Quantitative characterization of viscoelastic behavior in tissue-mimicking phantoms and ex vivo animal tissues.

Viscoelasticity of soft tissue is often related to pathology, and therefore, has become an important diagnostic indicator in the clinical assessment of suspect tissue. Surgeons, particularly within head and neck subsites, typically use palpation techniques for intra-operative tumor detection. This detection method, however, is highly subjective and often fails to detect small or deep abnormalities. Vibroacoustography (VA) and similar methods have previously been used to distinguish tissue with high-contrast, but a firm understanding of the main contrast mechanism has yet to be verified. The contributions of tissue mechanical properties in VA images have been difficult to verify given the limited literature on viscoelastic properties of various normal and diseased tissue. This paper aims to investigate viscoelasticity theory and present a detailed description of viscoelastic experimental results obtained in tissue-mimicking phantoms (TMPs) and ex vivo tissues to verify the main contrast mechanism in VA and similar imaging modalities. A spherical-tip micro-indentation technique was employed with the Hertzian model to acquire absolute, quantitative, point measurements of the elastic modulus (E), long term shear modulus (η), and time constant (τ) in homogeneous TMPs and ex vivo tissue in rat liver and porcine liver and gallbladder. Viscoelastic differences observed between porcine liver and gallbladder tissue suggest that imaging modalities which utilize the mechanical properties of tissue as a primary contrast mechanism can potentially be used to quantitatively differentiate between proximate organs in a clinical setting. These results may facilitate more accurate tissue modeling and add information not currently available to the field of systems characterization and biomedical research

Contactless Remote Induction of Shear Waves in Soft Tissues Using a Transcranial Magnetic Stimulation Device

This study presents the first observation of shear wave induced remotely within soft tissues. It was performed through the combination of a transcranial magnetic stimulation device and a permanent magnet. A physical model based on Maxwell and Navier equations was developed. Experiments were performed on a cryogel phantom and a chicken breast sample. Using an ultrafast ultrasound scanner, shear waves of respective amplitude of 5 and 0.5 micrometers were observed. Experimental and numerical results were in good agreement. This study constitutes the framework of an alternative shear wave elastography method

State-of-the art of acousto-optic sensing and imaging of turbid media

Acousto-optic (AO) is an emerging hybrid technique for measuring optical contrast in turbid media using coherent light and ultrasound (US). A turbid object is illuminated with a coherent light source leading to speckle formation in the remitted light. With the use of US, a small volume is selected,which is commonly referred to as the “tagging” volume. This volume acts as a source of modulated light, where modulation might involve phase and intensity change. The tagging volume is created by focusing ultrasound for good lateral resolution; the axial resolution is accomplished by making either the US frequency, amplitude, or phase time-dependent. Typical resolutions are in the order of 1 mm. We will concentrate on the progress in the field since 2003. Different schemes will be discussed to detect the modulated photons based on speckle detection, heterodyne detection, photorefractive crystal (PRC) assisted detection, and spectral hole burning (SHB) as well as Fabry-Perot interferometers. The SHB and Fabry-Perot interferometer techniques are insensitive to speckle decorrelation and therefore suitable for in vivo imaging. However, heterodyne and PRC methods also have potential for in vivo measurements. Besides measuring optical properties such as scattering and absorption, AO can be applied in fluorescence and elastography applications

Ultrasound Imaging Techniques for Spatiotemporal Characterization of Composition, Microstructure, and Mechanical Properties in Tissue Engineering

Ultrasound techniques are increasingly being used to quantitatively characterize both native and engineered tissues. This review provides an overview and selected examples of the main techniques used in these applications. Grayscale imaging has been used to characterize extracellular matrix deposition, and quantitative ultrasound imaging based on the integrated backscatter coefficient has been applied to estimating cell concentrations and matrix morphology in tissue engineering. Spectral analysis has been employed to characterize the concentration and spatial distribution of mineral particles in a construct, as well as to monitor mineral deposition by cells over time. Ultrasound techniques have also been used to measure the mechanical properties of native and engineered tissues. Conventional ultrasound elasticity imaging and acoustic radiation force imaging have been applied to detect regions of altered stiffness within tissues. Sonorheometry and monitoring of steady-state excitation and recovery have been used to characterize viscoelastic properties of tissue using a single transducer to both deform and image the sample. Dual-mode ultrasound elastography uses separate ultrasound transducers to produce a more potent deformation force to microscale characterization of viscoelasticity of hydrogel constructs. These ultrasound-based techniques have high potential to impact the field of tissue engineering as they are further developed and their range of applications expands.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140238/1/ten.teb.2015.0453.pd

Displacement of a bubble by acoustic radiation force into a fluid-tissue interface.

