Introduction to biomedical imaging

1.1 What is biomedical imaging?

Biomedical imaging is an area that visually characterizes living objects in vitro and in vivo such as cells, tissues, and organs in the human body through various spectroscopic techniques. Functional, biological, and metabolic processes can also be investigated. Nowadays biomedical imaging is an essential tool to diagnose and treat diseases such as cancer, and a variety of biomedical imaging modalities are now available. These include magnetic resonance imaging (MRI), X-ray computed tomography (CT), ultrasound imaging (USI), positron emission tomography (PET), single photon emission computed tomography (SPECT), and fluorescent imaging (FI). The operation of biomedical imaging critically depends on the imaging agent. In MRI, CT, and USI, images are improved with an imaging agent through contrast enhancement. In PET, SPECT, and FI, imaging agents are essential components in obtaining clear images.

Biomedical imaging rapidly developed in both imaging tools and imaging agents. As a result, both resolution and sensitivity have been improved. In addition, multi-imaging modalities, such as MRI-CT and MRI-PET, are now being developed. They can provide us with complementary information and some of them are already available in the market. Sensitivity is further improved by integration of a targeting molecule into the imaging agent. A drug can be conjugated to an imaging agent for both diagnosis and treatment (so-called theragnosis) of diseases such as cancer.

1.2 Various imaging modalities now available

It is worth briefly introducing some imaging modalities and imaging agents that are now available. Ultrasmall lanthanide oxide nanoparticles can be used in various imaging modalities, including MRI, CT, USI, PET, SPECT, and FI. USI costs are low and so is the most frequently used to check health and diagnose disease. CT and MRI are more expensive than USI and so are less frequently used. PET and SPECT are the most expensive and least frequently used, mainly due to radio-isotopes being used as imaging agents. FI is very sensitive but mostly used for research purposes owing to its imaging depth limits. Each one of these imaging techniques is described below.

1.2.1 Ultrasound imaging (USI)

Ultrasound imaging is a truly non-invasive imaging modality because it makes use of non-ionizing ultrasonic radiation [1]. Therefore, it does not harm the human body. The frequency in USI ranges from 2 to 18 MHz. The ultrasound wave is generated by a piezoelectric transducer (PZT) and travels through the body, where it can be focused to the desired depth for imaging. The returning ultrasound wave (i.e. the echo) to the tranducer is transformed into an electrical signal and finally into an image.

The ultrasound image can be improved by using contrast agents through echo signal enhancement [2,3]. The currently used USI contrast agents are microbubbles, which contain air or a specific gas such as nitrogen and perfluorocarbon in a lipid, galactose, polymer, or albumin shell. These microbubbles range from 1 to 5 μm in diameter. A USI contrast agent is intravenously injected into the body. When an ultrasound wave passes through a microbubble, the gas inside that microbubble compresses and oscillates, reflecting the ultrasound wave and thus enhancing the echo signal. The echo signal can be further enhanced if the ultrasound wave resonates inside the microbubble. Under such conditions, even a small blood vessel can be imaged. If a USI contrast agent is conjugated with a targeting molecule, such as an antibody or a peptide, the echo signal from the targeted region can be further boosted. A USI contrast agent can also be applied to theragnosis if a drug is conjugated with it. Some commercial USI contrast agents are listed in Table 1.1.

1.2.2 X-ray imaging and X-ray computed tomography (CT)

X-ray imaging is frequently used to check for the presence of disease during health examinations and is widely used to image bone structure. The energy of X-rays is so high that it corresponds to ionizing radiation. Therefore it is harmful to the human body if exposed to it for a long time and so cannot be considered a truly non-invasive imaging modality. It may damage DNA and so long-time exposure to X-rays should be avoided, especially for infants.

Wilhelm Röntgen discovered the X-ray and first applied it to bone imaging. The image is obtained by targeting a short pulse of hard X-rays (5–100 keV) to a specific part of the body and detecting the outgoing X-ray beam through the body. The image is then produced on a two-dimensional (2-D) photographic film. Thus, X-ray imaging is based on the reduction of the beam as it passes through the body, so the difference in attenuation of the X-ray beam between organs, tissues, and bones produces the contrast and thus an image. As the X-ray is nearly transparent for soft tissues, X-ray imaging is useful for bones and hardened parts such as diseased areas in tissues.

X-ray computed tomography (CT) is a 2-D image made up of slices that are obtained as both the X-ray beam and detector rotate around the body. After a complete rotation, a slice image is constructed with the help of a sophisticated computation using a computer. The X-ray beam and detector are moved along the body axis and another image slice is obtained from this further scan. A 3-dimensional (3-D) image can be constructed from a continuous set of 2-D image slices. Its spatial resolution and sensitivity are comparable to that of MRI.

X-ray and CT images can be improved using a contrast agent, which strongly attenuates the X-ray beam intensity reaching the detector. Therefore, even soft tissues and tiny blood vessels can be imaged at a high resolution. Two types (i.e. oral and intravascular) of contrast agents are in the market (Table 1.2). The intravascular contrast agents are mostly tri-iodinated organic compounds with hydrophilic functional groups for water-solubility [4,5]. The oral contrast agents are mainly used for imaging stomach and intestines. Improved images can be obtained if a contrast agent is conjugated with a targeting molecule such as an antibody or peptide. On the other hand, gold nanoparticles can provide an enhanced contrast superior to an iodine contrast agent, because gold has an X-ray attenuation power of ∼ 2.7 times that of iodine [6]. Therefore, even the tiniest of blood vessels can be imaged with gold nanoparticles.

1.2.3 Magnetic resonance imaging (MRI)

Magnetic resonance imaging (MRI) makes use of nuclear magnetic resonance (NMR) of protons in the body to produce images [7]. It is a truly non-invasive imaging technique, because radiofrequency is used as the radiation source. Due to an ample existence of protons in the body in the form of water, proteins, fats, etc., signal intensity and spatial resolution is better than with USI and comparable to CT. MRI is very useful for imaging soft tissues such as brain, muscles, heart, and so on. Local protons have different densities and relaxation rates, from which images are obtained from differences in contrast. A normal tissue can be differentiated from a cancerous tissue because of their different proton densities and relaxation rates related to angiogenesis.

MRI contrast agents help to improve images through contrast enhancement. There are two types of MRI contrast agents based on proton relaxation mechanisms: T1 and T2 MRI contrast agents. The former is called a positive contrast agent because it makes the contrast brighter...