Polymerized Pro-Estrogen Microneedles via Two Photon Polymerization.

Two-photon polymerization (TPP) is a powerful technique to create microscale structures with high precision, offering significant potential in tissue engineering and drug delivery. While conventional TPP-fabricated drug carriers rely on passive encapsulation, these systems often suffer from low payload capacity and diffusion-controlled release kinetics. To address these challenges, we present the first demonstration of TPP-printed polyprodrug microstructures, where the therapeutic agent is covalently integrated into the polymer network as the repeating unit itself. Estrogen-based diacrylate monomers derived from 17β-estradiol were synthesized via one-step esterification/transesterification to create a photocurable resin. Curing under flood UV irradiation yielded a rigid thermoset (E' ∼2.5 GPa at 25°C) with a glass transition temperature of about 50°C. Using TPP, we fabricated various microscale needles (100 × 100 × 400 µm, 2 µm resolution) from this resin, enabling direct printing of intrinsically therapeutic microstructures without post-processing drug loading. The cured polymer acts as both a structural matrix and a hydrolytically degradable polyprodrug, releasing estradiol through cleavage of ester bonds. By combining covalent drug-polymer integration with high-resolution 3D printing, this work establishes a platform for personalized transdermal drug delivery devices with spatially controlled release profiles determined by microstructure design and polymer degradation kinetics.