Torsional wave elastography to assess the mechanical properties of the cornea

Corneal mechanical changes are believed to occur before any visible structural alterations observed during routine clinical evaluation. This study proposed developing an elastography technique based on torsional waves (TWE) adapted to the specificities of the cornea. By measuring the displacements in the propagation plane perpendicular to the axis of the emitter, the effect of guided waves in platelike media was proven negligible. Ex vivo experiments were carried out on porcine corneal samples considering a group of control and one group of alkali burn treatment ( NH 4OH) that modified the mechanical properties. Phase speed was recovered as a function of intraocular pressure (IOP), and a Kelvin-Voigt rheological model was fitted to the dispersion curves to estimate viscoelastic parameters. A comparison with uniaxial tensile testing with thin-walled assumptions was also performed. Both shear elasticity and viscosity correlated positively with IOP, being the elasticity lower and the viscosity higher for the treated group. The viscoelastic parameters ranged from 21.33 to 63.17 kPa, and from 2.82 to 5.30 Pa s, for shear elasticity and viscosity, respectively. As far as the authors know, no other investigations have studied this mechanical plane under low strain ratios, typical of dynamic elastography in corneal tissue. TWE reflected mechanical properties changes after treatment, showing a high potential for clinical diagnosis due to its rapid performance time and paving the way for future in vivo studies.Ministerio de Educacion, Cultura y Deporte Grant DPI2017-83859-R DPI2014-51870-R UNGR15-CE-3664 EQC2018-004508-PSpanish Government DTS15/00093 PI16/00339Instituto de Salud Carlos III y Fondos FederJunta de Andalucia PI-0107-2017 PIN-0030-2017 IE2017-5537MCIN/AEI - European Social Fund "Investing in your future" PRE2018-086085Consejeria de economia, conocimiento, empresas y universidad SOMM17/6109/UGR B-TEP-026- IE2017-5537 P18-RT-1653European Commission SOMM17/6109/UGR B-TEP-026- IE2017-5537 P18-RT-165

Dual-Probe Shear Wave Elastography in a Transversely Isotropic Phantom

This project aimed to evaluate the possibility of obtaining a full mechanical characterization of a transversely isotropic (TI) phantom with dual-probe SWE. A TI phantom was developed and mechanical tests were performed to verify its anisotropy. Moreover, multiple wave propagation modes calculated with dual-probe SWE showed a good agreement with the theoretical curves and indicated the possibility of measuring all the elasticity constants needed to fully characterize a TI tissueope

Nonlinear fourth‐order elastic characterization of the cornea using torsional wave elastography

Measuring the mechanical nonlinear properties of the cornea remains challenging due to the lack of consensus in the methodology and in the models that effectively predict its behaviour. This study proposed developing a procedure to reconstruct nonlinear fourth-order elastic properties of the cornea based on a mathematical model derived from the theory of Hamilton et al. and using the torsional wave elastography (TWE) technique. In order to validate its diagnostic capability of simulated pathological conditions, two different groups were studied, non-treated cornea samples (n=7), and ammonium hydroxide (NH4OH) treated samples (n=7). All the samples were measured in-plane by a torsional wave device by increasing IOP from 5 to 25 mmHg with 5 mmHg steps. The results show a nonlinear variation of the shear wave speed with the IOP, with higher values for higher IOPs. Moreover, the shear wave speed values of the control group were higher than those of the treated group. The study also revealed significant differences between the control and treated groups for the Lamé parameter ���� (25.9–6.52 kPa), third-order elastic constant A (215.09–44.85 kPa), and fourth-order elastic constant D (523.5–129.63 kPa), with p-values of 0.010, 0.024, and 0.032, respectively. These findings demonstrate that the proposed procedure can distinguish between healthy and damaged corneas, making it a promising technique for detecting diseases associated with IOP alteration, such as corneal burns, glaucoma, or ocular hypertension

