CN112043286A - Sampling device and microfluidic chip combined blood concentration online monitoring system - Google Patents
Sampling device and microfluidic chip combined blood concentration online monitoring system Download PDFInfo
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Abstract
The invention provides a blood concentration on-line monitoring system combining a sampling device and a microfluidic chip, which comprises the blood sampling device, the microfluidic chip mixing reaction device and a monitoring device. The blood sampling device comprises a venous indwelling needle, the venous indwelling needle comprises an indwelling needle sleeve, and the indwelling needle sleeve comprises a first cavity, a second cavity and a third cavity or four cavities, five cavities and multiple cavities which are arranged according to requirements, so that the continuous online sampling of drug molecules in blood is realized; the microfluidic chip mixing reaction device comprises 2-dimensional and 3-dimensional channel structures with different sizes in a chip, so that drug molecules and a chemical sensing probe are subjected to full mixing reaction; the monitoring device realizes continuous online acquisition of signals, so that the concentration of drugs in blood (including narcotics, antibiotics, anti-tumor drugs, nervous system drugs, cardiovascular drugs, immunosuppressants, antiasthmatic drugs and other clinical injections and oral drugs) can be monitored in real time, and accurate drug delivery is realized.
Description
Technical Field
The invention belongs to the technical field of medical equipment, and relates to a blood concentration online monitoring system and method with a sampling device and a microfluidic chip combined.
Background
Clinical medicine develops rapidly nowadays, but at present, various substances in a body cannot be accurately monitored, and if the concentration of the medicine in blood in the body can be monitored in real time, doctors can be helped to accurately take medicine, the success rate of surgery is improved, and adverse reactions after surgery are reduced. The concentrations of substances such as narcotics, antibiotics, blood sugar and the like constantly influence the metabolic function of a human body, and how to realize real-time monitoring and accurate medical treatment of blood concentration needs related technologies to sample and monitor various substances in the human body in real time and provide a panoramic picture of real-time change of various substances in the human body. To date, there is no on-line monitoring system capable of monitoring blood drug concentration in real time.
The microdialysis technology is a novel membrane sampling technology which is developed from the field of neurochemistry and can sample endogenous substances and in-vivo medicines in real time. In recent years, with the emergence of a large number of modern analysis technologies with high sensitivity and good selectivity, the application of microdialysis in medical research is on the rise, and the real-time, continuous and online detection of medicines and chemical transmitters in body fluid of living animals is realized. The online combined analysis has great advantages compared with the offline measurement. The automatic continuous operation can effectively avoid enzymolysis of the sample due to sampling at room temperature, improve the stability of the sample, save complex sample pretreatment and sample loss and errors caused by the sample pretreatment, and save time and cost.
The microfluidic chip technology can integrate a plurality of complex processes of sample preparation, reaction, separation, monitoring and the like in the processes of biological, chemical and medical analysis on a micron-scale chip to automatically complete the analysis process, has the advantages of high reaction speed, small amount of samples and reagents, disposability, low cost and the like, and has become a new technical field in recent years. But at present, the lack of chemical sensing probes capable of reacting with drugs specifically and rapidly and the combined instrument analysis means can seriously limit the development of the micro-fluidic chip on-line monitoring technology.
Disclosure of Invention
The invention aims to provide a blood concentration online monitoring system combining a sampling device and a microfluidic chip, which realizes the selective detection of different drugs in blood by preparing a novel chemical sensing probe with good specificity, high stability and quick reaction time, and realizes the online real-time monitoring of the blood concentration based on micro-dialysis sampling, microfluidic chip reaction, and combined instrument technologies such as electrochemistry, optics, mass spectrometry and the like.
Wherein, the specific chemical sensing probe is capable of specifically recognizing the drug molecules extracted by dialysis and generating a response signal such as optical, electrical or mass spectrum. The specific chemical sensing probe is a liquid and reacts with a target substance in the microdialysis solution from which the sample is taken out.
