Transient and Microscale Deformations and Strains Measured under Exogenous Loading by Noninvasive Magnetic Resonance

Characterization of spatiotemporal deformation dynamics and material properties requires non-destructive methods to visualize mechanics of materials and biological tissues. Displacement-encoded magnetic resonance imaging (MRI) has emerged as a noninvasive and non-destructive technique used to quantify deformation and strains. However, the techniques are not yet applicable to a broad range of materials and load-bearing tissues. In this paper, we visualize transient and internal material deformation through the novel synchrony of external mechanical loading with rapid displacement-encoded MRI. We achieved deformation measurements in silicone gel materials with a spatial resolution of 100 µm and a temporal resolution (of 2.25 ms), set by the repetition time (TR) of the rapid MRI acquisition. Displacement and strain precisions after smoothing were 11 µm and 0.1%, respectively, approaching cellular length scales. Short (1/2 TR) echo times enabled visualization of in situ deformation in a human tibiofemoral joint, inclusive of multiple variable T2 biomaterials. Moreover, the MRI acquisitions achieved a fivefold improvement in imaging time over previous technology, setting the stage for mechanical imaging in vivo. Our results provide a general approach for noninvasive and non-destructive measurement, at high spatial and temporal resolution, of the dynamic mechanical response of a broad range of load-bearing materials and biological tissues

In vivo articular cartilage deformation: noninvasive quantification of intratissue strain during joint contact in the human knee

The in vivo measurement of articular cartilage deformation is essential to understand how mechanical forces distribute throughout the healthy tissue and change over time in the pathologic joint. Displacements or strain may serve as a functional imaging biomarker for healthy, diseased, and repaired tissues, but unfortunately intratissue cartilage deformation in vivo is largely unknown. Here, we directly quantified for the first time deformation patterns through the thickness of tibiofemoral articular cartilage in healthy human volunteers. Magnetic resonance imaging acquisitions were synchronized with physiologically relevant compressive loading and used to visualize and measure regional displacement and strain of tibiofemoral articular cartilage in a sagittal plane. We found that compression (of 1/2 body weight) applied at the foot produced a sliding, rigid-body displacement at the tibiofemoral cartilage interface, that loading generated subject- and gender-specific and regionally complex patterns of intratissue strains, and that dominant cartilage strains (approaching 12%) were in shear. Maximum principle and shear strain measures in the tibia were correlated with body mass index. Our MRI-based approach may accelerate the development of regenerative therapies for diseased or damaged cartilage, which is currently limited by the lack of reliable in vivo methods for noninvasive assessment of functional changes following treatment

Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling

Lamins are intermediate filament proteins that assemble into a meshwork underneath the inner nuclear membrane, the nuclear lamina. Mutations in the LMNA gene, encoding lamins A and C, cause a variety of diseases collectively called laminopathies. The disease mechanism for these diverse conditions is not well understood. Since lamins A and C are fundamental determinants of nuclear structure and stability, we tested whether defects in nuclear mechanics could contribute to the disease development, especially in laminopathies affecting mechanically stressed tissue such as muscle. Using skin fibroblasts from laminopathy patients and lamin A/C-deficient mouse embryonic fibroblasts stably expressing a broad panel of laminopathic lamin A mutations, we found that several mutations associated with muscular dystrophy and dilated cardiomyopathy resulted in more deformable nuclei; in contrast, lamin mutants responsible for diseases without muscular phenotypes did not alter nuclear deformability. We confirmed our results in intact muscle tissue, demonstrating that nuclei of transgenic Drosophila melanogaster muscle expressing myopathic lamin mutations deformed more under applied strain than controls. In vivo and in vitro studies indicated that the loss of nuclear stiffness resulted from impaired assembly of mutant lamins into the nuclear lamina. Although only a subset of lamin mutations associated with muscular diseases caused increased nuclear deformability, almost all mutations tested had defects in force transmission between the nucleus and cytoskeleton. In conclusion, our results indicate that although defective nuclear stability may play a role in the development of muscle diseases, other factors, such as impaired nucleo-cytoskeletal coupling, likely contribute to the muscle phenotyp

