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 (IFT) 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 low IFTs between a fluorocarbon oil (HFE‐7700) and water. The 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. Synthesis of ten non‐ionic fluorosurfactants composed of a polyethylene glycol (PEG) segment bonded to a perfluoropolyether (PFPE) segment of various hydrophilic–lipophilic balances allowed for identification of minimal interfacial tensions. A perfluorocarbon‐in‐water microdroplet formulation allowed for in vivo mechanical force measurements and increased sensitivity was observed, expanding the relevance of this microdroplet platform.