The blood concentration online monitoring system with the sampling device and the microfluidic chip combined can realize real-time monitoring of the concentration of the drug in the body of a patient in an operation (such as an ICU operation), so that a doctor can accurately control the injection dosage of the drug, reduce the operation risk and improve the success rate of the operation.
The system comprises microfluidic chips with various sizes, combines specific chemical sensing probes and an instrument analysis technology, and realizes continuous online real-time monitoring of clinical injections and oral drugs such as anesthetics, antibiotics, antitumor drugs, nervous system drugs, cardiovascular drugs, immunosuppressants, antiasthmatics and the like in blood based on a microdialysis sampling technology.
The invention provides a blood concentration on-line monitoring system with a sampling device and a microfluidic chip, which comprises: a blood sampling device, a microfluidic chip mixing reaction device and a monitoring device; the blood sampling device can realize continuous online sampling of drug molecules in blood; the monitoring device is used for continuously collecting signals generated by the mixing reaction on line so as to monitor the concentration of the drug molecules in the blood in real time; wherein,
the blood sampling device comprises: a venous indwelling needle;
the venous indwelling needle comprises: an indwelling needle cannula;
the indwelling needle cannula includes: a first cavity, a second cavity and a third cavity; a metal needle head is arranged in the first cavity; the second cavity is communicated with the third cavity; wherein the first cavity is a transfusion channel; the second cavity is a perfusion liquid input channel; the third cavity is a dialysate output channel; a slot is formed in the outer side of the third cavity, and a semipermeable membrane is arranged at the slot;
the blood sampling device provides stable perfusion liquid flow rate through an injection pump, a peristaltic pump or a pneumatic pump, and ensures stable sampling recovery rate; after sampling, the blood sampling device pipeline enters a micro-fluidic chip for mixing reaction based on the driving force of a pump, and reaction conditions are optimized by designing a pipeline structure; the monitoring device comprises an optical detection device, an electrochemical detection device and a mass spectrum detection device, wherein the optical detection device and the electrochemical detection device are integrated with a chip, so that the real-time online monitoring of the sample is realized; the mass spectrometry detection is to sample a target object after reaction marking in the chip and perform mass spectrometry analysis, and can achieve near real-time monitoring by optimizing detection time;
the monitoring device is used for continuously collecting signals generated by the mixing reaction on line so as to monitor the concentration of the drug molecules in the blood in real time.
The invention further comprises a multi-cavity structure, and any two cavities of the multi-cavity structure are communicated.
In the invention, the tail end of the first cavity is in an open shape.
In the invention, the semipermeable membrane is a polymer composite material; the semi-permeable membrane has a molecular cut-off of 3-200 kDa.
In the present invention, the microfluidic chip mixing reaction apparatus includes: 2-dimensional and 3-dimensional channels with different sizes are arranged in the chip, so that the drug molecules and the chemical sensing probes are subjected to full mixing reaction.
In the invention, the monitoring device further comprises a data analysis device, the data analysis device comprises a software analysis system, and the corresponding blood concentration is obtained by performing fitting calculation on the captured light, electricity and mass spectrum signals based on a calibration curve equation.
In the invention, the monitoring device further comprises a PLC automatic target control perfusion device; and according to the result obtained by the data analysis device, the PLC automatic target control perfusion device is used for carrying out accurate perfusion of the therapeutic drugs and real-time control of the blood concentration.
Based on the system, the invention also provides a blood concentration online monitoring method by combining the sampling device and the microfluidic chip, which comprises the following steps:
(1) real-time dynamic sampling is carried out by utilizing a blood sampling device based on the semi-permeable membrane diffusion principle;
(2) the microchip mixed reaction device is used as a reaction platform for sensing probe molecules and target drug molecules, and the reaction time is controlled through 2-dimensional and 3-dimensional channels with different sizes, so that the target drug is rapidly monitored;
(3) capturing a target signal by using a monitoring device;
(4) and carrying out data analysis, processing and operation on the target signal captured by the monitoring device by using a data analysis device, and detecting to obtain the blood concentration of the target drug.
