A non-invasive quantitative blood drug concentration monitoring system and method

Abstract

This invention relates to the field of medical diagnostic technology and discloses a non-invasive quantitative blood drug concentration monitoring system, comprising: an ultrasound data acquisition platform, an ultrasound transducer, a light source, a digital delay generator, an energy regulator, an optical fiber, and a computer. The ultrasound data acquisition platform receives signals from the ultrasound transducer and converts them into digital data for subsequent analysis and processing. Simultaneously, it outputs a trigger signal to the digital delay generator to control two light sources to automatically interleave data acquisition, ensuring synchronization between laser output and photoacoustic signal acquisition. The ultrasound transducer converts the acoustic wave signal generated by the photoacoustic effect into an electrical signal. This invention, based on photoacoustic pumping technology, provides a novel blood drug monitoring method that accurately obtains blood drug concentrations without considering tissue scattering characteristics. It also boasts advantages such as high sensitivity, rapid response, and non-invasiveness, thereby achieving real-time, continuous, and accurate blood drug concentration monitoring.

Description

Technical Field

[0001] This invention relates to the field of medical diagnostic technology, and in particular to a non-invasive quantitative blood drug concentration monitoring system and method. Background Technology

[0002] Precision medicine, based on a patient's individual pharmacokinetic characteristics, delivers treatment precisely at the optimal time and with the most appropriate dosage to maximize efficacy and minimize side effects, thereby ensuring the safety and effectiveness of treatment. Blood drug concentration is an important indicator for assessing drug efficacy and metabolism. Blood drug monitoring, by measuring drug concentration in the blood, helps doctors optimize drug dosage, prevent drug toxicity, improve treatment effectiveness, and ensure individualized and precise treatment, providing patients with safer, more effective, and more accurate treatment plans. In addition, during the new drug development process, blood drug monitoring provides important information on drug metabolism characteristics and pharmacokinetic parameters, supporting the safety and efficacy assessment of new drugs. Therefore, continuous blood drug monitoring has significant clinical importance in drug therapy.

[0003] Conventional drug monitoring methods, such as chromatography and immunoassay, typically require blood sampling and analysis to determine drug concentrations in the blood. These methods are time-consuming and labor-intensive, often taking hours or days to obtain results. This can prevent doctors from obtaining timely drug concentration information for patients, impacting subsequent diagnostic and treatment decisions. Furthermore, traditional in vitro monitoring methods often cannot provide continuous monitoring, limiting their clinical application. In contrast, electrochemical sensors for blood drug monitoring can provide a continuous, real-time data stream, facilitating timely intervention in disease treatment. However, implanting sensors under the skin can cause pain, and carries risks of infection and immune rejection, limiting the feasibility of widespread application. Therefore, a non-invasive, quantitative, real-time blood drug concentration monitoring method is needed to improve acceptance by hospitals and patients, thereby greatly popularizing blood drug monitoring.

[0004] Optical molecular detection is non-invasive, highly sensitive, and highly specific, which perfectly meets the accuracy requirements of circulating blood drug monitoring. However, traditional optical techniques are subject to strong tissue scattering, posing challenges to the accuracy of quantifying molecular concentrations in deep tissues. Quantitative photoacoustic tomography is a promising method for detecting molecular concentrations in deep tissues. However, most of these methods rely on various light propagation models to resolve light intensity distribution. This optical compensation is usually mathematically uncertain, and small input errors can easily lead to a significant decrease in accuracy. More importantly, due to the strong absorption of background tissues such as blood, the photoacoustic signals of a few key molecules can be submerged in the strong background signal.

[0005] In photoacoustic pump imaging, the pump light excites the probe molecule to a singlet state, which then transitions to a triplet state via intersystem crossing. The probe light then induces a nonradiative transition, generating a photoacoustic signal. These long-lived triplet probe molecules can be used as repeatedly activated photoswitched photoacoustic probes, altering their absorption spectrum within their triplet lifetime via the pump light. Biological background tissues, however, do not exhibit this effect because their excited-state lifetime is shorter than that of the light pulse. Therefore, by differentiating the photoacoustic signals generated by the probe light with and without the pump light, highly specific molecular detection can be achieved. In conclusion, photoacoustic pumping holds promise as an important tool for drug monitoring in personalized medicine, helping doctors optimize treatment plans based on individual drug responses. Summary of the Invention

[0006] To address the limitations of existing blood drug monitoring methods, which fail to meet the requirements of real-time, accurate, and non-invasive monitoring, and the technical problem that existing optical and photoacoustic blood drug detection methods struggle to compensate for the strong and specific light scattering from tissues above the target blood vessel, this invention provides a non-invasive quantitative blood drug concentration monitoring system and method.

