Photoacoustic tomography (PAT), which combines the best qualities of ultrasound and light absorption, can now provide clinicians with multicontrast images of biological tissue several inches below the skin’s surface. The technique, developed by Dr. Lihong V. Wang at Washington University in St. Louis, achieves the imaging depth by combining the high contrast resulting from light absorption by colored molecules such as hemoglobin or melanin with the spatial resolution of ultrasound. He is working with physicians at Washington University School of Medicine to move four applications of photoacoustic tomography to clinical trials: visualizing sentinel lymph nodes important in breast cancer staging; imaging melanomas; monitoring early response to chemotherapy; and imaging the gastrointestinal tract. Among the most exciting advances for PAT is its ability to reveal the use of oxygen by tissues. Excessive oxygen-burning, or hypermetabolism, is a hallmark of cancer. Almost all diseases, especially cancer and diabetes, cause abnormal oxygen metabolism. PAT would provide an early warning diagnostic test that does not require a contrast agent, which is a potential game-changer, Wang said. Current optical techniques produce images with quality resolution and strong contrasts, but only at tissue depths up to about 1 mm because of photon scattering. Scattering does not destroy the photons, which can reach a depth of about 7 cm. Major embodiments of PAT, with representative in vivo images. (A) OR-PAM of sO2 in a mouse ear. (B) AR-PAM of normalized total hemoglobin concentration, [hemoglobin], in a human palm. (C) Linear-array PACT of normalized Methylene Blue concentration, [dye], in a rat sentinel lymph node (SLN). (D) Circular-array PACT of cerebral hemodynamic changes, Δ[hemoglobin], in response to one-sided whisker stimulation in rat. (E) PAE of a rabbit esophagus and adjacent internal organs, including the trachea and lung. UST, ultrasonic transducer. (Image: Dr. Lihong V. Wang) The trick of PAT is to convert light absorbed at depth to sound waves, which scatter a thousand times less than light, for transmission back to the surface. In the technique, a nanosecond-pulsed laser is directed at the tissue of interest, and is irradiated at an optical wavelength. This thermoelastic expansion converts photons to sound waves that are used to form images with the resolution associated with the ultrasound wavelength, at tissue depths never before possible. “In current practice, we use optical microscopy to examine organelles and cells and nonoptical imaging techniques such as x-ray tomography for tissues and organs,” Wang said. “None of the clinical imaging technologies give you the strong contrast of the optical techniques. So between the microdomain and the macrodomain, there’s a huge divide because people can’t relate the images acquired at one length scale to those acquired at another. “My hope is that photoacoustic tomography, which has consistent contrast over all length scales, can help translate the microscopic lab discoveries to macroscopic clinical practice.” With help from exogenous contrast agents — hemoglobin, melanin, DNA, organic dyes, genes engineered to express colorful products — PAT can image tissues such as lymph nodes that would otherwise blend in with their surroundings. Wang also is experimenting with “reporter genes,” which encode a colored product and show up well in photoacoustic images. To prove the benefits of PAT over current imaging practices, Wang biopsied sentinel nodes, which are nearest a tumor to which cancerous cells would first migrate. A surgeon would inject a dye, a radioactive substance or both near a tumor during a sentinel node biopsy. The body would treat the injected substances as foreign, so they would flow to the first draining node to be filtered and flushed from the body. “A gamma probe or a Geiger counter is used to locate the radioactive particles, but it gives only a rough idea of the node’s location,” Wang said. To find the node, the surgeon would have to cut open the area and follow the dye visually to the sentinel lymph node. Instead of this technique, Wang proposed injecting an optical dye that shows up clearly in photoacoustic images. A hollow needle can be guided directly to the node and a tissue sample can be taken through the needle. In the current clinical trial, the surgeon is not taking tissue but rather deploying a tiny metal clip through the needle. The patient then undergoes a lymph node dissection, and the dissected lymph node is x-rayed to see whether or not it contains the clip. “If this technique proves accurate, we will be converting a surgical procedure into a needle biopsy possible on an outpatient basis,” Wang said. “In the US alone, 100,000 of these surgical biopsies are done every year, so the new procedure would spare many patients injury — not to mention expense.” Wang thinks that photoacoustic imaging also could be useful for systems biology, a new movement in bioscience that focuses on systems as a whole rather than on individual components. “We’re really just … builders who are going to help other scientists make the revolutionary discoveries in biology and medicine,” Wang said. “At least that’s my hope.” The findings were detailed in the March 23 issue of Science. For more information, visit: www.wustl.edu