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Method Article

Fabrication of a Master Mold for Microneedles with a Micron-sized Air-vent Hole

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DOI:

10.3791/69679

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December 5th, 2025

 ,  ,  ,  , 
1Department of Digital Anti-Aging Health Care, Inje University, 2Department of Biomedical Engineering, Inje University

* These authors contributed equally

In This Article

Summary

This article introduces a unique method for fabricating master molds with an air-vent hole to prevent air entrapment during viscous polymer casting, enabling the fabrication of gelatin microneedles with sharp tips. By reducing the casting volume of high-viscosity gelatin, thin-walled hollow pyramidal microneedles could also be fabricated.

Abstract

Microneedles (MNs) are a novel drug-delivery system that can penetrate the skin barrier in a minimally invasive way to deliver drugs. Because they are less painful than injections and easy to use, they are seeing expanding applications in the cosmetic and pharmaceutical fields. Conventional MN fabrication involves creating a master mold and then producing MNs in that mold. The primary methods for fabricating the master mold include micro-electromechanical system processes, metal machining, and 3D printing. However, the major weakness of master molds produced by these methods is that air can become trapped inside the mold while casting the very viscous polymer used to make MNs. As a result, the MN tips may not form completely. In MN array fabrication, this can reduce the reliability of the MN structures. This study proposes a solution to air entrapment that involves forming a microscale air-vent hole (AVH) at the tip of the master mold. The AVH allows air to escape, but prevents the viscous fluid from leaking out during the curing process. Because conventional metal machining or 3D printing methods have resolution limitations, silicon micromachining was used to create the AVH-equipped master mold. The side length of the fabricated AVH ranged from 1.4 to 7.0 µm. Using this mold, we successfully fabricated 375 µm-high gelatin MNs with sharp tips. Furthermore, by controlling the volume of gelatin applied, thin-walled hollow pyramidal MNs with 23 µm thick walls and an internal cavity volume of 0.027 µL were also fabricated. Since the AVH-equipped master mold allows fabrication of both water-soluble and water-insoluble MNs, it could serve as a next-generation high-efficiency drug delivery system for applications in cosmeceutical and biomedical fields.

Introduction

Microneedles (MNs) are a new drug delivery system capable of penetrating the skin barrier non-invasively to deliver drugs. This method overcomes the low bioavailability of oral administration and the pain and infection risk of injection-based delivery1. With their simple use and high patient compliance, MNs have seen expanding applications in cosmetics2, vaccines3, biomarker monitoring4, and polymer drug delivery5.

MN fabrication methods generally involve molding techniques6. Molds used for casting MNs are fabricated by metal machining7 and 3D printing8. However, one obstacle to the use of these methods is that they require expensive equipment and facilities. Furthermore, due to their resolution limits, it is challenging to produce the skin-penetrating structures used as MNs. Additionally, very viscous materials are used to produce biodegradable MNs9,10. When the MN material is applied to the mold, air trapped in the mold's microstructures can prevent proper formation of the MN tips and reduce the yield of MN arrays11. Studies have reported methods to address these problems, such as centrifugal casting12, vacuum degassing using a chamber13, and hydrophilic surface treatment of the mold14, which have been reported to mitigate this problem. Nevertheless, a simpler and more efficient mold-based fabrication process is still needed.

Typically, dissolving MNs are fabricated by mixing the target compound with a water-soluble polymer in liquid form and casting the mixture into a mold15. With water-soluble substances, fabrication is relatively straightforward using simple procedures such as dissolving the target compound in distilled water and mixing it with a soluble polymer16. However, with water-insoluble substances, a separate process must be developed to load them into the MNs. For example, an insoluble drug can be dissolved in a water/ethanol co-solvent and mixed, then vacuum-concentrated, filtered, and freeze-dried as a pretreatment, and subsequently mixed into a soluble polymer solution to fabricate MNs17. This process for loading insoluble drugs into MNs is complex and time-consuming. Therefore, it is necessary to develop a more efficient fabrication process and a method to accurately predict the amount of pure drug loaded. Beyond the drug-mixed type, methods also need to be developed to fabricate MNs that store the drug in a separate space.

