Porous hollow microneedle capable of dynamically collecting interstitial fluid

Abstract

The invention relates to the technical field of biomedical treatment, and discloses a porous hollow microneedle capable of dynamically collecting interstitial fluid, which comprises an inner core layer, a hollow layer and a filter layer which are sequentially sleeved from inside to outside and are of conical structures, the inner core layer is made of a material with adsorption performance and is used for adsorbing and collecting interstitial fluid; the hollow-out layer is used for supporting the hardness of the microneedle and realizing a puncturing function, a plurality of hollow-out holes are formed in the hollow-out layer, a plurality of filtering holes are formed in the filtering layer, the filtering area of each filtering hole is smaller than the hollow-out area of each hollow-out hole, and the filtering layer is used for filtering interfering substances or pollutants in interstitial fluid. The micromolecular target substances in the microneedle are enabled to enter the microneedle. In practical application, the porous hollow microneedle effectively solves the problem that the body of a patient feels uncomfortable and painful due to the fact that frequent sampling is needed in traditional biological monitoring, and painless sampling is achieved.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a porous hollow microneedle capable of dynamically collecting interstitial fluid. Background Art

[0002] Biomonitoring is the main way to detect human indicators and obtain physical health information. Specifically, it refers to the process of detecting and analyzing target substances in biological samples such as interstitial fluid in the body with the help of specific technical means and equipment, so as to obtain various information about the physiological state of the organism, the occurrence and development of the disease, and the response to therapeutic intervention.

[0003] Traditional biomonitoring primarily involves obtaining tissue samples through surgery or puncture, followed by analysis of the interstitial fluid within the tissue. Interstitial fluid, produced by the exchange of cells and blood, is rich in proteins, small molecules, and nucleic acids. The primary goal of biomonitoring is to detect specific small molecule targets within the interstitial fluid. These small molecule targets are often biomarkers that can indicate the presence, progression, or remission of various diseases. For example, certain small molecule metabolites may be elevated in the interstitial fluid of cancer patients, serving as early warning signs of the disease.

[0004] However, the sampling process of traditional biomonitoring is itself a major flaw. Surgical procedures are invasive and require certain skills and anesthesia, which can be physically and psychologically stressful for patients. Although puncture is relatively less invasive than surgery, it can still cause discomfort and pain. In addition, these traditional methods are usually limited to a single sampling and single detection model. This means that in order to conduct continuous monitoring or repeated evaluations, patients have to endure the painful sampling process multiple times, which not only increases the patient's physical pain, but also increases the risk of potential complications associated with repeated invasive procedures. Therefore, there is an urgent need for more advanced and patient-friendly biomonitoring technologies to overcome these limitations. Summary of the Invention

[0005] The present invention aims to provide a porous hollow microneedle that can dynamically collect interstitial fluid to solve the problem that traditional biological monitoring requires frequent sampling, which causes discomfort and pain to the patient's body.

[0006] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: a porous hollow microneedle capable of dynamically collecting interstitial fluid, comprising an inner core layer, a hollow layer, and a filter layer sequentially arranged from the inside to the outside, all of which are conical structures; the inner core layer is made of a material with adsorption properties and is used to adsorb and collect interstitial fluid; the hollow layer is used to support the hardness of the microneedle and realize the puncture function, the hollow layer is provided with a plurality of hollow holes, and the filter layer is provided with a plurality of filter holes, the filtration area of ​​a single filter hole is smaller than the hollow area of ​​a single hollow hole, and the filter layer is used to filter interfering substances or pollutants in the interstitial fluid, so that small molecule target substances therein enter the microneedle.

[0007] The principles and advantages of this solution are:

[0008] 1. This solution significantly reduces patient pain during the sampling process: Traditional biopsy procedures, such as surgical or puncture methods, can cause significant trauma and pain to patients due to large incisions or thick needle diameters. The porous, hollow microneedles in this solution utilize a tapered structure, minimizing the contact surface area between the microneedles and tissue during puncture. For example, while traditional puncture needles may have a diameter in the millimeter range, the tip diameter of the microneedles can be reduced to micrometers, significantly reducing damage to tissue cells during puncture. Furthermore, the microneedle's small size allows for controlled puncture depth, significantly reducing stimulation of peripheral nerve endings. This fundamentally alleviates pain during sampling, providing a gentler and more comfortable sampling experience. Furthermore, interstitial fluid has a certain viscosity. Using a traditional, thicker puncture needle would create significant resistance during extraction, potentially pulling on tissue and exacerbating patient pain. The microneedle's fine structure, however, effectively reduces resistance during extraction due to its small contact surface area with this viscous interstitial fluid, further alleviating patient discomfort.

