laser speckle rheological microscopy (SHEAR)

Maps of shear modulus (top left), relative viscosity (bottom left), and composite viscoelasticity (right) of a severely degenerative intra-articular tissue from knee replacement surgery. See Laser Speckle RHEologicAl MicRoscopy (SHEAR) and WB-SHEAR for more.
Maps of shear modulus (top left), relative viscosity (bottom left), and composite viscoelasticity (right) of a severely degenerative intra-articular tissue from knee replacement surgery. See Laser Speckle RHEologicAl MicRoscopy (SHEAR) and WB-SHEAR for more.
Cutaway view of a coronary test phantom evaluated with a custom intracoronary catheter. The colors represent spatially-varying mechanical properties. See intracoronary LSR for more.
Cutaway view of a coronary test phantom evaluated with a custom intracoronary catheter. The colors represent spatially-varying mechanical properties. See intracoronary LSR for more.
Viscoelastic modulus map of the tumor microenvironment in invasive ductal carcinoma obtained with an LSR microscope. See Laser Speckle RHEologicAl MicRoscopy (SHEAR) for more.
Viscoelastic modulus map of the tumor microenvironment in invasive ductal carcinoma obtained with an LSR microscope. See Laser Speckle RHEologicAl MicRoscopy (SHEAR) for more.
Non-contact mapping of shear viscoelastic properties in fresh unprocessed tissue with a laser speckle microscope (left). Speckle is a granular pattern that arises from the interference of light scattered by native microstructures within the tissue (right).
Non-contact mapping of shear viscoelastic properties in fresh unprocessed tissue with a laser speckle microscope (left). Speckle is a granular pattern that arises from the interference of light scattered by native microstructures within the tissue (right).

Biological tissues scale a broad range of mechanical properties, from pliant fatty tissue to hard bone. Abnormal changes in tissue mechanics are a powerful driver of various diseases including cancer, fibro-proliferative disorders, hematological disorders, and orthopedic conditions. Thus, mechanical signatures of tissue can enhance our understanding of the disease state and improve our ability to diagnose and treat diseases. However, current clinical pathology procedures do not comprehensively discern mechanical abnormalities of clinical tissue. Our lab develops a new tool in the form of a simple upright microscope, called SHEAR, to enable high-resolution mapping of tissue micromechanics in gross unprocessed tissue specimens. Of note, SHEAR has established the links between microscale heterogeneities of viscoelasticity and histopathological subtype, tumor grade, receptor expression, and lymph node status in breast carcinoma. Our other application areas include tissue engineering and regenerative medicine of knee joint tissues andatherosclerotic plaque biomechanics.

Micromechanical mapping of the breast tumor microenvironment

Of note, SHEAR measurements have established the links between microscale heterogeneities of viscoelasticity and histopathological subtype, tumor grade, receptor expression, and lymph node status in breast carcinoma. By providing detailed information about the mechanical properties of lesions, SHEAR has the potential to greatly enhance our understanding of the disease mechano-pathology and improve our ability to diagnose and treat diseases.

Tissues are composed of both solid and fluid constituents, and thus, exhibit a combination of elastic and viscous (dissipative) mechanical properties. High-resolution SHEAR maps of both the modulus magnitude (left) and relative viscosity (right) reveal distinct micromechanical heterogeneity in the microenvironment of native (top) and engineered (bottom) articular cartilage. Scale bar: 50 μm.
Tissues are composed of both solid and fluid constituents, and thus, exhibit a combination of elastic and viscous (dissipative) mechanical properties. High-resolution SHEAR maps of both the modulus magnitude (left) and relative viscosity (right) reveal distinct micromechanical heterogeneity in the microenvironment of native (top) and engineered (bottom) articular cartilage. Scale bar: 50 μm.
SHEAR map (left) and corresponding histology slide (right) of an invasive ductal carcinoma of the breast featuring the stiff tumor stroma (red to magenta to purple hues) in striking contrast with the soft tumor epithelium (blue to green to yellow hues). Scale bar: 1 mm.
SHEAR map (left) and corresponding histology slide (right) of an invasive ductal carcinoma of the breast featuring the stiff tumor stroma (red to magenta to purple hues) in striking contrast with the soft tumor epithelium (blue to green to yellow hues). Scale bar: 1 mm.
SHEAR map (left) and corresponding histology slide (right) of an invasive ductal carcinoma of the breast featuring areas of the reduced shear modulus that are pulled inwards and corresponds to round nodules of tumor cells. These nodules are infiltrating against a highly elastic fortress formed by the collagenous stroma. Scale bar: 1 mm.
SHEAR map (left) and corresponding histology slide (right) of an invasive ductal carcinoma of the breast featuring areas of the reduced shear modulus that are pulled inwards and corresponds to round nodules of tumor cells. These nodules are infiltrating against a highly elastic fortress formed by the collagenous stroma. Scale bar: 1 mm.
SHEAR map (left) and corresponding histology slide (right) of invasive micro-papillary carcinoma, a rare sub-type of breast cancer with extremely poor prognosis. An abrupt increase in the shear modulus is observed along the curved tumor-stroma interface termed the “invasive front”. Such mechanical heterogeneity and gradient are believed to drive the invasion and speaks to the highly aggressive nature of this tumor. Scale bar: 1 mm.
SHEAR map (left) and corresponding histology slide (right) of invasive micro-papillary carcinoma, a rare sub-type of breast cancer with extremely poor prognosis. An abrupt increase in the shear modulus is observed along the curved tumor-stroma interface termed the “invasive front”. Such mechanical heterogeneity and gradient are believed to drive the invasion and speaks to the highly aggressive nature of this tumor. Scale bar: 1 mm.

