Stiffness Regulation Research Articles

Aging impairs smooth muscle-mediated regulation of aortic stiffness: a defect in shock absorption function?

Increased aortic stiffness is an early and independent biomarker of cardiovascular disease. Here we tested the hypothesis that vascular smooth muscle cells (VSMCs) contribute significantly to aortic stiffness and investigated the mechanisms involved. The relative contributions of VSMCs, focal adhesions (FAs), and matrix to stiffness in mouse aorta preparations at optimal length and with confirmed VSMC viability were separated by the use of small-molecule inhibitors and activators. Using biomechanical methods designed for minimal perturbation of cellular function, we directly quantified changes with aging in aortic material stiffness. An alpha adrenoceptor agonist, in the presence of N(G)-nitro-l-arginine methyl ester (l-NAME) to remove interference of endothelial nitric oxide, increases stiffness by 90-200% from baseline in both young and old mice. Interestingly, increases are robustly suppressed by the Src kinase inhibitor PP2 in young but not old mice. Phosphotyrosine screening revealed, with aging, a biochemical signature of markedly impaired agonist-induced FA remodeling previously associated with Src signaling. Protein expression measurement confirmed a decrease in Src expression with aging. Thus we report here an additive model for the in vitro biomechanical components of the mouse aortic wall in which 1) VSMCs are a surprisingly large component of aortic stiffness at physiological lengths and 2) regulation of the VSMC component through FA signaling and hence plasticity is impaired with aging, diminishing the aorta's normal shock absorption function in response to stressors.

Clinical relevance of fascial tissue and dysfunctions.

Fascia is composed of collagenous connective tissue surrounding and interpenetrating skeletal muscle, joints, organs, nerves, and vascular beds. Fascial tissue forms a whole-body, continuous three-dimensional viscoelastic matrix of structural support. The classical concept of its mere passive role in force transmission has recently been disproven. Fascial tissue contains contractile elements enabling a modulating role in force generation and also mechanosensory fine-tuning. This hypothesis is supported by in vitro studies demonstrating an autonomous contraction of human lumbar fascia and a pharmacological induction of temporary contraction in rat fascial tissue. The ability of spontaneous regulation of fascial stiffness over a time period ranging from minutes to hours contributes more actively to musculoskeletal dynamics. Imbalance of this regulatory mechanism results in increased or decreased myofascial tonus, or diminished neuromuscular coordination, which are key contributors to the pathomechanisms of several musculoskeletal pathologies and pain syndromes. Here, we summarize anatomical and biomechanical properties of fascial tissue with a special focus on fascial dysfunctions and resulting clinical manifestations. Finally, we discuss current and future potential treatment options that can influence clinical manifestations of pain syndromes associated with fascial tissues.

Effect of exercise training on post-translational and post-transcriptional regulation of titin stiffness in striated muscle of wild type and IG KO mice

Exercise has beneficial effects on diastolic dysfunction but the underlying mechanisms are not well understood. Here we studied the effects of exercise on the elastic protein titin, an important determinant of diastolic stiffness, in both the left ventricle and the diaphragm. We used wild type mice and genetically engineered mice with HFpEF symptoms (IG KO mice), including diastolic dysfunction. In the diaphragm muscle, exercise increased the expression level of titin (increased titin:MHC ratio) which is expected to increase titin-based stiffness. This effect was absent in the LV. We also studied the constitutively expressed titin residues S11878 and S12022 that are known targets of CaMKIIδ and PKCα with increased phosphorylation resulting in an increase in titin-based passive stiffness. The phosphorylation level of S11878 was unchanged whereas S12022 responded to exercise with a reduction in the phosphorylation level in the LV and, interestingly, an increase in the diaphragm. These changes are expected to lower titin’s stiffness in the LV and increase stiffness in the diaphragm. We propose that these disparate effects reflect the unique physiological needs of the two tissue types and that both effects are beneficial.

