Non-invasive blood drug concentration monitoring system based on MIP-SERS coupling detection

Abstract

This non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection belongs to the field of medical monitoring. It includes: a shock wave generation and coupling module for generating and transmitting pulsed pressure waves; a patch-type microfluidic collection and volume control module for receiving the pulsed pressure waves transmitted by the shock wave generation and coupling module and applying them to the surface of isolated skin; a MIP-SERS coupled detection module for selectively capturing and enriching target drugs in extravasated fluids and performing high-sensitivity spectral fingerprint identification and quantitative reading of the enriched target drugs; a skin condition and contact quality monitoring module for acquiring online status parameters; and a control and signal processing module for controlling each module. This invention improves detection sensitivity and achieves quantitative, interference-resistant, and continuous-use capabilities for non-invasive monitoring through the combined detection of MIP and SERS.

Description

Technical Field

[0001] This invention belongs to the field of medical monitoring technology, specifically relating to a non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection. Background Technology

[0002] Blood drug concentration monitoring plays a crucial role in personalized medication, narrow therapeutic window drug dosage adjustment, adherence management, and adverse reaction early warning. Traditional blood drug monitoring mainly relies on venous blood collection combined with chromatographic analysis, which has drawbacks such as being invasive, having long testing cycles, and being difficult to monitor continuously. To reduce invasiveness, researchers have developed non-invasive and minimally invasive protocols, mainly focusing on two pathways: percutaneous extraction and / or sampling, and in vivo or patch-based detection. Wearable blood drug concentration monitoring protocols that have emerged in recent years are often limited by individual differences, changes in the skin barrier, contact instability caused by movement, and signal drift, resulting in quantitative accuracy that fails to meet clinical needs.

[0003] In existing technologies, a blood drug concentration monitoring solution using reverse electroosmosis percutaneous extraction combined with in-patch sensing utilizes reverse electroosmosis to generate an electroosmotic flow through low-intensity direct current, extracting small molecules from the interstitial fluid (ISF) from the inside of the skin to the skin surface. This extractor can then be combined with an in-patch sensor for continuous monitoring. This technology has been developed into representative devices and clinically validated in areas such as blood glucose monitoring.

[0004] In existing technologies, blood drug concentration monitoring techniques employing transdermal ultrasound and cavitation mechanisms typically utilize low-frequency ultrasound to induce cavitation activity, creating a locally highly permeable region in the stratum corneum. The cavitation process is accompanied by microjets and shock waves, which significantly enhance permeability. This technique is often used to promote transdermal drug delivery or enhance local penetration.

[0005] In existing technologies, the blood drug concentration monitoring technology using photomechanical / pressure wave short-term permeation of the stratum corneum utilizes photomechanical waves, which are high-amplitude pressure transients. These waves can expand the lipid interlayer gaps in the stratum corneum without significantly affecting deep tissues, forming a recoverable short-term channel, thereby increasing the flux of molecules through the stratum corneum.

[0006] In existing technologies, among the exploratory schemes using extracorporeal shock wave therapy (ESWT) to enhance transdermal effects, the acoustic pulses generated by ESWT can induce transient high pressure and cavitation-related effects in tissues. Previous studies have suggested that ESWT may enhance the local transdermal effect of topical medications, thus indirectly demonstrating the feasibility of shock waves / pressure waves promoting transdermal delivery.

[0007] Existing technologies have accumulated experience in mechanisms and devices for electrically driven extraction, ultrasonic / cavitation permeation, and short-term pressure wave permeation. However, to achieve wearable, repeatable, and quantitative blood drug concentration monitoring, challenges remain, including uncontrollable permeability windows, insufficient quantitative sampling, and inadequate compensation for individual differences. Specifically:

[0008] (1) The distribution of enhanced permeability is unstable: the enhanced permeability area may become patchy or drift with changes in coupling conditions, resulting in fluctuations in sample throughput and affecting quantitative feedback.

[0009] (2) Insufficient quantitative sampling: When there is a lack of fixed volume measurement and contamination control, the mixing of sweat / sebum will introduce systematic bias.

[0010] (3) Insufficient compensation for individual differences: Differences in skin thickness, water content, stratum corneum condition, and adhesion pressure significantly affect extraction efficiency, and a single calibration is insufficient to maintain monitoring accuracy over a long period of time.

[0011] (4) Insufficient safety closed loop: When there is a lack of feedback on contact quality and skin condition, discomfort or local irritation may occur, limiting continuous use.

