**8. Ultrasound and non-invasive therapy**

advanced visualization techniques and preoperative images, LUS can enhance an augmented reality scene to include updated images of details, important for high precision surgery thus enhancing the perception for surgeons during minimal access therapy. LUS integrated with miniaturized tracking technology is likely to play an important role in guiding future laparo‐

One of the first, and still one of the most important applications of ultrasound imaging is in diagnostics of various heart conditions. The dynamic real-time imaging makes ultrasound the modality of choice for characterization of a moving organ such as the heart. Some examples of the use of echocardiography are evaluation of cardiovascular anomalies in fetuses and newborns [139], assessment of aortic stenosis [140], evaluation of the function of the valves and examination of the flow and function after heart attacks. These examples are purely diagnostic applications without any kind of intervention associated, but ultrasound has also been used for guidance in cardiac surgery. One example was presented by Wang et al. [141]. They evaluated 129 patients who underwent robotic cardiac surgery. Transesophageal echocardiography was used for guidance of the cannula for peripheral cardiopulmonary bypass. Ultrasound imaging can potentially also be used for guidance in minimally invasive

Intra-operative guidance during endovascular procedures is usually performed with x-ray fluoroscopy. However, some investigators have reported the use of transabdominal ultra‐ sound for guidance. Lie et al. [142] studied the use of 2D transabdominal ultrasound during endovascular procedures. They found that ultrasound could be useful for guiding the insertion of guidewires, and control the wire position before connecting the second graft limb to the main limb of bifurcated grafts. Kaspersen et al. [143] reported a feasibility study registering ultrasound to pre-operatve CT data. This may be useful for updating the CT data used for navigation and correct for breathing motion and deformation of the blood vessels during the procedure. With recent advances in ultrasound technology, we believe that real-time 3D ultrasound have potential for further advancing the accuracy in the insertion of stentgrafts, and in particular the placement of fenestrated stentgrafts. Specifically, it is easier to track the tip of guidewires in three dimensions, while simultaneously visualizing a focused area of the 3D anatomy in real-time. A systematic review by Malkawi et al [144] concluded that percuta‐ neous endovascular repair was associated with fewer access related complications and reduced operative time. In a study by Arthurs et al [145], it was shown that use of ultrasound guided access significantly reduced access-related complications compared to percutanous access without ultrasound guidance. Successful ultrasound guidance in secondary interven‐ tions, for sealing endoleak after endovascular repair, has also been reported. Boks et al. [146] described transabdominal embolization using duplex ultrasound guidance, and Kasthuri et al. [147] used ultrasound for guiding percutaneous thrombin injection. Navigation of sten‐ tgrafts during endovascular procedures has also been demonstrated in patients using CT imaging [148]. However, 3D or 4D ultrasound integrated with navigation technology for

guidance of endovascular procedures has not yet been demonstrated in patients.

scopic surgery.

**7.3. Other applications**

64 Advancements and Breakthroughs in Ultrasound Imaging

mitral valve repair on the beating heart [123].

#### **8.1. High Intensity Focused Ultrasound (HIFU)**

High-intensity focused ultrasound (HIFU or FUS) has been known and developed for decades and can be applied to produce sharply delineated lesions in biological tissue (figure 26) [150-153]. The development of magnetic resonance (MR) thermometry enabled the thermal ablation progress to be monitored during sonication [154]. MR-guided HIFU (MRgFUS) has been approved by the FDA for the symptomatic treatment of uterine fibroids since 2004 [155]; clinical trials have been reported for breast [156, 157] and brain [158, 159] therapy, as well as pain palliation in bone [160, 161]. The MRgFUS treatment of abdominal organs, such as the kidney, pancreas or liver, poses additional technological and clinical challenges. First, for most therapeutic applications within the human body, tissue displacement caused by respiration and/or the cardiac cycle must be considered, and can be assumed to be periodic in anaesthe‐ tized patients. However, this may not be the case for free-breathing patients. This movement in addition to drift due to gravity and the intestine and bowel movement is important to account for during sonication in order to achieve accurately located FUS with respect to the target (e.g. tumour in the liver). Secondly, the presence of the rib cage affects the HIFU treatment planning and set-up. The rib cage acts as an aberrator that might affect the focusing [162, 163] and on the other hand, due to the high value of the absorption coefficient of the bone [164], the overheating on the ribs can be quite significant. These two aspects are currently the main challenges in order to achieve MRgFUS in moving abdominal organs.