Stretch Shortening Cycle in Childhood

The examination of stretch shortening cycle (SSC) in children became an interesting topic for research during the past years as it provides an important insight into the functioning of the neuromuscular system. This paper presents several studies related to children and their ability to jump. The reasons for children doing more poorly in jumping as compared to adults are complex and multi-factorial. Current data illustrate differences in biomechanical patterns, in the elicited ground reaction forces and in the neuromuscular activation obtained by electromyography (EMG) during jumping. Most of the findings converge towards the idea that children adopt a less mature and more inefficient technique which has some common characteristics with the “absorbing type” jump of adult jumpers displaying poor technique. The conclusion is that the children's deficit in jumping can be attributed to differences in technique that lead to less efficient stiffness regulation and in some cases, such as drop jumps, derive less benefit from the SSC mechanism.

Neuromechanical coupling in the regulation of muscle tone and joint stiffness.

The ability of the nervous system to accommodate changes to joint mechanics is crucial in the maintenance of joint stability and the prevention of injury. This neuromechanical coupling is achieved through several mechanisms such as the central and peripheral regulation of muscle tone and subsequent alterations to joint stiffness. Following joint injury, such as a ligamentous sprains, some patients develop functional instability or require surgery to stabilize the joint, while others are able to cope and display limited impairments. Several researchers have attempted to explain these divergent outcomes, although research using proprioceptive tasks and quantifying reaction times has led to equivocal results. Recent innovations have allowed for the simultaneous measurement of mechanical and nervous system function among these subsets. The intent of this review was to explore the relationships between joint stiffness and nervous system function, and how it changes following injury. By better understanding these mechanisms, researchers and clinicians may better develop and implement rehabilitation protocols to target individual deficits among injured populations.

A New Actuator With Adjustable Stiffness Based on a Variable Ratio Lever Mechanism

This paper presents the actuator with adjustable stiffness (AwAS-II), an enhanced version of the original realization AwAS. This new variable stiffness actuator significantly differs from its predecessor on the mechanism used for the stiffness regulation. While AwAS tunes the stiffness by regulating the position of the compliant elements along the lever arm, AwAS-II changes the position of the lever's pivot point. As a result of the new principle, AwAS-II can change the stiffness in a much broader range (from zero to infinity) even by using softer springs and shorter lever arm, compared to AwAS. This makes the setup of AwAS-II more compact and lighter and improves the stiffness regulation response. To evaluate the aptitude of the fast stiffness adjustment, experiments on reproducing the stiffness profile of the human ankle during the stance phase of a normal walking gait are conducted. Results indicate that AwAS-II is capable of reproducing an interpolated stiffness profile of the ankle while providing a net positive work and thus a sufficient amount of energy as required for the toe-off.

The regulation of limb stiffness in the context of locomotor tasks.

Locomotion on ramped surfaces requires modulation of both pattern-generating circuits and limb stiffness. To meet the mechanical demands of locomotion under these conditions, muscular activation patterns must correspond to the appropriate functions, whether the muscles are serving as force generators or brakes. Limb stiffness is a critical mechanical property that determines how the body interacts with the environment, and is regulated by both intrinsic and neural mechanisms. We have recently investigated how pattern generation, stiffness, and proprioceptive feedback are modulated in a task-specific way using the decerebrate cat preparation. Our results confirm previous research using intact animals that during level and upslope walking, hip and ankle extensors are recruited for propulsion during stance. During downslope walking, hip extensors are inhibited and hip flexors are recruited during stance to provide the needed braking action. Our new data further show that endpoint stiffness of the limb is correspondingly reduced for walking down a slope, and that the reduction in stiffness is likely due to an increase in inhibitory force feedback. Our results further suggest that a body orientation signal derived from vestibular and neck proprioceptive information is responsible for the required muscular activation patterns as well as a reduction in limb stiffness. This increased compliance is consistent with the function of the distal limb to cushion the impact during the braking action of the antigravity musculature.

Amputee locomotion: Spring-like leg behavior and stiffness regulation using running-specific prostheses

