Combinatorial screen of dynamic mechanical stimuli for predictive control of MSC mechano-responsiveness

Mechanobiological-based control of mesenchymal stromal cells (MSCs) to facilitate engineering and regeneration of load-bearing tissues requires systematic investigations of specific dynamic mechanical stimulation protocols. Using deformable membrane microdevice arrays paired with combinatorial experimental design and modeling, we probed the individual and integrative effects of mechanical stimulation parameters (strain magnitude, rate at which strain is changed, and duty period) on myofibrogenesis and matrix production of MSCs in three-dimensional hydrogels. These functions were found to be dominantly influenced by a previously unidentified, higher-order interactive effect between strain magnitude and duty period. Empirical models based on our combinatorial cue-response data predicted an optimal loading regime in which strain magnitude and duty period were increased synchronously over time, which was validated to most effectively promote MSC matrix production. These findings inform the design of loading regimes for MSC-based engineered tissues and validate a broadly applicable approach to probe multifactorial regulating effects of mechanobiological cues.

A comparison of different methods for estimating penetrative strain using natural and synthetic data: A study from the Sikkim Himalaya

<p>Convergence-related shortening gets primarily accommodated in faults, fault-related folds and penetrative strain in fold thrust belts (FTB). For example, in the Himalayan FTB, ~477-919 km minimum orogen-scale shortening is accommodated by a series of folded, south vergent thrust systems that vary laterally in their geometry resulting in laterally varying shortening distribution. From hinterland to foreland, these major thrust faults are the Main Central thrust, the Pelling-Munsiari thrust, the Lesser Himalayan duplex, the Main Boundary thrust, and the Main Frontal thrust. In the Sikkim Himalayan FTB, the structural geometry of these thrust sheets laterally varies over ~15 km. Based on two regional, transport-parallel balanced cross-sections, ~542-589 km minimum wedge-scale shortening has been estimated. To quantify grain-scale shortening, we analyzed 201 thin-sections cut from 96 quartz-rich samples (sandstone, quartzite, phyllite, schist, and gneiss) and calculated penetrative strain from them. Penetrative strain results indicate that ~25-26% of total Himalayan shortening is recorded at the grain-scale in this section of the eastern Himalaya.</p><p>In the internal thrust sheets, the strain magnitude (R<sub>S</sub>) remains higher (~1.4-2.43 ), and it progressively decreases in the frontal thrust sheets (~1.08-1.51). The normalized Fry and the R<sub>f</sub>-φ are the two most commonly used graphical methods to estimate best-fit strain ellipse parameters, i.e., R<sub>S</sub> and φ (long-axis orientation). However, in thrust sheets with less deformed sandstones, where initial grain shapes were not spherical, these graphical methods do not accurately estimate the best-fit strain ellipse parameters. The central vacancy in the Fry plot was objectively fitted using the enhanced normalized Fry (ENFRY), the point-count density (PCD), the continuous function method (CFM), and weighted least square (WLS) methods. From the R<sub>f</sub>-φ data, we calculated the best-fit strain ellipse using the shape matrix eigenvector (SME), centroids of the hyperbolic plot (HP), Elliot’s polar graph (EPG), and R<sub>f</sub>-φ graph, harmonic mean (HM) and vector mean (VM) methods. In this study, we calculate the accuracy of these strain methods as a function of the strain magnitude and structural position within the orogenic wedge. The SME and HP methods record the lowest bootstrap errors in the strain parameters in the internal thrust sheets. In contrast, R<sub>S</sub> and φ values estimated by the WLS method records the lowest bootstrap error in the frontal thrust sheets, followed by the SME, HP, and EPG methods. We also created six synthetic aggregates containing 150-170 random elliptical grains with random long-axis orientations. We deformed these aggregates under pure-shear, simple-shear, and general-shear conditions at various strain increments. We have generated 7560 strain data. To understand the accuracy of these strain methods in estimating penetrative strain, we calculated the Root Mean Square Error (RMSE) and Mean Absolute Error (MAE) for every strain method and every type of deformation. Experimental results indicate that the SME and HP methods record the lowest errors in the R<sub>S</sub> and φ values. In low strain conditions (R<sub>S</sub><1.5), the SME, HP, and EPG methods record lower errors in the strain parameters. Therefore, this study shows that the SME and HP methods overall yield a better penetrative strain estimate.</p>

Strain partitioning within thrust sheets of tectonic windows: Insights from eastern Himalaya