technical limitations, spatial and temporal resolution trade-offs, and low signal-to-noise ratio associated with fast 3D acquisition sequences [172]. In addition, the time duration between the actual target displacement and the availability of the motion information from MR data is not negligible [173]. Hence, MR information-based real-time motion compensation generally compromises spatial resolution, geometric distortion and the precision of the MR thermometry

Ultrasound-Based Guidance and Therapy http://dx.doi.org/10.5772/55884 67

A first attempt at ultrasound-based motion tracking during MRgFUS was reported in phan‐ toms undergoing periodic and rigid motion of small amplitude [173]. Continuous 1D ultra‐ sound echo detection, along a direction parallel to the main axis of motion was used. This setup is not suitable for clinical applications as the external ultrasound imaging probe cannot send beams parallel to the axis of respiratory motion. Moreover, the local motion in the liver is spatially dependent and a 1D projection would not be sufficient. Truly simultaneous ultra‐ sound and MR imaging has only been reported in literature recently [175-178]. Only one of these studies was targeted towards MRgFUS and moving abdominal organs sonication [175]. They demonstrated in moving phantoms the feasibility of ultrasound-based 2D motioncompensated sonications integrated with reference free MR temperature monitoring, using a clinical ultrasound probe and a phased-array HIFU transducer [175]. An overview of our own

[174], of which the latter is of crucial importance during MRgFUS.

efforts for motion correction using 4D ultrasound can be found in section 4.3.

high velocity micro jets piercing into nearby cell membranes.

Although diagnostic ultrasound is considered safe with no adverse effects, ultrasound can with high acoustic outputs induce significant bioeffects (e.g. HIFU) and these bioeffects are divided into thermal and mechanical effects. The thermal effect is related to energy absorption in the tissue where part of the mechanical wave energy is converted to thermal energy and hence results in an increase in tissue temperature. The mechanical effects are related to cavitation and to radiation forces. Radiation forces arise when part of the forward propagating wave is back-scattered or absorbed and result in a pushing force on the tissue along the direction of the forward propagating wave. Within fluids, such radiation forces can give rise to acoustic streaming. Cavitation is related to the oscillation and possible collapse of gas nuclei occurring naturally within the body or artificially introduced as contrast agent in the form of microbubbles. Oscillating gas bubbles will generate streaming currents in surrounding liquids and hence shear forces on nearby cells that potentially result in bioeffects. Collapsing gas bubbles can result in high local temperatures, release of free radicals, emitted shock waves and

**8.2. Ultrasound-induced drug delivery**

**Figure 26.** Illustration shows the targeting of a tumor in the liver using high intensity focused ultrasound. Currently, to perform this, the patient has to be anesthetized and breathing must be stopped during sonications. This results in long treatment times. In order to overcome this, emerging technologies in motion tracking (e.g. 4D ultrasound) can be used to track the target over time and at the same time simulate and predict the motion in order to target tumors moving due to free breathing patients.

Ultrasound is an inexpensive, flexible, real-time imaging modality, with high temporal and spatial resolution, i.e. sub-millimeter spatial resolution inplane along the beam direction. However, it provides little contrast between normal tissue and FUS-treated tissue and so far ultrasound-based temperature monitoring has not been validated under a clinical scenario.

Motion of the abdominal organs is an important issue to be accounted for during FUS treatment, but also in other therapies like radiotherapy [165, 166]. The motion estimation is useful in delineating the target and organs at risk and also determining the dosage of treatment during therapeutic irradiation. Several techniques exist and are in development to handle abdominal organ motion during FUS. A straightforward approach is to use respiratory gating. However, respiratory gating generally increases treatment time, which has been demonstrated in controlled apnea on anesthetized pigs [167, 168]. Another approach is to employ repeated breath-holds and breathing feedback to ensure a reproducible liver position [169]. De Senne‐ ville and coworkers [170] proposed a system that generates an atlas of motion fields during an initial learning phase based on magnitude data of temperature-sensitive gradient-recalled sequence acquisition. The motion field of the most similar image in the atlas is then used to correct the target position. Under the hypothesis of periodic motion, the focal point position for the next cycle is estimated. The method can only manage liver deformations caused by the periodic breathing cycle and is not capable of handling the non-rigid liver deformations, i.e. drift, caused by intestinal activity (peristalsis) or muscle relaxation [171]. Although it is established that MR imaging can provide motion estimates with a high spatial resolution, it is difficult in practice to acquire online three-dimensional (3D) isotropic images because of technical limitations, spatial and temporal resolution trade-offs, and low signal-to-noise ratio associated with fast 3D acquisition sequences [172]. In addition, the time duration between the actual target displacement and the availability of the motion information from MR data is not negligible [173]. Hence, MR information-based real-time motion compensation generally compromises spatial resolution, geometric distortion and the precision of the MR thermometry [174], of which the latter is of crucial importance during MRgFUS.

