinflammatory factors and the total effect values of the anti-inflammatory factors respectively. Based on the immune index data, a white blood cell count abnormal correction term is determined: Among them, ΔW is a white blood cell abnormal correction factor, is the current white blood cell count, is the baseline white blood cell count of the patient, wherein σ is a white blood cell fluctuation threshold: Among them, σ0 is a preset white blood cell fluctuation coefficient. Based on the total effect values of the proinflammatory factors , the total effect values of the anti-inflammatory factors and the white blood cell count abnormal correction term, an inflammatory imbalance coefficient is determined: Among them, is the inflammatory imbalance coefficient, and ϵ is a zero division constant.

[0026] In the embodiment, the baseline value of the white blood cell count is determined according to historical immune data of the patient or a reference range of healthy people.

[0027] In the embodiment, all factor concentrations are in the unified unit of pg / mL.

[0028] ​​The clinical calibration coefficients of pro-inflammatory factors and anti-inflammatory factors in this embodiment represent the importance and weight of each factor on the pathological progress of sepsis, which are determined according to a large amount of clinical statistical data. The calibration coefficient of a pro-inflammatory factor is used to measure the contribution of different pro-inflammatory factors (such as TNF-α and IL-6) to the inflammatory storm. For example, TNF-α: , which indicates that its effect is strong, and the mortality rate increases by about 5% for every 10 pg / mL increase. IL-1β: , which has a relatively weak effect. In this embodiment, the calibration coefficient of an anti-inflammatory factor measures the immunosuppressive effect of an anti-inflammatory factor (such as IL-10 and TGF-β). For example, IL-10: , which has a low regulatory effect. TGF-β: , because it can more widely suppress the immune response.

[0029] In this embodiment, the non-linear index is used to simulate the effect of the factor, which is not simply linear growth, but has a saturation or exacerbation trend when , the effect of a high concentration of pro-inflammatory factors is amplified. For example: : When IL-6 increases from 100 to 200 pg / mL, the effect is not 2 times, but about 2.83 times. When , the growth of the effect of a high concentration of anti-inflammatory factors is inhibited. For example: : When IL-10 increases from 50 to 100 pg / mL, the effect only grows by 1.74 times, not 2 times. This non-linear function more accurately reproduces the real dynamics of cytokines in the body, avoiding the risk of underestimation or overestimation of a simple linear model.

[0030] In this embodiment, the preset white blood cell fluctuation coefficient defines the allowable fluctuation range of white blood cell count within the normal range. The threshold is set based on the data distribution of healthy people and patients. For example, the baseline WBC is 6×10 9 / L, , the normal fluctuation range is 6±(2×6)=[0,18], but the WBC cannot be 0, and the actual range is [4,18]. If the current WBC=20×10 9 / L: If the threshold is exceeded, intervention or correction is required. This avoids misjudgment caused by individual differences or short-term fluctuations, ensuring the accuracy of the judgment.

[0031] The beneficial effects of the above technical solutions are: by dynamically calculating the total effect value of pro-inflammatory / anti-inflammatory factors, combining with the white blood cell abnormal correction term, the inflammation imbalance coefficient is accurately quantified, and the limitations of traditional single index evaluation are solved. The clinical calibration coefficient and the nonlinear adjustment index are introduced to more truly simulate the biological characteristics of immune response; the preset white blood cell fluctuation coefficient is used to distinguish physiological fluctuations and pathological abnormalities to avoid misjudgment. Finally, a multi-dimensional dynamic feedback closed-loop control system is formed, which significantly improves the diagnostic accuracy and intervention timeliness of sepsis immune imbalance.

[0032] Embodiment 4: The embodiment of the present application provides an electric stimulation targeted drug delivery and closed-loop control method for sepsis immune regulation. According to the inflammation imbalance coefficient, the electric stimulation parameters are dynamically adjusted, and the corresponding electric stimulation signal is output, which includes: If the inflammation imbalance coefficient is higher than the first preset threshold, the electric stimulation intensity is increased; If the inflammation imbalance coefficient is lower than the second preset threshold but higher than the preset immune imbalance threshold, the current electric stimulation intensity is maintained; If the inflammation imbalance coefficient is lower than the preset immune imbalance threshold, the electric stimulation intensity is reduced or the electric stimulation is turned off.

