Microdialysis device

Abstract

The present invention relates to a microdialysis device comprising a tube and a duct that are connected by means of a connector, thereby improving substance distribution as well as sample collection and analysis. In addition, the device has an integrated control to regulate the temperature of the samples and thus keep them under optimal conditions. The microdialysis device of the present invention is equipped with a cell that homogenises and provides a laminar flow to better visualise the substances contained, and analyse and monitor the fluid when it is inside the cell using an emitter and receiver, thereby providing accurate data in real time.

Description

[0001] DEVICE FOR MICRODIALYSIS

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to the technical field of biomedical, neurological, pharmacological and chemical research, medical instrumentation for the research and development of treatments, especially in preclinical and clinical trials and more specifically with the analysis of apparatus for methods of collection and analysis of biological fluids, since it provides a device for microdialysis.

[0004] BACKGROUND OF THE INVENTION

[0005] The microdialysis process is crucial for a variety of studies, including those in pharmacology and neuroscience, which require the accurate and continuous monitoring of the chemical composition of biological fluids.

[0006] Microdialysis is a technique used primarily in biomedical research to study biochemical processes in living tissues. Its objective is to measure, in real time, the concentration of small molecules (such as neurotransmitters, hormones, or metabolites) in the extracellular fluid of tissues. Through a small catheter inserted into the tissue of interest, these molecules are allowed to diffuse into a perfusion fluid, which is then analyzed.

[0007] Microdialysis has different areas of application depending on the objective pursued or the results sought. In neuroscience, it serves to monitor neurotransmitter levels in the brain, which helps to better understand neuronal behavior under normal or pathological conditions (such as in neurodegenerative diseases, epilepsy, or addictions).

[0008] Pharmacokinetics is used to assess how drugs are distributed and metabolized in tissues, allowing for the investigation of their efficacy and side effects.

[0009] In the study of metabolites from tissues such as muscle, liver or adipose tissue, to better understand metabolic processes in diseases such as diabetes.

[0010] In disease research, biochemical changes are monitored during the progression of diseases or in response to therapeutic interventions.

[0011] Microdialysis allows us to obtain valuable information about the chemical dynamics in living tissues in a minimally invasive and real-time manner.

[0012] Microdialysis has its roots in several decades of scientific development, evolving from experimental techniques that sought to study chemical processes in the brain and other living tissues.

[0013] Microdialysis derives from the classical dialysis technique, which was used to separate molecules through semipermeable membranes, a technique developed in the 19th century for chemical processes. In the 1960s, equilibrium dialysis began to be used in biological studies to investigate the release of chemicals in living tissues, marking the beginning of its application in biomedicine.

[0014] In 1966, Pushkar and Serebrov pioneered the use of a fluid perfusion system in the brains of animals, which allowed for the sampling of extracellular fluid and the measurement of neurotransmitter levels.

[0015] In the early 1970s, the technique of brain dialysis in animals was perfected, allowing the monitoring of neurotransmitters such as dopamine in laboratory experiments.

[0016] The term "microdialysis" was coined by Urban Ungerstedt in 1974, a Swedish neuroscientist who perfected the technique. Ungerstedt developed a microdialysis catheter small enough to be implanted in specific brain regions of animals without causing significant damage. This allowed for the real-time measurement of neurotransmitter activity, marking a milestone in neuroscience. Ungerstedt used microdialysis to study the effects of dopamine agonists and antagonists on the brain, a key area in research on Parkinson's disease and other neurological disorders.

[0017] In the 1980s, microdialysis began to expand beyond the brain, being used in other tissues, such as muscle, liver, and skin, to study aspects of metabolism and pharmacokinetics.

[0018] In the 1990s, its use became widespread for investigating drug release and distribution in the human body. The technique was refined to improve accuracy and control over sample collection.

[0019] Advances in microdialysis technology over the past few decades have resulted in smaller catheters, more precise dialysis membranes, and more efficient sample collection systems. This has led to greater accuracy in measuring analyte concentrations in small volumes of extracellular fluid.