A Left Ventricular Motion Phantom for Cardiac Magnetic Resonance Imaging

The mammalian left ventricle (LV) has two distinct motion patterns: wall thickening and rotation. The purpose of this study was to design and build a low-cost, non-ferromagnetic LV motion phantom, for use with cardiac magnetic resonance imaging (MRI), that is able to produce physiologically realistic LV wall thickening and rotation. Cardiac MRI is continuously expanding its range of techniques with new pulse sequences, including new tissue tagging techniques which allow intra-myocardial deformation to be visualized. An essential step in the development of new cardiac MRI techniques is validating their performance in the presence of motion. MRI-compatible dynamic motion phantoms are of substantial benefit in the development of cardiac specific-magnetic resonance imaging techniques. These phantoms enable the investigation of motion effects images by mimicking the three dimensional motion of the heart. To date, no single study has succeeded in duplicating both LV motion patterns, in an MRI-compatible cardiac motion phantom. In addition, a phantom that is 100 MRI-compatible with low cost to build would be desirable to researchers. We have built two MRI-compatible phantoms, housed within a common enclosure and each filled with MRI-visible dielectric gel (as a surrogate to myocardium),which model the wall thickening and rotation motions of the left ventricle independently. The wall motion phantom is pneumatic, driven by a custom non-ferromagnetic pump which cyclically fills and empties a latex balloon within the phantom. The rotation phantom is manually driven by a plastic actuator which rotates the phantom through a specified angular rotation. Each phantom also generates a TTL pulse for triggering the MRI scanner. Although this circuitry contains ferromagnetic materials, it can be located outside the scanner bore. The wall thickening motion phantom has been tested using segmented cine, real time cine and grid tagged MRI acquisition sequences. Results were significant with 4 average variability and physiologically

A Left Ventricular Motion Phantom for Cardiac Magnetic Resonance Imaging

The mammalian left ventricle (LV) has two distinct motion patterns: wall thickening and rotation. The purpose of this study was to design and build a low-cost, non-ferromagnetic LV motion phantom, for use with cardiac magnetic resonance imaging (MRI), that is able to produce physiologically realistic LV wall thickening and rotation. Cardiac MRI is continuously expanding its range of techniques with new pulse sequences, including new tissue tagging techniques which allow intra-myocardial deformation to be visualized. An essential step in the development of new cardiac MRI techniques is validating their performance in the presence of motion. MRI-compatible dynamic motion phantoms are of substantial benefit in the development of cardiac specific-magnetic resonance imaging techniques. These phantoms enable the investigation of motion effects images by mimicking the three dimensional motion of the heart. To date, no single study has succeeded in duplicating both LV motion patterns, in an MRI-compatible cardiac motion phantom. In addition, a phantom that is 100 MRI-compatible with low cost to build would be desirable to researchers. We have built two MRI-compatible phantoms, housed within a common enclosure and each filled with MRI-visible dielectric gel (as a surrogate to myocardium),which model the wall thickening and rotation motions of the left ventricle independently. The wall motion phantom is pneumatic, driven by a custom non-ferromagnetic pump which cyclically fills and empties a latex balloon within the phantom. The rotation phantom is manually driven by a plastic actuator which rotates the phantom through a specified angular rotation. Each phantom also generates a TTL pulse for triggering the MRI scanner. Although this circuitry contains ferromagnetic materials, it can be located outside the scanner bore. The wall thickening motion phantom has been tested using segmented cine, real time cine and grid tagged MRI acquisition sequences. Results were significant with 4 average variability and physiologically