In the step (1) of the invention, the flow rate of perfusion liquid is 1-30 mu L/min, and the recovery rate is 1-90% according to the detection limit control range of the system; the reaction time in the step (2) is 1-30 min; the detection limit of the monitoring device in the step (3) is 0.1 mu g/mL-500 mu g/mL.
The invention relates to a blood concentration on-line monitoring system combining a sampling device and a microfluidic chip, which comprises the blood sampling device, a microfluidic chip mixing reaction device and a monitoring device. The blood sampling device comprises a venous indwelling needle, the venous indwelling needle comprises an indwelling needle sleeve, and the indwelling needle sleeve comprises a first cavity, a second cavity and a third cavity or four cavities, five cavities and multiple cavities which are arranged according to requirements, so that the continuous online sampling of drug molecules in blood is realized; the microfluidic chip mixing reaction device comprises 2-dimensional and 3-dimensional channel structures with different sizes arranged in a chip, so that drug molecules and a chemical sensing probe are subjected to full mixing reaction; the monitoring device realizes continuous online acquisition of signals, and further monitors the concentration of drugs in blood (including narcotics, antibiotics, anti-tumor drugs, nervous system drugs, cardiovascular drugs, immunosuppressants, antiasthmatic drugs and other clinical injections and oral drugs) in real time.
The system provided by the invention can realize accurate real-time online monitoring of the concentration of the medicine, has an automatic monitoring process, and helps a doctor to accurately control the dosage of the medicine, thereby achieving the purpose of accurate medical treatment.
Drawings
Fig. 1 is a schematic structural view of the venous indwelling needle of the present invention.
Fig. 2a-2c are cross-sectional views of a venous indwelling needle of the present invention.
Fig. 3 is a schematic structural diagram of a continuous sampling and fluid infusion system based on microdialysis in the invention.
Fig. 4 is a schematic diagram of a blood concentration online monitoring system combining a sampling device and a microfluidic chip.
Fig. 5 is a schematic diagram of the online blood concentration monitoring method by combining the sampling device and the microfluidic chip.
FIGS. 6a and 6b are graphs showing the effect of the venous indwelling needle inserted into blood glucose levels of different concentrations according to the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and the accompanying drawings. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
In fig. 1-6 b, 1-first chamber (infusion tube); 2-second cavity (perfusion liquid inlet tube); 21-a liquid inlet; 3-third cavity (perfusate outlet pipe); 31-a liquid outlet; 4-a semi-permeable membrane; 5-a perfusion pump; 6-a sampling instrument; 7-metal needle.
The invention provides a blood concentration on-line monitoring system combining a sampling device and a microfluidic chip.
Wherein, the blood sampling device can realize continuous on-line sampling of drug molecules in blood; the monitoring device is used for continuously capturing signals generated by the mixing reaction on line so as to monitor the concentration of the drug molecules in the blood in real time; after sampling, the blood sampling device pipeline enters a micro-fluidic chip mixing reaction device for mixing reaction based on the driving force of a pump; the monitoring device comprises an optical detection device, an electrochemical detection device and a mass spectrum detection device, wherein the optical detection device and the electrochemical detection device are integrated with a chip, so that real-time online monitoring on a sample is realized; the mass spectrum detection device samples the target object after reaction marking in the chip and achieves near real-time monitoring through mass spectrum analysis.
The blood sampling device comprises a venous indwelling needle, and the venous indwelling needle comprises an indwelling needle sleeve which comprises a first cavity, a second cavity and a third cavity; a metal needle head is arranged in the first cavity; the second cavity is communicated with the third cavity; the blood sampling device can realize continuous online sampling of drug molecules in blood;
wherein, the first cavity is a transfusion channel; the tail end of the first cavity is open.
The first cavity is an independent channel, is an infusion part, does not relate to sampling, and is not communicated with sampling parts such as the second cavity and the third cavity.