[0020] Currently, microdialysis has begun to be used in clinical studies to monitor patients in real time, especially in intensive care units to observe glucose, lactate, or amino acid levels in tissues affected by ischemia or trauma.

[0021] Microdialysis has evolved from simple dialysis concepts into a sophisticated and highly precise tool, used primarily in neuroscience, pharmacology, and metabolism. The efforts of pioneers like Urban Ungerstedt have transformed this technique into one of the most important for studying biochemical processes in living tissues in real time.

[0022] A prior art search was conducted for microdialysis devices, where it was found that different devices have been developed for this purpose, as mentioned in the Chinese patent document number CN110559499 (B), dated February 22, 2022, entitled "MICRODIALYSIS PROBE CAPABLE OF PERFORMING OPTOGENETIC STIMULATION", which describes a microdialysis probe capable of carrying out optogenetic stimulation, comprising a probe housing, a limiting block and an optical fiber connector, wherein the head part of the probe housing is connected to the limiting block, the optical fiber connector is combined with the limiting block, and the three structures form a main structure of the microdialysis probe;It is only necessary to insert it into the target brain area when performing light stimulation and microdialysis, which can avoid neuronal injury and tissue reaction caused by the traditional method in the brain due to prolonged placement of the optical fiber, making it favorable for long-term follow-up experiments.

[0023] Also found was International Patent Application No. WO2014023552 (A1), dated February 13, 2014, entitled "FLUID EXCHANGE CATHETER", which describes a fluid exchange catheter comprising a proximal end and a distal end, as well as a mandatory lumen having a proximal end and a distal end, wherein a lumen wall of the mandatory lumen forms a distal wall portion at the distal end of the mandatory lumen, the distal wall portion comprising at least one lumen opening for unobstructed fluid exchange, and wherein the distal wall portion exhibits an unlocking function to clear catheter blockage to achieve stable fluid flow through the catheter.The unlocking function is implemented by structural means at the distal end of the catheter, and optionally, at least a distal wall portion is provided in at least one area surrounding at least one lumen opening with expandability. Furthermore, the invention provides a process for unlocking a fluid exchange catheter, the fluid exchange catheter having a proximal end and a distal end and comprising a mandatory lumen having a proximal end and a distal end, wherein a wall of the mandatory lumen forms a distal wall portion at the distal end of the mandatory lumen, the distal wall portion comprising at least one lumen opening, and wherein the process comprises the step of controlling the fluid flow through the mandatory lumen to create a nonlinear movement of the fluid flowing through the at least one opening.

[0024] Finally, the United States of America patent application document number US20090192445 (A1), dated July 30, 2009, was found, entitled "MICRODIALYSIS PROBE", which describes an improved linear microdialysis probe, comprising a continuous length of flexible tubing having at least one window formed therein, said window covering at least a portion of the circumference of the tubing, while the remaining portion forms at least one uninterrupted connection between a first end of said tubing and a second end of said tubing, said ends being adapted to be fixed to an inlet for perfusion fluid and the other end forming an outlet for the dialysate, said window exposing a tubular semipermeable membrane.

[0025] The documents cited above refer to probes for microdialysis, but they do not show evidence of integrating a bifurcated and a trifurcated duct, which would improve the distribution of the substances introduced into the ducts, as well as improve sample collection and analysis. Nor do they describe a connector for joining the ducts, which would ensure an uninterrupted flow transition between the various branches. The documents also do not show evidence of integrating thermal control to regulate the temperature of the substances and thus maintain optimal microdialysis conditions. Furthermore, they do not describe a module that homogenizes and flattens the flow, and, through a fiber optic transmitter and receiver, analyzes and monitors the fluid within the module, providing accurate real-time data.

[0026] OBJECT OF THE INVENTION

[0027] The present invention aims to provide a device for microdialysis, which has a duct and a conduit, which allows for improved distribution of substances, as well as improved collection and analysis of samples.