[0007] This invention is achieved using the following technical solution: a non-invasive quantitative blood drug concentration monitoring system, comprising:

[0008] Ultrasonic data acquisition platform, ultrasonic transducer, light source, digital delay generator, energy regulator, optical fiber and computer;

[0009] The ultrasonic data acquisition platform is used to receive signals from the ultrasonic transducer and convert them into digital data for subsequent analysis and processing. At the same time, it outputs a trigger signal to the digital delay generator to control the two light sources to automatically interleave data acquisition, so as to ensure the synchronization of laser output and photoacoustic signal acquisition.

[0010] The ultrasonic transducer can convert the acoustic wave signal generated by the photoacoustic effect into an electrical signal. When light shines on the drug molecules, a photoacoustic effect is generated. The drug absorbs the light energy and expands, thereby generating sound waves. These sound waves are captured and transmitted by the transducer.

[0011] The light source consists of two pulsed lasers, which generate two light pulses with the same pulse repetition frequency but different center wavelengths, namely a pump pulse laser and a probe pulse laser.

[0012] Under the excitation of pump light, the molecule transitions from the ground state (S0) to the first excited singlet state (S1). Due to the spin-orbit coupling effect, the molecule undergoes intersystem crossing and enters the first excited triplet state (T1). Since the transition from the T1 state to the ground state S0 is spin-forbidden, the T1 state has a very long lifetime. A molecule in state T1 is excited to a second excited triplet state T2 by probe light, and then returns to state T1 through nonradiative relaxation, generating a photoacoustic signal. Therefore, by writing the rate equations for the particle numbers N1, N2, and N3 in states S0, S1, and T1 during pump excitation, we obtain:

[0013] ,

[0014] Among them, A 21 Let S1 represent the spontaneous emission coefficient from S1 to S0, B be the light absorption coefficient, I(t) be the laser intensity distribution, and A be the emission coefficient from S1 to S0. 23 This represents the intersystem crossover rate from the S1 state to the T1 state. Since the T1 state has a long lifetime, spontaneous emission from the T1 state to the ground state S0 is not considered.

[0015] Since the lifetime of the S1 state is short, significantly shorter than the typical laser pulse width, it is assumed that particles in the S1 state do not accumulate and are in transient equilibrium, i.e., N²≈0. Therefore, the following formula can be derived:

[0016] ,

[0017] in, The initial number of particles in state S0, T is the pulse duration, and Φ is... P This is the pulse energy of the pump laser. Therefore, it can be seen that due to the existence of the metastable state T1, energy level inversion occurs between the T1 state and the S0 state. The particle in the T1 state... With pump laser energy Φ P Exponential growth, followed by gradual saturation, contrasts with the T1 state, where molecules may undergo multiple excitation-relaxation cycles due to the shorter lifetime of the T2 state. Therefore, the probe laser will not target the T1 state. This results in significant changes; therefore, the amplitude of the TTD signal is related to... and the energy Φ of the detection laser T Proportional, written as:

[0018] ,

[0019] in, It is the concentration of the target molecule. This is the value when the pump pulse energy reaches 63% saturation. It is the amplitude of TTD when fully saturated. It is the absorption coefficient. It is the thermal conversion efficiency. These are the Grueneisen parameters, where Δt is the delay time of the pump laser relative to the probe laser. It is the lifetime of the triplet state. This indicates acoustic influencing factors, including acoustic scattering from tissues, blood vessel size, and the angle of detection at which the object is tilted.

[0020] Assuming the photoacoustic signal mainly originates from hemoglobin, it will have a linear relationship with the energy of the probe laser. Therefore, equation (8) can be rewritten as:

[0021] ,

[0022] in, It detects the photoacoustic amplitude of a laser beam in a target blood vessel. K is a constant, obtained through known... The samples were calibrated with hemoglobin concentration samples, therefore, the energy of the pump laser was adjusted, and the maximum ratio was obtained by fitting formula (9). Then through To determine the concentration of the target molecule.