To address the two issues mentioned above, this study fabricated a silicon master mold for MN production that prevents air trapping during viscous polymer casting and validated its utility. During polymer casting for MN fabrication, as the viscous polymer fills the mold cavity, the residual air inside the cavity is naturally vented, and the cavity becomes completely filled. Owing to the high viscosity, this filling process stops without the polymer flowing out of the mold. Through this process, the mold geometry can be faithfully replicated, and MNs with sharp tips can be fabricated. When the volume of the viscous polymer is smaller than the internal cavity volume of the mold, the viscous polymer flows along the inclined mold walls toward the air-vent outlet, so that the MN is formed with an empty interior. Figure 1 outlines the typical MN fabrication method using a conventional mold (1) and our key concept of an AVH-equipped master mold (2).

This protocol used a double-sided etching process on a silicon wafer to produce a mold with a microscale AVH on its backside. After applying the polymer under vacuum, the viscous polymer fills the mold cavity to produce an MN with a sharp tip. By controlling the dispensed volume of the MN material, we can fabricate either a standard solid MN (with a filled interior) or, if a smaller volume is dispensed, a hollow MN where the viscous polymer coats the mold surface to a certain thickness, while leaving an empty interior. This provides a versatile process for fabricating various MN types.

Gelatin was selected as the matrix material for MN fabrication because it provides high biocompatibility and favorable mechanical properties, while also offering wide availability, low cost, water solubility, and biodegradability as a protein-based biomaterial that has been widely used in biomedical applications and in dissolving or hydrogel-forming MN systems18,19. Previous studies have also demonstrated that gelatin-based or gelatin-methacryloyl MNs can penetrate skin without bending or fracture, confirming that gelatin networks provide sufficient mechanical strength and structural integrity for reliable skin insertion20,21.

For the material used in MN fabrication, a 10.31% (w/v) gelatin solution was prepared by mixing 1 g of gelatin with 9 mL of distilled water. According to the literature, the viscosity of a 10% (w/v) gelatin solution at 25 °C is 39.43-46.63 mPa·s22, and the concentration difference between the 10.31% (w/v) gelatin solution used in this study and the 10% (w/v) reference solution is 0.31%, with both values falling within the 6.64-429 mPa·s viscosity range over which aqueous polymer formulations have been successfully used for mold-based fabrication of MNs23, indicating that the present AVH-assisted mold filling approach is, in principle, applicable to aqueous polymer solutions whose viscosities lie within this range.

Through controlled casting, this study fabricated and compared two types of MNs, selecting these instead of porous MNs, which exhibit a trade-off between porosity and mechanical strength that compromises mechanical robustness24: a solid MN exhibiting high mechanical strength and insertion reliability with superior skin-penetration efficiency25, and a hollow MN capable of storing water-insoluble drugs within its internal cavity, offering high applicability for subsequent conversion into drug-loaded solid MN designs26. When the drug can be mixed with the needle material, solid MNs are suitable, whereas hollow MNs are appropriate for poorly soluble substances that are difficult to mix.

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Protocol

Working in a controlled, clean environment and calibrating all equipment before starting are essential. Using dedicated tools for each step to avoid cross-contamination and adhering to the specified baking and cooldown times are recommended, along with following the protocol steps in order. The reagents and the equipment used are listed in the Table of Materials.