[0028] Another object of the present invention is to provide a device for microdialysis, which integrates a connector for joining the duct and the conduit, ensuring an uninterrupted transition of flow between the various branches of the ducts.

[0029] An additional object of the present invention is to provide a device for microdialysis, which has a control to regulate the temperature of the samples and thus keep them in optimal conditions.

[0030] Another object of the present invention is to provide a microdialysis device, which includes a cell that homogenizes and provides laminar flow for better visualization of the contained substances. A further object of the present invention is to provide a microdialysis device that integrates a transmitter and a receiver to analyze and monitor the fluid while it is inside the cell, providing accurate real-time data.

[0031] BRIEF DESCRIPTION OF THE FIGURES

[0032] The characteristic details of this novel microdialysis device are clearly shown in the following description and accompanying figures, as well as an illustration thereof, using the same reference symbols to indicate the parts shown. However, these figures are shown by way of example and should not be considered limiting to the present invention.

[0033] Figure 1 shows a side perspective view of the bifurcated conduit of the microdialysis device.

[0034] Figure 2 shows a side perspective view of the trifurcated conduit of the microdialysis device.

[0035] Figure 3 shows a top perspective view of the microdialysis device connector, attached to the bifurcated and trifurcated conduits.

[0036] Figure 4 shows a side perspective view of the microdialysis device, without the casing. Figure 5 shows a detailed view of the control unit and cell of the microdialysis device.

[0037] Figure 6 shows a top perspective view of the microdialysis device, without the casing. Figure 7 shows a side perspective view of the microdialysis device, without the cover. Figure 8 shows a side perspective view of the microdialysis device.

[0038] Figure 9 shows a side view of the microdialysis device, without the casing.

[0039] Figure 10 shows a detailed view of the opening of the microdialysis device

[0040] DETAILED DESCRIPTION OF THE INVENTION

[0041] For a better understanding of the present invention, the parts that make up the microdialysis device are listed below:

[0042] 1. Bifurcated duct

[0043] 2. Trifurcated conduit

[0044] 3. Connector

[0045] 4. Control

[0046] 5. Cell

[0047] 6. Outlet duct

[0048] 7. Issuer

[0049] 8. Receiver

[0050] 9. Housing

[0051] 10. Cover

[0052] 11. Opening

[0053] 12. Fixation method

[0054] The microdialysis device that is the subject of the present invention is an advanced mechanism designed to improve the accuracy and efficiency of biological sample collection and analysis. It is particularly well-suited for biomedical research, such as in the fields of pharmacology and neuroscience, where continuous and precise monitoring of the chemical composition of biological fluids is essential. This device overcomes the limitations of traditional microdialysis methods, which are often inefficient, prone to contamination, and difficult to control in terms of temperature and flow.

[0055] With reference to the figures, the microdialysis device consists of a bifurcated conduit (1), which has an inlet at the bottom and a Y-shaped bifurcation at the top. Its structure is tubular, with branches extending at symmetrical angles from the bifurcation point. This configuration allows for controlled fluid distribution within the mechanism, ensuring precise sample separation and eliminating potential turbulence in the fluid that could affect the accuracy of the analysis.

[0056] Adjacent to the bifurcated conduit (1) is a trifurcated conduit (2), which has an outlet at the bottom and a trifurcation at the top, so that it has a shape similar to a "T", with a main conduit that branches into two additional pathways; these allow the introduction of multiple substances simultaneously, optimizing the collection and analysis of the samples.

[0057] A connector (3) is installed at one end at one of the outlets of the upper part of the bifurcated conduit (1), and the opposite end is installed at one of the inlets of the upper part of the trifurcated conduit (2). This configuration allows both conduits to be connected to maintain the direction of flow, and the additional inlets of the trifurcated conduit (2) allow the introduction of different substances, which, for example, enables the study of neurotransmitter release in interaction with drugs. The connector (3) is cylindrical and ensures a smooth transition of flow between the bifurcated (1) and trifurcated (2) conduits, without interruption. This connector (3) maintains the integrity of the flow through the various branches of the mechanism.