[0023] As a further improvement to the above scheme, the digital delay generator is externally triggered by the ultrasonic data acquisition platform to control the pulse output of each channel. These output pulses are used to control the relative time delay of the two pulsed lasers, that is, the time difference between the pump light and the probe light, so as to ensure the synchronization of laser output and photoacoustic signal acquisition, as follows:

[0024] (1). Obtain At that time, the detection pulse arrives with a microsecond delay after the pump pulse reaches the tissue, and the time of detection pulse output is the time when the ultrasound data acquisition platform acquires the signal;

[0025] (2). Obtain At that time, the detection pulse will be appropriately delayed based on the original time.

[0026] (3). Obtain At this time, the pump pulse is appropriately delayed based on the original time.

[0027] As a further improvement to the above scheme, the energy regulator is placed at the front end of the pump light source outlet to adjust the intensity of the pump light source, and the optical fiber is used to couple the output signals of the two pulsed lasers to ensure that the two beams of light irradiate the same position of the tissue.

[0028] As a further improvement to the above scheme, the computer is used to receive and process ultrasound data, perform image reconstruction, analysis, and final blood drug concentration estimation. The computer can control the operation of the system and output the final monitoring results.

[0029] As a further improvement to the above scheme, the ultrasonic data acquisition platform activates the digital delay generator through a trigger signal, and controls two pulsed lasers to alternately emit pump light and probe light. After the pump light is adjusted in intensity by an energy regulator, it is coupled with the probe light through an optical fiber and focused on the same position of the target tissue. The drug molecules in the tissue absorb the light energy and expand, generating a photoacoustic signal. This signal propagates in the form of sound waves and is captured by the ultrasonic transducer.

[0030] As a further improvement to the above solution, the ultrasonic transducer converts the received acoustic signal into an electrical signal and transmits it to the ultrasonic data acquisition platform for digital processing. The acquisition platform then transmits the data to a computer for image reconstruction and analysis. The computer extracts the pump light signal, the probe light signal, and the superimposed signal of the two by combining the time delay data. Through the analysis and comparison of these signals, the blood drug concentration is accurately estimated, and the final monitoring result is generated. Throughout the process, the laser output and the photoacoustic signal acquisition are strictly synchronized to ensure the accuracy and timeliness of the data.

[0031] This invention also provides a non-invasive quantitative blood drug concentration monitoring method, comprising the following steps:

[0032] (1). High-specificity molecular detection is achieved by differentiating the photoacoustic signals generated by the probe light with and without pump light. Therefore, the TTD signal of the probe molecule is obtained using the following formula:

[0033] ,

[0034] in, The TTD signal is obtained by differential background removal. It is the photoacoustic signal when the pump and probe lights are excited simultaneously. It is a photoacoustic signal generated solely by pump light excitation. Only the photoacoustic signal generated by optical excitation is detected, and Δt represents the delay time of the probe laser relative to the pump laser.

[0035] As a further improvement to the above scheme, the triplet state is usually achieved when a drug molecule is excited by a pump laser, transitions to a singlet excited state, and then enters the triplet state through a non-radiative transition process. Therefore, the absorption spectrum of the drug molecule is selectively changed in response to pump laser irradiation, thereby allowing the probe laser to detect the drug molecule without background interference through signal differential.

[0036] As a further improvement to the above scheme, the TTD signal of triplet drug molecules increases exponentially with the pump laser intensity and linearly with the probe laser intensity. The intensity of the pump laser determines the proportion of drug molecules excited to the triplet state. By using the photoacoustic signal of the blood vessel probe as a reference, the drug concentration is proportionally quantified. Therefore, this method can overcome the challenge of inaccurate optical molecular measurement caused by strong and variable light scattering in tissues, thereby achieving non-invasive quantitative monitoring of the concentration of specific target molecules.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] 1. The novel blood drug monitoring method based on photoacoustic pumping technology of this invention can accurately obtain blood drug concentration without considering the scattering characteristics of tissues. It also has the advantages of high sensitivity, rapid response and non-invasiveness, thereby realizing real-time, continuous and accurate blood drug concentration monitoring. Attached Figure Description

[0039] Figure 1 This is a schematic diagram illustrating the principle of blood drug monitoring based on photoacoustic pump detection in this invention;

[0040] Figure 2 This is a schematic diagram of the blood drug monitoring system based on photoacoustic pumping according to the present invention;

[0041] Figure 3 This is a schematic diagram of the automatic interleaved data acquisition of the present invention;

[0042] Figure 4 (a) shows the increase in intensity of the pump image and TTD image as the pump laser intensity increases, while the intensity of the detector image remains unchanged; (b) shows the change of TTD / detector ratio with pump laser intensity in tubes with different drug molecule concentrations; (c) shows the change of TTD / detector ratio with drug molecule concentration; and (d) shows the change of TTD signal with detector laser intensity.