[0033] In this embodiment, the setting of the first preset threshold and the second preset threshold needs to be based on the dynamic response characteristics of clinical immune imbalance and the dose-effect relationship of electric stimulation intervention. For example, the first preset threshold T1=15 is the inflammation storm warning line: IDI exceeding this value indicates that the systemic inflammation is out of control, and the suppression intervention needs to be urgently enhanced. The second preset threshold T2=10 is the steady-state regulation starting line: when IDI is lower than this value but higher than the threshold, it enters the immune balance maintenance stage. In this embodiment, the preset immune imbalance threshold T0=5, when IDI≤T0, it indicates that the immune system has restored the self-steady function. The preset immune imbalance threshold is a dynamic variable, and its value is determined based on the baseline inflammation state of the patient, which is specifically given by the following formula: Wherein represents the C-reactive protein (CRP) level of the patient before the onset, and the unit is mg / L; when the baseline data is not available, the default value is 10 mg / L.

[0034] The beneficial effects of the above technical solutions are: based on the dynamic inflammation imbalance coefficient, the electric stimulation intensity is intelligently adjusted to realize precise closed-loop control. When the inflammation imbalance is serious, the stimulation is enhanced to inhibit excessive inflammation; in the critical range (higher than the immune imbalance threshold), the steady state is maintained to avoid excessive intervention; when the threshold is lower, the stimulation is weakened or turned off to prevent immune suppression. This scheme realizes the adaptive optimization of sepsis immune state, improves the safety and effectiveness of treatment, and reduces the need for manual intervention.

[0035] Embodiment 5: The embodiment of the present application provides a sepsis immune regulation electric stimulation targeted drug delivery and closed-loop control method, which adopts a microneedle array sensor to detect local tissue impedance of a drug targeted delivery area, generates an optimal drug delivery dose and a drug delivery frequency in combination with the electric stimulation signal, and comprises the following steps of: detecting, by the microneedle array sensor, a local tissue impedance change value of the drug targeted delivery area in real time, and generating a tissue ischemia degree grade according to the impedance change value; determining an initial drug delivery dose based on the inflammation imbalance coefficient and the tissue ischemia degree grade; correcting the initial drug delivery dose to obtain an optimal drug delivery dose based on a current electric stimulation signal intensity; determining a final drug delivery frequency based on the optimal drug delivery dose and the tissue ischemia degree grade.

[0036] In the embodiment, the tissue ischemia degree grade: if the impedance of the area rises by more than 5% in an electric stimulation cycle, it is determined as severe ischemia; if the impedance fluctuation range of the area is 1%-5%, it is determined as mild ischemia; if the impedance of the area decreases or fluctuates less than 1%, it is determined as normal blood flow, and severe ischemia, mild ischemia and normal blood flow are respectively mapped to 3, 2 and 1 based on a preset grade mapping table; In the embodiment, the initial drug delivery dose is determined: when the inflammation imbalance coefficient is greater than 10 and the tissue is severe ischemia, the initial drug delivery dose is set as 0.8mg / cm 2 ; when the inflammation imbalance coefficient is 5-10 and the tissue is mild ischemia, the initial drug delivery dose is set as 0.4mg / cm 2 ; and when the inflammation imbalance coefficient is less than 5 and the blood flow is normal, the initial drug delivery dose is set as 0.1mg / cm 2 ; In the embodiment, the initial drug delivery dose is corrected: if the electric stimulation intensity is more than 2mA / mm 2 , the initial drug delivery dose is increased by 50%; if the electric stimulation intensity is 1-2mA / mm 2 , the initial drug delivery dose is maintained; and if the electric stimulation intensity is less than 1mA / mm 2 , the initial drug delivery dose is reduced by 30%; In the embodiment, the final drug delivery frequency is determined based on the optimal drug delivery dose and the tissue ischemia degree grade, and the drug delivery frequency formula is: wherein: : the drug delivery frequency, unit [h⁻ 1 ] (times per hour), : the drug delivery dose, unit [mg / cm 2 ], : the degree of tissue ischemia (dimensionless), The unit is [h-1 1 ·cm 2 / mg], which is adjusted based on clinical trials or engineering experience, and specifically represents: the basic drug dose adjustment coefficient corresponding to 10 h-1 2 ·cm 1 / mg, that is, the proportional relationship of 10 times / (hour·mg / cm 2 )。 2 )。

[0037] The beneficial effects of the above technical solutions are: real-time monitoring of local tissue impedance by the microneedle array sensor, dynamic evaluation of the degree of ischemia, and precise initial dose calculation combined with the inflammation imbalance coefficient; further self-adaptive correction of the drug dose according to the electrical stimulation intensity, and finally determination of the optimal dose and frequency to ensure the targeting and safety of drug delivery. This scheme effectively avoids ischemic injury, improves the individualization level and efficacy of sepsis treatment, and reduces the risk of drug overdose or deficiency.

