Tailored Forest Microneedles Using Cross Over Lines Laser Writing for Simultaneous Delivery of Multiple Drugs

Microneedles (MNs) are gaining traction as a promising method for transdermal delivery of therapeutics via painless and user-friendly patches. Notably, direct write fabrication using CO2 laser-based cross-over-lines (COL) laser writing offers a cost-effective and scalable approach for MN production.<br/><br/>The COL method utilizes a three-step cleanroom-free method to make microneedles [1]. The microneedle master mold was engraved on clear cast acrylic sheet using a 60W CO2 laser cutter. The laser beam ablates a 2D pattern of crossing lines on the acrylic, creating conical microneedle molds. 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. We fabricated microneedles of different geometries and heights on one single patch by exploring different laser cutting parameters, like power, speed and focus. The resulting microneedles vary in in height, widths, and spacing, resembling a forest. This design, coupled with the specific formulation within each microneedle, allows for a controlled and unique drug release profile. To showcase the range of possibilities, a microneedle patch was formed into the letters "NANOLAB" with different heights and base diameters.<br/><br/>To demonstrate multiple drug loading capacity, we co-delivered two drugs: simvastatin (anti-inflammatory) and tetracycline hydrochloride (antibacterial) for treating burn wounds [2] from a single patch. 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. To the best of our knowledge, this is the first platform to have delivered multiple drugs using a single microneedle patch fabricated with any laser-based approach.<br/><br/>To make the dual drug loaded microneedle patch, 10 mg of each drug powder was separately added to 10mg/mL of zein solution (made in 80% ethanol) and loaded onto the PDMS negative microneedle molds. A flexible backing layer consisting of Elastic 50A resin was added for better conformability. The microneedle patch contained needles of different heights (1100±30 µm for simvastatin (tall) and 670±45 µm for TH (short)) while all other microneedle properties remained constant.<br/><br/>The mechanical properties of the microneedles were tested and they proved to have enough strength to penetrate the skin (&gt; 0.5 N/needle). The delivery profile of both the drugs were conducted invitro with phosphate buffer saline (PBS). For the same drug concentration,<br/>simvastatin and TH had different delivery profiles owing to the different heights of the microneedles and distinct interaction with zein. Zein's balanced hydrophilic and lipophilic nature makes it ideal for sustained drug/protein release [2]. Simvastatin, a lipophilic drug, enhanced the curvature of zein, leading to the formation of smaller, spherical particles with an increased surface area. In addition, the larger surface area from the tall microneedles promoted a faster initial release: 50% of simvastatin delivered within the first 24 hours, followed by a sustained release of the remaining drug over 3 days. In contrast, TH accumulated on the surface of zein due to its hydrophilic nature creating films with zein rather than spheres. Due to the hydrogen bonding of the TH with zein, a sustainable release profile is seen with only 30% within 24 hours, while 60% is released over 4 days. Identifying suitable polymer and drug combinations can further help with tailoring the release profiles for targeted applications.<br/><br/>In conclusion, we aim to fabricate of forest microneedles with tunable geometries using COL laser writing to deliver multiple drug cargos, with distinct release profiles at different depths, for the treatment of burn wounds, or other medical ailments.<br/><br/>References<br/>[1] A. Sadeqi et al., Scientific Reports, 12, 1 (2022).<br/>[2] S. Bhatnagar et al., AAPS PharmSciTech, 19, 1818 (2018).