1. Silicon master mold fabrication

  1. Perform Piranha cleaning on a 4 inch, 525 µm thick N-type (100) double-side polished (DSP) silicon wafer (H2SO4 + H2O2 = 4:1, 120 °C, 10 min).
    CAUTION: Piranha solution reacts violently with organics and poses a risk of strong heat release and gas generation. Always mix it slowly by adding hydrogen peroxide to the acid in a fume hood, and wear a face shield, acid-resistant apron, and acid-resistant gloves. After use, collect all remaining solution and rinses as acidic oxidizing waste in an acid-resistant, vented container. Do not neutralize in the laboratory. Request pickup through the institutional EHS hazardous-waste program in accordance with national laboratory waste regulations27.
  2. Perform dry-wet-dry thermal oxidation at 1100 °C for 90 min to grow a ~0.6 µm thick thermal oxide layer (Figure 2A).
  3. Front side photolithography: Perform the following steps on the front side of the wafer.
    1. Spin coat AZ GXR-601 photoresist (14 cP) at 3000 rpm for 35 s. Then, soft bake at 90 °C for 1 min.
    2. Using a mask aligner, expose the wafer to UV (365 nm, 10 mW/cm2) for 5 s, and then develop it in 2.38% (w/w) TMAH developer for 1-2 min.
      CAUTION: TMAH is toxic if absorbed through the skin. Handle it in a fume hood and wear double nitrile gloves, safety goggles, and an apron. In case of skin contact, wash immediately with water. After use, collect spent solutions and rinses as strongly alkaline quaternary-ammonium waste in a dedicated container. Do not mix with acids or oxidizers. Submit for EHS pickup following designated waste handling procedures27.
    3. Hard bake the wafer at 100 °C for 2 min.
  4. Front side etching:
    1. Place the patterned wafer in an ICP etching chamber and perform a dry etch for 2-3 min to remove the exposed thermal oxide layer selectively.
      NOTE: Set the gases (CHF3/CF4) to 10/30 sccm, RF power to 50 W (with ICP power 900 W), and pressure to 3.8 mTorr. The oxide etch rate under these conditions is ~260 nm/min.
    2. Remove the wafer from the chamber and strip the photoresist using a PR stripper (amine-based solvent, heated to 60 °C for 10 min in a static bath without ultrasonic agitation) (Figure 2B).
    3. Pour a 30% (w/w) KOH solution (or a 20% (w/w) TMAH solution) into an etching bath and cover it.
    4. Place the etching bath in a constant-temperature bath and set the temperature to 90 °C.
    5. After preheating for 1 h, open the lid, immerse the silicon wafer in the solution, and begin the etching. The etch rate is ~0.85 µm/min.
    6. After etching for at least 440 min, remove the silicon wafer and rinse it with water.
    7. Inspect the etched surface under a microscope to confirm that a V-groove has formed. (Figure 2C).
      CAUTION: KOH is a strong alkali etchant that can cause severe burns to skin and eyes. Always work in a fume hood and wear a face shield, chemical safety goggles, full-length chemical-resistant gloves, and a chemical apron. If exposed, immediately flush the area with water for at least 15 min and seek medical attention. After use, collect the used solution and contaminated materials as alkaline inorganic hazardous waste in compatible containers. Label clearly and request disposal through the EHS hazardous-waste program27.
      NOTE: The etch opening size is 530 µm × 530 µm, and the self-etch-stop depth is 375 µm. Because the etch is anisotropic, the process will stop automatically at that depth.
  5. Perform Piranha cleaning on the silicon wafer.
  6. Perform thermal wet oxidation at 1100 °C for 90 min to grow a new thermal oxide layer.
  7. Backside photolithography: On the backside of the wafer, perform photoresist coating, exposure, development, and baking with the same procedure and conditions as in step 1.3.
  8. Backside oxide patterning: Perform a buffered oxide etch (BOE) (HF: NH4F = 1:7) to pattern the backside oxide, then remove the photoresist with a stripper (Figure 2D).
    CAUTION: BOE solution contains HF, which can penetrate the skin and cause delayed tissue damage (necrosis) and hypocalcemia. Always work in a fume hood and wear HF-resistant gloves (over nitrile gloves). After use, collect all HF-containing liquids and solids in HDPE containers clearly labeled as HF/BOE waste. Keep calcium gluconate gel available nearby and request immediate EHS pickup according to designated-waste protocols27,28.
  9. During the BOE etch, perform a DI water wetting check to monitor the etch endpoint.
    1. Considering the BOE etch rate of the thermal oxide (110-120 nm/min), as the completion time nears, briefly dip the silicon wafer in deionized water and remove it to observe the wetting behavior of water droplets.
    2. Confirm that the oxide has been selectively removed (indicated by a lack of water wetting), marking the completion of thermal oxide removal.
  10. Perform backside anisotropic silicon etching under the same conditions as in step 1.4, at 90 °C for ~180 min (Figure 2E).
    NOTE: Given the wafer thickness tolerance of ±25 µm, start checking for through-hole formation at around 150 min (e.g., using a microscope) to determine when to stop the etch.
  11. After completing the backside etch, perform a BOE dip to remove any remaining oxide on the etched wafer (Figure 2F).
  12. Perform a DI water wetting check and confirm that all oxide has been removed ("sheet off" effect observed).
  13. Perform a hydrophobic surface treatment on the etched silicon wafer using C4F8 plasma deposition on the ICP etcher (60 sccm, ICP 800 W, RF 10 W, 10 mTorr, 60 s, static water contact angle ≥ 100°). Then dice the wafer using a dicing saw equipped with a nickel-bond diamond hub blade (spindle 30,000 rpm, feed 50 mm/s, exposure = 4× blade thickness, and DI-water coolant 0.5 L/min).
    NOTE: The hydrophobic plasma treatment makes the silicon mold surface non-wetting and facilitates the separation of the cured polymer MN from the silicon structure.

