Image-guided procedures are performed frequently by radiologists to insert a catheter within a target vessel or lumen or to perform biopsy of a lesion. For instance, an interventional radiologist uses fluoroscopy during percutaneous biliary drainage procedure (a procedure during which a catheter is inserted through the skin to drain the bile from liver) to identify the location of the needle tip within liver parenchyma, hepatic blood vessel or bile duct.
However, the identification of the target organ under fluoroscopy exposes the patient to x-ray irradiation, which may be significant if the time of procedure is prolonged.
We have designed a fiber core needle system that may help the radiologist identify the location of the needle tip in real time without exposing the patient to x-ray. Our needle system transmits a low power modulated light into the tissue through a fiber cable embedded in the needle and detects the backscattered light using another fiber inside the needle. We were able to successfully distinguish the location of our prototype needle tip inside a cow liver phantom to identify if the needle tip was within liver parenchyma, liver vessels, or in the bile duct based on the recorded backscattered light.
Ultrasound microbubbles are contrast agents used for diagnostic ultrasound imaging and as carriers for noninvasive payload delivery. Understanding the acoustic properties of individual microbubble formulations is important for optimizing the ultrasound imaging parameters for improved image contrast and efficient payload delivery. We report here a practical and simple optical tool for direct real-time characterization of ultrasound contrast microbubble dynamics based on light scattering. Fourier transforms of raw linear and nonlinear acoustic oscillations, and microbubble cavitations are directly recorded. Further, the power of this tool is demonstrated by comparing clinically relevant microbubble cycle-to-cycle dynamics and their corresponding Fourier transforms.
A three-dimensional laser optoacoustic imaging system was developed, which combines the advantages of optical
spectroscopy and high resolution ultrasonic detection, to produce high contrast maps of optical absorbance in tissues.
This system was tested in a nude mouse model of breast cancer and produced tissue images of tumors and vasculature.
The imaging can utilize either optical properties of hemoglobin and oxyhemoglobin, which are the main endogenous
tissue chromophores in the red and near-infrared spectral ranges, or exogenous contrast agent based on gold nanorods.
Visualization of tissue molecules targeted by the contrast agent provides molecular information. Visulization of blood at
multiple colors of light provides functional information on blood concentration and oxygen saturation. Optoacoustic
imaging, using two or more laser illumination wavelengths, permits an assessment of the angiogenesis-related
microvasculature, and thereby, an evaluation of the tumor stage and its metastatic potential.
The optoacoustic imaging system was also used to generate molecular images of the malignancy-related receptors
induced by the xenografts of BT474 mammary adenocarcinoma cells in nude mice. The development of the latter images
was facilitated by the use of an optoacoustic contrast agent that utilizes gold nanorods conjugated to monoclonal
antibody raised against HER2/neu antigens. These nanorods possess a very strong optical absorption peak that can be
tuned in the near-infrared by changing their aspect ratio. The effective conversion of the optical energy into heat by the
gold nanorods, followed by the thermal expansion of the surrounding water, makes these nanoparticles an effective
optoacoustic contrast agent. Optical scattering methods and x-ray tomography may also benefit from the application of
this contrast agent. Administration of the gold nanorod bioconjugates to mice resulted in an enhanced contrast of breast
tumors relative the background of normal tissues in the nude mouse model. The combination of this novel contrast agent
and optoacoustic imaging has the potential to become a useful imaging modality, for preclinical research in murine
models of cancer and other human diseases.
The development of gold nanoparticles for molecular optoacoustic imaging is a very promising area of research and development. Enhancement of optoacoustic imaging for molecular detection of tumors requires the engineering of nanoparticles with geometrical and molecular features that can enhance selective targeting of malignant cells while optimizing the sensitivity of optoacoustic detection.
In this article, cylindrical gold nanoparticles (i.e. gold nanorods) were fabricated with a plasmon resonance frequency in the near infra-red region of the spectrum, where deep irradiation of tissue is possible using an Alexandrite laser. Gold nanorods (Au-NRs) were functionalized by covalent attachment of Poly(ethylene glycol) to enhance their biocompatibility. These particles were further functionalized with the aim of targeting breast cancer cells using monoclonal antibodies that binds to Her2/neu receptors, which are over expressed on the surface of breast cancer cells. A custom Laser Optoacoustic Imaging System (LOIS) was designed and employed to image nanoparticle-targeted cancer cells in a phantom and PEGylated Au-NRs that were injected subcutaneously into a nude mouse. The results of our experiments show that functionalized Au-NRs with a plasmon resonance frequency at near infra-red region of the spectrum can be detected and imaged in vivo using laser optoacoustic imaging system.