[0009] 2. This solution enables efficient dynamic collection: The inner core layer is made of a material with special adsorption properties. Once the microneedles penetrate the tissue, interstitial fluid is continuously adsorbed to the inner core layer due to the dual effects of concentration differences and the adsorption force of the material. Moreover, this adsorption continues over time as long as the microneedles remain in the tissue, enabling continuous collection of interstitial fluid. This overcomes the limitations of traditional single-shot sampling, eliminating the need for frequent punctures and sampling, and reducing the discomfort and pain associated with sampling.

[0010] Secondly, the overall structure of the microneedle is an inner core layer, a hollow layer, and a filter layer, which are arranged in sequence from the inside to the outside, and all of them are conical structures. This conical structure is not only conducive to puncture, but more importantly, it creates good spatial conditions for dynamic collection. During the puncture process, as the microneedle gradually penetrates into the tissue, the various layers of structure work together to allow the interstitial fluid to pass through the filter layer and the hollow layer in turn and then flow smoothly to the inner core layer. Unlike the traditional single cavity collection structure, the layered structure of this solution makes the collection process more efficient, reduces the obstruction of interstitial fluid in the collection path, and further ensures the continuity and stability of dynamic collection.

[0011] Furthermore, due to its viscosity, interstitial fluid easily adheres to the inner wall of the collection device during collection, affecting flow efficiency. However, the layered tapered structure of this microneedle expands the contact area between the interstitial fluid and each layer, dispersing the adhesion effect caused by its viscosity. This allows the interstitial fluid to flow more smoothly along the layers to the inner core, ensuring efficient collection.

[0012] 3. This solution significantly improves the accuracy of biological testing: the filtration area of ​​a single pore in the filter layer is smaller than the hollow area of ​​a single aperture, making the filter layer a barrier before testing. The filter layer can screen substances based on molecular size and characteristics, allowing small molecule target substances in the interstitial fluid to enter through the pores of the hollow layer. This molecular size-based screening principle effectively removes impurities from the interstitial fluid, making the sample collected in the inner core layer purer, greatly improving the accuracy of subsequent testing and reducing the possibility of test result deviations due to impurity interference.

[0013] The viscosity of interstitial fluid can cause impurities and small molecule target substances to entangle during flow, making it difficult to accurately separate them using traditional filtration methods. The filter layer in this solution utilizes a filter pore structure that can, to a certain extent, overcome the effects of viscosity. When the viscous interstitial fluid flows through, large molecule impurities are more likely to be trapped outside the filter layer due to the dual effects of size and viscosity. Small molecule target substances, however, are able to pass through the filter layer more smoothly and enter the microneedle interior due to their smaller size, ensuring sample purity and detection accuracy.

[0014] Furthermore, in traditional biological monitoring, external contaminants can easily mix into samples during the sampling process, affecting test results. The filter layer in this solution not only filters endogenous interfering substances but also blocks any external pollutants that may enter. In actual operating environments, dust particles and microorganisms in the air may come into contact with the microneedles. The presence of the filter layer prevents these pollutants from entering the microneedles, ensuring that the collected interstitial fluid samples are free of external contamination, further guaranteeing the reliability of the test results, and providing strong support for accurate disease diagnosis.

[0015] 4. This solution effectively simplifies the operating process and lowers the operating threshold: Compared with traditional surgical operations that require complex surgical instruments, delicate operating skills and professional anesthesia support, this porous hollow microneedle structure is simple and clear. It consists of only three layers and the overall design is compact. In actual operation, medical staff only need to hold the microneedle and puncture it into the target tissue at a certain angle and depth, without the need for complex surgical incisions, tissue separation and other operations. This simplified operating process greatly reduces the requirements for the professional skills of medical staff. Even ordinary grassroots medical staff can master the use of microneedles after a short period of training, thereby improving the utilization efficiency of medical resources.

[0016] Traditional biomonitoring procedures often require well-equipped operating rooms with stringent environmental requirements. However, this microneedle technology has relatively low environmental requirements during operation. It does not require specialized operating room equipment like large anesthesia equipment and shadowless lamps, and can be performed in a standard clean medical environment. This enables high-quality biomonitoring work to be carried out in areas with relatively limited medical resources, such as clinics in remote mountainous areas and small community hospitals, expanding the application of biomonitoring technology and having important social significance.