Wherein, the second cavity is a perfusion liquid input channel;
wherein, the third cavity is a dialysate output channel; the second cavity is communicated with the third cavity. The perfusion liquid flows into the third cavity through the second cavity. The second cavity and the third cavity are not communicated with the first cavity.
Wherein, the outside of third cavity is equipped with the fluting, and fluting department sets up the pellicle. The two sides of the membrane can be subjected to material exchange. Preferably, the outer wall of the third cavity is a semi-permeable membrane material. The second and third chambers are sampled by a semi-permeable membrane based on concentration diffusion, preferably with a recovery rate in the range of 10-50%.
Wherein, the semipermeable membrane is a high molecular composite material such as regenerated cellulose or polyacrylonitrile material; the molecular interception of the semipermeable membrane is 20-50 KDa; preferably, the polymer composite material is regenerated cellulose or polyacrylonitrile. Preferably, the semi-permeable membrane has a molecular cut-off of 30 kDa.
In the invention, the blood sampling device is designed with a novel microdialysis sampling semipermeable membrane on the basis of the traditional venous indwelling needle, so that the continuous online sampling of drug molecules in blood, including blood sugar, antibiotics, anesthetics, cancer markers and the like, is realized; the semipermeable membrane is an existing high polymer material membrane, and dynamic exchange between blood medicines and indwelling needle perfusion fluid is realized based on a concentration gradient diffusion balance principle. The site is located on the outside of the intravenous indwelling needle cannula.
The microfluidic chip mixing reaction device comprises 2-dimensional and 3-dimensional channels with different sizes designed in a chip, so that drug molecules and a chemical sensing probe are subjected to full mixing reaction;
the 2-dimensional channel refers to an on-chip planar mixing channel. A 3-dimensional channel refers to an on-chip three-dimensional hybrid channel. The core principle is that the turbulence effect is enhanced by increasing the Reynolds coefficient.
The monitoring device continuously collects signals generated by the mixed reaction on line by using common analysis technologies including but not limited to fluorescence, ultraviolet, electrochemistry, Raman and the like, wherein the signals include fluorescence signals, electrochemical signals, optical signals, mass spectrum signals and the like, and then monitors the concentration of drug molecules in blood in real time.
According to the invention, the monitoring system can realize accurate real-time online monitoring of the concentration of the drug molecules, the monitoring process is automatic, and a doctor is helped to accurately control the drug dosage, so that the aim of accurate medical treatment is achieved. The invention realizes closed-loop control of drug dosage based on online real-time monitoring, which is the target of current clinicians but cannot be realized.
The invention can continuously sample and collect the medicine in the blood by the novel clinical real-time sampling vein indwelling needle based on the microdialysis sampling technology.
The invention also provides a blood concentration online monitoring method by combining the sampling device and the microfluidic chip, which comprises the following steps:
(1) real-time dynamic sampling is carried out by utilizing a blood sampling device based on the semi-permeable membrane diffusion principle;
(2) the microchip mixed reaction device is used as a reaction platform for sensing probe molecules and target drug molecules, and the reaction time is controlled through 2-dimensional and 3-dimensional channels with different sizes, so that the target drug is rapidly monitored;
(3) capturing a target signal by using a monitoring device; .
(4) And carrying out data analysis, processing and operation on the target signal captured by the monitoring device by using a data analysis device, and detecting to obtain the blood concentration of the target drug.
Wherein, in the step (1), the flow rate of the perfusion liquid is 5-10 mu L/min, and the recovery rate can be controlled within a range of 10-80% according to the detection limit of the system.
Wherein the reaction time in the step (2) is 1-5 min.
Wherein, the detection limit of the monitoring device in the step (3) is 0.1 mu g/mL-500 mu g/mL.
Wherein the method further comprises the steps of: including the automatic target control perfusion device of PLC among the monitoring devices, be responsible for the supply of medicine, according to data analysis device's result, through PLC automatic control system, can realize according to sampling-monitoring-dosing-the closed loop control system of sampling, reach the purpose of accurate dosing.