[0043] Figure 5 (a) is an ultrasound image of two closely placed tubes, with the drug molecule concentration in the left tube being 100 μM and the right tube being 400 μM. (b) is a schematic diagram of the photoacoustic images of the two tubes. (c) is a schematic diagram of the TTD / detector ratio as a function of pump laser intensity. (d)-(f) are schematic diagrams corresponding to the coverage of chicken breast tissue layers. Detailed Implementation

[0044] The present invention will now be further described in conjunction with the accompanying drawings and specific embodiments.

[0045] like Figure 2 As shown, a non-invasive quantitative blood drug concentration monitoring system includes...

[0046] Ultrasonic data acquisition platform, ultrasonic transducer, light source, digital delay generator, energy regulator, optical fiber and computer;

[0047] The ultrasonic data acquisition platform is used to receive signals from the ultrasonic transducer and convert them into digital data for subsequent analysis and processing. At the same time, it outputs a trigger signal to the digital delay generator to control the two light sources to automatically interleave data acquisition, so as to ensure the synchronization of laser output and photoacoustic signal acquisition.

[0048] The ultrasonic transducer can convert the acoustic wave signal generated by the photoacoustic effect into an electrical signal. When light shines on the drug molecules, a photoacoustic effect is generated. The drug absorbs the light energy and expands, thereby generating sound waves. These sound waves are captured and transmitted by the transducer.

[0049] The light source consists of two pulsed lasers, which generate two light pulses with the same pulse repetition frequency but different center wavelengths, namely a pump pulse laser and a probe pulse laser.

[0050] The digital delay generator is externally triggered by the ultrasonic data acquisition platform to control the pulse output of each channel. These output pulses are used to control the relative time delay of the two pulsed lasers, that is, the time difference between the pump light and the probe light, to ensure the synchronization of laser output and photoacoustic signal acquisition, as follows:

[0051] (1). Obtain At that time, the detection pulse arrives with a microsecond delay after the pump pulse reaches the tissue, and the time of detection pulse output is the time when the ultrasound data acquisition platform acquires the signal;

[0052] (2). Obtain At that time, the detection pulse will be appropriately delayed based on the original time.

[0053] (3). Obtain At this time, the pump pulse is appropriately delayed based on the original time.

[0054] The energy regulator is placed at the front end of the pump light source outlet to adjust the intensity of the pump light source. The optical fiber is used to couple the output signals of the two pulsed lasers to ensure that the two beams of light irradiate the same location of the tissue.

[0055] The computer is used to receive and process ultrasound data, perform image reconstruction, analysis, and final blood drug concentration estimation. The computer can control the operation of the system and output the final monitoring results.

[0056] The ultrasonic data acquisition platform activates a digital delay generator via a trigger signal, controlling two pulsed lasers to alternately emit pump light and probe light. After the pump light intensity is adjusted by an energy regulator, it is coupled with the probe light through an optical fiber and focused onto the same location of the target tissue. Drug molecules in the tissue absorb light energy and expand, generating a photoacoustic signal. This signal propagates in the form of sound waves and is captured by the ultrasonic transducer.

[0057] The ultrasonic transducer converts the received acoustic signal into an electrical signal, which is then transmitted to the ultrasonic data acquisition platform for digital processing. The acquisition platform transmits the data to a computer, where it performs image reconstruction and analysis. Combining time delay data, it extracts the pump light signal, the probe light signal, and the superimposed signal of the two. By analyzing and comparing these signals, it achieves accurate estimation of blood drug concentration and generates the final monitoring result. Throughout the entire process, the laser output and photoacoustic signal acquisition are strictly synchronized to ensure the accuracy and timeliness of the data.