[0017] Furthermore, the height of the microneedle is 600-1300 μm, and the bottom diameter is 600-1000 μm.

[0018] Beneficial effects: The microneedle size design of this solution has a smaller height and bottom diameter, which makes the microneedle cause less damage to the cross-sectional area of ​​the tissue during puncture, reduces the squeezing and tearing of surrounding tissue cells, and enables the microneedle to reach the target area in a more precise manner to obtain interstitial fluid, thereby reducing physical damage to the tissue from the root; in addition, there are a large number of nerve endings distributed in human tissue. Traditional larger-sized puncture instruments can easily stimulate these nerve endings during operation, causing strong pain reactions. The microneedle of this solution can cleverly avoid most nerve endings during the puncture process due to its finer size, and minimize the interference with peripheral nerve endings during the sampling process, thereby greatly reducing the patient's pain perception during the sampling process, further improving the patient's comfort during the sampling process, and providing patients with a gentler biomonitoring experience.

[0019] Secondly, the thickness and structure of different tissue parts are different. By precisely controlling the height and bottom diameter of the microneedle, the microneedle can safely and effectively perform puncture and interstitial fluid collection, whether it is a thinner skin area or some shallow areas of deep tissue, broadening the application scope of biomonitoring technology.

[0020] Furthermore, the total area of ​​the hollow holes accounts for 10%-15% of the area of ​​the hollow layer, and the hollow holes are distributed at the end of the hollow layer with a larger diameter.

[0021] Beneficial effect: In the above setting, the total area of ​​the hollow holes is 10%-15% of the area of ​​the entire hollow layer. This ratio range effectively reduces the risk of blockage caused by the viscosity of the interstitial fluid while ensuring the inflow of interstitial fluid. Although the filter layer will filter out some impurities in advance, some fine particles or sticky substances in the interstitial fluid may still remain. If the area of ​​the hollow holes is too large, these residual impurities are more likely to accumulate in the holes, causing blockages and affecting the collection effect. The hollow hole area ratio of this design can not only meet the interstitial fluid inflow requirements, but also make use of the flow characteristics inside the microneedle to make the filtered interstitial fluid quickly pass through the hollow holes, reduce the chances of impurities staying and gathering in the holes, avoid interrupting the collection process due to blockage, and ensure the continuity and stability of the collection. Even during a long collection process, the inflow channel of the interstitial fluid can be effectively maintained unobstructed.

[0022] Secondly, the hollow holes are distributed at the end of the hollow layer with a larger diameter, providing a relatively large gathering space for the interstitial fluid, reducing the flow resistance of the interstitial fluid during the transfer from the filtration layer to the hollow layer. According to the principles of fluid mechanics, under the same adsorption force of the inner core layer, the larger contact area and appropriate pore size distribution can promote the interstitial fluid to pass through the hollow layer more smoothly, accelerate the flow into the inner core layer, improve the collection speed and efficiency, and ensure that a sufficient amount of interstitial fluid sample can be obtained for testing in a shorter time.

[0023] The hollow hole design of this solution reduces the internal blockage and impurity accumulation of the microneedle due to the viscosity of the interstitial fluid, thereby extending the service life of the microneedle. The microneedle can still maintain good collection and filtration performance during multiple uses, reducing medical costs, and improving the feasibility and economy of microneedles in actual clinical applications. It provides a more economical and effective tool for patients who undergo long-term or frequent biological monitoring.

[0024] Furthermore, the shape of the hollow hole is circular, polygonal or V-shaped. When the hollow hole is V-shaped, the angle of the V-shaped tip is 30°-50°.

[0025] Beneficial Effects: The above-mentioned arrangement makes the shapes of the hollow holes diverse, and the circular, polygonal, and V-shaped hollow holes can optimize the interaction between the microneedle and the tissue during the puncture process through their respective structural characteristics. They all help to reduce the abnormal stress on the microneedle during puncture, ensure the stability of the microneedle structure, reduce the risk of bending or damage, make the puncture process smoother and more efficient, and lay a good foundation for the subsequent collection of interstitial fluid. Moreover, the three shapes of hollow holes can effectively promote the flow of interstitial fluid into the inner layer of the microneedle. Whether it is uniformly converging through circular holes, increasing the contact area through polygonal holes, or accelerating drainage through V-shaped holes, they can overcome the flow obstacles caused by the viscosity of the interstitial fluid to a certain extent, ensure the smooth, continuous and rapid inflow of interstitial fluid, improve collection efficiency, and meet the sample volume requirements of the test.