[0012] (5) When surface-enhanced Raman scattering (SERS) is used alone, salt, protein and background components in complex exudates are prone to non-specific adsorption and spectral interference; when molecularly imprinted polymer (MIP) sensing is used alone, if electrochemical readout is used, it may be affected by baseline drift and ion intensity fluctuation. Summary of the Invention

[0013] To address the shortcomings of existing technologies, such as unstable permeability enhancement distribution, systematic bias introduced by insufficient sampling quantification, insufficient compensation for individual differences affecting extraction efficiency and detection sensitivity, insufficient safety closed-loop, and the ease with which nonspecific adsorption and spectral interference can be caused by using SERS alone, and the susceptibility of using MIP sensors alone to baseline drift and ion intensity fluctuations, this invention provides a non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection.

[0014] This invention induces a short-term, recoverable permeability window in isolated skin using low-energy, short-duration, and closed-loop controllable pulsed pressure waves, allowing target drug molecules to enter a patch-type microfluidic collection and volume control module. Sampling and volume control are completed through a fixed-volume metering chamber. A MIP-SERS coupled detection module is used in the detection chamber to achieve selective enrichment and highly sensitive quantification of target drug molecules. Blood drug concentration is then obtained by combining the permeability window model and sample throughput relationship, thereby improving the quantification, anti-interference, and continuous use capability of non-invasive monitoring.

[0015] The technical solution adopted by this invention to solve the technical problem is as follows:

[0016] This invention provides a non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection, comprising:

[0017] Shock wave generation and coupling module, used to generate and conduct pulsed pressure waves;

[0018] A patch-type microfluidic collection and volume control module is used to receive pulsed pressure waves transmitted by the shock wave generator and coupling module and apply them to the surface of isolated skin.

[0019] The MIP-SERS coupled detection module, which is built into the patch-type microfluidic collection and volume control module, is used to selectively capture and enrich the target drug in the extravasation fluid, and to perform high-sensitivity spectral fingerprint recognition and quantitative reading of the enriched target drug.

[0020] The skin condition and contact quality monitoring module is used to collect online condition parameters;

[0021] The control and signal processing module receives data from the shock wave generation and coupling module, the patch microfluidic collection and volume control module, the MIP-SERS coupling detection module, and the skin condition and contact quality monitoring module. By processing the data, it controls each module.

[0022] Furthermore, the shock wave generation and coupling module includes a shock wave conductor and a coupling medium; the shock wave conductor generates a low-energy, short-duration, and closed-loop controllable pulse pressure wave and transmits it through the coupling medium to the patch-type microfluidic collection and volume control module, which then acts on the surface of the isolated skin.

[0023] Furthermore, the parameters of the pulsed pressure wave are as follows: peak pressure 0.1-5 MPa; pulse width 0.1-50 μs; repetition frequency 0.5-20 Hz; single induction duration 1-120 s; pulse number 50-3000.

[0024] Furthermore, the coupling medium is a water bladder, gel, or elastic coupling pad.

[0025] Furthermore, the patch-type microfluidic collection and volume control module includes:

[0026] Drainage / reservoir chamber;

[0027] Backing adhesive layer adhering to the outer surface of the drainage / storage cavity;

[0028] Metering chamber connected to the drain / storage chamber;

[0029] Microfluidic injection channel connected to the metering chamber;

[0030] The detection chamber is connected to the microfluidic sample inlet channel and the drain / storage chamber;

[0031] A selective membrane is attached to the outer surface of a microfluidic injection channel, and the selective membrane is in direct contact with the surface of isolated skin.

[0032] An independently designed Raman excitation window is used to illuminate the detection cavity.

[0033] Furthermore, the MIP-SERS coupled detection module includes a SERS substrate disposed at the bottom of the detection chamber, a molecularly imprinted polymer recognition layer covering the surface of the SERS substrate, and a sensing module covering the surface of the SERS substrate.

[0034] This invention provides a non-invasive method for monitoring blood drug concentration based on MIP-SERS coupled detection, comprising the following steps:

[0035] (1) The patch-type microfluidic collection and volume control module was worn on the surface of the ex vivo skin to collect the initial skin impedance, skin temperature, patch contact pressure and local skin water content;

[0036] (2) The generated pulsed pressure wave is applied to the surface of the isolated skin to induce the formation of a short-term recoverable permeability window in the local skin; the extravasated fluid enters the microfluidic injection channel through the selective membrane and is injected into the metering chamber to the required volume. Then switch to the infusion detection chamber;

[0037] (3) The target drug molecule first enters the imprinted site in the molecularly imprinted polymer recognition layer and approaches the hot spot of the SERS substrate; the SERS substrate is irradiated through the Raman excitation light window, the characteristic peak signal of the target drug molecule is collected and the drug concentration in the patch is calculated, and online status parameters are collected simultaneously.