[0058] The ultrasound data acquisition platform activates a digital delay generator via a trigger signal, controlling two pulsed lasers to alternately emit pump and probe beams. After the pump beam intensity is adjusted by an energy regulator, it is coupled to the probe beam via an optical fiber and focused onto the same location in the target tissue. Drug molecules in the tissue absorb the light energy and expand, generating a photoacoustic signal. This signal propagates in the form of sound waves and is captured by an ultrasound transducer. The ultrasound transducer converts the received sound wave signal into an electrical signal, which is transmitted to the ultrasound data acquisition platform for digital processing. The acquisition platform transmits the data to a computer, where it performs image reconstruction and analysis. Combining the time delay data, it extracts the pump beam signal, the probe beam signal, and the superimposed signal of the two. By analyzing and comparing these signals, it achieves accurate estimation of blood drug concentration and generates the final monitoring results. Throughout the process, the laser output and photoacoustic signal acquisition are strictly synchronized to ensure the accuracy and timeliness of the data.

[0059] This invention also provides a non-invasive quantitative blood drug concentration monitoring method, comprising the following steps:

[0060] (1). High-specificity molecular detection is achieved by differentiating the photoacoustic signals generated by the probe light with and without pump light. Therefore, the TTD signal of the probe molecule is obtained using the following formula:

[0061] ,

[0062] in, The TTD signal is obtained by differential background removal. It is the photoacoustic signal when the pump and probe lights are excited simultaneously. It is a photoacoustic signal generated solely by pump light excitation. Only the photoacoustic signal generated by optical excitation is detected, and Δt represents the delay time of the probe laser relative to the pump laser;

[0063] (2). Under the excitation of pump light, the molecule transitions from the ground state (S0) to the first excited singlet state (S1). Due to the spin-orbit coupling effect, the molecule undergoes intersystem crossing and enters the first excited triplet state (T1). Since the transition from the T1 state to the ground state S0 is spin-forbidden, the T1 state has a very long lifetime. A molecule in state T1 is excited to a second excited triplet state T2 by probe light, and then returns to state T1 through nonradiative relaxation, generating a photoacoustic signal. Therefore, by writing the rate equations for the particle numbers N1, N2, and N3 in states S0, S1, and T1 during pump excitation, we obtain:

[0064] ,

[0065] Among them, A 21 Let S1 represent the spontaneous emission coefficient from S1 to S0, B be the light absorption coefficient, I(t) be the laser intensity distribution, and A be the emission coefficient from S1 to S0. 23 This represents the intersystem crossover rate from the S1 state to the T1 state. Since the T1 state has a long lifetime, spontaneous emission from the T1 state to the ground state S0 is not considered.

[0066] (3). Since the lifetime of the S1 state is short, significantly shorter than the typical laser pulse width, it is assumed that particles in the S1 state do not accumulate and are in transient equilibrium, i.e., N2≈0, and Therefore, the following formula can be derived:

[0067] ,

[0068] in, The initial number of particles in state S0, T is the pulse duration, and Φ is... P This is the pulse energy of the pump laser. Therefore, it can be seen that due to the existence of the metastable state T1, energy level inversion occurs between the T1 state and the S0 state. The particle in the T1 state... With pump laser energy Φ P Exponential growth, followed by gradual saturation, contrasts with the T1 state, where molecules may undergo multiple excitation-relaxation cycles due to the shorter lifetime of the T2 state. Therefore, the probe laser will not target the T1 state. Therefore, the amplitude of the probe molecule (TTD) signal changes significantly with and the energy Φ of the detection laser T Proportional, written as:

[0069] ,

[0070] in, It is the concentration of the target molecule. This is the value when the pump pulse energy reaches 63% saturation. It is the amplitude of TTD when fully saturated. It is the absorption coefficient. It is the thermal conversion efficiency. These are the Grueneisen parameters, where Δt is the delay time of the pump laser relative to the probe laser. It is the lifetime of the triplet state. This indicates acoustic influencing factors, including acoustic scattering from tissues, blood vessel size, and the angle of detection at which the object is tilted.

[0071] (4). Assuming the photoacoustic signal mainly comes from hemoglobin, it will be linearly related to the energy of the detection laser. Therefore, formula (8) can be rewritten as:

[0072] ,

[0073] in, It detects the photoacoustic amplitude of a laser beam in a target blood vessel. K is a constant, obtained through known... The samples were calibrated with hemoglobin concentration samples, therefore, the energy of the pump laser was adjusted, and the maximum ratio was obtained by fitting formula (9). Then through To determine the concentration of the target molecule.

