Interaction mechanics of acoustic cavitation with fibrin networks

Abstract

Stiff and dense fibrin networks in chronic blood clots impede drug penetration, limiting the efficacy of thrombolytic therapies. Acoustic cavitation of microbubbles is a promising strategy to enhance drug delivery in soft tissues. However, the interaction of these bubbles with stiff fibrin networks has yet to be investigated. Here, we show that ultrasound-driven bubbles undergoing periodic oscillations can penetrate and alter dense fibrin networks. The penetrated bubbles create three-dimensional paths that enable nanobeads (matrix transport markers) to infiltrate up to 200 \textmu m deep into the mesh. Radial bubble oscillation is found to be the dominant forcing mechanism on fibrin fibers. Combining mechanical measurements with these observations reveals that the radial stress from a single bubble oscillation is far below the fracture strength of fibrin fibers. Instead, repeated sub-fracture loading from thousands of oscillations progressively accumulates damage and softens the network until it yields - the plausible mechanism for bubble penetration through the fiber mesh. We further explored this fibrin softening at a range of peak applied forces. At low force, the fibrin network initially softens, but is resistant to further damage after hundreds of cycles. At higher forces, networks continue to soften without reaching a stable state, indicating the progressive accumulation of damage. These results show that cavitation can enhance matrix transport in dense fiber mesh by softening and structurally altering fibrin networks. The underlying physics is governed by the viscoplastic mechanics of bubble-fibrin interactions. These findings establish a mechanistic framework to design comprehensive treatment strategies for fibrotic aged clots.