Oral ulcer intelligent microneedle patch based on guanosine vesicle slow release and preparation method thereof
By designing a smart microneedle patch for sustained-release guanosine vesicles in oral ulcers, the problems of rapid drug loss and lack of monitoring were solved, enabling targeted drug delivery and real-time monitoring of ulcer healing, thus improving treatment efficacy and patient compliance.
Patent Information
- Application Number
- CN202511575442.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-31
- Publication Date
- 2026-02-06
AI Technical Summary
Existing treatments for oral ulcers suffer from problems such as rapid drug loss, barrier blockage, and lack of monitoring. Traditional drug delivery methods make it difficult to achieve long-term drug retention on the ulcer surface and real-time monitoring of changes in the ulcer microenvironment.
A smart microneedle patch for oral ulcers based on guanosine vesicle sustained release is designed, comprising a flexible base layer, a microneedle array layer, a treatment module, and a monitoring module. The microneedles can penetrate the pseudomembrane to deliver drugs, and the monitoring module monitors the ulcer microenvironment in real time, integrating multi-parameter sensors and biosensors.
It achieves targeted drug delivery and long-lasting release, improves drug utilization, provides real-time monitoring data on ulcer healing, and enhances treatment precision and patient compliance.
Smart Images
Figure CN121466476A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of drug development technology, and more specifically, to a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release and its preparation method. Background Technology
[0002] Oral ulcers, also known as recurrent aphthous stomatitis (RAS), are a common oral mucosal disease. They are characterized by pain and recurrence, severely impacting patients' eating and quality of life.
[0003] Currently, the treatment of oral ulcers aims to reduce cost, reduce inflammation, relieve pain, and promote healing. Commonly used medications include corticosteroids, antibiotics, and local anesthetics. However, traditional administration methods (such as gels, lozenges, and films) have serious drawbacks:
[0004] Rapid drug loss: The moist oral environment, coupled with the continuous rinsing effect of saliva and the mechanical movement of the tongue, makes it difficult for topical medications to remain on the ulcer surface for an extended period, resulting in extremely low bioavailability.
[0005] Barrier barrier: A "pseudomembrane" composed of necrotic tissue and fibrin often forms on the surface of the ulcer. This physical barrier greatly hinders the penetration of drugs into the deeper lesion tissue.
[0006] Lack of monitoring: During treatment, patients and doctors cannot understand changes in the ulcer microenvironment in real time (such as infection, degree of inflammation, healing progress), which makes it impossible to adjust the treatment plan in a timely manner.
[0007] Microneedle technology offers a new approach to overcome these shortcomings. Microneedles can penetrate the pseudomembrane in a minimally invasive manner, delivering drugs directly to the submucosa. However, most existing therapeutic microneedle patches are single-function, limited to drug delivery and unable to combine treatment with monitoring. Therefore, there is an urgent need to develop a novel smart patch that can achieve precise and long-lasting drug release at the lesion site, while also monitoring the healing status of ulcers in real time. Summary of the Invention
[0008] The purpose of this invention is to provide a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release and its preparation method. This smart microneedle patch can penetrate the pseudomembrane of oral ulcers to achieve targeted drug delivery and monitoring of multiple key physiological parameters of the ulcer microenvironment, thus realizing "integrated diagnosis and treatment".
[0009] The above-mentioned technical objective of the present invention is achieved through the following technical solution: a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release, comprising the following five parts:
[0010] The smart microneedle patch includes:
[0011] The flexible substrate layer serves as the main support for the patch and integrates the circuitry of the monitoring module.
[0012] The microneedle array layer consists of multiple soluble microneedles disposed on a flexible substrate layer, which are capable of penetrating the oral mucosa;
[0013] The treatment module includes vesicles encapsulating guanosine, which are contained within the tip of the microneedle for continuous release of guanosine after the microneedle dissolves.
[0014] The monitoring module includes a multi-parameter sensor array integrated on the flexible substrate layer. Its sensing electrodes are connected to the microneedle array or located at the base of the microneedles, for contacting interstitial fluid and monitoring at least two physiological parameters of the ulcer microenvironment in real time.
[0015] The backing layer, located on the outermost layer of the smart microneedle patch, enhances conductivity, thermal conductivity, and mechanical strength. It integrates biosensors and transmits biological signals to the monitoring module through the conductive material of the backing layer. The backing layer is not only a physical support but also a key layer of the smart microneedle patch.