A Left Ventricular Motion Phantom for Cardiac Magnetic Resonance Imaging

The mammalian left ventricle (LV) has two distinct motion patterns: wall thickening and rotation. The purpose of this study was to design and build a low-cost, non-ferromagnetic LV motion phantom, for use with cardiac magnetic resonance imaging (MRI), that is able to produce physiologically realistic LV wall thickening and rotation. Cardiac MRI is continuously expanding its range of techniques with new pulse sequences, including new tissue tagging techniques which allow intra-myocardial deformation to be visualized. An essential step in the development of new cardiac MRI techniques is validating their performance in the presence of motion. MRI-compatible dynamic motion phantoms are of substantial benefit in the development of cardiac specific-magnetic resonance imaging techniques. These phantoms enable the investigation of motion effects images by mimicking the three dimensional motion of the heart. To date, no single study has succeeded in duplicating both LV motion patterns, in an MRI-compatible cardiac motion phantom. In addition, a phantom that is 100 MRI-compatible with low cost to build would be desirable to researchers. We have built two MRI-compatible phantoms, housed within a common enclosure and each filled with MRI-visible dielectric gel (as a surrogate to myocardium),which model the wall thickening and rotation motions of the left ventricle independently. The wall motion phantom is pneumatic, driven by a custom non-ferromagnetic pump which cyclically fills and empties a latex balloon within the phantom. The rotation phantom is manually driven by a plastic actuator which rotates the phantom through a specified angular rotation. Each phantom also generates a TTL pulse for triggering the MRI scanner. Although this circuitry contains ferromagnetic materials, it can be located outside the scanner bore. The wall thickening motion phantom has been tested using segmented cine, real time cine and grid tagged MRI acquisition sequences. Results were significant with 4 average variability and physiologically

Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells

Emery-Dreifuss muscular dystrophy can be caused by mutations in the nuclear envelope proteins lamin A/C and emerin. We recently demonstrated that A-type lamin-deficient cells have impaired nuclear mechanics and altered mechanotransduction, suggesting two potential disease mechanisms (Lammerding, J., P.C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R.D. Kamm, C.L. Stewart, and R.T. Lee. 2004. J. Clin. Invest. 113:370–378). Here, we examined the function of emerin on nuclear mechanics and strain-induced signaling. Emerin-deficient mouse embryo fibroblasts have abnormal nuclear shape, but in contrast to A-type lamin-deficient cells, exhibit nuclear deformations comparable to wild-type cells in cellular strain experiments, and the integrity of emerin-deficient nuclear envelopes appeared normal in a nuclear microinjection assay. Interestingly, expression of mechanosensitive genes in response to mechanical strain was impaired in emerin-deficient cells, and prolonged mechanical stimulation increased apoptosis in emerin-deficient cells. Thus, emerin-deficient mouse embryo fibroblasts have apparently normal nuclear mechanics but impaired expression of mechanosensitive genes in response to strain, suggesting that emerin mutations may act through altered transcriptional regulation and not by increasing nuclear fragility

Stress relaxation in epithelial monolayers is controlled by the actomyosin cortex

Epithelial monolayers are one-cell thick tissue sheets that separate internal and external environments. As part of their function, they have to withstand extrinsic mechanical stresses applied at high strain rates. However, little is known about how monolayers respond to mechanical deformations. Here, by subjecting suspended epithelial monolayers to stretch, we find that they dissipate stresses on a minute time-scale in a process that involves an increase in monolayer length, pointing to active remodelling of cell architecture during relaxation. Strikingly, monolayers consisting of tens of thousands of cells relax stress with similar dynamics to single rounded cells and both respond similarly to perturbations of actomyosin. By contrast, cell-cell junctional complexes and intermediate filaments do not relax tissue stress, but form stable connections between cells, allowing monolayers to behave rheologically as single cells. Taken together our data show that actomyosin dynamics governs the rheological properties of epithelial monolayers, dissipating applied stresses, and enabling changes in monolayer length.Peer ReviewedPostprint (published version