Optical fiber microneedle for extracting and monitoring tissue fluid and manufacturing method of optical fiber microneedle

Abstract

A sensing structure is fixed to one end of a single-core optical fiber, a containing cavity is formed in the sensing structure, an FP cavity is formed in the containing cavity, and the side wall of the containing cavity is provided with a light inlet arranged corresponding to a fiber core of the single-core optical fiber and a liquid inlet used for feeding tissue liquid. The liquid inlet is located on one side of the straight line where the optical fiber core is located. According to the optical fiber microneedle with the optimized design, the FP cavity is formed in the sensing structure at the end part of the optical fiber, tissue fluid is extracted into the accommodating cavity through the liquid inlet through thermal expansion and cold contraction during detection, and meanwhile, the temperature of a microenvironment during cell capture or cell in-vitro culture is detected by utilizing an optical signal in the FP cavity; and the sensing system is used for real-time measurement of glucose concentration and the like. The invention further provides a manufacturing method of the optical fiber microneedle for tissue fluid extraction and monitoring.

Description

Technical Field

[0001] The present invention relates to the technical field of tissue fluid monitoring, and in particular to an optical fiber microneedle for tissue fluid extraction monitoring and a manufacturing method thereof. Background Art

[0002] In the field of modern biomedicine, tissue fluid extraction and detection technology plays an important role in disease diagnosis, health monitoring and personalized medicine. Tissue fluid (such as interstitial fluid or serum) contains a variety of biomarkers that reflect the health status of the body, disease progression and treatment effects.

[0003] Traditional methods of tissue fluid extraction: The most commonly used method is to draw blood or tissue fluid through a syringe. Although this method is effective, it has disadvantages such as large trauma, strong pain, and complex operation. It is especially not suitable for patients who need frequent monitoring. For example, for diabetic patients who need to monitor blood sugar levels for a long time, frequent blood draws not only cause pain to the patients, but may also increase the risk of infection. Although, microneedle technology has attracted widespread attention due to its advantages of minimal invasion and less pain. The application range of microneedles includes vaccination, drug delivery, and tissue fluid extraction. However, most of the existing microneedles can only achieve a single function, that is, extraction or detection, and have not yet achieved an effective combination of the two. For example, some microneedles can only be used to extract tissue fluid, but cannot monitor the temperature and concentration of the sample in real time during the extraction process.

[0004] In addition to the measurement of cell tissue fluid, in vitro cell culture is one of the most important methods in cell research. The key to this technology is to accurately and strictly construct a microenvironment in vitro that simulates the survival of cells in vivo. Ensuring that the microenvironment has appropriate temperature, humidity, pH, gas concentration, and concentration of nutrients (such as glucose) required for cell growth is an important basis for achieving normal cell growth, proliferation, metabolism and other life activities.

[0005] Optical fiber Fabry-Perot (FP) sensors have the advantages of small size, high integration, low cost and in vivo measurement, and are widely used in the field of life sciences. Fabricating FP cavity micro-nanostructures on the end face of optical fiber can better and faster detect changes in cell microenvironment in real time.

[0006] Common existing sensors include fiber Fabry-Perot (FP) cavity sensors, fiber surface plasmon resonance (SPR) sensors, fiber Bragg grating (FBG) sensors, and fluorescent fiber sensors. These sensors have excellent performance in measuring the refractive index and temperature of samples, but they also have many disadvantages: the calibration and manufacturing of SPR sensors are relatively complex, FBG sensors are cross-sensitive to temperature and refractive index, and fluorescent fiber sensors have the advantages of high specificity and high sensitivity, but their service life is short and the response time is long. Complex and high-end sensors usually require complex manufacturing processes. The preparation of micro-nano structures involves precise laser processing, photolithography, and subsequent chemical treatment steps. These processes not only require high equipment investment, but also require operators to have high levels of technology and experience, which increases the difficulty and cost of production. In addition, any slight deviation in the manufacturing process of the microstructure of the fiber end face may affect the performance of the sensor, which makes mass production more difficult.

