A polyglycolide porous microneedle array with porosity gradient and its preparation process

Abstract

The present application relates to the field of medical devices and specifically discloses a polyglycolide porous microneedle array with a porosity gradient and a preparation process. The porous microneedle array comprises a base and a plurality of porous microneedles arrayed on the base. The porous microneedles comprise a needle body and a needle tip, and the base, needle body, and needle tip are integrally formed. The porous microneedle array has a porosity gradient, with the porosity gradually increasing from the needle tip to the needle body, resulting in the porous microneedle array having both high needle tip strength and good water absorption performance, and the microneedle array is biodegradable. A preparation process for a polyglycolide porous microneedle array with a porosity gradient comprises: subjecting polyglycolide particles to heat pressing and air quenching to obtain a low-crystallinity polyglycolide film; dissolving the low-crystallinity polyglycolide film in hexafluoroisopropanol and injecting it into a microneedle array negative mold; and directionally evaporating the hexafluoroisopropanol to obtain a porous microneedle array with a porosity gradient. The process is simple and conducive to large-scale production.

Description

Technical Field

[0001] The present application relates to the field of medical devices, and in particular to a polyglycolide porous microneedle array with a porosity gradient and a preparation process thereof. Background Art

[0002] The interior of a porous microneedle array contains an interconnected pore structure. After puncturing the skin, it can use the capillary effect to absorb the interstitial fluid of the organism's skin, transfer it to the sensor, and output the biomarker concentration results. It is a feasible solution for physiological information detection. Currently, common materials for preparing porous microneedle arrays are silicon, metals, and polymers. Because microneedles need to pierce the human skin barrier and penetrate deep into the epidermis during application, in order to avoid the health risks caused by structural shedding, the use of biodegradable materials to prepare porous microneedle arrays has good application prospects. In this context, polyglycolide acid (PGA), a polymer material that has been verified in clinical applications, has attracted much attention due to its excellent biocompatibility and degradability.

[0003] Existing biodegradable porous microneedles are mostly prepared using pore-forming agent technology. This technology forms a pore structure in the material by adding pore-forming agents. However, there are problems such as pore-forming agent residue, difficult to control the pore structure, and high requirements for process parameter control. These problems greatly affect the performance stability and product yield of the porous microneedle array, hindering its large-scale production and industrialization.

[0004] On the other hand, the performance of the porous microneedle array is affected by the porosity. When the porosity is high, the water absorption performance of the microneedle is better, but the strength of the microneedle will be reduced, especially the reduced strength of the needle tip, which can easily cause the needle tip to break under pressure, affecting the puncture performance of the microneedle; when the porosity is low, although the strength of the microneedle can be guaranteed, the water absorption performance will be reduced. When the porous microneedle array is used in a biosensor, it is not conducive to the rapid absorption and transfer of interstitial fluid. Summary of the Invention

[0005] In order to make the porous microneedle array have both high needle tip strength and good water absorption performance, the present application provides a polyglycolide porous microneedle array with a porosity gradient and a preparation process.

[0006] The present application provides a polyglycolide porous microneedle array with a porosity gradient and a preparation process using the following technical solutions:

[0007] A process for preparing a polyglycolide porous microneedle array with a porosity gradient comprises the following steps:

[0008] Preparation of a low-crystallinity polyglycolide film: subjecting polyglycolide particles to hot pressing and air quenching treatment to obtain a low-crystallinity polyglycolide film;

[0009] preparing a polyglycolide-hexafluoroisopropanol solution: dissolving a low-crystallinity polyglycolide film in hexafluoroisopropanol to obtain a polyglycolide-hexafluoroisopropanol solution;

[0010] Prepare the template: Prepare a positive mold of the microneedle array by 3D printing, cover the surface of the negative mold material on the positive mold of the microneedle array, and obtain the negative mold of the microneedle array after demoulding;

[0011] Preparation of porous microneedle array: A polyglycolide-hexafluoroisopropanol solution is injected into the negative mold of the microneedle array, and then the hexafluoroisopropanol is directionally volatilized, with the hexafluoroisopropanol in the needle body volatilizing first and the hexafluoroisopropanol in the needle tip volatilizing later; after demolding, a polyglycolide porous microneedle array with a porosity gradient is obtained, and the porosity gradually increases from the needle tip to the needle body.