A first attempt at ultrasound-based motion tracking during MRgFUS was reported in phan‐ toms undergoing periodic and rigid motion of small amplitude [173]. Continuous 1D ultra‐ sound echo detection, along a direction parallel to the main axis of motion was used. This setup is not suitable for clinical applications as the external ultrasound imaging probe cannot send beams parallel to the axis of respiratory motion. Moreover, the local motion in the liver is spatially dependent and a 1D projection would not be sufficient. Truly simultaneous ultra‐ sound and MR imaging has only been reported in literature recently [175-178]. Only one of these studies was targeted towards MRgFUS and moving abdominal organs sonication [175]. They demonstrated in moving phantoms the feasibility of ultrasound-based 2D motioncompensated sonications integrated with reference free MR temperature monitoring, using a clinical ultrasound probe and a phased-array HIFU transducer [175]. An overview of our own efforts for motion correction using 4D ultrasound can be found in section 4.3.

#### **8.2. Ultrasound-induced drug delivery**

**Figure 26.** Illustration shows the targeting of a tumor in the liver using high intensity focused ultrasound. Currently, to perform this, the patient has to be anesthetized and breathing must be stopped during sonications. This results in long treatment times. In order to overcome this, emerging technologies in motion tracking (e.g. 4D ultrasound) can be used to track the target over time and at the same time simulate and predict the motion in order to target tumors

Ultrasound is an inexpensive, flexible, real-time imaging modality, with high temporal and spatial resolution, i.e. sub-millimeter spatial resolution inplane along the beam direction. However, it provides little contrast between normal tissue and FUS-treated tissue and so far ultrasound-based temperature monitoring has not been validated under a clinical scenario. Motion of the abdominal organs is an important issue to be accounted for during FUS treatment, but also in other therapies like radiotherapy [165, 166]. The motion estimation is useful in delineating the target and organs at risk and also determining the dosage of treatment during therapeutic irradiation. Several techniques exist and are in development to handle abdominal organ motion during FUS. A straightforward approach is to use respiratory gating. However, respiratory gating generally increases treatment time, which has been demonstrated in controlled apnea on anesthetized pigs [167, 168]. Another approach is to employ repeated breath-holds and breathing feedback to ensure a reproducible liver position [169]. De Senne‐ ville and coworkers [170] proposed a system that generates an atlas of motion fields during an initial learning phase based on magnitude data of temperature-sensitive gradient-recalled sequence acquisition. The motion field of the most similar image in the atlas is then used to correct the target position. Under the hypothesis of periodic motion, the focal point position for the next cycle is estimated. The method can only manage liver deformations caused by the periodic breathing cycle and is not capable of handling the non-rigid liver deformations, i.e. drift, caused by intestinal activity (peristalsis) or muscle relaxation [171]. Although it is established that MR imaging can provide motion estimates with a high spatial resolution, it is difficult in practice to acquire online three-dimensional (3D) isotropic images because of

moving due to free breathing patients.

66 Advancements and Breakthroughs in Ultrasound Imaging

Although diagnostic ultrasound is considered safe with no adverse effects, ultrasound can with high acoustic outputs induce significant bioeffects (e.g. HIFU) and these bioeffects are divided into thermal and mechanical effects. The thermal effect is related to energy absorption in the tissue where part of the mechanical wave energy is converted to thermal energy and hence results in an increase in tissue temperature. The mechanical effects are related to cavitation and to radiation forces. Radiation forces arise when part of the forward propagating wave is back-scattered or absorbed and result in a pushing force on the tissue along the direction of the forward propagating wave. Within fluids, such radiation forces can give rise to acoustic streaming. Cavitation is related to the oscillation and possible collapse of gas nuclei occurring naturally within the body or artificially introduced as contrast agent in the form of microbubbles. Oscillating gas bubbles will generate streaming currents in surrounding liquids and hence shear forces on nearby cells that potentially result in bioeffects. Collapsing gas bubbles can result in high local temperatures, release of free radicals, emitted shock waves and high velocity micro jets piercing into nearby cell membranes.

