Preparation of Microneedle Array Mold Based on MEMS Lithography Technology

As a transdermal drug delivery technology, microneedle array (MNA) has the characteristics of painless, minimally invasive, and precise dosage. This work discusses and compares the new MNA mold prepared by our group using MEMS technology. First, we introduced the planar pattern-to-cross-section technology (PCT) method using LIGA (Photolithography, Galvanogormung, Abformung) technology to obtain a three-dimensional structure similar to an X-ray mask pattern. On this basis, combined with polydimethylsiloxane (PDMS) transfer technology and electroplating process, metal MNA can be prepared. The second method is to use silicon wet etching combined with the SU-8 process to obtain a PDMS quadrangular pyramid MNA using PDMS transfer technology. Third method is to use the tilting rotary lithography process to obtain PDMS conical MNA on SU-8 photoresist through PDMS transfer technology. All three processes utilize parallel subtractive manufacturing methods, and the error range of reproducibility and accuracy is 2–11%. LIGA technology produces hollow MNA with an aspect ratio of up to 30, which is used for blood extraction and drug injection. The height of the MNA prepared by the engraving process is about 600 μm, which can achieve a sustained release effect together with a potential systemic delivery. The height of the MNA prepared by the ultraviolet exposure process is about 150 μm, which is used to stimulate the subcutaneous tissue.


Introduction
One method to produce microneedle arrays (MNA) is micro-electro-mechanical system (MEMS) technology [1,2]. MNA refer to needle-like structures with a diameter of several tens of micrometers and a length of more than one hundred micrometers and are generally fabricated by micro-nano manufacturing technology. According to the manufacturing process, it is divided into the in-plane MNA and out-plane MNA; according to the material, it is divided into silicon MNA, metal MNA, ceramic MNA, hydrogel-forming MNA, and polymer MNA; according to internal structure, it is divided into solid MNA and hollow MNA [3,4]. Since the first report of the application of MNA in transdermal drug delivery (TDD) in the 1990s, the advantages of MNAs have attracted much attention. Especially in recent years, the gradual improvement of MEMS technology has made the establishment of MNA drug delivery system rapid [5,6]. The way of administration of MNA is different from traditional oral administration and intravenous administration. The MNA form a tiny channel on the surface of the human skin, so that drug can reach the specified depth of the skin, and have the advantages of accurate administration, high efficiency, simple operation, and pain-free [7,8]. It is precisely because of the many superiorities of MNA in TDD that people are constantly exploring and researching the combination of MNA and therapeutics, such as a vaccine, insulin, and low molecular weight heparin. With the development of biomacromolecules and nanomedicines, the demand for transdermal delivery of MNA is also increasing, and MNA have broad prospects for development [9][10][11].

Engraving Process
To achieve low-cost and mass manufacturing of polymer MNA, a MNA mold fabrication method was described. There are two parts of MNA mold: the tip part, which was fabricated by silicon wet etching and the column part, which was fabricated by SU-8 The shape of the PMMA MNA depends on lithography method and absorber pattern of the X-ray mask which has made of gold and polyimide layers with thicknesses of 3.5 µm and 50 µm, respectively. The gold material absorbs X-rays while the polyimide support film through X-rays. Therefore, MNA with different shapes and strengths can be fabricated by designing different X-ray mask absorber patterns and using different photolithography methods.
On the basis of the PCT, the out-planar metal MNA can be obtained by electroplating technology. Firstly, a PDMS solid MNA was fabricated by two PDMS transfer processes using a PMMA solid MNA as a master mold. Finally, a nickel metal MNA was fabricated by performing a nickel-plating process using the PDMS solid MNA.
Prior to electroplating the metallic nickel, a layer of chromium copper seed with a thickness of 250 nm is sputtered on the PDMS MNA mold. In order to reduce the deformation of the PDMS due to the downward pressure of the metal during electroplating, the PDMS first-level mold is bonded to the glass to strengthen the tolerance of the PDMS. The electroplating solution was sulfamate (PH = 4), stirring was continued and the temperature was maintained at 37 • C, the current density was 10 mA/cm 2 , and 350 µm thick metal nickel was electroplated at a plating rate of 0.2 µm/min.