2. Polymer solution preparation

  1. Using a 10 mL disposable syringe, add 9 mL of distilled water to a 50 mL conical centrifuge tube.
  2. Using an S/T spoon and greaseproof paper, weigh 1 g of gelatin powder on a precision balance and transfer it into the conical tube.
    NOTE: When transferring the gelatin powder from the greaseproof paper into the tube, static can cause some powder to cling to the paper, leading to less than 1 g being added. Compare the weights of the paper before and after transfer, and add any missing amount of gelatin powder.
  3. Use the S/T spoon to break up any clumps of gelatin in the tube by stirring for 5 min in a clockwise direction, making sure that the solution's rotation does not cause spillage.
  4. Fill a water bath with 4 L of distilled water.
  5. Set the water bath temperature to 60 °C and wait ~30 min for it to reach the target temperature.
  6. Place the tube containing the gelatin solution in a 60 °C water bath for 30 min to dissolve the gelatin.
  7. Remove the tube and vortex it at 3,300 rpm for 1 min to disperse any remaining gelatin particles fully.
  8. To prevent viscosity changes or gelation before use, the gelatin solution is maintained in a water bath at 60 °C, with the final volume of 9.7 mL corresponding to a 10.31% (w/v) gelatin solution.
    NOTE: Maintain the gelatin solution in the 60 °C water bath for at least 5 h before using it for MN fabrication.

3. Fabrication of solid and hollow MNs

  1. Lay two microscope slides (76 mm × 26 mm × 1 mm) flat in a Petri dish, spaced 7 mm apart, and secure them with double-sided non-woven tape.
  2. Place the fabricated silicon master mold on top of the two microscope slides, with its backside (the side containing the AVH) facing downward.
  3. Adjust the position of the mold so that the AVH is centered over the gap between the two slides.
  4. Place the Petri dish (with the silicon master mold) at the center of a vacuum desiccator (approximately 260 mm × 260 mm × 100 mm in size).
  5. Using a 1 mL disposable syringe, apply 0.3 mL of methanol to the center of the silicon master mold.
    CAUTION: Methanol is a flammable, volatile, toxic solvent; inhalation of its vapors or skin absorption can cause optic nerve damage, blindness, or systemic poisoning. Always wear safety goggles, a face shield, and double nitrile gloves, and handle it in a well-ventilated area (preferably in a fume hood). After use, collect residual methanol and rinses as flammable organic solvent waste in a closed, compatible container with secondary containment. Request pickup through the institutional EHS hazardous-waste program according to national laboratory waste rules27.
  6. Gently move the syringe tip along the surface of the mold to distribute the methanol evenly to the edges.
    NOTE: Methanol has a very low viscosity (~0.594 mPa·s), so even slight disturbances can cause it to spill off the mold. For precise application to avoid overflow, wet the syringe tip with methanol.
  7. Seal the vacuum desiccator and use a vacuum pump to apply a vacuum of -80 kPa for 2 min, allowing the methanol to infiltrate the silicon master mold fully.
  8. Release the vacuum to remove any remaining bubbles in the methanol.
  9. Remove the prepared gelatin solution from the water bath and wipe any water off the outside of the tube with a cleanroom wipe.
  10. For solid MNs, use a 20-200 µL micropipette to dispense 100 µL of the gelatin solution onto the center of the silicon master mold. For hollow MNs, dispense 40 µL of the gelatin solution.
  11. Seal the vacuum desiccator and apply -80 kPa for 2 min.
  12. Release the vacuum to eliminate any remaining bubbles in the gelatin solution.
  13. Keeping the Petri dish level, place it in a 60 °C water bath for 2 min.
    NOTE: Ensure the Petri dish does not contact the water in the bath directly. The 60 °C environment lowers the solution viscosity, and the 100% relative humidity inside the bath prevents the gelatin from drying out.
  14. Remove the Petri dish from the water bath, while keeping it level.
  15. Touch the surface of the gelatin solution with a pair of tweezers and spread it evenly to the edges of the mold, ensuring the entire mold surface is coated with a thin layer of the solution.
    NOTE: If the solution is too cool, its high viscosity will cause it to stick to the tweezers and stretch. Thus, spread the solution quickly, immediately after removing the mold from the 60 °C bath, while the gelatin viscosity is still low.
  16. Keeping the mold level, place it in an oven at 40 °C and dry it for at least 4 h.
  17. Once completely dry, insert tweezers between the silicon master mold and the MN base and carefully twist to lift and demold, obtaining the cured dissolving polymer MN.