Carbon fiber running-specific prostheses (RSPs) have allowed individuals with lower extremity amputation (ILEA) to participate in running. It has been established that as running speed increases, leg stiffness (Kleg) remains constant while vertical stiffness (Kvert) increases in able-bodied runners. The Kvert further depends on a combination of the torsional stiffnesses of the joints (joint stiffness; Kjoint) and the touchdown joint angles. Thus, an increased understanding of spring-like leg function and stiffness regulation in ILEA runners using RSPs is expected to aid in prosthetic design and rehabilitation strategies. The aim of this study was to investigate stiffness regulation to various overground running speeds in ILEA wearing RSPs. Eight ILEA performed overground running at a range of running speeds. Kleg, Kvert and Kjoint were calculated from kinetic and kinematic data in both the intact and prosthetic limbs. Kleg and Kvert in both the limbs remained constant when running speed increased, while intact limbs in ILEA running with RSPs have a higher Kleg and Kvert than residual limbs. There were no significant differences in Kankle, Kknee and touchdown knee angle between the legs at all running speeds. Hip joints in both the legs did not demonstrate spring-like function; however, distinct impact peaks were observed only in the intact leg hip extension moment at the early stance phase, indicating that differences in Kvert between limbs in ILEA are due to attenuating shock with the hip joint. Therefore, these results suggest that ILEA using RSPs has a different stiffness regulation between the intact and prosthetic limbs during running.

Differential regulation of stiffness, topography, and dimension of substrates in rat mesenchymal stem cells

The physiological microenvironment of the stem cell niche, including the three factors of stiffness, topography, and dimension, is crucial to stem cell proliferation and differentiation. Although a growing body of evidence is present to elucidate the importance of these factors individually, the interaction of the biophysical parameters of the factors remains insufficiently characterized, particularly for stem cells. To address this issue fully, we applied a micro-fabricated polyacrylamide hydrogel substrate with two elasticities, two topographies, and three dimensions to systematically test proliferation, morphology and spreading, differentiation, and cytoskeletal re-organization of rat bone marrow mesenchymal stem cells (rBMSCs) on twelve cases. An isolated but not combinatory impact of the factors was found regarding the specific functions. Substrate stiffness or dimension is predominant in regulating cell proliferation by fostering cell growth on stiff, unevenly dimensioned substrate. Topography is a key factor for manipulating cell morphology and spreading via the formation of a large spherical shape in a pillar substrate but not in a grooved substrate. Although stiffness leads to osteogenic or neuronal differentiation of rBMSCs on a stiff or soft substrate, respectively, topography or dimension also plays a lesser role in directing cell differentiation. Neither an isolated effect nor a combinatory effect was found for actin or tubulin expression, whereas a seemingly combinatory effect of topography and dimension was found in manipulating vimentin expression. These results further the understandings of stem cell proliferation, morphology, and differentiation in a physiologically mimicking microenvironment.

Design and analysis of cable-driven manipulators with variable stiffness

A manipulator with variable stiffness allows the manipulator to adjust its stiffness to suit for different task requirements. In this paper, a cable-driven manipulator with the ability to significantly regulate its stiffness through tension resolution is introduced. Variable stiffness for the cable-driven manipulators is achieved by attaching a novel variable stiffness device along each driving cable, in which the stiffness of the device is a function of the cable tension. As the cable-driven manipulator has actuation redundancy, the tension distribution can be manipulated even at a stationary pose. Such property allows the cable-driven manipulator to adjust the stiffness of each variable stiffness device, thereby regulating the stiffness of the manipulator. The design and analysis of the variable stiffness device are presented. The variable stiffness device uses commercial torsion springs, and has a compact and light-weight design. For a particular pose, a stiffness-oriented tension resolution algorithm is proposed to optimize the tension distribution to achieve an isotropic stiffness matrix with high stiffness magnitude. Experimental and simulation results verified that cable-driven manipulators with such variable stiffness devices are able to achieve significant stiffness regulation.

Calcium and its role in vascular smooth muscle cell cortical elasticity and adhesion

Calcium (Ca2+) plays an important role in regulating vascular smooth muscle cell (VSMC) contractility and cell signaling. The goal of this study was to investigate the role of Ca2+ in the regulation of VSMC cortex stiffness or elasticity and adhesion in VSMC. In this report, we used 0.2 μM Ionomycin or 0.2 μM BAPTA‐AM to increase or decrease, respectively, the intracellular level of Ca2+ in non‐passaged, freshly isolated rat cremaster VSMCs. An atomic force microscopy (AFM) was used to measure VSMC cortical elasticity using a nano‐indentation protocol (300 nm indentation) and AFM probes were bio‐functionalized with fibronectin to measure cell adhesion. The results demonstrate that the stiffness of the cell cortical cytoskeletal components and adhesion of vascular smooth muscle cells increases after Ionomycin treatment to increase intracellular Ca2+, whereas it decreases after BAPTA treatment to lower Ca2+. Ionomycin treatment was also observed to enhance alpha 5 integrin expression on the VSMC membrane and the F‐actin content of the cells. In contrast, BAPTA reduced the expression and F‐actin content of the cells and reduced cell membrane alpha 5 integrin expression. Our study indicates that Ca2+ is one important signaling molecule that plays a role in regulation of cortical elasticity and adhesion of VSMC by influencing the actin‐integrin cytoskeletal axis. (NIH P01HL095486 to G.A.M).

