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Imaging at Microscopic Resolution

The noninvasive visualization of living tissue at the microscopic level is a long cherished dream in the fields of medicine and biology. The high-resolution visualization of living tissues is possible with an advanced in-vivo imaging technology; namely, combined ultrasound, photoacoustic and elasticity microscopy, capable of visualizing both structural and functional properties of living tissue such as internal micro- and macro-architecture, surface topography, conformation, transformation, compliance, homogeneity, growth rate, biomechanics and even cell function within tissues.

The combined ultrasound, photoacoustic and elasticity imaging may be useful in many applications including cancer research, diagnostic imaging and therapy monitoring, cellular imaging, small animal imaging, microsurgery, etc. Several applications of the ultrasound, photoacoustic and elasticity imaging at microscopic resolution are discussed below.

Application 1: Assessment of anatomical and functional properties of engineered tissue constructs

Currently, tissue engineers are employing invasive techniques like histological analysis, to determine dynamic structural and functional properties of engineered tissues and to differentiate between normal and pathologically transformed tissues. Many of the tissue-engineering constructs are based on cellular or molecular mechanisms for incorporation and regeneration, hence it is very much required to have a non-invasive imaging system that could assay the qualitative and quantitative functions including internal micro and macro-architecture, surface topography, conformation, transformation, compliance, homogeneity, growth rate and biomechanics of these engineered tissues.

Compared to other microscopy imaging techniques, high-frequency ultrasound biomicroscopy has unique advantages for many biomedical applications. First, ultrasound biomicroscope operates in-vivo with a resolution approaching cellular level. Second, a large field of view and 3-D imaging either eliminates or simplifies sample preparation. Finally, ultrasound biomicroscopy is a non-invasive tool or can be used in conjunction with existing invasive procedures. However, ultrasound microscopy can provide mostly the anatomical properties of the tissue with limited abilities to assess functional and biomechanical properties of the tissue. To address this limitation, we developed a combined ultrasound biomicroscopy, photoacoustic and elasticity imaging technique to simultaneously evaluate morphological and functional properties of the tissue [1].

The integration of ultrasound microscopy with complementary photoacoustic and strain imaging techniques is simplified because of common ultrasonic detector and associated electronics [2]. A custom-built combined ultrasonic, photoacoustic and strain microscope was developed and tested on tissue-mimicking phantoms with varying ultrasonic, optical and elastic properties. Different structures within phantom were identified in the ultrasound, photoacoustic and strain images based on the mechanical properties and optical absorption of the material.

Application 2: Measurement of blood perfusion in microvasculature

In many clinical and research applications including cancer diagnosis, tumor response to therapy, reconstructive surgery, monitoring of transplanted tissues and organs, and quantitative evaluation of angiogenesis, sequential and quantitative assessment of microcirculation in tissue is required. We present an imaging technique capable of spatial and temporal measurements of blood perfusion through microcirculation. In simple words – Press hard on your arm and notice the skin turning pale, i.e., you are constricting the blood vessels and pushing out the blood in that region. Once the pressure is released, there is blood flow back to the region. The human eye can notice only superficial changes. The combined ultrasound, photoacoustic and strain imaging system can image deep structures.

To image microvasculature and monitor blood perfusion, the blood is forced out of the vessels by applying external deformation and the tissue response is then monitored continuously using both ultrasound and photoacoustic imaging. A strain-induced change in the blood volume alters the photoacoustic signal and, therefore, it should be possible to quantitatively relate the strain-induced changes in photoacoustic signal and the blood content of the tissue. However, the assessment of the internal deformation experienced by the tissue is required to correctly interpret the change in photoacoustic signal. Therefore, ultrasound based strain imaging is also performed simultaneously with photoacoustic imaging.

To demonstrate the technique, studies were conducted using phantoms with modeled small blood vessels of various diameters positioned at different depths. A change in the magnitude of the photoacoustic signal was observed during vessel constriction and subsequent displacement of optically absorbing liquid present in the vessels. The results of the study suggest that photoacoustic, ultrasound and strain imaging could be used to sequentially monitor and qualitatively assess blood perfusion through microcirculation [3].

References

[1]        S. Mallidi, S. R. Aglyamov, A. B. Karpiouk, S. Park, and S. Y. Emelianov, "Functional and morphological ultrasonic biomicroscopy for tissue engineers," Proceedings of the SPIE Medical Imaging, vol. 6147, pp. 61470Y1-7, 2006.

[2]        S. Y. Emelianov, S. R. Aglyamov, A. B. Karpiouk, S. Mallidi, S. Park, S. Sethuraman, J. Shah, R. W. Smalling, J. M. Rubin, and W. G. Scott, "Synergy and applications of combined ultrasound, elasticity, and photoacoustic imaging," IEEE International Ultrasonics Symposium, pp. 405-415, 2006.

[3]        S. Mallidi, A. B. Karpiouk, S. R. Aglyamov, S. Sethuraman, and S. Y. Emelianov, "Measurement of blood perfusion using photoacoustic, ultrasound and strain imaging," Proceedings of the SPIE Photonics West Symposium: Photons Plus Ultrasound: Imaging and Sensing, vol. 6437, pp. 07:1-9, 2007