Cost-Effective Method of Fabricating Hollow Microneedle Using Superimposed Arc Imprint Laser Writing for Tailored Drug Delivery

Microneedles (MN) have been widely studied for efficient and painless drug delivery. Among them, hollow MNs are used to deliver large quantities of drug cargoes either passively or actively. However, fabricating hollow MNs is considered challenging due to the precision required for a hollow center and a sharp tip to penetrate skin without clogging.<br/><br/>Our proposed method for hollow MN fabrication, named Superimposed Arc Imprint Laser (SAIL) writing, was adapted from our previous work [1]. To the best of our knowledge, laser writing has only been used to produce solid MNs; it has yet to be used to fabricate hollow MNs. SAIL utilizes a layered arc design to achieve hollow microneedle molds. The hollow microneedle master mold was engraved on clear cast acrylic sheet using a 60W CO2 laser cutter. The laser beam ablates the 2D arcs on an acrylic sheet to create sharp tips and tapered bases. By tuning the laser power, speed, and focus, we can precisely control the height, sharpness, inner diameter, outer diameter, and overall geometry of the hollow microneedles. Two PDMS molds were fabricated: a positive replica at a 5:1 pre-polymer to curing agent weight ratio and a final negative mold at a 10:1 ratio.<br/>In this study, we have fabricated hollow MNs using a biocompatible UV-curable resin, named BioMed Clear. The biomed clear resin was poured over the negative mold using a syringe and allowed to cure in a UV chamber. On peeling the hollow microneedles, there was clear evidence of a hollow channel that went from the needle through the back of the patch. The microneedles’ height was 1mm, with a bore size was 0.7mm, and pitch of 1.5mm.<br/><br/>To demonstrate drug delivery with SAIL hollow MNs, we simultaneously delivered two drugs on one patch: Naltrexone Hydrochloride (NH) and Clonidine (Clo). Naltrexone is a classical opioid antagonist prescribed for alcohol and opioid use disorders [2], while Clo is primarily used for its antihypertensive properties, but it has been shown to mitigate some of the side effects associated with naltrexone therapy [3]. Specific areas of the acrylic master mold were rastered to create individual wells for loading different drugs without any mixing. These patterns were then replicated onto the negative PDMS mold ensuring precise alignment. Solutions of the naltrexone (20mg/mL) and Clonidine (0.5mg/mL) were prepared in PBS and injected into separate acrylic reservoirs glued to the back of the negative PDMS mold. A PDMS sheath was added on top of the reservoir to prevent the drug solution from leaking. This also enables the refilling of drug solutions as needed.<br/>We performed compression tests on the hollow MN and they proved to have sufficient strength to penetrate the skin (Force/needle &gt; 0.5 N). Additionally, we performed an in vivo penetration test on mice skin and there were visible punctures showing successful penetration. The two drugs with vastly different dosing needs (NH: 20 mg/day, Clo: 0.5 mg/day) were co-delivered invitro using an agarose hydrogel. The drugs passively diffused into the hydrogel and were measured at periodic intervals using UV-Vis spectroscopy. Notably, all the loaded drug was released within 24 hours indicating therapeutics can be delivered in highly customizable amounts.<br/>In conclusion, SAIL combines the creation of microneedles and the microfluidic channel into one step. This innovation offers the potential for both passive/active drug delivery and can be integrated with wireless pumps, reservoirs, and actuators. SAIL's compatibility with various polymers broadens the possibilities for microneedle design and applications. Our goal is to be able to combine drug delivery with sensing/diagnostics using the hollow microneedle platform for closed loop theranostic applications for truly personalized medicine.<br/><br/>References<br/>[1] A. Sadeqi et al., Sci. Rep., 12, 1 (2022).<br/>[2] K. Toljan et al., Med. Sci., 6, 4 (2018).<br/>[3] P. Mannelli et al., AJDAA, 38, 3 (2012).