[0026] Secondly, when the hollow hole is V-shaped, the angle α of the V-shaped tip is 30°-50°. This angle design ensures that the hollow hole has sufficient hollow area to allow interstitial fluid to pass through, so as to prevent the interstitial fluid from having excessive resistance when passing through the hollow hole due to its viscosity, thereby hindering the collection of interstitial fluid and affecting the accuracy and efficiency of subsequent detection.

[0027] Furthermore, the pore size of the filter pores on the filter layer is 100nm-500nm.

[0028] Beneficial Effects: The aforementioned pore size range allows for precise screening of substances in interstitial fluid based on molecular size. In interstitial fluid, interfering substances such as large proteins and cell debris are typically much larger than 100 nanometers, while some disease-related small molecule targets, such as specific small metabolites, are often 50-100 nanometers or smaller. This pore size design effectively intercepts large interfering substances, preventing them from passing through the filter layer and into the microneedle interior, thereby significantly improving the accuracy of subsequent testing and reducing test result deviations caused by impurity interference.

[0029] The appropriate filter pore diameter optimizes the flow of interstitial fluid within the microneedle. When the pore diameter is between 100nm and 500nm, the flow resistance of the interstitial fluid will not be too large due to a small pore diameter, slowing the collection speed, nor will the filtration effect be reduced due to an overly large pore diameter. When dealing with interstitial fluid with a certain viscosity, this pore diameter can maintain the flow rate of the interstitial fluid through the filter layer at a reasonable level, ensuring that while filtering impurities, the overall inflow efficiency of the interstitial fluid is not affected.

[0030] Furthermore, the inner core layer is detachably connected to the hollow layer.

[0031] Beneficial effects: The above arrangement, on the one hand, requires cleaning and disinfection after the microneedles are used to ensure safety and effectiveness for the next use. The inner core layer is detachably connected to the hollow layer, making cleaning and disinfection more convenient and efficient. Medical staff can perform targeted cleaning on the inner core layer and the hollow layer respectively, and can thoroughly remove interstitial fluid residues, impurities, and possible microorganisms attached to each layer. Compared with integral microneedles, this detachable design can penetrate into various subtle parts for cleaning, effectively reducing the risk of cross-infection and ensuring the hygiene standards of the microneedles.

[0032] On the other hand, the detachable inner core layer design helps extend the overall service life of the microneedles. During actual use, the inner core layer is more susceptible to wear, corrosion, and impurities due to direct contact with the interstitial fluid, causing damage. When the inner core layer is damaged or its performance degrades, only the inner core layer needs to be replaced without replacing the entire microneedle. This not only reduces medical costs but also reduces resource waste. For example, after repeated use, if the adsorption performance of the inner core layer is found to have declined, a new inner core layer can be directly replaced, and the hollow layer and filter layer can continue to be used normally, greatly improving the cost-effectiveness and practicality of the microneedles.

[0033] Moreover, the replaced inner core layer can also be deeply integrated into the "diagnosis-treatment-recovery-analysis" closed-loop chain to achieve efficient utilization of biomarkers. As an in situ biological information carrier, the inner core layer directly enriches target molecules such as metabolites, proteins, and exosomes when in contact with interstitial fluid. After replacement, it can be used for laboratory testing such as mass spectrometry without any processing, and dynamic biochemical information is fully preserved. At the same time, regular replacement of the inner core layer can build an individual's longitudinal health map. For example, postoperative cancer patients can continuously track the concentration of circulating tumor DNA (ctDNA) through monthly replacement to warn of the risk of recurrence; a large number of recovered inner core layer samples can be used as a database, combined with AI analysis to explore the correlation between biomarkers and diseases, and promote group disease prediction. This design transforms microneedles from one-way consumables into recyclable bioinformation nodes, which not only reduces testing costs (avoiding complex pre-processing), but also provides dynamic data support with high temporal and spatial resolution for precision medicine, ultimately achieving a cross-scale value upgrade from individual health management to group medical research.

[0034] Furthermore, the filter layer is fixed on the hollow layer by electrostatic spinning or screen printing.