Biomechanical Comparison in Different Jumping Tasks Between Untrained Boys and Men

This study examines the biomechanical differences during different vertical jump tasks in 12 prepubescent and 12 adult males. The sagittal knee kinematics, vertical ground reaction force (vGRF) and electromyographic (EMG) activity of 5 lower extremity muscles were recorded. Compared with boys, men presented higher peak vGRF during the propulsive phase in all examined jumps, but lower values during the braking phase, even when related to body mass. Normalized EMG agonist activity in all phases was higher in men (p < .05), while antagonist coactivation was enhanced in boys (p < .05). The knee joint was on average 9 degrees more flexed at touchdown in men during drop jump tasks, but boys exhibited 12 degrees and 17 degrees higher knee flexion at the deepest point when performing drop jump from 20 and 40 cm, respectively. In conclusion, the performance deficit observed in boys in all jump types is a reflection of their immature technique, which could be partly attributed to the less efficient stiffness regulation and activation of their neuromuscular system.

A Novel Intrinsically Energy Efficient Actuator With Adjustable Stiffness (AwAS)

In this paper, a new actuator with adjustable stiffness (AwAS) is presented. AwAS is capable of controlling the position and stiffness of a joint, independently. The proposed actuator can regulate the joint stiffness through a wide range with minimum energy consumption by means of a small motor. This is possible due to its novel mechanical configuration that achieves the stiffness regulation not through the control of spring pretension (as in most of the existing variable stiffness joints) but by using the variable lever arm principle. The regulation of the lever arm length is achieved through the displacement of the spring elements. An important consequence of this mechanism is that the displacement needed to change the stiffness is perpendicular to the forces generated by the spring. This helps to reduce the energy/power required to regulate the stiffness. It is experimentally shown that AwAS is capable of minimizing energy consumption through exploiting the natural dynamics in real time for both fixed and variable frequency motions.

Chorein Sensitivity of Actin Polymerization, Cell Shape and Mechanical Stiffness of Vascular Endothelial Cells

Background/Aims: Endothelial cell stiffness plays a key role in endothelium-dependent control of vascular tone and arterial blood pressure. Actin polymerization and distribution of microfilaments is essential for mechanical cell stiffness. Chorein, a protein encoded by the VPS13A gene, defective in chorea-acanthocytosis (ChAc), is involved in neuronal cell survival as well as cortical actin polymerization of erythrocytes and blood platelets. Chorein is expressed in a wide variety of further cells, yet nothing is known about the impact of chorein on cells other than neurons, erythrocytes and platelets. The present study explored whether chorein is expressed in human umbilical vein endothelial cells (HUVECs) and addressed the putative role of chorein in the regulation of cytoskeletal architecture, stiffness and survival of those cells. Methods: In HUVECs with or without silencing of the VPS13A gene, VPS13A mRNA expression was determined utilizing quantitative RT-PCR, cytoskeletal organization visualized by confocal microscopy, G/F actin ratio and phosphorylation status of focal adhesion kinase quantified by western blotting, cell death determined by flow cytometry, mechanical properties studied by atomic force microscopy (AFM) and cell morphology analysed by scanning ion conductance microscopy (SICM). Results: VPS13A mRNA expression was detectable in HUVECs. Silencing of the VPS13A gene attenuated the filamentous actin network, decreased the ratio of soluble G-actin over filamentous F-actin, reduced cell stiffness and changed cell morphology as compared to HUVECs silenced with negative control siRNA. These effects were paralleled by a significant decrease in FAK phosphorylation following VPS13A silencing. Moreover, silencing of the VPS13A gene increased caspase 3 activity and induced necrosis in HUVECs. Conclusions: Chorein is a novel regulator of cytoskeletal architecture, cell shape, mechanical stiffness and survival of vascular endothelial cells.