Engraving Process
To achieve low-cost and mass manufacturing of polymer MNA, a MNA mold fabrication method was described. There are two parts of MNA mold: the tip part, which was fabricated by silicon wet etching and the column part, which was fabricated by SU-8 lithography. The fabrication process of the MNA tip is shown in Figure 2. First, we prepared a piece of <100> crystal orientation, a thickness of about 525 µm of double-oxygen single crystal silicon wafer, and washed the surface with oil stain, organic and matter with acetone, alcohol and deionized water which enhanced the bonding force between the silicon wafer and the photoresist. Afterwards, we dried the silicon wafer with pure high-pressure nitrogen gas, and put it into a 180 • C oven for baking for at least 1 h. Secondly, we deposited a layer of AZ4620 series positive photoresist on the oxide layer of the silicon wafer to a thickness of 5 µm, and subjected it to hard bake treatment under the condition of 180 • C for 30 min. Thirdly, photolithography was conducted using CA800 deep ultraviolet lithography machine, for which the exposure intensity was 8.2 mW/cm 2 and the exposure time was 60 s. As shown in Figure 2a, the mask is a 400 × 400 array of transparent square patterns (200 µm side length), and the structure shown in Figure 2b was fabricated by development. Etching was further conducted in a buffered etchant at 45 • C (solution ratio of 28 mL hydrofluoric acid, 117 g ammonium fluoride and 170 mL deionized water) for 10 min, after the remaining photoresist was removed by ultrasonication with acetone solution. To determine whether the SiO 2 layer is inscribed, the resistance between the etched holes can be measured with a multimeter, if there is an indication, the etch is successful, as shown in Figure 2c. Finally, the exposed silicon was anisotropically etched at 85 • C with a 30% KOH solution, and the substrate was placed at a 45 • in the solution by using a fixture. At the same time, the stirrer was continuously stirred to ensure uniform etching; the etching rate was 1 µm/min, and the time is 2 h. The silicon MNA tip structure is shown in Figure 2d. The silicon wafer was cleaned after the final etching, and the surface profiler can be used for preliminary depth detection to ensure the smooth completion of the experiment.
The process of the column part of the MNA is shown in Figure 3. First, a 250 µm thick SU-8 photoresist was deposited on the etched silicon wafer (Figure 3b), which is a negative, epoxy-type and near-ultraviolet photoresist. The exposure of the entire SU-8 photoresist layer is uniform because of low light absorption in the near-ultraviolet range, and a thick film pattern with vertical sidewalls and high aspect ratio can be fabricated. It also has good mechanical properties, chemical resistance, and thermal stability. Photolithography was then performed using an ultraviolet lithography process (Figure 3c), which was an array of 4-hole trench patterns that are developed to provide the structure shown in Figure 3d. This structure is the MNA master mold through which a PDMS MNA can be fabricated. In the experiment, the PDMS pre-polymer was prepared by mixing the base and curing agent at the ratio of 10 and stirred for 5 min, evacuated in a vacuum desiccator to remove air bubbles, and then the PDMS prepolymer was poured onto the master mold with the thickness was about 2 mm, evacuated again in the vacuum desiccator. After that, it was solidified in an oven at 65 • C for 2 h and kept at room temperature to cool down, the PDMS layer was peeled off from the SU-8 master mold and finally a PDMS MNA can be fabricated. The process of the column part of the MNA is shown in Figure 3. First, a 250 μm thick SU-8 photoresist was deposited on the etched silicon wafer (Figure 3b), which is a negative, epoxy-type and near-ultraviolet photoresist. The exposure of the entire SU-8 photoresist layer is uniform because of low light absorption in the near-ultraviolet range, and a thick film pattern with vertical sidewalls and high aspect ratio can be fabricated. It also has good mechanical properties, chemical resistance, and thermal stability. Photolithography was then performed using an ultraviolet lithography process ( Figure  3c), which was an array of 4-hole trench patterns that are developed to provide the structure shown in Figure 3d. This structure is the MNA master mold through which a PDMS MNA can be fabricated. In the experiment, the PDMS pre-polymer was prepared by mixing the base and curing agent at the ratio of 10 and stirred for 5 min, evacuated in a vacuum desiccator to remove air bubbles, and then the PDMS prepolymer was poured onto the master mold with the thickness was about 2 mm, evacuated again in the vacuum desiccator. After that, it was solidified in an oven at 65 °C for 2 h and kept at room temperature to cool down, the PDMS layer was peeled off from the SU-8 master mold and finally a PDMS MNA can be fabricated.