[0038] Embodiment 6: The embodiment of the present application provides an electric stimulation targeted drug delivery and closed-loop control method for immune regulation of sepsis, based on the optimal drug dose and drug delivery frequency, controlling the electrically controlled micro-pump to perform targeted drug delivery, and simultaneously collecting real-time immune feedback data after drug delivery, calculating the immune regulation error based on the real-time immune feedback data and self-adaptively adjusting the electric stimulation parameters, including: The electrically controlled micro-pump performs targeted drug delivery according to the optimal drug dose and the final drug delivery frequency; After each drug delivery cycle is completed, the updated pro-inflammatory factor level, anti-inflammatory factor level and white blood cell count are synchronously collected by the electrochemical sensor and the optical sensor as real-time immune feedback data; The immune regulation deviation degree is calculated according to the real-time immune feedback data, wherein the immune regulation deviation degree is obtained by comparing the relative deviation degree of the current inflammation imbalance coefficient and the target threshold interval; When the immune regulation deviation degree exceeds the set allowable range, the electric stimulation parameters are adjusted in steps according to the deviation direction and amplitude until the real-time immune feedback data indicates that the inflammation imbalance coefficient is continuously and stably within the target threshold interval, and the closed-loop control of immune homeostasis is completed.

[0039] In this embodiment, the target threshold interval refers to the balance range of pro-inflammatory factors and anti-inflammatory factors during the immune regulation of sepsis patients, and this interval is the optimal immune homeostasis range preset based on clinical data or individualized treatment needs.

[0040] ​In this embodiment, the relative deviation degree refers to the deviation size and direction of the current inflammation imbalance coefficient from the target threshold interval, usually expressed in percentage or standard deviation.

[0041] In this embodiment, stepwise adjustment is performed: if the deviation is directed to insufficient suppression of immune hyperactivity, the intensity and frequency of the electric stimulation are increased, and if the deviation is directed to excessive immune suppression, the intensity of the electric stimulation is reduced or the stimulation is suspended.

[0042] The beneficial effects of the above technical solution are: by real-time monitoring of pro-inflammatory / anti-inflammatory factors and white blood cell count, dynamically calculating the immune regulation deviation degree, and adaptively adjusting the electric stimulation parameters, precise and closed-loop control of sepsis immune regulation is realized.

[0043] Embodiment 7: The embodiment of the present application provides an electric stimulation targeted drug delivery and closed-loop control method for sepsis immune regulation, and a dynamic termination condition, which includes: The continuous monitoring results of the inflammation imbalance coefficient for a preset number of times are all lower than the preset immune imbalance threshold; And the dynamic balance rate of the concentrations of pro-inflammatory factors and anti-inflammatory factors is maintained in a preset safe interval; And the fluctuation amplitude of the white blood cell count does not exceed the preset allowable deviation range of the baseline value.

[0044] In this embodiment, the preset safe interval refers to the safe range of the dynamic balance rate of the concentrations of pro-inflammatory factors and anti-inflammatory factors (such as the ratio of IL-6 / IL-10 or other inflammatory factor ratio), which is allowed to fluctuate, and is used to judge whether the immune system has returned to a steady state. This interval is set based on clinical research or individualized treatment goals. For example, if the preset safe interval of the dynamic balance rate is 0.9-1.1, the system will continue to monitor: the detection value 1.05 is within the safe interval (meets the steady state condition), and the detection value 1.3 exceeds the safe interval (needs to continue regulation).

[0045] In this embodiment, the preset allowable deviation range of the baseline value refers to the maximum fluctuation amplitude of the white blood cell count (or other immune indicators) compared to the stable level (baseline value) before treatment of the patient individual, which is usually expressed in percentage. Exceeding this range may indicate recurrence of infection or excessive immune suppression. Calculation and example: if the baseline white blood cell count of a patient is 8.0×10 9 / L, the preset allowable deviation is ±15%: allowable range→6.8-9.2×10 9 / L, the monitoring value 7.0×10 9 / L→within the allowable range (meets the termination condition), and the monitoring value 5.5×10 9 / L→exceeds the lower limit (needs to continue intervention).

[0046] The beneficial effects of the above technical solution are as follows: By setting multidimensional dynamic termination conditions, the safety and precision of sepsis immune regulation are ensured, avoiding secondary imbalances caused by premature drug discontinuation; simultaneous detection of the inflammatory imbalance coefficient, cytokine dynamic balance, and white blood cell count comprehensively guarantees the treatment effect. Ultimately, it achieves safe withdrawal from treatment and long-term maintenance of immune homeostasis.