[0058] The bifurcated conduit (1) is configured to collect samples of biological fluids from the bottom, and by means of the connector (3), to make the transition of said fluid to the trifurcated conduit (2), ensuring that the fluid circulates uninterruptedly and without leaks to avoid fluctuations in precision that may affect the procedure for the detailed study of the properties of the biological samples.

[0059] A control (4), preferably thermal, is connected at its upper end to the outlet of the trifurcated conduit (2). This configuration encapsulates the fluid outlet within the trifurcated conduit (2), thereby regulating the temperature of the fluid sample circulating through the microdialysis device via the bifurcated (1) and trifurcated (2) conduits. This ensures optimal operating conditions for the microdialysis process, preserving the samples and preventing thermal degradation. The control (4) is essential for ensuring the chemical stability of the samples and guaranteeing accurate and reproducible results. The control (4) has a compact, rectangular shape.

[0060] A cell (5), preferably of laminar flow, is installed at its top, at the bottom of the thermal control (4), and the bottom of said cell (5) is placed at the opposite end where the outlet of the trifurcated conduit (2) is connected; the cell (5) is a rectangular structure with two flat faces, this configuration helps to homogenize the flow of the sample fluid and distribute the fluid in a thin layer without turbulence, obtaining a smooth, uniform flow without abrupt fluctuations along the cell (5), which is crucial for consistency in sampling.

[0061] An outlet conduit (6), which is a tube, is installed at one end at the bottom of the cell (5), preferably projecting laterally on one side, and the opposite end of the outlet conduit (6) is free. This configuration allows a device (not illustrated) to be connected for controlled outlet and collection of the processed biological fluid sample.

[0062] An emitter (7) is installed at one end, at the bottom of the cell (5), preferably in the center, and the opposite end of the emitter (7) is free. This configuration allows the free end of the emitter (7) to be connected to a source (not illustrated) which can be a modem or a data transmitter. A receiver (8) is installed at one end, on one of the flat faces of the cell (5), preferably positioned perpendicular to said cell (5) and parallel to the emitter (7), and the opposite end of the receiver (8) is free. This configuration allows the free end of the receiver (8) to be connected to a piece of equipment (not illustrated) which is preferably for data analysis, such as a computer, a tablet, or a smart device.The emitter (7) and the receiver (8) are preferably made of fiber optics. This configuration allows the emitter (7) to convert an electrical signal into an optical signal to illuminate the sample inside the cell (5). Subsequently, the receiver (8) converts the optical signal back into an electrical signal that can be interpreted by the equipment (not illustrated), and in this way monitor the laminar flow of the sample circulating inside the cell (5), sending information in real time.

[0063] A housing (9) having a perforation (not illustrated) at the bottom is configured to house the bifurcated (1) and trifurcated (2) conduits, the connector (3), the control (4), the cell (5), the outlet conduit (6), the emitter (7), and the receiver (8); the lower end of the bifurcated conduit (1) protrudes through the perforation (not illustrated) of the housing (9), being positioned centrally at the bottom of said housing (9); the free ends of the outlet conduit (6), the emitter (7), and the receiver (8) protrude from one side of the housing (9).

[0064] A cover (10) having a perforation (not illustrated) at the bottom is configured to house the housing (9); the perforation (not illustrated) in the cover (10) is aligned with the perforation in the housing (9) such that the lower part of the bifurcated conduit (1) protruding from said housing (9) protrudes from the cover (10); an opening (11) is located on the side of the cover (10); this configuration allows the free ends of the outlet conduit (6), emitter (7), and receiver (8) protruding from the housing (9) to be exposed so that they can be manipulated for the connection of the devices (not illustrated) for carrying out the microdialysis process. The housing (9) and cover (10) are configured to encapsulate and protect the internal components, as well as to provide structural stability to the microdialysis device.The casing (9) and the cover (10) are preferably conical in shape.