[0038] (4) Combine the permeability window model to estimate the effective permeability coefficient online, calculate the constant volume and flux parameters of the metering chamber and invert to obtain the blood drug concentration, and output the quality indicators at the same time;

[0039] (5) Based on the comparison results of quality indicators and safety thresholds, the parameters and sampling period of the next pulse pressure wave are adaptively adjusted.

[0040] Furthermore, in step (3), for the case of single-peak quantification, a univariate linear or quasi-linear relationship between the intensity of the characteristic Raman peak and the drug concentration within the patch is adopted: I ν (t)=a ν ·C patch (t)+b ν ;I ν (t) represents the intensity of the characteristic Raman peak at wavenumber ν, a ν With b ν All are calibration coefficients, C patch (t) represents the drug concentration within the patch;

[0041] For quantitative scenarios with multiple peaks or complex backgrounds, multi-peak joint regression or principal component regression is used to construct a mapping between the drug concentration within the patch and the characteristic peak signal: C patch (t)=F(I ν1 (t), I ν2 (t), …, I νn (t)); I ν1 (t), I ν2 (t),…, I νn (t) represents the peak height, peak area, or peak area ratio of the n characteristic peaks, and F(·) is the calibration function.

[0042] Furthermore, in step (4), the mathematical expression for the transparent window model is:

[0043] ;

[0044] in, For effective permeability, Baseline transparency coefficient, To induce antireflection intensity, τ is the window decay time constant. For the detection time, The starting moment of the applied pulsed pressure wave;

[0045] The mathematical expression for the induced antireflection intensity is:

[0046] ;

[0047] in, For regression models, lookup table interpolation, or least squares estimation functions with physical constraints; E is peak pressure, f is repetition frequency, N is pulse number, Z is skin impedance, T is skin temperature, P is patch contact pressure, and H is local skin moisture content.

[0048] The mathematical expression for the constant volume parameter of the metering cavity is:

[0049] ;

[0050] Among them, C patch (t) represents the drug concentration within the patch;

[0051] The mathematical expression for the flux parameter of the metering cavity is:

[0052] ;

[0053] Where α is the sampling efficiency coefficient;

[0054] The mathematical expression for the blood drug concentration inversion is:

[0055] ;

[0056] ;

[0057] in, This refers to the blood drug concentration.

[0058] Furthermore, the quality indicators The mathematical expression is:

[0059] ;

[0060] in, , , , These are the weighting coefficients for each item; For impedance stability, For pressure stability, For signal-to-noise ratio, This is due to drift.

[0061] The beneficial effects of this invention are:

[0062] 1. This invention solves the problem of insufficient safety closed loop in the prior art by combining the shock wave generation and coupling module with the MIP-SERS coupling detection module to form a closed loop of sampling, enrichment, detection and inversion, rather than independent splicing units.

[0063] 2. This invention achieves joint detection of MIP and SERS through a MIP-SERS coupled detection module: MIP selectively captures and separates target drugs in complex extravasated fluids with anti-interference capabilities, while SERS performs highly sensitive, multi-peak feature identification of the enriched drug. This invention spatially couples the imprinted site with the SERS substrate hotspot, allowing the target drug to simultaneously enter the SERS high-enhancement region after entering the imprinted site, thus improving detection sensitivity, compensating for insufficient compensation for individual differences, and solving the problems of non-specific adsorption and spectral interference easily caused by using SERS alone, and the susceptibility of baseline drift and ion intensity fluctuations to MIP sensing alone.

[0064] 3. This invention completes sampling and volume determination and online estimation of effective permeability coefficient through a fixed-volume metering chamber, which can effectively avoid reading distortion caused by simply relying on fluctuations in extravasation. The quantitative method is repeatable, reduces cross-person / cross-time errors, and makes up for the systematic bias problem introduced by insufficient sampling quantitativeity in the prior art.

[0065] 4. This invention obtains blood drug concentration through transparent window model inversion, realizing an interpretable link from sample collection to the provision of blood drug concentration value. No blood collection is required, making it suitable for continuous or quasi-continuous monitoring, and it is more robust than empirical mapping.