[0035] Beneficial effects: The above-mentioned setting gives the filter layer the characteristics of high porosity, ultra-large specific surface area and high-precision mass production. The high porosity ensures efficient filtration and permeability, prevents blockage, and ensures that the interstitial fluid flows smoothly into the inner core layer; the ultra-large specific surface area enhances adsorption capacity, promotes chemical reactions, and is conducive to enriching low-content biomarkers and improving detection sensitivity; high-precision mass production ensures product consistency, reduces production costs, and facilitates quality control. The performance of microneedles in different batches is similar, which is conducive to large-scale promotion and application, and provides reliable and economical technical support for biological monitoring.

[0036] Furthermore, the hollow layer is made of resin or PDMS material and is formed by photolithography or 3D printing.

[0037] Beneficial Effects: Resin or PDMS materials have high strength and hardness, providing sufficient support for the microneedles during the puncture process, ensuring that the microneedles are not easily broken or deformed. Furthermore, PDMS material has excellent biocompatibility. When the hollow layer is made of PDMS material, it can effectively reduce irritation and inflammatory reactions to tissues during the puncture process, improving patient comfort. PDMS material also has good flexibility, which allows the microneedles to better adapt to tissue deformation during puncture, reducing puncture resistance caused by tissue elasticity, and further improving the success rate of puncture.

[0038] Both photolithography and 3D printing can precisely define the position, shape, and size of the microneedles, ensuring high consistency across each hole. During the puncture process, the precise pore structure ensures uniform force distribution across the microneedle, minimizing puncture deviation and improving accuracy and stability. Furthermore, the precise pore structure helps optimize the flow path of interstitial fluid within the microneedle, enhancing collection efficiency and filtration effectiveness.

[0039] Furthermore, the filter layer is made of fiber material and is made through electrostatic spinning or screen printing process; the fiber material includes PVP, PVB, and mulberry silk.

[0040] Beneficial effects: The above-mentioned electrospinning or screen printing process is used to make the filter layer, which can accurately control the size of the pores formed between the fibers, ensuring the effective interception of large molecular interfering substances, such as proteins, cell fragments, etc., under the premise of ensuring mass production, while allowing small molecular target substances to pass smoothly, greatly improving the accuracy of the test results. The fiber material itself has the characteristic of high specific surface area. After PVP, PVB, and mulberry silk are formed into a filter layer through electrospinning or screen printing, the specific surface area is further increased. This high specific surface area enables the filter layer to not only filter the interstitial fluid through physical screening, but also to adsorb some impurities and small molecular target substances. For interstitial fluid with a certain viscosity, the impurities therein may be difficult to completely remove through simple pore screening due to the viscosity. At this time, the adsorption effect of the filter layer can make up for this deficiency, further purify the interstitial fluid, improve the purity of the sample, and provide a more reliable sample basis for subsequent testing.

[0041] Secondly, fiber materials such as PVP, PVB, and mulberry silk have excellent biocompatibility. When microneedles are used to puncture human tissue to collect interstitial fluid, the biocompatibility of the filter layer can reduce tissue irritation and inflammatory responses, improving patient comfort. This is especially true in cases of multiple punctures or long-term wear of microneedles for continuous monitoring. Good biocompatibility can reduce patient discomfort and increase patient acceptance of microneedle testing.

[0042] Furthermore, the inner core layer is made of cotton pulp, bamboo pulp or polymer sponge.

[0043] Beneficial effects: The above-mentioned materials all have rich fiber structures and pores, and can efficiently absorb interstitial fluid. When the microneedle penetrates the tissue, the cotton pulp, bamboo pulp or polymer sponge in the inner core layer can quickly come into contact with the interstitial fluid, and use its porous structure to absorb a large amount of interstitial fluid in a short time, providing sufficient samples for subsequent testing, and meeting the high efficiency requirements of dynamic collection of interstitial fluid. In addition, the above-mentioned materials have good tolerance for various components in the interstitial fluid and can stably maintain the sample. After adsorbing the interstitial fluid, its fiber structure can fix small molecule target substances, proteins and other components to prevent the loss or uneven distribution of sample components due to shaking or the passage of time. This is especially important for some interstitial fluid samples that require long-term transportation or staged testing, which ensures the stability and reliability of the sample in the subsequent processing process and improves the accuracy of the test results.