Tilting Rotary Ultraviolet (UV) Lithography
The tilt-rotation exposure process uses a 4-inch photolithography mask. The circular diameter of the mask pattern is 75 μm, the pitch is 300 μm, and the density is 35 × 35 stitches/cm 2 . The mechanism of conical pit formation is shown in the figure below, and  The process of the column part of the MNA is shown in Figure 3. First, a 250 μm thick SU-8 photoresist was deposited on the etched silicon wafer (Figure 3b), which is a negative, epoxy-type and near-ultraviolet photoresist. The exposure of the entire SU-8 photoresist layer is uniform because of low light absorption in the near-ultraviolet range, and a thick film pattern with vertical sidewalls and high aspect ratio can be fabricated. It also has good mechanical properties, chemical resistance, and thermal stability. Photolithography was then performed using an ultraviolet lithography process ( Figure  3c), which was an array of 4-hole trench patterns that are developed to provide the structure shown in Figure 3d. This structure is the MNA master mold through which a PDMS MNA can be fabricated. In the experiment, the PDMS pre-polymer was prepared by mixing the base and curing agent at the ratio of 10 and stirred for 5 min, evacuated in a vacuum desiccator to remove air bubbles, and then the PDMS prepolymer was poured onto the master mold with the thickness was about 2 mm, evacuated again in the vacuum desiccator. After that, it was solidified in an oven at 65 °C for 2 h and kept at room temperature to cool down, the PDMS layer was peeled off from the SU-8 master mold and finally a PDMS MNA can be fabricated.

Tilting Rotary Ultraviolet (UV) Lithography
The tilt-rotation exposure process uses a 4-inch photolithography mask. The circular diameter of the mask pattern is 75 μm, the pitch is 300 μm, and the density is 35 × 35 stitches/cm 2 . The mechanism of conical pit formation is shown in the figure below, and the size of the MNA is controllable. The height of the MNA can be changed by adjusting the inclination angle of the bracket and the diameter of the small solid circle on the mask. The formula is as follows:

Tilting Rotary Ultraviolet (UV) Lithography
The tilt-rotation exposure process uses a 4-inch photolithography mask. The circular diameter of the mask pattern is 75 µm, the pitch is 300 µm, and the density is 35 × 35 stitches/cm 2 . The mechanism of conical pit formation is shown in the figure below, and the size of the MNA is controllable. The height of the MNA can be changed by adjusting the inclination angle of the bracket and the diameter of the small solid circle on the mask. The formula is as follows: where h is the height of the MNA; θ is the tilt angle of the stent; d is the diameter of the small solid circle on the mask.
In this process, a conical array is prepared on the SU-8 using the mask tilting rotary exposure technology on the back side, afterward the PDMS MNA first-level mold is obtained by the PDMS transfer technology. The process flow chart is shown in Figure 4. The inclined and freely rotatable exposure platform consists of a platform and motor which is placed on a freely adjustable bracket. By adjusting the height of the bracket, the rotating platform can be varied from 0 • to 90 • , as shown in Figure 5. The speed of the motor is controlled applying a DC voltage, so that the motor can drive the rotating platform freely. For exposure, the bench is placed under the URE-2000/35A UV deep lithography mirror without the need to modify the lithography equipment.