A contrast agent for optoacoustic imaging and laser therapy of early tumors is being developed based on gold
nanocolloids strongly absorbing visible and near-infrared light. The optoacoustic signals obtained from gold nanospheres
and gold nanorods solutions are studied. In the case of 100 nm nanospheres as an example, a sharp increase in the total
area under the curve of the optoacoustic signal is observed when the laser fluence is increased beyond a threshold value
of about 0.1 J/cm2. The change in the optoacoustic signal profile is attributed to the formation of water vapor bubbles
around heated nanoparticles, as evidenced via thermoacoustic microscopy experiments. It has been determined that,
surprisingly, gold nanoparticles fail to generate detectable nanobubbles upon irradiation at the laser fluence of ~2
mJ/cm2, which heats the nanoparticles up to 374°C, the critical temperature of water. Only when the estimated
temperature of the particle reaches about 10,000°C, a marked increase of the optoacoustic pressure amplitude and a
changed profile of the optoacoustic signals indicate nanobubble formation. A nanoparticle based contrast agent is the
most effective if it can be activate by laser pulses with low fluence attainable in the depth of tissue. With this goal in
mind, we develop targeting protocols that form clusters of gold nanocolloid in the target cells in order to lower the
bubble formation threshold below the level of optical fluence allowed for safe laser illumination of skin. Experiments
and modeling suggest that formation of clusters of nanocolloids may improve the sensitivity of optoacoustic imaging in
the detection of early stage tumors.
Optoacoustic Tomography (OAT) is a rapidly growing technology that enables noninvasive deep imaging of biological tissues based on their light absorption. In OAT, the interaction of a pulsed laser with tissue increases the temperature of the absorbing components in a confined volume of tissue. Rapid perturbation of the temperature (<1°C) deep within tissue produces weak acoustic waves that easily travel to the surface of the tissue with minor attenuation. Abnormal angiogenesis in a malignant tumor, that increases its blood content, makes a native contrast for optoacoustic imaging; however, the application of OAT for early detection of malignant tumors requires the enhancement of optoacoustic signals originated from tumor by using an exogenous contrast agent. Due to their strong absorption, we have used gold nanoparticles (NP) as a contrast agent. 40nm spherical gold nanoparticles were attached to monoclonal antibody to target cell surface of breast cancer cells. The targeted cancer cells were implanted at depth of 5-6cm within a gelatinous object that optically resembles human breast. Experimental sensitivity measurements along with theoretical analysis showed that our optoacoustic imaging system is capable of detecting a phantom breast tumor with the volume of 0.15ml, which is composed of 25 million NP-targeted cancer cells, at a depth of 5 centimeters in vitro.
Optoacoustic tomography (OAT) is a medical imaging method for detection of cancerous tumors that uses laser pulses to produce transi ultrasonic waves with spatial profiles replicating distribution of absorbed optical energy. Unlike conventional ultrasonography that uses an external source of acoustic waves, OAT uses transient acoustic waves generated as result of thermal expansion of tissue preferentially heated with short laser pulses. Tissues with different optical properties have different optoacoustic profiles and this enables reconstruction of an acoustic image based on distribution of optical absorption. It is anticipated that the difference in optical absorption between very early tumors and normal tissues might be minimal, justifying application of a contrast agent. Gold Nanoparticles (NP) can be designed to strongly absorb desirable color of laser pulses and effectively produce acoustic waves. Therefore, gold NP can be potentially employed as an optoacoustic contrast agent. We studied sensitivity of optoacoustic imaging in phantoms resembling dimensions and properties of the breast with small objects loaded with gold NPs of various concentrations. Targeted selective loading of breast cancer cells in culture with 40-nm diameter NPs was experimentally demonstrated with electron microscopy and fluorescence labeling techniques. To achieve selective targeting, Herceptin, a monoclonal antibody raised against Her2 receptor was conjugated to NPs using streptavidin-biotin conjugation as a linker. Targeting experiments simultaneously demonstrated that Mab/NPs conjugates inhibit cell proliferation of Her/neu positive cells. These data present the first step in development of a new technology for highly selective cancer chemotherapy with capability to diagnose the presence of malignant tumors and monitor the effects of the treatment.