resulted in significantly improved image quality and make ultrasound the modality of choice for several applications. Some of the obvious advantages being real-time imaging even for blood flow, portability, flexibility, safety and low cost. In addition, ultrasound images can be acquired in the coordinate system of a patient when combined with a tracking system without any need for registration. This makes surgical guidance based on intra-operative ultrasound highly accurate. The combination of several image modalities such as MR, CT and ultrasound registered to each other and to the patient make the interpretation of the individual images easier and enables the surgeon to take advantage of the complimentary information contained in each image. In this context, the ultrasound images provide real-time information in the region of interest, while MR and CT provide anatomical overview facilitating the interpretation of the ultrasound data. The use of contrast agents enhance the visualization of vessels and increase the number and types of lesions that can be detected using ultrasound. New technol‐ ogies such as high-intensity focused ultrasound and the use of microbubbles for targeted drug delivery are examples of non-invasive therapeutic applications where ultrasound will play an

Ultrasound-Based Guidance and Therapy http://dx.doi.org/10.5772/55884 69

increasingly important role in the future.

1 SINTEF Medical Technology, Norway

3 St. Olavs University Hospital, Norway

31(10): p. 1912-21.

Ronald Mårvik2,3,4 and Toril A. Nagelhus Hernes1,2,4

\*Address all correspondence to: Frank.Lindseth@sintef.no

Frank Lindseth1,2,4, Thomas Langø1,4, Tormod Selbekk1,2,4, Rune Hansen1,2,4,

2 The Norwegian University of Science and Technology (NTNU), Norway

4 National Centre for Ultrasound and Image Guided Therapy, Norway

sized ultrasound. Fam Pract, 2012. 29(5): p. 534-40.

[1] Mehdizadeh, S., et al., Eigenspace based minimum variance beamforming applied to ultrasound imaging of acoustically hard tissues. IEEE Trans Med Imaging, 2012.

[2] Mjolstad, O.C., et al., Assessment of left ventricular function by GPs using pocket-

Ingerid Reinertsen1,4, Christian Askeland1,4, Ole Solheim2,3,4, Geirmund Unsgård2,3,4,

**Author details**

**References**

**Figure 27.** Ultrasound-induced drug delivery. Microbubbles carrying drugs are destructed by ultrasound (A) and the transported substances are released into the surrounding tissue (B).

The indicated bioeffects can be utilized in ultrasound induced drug delivery. The general goal of encapsulated drug delivery and targeting is to improve the efficacy of drugs within the region of diseased tissue while reducing undesired side effects in the healthy tissues. As an example, with non-encapsulated conventional chemotherapy systemic toxicity limits the drug concentration that can be obtained within the tumor and hence the efficacy of the therapy. With focused ultrasound, it is possible to obtain release of encapsulated drugs and this release can be controlled both temporally and spatially.

Ultrasound energy deposition within a localized tissue region provides a potentially efficient way of releasing drugs encapsulated in thermally sensitive carriers [179-181] by inducing a temperature increase and in sonosensitive carriers [182-184] by inducing cavitation (figure 27). The thermal and especially the mechanical cavitation effects of ultrasound also pro‐ vide ways of perturbing cell membranes and thus increasing their permeability for im‐ proved drug delivery. With the introduction of microbubbles administered intraveneously that will serve as cavitation nuclei, the threshold for cavitation is significantly reduced hence facilitating this effect for endothelial cells that are close to the administered microbubbles. This effect of increased cell membrane permeability has been investigated extensively in the brain where the blood-brain barrier acts as an effective barrier for delivery of more than 95% of the drugs that potentially could be interesting for treatment of diseases in the central nervous system [185, 186]. For blood clot dissolution the combined use of ultrasound, microbubbles and thrombolytic agents have been demonstrated in several clinical trials to result in faster clot dissolution without release of large amounts of potentially hazardous clot fragments [187, 188].