[0066] 5. This invention employs low-energy, short-time, and closed-loop controllable pulse pressure waves and closed-loop safety threshold constraints, which can significantly reduce the risk of skin irritation and make the monitoring process safe and controllable. Attached Figure Description

[0067] Figure 1 The present invention provides a structural block diagram of a non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection.

[0068] Figure 2 This is a schematic diagram of the structure of a patch-type microfluidic collection and volume control module.

[0069] Figure 3 This is a schematic diagram of the structure of the MIP-SERS coupling detection module.

[0070] Figure 4 The flowchart illustrates a non-invasive blood drug concentration monitoring method based on MIP-SERS coupled detection provided by this invention.

[0071] In the figure, the components are: shock wave generation and coupling module 1, shock wave conductor 101, coupling medium 102, patch microfluidic collection and volume control module 2, backing adhesion layer 201, drainage / storage cavity 202, Raman excitation window 203, metering cavity 204, microfluidic sample introduction channel 205, selective membrane 206, detection cavity 207, MIP-SERS coupling detection module 3, SERS substrate 301, molecularly imprinted polymer recognition layer 302, sensing module 303, skin condition and contact quality monitoring module 4, and control and signal processing module 5. Detailed Implementation

[0072] The present invention will be further described in detail below with reference to the accompanying drawings.

[0073] In a first aspect, the present invention provides a non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection.

[0074] See Figure 1 As shown, the present invention provides a non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection, which mainly includes the following modules:

[0075] The system comprises a shock wave generation and coupling module 1, a patch-type microfluidic collection and volume control module 2, a MIP-SERS coupling detection module 3, a skin condition and contact quality monitoring module 4, and a control and signal processing module 5. Specifically, the shock wave generation and coupling module 1, the patch-type microfluidic collection and volume control module 2, the MIP-SERS coupling detection module 3, and the skin condition and contact quality monitoring module 4 are all connected to the control and signal processing module 5. The shock wave generation and coupling module 1 is connected to both the patch-type microfluidic collection and volume control module 2 and the skin condition and contact quality monitoring module 4. The MIP-SERS coupling detection module 3 is integrated within the patch-type microfluidic collection and volume control module 2.

[0076] According to the present invention, the shock wave generation and coupling module 1 mainly includes a shock wave conductor 101 and a coupling medium 102. The shock wave conductor 101 is mainly used to generate low-energy, short-time, and closed-loop controllable pulse pressure waves, and the coupling medium 102 is mainly used to transmit the pulse pressure waves generated by the shock wave conductor 101 to the patch-type microfluidic collection and volume control module 2, and finally act on the surface of the ex vivo skin through the patch-type microfluidic collection and volume control module 2.

[0077] Preferably, the parameter range of the pulse pressure wave generated by the shock wave transmitter 101 is as follows:

[0078] Peak pressure: 0.1-5 MPa;

[0079] Pulse width 0.1-50 μs;

[0080] Repetition frequency: 0.5-20 Hz;

[0081] The duration of a single induction session is 1-120 seconds.

[0082] Pulse count: 50-3000.

[0083] Preferably, the coupling medium 102 can be selected from materials such as water bladders, gels, or elastic coupling pads.

[0084] According to the present invention, such as Figure 2As shown, the patch-type microfluidic collection and volume control module 2 mainly includes a backing adhesive layer 201, a drain / storage chamber 202, a Raman excitation window 203, a metering chamber 204, a microfluidic sample introduction channel 205, a selective membrane 206, and a detection chamber 207; arranged sequentially in the order of backing adhesive layer 201, drain / storage chamber 202, metering chamber 204, microfluidic sample introduction channel 205, and selective membrane 206, with the selective membrane 206 able to directly contact the surface of the ex vivo skin. A backing adhesive layer 201 adheres to the outer surface of the drainage / storage chamber 202, which is connected to the metering chamber 204. The metering chamber 204 and the detection chamber 207 are respectively connected to the microfluidic injection channel 205. A selective membrane 206 is attached to the outer surface of the microfluidic injection channel 205. A Raman excitation window 203 is independently provided and is mainly used to irradiate the detection chamber 207. After detection, the extravasated liquid in the metering chamber 204 and the detection chamber 207 can be stored or discharged through the drainage / storage chamber 202. The patch-type microfluidic collection and volume control module 2 can be fixedly connected to external devices via the backing adhesive layer 201 for convenient detection.

