Significance Optical imaging of biological tissue has become a powerful tool for biologists and clinicians. Photoacoustic imaging (PAI) is an acoustic-mediated optical imaging method that uses the photoacoustic effect to offer a highly sensitive and abundant optical contrast over a wide spatial and spectral range. PAI has achieved remarkable success in blood oxygen saturation imaging, brain vasculature functional imaging, histology-like tissue imaging, and so on. In most PAI systems, piezoelectric transducers (PZT) and coupled water are essential. However, these contact-configurations limit the application fields of PAI. Furthermore, PZT is bulky for system design, and it can degrade imaging performance.

Non-contact PAI is one of the most important directions of PAI, having the potential to realize better imaging performance and a wider range of applications without water coupling. Non-contact PAI is especially suitable for PA ophthalmic imaging, intraoperative margin diagnosis, and burn diagnostics, which can avoid infection and discomfort. Meanwhile, the all-optical non-contact PA detection method can obtain a wider bandwidth and angular coverage. Minute-sized optical detection configuration makes for unblocked excitation and the multimodal design. Hence, it is of great significance to introduce and summarize the recent research in non-contact PAI and get an insight onto the characteristic application of the non-contact PAI technique in biomedical imaging.

Progress Various non-contact methods on interference and noninterference have been developed to implement a non-contact PAI. Air-coupled PAI based on a special low-frequency transducer has played a significant role in non-contact PAI. Low frequency contributes to less attenuation of PA waves. Deán-Ben et al. from Technical University Munich proposed an air-coupled PAI system using a homemade transducer with 800 kHz center frequency, which realized acoustic-resolution imaging [Fig.2 (a)]. Ma et al. from South China Normal University proposed an optical-resolution imaging system. Burned rabbit’s skin imaging [Fig. 2(b)] has been implemented to show that the non-contact PAI technique can be valuable in the adjuvant diagnosis and observation of burns. A frequency-domain PA detection based on a PA cell can realize non-contact imaging and spectral measurement [Fig.2 (c)].

All-optical methods were also used to achieve a higher sensitivity for non-contact PAI, including interferometric and noninterferometric method. Interferometric methods can be divided into homodyne, heterodyne, and speckle modes. We use the interferometer to detect the phase difference, which is the result of the pressure. In homodyne mode, Wang et al. from the University of Washington reported a non-contact PAM (PA microscopy) system in which a low-coherence interferometer was utilized. Yang Sihua’s team from South China Normal University proposed a PA-optical coherence tomography (PA-OCT) dual-modal system, which could provide complementary anatomical and functional information for imaging of biological tissues [Fig. 3(b)]. Based on the all-optical PA doppler effect, blood flow imaging was proposed to significantly broaden the scope of applications for obtaining the blood flow velocity of the microvasculature in biomedicine [Fig. 3(c)]. To adapt to the uneven surface, Hu et al. reported an extended depth-of-field non-contact PAM system using a dual nondiffracting Bessel beam. This system could image nonfat tissues with a high resolution (2.4 μm) and large depth-of-field (635 μm) [Fig. 3(e)], cooperated with a long coherence source. Furthermore, a 3×3 fiber coupler was used to eliminate phase noise and maintain phase stabilization. Wang et al. from Northeastern University demonstrated a 3×3 coupler-based fiber-optic interferometric system to detect local initial PA pressure. This method is fully non-contact and convenient for in vivo imaging [Fig. 4(d)]. In heterodyne mode, an acousto-optic modulator and IQ demodulator are needed for PA detection. Moreover, Eom et al. presented three-dimensional in vivo PA images of the blood vasculature of a chicken chorioallantois membrane obtained using a fiber-based non-contact PA tomography system [Fig. 5(a)]. Tian et al. proposed a non-contact PAI system using circular scan geometry, suggesting that the heterodyne interferometer could be potentially used in biomedical imaging. In speckle mode, the system configuration is simple, and it does not even need the reference light. Buj et al. developed a fast innovative holographic off-axis non-contact detection method for PAI, successfully imaging tissue phantoms with an embedded complex absorber structure, which imitated vascular networks [Fig. 6(a)]. Some methods based on correlation analysis of speckle were also utilized for imaging.

For the noninterferometric method, photoacoustic remote sensing (PARS) was first introduced by Hajireza et al. in 2017. In PARS, elasto-optical refractive index changes due to the transients of the PA initial pressure producing a significant time-varying reflection of a probe beam. Based on this mechanism, PA images can be obtained without any coherence noise (Fig. 7). The reason is that PARS has better sensitivity than traditional PAM in all-optical nature. PARS has been utilized for blood oxygen saturation imaging, virtual histology imaging, and ophthalmic imaging.

Furthermore, non-contact PAI has shown broad applications in the life sciences, especially in intraoperative margin diagnosis, ophthalmic imaging,and optical biopsy of cancer cells. Various tissue blocks were imaged by PARS with 266 nm excitation, and the results were highly consistent with H&E stained images (Fig. 8). A non-contact ophthalmic PA-OCT imaging could provide complementary structural and functional information of the eye (Fig. 9). Moreover, Zhou et al. demonstrated a preclinical device, all-optically integrated PA and OCT (AOPA/OCT), which can simultaneously provide label-free biomarkers of vascular patterns, temporal and spatial heterogeneity of blood flow, and tissue micro-structure changes during tumor growth with pathophysiological correlations in mice models (Fig. 10). However, these methods and systems have their advantages and disadvantages (Table 1).

Conclusions and Prospects Air-coupled, interferometric, and noninterferometric methods provide new ideas and technical strategies for non-contact PAI. Therefore, a clinical transformation that uses different technical characteristics is the focus of the exploration. As technology continues to evolve, non-contact methods are expected to replace traditional contact methods, making PAI a more attractive tool for biomedical applications.