Design and Development of a Bioink for Fabricating Crosslinked Hydrogel Microneedles via 3D Printing for Transdermal Delivery of Estradiol Nanoparticles

Background: Conventional transdermal drug delivery systems are often limited by poor skin permeability and low drug loading efficiency, necessitating the development of advanced delivery platforms. Objectives: This study aimed to develop and optimize photopolymerizable bioinks (PBs) for liquid crystal display (LCD)-based 3D printing of crosslinked hydrogel microneedles (cHMNs) to enhance transdermal delivery of estradiol valerate (E2V). Methods: A Box–Behnken design (BBD) was used to optimize the effects of Gantrez™ S-97, Jurymer™, and polyvinyl alcohol (PVA) on viscosity, exposure time, hardness, and elasticity, with strong predictive performance (R2 = 0.9702–0.9907). Results: Estradiol valerate-loaded nanoparticles (E2V-NPs) were prepared via ionotropic gelation, exhibiting a particle size of 698.33 (0.78) nm, PDI of 0.50 (0.06), zeta potential of −39.09 (7.32) mV, and high encapsulation efficiency (86.87 (0.78)%). The optimized PBs enabled fabrication of uniform cHMNs (~800 µm height) with adequate mechanical strength (hardness 20.45 (1.23) N; elasticity 2.97 (0.49) MPa) and effective insertion capability. The E2V-NPs-loaded cHMNs exhibited sustained drug release over 12 days (~56.92 (4.27)%). Skin permeation studies showed a significantly enhanced flux (10.81 (4.55) µg/cm2/h) and cumulative permeation (12.94 (2.06) µg/cm2) compared to topical E2V-NPs and suspension, along with increased skin accumulation (38.55 (0.10) µg). Cytotoxicity studies confirmed that E2V and E2V-NPs were biocompatible (>80% viability), while PBs showed concentration-dependent cytotoxicity. Conclusions: Overall, this integrated platform combining design of experiment, nanoparticles, microneedles, and LCD 3D printing offered a promising strategy for enhancing transdermal drug delivery efficiency and reproducibility.