Examples
The venous indwelling needle based on micro-dialysis continuous sampling and fluid infusion, provided by the invention, is a flexible catheter for indwelling the indwelling needle in a blood vessel, is constructed into a three-cavity pipeline and comprises a perfusion tube, a perfusion fluid inlet tube and a perfusion fluid outlet tube; the infusion tube is a No. 1 passage which is used as a common vein fluid infusion passage; the second cavity 2 is a perfusion liquid inlet pipe and is used as a perfusion liquid inlet passage; the third cavity 3 is a perfusion liquid outlet pipe and is used as a perfusion liquid outlet passage after dialysis.
As shown in fig. 1-2c, the pipeline of the present invention uses an extrusion process to produce a plurality of parallel passages, wherein the second cavity 2 and the third cavity 3 are communicated with each other, and a groove is formed on the outer side of the third cavity 3, and the groove is covered with a semipermeable membrane. The semipermeable membrane is made of medical grade semipermeable membranes such as regenerated cellulose or polyacrylonitrile, and the molecular interception amount is 20-50 KDa.
The tubing of the venous indwelling needle of the present invention can take many different forms: as shown in fig. 2a, the second cavity 2 and the third cavity 3 are respectively attached to the tube wall of the first cavity 1; or as shown in fig. 2b, the passages 1, 2 and 3 of the cavities are coaxially and sequentially nested outwards; or as shown in fig. 2c, the third cavity 3 is attached to the wall of the passageway of the first cavity 1, and the passageway of the third cavity 2 is attached to the wall of the passageway of the third cavity 3. As long as the structure of the sampling principle of the present invention can be implemented.
As shown in FIG. 3, the continuous sampling and fluid infusion system based on microdialysis provided by the invention comprises the venous indwelling needle, the perfusion pump and the sampler. The venous indwelling needle is based on the microdialysis principle, and aiming at target molecules in a venous blood vessel, the target molecules are diffused into perfusion liquid based on the concentration gradient between the perfusion liquid and blood to obtain dialysate, and the dialysate continuously flows out of the body through the third cavity 3, so that the target molecules are continuously sampled, and a foundation is laid for reflecting the concentration of substances in the blood in real time. The invention can sample in vivo, in real time and on line without interfering normal physiological process in vivo, and has the advantages of realizing dynamic observation and quantitative analysis, avoiding multiple blood sampling, and reducing pain of patients.
Preferably, the flow rate of the perfusion fluid is 2-10. mu.L/min. Preferably, the sampler has continuous, on-line, real-time sampling functionality. Preferably, the sample recovery is 10-50%.
As shown in fig. 4, the present invention further provides a continuous sampling and fluid infusion method based on microdialysis, which adopts the continuous sampling and fluid infusion system based on microdialysis, and comprises the following steps: when a patient needs to be replenished with liquid, the liquid can be replenished in a traditional infusion mode, and the liquid can be accurately infused through a micropump. Meanwhile, when the concentration and the metabolic information of the target object in the patient body need to be measured, physiological saline only needs to be filled through the micropump, as shown in fig. 2, the physiological saline flows in through the second cavity 2 pipeline, passes through the semipermeable membrane and is dynamically extracted with the target object in the blood based on the microdialysis principle, so that a stable sampling recovery rate is formed, the physiological saline flows out through the third cavity 3 pipeline and is analyzed through a corresponding analyzer, and finally continuous real-time monitoring of the information molecules in the patient body is realized. The invention is based on a continuous sampling and fluid infusion method of microdialysis, and fluid infusion and sampling can be carried out simultaneously or separately.