tan
where ℎ is the height of the MNA; is the tilt angle of the stent; is the diameter of the small solid circle on the mask.
In this process, a conical array is prepared on the SU-8 using the mask tilting rotary exposure technology on the back side, afterward the PDMS MNA first-level mold is obtained by the PDMS transfer technology. The process flow chart is shown in Figure 4. The inclined and freely rotatable exposure platform consists of a platform and motor which is placed on a freely adjustable bracket. By adjusting the height of the bracket, the rotating platform can be varied from 0° to 90°, as shown in Figure 5. The speed of the motor is controlled applying a DC voltage, so that the motor can drive the rotating platform freely. For exposure, the bench is placed under the URE-2000/35A UV deep lithography mirror without the need to modify the lithography equipment.  In this process, SUEX Dry Film Resist (DFR) replaces the traditional SU-8 photoresist, the thermal lamination process replaces the original silicone technology. DFR is directly adhered to the glass substrate, thereby saving time and efficiency. Moreover, the thickness of the DFR is given, and it is not necessary to adjust the complicated tannin parameters, where ℎ is the height of the MNA; is the tilt angle of the stent; is the diameter of the small solid circle on the mask.
In this process, a conical array is prepared on the SU-8 using the mask tilting rotary exposure technology on the back side, afterward the PDMS MNA first-level mold is obtained by the PDMS transfer technology. The process flow chart is shown in Figure 4. The inclined and freely rotatable exposure platform consists of a platform and motor which is placed on a freely adjustable bracket. By adjusting the height of the bracket, the rotating platform can be varied from 0° to 90°, as shown in Figure 5. The speed of the motor is controlled applying a DC voltage, so that the motor can drive the rotating platform freely. For exposure, the bench is placed under the URE-2000/35A UV deep lithography mirror without the need to modify the lithography equipment.  In this process, SUEX Dry Film Resist (DFR) replaces the traditional SU-8 photoresist, the thermal lamination process replaces the original silicone technology. DFR is directly adhered to the glass substrate, thereby saving time and efficiency. Moreover, the thickness of the DFR is given, and it is not necessary to adjust the complicated tannin parameters, In this process, SUEX Dry Film Resist (DFR) replaces the traditional SU-8 photoresist, the thermal lamination process replaces the original silicone technology. DFR is directly adhered to the glass substrate, thereby saving time and efficiency. Moreover, the thickness of the DFR is given, and it is not necessary to adjust the complicated tannin parameters, and the thickness of the DFR used in this experiment is 250 µm. During exposure, the tilt angle of the rotating platform was set to 18 • , the platform rotation speed was 400 rpm/min, and the exposure time was 70 s. The lithography mask used in the experiment was a film version with a circular diameter of 75 µm, a center distance of 300 µm, and a density of 35 × 35 needles per square centimeter. By designing the shape of the mask, different styles of microneedle arrays can be prepared. When the mask absorber pattern is a triangle, the PMMA out-plane solid MNA shown in Figure 6(a2) can be obtained by twice moving X-ray exposures, and Figure 6(a3) is a close-up image of a single solid MNA. The MNA height is 350 µm, the bottom width is 100 µm, the center distance of the needle is 330 µm, and the tip width is 2 µm. When the mask pattern of the absorber is as shown in Figure 6(b1), the structure shown in Figure 6(b2) can be fabricated by two moving X-ray lithography, and the density of the PMMA out-plane MNA reaches 1024 needles per square centimeter. This MNA can perform painless micro blood extraction by capillary force. When the obelisk absorber pattern is a pointed shape (Figure 6(c1)), the PMMA out-plane hollow MNA shown in Figure 6(c2) can be manufactured by twice moving X-ray lithography and one alignment fixed exposure.   It can be proven by experiments that by using PCT, designing different X-ray mask absorber patterns and different lithography methods can be used to fabricate different plane solid MNA arrays with different shapes and strengths, such as out-plane hollow MNA and in-plane solid MNA.
In the experiment, the mask pattern is an isosceles triangle which the base of the isosceles triangle is 100 µm, the height is 1500 µm, the tip is 2 µm wide, and the tip is 25 µm from the boundary of the mask, as shown in Figure 7a. The gold absorber has a thickness of 3 µm and the polyimide has a thickness of 38 µm. After twice moving X-ray lithography processes (exposure dose of 0.06 Ah), developed in a GG developer at 37 • C for 3 h to obtain a PMMA MNA mold with a height of 300 µm and a tip width of 2 µm. The PMMA solid MNA prepared by the above method is used as a master model, and the secondary PDMS solid MNA is obtained through the transfer process. The secondary MNA is electroplated by the electroplating solution, finally, the metallic nickel MNA is fabricated by electroplating nickel on the PDMS MNA mold. The pattern after electroplating has a good reproduction effect, and the metal MNA has a complete structure and a high aspect ratio. The SEM image as shown in Figure 7b,c.

