The first atomic view of strongly driven phase transitions (Siwick et al, Science 2003) illustrated the mechanism to control nucleation growth to nm scales (nucleation as small as 10 molecules), which eliminates cavitation and associated highly damaging shock waves.  To fully exploit this new insight, a laser concept was developed based on a seeded Optical Parametric Amplifier and microchip laser technology to provide a compact robust source engineered to excite the OH stretch of water in biological tissue for use in laser surgery.  The laser ablation process is driven on the picosecond timescale faster than nucleation growth, deliberately below peak powers leading to multiphoton ionizing radiation effects.  Localization of the laser energy to single cell dimensions is provided by the extremely strong absorption of water in the 3 micron range.  The most common conventional lasers in clinical use involve either significant tissue damage due to shock wave and thermal transport resulting in burning and tissue necrosis or are highly ionizing.  The Picosecond InfraRed (PIRL) scalpel readily cuts all tissues types and most importantly, the damage to surrounding tissue is negligible, with no discernable scar tissue formation.  Damage is confined to a single cell border.  In this respect, the long held promise of the laser for achieving the fundamental (single cell) limit to minimally invasive surgery has now been realized.  However, this statement needs to be further qualified.  If the wrong tissue or excessive tissue is removed, it hardly counts as minimally invasive even if done with single cell precision.  It was also discovered that the PIRL interaction ejects entire proteins, even protein complexes into the gas phase intact, i.e., faster than fragmentation processes.   This new laser ablation mechanism referred to as Desorption by Impulsive Vibrational Excitation (DIVE) provides a new means for in situ spatial mapping with mass spectroscopy (MS) in which very detailed molecular fingerprints of different tissue types can be retrieved, as a “frozen snapshot” of the proteome, with cancer margins delineated.  On the fly, molecular level pathology during surgery is now well within reach.  Surgeons will soon have hundreds of molecular markers, a veritable molecular bar code, to guide their surgery.   This PIRL-DIVE-MS concept may provide the enabling technology to map the Human Proteoform as a basis to good health and ultimate guidance for surgical intervention.  Could we push the limits to “Make a Molecular Map of the Cell”?

The basic concepts for the laser ablation process, as well as applications for mass spectroscopy as feedback in laser surgery, and towards fundamental limits in spatial mapping and biodiagnostics will be discussed - with the ultimate aim to map the cell.