[0085] Preferably, the volume of the metering cavity 204 is... The range is 1-50 μL; more preferably, the volume of the metering chamber 204 is... The range is 5-20 μL.

[0086] Preferably, the microfluidic injection channel 205 may have a built-in capillary drive or micro-negative pressure structure (-0.5kPa to -15kPa), and the volume fixation and detection stability are ensured by bubble isolation and flow resistance control.

[0087] Preferably, the selective membrane 206 can be an ion exchange membrane.

[0088] According to the present invention, such as Figure 3 As shown, the MIP-SERS coupled detection module 3 is disposed inside the detection cavity 207. The MIP-SERS coupled detection module 3 mainly includes a SERS substrate 301, a molecularly imprinted polymer recognition layer 302, and a sensing module 303. The SERS substrate 301 is disposed at the bottom of the detection cavity 207, and the molecularly imprinted polymer recognition layer 302 covers the surface of the SERS substrate 301. The sensing module 303 is connected to the SERS substrate 301.

[0089] Preferably, the SERS substrate 301 can be an Au / Ag nano-reinforced substrate.

[0090] Preferably, the molecularly imprinted polymer recognition layer 302 may specifically be made of NIPAAm polymer.

[0091] Preferably, the sensing module 303 can specifically employ an aptamer electrochemical sensor, a molecularly imprinted polymer sensor, or an immunoelectrochemical sensor, etc. Its detection method can specifically be differential pulse voltammetry (DPV), square wave voltammetry (SWV), or electrochemical impedance spectroscopy (EIS). A mapping between the detection signal and the drug concentration within the patch is established through multi-point calibration, and an internal standard channel or differential channel can be introduced to compensate for temperature drift.

[0092] According to the present invention, the skin condition and contact quality monitoring module 4 is mainly used to collect online condition parameters, including but not limited to: skin impedance Z(t), skin temperature T(t), patch contact pressure P(t), and local skin moisture content H(t). Skin impedance Z(t) and local skin moisture content H(t) are mainly used to characterize the recovery of the stratum corneum barrier and permeability window; patch contact pressure P(t) is mainly used to characterize coupling consistency. The skin condition and contact quality monitoring module 4 measures the patch contact pressure P(t) between the patch-type microfluidic collection and volume control module 2 and the skin, and transmits the measured patch contact pressure P(t) to the control and signal processing module 5 in real time. The control and signal processing module 5 displays and monitors the patch contact pressure P(t) in real time, so that the patch contact pressure P(t) is controlled within 1-30 kPa, thereby reducing coupling fluctuations; skin temperature T(t) is mainly used for temperature drift compensation and safety threshold control.

[0093] Preferably, the skin condition and contact quality monitoring module 4 includes a pressure sensor, a temperature sensor, a humidity sensor, and an impedance sensor. The impedance sensor is used to measure the skin impedance Z(t), the temperature sensor is used to measure the skin temperature T(t), the pressure sensor is used to measure the patch contact pressure P(t), and the humidity sensor is used to measure the local skin moisture content H(t).

[0094] According to the present invention, the control and signal processing module 5 is mainly used to receive data sent by the shock wave generation and coupling module 1, the patch microfluidic collection and volume control module 2, the MIP-SERS coupling detection module 3, and the skin condition and contact quality monitoring module 4, and to control each module by processing the data.

[0095] Preferably, the control and signal processing module 5 can be a microcontroller MCU.

[0096] Secondly, this invention provides a non-invasive blood drug concentration monitoring method based on MIP-SERS coupled detection. This method is implemented using a non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection provided in the first aspect.

[0097] See Figure 4 As shown, the present invention provides a non-invasive blood drug concentration monitoring method based on MIP-SERS coupled detection, the specific implementation process of which is as follows:

[0098] Step S1: Attachment and sensor baseline establishment;

[0099] The patch-type microfluidic collection and volume control module 2 is worn on the surface of the detached skin; the skin condition and contact quality monitoring module 4 collects the initial skin impedance Z(0), initial skin temperature T(0), initial patch contact pressure P(0), and initial local skin water content H(0) and uploads them to the control and signal processing module 5.

