Imaging tumor microenvironment with ultrasound
10 Jul 2005-Vol. 19, pp 516-528
TL;DR: In this article, the authors used ultrasound to image viscoelastic features of tumors, which describe microenvironmental factors that stimulate signaling pathways in tumors that ultimately affect metastatic potential and response to traditional therapeutics.
Abstract: Recent advances in molecular biology are providing new opportunities for breast cancer imaging. Our approach uses ultrasound to image viscoelastic features of tumors. These features describe microenvironmental factors that stimulate signaling pathways in tumors that ultimately affect metastatic potential and response to traditional therapeutics. This paper explains the motivation for the approach, describes measurements in phantoms and patients, and defines measurement sensitivity using hydrogels with tissue-like features.
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TL;DR: The focus of this paper is on imaging parameter estimation from ultrasonic echo data, and how jitter from hand-held force applicators used for clinical applications propagate through the imaging chain to generate image noise.
Abstract: Techniques are being developed to image viscoelastic features of soft tissues from time-varying strain. A compress-hold-release stress stimulus commonly used in creep-recovery measurements is applied to samples to form images of elastic strain and strain retardance times. While the intended application is diagnostic breast imaging, results in gelatin hydrogels are presented to demonstrate the techniques. The spatiotemporal behaviour of gelatin is described by linear viscoelastic theory formulated for polymeric solids. Measured creep responses of polymers are frequently modelled as sums of exponentials whose time constants describe the delay or retardation of the full strain response. We found the spectrum of retardation times τ to be continuous and bimodal, where the amplitude at each τ represents the relative number of molecular bonds with a given strength and conformation. Such spectra indicate that the molecular weight of the polymer fibres between bonding points is large. Imaging parameters are found by summarizing these complex spectral distributions at each location in the medium with a second-order Voigt rheological model. This simplification reduces the dimensionality of the data for selecting imaging parameters while preserving essential information on how the creeping deformation describes fluid flow and collagen matrix restructuring in the medium. The focus of this paper is on imaging parameter estimation from ultrasonic echo data, and how jitter from hand-held force applicators used for clinical applications propagate through the imaging chain to generate image noise.
73 citations
TL;DR: Variable projection (VP) is proposed, a new technique named variable projection to estimate accurately and robustly the TC and steady-state value of the elastographic parameter of interest from its temporal curve that is robust to noise and capable of estimating the time constant with accuracy higher than that of typically employed curve-fitting techniques.
Abstract: Novel viscoelastic and poroelastic elastography techniques rely on the accurate estimation of the temporal behavior of the axial or lateral strains and related parameters. From the temporal curve of the elastographic parameter of interest, the time constant (TC) is estimated using analytical models and curve-fitting techniques such as Levenberg–Marquardt (LM), Nelder–Mead (NM), and trust-region reflective (TR). In this paper, we propose a new technique named variable projection (VP) to estimate accurately and robustly the TC and steady-state value of the elastographic parameter of interest from its temporal curve. As a testing platform, the method is used with a novel analytical model, which can be used for both poroelastic and viscoelastic tissues and in most practical experimental conditions of clinical interest. Finite element and ultrasound simulations and experimental results demonstrate that VP is robust to noise and capable of estimating the TC of the elastographic parameter with accuracy higher than that of typically employed curve-fitting techniques. The results also demonstrate that the performance of VP is not affected by an incorrect initial TC guess. For example, in simulations, VP can estimate the TC of axial strain and effective Poisson’s ratio accurately for initial guesses ranging from 0.001 to infinite times of the true TC value even in fairly noisy conditions (30-dB signal to noise ratio). In experiments, VP always estimates the axial strain TC reliably, whereas the LM, NM, and TR methods fail to converge or converge to wrong solutions in most of the cases.
9 citations
Posted Content•
TL;DR: A cubic spline–based interpolation method, which allows to use only good quality strain frames (i.e., frames with sufficiently high signal-to-noise ratio [SNR]) to estimate the strain TC, and is of great help in applications relying on the accurate assessment of the temporal behavior of strain data.
Abstract: Ultrasound poroelastography is a cost-effective non-invasive imaging technique, which is able to reconstruct several mechanical parameters of cancer and normal tissue such as Young's modulus, Poisson's ratio, interstitial permeability and vascular permeability To estimate the permeabilities, estimation of the strain time constant (TC) is required, which is a challenging task because of non-linearity of the exponential strain curve and noise present in the experimental data Moreover, noise in many strain frames becomes very high because of motion artifacts from the sonographer, animal/patient and/or the environment Therefore, using these frames in computation of strain TC can lead to inaccurate estimates of the mechanical parameters In this letter, we introduce a cubic spline based interpolation method, which uses only the good frames (frame of high SNR) to reconstruct the information of the bad frames (frames of low SNR) and estimate the strain TC We prove with finite element simulation that the proposed reconstruction method can improve the estimation accuracy of the strain TC by 46% in comparison to the estimates from noisy data, and 37% in comparison to the estimates from Kalman filtered data at an SNR of 30dB Based on the high accuracy of the proposed method in estimating strain TC from poroelastography data, the proposed method can be preferred technique by the clinicians and researchers interested in non-invasive imaging of tissue mechanical parameters
1 citations
TL;DR: In this article, a cost-effective and non-invasive imaging technique, which can be used to reconstruct mechanical parameters of tissues such as Young's modulus, Poisson's ratio, inters...
1 citations
01 Oct 2006
TL;DR: In this article, the authors used low order discrete rheological models from linear viscoelastic theory to reduce data dimensionality yielding parameters related to stiffness and viscosity: elastic strain and two retardation time constants.