[0012] Furthermore, in the step of preparing the low-crystallinity polyglycolide film, the hot pressing method includes: wrapping the polyglycolide particles in aluminum foil and placing the foil in a hot press, heating the foil to melt the polyglycolide particles, and then maintaining the temperature and applying pressure.

[0013] Furthermore, in the step of preparing the low-crystallinity polyglycolide film, the air quenching treatment method includes: after the hot pressing treatment, taking out the aluminum foil wrapped with polyglycolide from the hot press, cooling it at room temperature, and peeling it from the aluminum foil to obtain the low-crystallinity polyglycolide film.

[0014] Furthermore, in the polyglycolide-hexafluoroisopropanol solution, the concentration of polyglycolide is 50-125 mg / mL.

[0015] Furthermore, in the template preparation step, the microneedle array negative mold is subjected to oxygen plasma treatment.

[0016] Furthermore, in the step of preparing the porous microneedle array, the upper portion of the microneedle array female mold is open, and during the directional volatilization of hexafluoroisopropanol, the open end of the microneedle array female mold faces upward and is exposed to the external environment, with the needle tips facing downward.

[0017] Hot pressing compresses polyglycolide particles, each a few millimeters in diameter, into a film hundreds of microns thick, significantly increasing the heat exchange area and enabling rapid cooling in room-temperature air. Furthermore, utilizing the high thermal conductivity of aluminum foil, the polyglycolide film is quenched and cooled in air, blocking the polyglycolide's recrystallization process and thereby reducing its crystallinity, making it more soluble in organic solvents such as hexafluoroisopropanol. Compared to the more common process of reducing crystallinity by high-temperature heating followed by liquid nitrogen quenching, the hot pressing-air quenching process provided by this application uses simple equipment and effectively reduces crystallinity.

[0018] As the hexafluoroisopropanol solvent evaporates, the polyglycolide-hexafluoroisopropanol solution gradually becomes saturated, with a particularly high-saturation region appearing at the solid-liquid-gas boundary. A small amount of polyglycolide precipitates first, becoming crystallization nuclei. Subsequently, the polyglycolide components in the solution precipitate and grow around the crystallization nuclei. Influenced by the semi-crystalline nature of polyglycolide, the growth is undirectional and ultimately exhibits a high-porosity spatial network structure. The higher the polyglycolide concentration, the higher the supersaturation of the solution, resulting in an increase in the number of crystallization nuclei in the solution and an increase in the rate of polyglycolide precipitation. However, the volume of the individual crystallization regions decreases, and the resulting spatial network structure has a low porosity.

[0019] In order to study the relationship between the concentration of polyglycolide-hexafluoroisopropanol solution and the porosity of the polyglycolide porous structure, polyglycolide-hexafluoroisopropanol solutions with polyglycolide concentrations of 50 mg / mL, 75 mg / mL, 100 mg / mL and 125 mg / mL were prepared, and then 100 μL of each solution was dropwise added to the surface of the silicon wafer and placed in a fume hood to allow the hexafluoroisopropanol solvent to evaporate at room temperature.

[0020] Figure 1 The effect of the concentration of polyglycolide-hexafluoroisopropanol solution on the porosity of the porous structure was demonstrated. When the concentration of polyglycolide in the solution gradually increased in the range of 50 mg / mL-125 mg / mL, it was observed that the prepared polyglycolide porous structure showed increasingly dense characteristics, and the porosity gradually decreased from 50.17±2.09% to 10.16±2.58%.

