METALS IN MEDICINE AND THE ENVIRONMENT

The Photoacoustic Effect

Photoacoustic imaging is based on the photoacoustic effect.  The photoacoustic effect was discovered in 1880 by Alexander Graham Bell.  In 1880, Bell demonstrated the photoacoustic effect by showing that thin discs emitted sounds when they were exposed to a beam of sunlight that was rapidly interrupted with a rotating slotted disk.  The thin disks absorbed energy from the sunlight and transformed it into kinetic energy through energy exchange processes.  When this happens, local heating results and creates a pressure wave or sound.  Some time later Bell demonstrated that the photoacoustic effect occurred when materials were exposed to non-visible light as well.  He showed that materials exposed to infrared and ultraviolet light could also produce sounds.  Then, by measuring the sound at different wavelengths, he created a photoacoustic spectrum that could be used to identify the components of the sample that absorbed light.  The photoacoustic effect was later demonstrated on liquids and gases.

Photoacoustic Imaging
           
Photoacoustic imaging is a new imaging technique that is finding more and more uses in biomedicine.  Specifically, photoacoustic imaging is a hybrid imaging modality based on the photoacoustic effect.  In most photoacoustic imaging cases, either a non-ionizing laser or a radio frequency are used to deliver pulses to biological tissues.  As with the thin disks Bell used, some of the delivered energy will be absorbed and converted to heat.  This heat leads to transient thermoelastic expansion which leads to wideband ultrasonic emission in the MHz range.  These ultrasonic waves are detected and used to construct an image.  It has been discovered that optical absorption is directly associated with physiological properties.  Therefore, the magnitude of the photoacoustic signal reveals physiologically specific optical absorption contrast.  Depending on how the absorption spectrum is used to construct the image, either a 2D or 3D image can be created of the area.  The optical absorption in the target tissue can come from either endogenous molecules or exogenously delivered functional contrast agents.

Advantages of Photoacoustic Imaging
           
The reason optical imaging is so desirable, especially in early cancer diagnosis, is because a strong correlation exists between optical absorption and hemoglobin concentration/oxygenation.  The problem is that the existing high-resolution optical imaging techniques, like two-photon microscopy, don’t sense optical absorption directly.  Another problem with existing techniques is that they rely on ballistic photons for imaging, which limits their imaging depths because of strong optical scattering in biological tissues.  However, since photoacoustic imaging doesn’t rely on ballistic photons for excitation, it provides high resolution with relatively larger imaging depths.  In fact, the scattering of ultrasonic waves is in the range of two to three orders of magnitude less that optical scattering in biological tissues.            

table of existing imaging technologies

Figure 1.  Comparison Table of Existing Imaging Techniques
Image courtesy of Wikipedia

Not unlike ultrasound imaging, the parameters of resolution and imaging depth of photoacoustic imaging are can be scaled by changing the frequency of the ultrasound transducer used.  So, photoacoustic imaging combines the advantages of optical absorption contrast with ultrasonic spatial resolution for deep imaging beyond ballistic techniques.

Some Examples of Functional Uses

Recent research has shown that photoacoustic imaging can be used in vivo for tumor angiogenesis monitoring, blood oxygenation mapping, functional brain imaging, and skin melanoma detection.
Thermoacoustic tomography is can be used for breast cancer detection by using low scattered microwaves for excitation instead of laser pulses.  This is because TAT can penetrate biological tissues several centimeters thick with less than millimeter spatial resolution.  Because the normal tissue and the cancer tissue have different responses to radio frequency, thermoacoustic tomography is showing a lot of potential in early breast cancer diagnosis.  Figure 2 shows a thermoacoustic tomography image of a mastectomy specimen.  It is easy to see in this image that the malignant breast tissue has a higher microwave absorption, and therefore a stronger thermoacoustic signal, than the surrounding normal tissue.

breast tissue thermal image

Figure 2.  Thermoacoustic Tomography Image of Malignant Breast Tissue Image courtesy of Wikipedia


Functional brain mapping is another example from the wide range of uses of photoacoustic imaging, whether it is the detection of legions or hemodynamics monitoring.  The soft tissues of the brain can easily be distinguished through photoacoustic imaging because they have different optical absorption properties than other tissues.  Figure 3 shows the absorption contrast between a lesion area and the parenchyma in a rat brain through photoacoustic imaging as well as an open-skull photograph.

