A method of generating in situ shock wave–inertial microbubble interaction by a modified electrohydraulic shock wave lithotripter is proposed and tested in vitro. An annular brass ellipsoidal reflector (thickness=28 mm) that can be mounted on the aperture rim of a Dornier XL-1 lithotripter was designed and fabricated. This ring reflector shares the same foci with the XL-1 reflector, but is 15 mm short in major axis. Thus, a small portion of the spherical shock wave, generated by a spark discharge at the first focus (F1) of the reflector, is reflected and diffracted by the ring reflector, producing a weak shock wave approximately 8.5 μs in front of the lithotripter pulse. Based on the configuration of the ring reflector (different combinations of six identical segments), the peak negative pressure of the preceding weak shock wave at the second focus (F2) can be adjusted from −0.96 to −1.91 MPa, at an output voltage of 25 kV. The preceding shock wave induces inertial microbubbles, most of which expand to a maximum size of 100–200 μm, with a few expanding up to 400 μm before being collapsed in situ by the ensuing lithotripter pulse. Physical characterizations utilizing polyvinylidene difluoride (PVDF) membrane hydrophone, high-speed shadowgraph imaging, and passive cavitation detection have shown strong secondary shock wave emission immediately following the propagating lithotripter shock front, and microjet formation along the wave propagation direction. Using the modified reflector, injury to mouse lymphoid cells is significantly increased at high exposure (up to 50% with shock number >100). With optimal pulse combination, the maximum efficiency of shock wave-induced membrane permeabilization can be enhanced substantially (up to 91%), achieved at a low exposure of 50 shocks. These results suggest that shock wave–inertial microbubble interaction may be used selectively to either enhance the efficiency of shock wave-mediated macromolecule delivery at low exposure or tissue destruction at high exposure.

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