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Results

This study introduced a master mold with an AVH to enable the fabrication of MNs with sharp tips, representing a departure from the use of conventional master molds. Using high-precision silicon etching, we successfully fabricated the AVH-equipped master mold and produced MNs from it. The fabricated silicon master mold was imaged with field-emission scanning electron microscopy (SEM), and the fabricated MNs were observed using both digital microscopy and field-emission SEM.

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Discussion

This study fabricated a silicon master mold with an AVH using double-sided etching to prevent air entrapment while filling it with a viscous polymer, thereby achieving complete filling up to the MN tip and enabling the formation of sharp, uniform MNs. A key factor for proper tip formation is the size of the AVH created by the backside etch. Considering the variation in silicon wafer thickness (±25 µm), it is challenging to predict the backside etch duration precisely. If the etch proceeds for too long, the AVH ...

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Acknowledgements

This work was supported by a Korea Innovation Foundation (INNOPOLIS) grant funded by the Korean Government (Ministry of Science and ICT) (grant no. NTIS-2710084968), by the Commercialization Promotion Agency for R&D Outcomes (COMPA) funded by the Ministry of Science and ICT (grant no. RS-2024-00423871 to aid IP advancement and commercialization/industrialization of touch-off micro-needle manufacturing technology), and by the Regional Innovation System Education (RISE) program through the RISE Center, Gyeongsangnam-do, funded by the Ministry of Education (MOE) and the Gyeongsangnam-do Provincial Government, Republic of Korea (2025-RISE-16-008-0008).

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Materials

List of materials used in this article
NameCompanyCatalog NumberComments
cleanroom wipeAsahi KaseiBEMCOT M-325 mm × 25 mm
conical centrifuge tubeCorning35207050 mL
dicing sawDISCODAD-3220spindle 30,000 rpm, feed 50 mm/s, exposure = 4× blade thickness, DI-water coolant 0.5 L/min
digital microscopyHiroxKH-7700Used with an MXG-5040RZ camera lens
disposable syringeKorea VaccineKOVAX-SYRINGE1 mL & 10 mL
distilled waterSamchun Pure Chemical000W0054
double-sided non-woven tape3MID-8370S0.16 mm thickness
field-emission SEM Hitachi High-TechS-4300SE
gelatin powderSigma-AldrichG1890From porcine skin, Type A, powder, gel strength ~300 g Bloom
greaseproof paperPT. Parisindo Pratama100 mm × 100 mm
ICP etcherOxford Instruments Plasma TechnologyPlasmaPro 100 Cobra
mask alignerPRO WinM-150
methanolSigma-Aldrich34860
micropipettePZ HTL S.A.4045-DV20–200 µL
microscope slidesPaul Marienfeld GmbH & Co. KGMarienfeld Superior76 mm × 26 mm × 1 mm
ovenJeio TechOF-02G
petri dishSPL Life Sciences10150150 mm × 20 mm
precision balanceRADWAG Wagi ElektroniczneWTC 200
PR-stripperMerckAZ 100 RemoverProduct No. 1000100
S/T spoonKorea Material Science20 cm
tweezersIdeal-tek S.A.2AB.TA
vacuum desiccatoriNexusIN-VS260 mm × 260 mm × 100 mm, 6.7 L
vacuum pumpRocker ScientificRocker 300
vortex mixerDAIHAN ScientificVM-10
water bathHanbaek ScientificHS-205WS330 mm × 300 mm × 150mm, 15 L

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Microneedle FabricationSilicon MicromachiningVacuum-Assisted MoldingGelatin MicroneedlesHollow MicroneedlesScanning Electron MicroscopyDrug Delivery SystemPolymer Casting
Fabrication of a Master Mold for Microneedles with a Micron-sized Air-vent Hole
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