[0007] At the same time, in the field of life sciences, the existing detection structures and technologies have the following single functions: they can only extract or detect separately, and lack integrated design. This leads to operational complexity and time delays, making it impossible for clinicians to obtain the required information in time when making a diagnosis. For example, when diagnosing certain diseases, doctors need to obtain tissue fluid samples and related biomarker information at the same time, but existing technologies cannot meet both needs at the same time; at the same time, real-time monitoring is insufficient: traditional biological sample testing often requires samples to be sent to the laboratory for analysis, which not only prolongs the feedback time, but may also affect the integrity of the sample and the accuracy of the test results. For example, in emergency situations, doctors need to quickly obtain the patient's biomarker information to make a diagnosis, but traditional methods cannot meet this demand; operational complexity: during the extraction and detection process, there are many operating steps and strict requirements, which are prone to errors and increase the difficulty of use. For example, when using a syringe to extract tissue fluid, the extraction speed and amount need to be strictly controlled, otherwise the sample may be contaminated or damaged; lack of environmental adaptability: existing equipment is often affected by multiple factors in complex biological environments, resulting in insufficient stability and reliability of the results. For example, in a high temperature or high humidity environment, some biological sample testing equipment may not work properly, affecting the accuracy of the test results. Summary of the invention

[0008] In order to solve the technical problems existing in the background technology, the present invention proposes an optical fiber microneedle for tissue fluid extraction monitoring and a manufacturing method thereof.

[0009] The present invention provides an optical fiber microneedle for monitoring tissue fluid extraction, comprising: a single-core optical fiber and a sensing structure;

[0010] The sensing structure is fixed at one end of the single-core optical fiber, and has an accommodating cavity inside the sensing structure, in which an FP cavity is formed, and the side wall of the accommodating cavity has a light inlet arranged corresponding to the core of the single-core optical fiber and a liquid inlet for inletting tissue fluid, and the liquid inlet is located on one side of the straight line where the optical fiber core is located.

[0011] Preferably, the sensing structure has a first side wall and a second side wall that are arranged relatively parallel to each other, the light inlet is located on the first side wall, and the liquid inlet is located on the second side wall.

[0012] Preferably, the sensing structure has a drum-shaped structure.

[0013] Preferably, the end face radius of the sensing structure is larger than the fiber core radius and smaller than the outer diameter of the optical fiber, and the thickness of the side wall of the accommodating cavity is larger than the fiber core radius.

[0014] Preferably, the sensing structure is made of photoresist.

[0015] In the present invention, the proposed optical fiber microneedle for tissue fluid extraction monitoring has a sensing structure fixed at one end of a single-core optical fiber, and a receiving cavity is provided inside the sensing structure, and an FP cavity is formed in the receiving cavity, and the side wall of the receiving cavity has a light inlet and a liquid inlet for tissue fluid inlet arranged corresponding to the core of the single-core optical fiber, and the liquid inlet is located on one side of the straight line where the optical fiber core is located. Through the above-mentioned optimized optical fiber microneedle, an FP cavity is formed in the sensing structure at the end of the optical fiber, and during detection, tissue fluid is extracted into the receiving cavity through the liquid inlet through thermal expansion and contraction, and at the same time, a sensing system is formed to capture cells or to perform real-time measurement of the temperature, glucose concentration, etc. of the microenvironment during in vitro cell culture using the optical signal in the FP cavity.

[0016] The present invention also proposes a method for making an optical fiber microneedle for monitoring tissue fluid extraction, comprising the following steps:

[0017] Glue is dispensed on the end face of the single-mode optical fiber, and the glue-dispensed single-mode optical fiber is cured to form a colloid structure. The colloid structure is then processed into a polymer structure with a housing cavity by two-photon polymerization using a femtosecond laser. The housing cavity has a light inlet and a liquid inlet. Finally, the polymer structure is baked and developed in a developer to obtain a sensing structure.

[0018] Preferably, the method further includes pre-processing the single-mode optical fiber before dispensing the glue: using an optical fiber cutter to cut the end of the single-mode optical fiber flat and using an optical fiber fusion splicer to perform end face discharge processing.

