A43Session 12: Cell Death Continuum: It’s Role in Cryomedicine

Abstract

Investigations into the molecular mechanisms underpinning cellular responses to low temperature exposure have highlighted the important role that biochemical cell death plays in procedural outcome. Following cryosurgery, both necrotic and apoptotic cell death are found throughout the cryolesion. Though biochemical cell death (apoptosis) was initially believed to play a major role in only the periphery of the lesion, where cell death through physical rupture wanes and incomplete tissue destruction begins, more recent studies have also shown it to be prevalent at colder isotherms deep within a cryolesion. The mechanisms of this molecular based cell death at ultra cold temperatures ( < −25 °C) have been shown to differ from the cell death in the periphery in both its time of onset (1–3 h post thaw vs. 6–24 h) and its induction pathway (extrinsic vs. intrinsic). As studies continue to show the innate, multi-faceted nature of cryosurgery, which includes multiple physical and molecular targets to achieve cell destruction, a window has opened for the development of new strategies and technologies to more effectively ablate targeted tissues. These improvements in our understanding of the cellular responses to freezing are now driving a series of technological advancements in cryosurgical devices. The identification of the combination of physical and molecular cell death throughout the lesion has resulted in the drive to develop new technologies designed to deliver colder temperatures more rapidly and within a more defined area to maximize physical and molecular cell death. This has led, in part, to the development and optimization of a novel cryosurgical device utilizing super critical nitrogen (SCN) as the cryogen. Utilizing this next generation device allows for cryolesions with a lethal volume (the volume of the lesion below −40 °C) 300% larger than current Joule–Thompson (JT) devices. The SCN system is also capable of generating these ultra cold lesions in less than half the time of a JT device and with more precision. This presentation will focus on the recent findings of rapid-onset cell death and the resulting apoptotic wave, and how the integration of the molecular response with the technological advances of SCN are providing a next generation approach to cryosurgery. As novel cryoablative strategies continue to evolve, it is critical that the impact on the biology of cells, tissues, and organs be understood through both device development and laboratory/clinical research. This is of particular significance as the new technologies begin to offer clinically effective, cryoablative treatments for disease states beyond the reach of current cryosurgical devices.