Microbubbles in an ultrasound beam experience a primary Bjerknes force, which pushes the microbubbles against a fluid-tissue interface and deforms the tissue. This interaction has been used to measure tissue elasticity and is a common interaction in many therapeutic and diagnostic applications, but the mechanisms of deformation, and how the deformation dynamic depends on the bubble and ultrasound parameters, remain unknown. In this study, a mathematical model is proposed for the displacement of a bubble onto a fluid-tissue interface and the tissue deformation in response to the primary Bjerknes force. First, a model was derived for static loading and the model's prediction of bubble-mediated tissue displacement and stresses in tissue were explored. Second, the model was updated for dynamic loading. The results showed that the bubble is both displaced by the applied force and changes its shape. The bubble displacement changes nonlinearly with the applied force. The stress values in tissue are quite high for a distance within one radius of the bubble from the bubble surface. The model proposed here is permissible in human tissue and can be used for biomedical ultrasound applications, including material characterization

Development and Applications of Advanced Ultrasound Techniques for Characterization and Stimulation of Engineered Tissues

Mechanobiology is central in the development, pathology, and regeneration of musculoskeletal tissues, in which mechanical factors play important roles. Therefore, there is a need for methods to characterize the composition and mechanical properties of developing musculoskeletal tissues over time. Ultrasound elastographic techniques have been developed for noninvasive imaging of spatial heterogeneity in tissue stiffness. However, their application for quantitative assessment of tissue mechanical properties, especially viscoelastic properties, has not been exploited. Additionally, ultrasound energy may be used to apply mechanical stimulation to engineered constructs at the microscale, and thereby to enhance tissue regeneration. We have developed a multimode ultrasound viscoelastography (MUVE) system for assessing microscale mechanical properties of engineered hydrogels. MUVE uses focused ultrasound pulses to apply acoustic radiation force (ARF) to deform samples, while concurrently measuring sample dimensions using coaxial high frequency ultrasound imaging. We used MUVE to perform creep tests on agarose, collagen, and fibrin hydrogels of defined concentrations, as well as to monitor the mechanical properties of cell-seeded constructs over time. Local and bulk viscoelastic properties were extracted from strain-time curves through fitting of relevant constitutive models, showing clear differences between concentrations and materials. In particular, we showed that MUVE is capable of mapping heterogeneity of samples in 3D. Using inclusion of dense agarose microbeads within agarose, collagen and fibrin hydrogels, we determined the spatial resolution of MUVE to be approximately 200 μm in both the lateral and axial directions. Comparison of MUVE to nanoindentation and shear rheometry showed that our ultrasound-based technique was superior in generating consistent, microscale data, particularly for very soft materials. We have also adapted MUVE to generate localized cyclic compression, as a means to mechanically stimulate engineered tissue constructs at the microscale. Selected treatment protocols were shown to enhance the osteogenic differentiation of human mesenchymal stem cells in collagen-fibrin hydrogels. Constructs treated at 1 Hz at an acoustic pressure of 0.7 MPa for 30 minutes per day showed accelerated osteogenesis and increased mineralization by 10 to 30 percent, relative to unstimulated controls. In separate experiments, the ultrasound pulse intensity was increased over time to compensate for changes in matrix properties over time, and a 35 percent increase in mineralization was achieved. We also extended the application of a previously-developed spectral ultrasound imaging (SUSI) technique to an animal model for early detection of heterotopic ossification (HO). The quantitative information on acoustic scatterer size and concentration derived from SUSI was used to differentiate tissue composition in a burn/tenotomy mice model from the control model. Importantly, HO foci were detected as early as one week after injury using SUSI, which is 3-5 weeks earlier than when using conventional micro-computed tomography. Taken together, these results demonstrate that ultrasound-based techniques can non-invasively and quantitatively characterize viscoelastic properties of soft materials in 3D, as well as their composition over time. Ultrasound pulses can also be used to stimulate engineered constructs to promote musculoskeletal tissue formation. MUVE, SUSI, and ultrasound stimulation can be combined into an integrated system to investigate the roles of matrix composition, static mechanical environment, and dynamic mechanical stimuli in tissue regeneration, as well as the interactions of these factors and their evolution over time. Ultrasound-based techniques therefore have promising potential in noninvasively characterizing the composition and biomechanics, as well as providing mechanical intervention in native and engineered tissues as they develop over time.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144116/1/xho_1.pd

Non-contact acoustic radiation force impulse microscopy via photoacoustic detection for probing breast cancer cell mechanics

We demonstrate a novel non-contact method: acoustic radiation force impulse microscopy via photoacoustic detection (PA-ARFI), capable of probing cell mechanics. A 30 MHz lithium niobate ultrasound transducer is utilized for both detection of phatoacoustic signals and generation of acoustic radiation force. To track cell membrane displacements by acoustic radiation force, functionalized single-walled carbon nanotubes are attached to cell membrane. Using the developed microscopy evaluated with agar phantoms, the mechanics of highly- and weakly-metastatic breast cancer cells are quantified. These results clearly show that the PA-ARFI microscopy may serve as a novel tool to probe mechanics of single breast cancer cells. © 2014 Optical Society of America.1

Elastography: modality-specific approaches, clinical applications, and research horizons

Manual palpation has been used for centuries to provide a relative indication of tissue health and disease. Engineers have sought to make these assessments increasingly quantitative and accessible within daily clinical practice. Since many of the developed techniques involve image-based quantification of tissue deformation in response to an applied force (i.e., "elastography”), such approaches fall squarely within the domain of the radiologist. While commercial elastography analysis software is becoming increasingly available for clinical use, the internal workings of these packages often remain a "black box,” with limited guidance on how to usefully apply the methods toward a meaningful diagnosis. The purpose of the present review article is to introduce some important approaches to elastography that have been developed for the most widely used clinical imaging modalities (e.g., ultrasound, MRI), to provide a basic sense of the underlying physical principles, and to discuss both current and potential (musculoskeletal) applications. The article also seeks to provide a perspective on emerging approaches that are rapidly developing in the research laboratory (e.g., optical coherence tomography, fibered confocal microscopy), and which may eventually gain a clinical foothol