[0074] like Figure 1 As shown, the triplet state is typically the state in which a drug molecule transitions to a singlet excited state after being excited by a pump laser, and then enters the triplet state through a non-radiative transition process. Therefore, the absorption spectrum of the drug molecule is selectively changed in response to pump laser irradiation, thus allowing the probe laser to detect the drug molecule without background interference through signal differential.

[0075] The TTD signal of triplet drug molecules increases exponentially with the pump laser intensity and linearly with the probe laser intensity. The intensity of the pump laser determines the proportion of drug molecules excited to the triplet state. By using the photoacoustic signal of the blood vessel probe as a reference, the drug concentration can be proportionally quantified. Therefore, this method can overcome the challenge of inaccurate optical molecular measurement caused by strong and variable light scattering in tissues, thereby achieving non-invasive quantitative monitoring of the concentration of specific target molecules.

[0076] It should be noted that, without conflict, relevant phantom experiments were conducted to verify the effectiveness of the present invention, demonstrating that the method can accurately quantify drug concentration under different light scattering conditions.

[0077] Example 1

[0078] S1. In the experiment, methylene blue (MB) was used as the target drug molecule. MB is an FDA-approved water-soluble dye that is widely used in clinical and biomedical research. Its T1 lifetime in water is about 2 μs, and its maximum absorption peaks in the S0 and T1 states are about 650 nm and 820 nm, respectively. Therefore, these two wavelengths were set as the pump light and probe light wavelengths, respectively, with a delay time Δt of 0.3 μs.

[0079] S2. It is a photoacoustic signal obtained when both the pump and probe lasers are turned on simultaneously. It is a photoacoustic signal generated solely by pump light excitation. The photoacoustic signal was obtained when only the detection laser was turned on. The three data acquisition sequences were acquired using an interleaved method and averaged 300 times to improve the signal-to-noise ratio.

[0080] S3. To obtain the pump intensity dependence of the TTD signal, the pump laser intensity was controlled by an energy regulator, and data were collected at approximately 10 different laser energy levels, such as... Figure 4 As shown in (a), the intensity of the pump image and TTD image increases with the increase of the pump laser intensity, while the probe image remains stable;

[0081] S4. Transparent plastic tubes with a diameter of 3 mm and negligible wall thickness were used to simulate blood vessels. The tubes were filled with a 12% hemoglobin solution and different concentrations of MB. In the first phantom experiment, changes in the TTD signal under different pump and probe light intensities were monitored. The signal peak values ​​in the images were used to plot the TTD / TR (Φ) ratio. P The relationship between ) and pump laser intensity, such as Figure 4 As shown in (b), initially, with the increase in pump laser intensity Φ P As the value increases, this ratio rises rapidly, then reaches a saturation point. In a stable state, such as Figure 4 As shown in (c) The increase depends on MB concentration, and thus can be achieved through... Measurements were used to determine the concentration of MB in blood vessels;

[0082] S5. The energy conditioner was placed in front of the probe laser, and the TTD signal was measured as the probe laser intensity changed, such as... Figure 4 As shown in (d), the TTD signal increases linearly with the intensity of the probe laser. In short, the TTD signal increases exponentially with the intensity of the pump laser and linearly with the intensity of the probe laser.

[0083] Example 2

[0084] S1. In the second phantom experiment, two tubes with different MB concentrations were placed under 2 mm thick slices of chicken breast to simulate tissue-induced light attenuation and to evaluate the ability of the method in this study to compensate for unknown light attenuation from tissue. Figure 5 (a) and 5(b) show the ultrasound and photoacoustic images of two closely packed tubes containing 100 and 400 μM MB, respectively. Figure 5 (c) shows the variation of the TTD / detector ratio with pump laser intensity;

[0085] S2. By fitting these two curves, the 400μM and 100μM MB tubes were determined. The values ​​are 0.2707 and 0.084 respectively. Figure 5 (d)-(f) show the results when the tube is covered with 2 mm thick chicken breast tissue, from Figure 5 (e) It can be seen that the photoacoustic amplitude is significantly reduced due to the light attenuation of chicken breast tissue. Figure 5 (f) The fitting values ​​were 0.2326 and 0.0783, corresponding to 400 μM and 100 μM MB tubes, respectively;

[0086] S3. Based on the above results, it is confirmed that the method used in this study can quantitatively and accurately assess blood drug concentrations in deep tissues without prior knowledge of the tissue's scattering characteristics. It is noteworthy that as MB concentration increases, The rate of increase gradually slowed down, such as Figure 4 As shown in (b), this may be due to the formation of dimers at high concentrations of MB, leading to a decrease in the effective concentration. Therefore, in Figure 5 In (c) and 5(f), although the 400 μM and 100 μM tubes The values ​​differ by only about three times, but these values ​​are related to Figure 4 The results in (b) are consistent, which further validates the high repeatability and reliability of the method.

