Liver transplantation (LT) is the mainstay of treatment for end stage liver diseases, including inherited liver disorders. Organ donation, however, has not kept up with the demand, leading to increased morbidity and mortality. Alternatives to LT have been sought over the last decade to overcome the shortage of donor organs, and cell therapy has emerged as a highly effective “bridging therapy” to LT or even as a curative option in some reported experiments on inherited liver disorders (Dhawan et al. 2010; Forbes and Rosenthal 2014; Stéphenne et al. 2006).
To adequately restore the liver function, delivery of a large number of NS-398 (approximately 5%–10% of the liver mass or transplantation of 200–400 million cells/kg weight) is necessary over a short period of time and often needs repetition. It is challenging to effectively deliver such a large number of cells by the intra-portal approach (Baccarani et al. 2005). When the cells are injected into the vascular compartments (portal vein/artery), the liver engraftment efficiency ranges from 5%–30% depending on the type and size of the cells and the majority of the cells end up in a different organ (Hoppo et al. 2011; Puppi et al. 2012). The cell engraftment and retention might increase when they are directly injected into the liver parenchyma (Turner et al. 2013). A possible mismatch between the cell size and the sinusoidal endothelial pore size, resistance to the uptake and integration of injected cells in a histologically normal liver and occurrence of portal venous thrombosis are thought to be the possible hurdles (Kocken et al. 1997). Cell therapy is much more challenging unless the recipient liver is damaged by iatrogenic methods. Liver irradiation, reperfusion injury and types of noxious chemical agents have been used to create damage to the recipient liver to increase the integration of transfused cells with excellent outcomes in reported experiments (Malhi et al. 2002; Morán-Jiménez et al. 2008; Stéphenne et al. 2006; Turner et al. 2011). However, so far the overall clinical outcomes have been mixed. For instance, radiation-induced liver disease is a concern when whole-liver radiation at doses above 30 Gy is used (Jorns et al. 2012; Schlachterman et al. 2015). With portal vein embolization-mediated ischemia reperfusion injury, an increase in portal pressure and the risk of portal thrombosis are possible (Jorns et al. 2012). Administration of noxious chemical agents such as carbon tetrachloride (CCl4) can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma (Fujii et al. 2010).
High intensity focused ultrasound (HIFU) has been traditionally used for non-invasive tumor ablation (Aubry et al. 2013). In recent years, significant interest has been garnered in alternative applications of HIFU. HIFU techniques can be used to mechanically fractionate soft tissue with a high degree of precision (Khokhlova et al. 2011; Kieran et al. 2007). This is known as histotripsy. A well-defined lesion in the form of a cavity could be produced by histotripsy without any significant thermal damage at the periphery of the cavity. In soft tissues, the distortion of an initially harmonic acoustic waveform due to tissue non-linearity causes enhanced heating. This is because the absorption of ultrasound energy in tissue increases with frequency (ter Haar and Coussios 2007). Significant wave distortion in tissue leads to the generation of a shock wavefront, which contains tens of harmonics of the fundamental frequency. Once shockwaves are developed at the focal point of the HIFU transducer, where the non-linear propagation effects are the strongest, the heating rate can be increased significantly. In the case of plane harmonic waves, for example, heat deposition is proportional to the acoustic pressure amplitude squared whereas for shock waves the heating rate is proportional to the shock pressure amplitude cubed. This localized super-heating by the shock waves can raise tissue temperature to 100°C in a few milliseconds (Canney et al. 2010; Maxwell et al. 2012). A boiling vapor bubble is subsequently formed and grows to millimeter size at the focus followed by the production of tissue fractionation. The growth of this millimeter-sized bubble is likely to be due to the asymmetry in the shock waveforms (Kreider et al. 2011). As the peak positive pressure phase has a shorter duration than the negative pressure part in the shockwaves, the bubble has a relatively longer time to undergo expansion rather than collapsing leading to an explosive growth within a few acoustic cycles.