Fig. 6a is a graph showing the effect of inserting a venous indwelling needle into blood glucose of different concentrations, and it can be clearly seen that the signal shows a corresponding change with the change of the concentration. FIG. 6b is a rat vein experiment, in which the on-line monitoring system is applied to firstly realize the response to the blood sugar signal, and simultaneously, the blood sugar content in the body is increased along with the perfusion of the glucose solution to the rat, and the blood sugar content returns to a normal value along with the progress of metabolism; the rats were then perfused with insulin and found to have significantly reduced blood glucose levels, with the end of the experiment, the rats died without pain.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (9)
1. The utility model provides a blood concentration on-line monitoring system that sampling device and micro-fluidic chip used together which characterized in that includes: a blood sampling device, a microfluidic chip mixing reaction device and a monitoring device; wherein,
the blood sampling device can realize continuous online sampling of drug molecules in blood; the monitoring device is used for continuously capturing signals generated by the mixing reaction on line so as to monitor the concentration of the drug molecules in the blood in real time;
after sampling, the blood sampling device pipeline enters the microfluidic chip mixed reaction device for mixed reaction based on the driving force of a pump; the monitoring device comprises an optical detection device, an electrochemical detection device and a mass spectrum detection device, wherein the optical detection device and the electrochemical detection device are integrated with a chip, so that real-time online monitoring on a sample is realized; the mass spectrum detection device samples a target object after reaction marking in the chip and achieves near real-time monitoring through mass spectrum analysis;
wherein the blood sampling device comprises: a venous indwelling needle;
the venous indwelling needle comprises: an indwelling needle cannula;
the indwelling needle cannula includes: a first cavity, a second cavity and a third cavity; a metal needle (7) is arranged in the first cavity (1); the second cavity (2) is communicated with the third cavity (3); wherein the first cavity (1) is a transfusion channel; the second cavity (2) is a perfusion liquid input channel; the third cavity (3) is a dialysate output channel; the outside of third cavity (3) is equipped with the fluting, fluting department sets up pellicle (4).
2. The on-line monitoring system according to claim 1, further comprising a multi-chamber structure, wherein any two chambers of the multi-chamber structure are in communication.
3. An on-line monitoring system according to claim 1, characterized in that the end of the first cavity (1) is open.
4. The on-line monitoring system according to claim 1, wherein the semi-permeable membrane (4) is a polymer composite; the molecular cutoff of the semipermeable membrane (4) is 3-200 KDa.
5. The on-line monitoring system of claim 1, wherein the microfluidic chip mixing reaction device comprises: 2-dimensional and 3-dimensional channels with different sizes are arranged in the chip, so that the drug molecules and the chemical sensing probes are subjected to full mixing reaction.
6. The on-line monitoring system of claim 1, wherein the monitoring device further comprises a data analysis device, the data analysis device comprises a software analysis system, and the corresponding blood concentration is obtained by performing fitting calculation based on a calibration curve equation for the captured optical, electrical and mass spectrum signals.
7. The on-line monitoring system of claim 1, wherein the monitoring device further comprises a PLC automatic target-controlled perfusion device; and according to the result obtained by the data analysis device, the PLC automatic target control perfusion device is used for carrying out accurate perfusion of the therapeutic drugs and real-time control of the blood concentration.
8. An on-line blood concentration monitoring method combining a sampling device and a microfluidic chip, which is characterized in that the on-line blood concentration monitoring system according to any one of claims 1 to 7 is adopted, and comprises the following steps:
(1) real-time dynamic sampling is carried out by utilizing a blood sampling device based on the semi-permeable membrane diffusion principle;
(2) the microchip mixed reaction device is used as a reaction platform for sensing probe molecules and target drug molecules, and the reaction time is controlled through 2-dimensional and 3-dimensional channels with different sizes, so that the target drug is rapidly monitored;
(3) capturing a target signal by using a monitoring device;
(4) and carrying out data analysis, processing and operation on the target signal captured by the monitoring device by using a data analysis device, and detecting to obtain the blood concentration of the target drug.
9. The on-line blood concentration monitoring method based on the combination of the sampling device and the microfluidic chip as claimed in claim 8, wherein in the step (1), the flow rate of the perfusion solution is 1-30 μ L/min, and the recovery rate is 1-90% according to the system detection limit control range; the reaction time in the step (2) is 1-30 min; the detection limit of the monitoring device in the step (3) is 0.1 mu g/mL-500 mu g/mL.
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