[0047] Example 8: This invention provides a method for targeted drug delivery and closed-loop control of sepsis immune modulation via electrical stimulation, including executing a modulation termination procedure: Gradually reduce the intensity of electrical stimulation until it is completely turned off; The dosing frequency was gradually reduced to the maintenance dose according to the preset decay curve; Continue monitoring with the microneedle array sensor. If the indicator rebounds, restart the closed-loop control from step 1 to step 4.

[0048] In this embodiment, the phased reduction of electrical stimulation intensity until complete shutdown means that when treatment is terminated, the electrical stimulation intensity is not stopped immediately, but gradually reduced (e.g., by 20% each time) to avoid the immune system losing its homeostasis due to sudden withdrawal of stimulation. For example: Initial electrical stimulation intensity: 100mA; Decrease phase (20% reduction each time): First adjustment: 80mA; Second adjustment: 64mA; Third adjustment: 51.2mA; Complete shutdown: 0mA (monitoring indicators are stable).

[0049] In this embodiment, the preset decay curve refers to the dosing frequency decreasing over time according to a predetermined mathematical model (such as exponential decay or linear decay), rather than abruptly stopping the drug, in order to maintain the stability of the drug concentration. For example (exponential decay): Initial dosing frequency: once every 4 hours. Decay formula: Tn = T0 × (k1 = decay rate, t = time), decay process: Day 1: once every 6 hours, Day 2: once every 8 hours, Day 3: once every 12 hours (maintenance dose).

[0050] In this embodiment, indicator rebound refers to the recurrence of immune imbalance after treatment intensity is terminated or reduced, with key immune indicators such as pro-inflammatory / anti-inflammatory factors and white blood cell count exceeding the safe threshold again (e.g., a sudden increase in IL-6). For example, when the termination conditions are met: IL-6 / IL-10 = 1.0 (safe range 0.9~1.1), white blood cell count 8.0 × 10⁻⁶. 9 / L (baseline ± 10%), rebound phenomenon: 24 hours after drug withdrawal, IL-6 / IL-10 increased to 1.5, and white blood cell count decreased to 5.0 × 10⁹ / L. 9 / L→ Triggers restart of closed-loop control.

[0051] The beneficial effects of the above technical solutions are: through phased termination regulation, the safe exit of sepsis immunotherapy is ensured. The combination of decreasing electric stimulation intensity and decreasing drug administration frequency curve avoids the induction of immune rebound due to sudden stop; the microneedle array monitors key indicators throughout the process, dynamically adjusts the closed-loop intervention, and prevents disease recurrence. This scheme takes into account the gradual exit of treatment and real-time feedback control, effectively maintains immune homeostasis, and reduces the risk of recurrence.

[0052] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application, and not to limit them; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for targeted administration and closed-loop control of electrical stimulation for immune modulation in sepsis, characterized in that, The method comprises the following steps: Step 1: Real-time monitoring of immune index data of a patient, wherein the immune index data comprises pro-inflammatory factor level, anti-inflammatory factor level and white blood cell count, abnormal analysis of the immune index data is performed to determine an inflammation imbalance coefficient; Step 2: Dynamic adjustment of electric stimulation parameters according to the inflammation imbalance coefficient, and output of corresponding electric stimulation signals; Step 3: Detection of local tissue impedance of a drug targeted delivery area by using a microneedle array sensor, and generation of optimal drug dosage and drug frequency in combination with the electric stimulation signals; Step 4: Control of an electrically controlled micropump to perform targeted drug delivery based on the optimal drug dosage and drug frequency, and collection of real-time immune feedback data after drug delivery, calculation of immune regulation error based on the real-time immune feedback data, and adaptive adjustment of electric stimulation parameters to form a closed loop control; Step 5: Repeating the above steps 1 to 4 until the inflammation imbalance coefficient and the real-time immune feedback data reach a dynamic termination condition to perform a control termination program, and completion of sepsis immune regulation.

2. The sepsis immunomodulation electrostimulation targeted administration and closed loop control method according to claim 1, characterized in that, Real-time monitoring of immune index data of a patient, wherein the immune index data comprises pro-inflammatory factor level, anti-inflammatory factor level and white blood cell count, comprising: Periodic collection of blood samples of the patient; Measurement of the blood samples by an electrochemical sensor to obtain pro-inflammatory factor level and anti-inflammatory factor level, and measurement of the blood samples by an optical sensor to obtain white blood cell count, wherein the electrochemical sensor measurement and the optical sensor measurement are both based on blood samples collected at the same time point.