[0021] Therefore, the correlation between the concentration of the polyglycolide-hexafluoroisopropanol solution and the porosity of the polyglycolide porous structure can be utilized. By controlling the volatilization direction of the hexafluoroisopropanol solvent, the concentration of the polyglycolide-hexafluoroisopropanol is continuously increased while the polyglycolide component is continuously precipitated, and a polyglycolide porous structure with a porosity gradient can be prepared, as follows:

[0022] In the steps for preparing a porous microneedle array in this application, the open end of the microneedle array female mold (the side closest to the needle body) is at the top, with the needle tips at the bottom. This allows for directional solvent evaporation, with the solvent at the needle body evaporating first and the solvent at the needle tips evaporating later. The closer to the needle tips, the slower the solvent evaporation rate and the higher the concentration of the residual polyglycolide-hexafluoroisopropanol solution, resulting in a lower porosity in the resulting polyglycolide porous structure. In this way, by controlling the direction of solvent evaporation, a porous microneedle array with a porosity gradient can be prepared.

[0023] The present application also provides a polyglycolide porous microneedle array with a porosity gradient, comprising a base and a plurality of porous microneedles arrayed on the base, wherein the porous microneedles include a needle body and a needle tip, and the base, needle body and needle tip are integrally formed; the porous microneedle array has a porosity gradient, and the porosity gradually increases from the needle tip to the needle body.

[0024] Furthermore, the porosity gradient of the porous microneedles ranges from 7% to 48%.

[0025] The low porosity of the needle tip gives the needle tip higher mechanical strength and makes it easier to penetrate the epidermis of the skin; the high porosity of the needle body gives the microneedle array good water absorption performance.

[0026] Furthermore, the porous microneedles have a micrometer-scale spatial network structure.

[0027] The porous structure obtained by the traditional porogen method usually has uneven pore distribution, which will form unstable points locally and easily collapse when subjected to stress; the pores of the porous microneedles provided in the present application are spatially network-connected, with good mechanical stability and good water absorption performance.

[0028] In summary, this application includes at least one of the following beneficial technical effects:

[0029] The polyglycolide porous microneedle array prepared in this application has a micron-scale spatial network structure and a porosity gradient, with the porosity gradually increasing from the needle tip to the needle body. The low porosity of the needle tip gives the needle tip high mechanical strength, making it easy to pierce the skin epidermis. The high porosity of the needle body gives the microneedle array excellent water absorption performance. When used in a biosensor, it can quickly absorb sufficient interstitial fluid for detection, which is beneficial for improving detection sensitivity and accuracy.

[0030] 2. Because polyglycolide has good biocompatibility and biodegradability, the microneedles can slowly degrade after penetrating the skin. They are non-toxic and harmless and will not cause adverse effects on human health.

[0031] 3. The porous microneedle array preparation method provided in this application has a simple overall process and is conducive to large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the result graph showing the effect of polyglycolide-hexafluoroisopropanol solution concentration on the porosity of the porous structure;

[0033] Figure 2 1 is a flow chart of the preparation process of a polyglycolide porous microneedle array with a porosity gradient in an embodiment of the present application;

[0034] Figure 3Schematic diagram of a polyglycolide porous microneedle array with a porosity gradient in an embodiment of the present application;

[0035] Figure 4 This is a schematic diagram mainly used to illustrate the porous microneedle structure in the embodiments of the present application;

[0036] Figure 5 This is a physical picture of a polyglycolide porous microneedle array with a porosity gradient in an embodiment of the present application;

[0037] Figure 6 is a partial view of a polyglycolide porous microneedle with a porosity gradient in an embodiment of the present application;

[0038] Figure 7 This is a scanning electron microscope image used to demonstrate the spatial network structure of the porous microneedles in the examples of this application;

[0039] Figure 8 2 is a graph showing the pressure-displacement test results of a polyglycolide porous microneedle with a porosity gradient in an embodiment of the present application;

[0040] Figure 9 This is a graph showing the water absorption performance test results of the polyglycolide porous microneedle array with a porosity gradient in an embodiment of the present application.