brain lesion

Figure 3.  Brain Lesion Detection with PAT and Open-Skull Photo after PAT Image courtesy of Wikipedia

Gold and Photoacoustic Imaging
           
Gold is the perfect example of an exogenously delivered functional contrast agent.  The reason gold nanoparticles, especially gold nanorods, are so important is that their optical absorption is tunable and they are fully biocompatible.  Gold nanorods can be designed with a specific size and aspect ratio that cause them to absorb light very strongly.  The gold nanorods most commonly used are 45 nm long and 20 nm wide.  These dimensions cause them to absorb near infrared light strongly.

gold nanorods

Figure 4.  Gold Nanorods Image courtesy of Optics.org

A New “Gold Standard” for Cancer Detection

Cancer has an endogenous contrast for photoacoustic tomography because of its high angiogenesis driven absorption.  However, this endogenous contrast may not be enough to create a PAT image of high enough resolution, and if it does produce enough contrast it is likely that the cancer has progressed to a later stage than hoped for.  The problem now becomes getting the gold to the cancer site, and more specifically getting the gold onto the cancerous cells.  Luckily, there are multiple ways this can be done.  The most promising answer comes from the development of a cancerous cell.  Most all cells express a protein called the Epidermal Growth Factor Receptor (EFGR) on their surface.  However, cancer cells are known to greatly overexpress this protein.  So, by conjugating the gold nanorods to an antibody for EFGR, the nanoparticles can be stuck all over the outside of a cancerous cell.  Figure 5 shows cancerous cells glowing gold under a microscope because they have these antibodies bound to their EFGR’s.

gold efgr


Figure 5.  Photograph of Gold-EFGR Antibodies Bound to Cancerous Cells
Image courtesy of Georgia Institute of Technology

By exposing the cancer cells to the gold-antibody conjugate, it’s very easy to distinguish between normal cells and cancer cells.  Because a healthy cell won’t bind the nanoparticles specifically, they don’t show up.  Actually, the gold-antibody conjugates have a 600 percent higher affinity for the cancerous cells than for normal cells.  So, if a solution of these gold-antibody conjugates is added to a mixture of normal and cancerous cells, the cancerous cells shine brightly.  However, that doesn’t do a lot of good for in vivo studies.  But, it has been shown that these gold nanoparticles can be attached to other tumor-specific antibodies, to bind them specifically to a certain type of cancer, like breast cancer.  This way ensures that the area of high contrast in the image is a breast cancer tumor. 

Other Applications of Gold Nanoparticles

Another very important application of these gold nanoparticles, once they’re stuck to the cancer cells, is photothermal therapy.  During the laser irradiation process, the temperature of these gold nanorods can increase enough to induce apoptosis in the cancer cells.  This would be a very big deal because it could lay the foundation for a highly selective, non-invasive, cancer therapy.  

References

A. Grinvald et al. (1986). "Functional architecture of cortex revealed by optical imaging of intrinsic signals". Nature 324: 361-364. 

M. Xu and L.H. Wang (2006). "Photoacoustic imaging in biomedicine". Review of Scientific Instruments 77: 041101.

M. Xu et al. (2005). "Universal back-projection algorithm for photoacoustic-computed tomography". Physical Review E 71(1): 016706.

X. Wang, et al. (2003). "Non-invasive laser-induced photoacoustic tomography for structural and functional imaging of the brain in vivo". Nature Biotechnology 21(7): 803-806. 

X. Wang, et al. (2006). "Non-invasive imaging of hemoglobin concentration and oxygenation in the rat brain using high-resolution photoacoustic tomography". Journal of Biomedical Optics 11(2): 024015. 

G. Ku, et al. (2005). "Thermoacoustic and photoacoustic tomography of thick biological tissues toward breast imaging". Technology in Cancer Research and Treatment 4(5): 559-566. 

Zhang, H. F. et al. (2006). "Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging". Nature biotechnology 24: 84851.

Zhang, H. F. et al. (2007). "Imaging of hemoglobin oxygen saturation variations in single vessels in vivo using photoacoustic microscopy". Applied Physics Letters 90: 053901.

Wikipedia.  Photoacoustic Imaging.

Science Daily.  Gold Nanoparticles May Simplify Cancer Detection.

Optics.org.  Photoacoustic imaging goes for gold.

Author:  Jarrod Rasnake