3. The sepsis immunomodulation electrostimulation targeted administration and closed loop control method according to claim 1, wherein, Abnormal analysis of the immune index data to determine an inflammation imbalance coefficient, comprising: According to the immune index data, the total effect value of pro-inflammatory factors was calculated respectively and the total effect value of anti-inflammatory factors : wherein, Ci is the concentration of the ith pro-inflammatory factor, Cj is the concentration of the jth anti-inflammatory factor, n is the number of pro-inflammatory factors, and m is the number of anti-inflammatory factors, wi is the weight corresponding to the jth anti-inflammatory factor, wi is the weight corresponding to the ith pro-inflammatory factor, and a and b are the non-linear adjustment indexes corresponding to the total effect value of the pro-inflammatory factors and the total effect value of the anti-inflammatory factors, respectively. Determination of a white blood cell count abnormal correction term based on the immune index data: where ΔW is a white blood cell abnormality correction factor, is the current white blood cell count, is the patient baseline white blood cell count, where σ is a white blood cell fluctuation threshold: wherein σ0 is a preset white blood cell fluctuation coefficient. Based on the total effect value of pro-inflammatory factors the total effect value of anti-inflammatory factors and the abnormal correction term of leukocyte count to determine the inflammation imbalance coefficient: wherein, is the inflammation imbalance coefficient, and ε is a guard against division by zero constant.

4. The sepsis immunomodulation electrostimulation targeted administration and closed loop control method according to claim 1, wherein, Dynamic adjustment of electric stimulation parameters according to the inflammation imbalance coefficient, and output of corresponding electric stimulation signals, comprising: If the inflammation imbalance coefficient is higher than a first preset threshold, the electric stimulation intensity is increased; If the inflammation imbalance coefficient is lower than a second preset threshold but higher than a preset immune imbalance demarcation threshold, the current electric stimulation intensity is maintained; If the inflammation imbalance coefficient is lower than the preset immune imbalance demarcation threshold, the electric stimulation intensity is decreased or the electric stimulation is turned off.

5. The sepsis immunomodulation electrostimulation targeted administration and closed loop control method according to claim 1, wherein, Detection of local tissue impedance of a drug targeted delivery area by using a microneedle array sensor, and generation of optimal drug dosage and drug frequency in combination with the electric stimulation signals, comprising: Real-time monitoring of local tissue impedance change value of the drug targeted delivery area by the microneedle array sensor, and generation of tissue ischemia degree grade according to the impedance change value; Determination of initial drug dosage based on the inflammation imbalance coefficient and the tissue ischemia degree grade; Correction of the initial drug dosage based on the current electric stimulation signal intensity to obtain optimal drug dosage; Determination of final drug frequency based on the optimal drug dosage and the tissue ischemia degree grade.

6. The sepsis immunomodulation electrostimulation targeted administration and closed loop control method according to claim 1, wherein, Control of an electrically controlled micropump to perform targeted drug delivery based on the optimal drug dosage and drug frequency, and collection of real-time immune feedback data after drug delivery, calculation of immune regulation error based on the real-time immune feedback data, and adaptive adjustment of electric stimulation parameters, comprising: Targeted drug delivery by the electrically controlled micropump according to the optimal drug dosage and the final drug frequency; After each administration cycle, the updated pro-inflammatory factor level, anti-inflammatory factor level and white blood cell count are synchronously collected by the electrochemical sensor and the optical sensor as real-time immune feedback data; According to the real-time immune feedback data, an immune regulation deviation degree is calculated, wherein the immune regulation deviation degree is obtained by comparing the relative deviation degree of the current inflammation imbalance coefficient and the target threshold interval; When the immune regulation deviation degree exceeds the set allowed range, the electric stimulation parameters are adjusted in a stepwise manner according to the deviation direction and amplitude, until the real-time immune feedback data indicates that the inflammation imbalance coefficient is continuously and stably within the target threshold interval, and the closed-loop regulation of immune homeostasis is completed.

7. The sepsis immunomodulation electrostimulation targeted administration and closed loop control method according to claim 1, wherein, The dynamic termination condition includes: The inflammation imbalance coefficient is continuously monitored for a preset number of times, and the monitoring result is lower than the preset immune imbalance threshold; And the dynamic balance rate of the concentrations of the pro-inflammatory factor and the anti-inflammatory factor is maintained in a preset safe interval; And the fluctuation amplitude of the white blood cell count does not exceed the preset allowed deviation range of the baseline value.

8. The sepsis immunomodulation electrostimulation targeted administration and closed loop control method according to claim 1, wherein, The control termination procedure includes: The electric stimulation intensity is gradually decreased in stages until it is completely turned off; The administration frequency is gradually reduced according to a preset attenuation curve to a maintenance dose; The microneedle array sensor is kept monitoring, and if the indicators rebound, the closed-loop regulation of steps 1 to 4 is restarted.

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