[0087] The above embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-substantial changes and substitutions made by those skilled in the art based on the present invention shall fall within the scope of protection claimed by the present invention.

Claims

1. A non-invasive quantitative blood drug concentration monitoring system, characterized in that, include Ultrasonic data acquisition platform, ultrasonic transducer, light source, digital delay generator, energy regulator, optical fiber and computer; The ultrasonic data acquisition platform is used to receive signals from the ultrasonic transducer and convert them into digital data for subsequent analysis and processing. At the same time, it outputs a trigger signal to the digital delay generator to control the two light sources to automatically interleave data acquisition, so as to ensure the synchronization of laser output and photoacoustic signal acquisition. The ultrasonic transducer can convert the acoustic wave signal generated by the photoacoustic effect into an electrical signal. When light shines on the drug molecules, a photoacoustic effect is generated. The drug absorbs the light energy and expands, thereby generating sound waves. These sound waves are captured and transmitted by the transducer. The light source consists of two pulsed lasers, which generate two light pulses with the same pulse repetition frequency but different center wavelengths, namely a pump pulse laser and a probe pulse laser. Under the excitation of pump light, the molecule transitions from the ground state (S0) to the first excited singlet state (S1). Due to the spin-orbit coupling effect, the molecule undergoes intersystem crossing and enters the first excited triplet state (T1). Since the transition from the T1 state to the ground state S0 is spin-forbidden, the T1 state has a very long lifetime. A molecule in state T1 is excited to a second excited triplet state T2 by probe light, and then returns to state T1 through nonradiative relaxation, generating a photoacoustic signal. Therefore, by writing the rate equations for the particle numbers N1, N2, and N3 in states S0, S1, and T1 during pump excitation, we obtain: ， Among them, A 21 Let S1 represent the spontaneous emission coefficient from S1 to S0, B be the light absorption coefficient, I(t) be the laser intensity distribution, and A be the emission coefficient from S1 to S0. 23 This represents the intersystem crossover rate from the S1 state to the T1 state. Since the T1 state has a long lifetime, spontaneous emission from the T1 state to the ground state S0 is not considered. Because the lifetime of the S1 state is short, significantly shorter than the typical laser pulse width, it is assumed that particles in the S1 state do not accumulate and are in a transient equilibrium state, i.e. Therefore, the following formula can be derived: ， in, The initial number of particles in state S0, T is the pulse duration, and Φ is... P This is the pulse energy of the pump laser. Therefore, it can be seen that due to the existence of the metastable state T1, energy level inversion occurs between the T1 state and the S0 state. The particle in the T1 state... With pump laser energy Φ P Exponential growth, followed by gradual saturation, contrasts with the T1 state, where molecules may undergo multiple excitation-relaxation cycles due to the shorter lifetime of the T2 state. Therefore, the probe laser will not target the T1 state. Significant changes occur, therefore, the amplitude of the probe molecule (TTD) signal is related to... and the energy Φ of the detection laser T Proportional, written as: ， in, It is the concentration of the target molecule. This is the value when the pump pulse energy reaches 63% saturation. It is the amplitude of TTD when fully saturated. It is the absorption coefficient. It is the thermal conversion efficiency. These are the Grueneisen parameters, where Δt is the delay time of the pump laser relative to the probe laser. It is the lifetime of the triplet state. This indicates acoustic influencing factors, including acoustic scattering from tissues, blood vessel size, and the angle of detection at which the object is tilted. Assuming the photoacoustic signal mainly originates from hemoglobin, it will have a linear relationship with the energy of the probe laser. Therefore, equation (8) can be rewritten as: ， in, It detects the photoacoustic amplitude of a laser beam in a target blood vessel. K is a constant, obtained through known... The samples were calibrated with hemoglobin concentration samples, therefore, the energy of the pump laser was adjusted, and the maximum ratio was obtained by fitting formula (9). Then through To determine the concentration of the target molecule.