Abstract: In elasticity imaging, tissues are stimulated with mechanical forces while spatiotemporal strain responses are observed. The basis for diagnostic imaging is that disease processes characteristically alter the structure of connective tissues that determine viscoelastic properties. Time-varying strains for step-like stress stimuli were measured in gelatin hydrogels and normal breast tissue. The medium's mechanical response function - the retardance-time spectrum - was computed. This spectrum is the continuous distribution of time constants that characterizes viscoelastic behavior. Spectra were parameterized using low order discrete rheological models from linear viscoelastic theory to reduce data dimensionality yielding parameters related to stiffness and viscosity: elastic strain and two retardation time constants. Broadband, continuous, bi-modal spectra was obtained for gelatin samples. Similar spectra with narrow bandwidth were found for breast tissue, both characteristic of lightly cross-linked amorphous polymers. Measured time constants in gelatin indicated fast (1-10 s) fluidic behavior and a slower (50-400 s) matrix restructuring. Corresponding parameters in breast were 3.2 plusmn 0.8 s and 42.0 plusmn 28 s. Phantom imaging studies showed that these parameters provided consistently high target contrast. Although the ultra-structure of collagen within gelatin and breast stroma is different, their mechanical behavior is quite similar. Creep in both media are consistent with the molecular theory of entanglement coupling proposed to explain amorphous polymer behavior
References
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TL;DR: The observed experimental results provide compelling evidence that electrostatic interactions play an important role in the dimensional stability of RTT collagen.
Abstract: The organized molecular structure of collagen is related to its dimensional stability. The dimensional stability of collagen arises from the interplay of various intermolecular forces such as covalent, hydrogen bonding, electrostatic interactions, hydrophobic interactions, London or van der Waals forces, and weak interactions. A structure–function relationship exists in collagen. Electrostatic interactions play an important role in dimensional stabilization. The dimensional stability of rat tail tendon (RTT) collagen fiber is affected by the change in the net fixed charge on the molecule as a function of pH. Thermal and mechanical properties are dependent on molecular and lattice orders. The pH dependence of thermal shrinkage, isometric tension, differential scanning calorimetry, swelling behavior, tensile strength, and percent extension and stress relaxation behavior are studied in 0.02M Tris-maleate buffer at pH 4–8. The observed experimental results provide compelling evidence that electrostatic interactions play an important role in the dimensional stability of RTT collagen. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 75: 1577–1584, 2000
35 citations
07 Oct 2001
TL;DR: In this article, the capability of strain imaging for sensing directionally dependent soft-tissue elastic properties was assessed using measurements and FEA models of gelatin phantoms and ex vivo bovine skeletal muscle, and they found that for elastically heterogeneous tissue-like media, differences in elastic constants smaller than a factor of two were observed.
Abstract: It has been conjectured that the mechanical structure of some early-forming neoplasms is anisotropic. If true then strain imaging at different scan angles may provide important diagnostic features for accurate classification of early malignant disease. We are assessing the capability of strain imaging for sensing directionally dependent soft-tissue elastic properties. The studies include measurements and FEA models of gelatin phantoms and ex vivo bovine skeletal muscle. Passive muscle deformation is nonlinear, viscoelastic, and transverse isotropic, in stark contrast to the reference gelatin materials that are isotropic, Hookean solids at very low cycling frequency. We found that for elastically heterogeneous tissue-like media, differences in elastic constants smaller than a factor of two were observed. However changes in directionally-dependent geometry and boundary conditions compete with material anisotropy and are difficult to distinguish. The role of strain imaging for detecting elastic anisotropy depends on the separability of these effects.
17 citations
28 Apr 2004
TL;DR: In this article, a cone-plate viscometer measured the elastic as well as the viscous response of the polymer to a shear stress stimulus in the pH range of 6 to 8.
Abstract: Ultrasonic Mechanical Relaxation (UMR) imaging is a new research technique for visualizing viscoelastic properties of tumors. Tissues behave mechanically as water-based polymers, similar to gelatin, with time-varying viscoelastic properties that depend on the chemical environment. We hypothesized that changes in pH, alter the polymer-fiber surface charge density that determines extent of polymer cross-linking. Gelatin samples with similar material properties and variable pH were prepared. A cone-plate viscometer measured the elastic as well as the viscous response of the polymer to a shear stress stimulus in the pH range of 6 to 8. To image local pH changes, two homogeneous gelatin samples were constructed, one made from buffered saline and the other was unbuffered. 0.05ml NaOH (pH 12) was injected into both samples and subsequent dynamic changes were imaged using UMR methods at 5, 20 and 50 minutes. UMR images include elastic strain and viscous creep relaxation maps produced by applying a compressive step-stress stimulus while recording RF echo frames at a high rate. Estimated local displacements occurring between frames in the echo sequence yield strain images. Relaxation parameters are estimated and mapped for each pixel using the strain time series to produce parametric UMR images. Viscometer experiments indicate that the viscoelastic properties of gelatin vary with pH. Also, elastic strain and viscous creep UMR images show contrast in the region of pH change. These results suggest that UMR methods can be used to explore the microenvironments of living tumors, where their viscoelastic properties are influenced by changes in pO 2 , pH and collagen density that predict metastatic potential and resistance to treatments.
9 citations
23 Aug 2004
TL;DR: The results suggest that pulse-echo ultrasound without contrast enhancement has the potential to image alterations in stromal tissue structures caused by biochemical changes as well as preliminary clinical applications.
Abstract: 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.
8 citations