[0019] Preferably, the curing treatment of the optical fiber after the glue is applied is specifically, the single-mode optical fiber after the glue is applied is baked, firstly baked at 60-70° C. for 10-20 minutes, and then baked at 90-100° C. for 40-50 minutes.

[0020] Preferably, the polymerized structure is baked, specifically, at 60-70° C. for 10-20 min, and then at 85-95° C. for 35-45 min.

[0021] In the present invention, the proposed method for preparing the optical fiber microneedle for monitoring tissue fluid extraction and the prepared optical fiber microneedle sensing structure have good thermal expansion effect, and their characteristics can be used to achieve the capture of selected cells and the extraction and transfer of cell fluid. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is a schematic structural diagram of an embodiment of a fiber optic microneedle for tissue fluid extraction monitoring proposed by the present invention.

[0023] Figure 2 This is a schematic diagram of the optical path of an embodiment of a fiber optic microneedle for tissue fluid extraction monitoring proposed by the present invention. DETAILED DESCRIPTION

[0024] like Figure 1 and 2 As shown, Figure 1 This is a schematic diagram of the structure of an embodiment of an optical fiber microneedle for tissue fluid extraction monitoring proposed by the present invention. Figure 2 This is a schematic diagram of the optical path of an embodiment of a fiber optic microneedle for tissue fluid extraction monitoring proposed by the present invention.

[0025] Reference Figure 1 and 2 , the present invention proposes an optical fiber microneedle for tissue fluid extraction monitoring, comprising: a single-core optical fiber 1 and a sensing structure 2;

[0026] The sensing structure 2 is fixed at one end of the single-core optical fiber 1, and has an accommodating cavity inside. An FP cavity is formed in the accommodating cavity. The side wall of the accommodating cavity has a light inlet 22 arranged corresponding to the core of the single-core optical fiber 1 and a liquid inlet 21 for inletting tissue fluid. The liquid inlet 21 is located on one side of the straight line where the optical fiber core is located.

[0027] In the specific working process of the optical fiber microneedle for tissue fluid extraction monitoring of this embodiment, one end of the sensing structure at the end of the single-core optical fiber is placed in the tissue fluid to be extracted or inserted into the human tissue, and the sensing structure is heated to expand the receiving cavity by heating, so that the tissue fluid is sucked into the receiving cavity through the liquid inlet. During detection, the optical signal enters the FP cavity through the core of the single-mode optical fiber, detects the tissue fluid therein, and then returns.

[0028] In the specific signal processing process, the free spectral range (FSR) can be used to calculate the effective cavity length of the Fabry-Perot (FP) cavity sensor. Therefore, the effective cavity length of the Fabry-Perot (FP) cavity sensor can be obtained by measuring the FSR of the Fabry-Perot (FP) interferometer at the tip of the optical fiber.

[0029]

[0030] Where λ is the tilt wavelength, n represents the average RI in the cavity, and L is the cavity length. Therefore, the effective cavity length of the FP cavity sensor (L) is:

[0031]

[0032] At the same time, the FP cavity can be simplified as a double-beam light interference. During the detection process, the reflected light intensity can be calculated as:

[0033]

[0034] Where I1 and I2 are the reflection intensities from the upper and lower surfaces 1 and 2 of the middle cavity, is the initial phase of interference, L is the cavity length, and n is the refractive index of the hollow cavity.

[0035] From formula (1), we can get that when the cosine term When it is equal to an odd multiple of π, the reflected light intensity reaches the minimum value, that is:

[0036]

[0037] Where m is an integer. When the cavity length is a constant, the corresponding relationship between the wavelength drift and the average RI change of the FP cavity is as follows:

[0038]

[0039] Among them, Δn is the refractive index change of the medium in the microcavity, and Δλ is the wavelength drift caused by the refractive index change. From this, all the required characteristic parameters can be calculated.