2. The non-invasive quantitative blood drug concentration monitoring system as described in claim 1, characterized in that, The digital delay generator is externally triggered by the ultrasonic data acquisition platform to control the pulse output of each channel. These output pulses are used to control the relative time delay of the two pulsed lasers, that is, the time difference between the pump light and the probe light, to ensure the synchronization of laser output and photoacoustic signal acquisition, as follows: (1). Obtain At that time, the detection pulse arrives with a microsecond delay after the pump pulse reaches the tissue, and the time of detection pulse output is the time when the ultrasound data acquisition platform acquires the signal; (2). Obtain At that time, the detection pulse will be appropriately delayed based on the original time. (3). Obtain At this time, the pump pulse is appropriately delayed based on the original time.

3. The non-invasive quantitative blood drug concentration monitoring system as described in claim 1, characterized in that, The energy regulator is placed at the front end of the pump light source outlet to adjust the intensity of the pump light source. The optical fiber is used to couple the output signals of the two pulsed lasers to ensure that the two beams of light irradiate the same location of the tissue.

4. The non-invasive quantitative blood drug concentration monitoring system as described in claim 1, characterized in that, The computer is used to receive and process ultrasound data, perform image reconstruction, analysis, and final blood drug concentration estimation. The computer can control the operation of the system and output the final monitoring results.

5. The non-invasive quantitative blood drug concentration monitoring system as described in claim 1, characterized in that, The ultrasonic data acquisition platform activates a digital delay generator via a trigger signal, controlling two pulsed lasers to alternately emit pump light and probe light. After the pump light intensity is adjusted by an energy regulator, it is coupled with the probe light through an optical fiber and focused onto the same location of the target tissue. Drug molecules in the tissue absorb light energy and expand, generating a photoacoustic signal. This signal propagates in the form of sound waves and is captured by the ultrasonic transducer.

6. The non-invasive quantitative blood drug concentration monitoring system as described in claim 1, characterized in that, The ultrasonic transducer converts the received acoustic signal into an electrical signal, which is then transmitted to the ultrasonic data acquisition platform for digital processing. The acquisition platform transmits the data to a computer, where it performs image reconstruction and analysis. Combining time delay data, it extracts the pump light signal, the probe light signal, and the superimposed signal of the two. By analyzing and comparing these signals, it achieves accurate estimation of blood drug concentration and generates the final monitoring result. Throughout the entire process, the laser output and photoacoustic signal acquisition are strictly synchronized to ensure the accuracy and timeliness of the data.

7. A non-invasive quantitative blood drug concentration monitoring method, characterized in that, Includes the non-invasive quantitative blood drug concentration monitoring system as described in claim 1 and the following steps: Highly specific molecular detection is achieved by differentiating the photoacoustic signals generated by the probe light with and without pump light. Therefore, the TTD signal of the probe molecule is obtained using the following formula: ， in, The TTD signal is obtained by differential background removal. It is the photoacoustic signal when the pump and probe lights are excited simultaneously. It is a photoacoustic signal generated solely by pump light excitation. Only the photoacoustic signal generated by optical excitation is detected, and Δt represents the delay time of the probe laser relative to the pump laser.

8. The non-invasive quantitative blood drug concentration monitoring method as described in claim 7, characterized in that, The triplet state is typically formed when a drug molecule, after being excited by a pump laser, transitions to a singlet excited state and then undergoes a non-radiative transition to enter the triplet state. Therefore, the absorption spectrum of the drug molecule is selectively altered in response to pump laser irradiation, allowing the probe laser to detect the drug molecule through signal differential detection without background interference.

9. The non-invasive quantitative blood drug concentration monitoring method as described in claim 7, characterized in that, The TTD signal of triplet drug molecules increases exponentially with the pump laser intensity and linearly with the probe laser intensity. The intensity of the pump laser determines the proportion of drug molecules excited to the triplet state. By using the photoacoustic signal of the blood vessel probe as a reference, the drug concentration can be proportionally quantified. Therefore, this method can overcome the challenge of inaccurate optical molecular measurement caused by strong and variable light scattering in tissues, thereby achieving non-invasive quantitative monitoring of the concentration of specific target molecules.

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