In simulation studies by Fan and Hynynen, minimizing the number of ultrasound pulses required to cover the targeted tissue volume was the most important factor in determining treatment time. Many strategies have been employed to minimize treatment times including the use of phased array transducers for more efficient treatment, and by increasing the effective volume of treatment of individual exposures by modifying exposure parameters (such as increasing pulse duration), or by using split focus HIFU transducers. Prolonged treatment times require patient immobility and sedation that can reduce the appeal of such procedures and adversely affect their widespread adoption. were able to use pulsed HIFU with relative low duty cycles as a controlled source of image-guided, low-level hyperthermia (39–41☌) that caused deployment of drug payload from low temperature sensitive liposome (LTSL) to improve tumor regression.Īs the number of continuous (and pulsed) HIFU applications grows, technical barriers must be addressed regarding the time requirements for safe and effective large volume treatment. By providing HIFU exposures in pulsed mode, temporal averaged intensities normally sufficient for ablating tissue are lowered and heat generation can be reduced below levels for tissue destruction. Thermosensitive liposomes (TSLS) are normally stable at physiological temperatures but undergo predictable phase changes when heated, which releases their drug payloads. Targeted delivery of drug is achieved by the use of thermosensitive drug carriers, improving drug toxicity profiles and increasing the effective dose delivered to targeted tissues. Recent advances in chemical engineering have given rise to a new generation of temperature sensitive macromolecular drug carriers that can be paired with external heating sources such as HIFU. These exposures have been shown to increase the delivery and consequent therapeutic effects of small molecules, liposomes, and plasmid DNA. Heat generation can be significantly reduced to sub-cytotoxic levels with pulsed HIFU exposures, where relatively short duty cycles (in the order of 5–10%) allow non-thermal mechanisms to predominate, such as acoustic cavitation and radiation forces. Continuous wave HIFU exposures (in the order of seconds) have been used to ablate tissues such as prostate cancer, breast cancer, liver cancer, and uterine fibroids. Focused ultrasound can deposit energy and produce clinically relevant bio-effects in the targeted tissue, and has been used in a variety of clinical and pre-clinical disease models. microwaves), at a distance remote from the transducer, using various modalities of image guidance. High-intensity focused ultrasound (HIFU) can be used to non-invasively deposit energy in a relatively small focal zone, compared to other hyperthermia devices (e.g.