[0016] The present invention is further configured such that the microneedle patch is prepared by the following method:
[0017] S1. Preparation of Treatment Module:
[0018] (1) Add 2 μg of α-galactosylceramide to 25 μL of a mixed ethanol solution of LD022, DOTAP, DMG-PEG2000 and cholesterol in a molar ratio of 15:42:41.5:1.5, and then add it to 75 μL of sodium citrate buffer containing 10 μg of Poly(I:C) at pH=4, fixing the charge ratio at 10 / 1; dialyze the sample at 4°C for 2 hours using PBS buffer solution at pH=7.4, collect the sample, and obtain lung-targeting LNP containing α-galactosylceramide and Poly(I:C), labeled as αGP, i.e. vesicle;
[0019] The structure of the vesicle is as follows:
[0020] ;
[0021] (2) GBG hydrogel was synthesized by one-pot method: 0.145 mmol guanosine and 0.0725 mmol H3BO3 aqueous solution were added to 4.5 mL of ultrapure water, and after sonication for 30 s, the solution was heated in a 90 ℃ drying oven until the guanosine was completely dissolved; then 0.0725 mmol KOH aqueous solution was added and the reaction was carried out for 20 minutes. When the reaction was completed, the solution was cooled to room temperature to form a stable GBG hydrogel.
[0022] S2. Inject ultrapure water into a microneedle mold made of PDMS material and sonicate for 10 minutes to ensure that each needle cavity is completely filled. Then, place the water-filled mold in a 90 ℃ drying oven for 5 minutes to preheat, taking care to prevent the water from evaporating completely. Subsequently, remove the water from the surface of the mold grooves, mix GBG hydrogel preparation solution and αGP, and add it to the sonicated mold. Then, place the mold at 90 ℃ for 10 minutes to allow the GBG hydrogel preparation solution to fully fill the needle tip through water penetration, so that the guanosine vesicles are encapsulated inside the microneedle tip. Subsequently, transfer the mold to a 25 ℃ drying oven and dry for 1 hour to obtain the microneedle array layer.
[0023] S3. While the hydrogel in S2 is not completely dry, apply 0.8 ml of 5% HA solution to the surface using a pipette to form a backing layer;
[0024] S4. Press the prepared monitoring module onto the substrate solution of the microneedle array layer that is not completely dried to make the two bond firmly. After the material is completely dried, remove the mold to obtain the final smart microneedle patch.
[0025] The present invention is further configured such that the monitoring module consists of a pH sensor containing an iridium oxide electrode, a temperature sensor containing a metal thermistor, and a ROS or MMP sensor having a processed functionalized gold working electrode.
[0026] The invention is further configured such that the monitoring module also includes a microprocessor, a wireless communication unit, and a smartphone.
[0027] The present invention is further configured to: fabricate the multi-parameter sensor array by screen printing on a flexible substrate to prepare multi-parameter sensing electrodes and reference electrodes, and integrate an NFC chip.
[0028] The present invention is further configured such that the backing layer may also be made of PDMS material.
[0029] In summary, the present invention has the following beneficial effects:
[0030] 1. Precise targeting and efficient penetration: The microneedle design can penetrate the ulcer pseudomembrane, delivering drugs directly to the depths of the lesion, significantly improving drug utilization.
[0031] 2. Long-acting sustained-release therapy: Guanosine (which has the potential to reduce inflammation and promote tissue repair) is encapsulated in vesicles, enabling slow and sustained release at the ulcer site, thus prolonging the therapeutic window.
[0032] 3. Integrated Intelligent Diagnosis and Treatment: For the first time, multi-parameter monitoring functions are integrated into the oral ulcer microneedle patch. By monitoring key indicators such as pH (reflecting inflammation / infection) and temperature (reflecting infection) in real time, objective data is provided for assessing the healing process and guiding personalized medication.
[0033] 4. Convenient to use and highly compliant: The patch has good mucosal adhesion, allowing patients to use it themselves and read data via mobile phones and other devices, greatly improving patient compliance. Attached Figure Description
[0034] Figure 1 These are actual photographs of mouse experiments in embodiments of the present invention;
[0035] Figure 2 These are the statistical analysis results of the relative ulcer areas of different groups in the embodiments of the present invention;
[0036] Figure 3 These are schematic diagrams, actual photographs, and actual photographs of the patch in use in embodiments of the present invention. Detailed Implementation
[0037] The following is in conjunction with the appendix Figure 1-3 The present invention will be described in further detail below.
