Energetics and kinetics of membrane permeation of photoresists for bioprinting

Three-dimensional (3D) bioprinting is a promising technology which typically uses bioinks to pattern cells and their scaffolds. The selection of cytocompatible inks is critical for the printing success. In laserbased 3D bioprinting, photoresist molecules are used as bioinks. We propose that cytotoxicity can be a consequence of the interaction of photoresists with lipid membranes and their permeation into the cell. Here, molecular dynamics simulations and in vitro assays address this issue, retrieving partition coefficients, free energies, and permeabilities for eight commonly-used photoresists in model lipid bilayers. Crossing the hydrophobic center of the membrane constitutes the rate limiting step during permeation. In addition, three photoresists feature a preferential localization site at the acyl chain headgroup interface. Photoresist permeabilities range over eight orders of magnitude, with some molecules being membrane-permeable on bioprinting timescales. Moreover, permeation correlates well with the oil-water partition coefficients and is severely hampered by the lipid ordering imposed by the lipid saturation. Overall, the mechanism of interaction of photoresists with model lipid bilayers is provided here, helping to classify them according to their residence in the membrane and permeation through it. This is useful information to guide the selection of cytocompatible photoresists for 3D bioprinting.