[0100] Step S2: Transparent window induction:

[0101] The control and signal processing module 5 sends a start signal to the shock wave generation and coupling module 1, thereby activating the shock wave transmitter 101 to generate a pulsed pressure wave sequence. This sequence is transmitted through the coupling medium 102 to the patch-type microfluidic collection and volume control module 2 and applied to the isolated skin. The pulsed pressure wave induces a short-term recoverable permeability window in the local skin, prompting the target drug molecules in the complex extravasation to enter the metering chamber 204 through the selective membrane 206. The control and signal processing module 5 fine-tunes the pulsed pressure wave parameters based on the skin impedance Z(t) and patch contact pressure P(t) collected by the skin condition and contact quality monitoring module 4, ensuring that the induced permeability enhancement intensity reaches the target induced permeability enhancement intensity. .

[0102] Step S3: Sampling and volume determination;

[0103] During the permeation window, the extravasated fluid passes through the selective membrane 206 into the microfluidic injection channel 205 and fills the metering chamber 204 to the required volume. Then switch to the infusion detection chamber 207.

[0104] Step S4: Patch Inspection:

[0105] This invention employs molecularly imprinted polymers (MIPs) coupled with surface-enhanced Raman scattering (SERS) for detection. The MIPs are used to selectively capture and enrich target drugs in complex extravasation fluids, while the SERS are used to perform highly sensitive spectral fingerprinting and quantitative reading of the enriched target drugs.

[0106] Specifically, a SERS substrate 301 is disposed at the bottom of the detection cavity 207, and the surface of the SERS substrate 301 is covered with a molecularly imprinted polymer recognition layer 302. Target drug molecules preferentially enter the imprinted sites in the molecularly imprinted polymer recognition layer 302 and approach the hot spots of the SERS substrate. Subsequently, the SERS substrate 301 inside the detection cavity 207 is irradiated through the Raman excitation window 203, and the characteristic peak signal of the target drug molecule is collected by the sensing module 303 and uploaded to the control and signal processing module 5 to calculate the drug concentration C within the patch.patch (t), synchronously collect online status parameters (skin impedance Z(t), skin temperature T(t), patch contact pressure P(t) and local skin moisture content H(t)).

[0107] After the extravasated fluid enters the metering chamber 204, it forms a fixed-volume sample, which then enters the detection chamber 207 and contacts the molecularly imprinted polymer recognition layer 302. Target drug molecules enter the imprinted sites that match their structure, while non-target drug components are repelled or eluted due to spatial configuration mismatch or weak interactions. Once the target drug molecule is located near the SERS substrate hotspot within the imprinted site, Raman excitation light emitted through the Raman excitation window 203 illuminates the detection chamber 207, and the characteristic peak signal is acquired by the sensing module 303.

[0108] For single-peak quantification, the intensity of the characteristic Raman peak and the drug concentration C within the patch can be used. patch A univariate linear or quasi-linear relationship between (t) and: I ν (t)=a ν ·C patch (t)+b ν Among them, I ν (t) represents the intensity of the characteristic Raman peak at wavenumber ν, a ν With b ν All of these are calibration coefficients.

[0109] For quantitative scenarios with multiple peaks or complex backgrounds, multi-peak joint regression or principal component regression can be used to construct the intrapatch drug concentration Cpatch. patch Mapping between (t) and characteristic peak signal: C patch (t)=F(I ν1 (t), I ν2 (t), …, I νn (t)); where I ν1 (t), I ν2 (t), …, I νn (t) represents the peak height, peak area, or peak area ratio of n characteristic peaks, and F(·) is the calibration function, which can be obtained by standard solution series calibration.

[0110] Step S5: Inversion and Output;

[0111] Inverting blood drug concentration using a permeability window model: Online estimation of effective permeability coefficient The constant volume and flux parameters of metering chamber 204 were calculated and inverted to obtain the blood drug concentration. Output quality indicators Safety tips.

[0112] Specifically, the mathematical expression for the transparent window model is as follows:

[0113]

[0114] in, For effective permeability, Baseline transparency coefficient, To induce antireflection intensity, τ is the window decay time constant. For the detection time, The starting moment of the applied pulse pressure wave.

[0115] Specifically, the mathematical expression for the induced anti-reflection intensity is as follows:

[0116]

[0117] in, For regression models, lookup table interpolation, or least squares estimation functions with physical constraints; E is peak pressure, f is repetition frequency, N is pulse number, Z is skin impedance, T is skin temperature, P is patch contact pressure, and H is local skin moisture content.

[0118] Specifically, the mathematical expression for the constant volume parameter of the metering cavity 204 is as follows:

[0119]

[0120] Specifically, the mathematical expression for the flux parameter of metering cavity 204 is as follows:

[0121]

[0122] Where α is the sampling efficiency coefficient.