[0038] Example 1: A smart microneedle patch for oral ulcers based on guanosine vesicle sustained release
[0039] The oral ulcer smart microneedle patch based on guanosine vesicle sustained release provided in this embodiment includes the following five parts:
[0040] Flexible backing layer: Serves as the main support for the patch and integrates the circuitry of the monitoring module;
[0041] Microneedle Array Layer: Composed of multiple soluble microneedles disposed on a flexible substrate layer, which can penetrate the oral mucosa;
[0042] Therapeutic Module: Contains vesicles encapsulating guanosine, which are loaded inside the tip of the microneedle to enable the continuous release of guanosine after the microneedle dissolves.
[0043] Monitoring Module: Contains a multi-parameter sensor array integrated on the flexible substrate. Its sensing electrodes are connected to the microneedle array or located at the base of the microneedles. It is used to contact the interstitial fluid and monitor at least two physiological parameters of the ulcer microenvironment in real time.
[0044] The backing layer, located on the outermost layer of the smart microneedle patch, enhances conductivity, thermal conductivity, and mechanical strength. It integrates biosensors and transmits biological signals to the monitoring module through the conductive material of the backing layer. The backing layer is not only a physical support but also a key layer of the smart microneedle patch.
[0045] Example 2: A method for preparing a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release.
[0046] S1. Preparation of Treatment Module:
[0047] (1) Add 2 μg of α-galactosylceramide to 25 μL of a mixed ethanol solution of LD022, DOTAP, DMG-PEG2000 and cholesterol in a molar ratio of 15:42:41.5:1.5, and then add it to 75 μL of sodium citrate buffer containing 10 μg of Poly(I:C) at pH=4, fixing the charge ratio at 10 / 1; dialyze the sample at 4°C for 2 hours using PBS buffer solution at pH=7.4, collect the sample, and obtain lung-targeting LNP containing α-galactosylceramide and Poly(I:C), labeled as αGP, i.e. vesicle;
[0048] The structure of the vesicle is as follows:
[0049] ;
[0050] (2) GBG hydrogel was synthesized by one-pot method: 0.145 mmol guanosine and 0.0725 mmol H3BO3 aqueous solution were added to 4.5 mL of ultrapure water, and after sonication for 30 s, the solution was heated in a 90 ℃ drying oven until the guanosine was completely dissolved; then 0.0725 mmol KOH aqueous solution was added and the reaction was carried out for 20 minutes. When the reaction was completed, the solution was cooled to room temperature to form a stable GBG hydrogel.
[0051] S2. Inject ultrapure water into a microneedle mold made of PDMS material and sonicate for 10 minutes to ensure that each needle cavity is completely filled. Then, place the water-filled mold in a 90 ℃ drying oven for 5 minutes to preheat, taking care to prevent the water from evaporating completely. Subsequently, remove the water from the surface of the mold grooves, mix GBG hydrogel preparation solution and αGP, and add it to the sonicated mold. Then, place the mold at 90 ℃ for 10 minutes to allow the GBG hydrogel preparation solution to fully fill the needle tip through water penetration, so that the guanosine vesicles are encapsulated inside the microneedle tip. Subsequently, transfer the mold to a 25 ℃ drying oven and dry for 1 hour to obtain the microneedle array layer.
[0052] S3. While the hydrogel in S2 is not completely dry, apply 0.8 ml of 5% HA solution to the surface using a pipette to form a backing layer;
[0053] Furthermore, its conductivity can be further improved when the backing layer is replaced with PDMS material.
[0054] S4. The prepared monitoring module is pressed onto the substrate solution of the partially dried microneedle array layer to ensure a firm bond. After the material is completely dried, the mold is removed to obtain the final smart microneedle patch. The monitoring module consists of a pH sensor with an iridium oxide electrode, a temperature sensor with a metal thermistor, and a ROS or MMP sensor with a treated functionalized gold working electrode. The monitoring module also includes a microprocessor, a wireless communication unit, and a smartphone.
[0055] The monitoring module includes a multi-parameter sensor array. The multi-parameter sensor array is fabricated by screen printing multi-parameter sensing electrodes and reference electrodes on a flexible substrate, and an NFC chip is integrated therein.
[0056] Example 3. Application of a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release.
[0057] A wild-type mouse model of oral ulcer induced by acetic acid was established. Mice were divided into a control group, a dosage form control group, and a guanosine vesicle microneedle group. Treatment with acetic acid was performed on days 1, 3, 5, and 7, and the wounds were photographed simultaneously. Figure 1 As shown, the white dashed lines represent the ulcer boundaries. Results showed that, compared to the control group and the dosage form control group, the guanosine vesicle microneedle group exhibited a continuous reduction in wound area at each time point, with epithelialization essentially completed by day seven.
