Ultrasonic imaging of biochemical changes in tissues

Advanced breast carcinomas are complex mixtures of epithelial, stromal and inflammatory cells with heterogenous, chaotic blood flow. Elevated cell metabolism and poor perfusion causes an acidic (pH 6.2) and hypoxic environment that has a significant influence on the effectiveness of therapies and leads to aggressive cancer cell phenotypes. We propose to indirectly image the effects of metabolism (acidity) using viscoelastic imaging on the basis that environmental pH alters the stromal collagen structure. Viscoelastic imaging describes elastic properties of tissue in addition to viscous components characterized by time constants. We first prove our hypothesis using a physical model such as tissue mimicking gelatin and demonstrate the feasibility of imaging effects of local pH changes. Injecting acids and bases produced dark strain contrast that grew in size and intensified over time unlike neutral pH injections that produced no strain contrast. We interpreted the images using an independent measurement of pH dependent viscoelasticity using a cone viscometer that showed that average elastic strain was double valued around neutral pH while viscous relaxation time constants increased with pH. Acidic regions in ex-vivo liver samples produced similar trends with greater contrast intensity compared to gelatin because of gelatin's greater buffering capacity. A clear advantage of mapping viscous time constants over just strain (elasticity), is a much weaker dependence on boundary effects. We also show preliminary clinical applications and found that trained operators tended to naturally apply constant stress rather than constant strain in hand-held situations unlike mechanically driven devices. Above results suggest that pulse-echo ultrasound without contrast enhancement has the potential to image alterations in stromal tissue structures caused by biochemical changes.