A composite contrast agent, a nanoemulsion bead with assembled gold nanospheres at the interface, is proposed to improve the specific contrast of photoacoustic molecular imaging. A phase transition in the bead's core is induced by absorption of a nanosecond laser pulse with a fairly low laser fluence (∼3.5 mJ/cm2), creating a transient microbubble through dramatically enhanced thermal expansion. This generates nonlinear photoacoustic signals with more than 10 times larger amplitude compared to that of a linear agent with the same optical absorption. By applying a differential scheme similar to ultrasound pulse inversion, more than 40 dB contrast enhancement is demonstrated with suppression of background signals.

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