Cell membrane deformation and bioeffects produced by tandem bubble-induced jetting flow

Abstract

Cavitation with bubble-bubble interaction is a fundamental feature in therapeutic ultrasound. However, the causal relationships between bubble dynamics, associated flow motion, cell deformation, and resultant bioeffects are not well elucidated. Here, we report an experimental system for tandem bubble (TB; maximum diameter = 50 ± 2 μm) generation, jet formation, and subsequent interaction with single HeLa cells patterned on fibronectin-coated islands (32 × 32 μm) in a microfluidic chip. We have demonstrated that pinpoint membrane poration can be produced at the leading edge of the HeLa cell in standoff distance Sd ≤ 30 μm, driven by the transient shear stress associated with TB-induced jetting flow. The cell membrane deformation associated with a maximum strain rate on the order of 104 s-1 was heterogeneous. The maximum area strain (εa,m) decreased exponentially with Sd (also influenced by adhesion pattern), a feature that allows us to create distinctly different treatment outcome (i.e., necrosis, repairable poration, or nonporation) in individual cells. More importantly, our results suggest that membrane poration and cell survival are better correlated with area strain integral (∫ε2Adt) instead of εa,m, which is characteristic of the response of materials under high strain-rate loadings. For 50% cell survival the corresponding area strain integral was found to vary in the range of 56 ∼ 123 μs with εa,m in the range of 57 ∼ 87%. Finally, significant variations in individual cell's response were observed at the same Sd, indicating the potential for using this method to probe mechanotransduction at the single cell level.