[0044] Secondly, both cotton and bamboo pulp are derived from natural plants and possess excellent biocompatibility. When the inner core layer comes into direct contact with human tissue for extended periods, it can significantly reduce the risk of immune responses and inflammation. Furthermore, the raw materials for cotton and bamboo pulp are widely available. Cotton and bamboo are cultivated in large quantities worldwide, ensuring an abundant supply. This significantly reduces the production cost of the inner core layer, significantly reducing the manufacturing cost of microneedles compared to some rare or expensive adsorbent materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 4 is a cross-sectional view of a microneedle according to an embodiment of the present invention.

[0046] Figure 2 Schematic diagram of the hollow layer structure in the microneedle of the embodiment of the present invention Figure 1 .

[0047] Figure 3 Schematic diagram of the hollow layer structure in the microneedle of the embodiment of the present invention Figure 2 .

[0048] Figure 4 This is a real-time blood sugar monitoring chart for 24 hours.

[0049] Figure 5 This is a real-time blood sugar monitoring chart for 7 consecutive days.

[0050] Figure 6 Schematic diagram of the patient's skin recovery after the microneedles are removed.

[0051] The reference numerals in the drawings of the specification include: inner core layer 1 , hollow layer 2 , filter layer 3 , hollow hole 4 . DETAILED DESCRIPTION

[0052] The following is further described in detail through specific implementation methods:

[0053] The embodiment is basically as shown in the attached Figure 1-Figure 3 As shown:

[0054] A porous hollow microneedle that can dynamically collect interstitial fluid has a height of 600-1300μm and a bottom diameter of 600-1000μm. The microneedle comprises an inner core layer 1, a hollow layer 2, and a filter layer 3, which are sequentially arranged from the inside out, and all three layers have a conical structure. The inner core layer 1 is made of a material with adsorption properties and is used to adsorb and collect interstitial fluid. The hollow layer 2 is used to support the hardness of the microneedle and realize the puncture function. The hollow layer 2 is provided with a plurality of hollow holes 4. The filter layer 3 is provided with a plurality of filter holes. The filtration area of ​​a single filter hole is smaller than the hollow area of ​​a single hollow hole 4. The filter layer 3 is used to filter interfering substances or pollutants in the interstitial fluid, such as albumin, immunoglobulin, and stratum corneum debris, and then allow small molecule target substances therein to enter the microneedle.

[0055] The total area of ​​the hollow holes 4 accounts for 10%-15% of the area of ​​the hollow layer 2. This ratio effectively reduces the risk of clogging due to the viscosity of the interstitial fluid while ensuring the inflow of interstitial fluid. It also effectively avoids the hollow area being too large, which leads to a decrease in the overall hardness of the microneedles and the risk of breakage during use. Secondly, although the filter layer 3 will filter out some impurities in advance, some fine particles or sticky substances in the interstitial fluid may still remain. If the area of ​​the hollow hole 4 is too large, these residual impurities are more likely to accumulate in the hole, causing blockage and affecting the collection effect.

[0056] Therefore, the aforementioned area ratio of the hollow holes 4 not only meets the interstitial fluid inflow requirements, but also leverages the flow characteristics within the microneedles to allow filtered interstitial fluid to quickly pass through the hollow holes 4, reducing the chance of impurities accumulating and accumulating within the holes, avoiding blockage and interruption of the collection process, and ensuring continuous and stable collection. This effectively maintains the unobstructed flow of interstitial fluid even during prolonged collection processes.

[0057] like Figure 1 、 Figure 2 As shown, the hollow holes 4 are distributed at the end of the hollow layer 2 with a larger diameter, which can provide a relatively large gathering space for the interstitial fluid and reduce the flow resistance of the interstitial fluid during the transfer from the filter layer 3 to the hollow layer 2, thereby promoting the interstitial fluid to pass through the hollow layer 2 more smoothly and accelerate the flow into the inner core layer 1, thereby improving the collection speed and efficiency, and ensuring that a sufficient amount of interstitial fluid sample can be obtained for detection in a relatively short time.

[0058] Among them, the shape of the hollow hole 4 is circular, polygonal or V-shaped, which makes the hollow hole 4 and the microneedle design flexible, and the circular, polygonal or V-shaped holes can effectively promote the interstitial fluid to flow into the microneedle inner core layer 1, uniformly converge through the circular holes, increase the contact area through the polygonal holes, and accelerate the drainage through the V-shaped holes, all of which overcome the flow obstacles caused by the viscosity of the interstitial fluid to a certain extent, ensure the smooth, continuous and rapid inflow of the interstitial fluid, improve the collection efficiency, and meet the sample volume requirements of the test.

