Fabrication of biodegradable particles with tunable morphologies by the addition of resveratrol to oil in water emulsions.

Particles for biomedical applications can be produced by emulsifying biocompatible polymers dissolved in an organic solvent in water. The emulsion is then transferred to an extraction bath that removes the solvent from the dispersed droplets, which leads to polymer precipitation and particle formation. Typically, the particles are smooth and spherical, likely because the droplets remain fluid throughout the solvent extraction process allowing minimization of surface area as the volume decreases. Few modifications to this technique exist that alter the spherical geometry, even though particle performance, from drug delivery to engaging cells of the body, can be tuned with morphology. Here we demonstrate that incorporation of resveratrol, with the aid of ethanol, into the oil phase of an emulsion of poly(lactide-co-glycolide) and dichloromethane in aqueous poly(vinyl alcohol) leads to a crumpled particle morphology. Video microscopy of particle formation revealed that during solvent extraction the droplet crumples in on itself, which does not occur when only ethanol is added to the emulsion. It is unclear why this occurs with resveratrol, but its hydroxyl groups appear to be optimally positioned because removal of the 4' hydroxyl or addition of a 3' hydroxyl resulted in a loss of crumpled particle morphology. We demonstrate that particle morphology can be tuned from that of a crumpled sheet of paper to a deflated sphere by switching out ethanol for a different cosolvent. We quantify the degree of particle deformation with surface area calculated from krypton adsorption isotherms and BET theory and find surface area correlates with resveratrol loading in the particle. Furthermore, spherical particles are achieved when ethyl acetate is used in lieu of dichloromethane and a cosolvent. We propose that during solvent extraction, resveratrol accumulates at the droplet surface where it inhibits polymer chain motion necessary to maintain a spherical geometry and the role of cosolvent is to redistribute resveratrol from the droplet bulk to its surface. This method of producing nonspherical particles extends to polycaprolactone and poly(L-lactic acid) and is compatible with the encapsulation of a hydrophobic fluorescent dye, suggesting hydrophobic bioactive agents could be encapsulated. Taken together, we demonstrate an ability to control morphology of biocompatible polymer particles produced by the widely practiced oil-in-water/solvent extraction protocol via the addition of resveratrol and a cosolvent to the oil phase. The methodology reported is straight forward, and scalable, and expected to be of utility in applications in which a deviation from the default smooth, spherical morphology is desired.