[0065] At least one fixing means (12), preferably a plate, is installed on the outer periphery of the base of the cover (10). This configuration allows the microdialysis device to be fixed to the living being, for example, an animal, for the study, avoiding unnecessary movements and ensuring that the microdialysis process is carried out under controlled conditions. The fixing means (12) may consist of a single plate covering the entire outer periphery of the lower part of the cover (10), or of several rectangular plates, preferably four, distributed equidistantly, which provide anchoring points on the outer periphery of the lower part of the cover (10).

[0066] Overall, the microdialysis device is a robust mechanism that optimizes the process of collecting and analyzing biological samples. Its modular configuration offers significant improvements in the accuracy and reproducibility of experiments, reducing the need for constant supervision. This technological advancement makes it an essential tool in modern biomedical research.

[0067] Overall, the microdialysis device is a robust mechanism that optimizes the process of collecting and analyzing biological samples. Its modular configuration offers significant improvements in the accuracy and reproducibility of experiments, reducing the need for constant supervision. This technological advancement makes it an essential tool in modern biomedical research.

[0068] PREFERRED EMBODIMENT OF THE INVENTION

[0069] The following examples illustrate a preferred way of carrying out the present invention, and should therefore not be considered as limiting it.

[0070] Example 1. Placement and obtaining samples from the microdialysis device.

[0071] With reference to the figures mentioned above, a surgical preparation is made to insert a cannula (not illustrated) into the brain of a rodent, subsequently the microdialysis device is placed in the skull of the animal and secured with the fixation medium ( 12 ) and the cannula (not illustrated) is connected to the bifurcated duct ( 1 ) for the extraction of the sample.

[0072] Having done the above, the sample flows through the bifurcated conduit (1) and by means of the connector (3), is directed to the trifurcated conduit (2); with the help of the additional inlets, the substance necessary for the performance of the microdialysis is introduced, the fluid sample and the added substances, pass from the trifurcated conduit (2) to the control (4) for the regulation of the temperature in the fluid and subsequently reach the cell (5) for its homogenization.

[0073] The laminar flow of the sample circulating inside the cell (5) is monitored by means of the emitter (7) and receiver (8), which are connected to the devices (not illustrated), and the processed biological fluid sample is collected by means of the tube (6). In view of what has been stated in this descriptive chapter, it is reiterated that the scope of the present invention shall not be limited by the embodiments particularly described, and it is understood that variations in several respects may be made. Such variations shall not be considered a departure from the spirit and scope of the invention, and all such modifications may be obvious to a person skilled in the art and shall be included within the scope of the following claims.