[0040] In this embodiment, the proposed optical fiber microneedle for tissue fluid extraction monitoring has a sensing structure fixed at one end of a single-core optical fiber, and a receiving cavity is provided inside the sensing structure, and an FP cavity is formed in the receiving cavity. The side wall of the receiving cavity has a light inlet arranged corresponding to the core of the single-core optical fiber and a liquid inlet for tissue fluid inlet, and the liquid inlet is located on one side of the straight line where the optical fiber core is located. Through the above-mentioned optimized optical fiber microneedle, an FP cavity is formed in the sensing structure at the end of the optical fiber, and during detection, tissue fluid is extracted into the receiving cavity through the liquid inlet through thermal expansion and contraction, and at the same time, the optical signal in the FP cavity is used to capture cells or to perform real-time measurement of the temperature, glucose concentration, etc. of the microenvironment during in vitro cell culture.

[0041] In a specific design of the sensing structure, the sensing structure 2 has a first side wall and a second side wall arranged relatively parallel, the light inlet 22 is located on the first side wall, and the liquid inlet 21 is located on the second side wall. The two openings are located on opposite side walls to increase the capacity of the FP cavity.

[0042] In order to improve the space utilization of the accommodation cavity, the sensing structure 2 has a drum-shaped structure to ensure that the surface is not prone to collapse during use.

[0043] In a further specific design, the end face radius of the sensing structure 2 is greater than the core radius and less than the outer diameter of the optical fiber, and the thickness of the side wall of the accommodating cavity is greater than the core diameter. Preferably, the cladding diameter of the single-mode optical fiber is 125 μm, and the core diameter is 8 μm. The upper and lower end face radii of the sensing structure are 40 μm, the height is 73 μm, and the width is 104 μm, wherein the thickness of the side wall of the accommodating cavity is 10 μm. The diameter of the light inlet is 10 μm, and the diameter of the liquid inlet is 8 μm.

[0044] The optical fiber microneedle of this embodiment has a Fabry-Perot cavity sensing structure; it can monitor samples in real time while extracting tissue fluid, which solves the limitations of traditional technology; it solves the problem of achieving efficient extraction of tissue fluid and simultaneous monitoring of multiple parameters, overcoming the limitations of a single function; it also provides instant biological information feedback to help make quick decisions during diagnosis and treatment; and in complex biological environments, it ensures the sensitivity and accuracy of the equipment and improves the reliability of the test results. This solution can provide more comprehensive diagnostic information, a comprehensive and in-depth understanding of the health status of patients or cells, so as to make more accurate diagnosis and treatment decisions, with high detection accuracy, wide detection range, strong stability, simple implementation process and low cost.

[0045] This embodiment also provides a method for making the above-mentioned optical fiber microneedle for tissue fluid extraction monitoring, comprising the following steps:

[0046] Glue is dispensed on the end face of the single-mode optical fiber, and the glue-dispensed single-mode optical fiber is cured to form a colloid structure, and then the colloid structure is processed into a polymer structure with a accommodating cavity by two-photon polymerization using a femtosecond laser, wherein the accommodating cavity has a light inlet 22 and a liquid inlet 21, and finally the polymer structure is baked and developed in a developer to obtain a sensing structure 2.

[0047] Specifically, the single-mode optical fiber is pre-processed before dispensing: the end of the single-mode optical fiber is cut flat with an optical fiber cutter and the end face is discharged using an optical fiber fusion splicer to remove any debris that may remain on the end face and make the end face smooth.

[0048] In a specific operation mode, the sensing structure 2 is prepared by using photoresist. SU-8 photoresist can be used for dispensing under an optical microscope. Then, the optical fiber after dispensing is cured, specifically, the single-mode optical fiber after dispensing is baked, first at 60-70°C for 10-20min, and then at 90-100°C for 40-50min. Preferably, it is baked at 65°C for 15min, and then at 95°C for 45min.

[0049] Then, it is placed on a femtosecond laser processing platform for two-photon polymerization micro-nano processing. Specifically, the position of the optical fiber fixing fixture is adjusted so that the end face of the single-mode optical fiber is flush with the three-dimensional displacement moving platform, and the femtosecond laser equipment is used to perform two-photon polymerization to prepare the required micro-nano structure.