[0041] Figure numerals: 1, microneedle; 2, base; 3, needle tip; 4, needle body. DETAILED DESCRIPTION

[0042] The following is combined with Figure 1-9 This application is described in further detail.

[0043] The present invention discloses a method for preparing a polyglycolide porous microneedle array having a porosity gradient. Figure 2 The preparation process of the polyglycolide porous microneedle array with a porosity gradient includes the following steps:

[0044] Step 1: preparing a low-crystallinity polyglycolide film: subjecting polyglycolide particles to hot pressing and air quenching treatment to obtain a low-crystallinity polyglycolide film. The specific method includes:

[0045] Take 10×10cm 2 Aluminum foil with a thickness of 20 μm, folded in the center to form 10×5 cm 2 Then, 1 g of polyglycolide particles were weighed and wrapped in aluminum foil so that the particles were evenly distributed.

[0046] The aluminum foil wrapped around the polyglycolide particles was placed on the bottom plate of a hot press preheated to 230°C and heated for 100 seconds to completely melt the polyglycolide particles. The temperature was then maintained and the hot press was operated to apply pressure for 100 seconds. The crystallinity of the prepared polyglycolide film decreased with increasing heat pressure.

[0047] After the hot pressing treatment, the aluminum foil wrapped with the polyglycolide was taken out from the hot press, cooled at room temperature for 15 seconds, and peeled off from the aluminum foil to obtain a low-crystallinity polyglycolide film.

[0048] Step 2: Prepare a polyglycolide-hexafluoroisopropanol (PGA-HFIP) solution: Dissolve the low-crystallinity polyglycolide film in hexafluoroisopropanol (HFIP) to obtain a polyglycolide-hexafluoroisopropanol solution with a concentration of 100 mg / mL.

[0049] Step 3: Prepare a template: Prepare a positive mold of the microneedle array by 3D printing, cover the surface of the negative mold material on the positive mold of the microneedle array, and obtain the negative mold of the microneedle array after demoulding. The specific method includes:

[0050] Step 3-1. Prepare the positive mold of the microneedle array by 3D printing: Draw the microneedle pattern using AUTOCAD. The substrate size is 10 mm × 10 mm. A total of 36 quadrangular pyramidal microneedles (6 × 6) are processed by 3D printing technology to obtain the positive mold of the microneedle array. The spacing between adjacent microneedles is 1 mm. The length and width of the base of a single microneedle are both 480 μm, the height is 900 μm, and the tip angle is 30°.

[0051] Step 3-2, preparation of polydimethylsiloxane (PDMS) negative mold: the silicone rubber matrix and the cross-linking agent are mixed in a ratio of 10:1, and the two components are stirred using a degassing mixer to obtain a mixed PDMS liquid; the microneedle array positive mold is placed in a disposable culture dish with the needle tip facing up, and then the mixed PDMS liquid is evenly poured on the surface of the positive mold; the culture dish containing the positive mold and PDMS is placed in a constant temperature vacuum drying oven, and vacuum is applied to remove all bubbles in the mixture. The degassed PDMS and positive mold are placed in an oven preheated to 85°C and heated at a constant temperature for 30 minutes to solidify the PDMS; after cooling, the positive mold is peeled off from the solidified PDMS to obtain a microneedle array negative mold.

[0052] Step 3-3, oxygen plasma treatment of the microneedle array negative mold: Place the microneedle array negative mold in a plasma cleaning machine, set the plasma power to 120 W, and the treatment time to 150 s to complete the modification.

[0053] Step 4. Prepare a porous microneedle array: inject 100 μL of polyglycolide-hexafluoroisopropanol solution into the microneedle array negative mold, and then place it in a fume hood to allow the hexafluoroisopropanol to evaporate in a direction. The microneedle array negative mold is upright with the open end facing up and the needle tip facing down, so that the hexafluoroisopropanol in the needle body evaporates first and the hexafluoroisopropanol in the needle tip evaporates later; after demolding, a polyglycolide porous microneedle array with a porosity gradient is obtained.