Wideband (WB)-SHEAR

Mechanical properties of biological issues are not merely a single fixed value of modulus. Both the elastic and viscous moduli are dynamically modulated over the frequency at which the tissue is being probed, yielding fingerprint-like frequency-dependent viscoelastic spectra that span a wide frequency band. Living cells, in fact, sense and respond to elastic and viscous mechanical cues at distinct frequencies ranging from sub-Hz to sub-MHz, depending on their activity and how fast they interact with the microenvironment. To capture these intricate multiscale behaviors, we develop a wideband variant of SHEAR (WB-SHEAR) that utilizes an ultra-high-speed camera to probe shear elastic and viscous moduli up to the sub-MHz regime.  These wideband ‘viscoelastic fingerprints’ uniquely characterize tissue micromechanics in far more comprehensive ways than a typical measurement of stiffness at a single frequency.

Micromechanical mapping of the frequency-dependent wideband elastic (top) and viscous (middle) moduli in the breast tumor microenvironment. A prominent mechanical contrast is observed at the tumor-stroma interface visible on the histology slides (bottom), where tumor cells from the tumor epithelium on the left side are infiltrating the collagenous stroma on the left side. Scale bar: 50 μm.
Micromechanical mapping of the frequency-dependent wideband elastic (top) and viscous (middle) moduli in the breast tumor microenvironment. A prominent mechanical contrast is observed at the tumor-stroma interface visible on the histology slides (bottom), where tumor cells from the tumor epithelium on the left side are infiltrating the collagenous stroma on the left side. Scale bar: 50 μm.
Viscoelastic fingerprints of dense cortical bone (green arrows and boxes) and ‘spongey’ trabecular bone (pink arrows and boxes) in bovine rib. |G*|: magnitude of shear modulus (black), G′: elastic modulus (blue), G″: viscous modulus (red), α: relative viscosity, ω: angular frequency. Of note, the α spectrum may provide unique insights on the interstitial fluid constituents and hydration state of the bone, which are believed to also play an important role in fracture risks and bone diseases.
Viscoelastic fingerprints of dense cortical bone (green arrows and boxes) and ‘spongey’ trabecular bone (pink arrows and boxes) in bovine rib. |G*|: magnitude of shear modulus (black), G′: elastic modulus (blue), G″: viscous modulus (red), α: relative viscosity, ω: angular frequency. Of note, the α spectrum may provide unique insights on the interstitial fluid constituents and hydration state of the bone, which are believed to also play an important role in fracture risks and bone diseases.
Viscoelastic fingerprints of different tissue constituents in the benign breast and breast tumor microenvironment. |G*|: magnitude of shear modulus (black), G′: elastic modulus (blue), G″: viscous modulus (red), ω: angular frequency. Of note, the fibrous tumor stroma at the invasive front features a distinct undulation pattern in the viscous behavior with G″ multiple minima, whereas the highly cellular tumor epithelium exhibits significantly higher viscous contribution with G″ matching G′.
Viscoelastic fingerprints of different tissue constituents in the benign breast and breast tumor microenvironment. |G*|: magnitude of shear modulus (black), G′: elastic modulus (blue), G″: viscous modulus (red), ω: angular frequency. Of note, the fibrous tumor stroma at the invasive front features a distinct undulation pattern in the viscous behavior with G″ multiple minima, whereas the highly cellular tumor epithelium exhibits significantly higher viscous contribution with G″ matching G′.

 

Micromechanical mapping of the frequency-dependent
wideband viscoelastic spectra in breast tumor. Right: Frequency-dependent maps
of G′(ω) (top) and G″(ω) (bottom). Scale bar: 50
μm. Left: Frequency-dependent |G*(ω)| (black), G′(ω)
(blue), and G″(ω) (red) spectra at the locations indicated by +
(top) and ○ (bottom) on the maps.

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