Precision Trajectory Tracking Control of a Pneumatic Cylinder and Output Stiffness Regulation

Precision motion trajectory tracking control of a single rod pneumatic cylinder driven by two proportional pressure valves is considered. Rather severe nonlinearities and uncertainties exist in the dynamic modeling of the system. In order to guarantee both the transient performance and final accuracy, a nonlinear adaptive robust controller is developed. The proposed controller comprises a sliding mode controller (SMC) and an on-line recursive least squares estimator (RLSE). The RLSE is utilized to reduce the extent of parametric uncertainties, and the SMC is adopted to attenuate the effects of parameter estimation errors, unmodelled dynamics and disturbance. Since pressure in each cylinder chamber is controlled independently, output stiffness regulation can be achieved by changing the nominal control voltage. Several experiments are conducted to test the proposed control strategy, and the results well fulfill the design requirements.

Active Joint Stiffness Regulation to Achieve Isotropic Compliance in the Euclidean Space

This paper is dedicated to the relationship between the external force applied on a point of a robot end-effector and its consequent displacement in static conditions. Both the force and the displacement are herein considered in the Euclidean space E(3). This fact represents a significant simplification of the approach, since it avoids some problems related to the absence of a natural positive definite metric on the Special Euclidean Group SE(3). On the other hand, such restriction allows the method to find closed-form solutions to a large class of problems in robot statics. The peculiar goal of this investigation consists of setting up a procedure which guarantees at least one pose at which any force applied (in E(3)) to an end-effector point is always parallel to its consequent displacement (also in E(3)). This property, which will be referred to as isotropic compliance in E(3), makes the robot tip static behavior uniform with respect to all directions, namely, isotropic, although not homogeneous, since it holds only in some poses. Achieving isotropic compliance in E(3) is a task more general than the classical problem of finding a pose with unit condition number, which does not include the case of different elements in the diagonal joint stiffness matrix. For this reason, the object of the present investigation could not be furtherer simplified to the classical kinetostatic problem in terms of the jacobian matrix alone. The paper reveals how the force–displacement parallelism can be achieved by using a method based on a simple proportional-derivative (PD) controller strategy. The method can be applied when the passive and active stiffness act, on the joints, either in parallel or in series, and the magnitude of the displacement response can be chosen by imposing appropriate values for the overall joints compliance. Results show that for the three analyzed examples, namely, the RR, RRP, and RRR manipulators, with arbitrary lengths of the links, there is, at least, one pose for which the sought property is achieved.

Abstract 15: Increased Intrinsic Stiffness of Aortic Vascular Smooth Muscle Cells as a Mechanism for Increased Aortic Stiffness in Spontaneously Hypertensive Rats

An increase in vascular stiffness is a fundamental component of hypertension. Our hypothesis is that increased large artery stiffness in hypertension is due in part to intrinsic mechanical properties of vascular smooth muscle cells (VSMC). Adult spontaneously hypertensive rats (SHR) (16 weeks old) and age-matched Wistar-Kyoto normotensive (WKY) rats were studied. Aortic pressure, measured with a Millar catheter, was higher in SHR than WKY (MAP 123±4 versus 96±6 mmHg, p &lt;0.05). Aortic stiffness, measured with pulse wave velocity, in vivo, was 2 to 2.5 fold higher in SHR rats (7.65 mm/ms) compared to normotensive rats(3.27 mm/ms, p&lt;0.01 ). Aortic VSMCs were isolated from the SHR and WKY rats. Stiffness in single VSMC was continuously recorded in vitro using atomic force microscopy and temporal oscillations in VSMC elasticity, which represent the dynamic properties of elasticity, were observed and analyzed by Eigen decomposition. VSMC stiffness was consistently increased by 1.5 to 2 fold in SHR (24.0 kPa) versus WKY (11.8 kPa) ( p&lt;0.05) . Moreover, the oscillations in elasticity were significantly different between the two groups in terms of frequency and amplitude ( p&lt;0.05) . ML-7, a highly specific inhibitor of myosin light chain kinase (MLCK), produced a greater reduction in the VSMC elasticity from SHR aorta compared to WKY rats ( p&lt;0.05 ), and also eliminated the difference between the SHR and WKY. Furthermore, ML-7 altered the oscillation in VSMC elasticity in SHR, but not WKY. These observations indicate that there is an inherently altered VSMC stiffness in hypertension that is associated with unique dynamic cytoskeletal behavior. These dynamic elements may be involved mechanistically in increasing aortic stiffness in SHR rats. MLCK participates in the regulation of VSMC stiffness in hypertension via altering both basal VSMC elasticity and temporal oscillations.