[0054] Reference Figure 3 、 Figure 4 and Figure 5 The polyglycolide porous microneedle array with a porosity gradient includes a base 2 and a plurality of porous microneedles 1 arrayed on the base. The porous microneedles 1 include a needle body 4 and a needle tip 3. The base 2, needle body 4, and needle tip 3 are integrally formed. The porous microneedles 1 are in the shape of a quadrangular pyramid. The base of a single microneedle 1 is 480 μm long and wide, 900 μm high, with a 30° angle. The spacing between adjacent microneedles 1 is 1 mm.

[0055] The polyglycolide porous microneedle array has a porosity gradient, and the porosity increases gradually from the needle tip to the needle body. Figure 6 As shown, in the polyglycolide porous microneedle array with a porosity gradient prepared in this embodiment, the area of ​​the needle body close to the base presents an obvious spatial network structure with a large porosity (48.54±1.06%); the middle area of ​​the needle body presents a relatively small porosity (30.46±3.09%); and the area close to the needle tip presents a lower porosity (7.18±2.33%), and an obvious pore structure can still be observed on the surface of the needle tip.

[0056] The polyglycolide porous microneedle array with a porosity gradient maintains a good spatial network structure to ensure water absorption capacity. The needle tip area, which is the most vulnerable part, is strengthened, allowing it to effectively puncture the skin. The needle body still has a good porosity, so after puncturing the skin, it can efficiently absorb skin interstitial fluid and transfer it to the porous microneedle array base. This improves the problem faced by other technologies such as the pore-forming agent method when preparing porous microneedle arrays, such as insufficient microneedle tip strength, leading to needle tip breakage and subsequent failure to successfully puncture the skin.

[0057] Figure 7 This is a partial scanning electron micrograph of the microneedles in the polyglycolide porous microneedle array with a porosity gradient prepared in this example. It can be observed that the porous microneedles exhibit a complex spatial network structure at the microscopic level. Their morphological characteristics are mainly characterized by interconnected sheet structures and a locally smooth surface. Various irregularly shaped holes are widely distributed within these sheet structures, some of which are approximately circular and have a diameter of approximately 1 μm. The sheet structures and holes are generally distributed relatively evenly. The spatial network structure of the porous microneedles is very conducive to the rapid flow and transmission of skin interstitial fluid along these internal micron-sized channels.

[0058] Figure 8 Figure 2 is a schematic diagram of the pressure-displacement test results for the microneedles in the porous polyglycolide microneedle array with a porosity gradient prepared in this example. The pressure-displacement curve shows a slow, small rise in the initial 0-0.35 mm range. After the displacement exceeds 0.35 mm, the pressure detected by the probe begins to increase rapidly. When the displacement reaches 0.41 mm, the detected pressure fluctuates slightly around 0.51 N. After the displacement exceeds 0.44 mm, the detected pressure rises rapidly until the displacement reaches the set limit of 0.6 mm, at which point the pressure detected by the probe exceeds 12 N, and observation of the microneedle structure reveals that it has broken to one side.

[0059] After repeated experiments and statistical analysis, the microneedles' compressive failure stress was determined to be approximately 0.51 N. According to prior research, a single needle is capable of piercing the skin when it can withstand a pressure greater than 0.1 N. Therefore, the polyglycolide porous microneedles with a porosity gradient proposed in this invention are theoretically capable of piercing the skin.

[0060] Figure 9 : This is a schematic diagram of the water-absorbing performance test results of the polyglycolide porous microneedle array with a porosity gradient prepared in this embodiment. It can be observed that as the amount of water absorbed increases, the color of the base of the porous microneedle array gradually becomes darker. The results show that the porous microneedle array absorbed 1.4 μL, 1.7 μL and 1.8 μL of simulated interstitial fluid at 1 min, 2 min and 3 min, respectively. The above water-absorbing performance test data show that the polyglycolide porous microneedle array with a porosity gradient prepared in this embodiment has good water-absorbing performance and can meet the needs of absorbing interstitial fluid after puncturing the skin. In addition, the porous microneedle array is used as a channel tool for absorbing interstitial fluid from the skin. After other materials are added to its base, it can absorb more interstitial fluid.