[0059] When the hollow hole 4 is V-shaped, Figure 2 As shown, the angle of the V-shaped tip is 30°-50°. This angle is designed to ensure that the hollow hole 4 has sufficient hollow area to allow interstitial fluid to pass through, so as to prevent the interstitial fluid from having excessive resistance when passing through the hollow hole 4 due to its viscosity, thereby hindering the collection of interstitial fluid and affecting the accuracy and efficiency of subsequent detection.

[0060] The pores in filter layer 3 have a pore size of 100nm-500nm, allowing precise screening of substances in the interstitial fluid based on molecular size. In interstitial fluid, interfering substances such as large molecular proteins and cell debris are typically much larger than 100 nanometers, while some disease-related small molecule targets, such as specific small molecule metabolites, are often 50-100 nanometers or smaller. This pore size design effectively intercepts large interfering substances, preventing them from passing through filter layer 3 and entering the microneedle interior, thereby greatly improving the accuracy of subsequent testing and reducing test result deviations caused by impurity interference.

[0061] Preferably, the inner core layer 1 is detachably connected to the hollow layer 2, for example, clamped in the hollow layer 2 by interference fit. On the one hand, after the microneedle is used, the inner core layer 1 can be taken out and the hollow layer 2 can be disinfected separately. On the other hand, the damaged inner core layer 1 can be replaced so that the microneedle can continue to be used, and the replaced inner core layer 1 can be deeply integrated into the "diagnosis-treatment-recovery-analysis" closed-loop chain to achieve efficient utilization of biomarkers and provide dynamic data support with high temporal and spatial resolution for precision medicine.

[0062] The filter layer 3 is fixed on the hollow layer 2 by electrospinning or screen printing, so that the filter layer 3 has the characteristics of high porosity, ultra-large specific surface area and high-precision mass production, thereby improving the reliability of biological monitoring.

[0063] In this embodiment, the inner core layer 1 is made of cotton pulp, bamboo pulp or polymer sponge. The above materials have rich fiber structures and pores, which can efficiently absorb interstitial fluid. When the microneedle penetrates the tissue, the inner core layer 1 can quickly come into contact with the interstitial fluid, and use its porous structure to absorb a large amount of interstitial fluid in a short period of time, providing sufficient samples for subsequent testing, and meeting the high efficiency requirements for dynamic collection of interstitial fluid. Since the microneedle is mainly used to monitor relevant information of cancer patients in real time and needs to be inserted into the body for a long time (1 month to half a year), cotton pulp, bamboo pulp or polymer sponge all have good biocompatibility, reducing the risk of inflammatory reactions in patients who wear them for a long time. In addition, cotton pulp and bamboo pulp are widely planted and easily available, making the overall cost of the microneedle low and affordable for patients.

[0064] The hollow layer 2 is made of resin or PDMS material, produced by photolithography or 3D printing. Resin or PDMS materials have high strength and hardness, providing sufficient support for the microneedles during the puncture process, ensuring that the microneedles are not easily broken or deformed. Furthermore, PDMS material has excellent biocompatibility. When PDMS is used for the hollow layer 2, it can effectively reduce irritation and inflammatory reactions to tissues during the microneedle puncture process, thereby improving patient comfort.

[0065] Both photolithography and 3D printing can precisely define the position, shape, and size of the hollow hole 4 and ensure that each hole is highly consistent, ensuring that the microneedle is evenly stressed during the puncture process, reducing puncture deviation and improving puncture accuracy and stability. At the same time, the precise hollow hole 4 structure helps optimize the flow path of interstitial fluid in the microneedle, improving collection efficiency and filtration effect.

[0066] The filter layer 3 is made of fiber material and is made through an electrospinning process; the fiber materials include PVP, PVB, and mulberry silk. The electrospinning process is used to make the filter layer 3, which can accurately control the size of the pores formed between the fibers, ensuring the effective interception of large molecular interfering substances such as proteins, cell fragments, etc., while allowing small molecular target substances to pass smoothly, greatly improving the accuracy of the test results. Secondly, fiber materials such as PVP, PVB, and mulberry silk have good biocompatibility. When microneedles are used to puncture human tissue to collect interstitial fluid, the biocompatibility of the filter layer 3 can reduce irritation and inflammatory response to the tissue and improve the patient's comfort. Especially in the case of multiple punctures or long-term wearing of microneedles for continuous monitoring, good biocompatibility can reduce the patient's discomfort and increase the patient's acceptance of microneedle testing.

