Mechanistic study of ultrasound and microbubble enhanced cancer therapy in a 3D vascularized microfluidic cancer model

Accumulating evidence has shown that ultrasound exposure combined with microbubbles can enhance cancer therapy. However, the underlying mechanisms at the tissue level have not been fully understood yet. The conventional cell culture in vitro lacks complex structure and interaction, while animal studies cannot provide micron-scale dynamic information. To bridge the gap, we designed and assembled a 3D vascularized microfluidic cancer model, particularly suitable for ultrasound and microbubble involved mechanistic studies. Using this model, we first studied SonoVue microbubble traveling dynamics in 3D tissue structure, then resolved SonoVue microbubble cavitation dynamics in tissue mimicking agarose gels at a frame rate of 0.675 M fps, and finally explored the impacts of ultrasound and microbubbles on cancer cell spheroids. Our results demonstrate that microbubble penetration in agarose gel was enhanced by increasing microbubble concentration, flow rate and decreasing viscosity of the gel, and little affected by mild acoustic radiation force. SonoVue microbubble exhibited larger expansion amplitudes in 2 %(w/v) agarose gels than in water, which can be explained theoretically by the relaxation of the cavitation medium. The immediate impacts of ultrasound and SonoVue microbubbles to cancer cell spheroids in the 3D tissue model included improved cancer cell spheroid penetration in micron-scale and sparse direct permanent cancer cell damage. Our study provides new insights of the mechanisms for ultrasound and microbubble enhanced cancer therapy at the tissue level.