In-Plane MNA
We introduce a method for manufacturing a PMMA MNA with a tip and a fluid channel, and Figure 8a shows the mask pattern for preparing the MNA. The mask plate used was selected from Au as an absorber which had a thickness of 3 µm, and polyimide as a light-transmitting portion having a thickness of 38 µm. The MNA height and the base width are designed to be 1500 µm and 100 µm, respectively, and the channel width is 10 µm. After a fixed alignment exposure, development on a 0.5 mm PMMA sheet yielded the in-plane MNA array structure shown in Figure 8b,c. The method can obtain a row of MNAs in the same plane, so the preparation of the MNA can be completed by layer-by-layer bonding of 0.5 mm PMMA sheets, and the depth of the pattern can be controlled by the exposure time and the development time. The tip of the prepared MNA is sharp enough to pierce the skin, and the flow channel can be used to store the extracted blood.   Figure 9a,b are mask patterns to fabricate the tip part and the column part of MNA, respectively, and the small square in Figure 10a has a side length of 200 µm and a density of 300 needles per square centimeter. The mask pattern in Figure 9b is modified on the basis of Figure 9a. The purpose is to make the prepared MNA column part with four grooves to facilitate demolding and drug loading.  Figure 9a,b are mask patterns to fabricate the tip part and the column part of MNA, respectively, and the small square in Figure 10a has a side length of 200 μm and a density of 300 needles per square centimeter. The mask pattern in Figure 9b is modified on the basis of Figure 9a. The purpose is to make the prepared MNA column part with four grooves to facilitate demolding and drug loading. After the original silicon MNA mold is prepared by the silicon wet etching combined with SU-8 lithography, considering that the direct use of the original mold will cause its manufacturing cost to rise, PDMS materials with better biocompatibility and mechanical properties can be cast, and the quadrangular pyramidal MNA can be obtained by using the mold-transforming technique (first-level positive mold). The electron micrograph of the MNA tip and the entire MNA is shown in Figure 10. The overall height of the needle is about 600 μm, the width is about 300 μm, the center distance is about 800 μm, and the density is 300 needles per square centimeter. The tip is anisotropically etched at 54.7°. The results show that the quadrangular pyramid shaped MNAs prepared by this process have a long service life, can be used repeatedly and are resistant to abrasion, can maintain the sharpness of the MNAs, have consistent repeated effects, and meet the requirements of controllable MNA parameters. We then translate the first-level positive mold into the second-level negative mold, and use L-polylactic acid (PLLA), polystyrene (PS), hyaluronic acid (HA) and other polymer materials as the mold transfer material, which can greatly improve the efficiency and success of the transfer technology, and there is no distortion, so as to achieve low-cost, mass production of various polymer MNA arrays.