[0067] During specific use, the conical bottom of the microneedle is also connected to a base, and a biosensor for analyzing the collected interstitial fluid is installed in the base. When the microneedle enters the human tissue, the interstitial fluid flows through the microneedle. Due to the concentration difference and the adsorption of the inner core layer 1, the small molecule target substances in the interstitial fluid pass through the filter side and the hollow layer 2 in turn into the inner core layer 1, and then the biosensor senses a certain type of specific small molecule target substance to achieve biological monitoring.

[0068] Table 1 below shows the relevant data of using the hollow microneedle of this solution to collect and monitor a certain type of small molecule target substances in interstitial fluid.

[0069]

[0070] From Table 1 and Figure 4 、 Figure 5 、 Figure 6It can be seen that the microneedles of this solution can not only achieve continuous monitoring, but also reduce damage to the patient's body. After the microneedles are removed, the patient's skin can be fully recovered in about 15 minutes, and there will be no subsequent secondary infection, achieving minimally invasive and painless biological monitoring. In addition, the sample capacity is richer, and the sample collection success rate is significantly higher than that of traditional puncture collection. More importantly, during the collection and monitoring process, the damage to substances of different molecular weights is relatively small. The average spike recovery rate of different molecular weights is significantly improved compared to traditional puncture collection. The spike recovery rate is within 90%-110%, effectively ensuring the high integrity of tissue materials, ensuring that there is basically no loss or degradation, so that the sample concentration meets the monitoring requirements, and improves the accuracy and sensitivity of biological monitoring.

[0071] The above is only an embodiment of the present invention, and the common knowledge such as the specific technical solutions and / or characteristics in the solution are not described in detail here. It should be pointed out that for those skilled in the art, without departing from the technical solution of the present invention, several variations and improvements can be made, which should also be regarded as the scope of protection of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the description can be used to interpret the content of the claims.

Claims

1. A porous hollow microneedle capable of dynamically collecting interstitial fluid, characterized by: It includes an inner core layer, a hollow layer and a filter layer which are arranged in sequence from the inside to the outside, and all of the three are conical structures; the inner core layer is made of a material with adsorption properties and is used to adsorb and collect interstitial fluid; the hollow layer is used to support the hardness of the microneedle and realize the puncture function, and a number of hollow holes are provided on the hollow layer, and a number of filter holes are provided on the filter layer. The filtration area of ​​a single filter hole is smaller than the hollow area of ​​a single hollow hole. The filter layer is used to filter interfering substances or pollutants in the interstitial fluid, so that the small molecule target substances therein enter the microneedle.

2. The porous hollow microneedle capable of dynamically collecting interstitial fluid according to claim 1, characterized in that: The height of the microneedles is 600-1300 μm and the bottom diameter is 600-1000 μm.

3. The porous hollow microneedle capable of dynamically collecting interstitial fluid according to claim 1 or 2, characterized in that: The total area of ​​the hollow holes accounts for 10%-15% of the area of ​​the hollow layer, and the hollow holes are distributed at the end of the hollow layer with a larger diameter.

4. The porous hollow microneedle capable of dynamically collecting interstitial fluid according to claim 3, characterized in that: The shape of the hollow hole is circular, polygonal or V-shaped. When the hollow hole is V-shaped, the angle of the V-shaped tip is 30°-50°.

5. The porous hollow microneedle capable of dynamically collecting interstitial fluid according to claim 1 or 2, characterized in that: The pore size of the filter holes on the filter layer is 100nm-500nm.

6. The porous hollow microneedle capable of dynamically collecting interstitial fluid according to claim 5, characterized in that: The inner core layer is detachably connected to the hollow layer.

7. The porous hollow microneedle capable of dynamically collecting interstitial fluid according to claim 5, characterized in that: The filter layer is fixed on the hollow layer by electrostatic spinning or screen printing.

8. The porous hollow microneedle capable of dynamically collecting interstitial fluid according to claim 4, characterized in that: The hollow layer is made of resin or PDMS material and is formed by photolithography or 3D printing.

9. The porous hollow microneedle capable of dynamically collecting interstitial fluid according to claim 5, characterized in that: The filter layer is made of fiber material and is made through electrostatic spinning or screen printing technology; the fiber material includes PVP, PVB, and mulberry silk.

10. The porous hollow microneedle capable of dynamically collecting interstitial fluid according to claim 6, characterized in that: The inner core layer is made of cotton pulp, bamboo pulp or polymer sponge.

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