<p>In a fold-thrust belt (FTB), penetrative strain within thrust sheets vary in its magnitude, orientation and type. Addressing variation in magnitude and orientation of strain from major thrust sheets in a FTB, both along the transport direction and along-strike, enable us to understand the complexity of strain partitioning during orogeny. Tectonic windows provide an opportunity to understand the impact of footwall structures on finite strain geometry and orientations of the overlying thrust sheets. In this study, we investigate how penetrative strain is partitioned from the internal to the external major thrust sheets in the Siang window in far-eastern Arunachal Himalayan FTB. We also compare these results with similar thrust sheets from well preserved tectonic windows in the eastern Himalaya, i.e., the Teesta window of the Sikkim and Kuru Chu window of the Bhutan Himalayan FTB.</p><p>We conduct finite strain analysis on quartz grains using R<sub>f</sub>-φ, normalized Fry and Shape Matrix Eigenvector methods. The studied lithologies are gneiss for the internal Pelling-Munsiari-Bomdilla thrust (PT) sheet, while quartzite and sandstone dominantly comprise the external Main Boundary thrust (MBT) and the Main Frontal thrust (MFT) sheets. The rocks north of the PT sheet are not accessible. Results from this study indicate that all the studied rocks record an overall flattening strain. Magnitude of the finite penetrative strain decreases from the internal PT sheet to the external MBT, MFT sheets in the Siang window. The long axes of the finite strain ellipsoids (X) generally have a low plunge and vary in bearing, irrespective of the structural positions of the different thrust sheets. Finite strain ellipses are folded along with the thrust sheets indicating that the penetrative strain developed prior to folding of the thrust sheets. The results also indicate that the footwall structures affect the strain geometry in the interior part of the Himalayan wedge. The grain scale shortening percentage is highest for internal PT sheet and it progressively decreases towards the external MFT sheet. The results indicate greater contribution of thrust-parallel stretch than thrust-perpendicular component, in both internal and external thrust sheets in the Siang window. Preliminary results also suggest that the strain magnitude and grain-scale shortening percentage are the lowest, and orientations of X-axes are more variable with respect to the regional transport direction in the far-eastern Siang window as compared to the other westerly lying regional transects of the Himalayan FTB.</p>

Biomechanics effect of two implant system with different bone height under axial and non–axial loading conditions

The objective of this current in silico study was to evaluate the influence of axial and non-axial loads on unitary implant-supported implants, with external hexagon or Morse-taper connection in two different bone level, using finite element analysis. Two implant models with the same length (13 x 3.75 mm) were analyzed according to the prosthetic connection (external hexagon or morse Taper) and bone height (bone level or 5 mm of bone loss). Both implant systems received screw-retained metallic crowns in chromium-cobalt. The peri-implant tissue was simulated as an isotropic material (polyurethane resin). The polyurethane block has been fixed and a load of 300 N was applied on the occlusal surface in two different directions (Axial or Non-axial) for each implant model and bone condition. The results were analyzed in terms of von-Mises stress and bone microstrain. The materials were considered isotropic, homogeneous, linear and elastic. The results showed that there is no difference regarding the prosthetic connection for the generated stress and strain under the same load incidence. However, bone loss and non-axial loadings increased the stress and strain magnitude regardless the prosthetic connections. In conclusion, the load incidence is more prone to modify the implant stress and bone microstrain than the prosthethic connection. In addition, the higher the bone loss the higher the stress and strain magnitude generated, regardless the loading condition.

Mechanoadaptive organization of stress fiber subtypes in epithelial cells under cyclic stretches and stretch release

Cyclic stretch applied to cells induces the reorganization of stress fibers. However, the correlation between the reorganization of stress fiber subtypes and strain-dependent responses of the cytoplasm and nucleus has remained unclear. Here, we investigated the dynamic involvement of stress fiber subtypes in the orientation and elongation of cyclically stretched epithelial cells. We applied uniaxial cyclic stretches at 5%, 10%, and 15% strains to cells followed by the release of the mechanical stretch. Dorsal, transverse arcs, and peripheral stress fibers were mainly involved in the cytoplasm responses whereas perinuclear cap fibers were associated with the reorientation and elongation of the nucleus. Dorsal stress fibers and transverse arcs rapidly responded within 15 min regardless of the strain magnitude to facilitate the subsequent changes in the orientation and elongation of the cytoplasm. The cyclic stretches induced the additional formation of perinuclear cap fibers and their increased number was almost maintained with a slight decline after 2-h-long stretch release. The slow formation and high stability of perinuclear cap fibers were linked to the slow reorientation kinetics and partial morphology recovery of nucleus in the presence or absence of cyclic stretches. The reorganization of stress fiber subtypes occurred in accordance with the reversible distribution of myosin II. These findings allowed us to propose a model for stretch-induced responses of the cytoplasm and nucleus in epithelial cells based on different mechanoadaptive properties of stress fiber subtypes.

Relating Bone Strain to Local Changes in Radius Microstructure Following 12 Months of Axial Forearm Loading in Women

Work in animal models suggests that bone structure adapts to local bone strain, but this relationship has not been comprehensively studied in humans. Here, we quantified the influence of strain magnitude and gradient on bone adaptation in the forearm of premenopausal women performing compressive forearm loading (n = 11) and nonloading controls (n = 10). High resolution peripheral quantitative computed tomography (HRpQCT) scans of the distal radius acquired at baseline and 12 months of a randomized controlled experiment were used to identify local sites of bone formation and resorption. Bone strain was estimated using validated finite element (FE) models. Trabecular strain magnitude and gradient were higher near (within 200 μm) formation versus resorption (p < 0.05). Trabecular formation and resorption occurred preferentially near very high (>95th percentile) versus low (<5th percentile) strain magnitude and gradient elements, and very low strain elements were more likely to be near resorption than formation (p < 0.05). In the cortical compartment, strain gradient was higher near formation versus resorption (p < 0.05), and both formation and resorption occurred preferentially near very high versus low strain gradient elements (p < 0.05). At most, 54% of very high and low strain elements were near formation or resorption only, and similar trends were observed in the control and load groups. These findings suggest that strain, likely in combination with other physiological factors, influences adaptation under normal loads and in response to a novel loading intervention, and represents an important step toward defining exercise interventions to maximize bone strength.