[0058] The relative ulcer areas of different groups were statistically analyzed using ImageJ software, and the results are as follows: Figure 2As shown in the figure, compared with the control group, the guanosine vesicle microneedling group had a higher overall ulcer healing rate on days 3–7, and the healing speed was significantly faster, with statistical significance (*P < 0.05), suggesting that the guanosine vesicle microneedling group can promote ulcer healing speed and accelerate wound healing.
[0059] This specific embodiment is merely an explanation of the present invention and is not intended to limit the invention. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they are within the scope of the claims of the present invention.
Claims
1. A smart microneedle patch for oral ulcers based on guanosine vesicle sustained release, characterized in that: The smart microneedle patch includes: The flexible substrate layer serves as the main support for the patch and integrates the circuitry of the monitoring module. The microneedle array layer consists of multiple soluble microneedles disposed on a flexible substrate layer, which are capable of penetrating the oral mucosa; The treatment module includes vesicles encapsulating guanosine, which are contained within the tip of the microneedle for continuous release of guanosine after the microneedle dissolves. The monitoring module includes a multi-parameter sensor array integrated on the flexible substrate layer. Its sensing electrodes are connected to the microneedle array or located at the base of the microneedles, for contacting interstitial fluid and monitoring at least two physiological parameters of the ulcer microenvironment in real time. The backing layer, located on the outermost layer of the smart microneedle patch, enhances conductivity, thermal conductivity, and mechanical strength. It integrates biosensors and transmits biological signals to the monitoring module through the conductive material of the backing layer. The backing layer is not only a physical support but also a key layer of the smart microneedle patch.
2. The method for preparing a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release according to claim 1, characterized in that: The microneedle patch is prepared as follows: S1. Preparation of Treatment Module: (1) Add 2 μg of α-galactosylceramide to 25 μL of a mixed ethanol solution of LD022, DOTAP, DMG-PEG2000 and cholesterol in a molar ratio of 15:42:41.5:1.5, and then add it to 75 μL of sodium citrate buffer containing 10 μg of Poly(I:C) at pH=4, fixing the charge ratio at 10 / 1; dialyze the sample at 4°C for 2 hours using PBS buffer solution at pH=7.4, collect the sample, and obtain lung-targeting LNP containing α-galactosylceramide and Poly(I:C), labeled as αGP, i.e. vesicle; The structure of the vesicle is as follows: ； (2) One-pot synthesis of GBG hydrogel: 0.145 mmol of guanosine and 0.0725 mmol of H3BO3 aqueous solution were added to 4.5 mL of ultrapure water, sonicated for 30 s, and then heated in a 90 ℃ drying oven until the guanosine was completely dissolved; then 0.0725 mmol of KOH aqueous solution was added. The reaction was carried out for 20 minutes. When the reaction was complete, the solution was cooled to room temperature to form a stable GBG hydrogel. S2. Inject ultrapure water into a microneedle mold made of PDMS material and sonicate for 10 minutes to ensure that each needle cavity is completely filled. Then, place the water-filled mold in a 90 ℃ drying oven for 5 minutes to preheat, taking care to prevent the water from evaporating completely. Subsequently, remove the water from the surface of the mold grooves, mix GBG hydrogel preparation solution and αGP, and add it to the sonicated mold. Then, place the mold at 90 ℃ for 10 minutes to allow the GBG hydrogel preparation solution to fully fill the needle tip through water penetration, so that the guanosine vesicles are encapsulated inside the microneedle tip. Subsequently, transfer the mold to a 25 ℃ drying oven and dry for 1 hour to obtain the microneedle array layer. S3. While the hydrogel in S2 is not completely dry, apply 0.8 ml of 5% HA solution to the surface using a pipette to form a backing layer; S4. Press the prepared monitoring module onto the substrate solution of the microneedle array layer that is not completely dried to make the two bond firmly. After the material is completely dried, remove the mold to obtain the final smart microneedle patch.
3. The method for preparing a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release according to claim 2, characterized in that: The monitoring module consists of a pH sensor with an iridium oxide electrode, a temperature sensor with a metal thermistor, and a ROS or MMP sensor with a treated functionalized gold working electrode.
4. The method for preparing a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release according to claim 3, characterized in that: The monitoring module also includes a microprocessor, a wireless communication unit, and a smartphone.
5. The method for preparing a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release according to claim 3, characterized in that: Fabrication of the multi-parameter sensor array: Multi-parameter sensing electrodes and reference electrodes are fabricated on a flexible substrate by screen printing, and an NFC chip is integrated.
6. The method for preparing a smart microneedle patch for oral ulcers based on guanosine vesicle sustained release according to claim 2, characterized in that: The backing layer can also be made of PDMS material.