Fabrication Results of Tilting Rotary UV Lithography
After the array of conical pits fabricated by the inclined and rotating UV lithography, a conical MNA was fabricated by PDMS transfer technology. First, we mixed the Dow Corning sygard 184 prepolymer with the curing agent in a ratio of 10:1, vacuum to remove the bubbles, then filled the processed conical MNA mold, vacuum again to remove the bubbles, and solidified it in an oven at 60 °C . After 3 h, the mold was released to obtain a PDMS conical MNA, as shown in Figure 11. According to the SEM image, the actually prepared conical MNA has a width of about 75-80 μm, a height of about 200-210 μm, a taper angle of 5.1°-15.6°, a center-to-center distance of about 310-318 μm, and a density of 35 × 35 needles per square centimeter [22]. The results show that the MNA structure with high aspect ratio can be fabricated by this method, and the MNA pattern was copied well and the copy success rate was high. The ultraviolet rotating exposure process was applied to fix the light source, and the mask was rotated by the inclined rotating platform to prepare the conical MNA. At the same time, the hot-pressing process was used to replace the traditional SU-8 photoresist with SUEX Dry Film Resist (DFR), which improves efficiency and convenience. Therefore, the MNA mold can be applied to prepare MNA of various polymer materials. After the original silicon MNA mold is prepared by the silicon wet etching combined with SU-8 lithography, considering that the direct use of the original mold will cause its manufacturing cost to rise, PDMS materials with better biocompatibility and mechanical properties can be cast, and the quadrangular pyramidal MNA can be obtained by using the mold-transforming technique (first-level positive mold). The electron micrograph of the MNA tip and the entire MNA is shown in Figure 10. The overall height of the needle is about 600 µm, the width is about 300 µm, the center distance is about 800 µm, and the density is 300 needles per square centimeter. The tip is anisotropically etched at 54.7 • . The results show that the quadrangular pyramid shaped MNAs prepared by this process have a long service life, can be used repeatedly and are resistant to abrasion, can maintain the sharpness of the MNAs, have consistent repeated effects, and meet the requirements of controllable MNA parameters. We then translate the first-level positive mold into the second-level negative mold, and use L-polylactic acid (PLLA), polystyrene (PS), hyaluronic acid (HA) and other polymer materials as the mold transfer material, which can greatly improve the efficiency and success of the transfer technology, and there is no distortion, so as to achieve low-cost, mass production of various polymer MNA arrays.

Fabrication Results of Tilting Rotary UV Lithography
After the array of conical pits fabricated by the inclined and rotating UV lithography, a conical MNA was fabricated by PDMS transfer technology. First, we mixed the Dow Corning sygard 184 prepolymer with the curing agent in a ratio of 10:1, vacuum to remove the bubbles, then filled the processed conical MNA mold, vacuum again to remove the bubbles, and solidified it in an oven at 60 • C. After 3 h, the mold was released to obtain a PDMS conical MNA, as shown in Figure 11. According to the SEM image, the actually prepared conical MNA has a width of about 75-80 µm, a height of about 200-210 µm, a taper angle of 5.1-15.6 • , a center-to-center distance of about 310-318 µm, and a density of 35 × 35 needles per square centimeter [22]. The results show that the MNA structure with high aspect ratio can be fabricated by this method, and the MNA pattern was copied well and the copy success rate was high. The ultraviolet rotating exposure process was applied to fix the light source, and the mask was rotated by the inclined rotating platform to prepare the conical MNA. At the same time, the hot-pressing process was used to replace the traditional SU-8 photoresist with SUEX Dry Film Resist (DFR), which improves efficiency and convenience. Therefore, the MNA mold can be applied to prepare MNA of various polymer materials.

Fabrication Results of Tilting Rotary UV Lithography
After the array of conical pits fabricated by the inclined and rotating UV lithography, a conical MNA was fabricated by PDMS transfer technology. First, we mixed the Dow Corning sygard 184 prepolymer with the curing agent in a ratio of 10:1, vacuum to remove the bubbles, then filled the processed conical MNA mold, vacuum again to remove the bubbles, and solidified it in an oven at 60 °C . After 3 h, the mold was released to obtain a PDMS conical MNA, as shown in Figure 11. According to the SEM image, the actually prepared conical MNA has a width of about 75-80 μm, a height of about 200-210 μm, a taper angle of 5.1°-15.6°, a center-to-center distance of about 310-318 μm, and a density of 35 × 35 needles per square centimeter [22]. The results show that the MNA structure with high aspect ratio can be fabricated by this method, and the MNA pattern was copied well and the copy success rate was high. The ultraviolet rotating exposure process was applied to fix the light source, and the mask was rotated by the inclined rotating platform to prepare the conical MNA. At the same time, the hot-pressing process was used to replace the traditional SU-8 photoresist with SUEX Dry Film Resist (DFR), which improves efficiency and convenience. Therefore, the MNA mold can be applied to prepare MNA of various polymer materials.