A review of corneal biomechanics: Mechanisms for measurement and the implications for refractive surgery

Detailed clinical assessment of corneal biomechanics has the potential to revolutionize the ophthalmic industry through enabling quicker and more proficient diagnosis of corneal disease, safer and more effective surgical treatments, and the provision of customized and optimized care. Despite these wide-ranging benefits, and an outstanding clinical need, the provision of technology capable of the assessment of corneal biomechanics in the clinic is still in its infancy. While laboratory-based technologies have progressed significantly over the past decade, there remain significant gaps in our knowledge regarding corneal biomechanics and how they relate to shape and function, and how they change in disease and after surgical intervention. Here, we discuss the importance, relevance, and challenges associated with the assessment of corneal biomechanics and review the techniques currently available and underdevelopment in both the laboratory and the clinic

Viscoelasticity Imaging of Biological Tissues and Single Cells Using Shear Wave Propagation

Changes in biomechanical properties of biological soft tissues are often associated with physiological dysfunctions. Since biological soft tissues are hydrated, viscoelasticity is likely suitable to represent its solid-like behavior using elasticity and fluid-like behavior using viscosity. Shear wave elastography is a non-invasive imaging technology invented for clinical applications that has shown promise to characterize various tissue viscoelasticity. It is based on measuring and analyzing velocities and attenuations of propagated shear waves. In this review, principles and technical developments of shear wave elastography for viscoelasticity characterization from organ to cellular levels are presented, and different imaging modalities used to track shear wave propagation are described. At a macroscopic scale, techniques for inducing shear waves using an external mechanical vibration, an acoustic radiation pressure or a Lorentz force are reviewed along with imaging approaches proposed to track shear wave propagation, namely ultrasound, magnetic resonance, optical, and photoacoustic means. Then, approaches for theoretical modeling and tracking of shear waves are detailed. Following it, some examples of applications to characterize the viscoelasticity of various organs are given. At a microscopic scale, a novel cellular shear wave elastography method using an external vibration and optical microscopy is illustrated. Finally, current limitations and future directions in shear wave elastography are presented

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

A hybrid approach to determining cornea mechanical properties using a combination of inverse finite element analysis and experimental techniques

It is of great clinical importance to predict the behaviour of the cornea in various diseases and post-surgical recovery. Therefore, a numerical model that is able to simulate the corneal behaviour, considering corneal material properties obtained from individuals is highly desirable. In this work a combined numerical-experimental technique has been developed that can characterize the mechanical properties of a cornea properties from two aspects: time-dependency and spatial variation. Initially, an analysis of the material properties of porcine corneas was performed to investigate the time-dependent behaviour of the cornea. A simple stress relaxation test was used to determine the viscoelastic properties of a cornea and a rheological model was built based on the Generalized Maxwell (GM) approach. A validation experiment using nano-indentation showed that an isotropic GM model was insufficient for describing the corneal time-dependent behaviour when exposed to a complex stress state. A technique was proposed that takes into account the microstructural composition of the cornea and is based on a combination of nano-indentation experiment, isotropic and transversely isotropic numerical models, and an inverse finite element method. The good agreement using this method suggests that this is a promising technique for measuring the time-dependent properties of the cornea. The spatial variation of the properties was then investigated. This time, the long term structural response of the cornea was targeted. A full field displacement response of a loaded cornea was evaluated from Optical Coherence Tomography (OCT) volume reconstructions of the cornea using Digital Volume Correlation (DVC). The inverse finite element method was employed with two models sequentially; first, a radially partitioned model and then a circumferentially partitioned model, in order to recover the elastic parameters in radial and circumferential directions. The good agreement using this method suggests that this is a promising and reliable technique for identifying the distribution of the corneal properties. In this research, we have shown that it is possible to determine the local time-dependent properties of the cornea and the in-depth (2D) distribution of the properties using the hybrid technique. This technique has the potential to be implemented in vivo. However, further work should focus on the feasibility of this technique in practice