Neuromuscular and stiffness adaptations in division I collegiate baseball players

To compare bi-lateral shoulder EMG, active and short range glenohumeral stiffness, and examine its correlation to posterior capsule thickness (PCT) in collegiate baseball players. Surface and fine wire EMG was recorded on shoulder and scapular musculature during stiffness testing. Posterior capsule thickness was assessed separately using a diagnostic ultrasound. Serratus anterior EMG area and peak on the dominant arm was significantly greater compared to the non-dominant arm. The dominant arm had significantly greater active and short range glenohumeral stiffness compared to the non-dominant arm. Active glenohumeral stiffness was significantly correlated with PCT, however short range glenohumeral stiffness was not significantly correlated with PCT. Healthy collegiate baseball players present with adaptations of their stiffness regulation strategies. There were also correlations between stiffness and morphologic changes. Our results support the theory that PCT has an impact on the energy absorption capabilities of the shoulder during the deceleration phase of throwing. It also seems that tightening of the series elastic component within the posterior rotator cuff may be causing the increase in short range stiffness on the dominant arm.

Biomechanical constraints on the feedforward regulation of endpoint stiffness

Although many daily tasks tend to destabilize arm posture, it is still possible to have stable interactions with the environment by regulating the multijoint mechanics of the arm in a task-appropriate manner. For postural tasks, this regulation involves the appropriate control of endpoint stiffness, which represents the stiffness of the arm at the hand. Although experimental studies have been used to evaluate endpoint stiffness control, including the orientation of maximal stiffness, the underlying neural strategies remain unknown. Specifically, the relative importance of feedforward and feedback mechanisms has yet to be determined due to the difficulty separately identifying the contributions of these mechanisms in human experiments. This study used a previously validated three-dimensional musculoskeletal model of the arm to quantify the degree to which the orientation of maximal endpoint stiffness could be changed using only steady-state muscle activations, used to represent feedforward motor commands. Our hypothesis was that the feedforward control of endpoint stiffness orientation would be significantly constrained by the biomechanical properties of the musculoskeletal system. Our results supported this hypothesis, demonstrating substantial biomechanical constraints on the ability to regulate endpoint stiffness throughout the workspace. The ability to regulate stiffness orientation was further constrained by additional task requirements, such as the need to support the arm against gravity or exert forces on the environment. Together, these results bound the degree to which slowly varying feedforward motor commands can be used to regulate the orientation of maximum arm stiffness and provide a context for better understanding conditions in which feedback control may be needed.

Muscle Preactivation Control: Simulation of Ankle Joint Adjustments at Touchdown During Running on Uneven Ground

In locomotion, humans have to deal with irregularities in the ground. When they encounter uneven terrain with changes in vertical height, they adjust the geometry of their legs. Recent investigations have shown that the preactivation of the gastrocnemius muscle (GM) correlates with the ankle angle at touchdown, but it is as of yet unclear why these adjustments were achieved by the GM and not by the preactivation of the tibialis anterior (TA). To examine the differences between TA regulation and GM regulation regarding (1) ankle angle adjustment and (2) joint stiffness, we used a three-segment musculoskeletal model with two antagonistic muscles (GM, TA). During the GM regulation, the ankle angle was adjusted from 121° to 109° (dorsiflexion) by a 41% decrease in the GM activation. During the TA regulation, the activation of TA must be increased by about 52%. In addition, we found that the ankle stiffness was most sensitive to changes in activation of the GM and decreased by about 20% while adjusting the angle. In contrast, the ankle stiffness remains similar when using TA regulation. Thus, the GM regulation is more adequate for adjustment in the ankle joint, enabling sufficient regulation of angle and stiffness.