Claims

CLAIMS 1. A device for microdialysis, characterized in that it comprises: a bifurcated conduit (1) having an inlet at the bottom, and the upper part having a Y-shaped bifurcation; a trifurcated conduit (2) adjacent to the bifurcated conduit (1), said trifurcated conduit (2) having an outlet at the bottom and a trifurcation at the top, such that it has a T-shaped form; a connector (3) is installed at one end in one of the outlets of the upper part of the bifurcated conduit (1), and the opposite end is installed in one of the inlets of the upper part of the trifurcated conduit (2), this configuration allowing both conduits to be connected to maintain the direction of flow;A thermal control (4) is connected at its upper end to the outlet of the trifurcated conduit (2), encapsulating the outlet of the fluid in said trifurcated conduit (2) and thus regulating the temperature of the fluid sample circulating through the microdialysis device by means of the bifurcated (1) and trifurcated (2) conduits; a laminar flow cell (5) is installed at its upper end, at the bottom of the thermal control (4), and the lower part of said cell (5) is placed at the opposite end where the outlet of the trifurcated conduit (2) is connected; an outlet conduit (6) is installed at one end at the bottom of the cell (5) and the opposite end is free; an emitter (7) is installed at one end at the bottom of the cell (5) and the opposite end of the emitter (7) is free;A receiver (8) is installed at one end, on one of the flat faces of the cell (5) and the opposite end of the receiver (8) is; finds free; a housing (9) with a perforation in its lower part houses the bi-furcated (1) and tri-furcated (2) conduits, the connector (3), the control (4), the cell (5), the output conduit (6), the emitter (7) and the receiver (8), in such a way that the lower end of the bi-furcated conduit (1) protrudes through the perforation of the housing (9), being positioned in a centered manner in the lower part of said housing (9); the free ends of the output conduit (6), the emitter (7) and the receiver (8) protrude from one of the sides of the housing (9); a cover (10) having a perforation in the lower part houses the housing (9); An opening (11) is located on the side of the cover (10); this configuration allows the free ends of the outlet conduit (6), emitter (7), and receiver (8) protruding from the housing (9) to be exposed so that they can be handled;and at least one means of fixing (12) is installed on the outer periphery of the base of the roof (10).; 2. The device according to claim 1 characterized in that the structure of the bifurcated conduit (1) is tubular, with branches extending at symmetrical angles from the bifurcation point, allowing a controlled distribution of the fluid within the mechanism, ensuring precise separation of the samples, eliminating possible turbulence in said fluid that may affect the accuracy of the analysis.

3. The device according to claim 1 characterized in that the trifurcated conduit (2) has a main conduit which branches into two additional pathways; which allow the introduction of multiple substances simultaneously, optimizing the collection and analysis of the samples.

4. The device according to claim 1 characterized in that the connector (3) is cylindrical and ensures a smooth transition of flow between the bifurcated (1) and trifurcated (2) conduits, without interruptions.

5. The device according to claim 1 characterized in that the control (4) has a compact rectangular shape.

6. The device according to claim 1 characterized in that the cell (5) is a rectangular structure with two flat faces, allowing the flow of the sample fluid to be homogenized and the fluid to be distributed in a thin layer without turbulence, obtaining a smooth, uniform flow without abrupt fluctuations along the cell (5), which is crucial for consistency in sampling.

7. The device according to claim 1 characterized in that the outlet conduit (6) is a tube that projects laterally on one side of the cell (5), such that it is connected to a device for the controlled outlet and collection of the processed biological fluid sample.

8. The device according to claim 1 characterized in that the emitter (7) is located in the center of the cell (5), to connect the free end of the emitter (7) to a source which may be a modem or a data transmitter.

9. The device according to claim 1 characterized in that the receiver (8) is positioned perpendicularly in the cell (5) and parallel to the emitter (7), to connect the free end of the receiver (8) to equipment that is preferably for data analysis.

10. The device according to claim 9 characterized in that the equipment that connects to the receiver (8) is a computer, a tablet or a smart device.

11. The device according to claim 1 characterized in that the emitter (7) and the receiver (8) are made of optical fiber, such that the emitter (7) converts an electrical signal into an optical signal to illuminate the sample inside the cell (5), so that subsequently the receiver (8) converts the optical signal back into an electrical signal that can be interpreted by the equipment connected to the receiver (8), and thus monitor the laminar flow of the sample circulating inside the cell (5), sending information in real time.

12. The device according to claim 1 characterized in that the perforation of the cover (10) is aligned with the perforation of the housing (9) such that the lower part of the bifurcated conduit (1) protruding from said housing (9) protrudes from the cover (10).

13. The device according to claim 1 characterized in that the housing (9) and the cover (10) are conical in shape, this configuration allows encapsulation and protection of the internal components, as well as providing structural stability.

14. The device according to claim 1 characterized in that the fastening means (12) are plates.

15. The device according to claim 14 characterized in that the fixing means (12) may consist of a single plate covering the entire outer periphery of the lower part of the cover (10), or of several rectangular plates, equidistantly distributed, which provide anchoring points on the outer periphery of the lower part of the cover (10).

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