[0123] Specifically, the mathematical expression for blood drug concentration inversion is as follows:

[0124]

[0125]

[0126] in, The flux parameters of metering cavity 204, The effective permeability coefficient.

[0127] Specifically, the quality indicators are defined by integrating impedance stability, pressure stability, signal-to-noise ratio, and drift. :

[0128]

[0129] in, , , , These are the weighting coefficients for each item; For impedance stability, For pressure stability, For signal-to-noise ratio, This is due to drift.

[0130] Step S6: Closed-loop adjustment;

[0131] The parameters and sampling period of the next pulse pressure wave are adaptively adjusted based on the comparison between the quality index Q(t) and the safety threshold.

[0132] When quality indicators When the voltage drops below the safety threshold or an anomaly occurs (e.g., |dZ / dt| exceeds the threshold, patch contact pressure P(t) exceeds the threshold, or skin temperature T(t) rises above the threshold), the pulse pressure wave parameter is automatically reduced or the pulse pressure wave is stopped, and a prompt is made to re-attach / replace the patch-type microfluidic collection and volume control module 2.

[0133] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0134] Example 1: Validation of small molecule tracers in an isolated porcine skin model

[0135] (1) Objects and materials;

[0136] Isolated porcine skin, 1.5-2.5 mm thick; vancomycin solution as the small molecule tracer; volume of metering chamber 204. =10 μL; the sensing module 303 specifically adopts an electrochemical sensor with a calibration range of 0.05-5.0 μg / mL.

[0137] (2) Experimental methods;

[0138] 1) The isolated pig skin was fixed in a diffusion cell, and a buffer solution containing tracers was maintained under the skin;

[0139] 2) The patch-type microfluidic collection and volume control module 2 is worn on the surface of the ex vivo pig skin. The skin condition and contact quality monitoring module 4 collects the initial skin impedance Z(0), initial skin temperature T(0), initial patch contact pressure P(0), and initial local skin water content H(0) and uploads them to the control and signal processing module 5.

[0140] 3) Transparent window induction: Apply pressure wave: peak pressure E=1.0 MPa, repetition frequency f=4 Hz, pulse number N=1000;

[0141] 4) After induction, sample at a fixed volume within 0-10 min and measure the drug concentration C within the patch. patch (t);

[0142] 5) Synchronously acquire skin impedance Z(t) and fit the decay time constant τ within the window;

[0143] 6) Calculate blood drug concentration using the transparent window model. (Based on subcutaneous concentration).

[0144] Compared with the control group (simple electroosmosis detection), the flux parameters of metering chamber 204 With a 5-fold increase, the skin impedance Z(t) shows a recoverable change; the window decay time constant τ varies with the pulse pressure wave parameters.

[0145] This invention discloses a non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection. Those skilled in the art can refer to the content of this document and appropriately modify the process parameters to achieve the system. It is particularly important to note that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The product of this invention has been described through preferred embodiments, and those skilled in the art can clearly modify or appropriately change and combine the product described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

Claims

1. A non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection, characterized in that, include: The shock wave generation and coupling module is used to generate and conduct pulsed pressure waves; A patch-type microfluidic collection and volume control module is used to receive pulsed pressure waves transmitted by the shock wave generator and coupling module and apply them to the surface of isolated skin. The MIP-SERS coupled detection module, which is built into the patch-type microfluidic collection and volume control module, is used to selectively capture and enrich the target drug in the extravasation fluid, and to perform high-sensitivity spectral fingerprint recognition and quantitative reading of the enriched target drug. The skin condition and contact quality monitoring module is used to collect online condition parameters; The control and signal processing module receives data from the shock wave generation and coupling module, the patch microfluidic collection and volume control module, the MIP-SERS coupling detection module, and the skin condition and contact quality monitoring module. By processing the data, it controls each module.

2. The non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection according to claim 1, characterized in that, The shock wave generation and coupling module includes a shock wave conductor and a coupling medium; the shock wave conductor generates a low-energy, short-duration, closed-loop controllable pulse pressure wave and transmits it through the coupling medium to the patch-type microfluidic collection and volume control module, which then acts on the surface of the isolated skin.

3. The non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection according to claim 1, characterized in that, The parameter range of the pulse pressure wave is: peak pressure 0.1-5 MPa; Pulse width 0.1-50 μs; repetition frequency 0.5-20 Hz; single induction duration 1-120 s; number of pulses 50-3000.

4. The non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection according to claim 2, characterized in that, The coupling medium is a water bladder, gel, or elastic coupling pad.

