Non‐Ionic Fluorosurfactants for Droplet‐Based in vivo Applications

Fluorocarbon oils are uniquely suited for many biomedical applications due to their inert, bioorthogonal properties. In order to interface fluorocarbon oils with biological systems, non‐ionic fluorosurfactants are necessary. However, there is a paucity of non‐ionic fluorosurfactants with low interfacial tension to stabilize fluorocarbon phases in aqueous environments (such as oil‐in‐water emulsions). We developed non‐ionic fluorosurfactants composed of a polyethylene glycol (PEG) segment covalently bonded to a flexible perfluoropolyether (PFPE) segment that confer lower interfacial tensions (IFTs) between a fluorocarbon oil, HFE‐7700, and water. Synthesis of a panel of surfactants spanning a molecular weight range of 0.64–66 kDa with various hydrophilic‐lipophilic balances allowed for identification of minimal IFTs, ranging from 1.4 to 17.8 mN m‐1. The majority of these custom fluorosurfactants display poor solubility in water, allowing their co‐introduction with fluorocarbon oils and minimal leaching. We applied the PEG5PFPE1 surfactant for mechanical force measurements in zebrafish, enabling exceptional sensitivity.