Edwin L. Carstensen - US grants

This program seeks an understanding of the interaction of ultrasound with biological material in two broad perspectves: (1) Propagation of Sound in Tissue with particular emphasis on nonlinear phenomena and (2) the Biological Effects of Ultrasound. In the latter work, both thermal and nonthermal mechanisms have been demonstrated. Particularly important are studies of the mechanism of killing of Drosophila at low temporal average intensities of pulsed ultrasound, and implications of these studies for human safety.

The proposed research program focuses specifically on the role of cavitation in lithotripsy. Although purely mechanical processes may be primiarily responsible for the break-up kidney stones by intense shock waves, it is clear that the pressures involved greatly exceed the thresholds for transient cavitation. Cavitation is probably responsible for many of the reported side efforts of the treatment and even may play a role in reduction of the stones. As used here, the term lithotripsy includes all of the physical and biological phenomena associated with the intense shock waves of the modern clinical devices called lithotripters and hence the proposal is much broarder in its implications than the specific applications which these devices have found in clinical medicine up to the present time. To study cavitation in lithotropter fields, it will be necessary to consider all mechanisms by which shock waves interact with tissues. The specific aims in greater detail include (a) Development of relatively inexpensive, convenient and reliable, custom built, focused and spherically divergent, spark- generated and piezoelectric sources for use in the proposed experimental studies, (b) Development of acoustic and optical methods for measurement of the shock fields, (c) Develop and test theoretical models of shock wave propagation, (d) Develop and test models for the interaction of bubbles with shock waves, (e) Use lower organisms such as multicellular spheroids and insert for biological tests of theroetical predictions, (f) Study the effects of shok-induced cavitation in representative vertebrates, and (g) Investigate the mechanisms of fracture of kidney stones by shock fields and determine the causes of reported side efforts of these procedures.

The proposed research program focuses specifically on the role of cavitation in lithotripsy. Although purely mechanical processes may be primiarily responsible for the break-up kidney stones by intense shock waves, it is clear that the pressures involved greatly exceed the thresholds for transient cavitation. Cavitation is probably responsible for many of the reported side efforts of the treatment and even may play a role in reduction of the stones. As used here, the term lithotripsy includes all of the physical and biological phenomena associated with the intense shock waves of the modern clinical devices called lithotripters and hence the proposal is much broarder in its implications than the specific applications which these devices have found in clinical medicine up to the present time. To study cavitation in lithotropter fields, it will be necessary to consider all mechanisms by which shock waves interact with tissues. The specific aims in greater detail include (a) Development of relatively inexpensive, convenient and reliable, custom built, focused and spherically divergent, spark- generated and piezoelectric sources for use in the proposed experimental studies, (b) Development of acoustic and optical methods for measurement of the shock fields, (c) Develop and test theoretical models of shock wave propagation, (d) Develop and test models for the interaction of bubbles with shock waves, (e) Use lower organisms such as multicellular spheroids and insert for biological tests of theroetical predictions, (f) Study the effects of shok-induced cavitation in representative vertebrates, and (g) Investigate the mechanisms of fracture of kidney stones by shock fields and determine the causes of reported side efforts of these procedures.

The proposed research program will continue to evaluate the biological effects that results from the exposure of tissues to the field of lithotripters and pulsed ultrasound. The overall strategy which has been fruitful in earlier research will be followed. First, biological effects are identified using the very large fields of lithotripters and the thresholds for these effects are determined. Then, this information is used in the search for similar biological effects with pulsed ultrasound. The nature and extent of the biological effects provide tests of the hypothetical physical mechanisms, which in turn, are the basis for extrapolating the results of experiments with laboratory animals to the clinical setting to manage the side effects of lithotripter treatments and to avoid adverse biological effects in diagnostic ultrasound. Each organ system has its own characteristic response and research challenges. Hemorrhage in the kidney is qualitatively and quantitatively different for endoscopic, electrohydraulic lithotripters and piezoelectric, extracorporeal shock wave lithotripters (ESWL) and no effects have been detected with pulsed ultrasound at the highest levels available. The proposed studies will extend these remarkable findings through the use of two additional qualitatively different ESWL sources and by manipulating the physical characteristics of exposure to determine those properties of the field that correlate with the observed tissue damage. Lung hemorrhage in mice occurs with lithotripter fields or pulsed ultrasound at positive pressure amplitudes of 1 MPa, making it a serious concern for clinical applications in both forms of radiation. The proposed investigation will determine how the studies with mice extrapolate to man, evaluate the long term implications of the insult and differentiate among competing mechanisms for the effect. Intestinal petechiae, like lung hemorrhage, are probably related to the presence of gas bodies, and occur both with lithotripter fields and pulsed ultrasound but are sufficiently different that the phenomena must be evaluated from the most basic level following the pattern that has been successful in studies of the lung. Active tissues (heart and nerves) respond acutely to both lithotripter fields and pulsed ultrasound. The proposed study will differentiate among radiation force, cavitation and first order mechanical stresses as mechanisms for these effects. Acoustic cavitation appears to be responsible for most of the observed biological effects but we hypothesize that, because of limits on the expansion of the gaseous nuclei imposed by the surrounding tissue structures, cavitation in tissue differs qualitatively from that described by classical cavitation theory for a spherical bubble in an infinite fluid. This requires a new conceptual approach to bubble behavior in tissues. The proposed in an infinite fluid. This requires a new conceptual approach to bubble behavior in tissues. The proposed research will use novel applications of classical cavitation theory and a new numerical analytical techniques to study the behavior of bubbles under these conditions. New theoretical methods for predicting the nonlinear propagation of acoustic waves that have come from this project over the last two years will be used to determine experimental fields and to design improved lithotripters.