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

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 ....

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).

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.

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 .......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
cleanroom wipe	Asahi Kasei	BEMCOT M-3	25 mm × 25 mm
conical centrifuge tube	Corning	352070	50 mL
dicing saw	DISCO	DAD-3220	spindle 30,000 rpm, feed 50 mm/s, exposure = 4× blade thickness, DI-water coolant 0.5 L/min
digital microscopy	Hirox	KH-7700	Used with an MXG-5040RZ camera lens
disposable syringe	Korea Vaccine	KOVAX-SYRINGE	1 mL & 10 mL
distilled water	Samchun Pure Chemical	000W0054
double-sided non-woven tape	3M	ID-8370S	0.16 mm thickness
field-emission SEM	Hitachi High-Tech	S-4300SE
gelatin powder	Sigma-Aldrich	G1890	From porcine skin, Type A, powder, gel strength ~300 g Bloom
greaseproof paper	PT. Parisindo Pratama		100 mm × 100 mm
ICP etcher	Oxford Instruments Plasma Technology	PlasmaPro 100 Cobra
mask aligner	PRO Win	M-150
methanol	Sigma-Aldrich	34860
micropipette	PZ HTL S.A.	4045-DV	20–200 µL
microscope slides	Paul Marienfeld GmbH & Co. KG	Marienfeld Superior	76 mm × 26 mm × 1 mm
oven	Jeio Tech	OF-02G
petri dish	SPL Life Sciences	10150	150 mm × 20 mm
precision balance	RADWAG Wagi Elektroniczne	WTC 200
PR-stripper	Merck	AZ 100 Remover	Product No. 1000100
S/T spoon	Korea Material Science		20 cm
tweezers	Ideal-tek S.A.	2AB.TA
vacuum desiccator	iNexus	IN-VS	260 mm × 260 mm × 100 mm, 6.7 L
vacuum pump	Rocker Scientific	Rocker 300
vortex mixer	DAIHAN Scientific	VM-10
water bath	Hanbaek Scientific	HS-205WS	330 mm × 300 mm × 150mm, 15 L