[0050] Finally, the polymerized structure is baked, specifically, at 60-70°C for 10-20 minutes, and then at 85-95°C for 35-45 minutes. Preferably, it is baked at 65°C for 15 minutes, and then at 90°C for 40 minutes. After baking, it is placed in a developer for development. The sensing structure is compact and not prone to deformation. The micro-nano structure in contact with the end face of the optical fiber is firm and has high sensitivity. The sensing structure prepared by this method has good mechanical properties and effectively prevents breakage. The structure also has high sensitivity, good mechanical properties and deformation resistance.

[0051] In the selection of materials, the photoresist used in this embodiment is SU-8GM1075, which is composed of EPON SU-8 resin, glucoside (GBL) solvent and triaryl sulfonium salt as a photosensitizer. Other polymers that can be absorbed by the human body can also be used, such as: hyaluronic acid, chitosan, polyvinyl pyrrolidone, chondroitin sulfate gelatin and starch, etc. These materials have good compatibility with human tissues, can reduce rejection and inflammation, thereby reducing the risk of complications after implantation. Degradability is another key advantage. These polymers can be degraded into small molecules or monomers under the action of acids, alkalis or enzymes in the body, and are eventually metabolized into carbon dioxide and water, thereby avoiding the need for secondary surgery to remove the implant. These advantages will make the fiber end face drum-shaped Fabry-Perot (FP) cavity sensor proposed by the present invention have various applications in the medical field.

[0052] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. An optical fiber microneedle for tissue fluid extraction monitoring, characterized in that: include: Single-core optical fiber (1) and sensing structure (2); The sensing structure (2) is fixed at one end of the single-core optical fiber (1), and the sensing structure (2) has an accommodating cavity inside, and an FP cavity is formed in the accommodating cavity. The side wall of the accommodating cavity has a light inlet (22) arranged corresponding to the core of the single-core optical fiber (1) and a liquid inlet (21) for inletting tissue fluid, and the liquid inlet (21) is located on one side of the straight line where the optical fiber core is located.

2. The optical fiber microneedle for interstitial fluid extraction monitoring according to claim 1, characterized in that: The sensing structure (2) has a first side wall and a second side wall that are arranged relatively parallel to each other, the light inlet (22) is located on the first side wall, and the liquid inlet (21) is located on the second side wall.

3. The optical fiber microneedle for interstitial fluid extraction monitoring according to claim 2, characterized in that: The sensing structure (2) has a drum-shaped structure.

4. The optical fiber microneedle for interstitial fluid extraction monitoring according to claim 3, characterized in that: The end face radius of the sensing structure (2) is greater than the fiber core radius and smaller than the outer diameter of the optical fiber, and the thickness of the side wall of the accommodating cavity is greater than the fiber core radius.

5. The optical fiber microneedle for interstitial fluid extraction monitoring according to claim 1, characterized in that: The sensing structure (2) is made of photoresist.

6. A method for manufacturing an optical fiber microneedle for interstitial fluid extraction monitoring according to any one of claims 1 to 5, characterized in that: The following steps are involved: Glue is dispensed on the end face of the single-mode optical fiber, and the glue-dispensed single-mode optical fiber is cured to form a glue structure. The glue structure is then processed into a polymer structure with a housing cavity by two-photon polymerization using a femtosecond laser. The housing cavity has a light inlet (22) and a liquid inlet (21). Finally, the polymer structure is baked and developed in a developer to obtain a sensing structure (2).

7. The manufacturing method according to claim 6, characterized in that: It also includes pre-processing the single-mode optical fiber before dispensing: using a fiber cleaver to cut the end of the single-mode optical fiber flat and using a fiber fusion splicer to perform end face discharge processing.

8. The manufacturing method according to claim 6, characterized in that: The curing treatment of the optical fiber after the glue is applied is specifically, the single-mode optical fiber after the glue is applied is baked, firstly baked at 60-70° C. for 10-20 minutes, and then baked at 90-100° C. for 40-50 minutes.

9. The manufacturing method according to claim 6, characterized in that: The polymer structure is baked, specifically, at 60-70° C. for 10-20 min, and then at 85-95° C. for 35-45 min.

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