5. The non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection according to claim 1, characterized in that, The patch-type microfluidic collection and volume control module includes: Drainage / reservoir chamber; Backing adhesive layer adhering to the outer surface of the drainage / storage cavity; Metering chamber connected to the drain / storage chamber; Microfluidic injection channel connected to the metering chamber; The detection chamber is connected to the microfluidic sample inlet channel and the drain / storage chamber; A selective membrane is attached to the outer surface of a microfluidic injection channel, and the selective membrane is in direct contact with the surface of isolated skin. An independently designed Raman excitation window is used to illuminate the detection cavity.

6. The non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection according to claim 5, characterized in that, The MIP-SERS coupled detection module includes a SERS substrate disposed at the bottom of the detection chamber, a molecularly imprinted polymer recognition layer covering the surface of the SERS substrate, and a sensing module covering the surface of the SERS substrate.

7. A non-invasive blood drug concentration monitoring method based on MIP-SERS coupled detection, implemented using the non-invasive blood drug concentration monitoring system based on MIP-SERS coupled detection as described in any one of claims 1-6, characterized in that, Includes the following steps: (1) The patch-type microfluidic collection and volume control module was worn on the surface of the ex vivo skin to collect the initial skin impedance, skin temperature, patch contact pressure and local skin water content; (2) The generated pulsed pressure wave is applied to the surface of the isolated skin to induce the formation of a short-term recoverable permeability window in the local skin; the extravasated fluid enters the microfluidic injection channel through the selective membrane and is injected into the metering chamber to the required volume. Then switch to the infusion detection chamber; (3) The target drug molecule first enters the imprinted site in the molecularly imprinted polymer recognition layer and approaches the SERS substrate hot spot; The SERS substrate was irradiated by Raman excitation light window, the characteristic peak signals of the target drug molecules were collected and converted to obtain the drug concentration in the patch, and online status parameters were collected simultaneously. (4) Combine the permeability window model to estimate the effective permeability coefficient online, calculate the constant volume and flux parameters of the metering chamber and invert to obtain the blood drug concentration, and output the quality indicators at the same time; (5) Based on the comparison results of quality indicators and safety thresholds, the parameters and sampling period of the next pulse pressure wave are adaptively adjusted.

8. The non-invasive blood drug concentration monitoring method based on MIP-SERS coupled detection according to claim 7, characterized in that, In step (3), for the case of single-peak quantification, a univariate linear or quasi-linear relationship between the intensity of the characteristic Raman peak and the drug concentration within the patch is adopted: I ν (t)=a ν ·C patch (t)+b ν ;I ν (t) represents the intensity of the characteristic Raman peak at wavenumber ν, a ν With b ν All are calibration coefficients, C patch (t) represents the drug concentration within the patch; For quantitative scenarios with multiple peaks or complex backgrounds, multi-peak joint regression or principal component regression is used to construct a mapping between the drug concentration within the patch and the characteristic peak signal: C patch (t)=F(I ν1 (t), I ν2 (t), …, I νn (t)); I ν1 (t), I ν2 (t), …,I νn (t) represents the peak height, peak area, or peak area ratio of the n characteristic peaks, and F(·) is the calibration function.

9. The non-invasive blood drug concentration monitoring method based on MIP-SERS coupled detection according to claim 7, characterized in that, In step (4), the mathematical expression for the transparent window model is: ； in, For effective permeability, Baseline transparency coefficient, To induce antireflection intensity, τ is the window decay time constant. For the detection time, The starting time of the applied pulsed pressure wave; the mathematical expression for the induced anti-reflection intensity is: ； in, For regression models, lookup table interpolation, or least squares estimation functions with physical constraints; E is the peak pressure, f is the repetition frequency, N is the number of pulses, Z is the skin impedance, T is the skin temperature, P is the patch contact pressure, and H is the local skin moisture content; the mathematical expression for the constant volume parameters of the metering chamber is: ； Among them, C patch (t) represents the drug concentration within the patch; The mathematical expression for the flux parameter of the metering cavity is: ； Where α is the sampling efficiency coefficient; The mathematical expression for the blood drug concentration inversion is: ； ； in, This refers to the blood drug concentration.

10. The non-invasive blood drug concentration monitoring method based on MIP-SERS coupled detection according to claim 7, characterized in that, The quality indicators The mathematical expression is: ； in, , , , These are the weighting coefficients for each item; For impedance stability, For pressure stability, For signal-to-noise ratio, This is due to drift.

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