Comparison of Three Processes and Special Processing Technology
In recent years, special processing technology has developed rapidly. In addition to the above three methods, it also includes some novel preparation methods such as 3D printing technology [23], laser processing [24], drawing lithography [25], etc. The MEMS process can manufacture microneedles with different shapes, angles, and surface contours, and effectively enhance the strength and toughness of the microneedles, enabling them to perform different functions in various fields. The prepared MNA can

Comparison of Three Processes and Special Processing Technology
In recent years, special processing technology has developed rapidly. In addition to the above three methods, it also includes some novel preparation methods such as 3D printing technology [23], laser processing [24], drawing lithography [25], etc. The MEMS process can manufacture microneedles with different shapes, angles, and surface contours, and effectively enhance the strength and toughness of the microneedles, enabling them to perform different functions in various fields. The prepared MNA can control the aspect ratio by controlling the exposure time and the development time to meet the requirements of the controllable parameters. The special processing technology does not require a mask, and the use of biodegradable polymer as the material can realize simple and low-cost rapid prototyping, thereby providing mild and rapid preparation conditions. All the above processes can prepare MNA that have a long service life and can be used repeatedly. However, each process has different characteristics, such as the shape and type of MNA, the operability of the preparation process, etc., as shown in Table 1. For the type of MNA, A can prepare in-plane MNA and out-plane MNA, but the other three processes can only prepare out-plane MNA. Regarding the shape of the MNA, B and C can prepare quadrangular pyramid shaped MNA and conical MNA, respectively, but A can prepare MNA of various shapes according to different masks to achieve the purpose of customized production. For D, the layered structure of MNA is prepared using additive manufacturing methods. A and B can prepare solid MNA and hollow MNA, but B and C can only prepare solid MNA by wet etching of silicon combined with SU-8 photolithography and tilting rotary exposure. The aspect ratio of A is greater than 2, up to 30. However, the equipment used in this process is expensive, the process is complicated, and the process requirements are high. In terms of B, C, and D, the aspect ratio of about 5 can be achieved through lower cost and simple process flow. Regarding the processing methods, A, B, and C are manufactured in parallel, which saves time and has good reproducibility, while D is manufactured in serial, which wastes time and has a larger error range. Regarding A, its preparation cost is high, but its accuracy and scalability can reach the nano-level. However, for B, C, and D, due to the lower cost, the accuracy and scalability of the prepared MNA can only be reach the micron-level. With respect to B, the tip is prepared by an anisotropic etching method, so the etching is performed at an angle of 54.7 • . The cutting-edge precision prepared by C and D can reach the µm level, while the A can reach the nano-level.

Conclusions
This paper introduces three methods for manufacturing MNA based on MEMS technology. The first method is to obtain the PMMA MNA based on the PCT process, which is prepared by different exposure methods and masks of different shapes, and then the metal nickel MNA mold can be prepared by the nickel-plating process. The MNA prepared by this method can be used for blood extraction and drug injection. The second method is to use the wet etching of silicon and UV-LIGA process to prepare the MNA tip part and the SU-8 photoresist column part respectively, which constitutes the MNA mold as a whole, and the PDMS transfer technology can be used to different out-plane MNA structure. The last method is to prepare a conical MNA mold on a SU-8 dry film by using inclined and rotating UV lithography, and finally, a conical MNA is obtained by a transfer process.
The experimental results indicate that these three methods can fabricate MNA with high aspect ratios and sharp tips, which provides a good guarantee for the MNA to penetrate the skin. We discovered that the error range of reproducibility and accuracy is 2-11% by compared the dimensions of designed and actual MNs. For the PCT technology, although the cost is high and the process is complicated, of in-plane and out-plane can be prepared for blood extraction and drug injection, due to the hollow MNA having a very high aspect ratio. For the engraving process and the tilting rotary exposure process, they are simple to operate, and the prepared MNA mold has good repeatability and accuracy. After that, PDMS MNA molds can be obtained by employing the PDMS transfer technology. Using these molds, it is possible to prepare drug loaded MNA of dissolved materials, which further provides support for research on transdermal drug delivery. Through comparison with special processing technology, we found that MNA prepared based on MEMS technology have many characteristics such as parallel manufacturing, good reproducibility, high processing accuracy, time saving, etc. The MEMS process can manufacture MNA with different shapes, angles, and surface contours, and effectively enhance the strength and toughness of the microneedles, enabling them to perform different functions in various fields.  Data Availability Statement: Data available on request due to restrictions e.g., privacy or ethical. The data presented in this study are available on request from the corresponding author.