## 6 Cellular Basis of Laser-driven Radiation Therapy
### Dose Rate Picture  
The most notable difference between particle irradiation from laser-driven and conventional sources is the dose rate. Dose rates provided by a conventional accelerator are usually below 1 Gy/sec (but can be as high as \(\sim\)10\({}^{3}\) Gy/sec for the spot scanning mode). At dose rates below 1 Gy/min, where the \"low dose rate effect\" is observed, the total irradiation time is in the range of minutes to hours. Because the irradiation time scale is comparable to that of DNA repair, the low dose rate effect is associated with repair. Previous studies have established that cellular radiosensitivity is reduced when cells are irradiated at such low dose rates. By contrast, with laser-driven radiation, the dose rate can exceed 10\({}^{9}\) Gy/sec and the irradiation time can be much shorter (typically nanoseconds). Relatively fewer studies have been conducted on ultra-high dose rates. One can assume that if an ultra-high dose rate effect exists it must be associated with specific early time physical interactions such as ionizations, excitations, and subsequently generated radicals. We attribute an ultra-high dose rate effect to events generated by neighboring tracks that are coincident with each other. Details of this coincidence are now explained. In the low-LET case (X-rays or fast electrons) the mean energy loss per collision event is approximately 48-64 electron volts, eV (we assume 50 eV as an average value) [93]. The absorbed energy is converted to secondary electrons, ions and radicals. The small volume of ionized water and secondary electrons along the particle track is called a \"spur\". The entire radiation track from a single particle is then a random succession of spurs. An ionized water molecule (H\({}_{2}\)O\") quickly decomposes to H\({}^{+}\)\({}_{\text{aq}}\) and an OH radical which is mainly responsible for the DNA damage. H\({}^{+}\)\({}_{\text{aq}}\) is almost motionless (diffusion distance \(\sim\)1 nm), the secondary electron range is several nm and the OH radical average diffusion distance is about 6 nm (and ultimately scavenged by cellular components) [94,95]. The key issue is the proximity of a spur to DNA. DNA damage is correlated to a local high density of OH radicals in the volume of a nearby spur which can expand to as much as 5 \(\times\) 10\({}^{2}\) nm\({}^{3}\) according to their diffusion range. For an isolated cell, the coincidence responsible for an ultra-high dose rate effect (if it exists) is therefore the coincidence of spurs. In this picture, the temporal part of this coincidence (simultaneity) is limited by the spur lifetime (of order nanoseconds). The spatial part is limited to approximately twice the spur volume (of order 10\({}^{3}\) nm\({}^{3}\)). In the low-LET cases, a spur coincidence would involve multiple tracks within the short lifetime of a spur. For a lethal dose such as 10 Gy (for which typical mammalian survival is less than 1%) the spur density is about 10\({}^{-6}\) nm\({}^{-3}\). Because the single spur volume is also very low, an ultra-high dose rate effect attributed to a coincidence of spurs is unlikely. This conclusion is supported by laser-driven X-ray experiments [96, 97, 98], simulations based on precise physical/chemical parameters [99] and other experimental results [73]. Consequently, for an isolated cell, the effect of laser-driven radiation at an ultra-high dose rate does not likely differ from that of radiation at a moderate or a low dose rate generated by conventional accelerators. In the high-LET case (_i.e._, heavier ions such as C\({}^{6+}\)), we can consider the coincidence of spurs along a single track where significantly more energy is deposited. The single track picture makes simultaneity of spurs more likely so that ultra-high dose rate effects in radiobiology, if they exist, are more likely to occur in response to high-LET irradiation.