[0061] The above are all preferred embodiments of the present application, and are not intended to limit the scope of protection of the present application. Therefore, any equivalent changes made based on the structure, shape, and principle of the present application should be included in the scope of protection of the present application.

Claims

1. A process for preparing a polyglycolide porous microneedle array with a porosity gradient, characterized by: The following steps are involved: Preparation of a low-crystallinity polyglycolide film: subjecting polyglycolide particles to hot pressing and air quenching treatment to obtain a low-crystallinity polyglycolide film; preparing a polyglycolide-hexafluoroisopropanol solution: dissolving a low-crystallinity polyglycolide film in hexafluoroisopropanol to obtain a polyglycolide-hexafluoroisopropanol solution; Prepare the template: Prepare a positive mold of the microneedle array by 3D printing, cover the surface of the negative mold material on the positive mold of the microneedle array, and obtain the negative mold of the microneedle array after demoulding; Preparation of porous microneedle array: A polyglycolide-hexafluoroisopropanol solution is injected into the negative mold of the microneedle array, and then the hexafluoroisopropanol is directionally volatilized, with the hexafluoroisopropanol in the needle body volatilizing first and the hexafluoroisopropanol in the needle tip volatilizing later; after demolding, a polyglycolide porous microneedle array with a porosity gradient is obtained, and the porosity gradually increases from the needle tip to the needle body.

2. The process for preparing a polyglycolide porous microneedle array with a porosity gradient according to claim 1, wherein: In the step of preparing the low-crystallinity polyglycolide film, the hot pressing method includes: wrapping the polyglycolide particles in aluminum foil and placing the foil in a hot press, heating the foil to melt the polyglycolide particles, and then maintaining the temperature and applying pressure.

3. The process for preparing a polyglycolide porous microneedle array with a porosity gradient according to claim 2, wherein: In the step of preparing the low-crystallinity polyglycolide film, the air quenching treatment method includes: after the hot pressing treatment, taking out the aluminum foil wrapped with polyglycolide from the hot press, cooling it at room temperature, and peeling it from the aluminum foil to obtain the low-crystallinity polyglycolide film.

4. The process for preparing a polyglycolide porous microneedle array with a porosity gradient according to claim 1, wherein: In the polyglycolide-hexafluoroisopropanol solution, the concentration of polyglycolide is 50-125 mg / mL.

5. The process for preparing a polyglycolide porous microneedle array with a porosity gradient according to claim 1, wherein: In the template preparation step, the microneedle array negative mold is treated with oxygen plasma.

6. The process for preparing a polyglycolide porous microneedle array with a porosity gradient according to claim 1, wherein: In the step of preparing the porous microneedle array, the upper portion of the microneedle array female mold is open. During the directional volatilization of hexafluoroisopropanol, the open end of the microneedle array female mold faces upward and is exposed to the external environment, with the needle tips facing downward.

7. A polyglycolide porous microneedle array with a porosity gradient, prepared using the process for preparing a polyglycolide porous microneedle array with a porosity gradient according to any one of claims 1 to 6, characterized in that: It includes a base and a plurality of porous microneedles arrayed on the base, wherein the porous microneedles include a needle body and a needle tip, and the base, needle body and needle tip are integrally formed; the porous microneedle array has a porosity gradient, and the porosity gradually increases from the needle tip to the needle body.

8. The polyglycolide porous microneedle array with a porosity gradient according to claim 7, characterized in that: The porosity gradient of the porous microneedles ranges from 7% to 48%.

9. The polyglycolide porous microneedle array with a porosity gradient according to claim 7, characterized in that: The porous microneedles have a micron-scale spatial network structure.

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