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PubMed1999

Multijoint muscle regulation mechanisms examined by measured human arm stiffness and EMG signals.

Stiffness properties of the musculo-skeletal system can be controlled by regulating muscle activation and neural feedback gain. To understand the regulation of multijoint stiffness, we examined the relationship between human arm joint stiffness and muscle activation during static force control in the horizontal plane by means of surface electromyographic (EMG) studies. Subjects were asked to produce a specified force in a specified direction without cocontraction or they were asked to keep different cocontractions while producing or not producing an external force. The stiffness components of shoulder, elbow, and their cross-term and the EMG of six related muscles were measured during the tasks. Assuming that the EMG reflects the corresponding muscle stiffness, the joint stiffness was predicted from the EMG by using a two-link six-muscle arm model and a constrained least-square-error regression method. Using the parameters estimated in this regression, single-joint stiffness (diagonal terms of the joint-stiffness matrix) was decomposed successfully into biarticular and monoarticular muscle components. Although biarticular muscles act on both shoulder and elbow, they were found to covary strongly with elbow monoarticular muscles. The preferred force directions of biarticular muscles were biased to the directions of elbow monoarticular muscles. Namely, the elbow joint is regulated by the simultaneous activation of monoarticular and biarticular muscles, whereas the shoulder joint is regulated dominantly by monoarticular muscles. These results suggest that biarticular muscles are innervated mainly to control the elbow joint during static force-regulation tasks. In addition, muscle regulation mechanisms for static force control tasks were found to be quite different from those during movements previously reported. The elbow single-joint stiffness was always higher than cross-joint stiffness (off-diagonal terms of the matrix) in static tasks while elbow single-joint stiffness is reported to be sometimes as small as cross-joint stiffness during movement. That is, during movements, the elbow monoarticular muscles were occasionally not activated when biarticular muscles were activated. In static tasks, however, monoarticular muscle components in single-joint stiffness were increased considerably whenever biarticular muscle components in single- and cross-joint stiffness increased. These observations suggest that biarticular muscles are not simply coupled with the innervation of elbow monoarticular muscles but also are regulated independently according to the required task. During static force-regulation tasks, covariation between biarticular and elbow monoarticular muscles may be required to increase stability and/or controllability or to distribute effort among the appropriate muscles.

Adult↗
PubMed1994

Mechanical properties of canine articular cartilage are significantly altered following transection of the anterior cruciate ligament.

The compressive, tensile, and swelling properties of articular cartilage were studied at two time periods following transection of the anterior cruciate ligament in the knee of greyhound dogs. An experimental protocol was designed to quantify the essential equilibrium and biphasic material properties of cartilage in tension, compression, and shear, as well as the parameters of isometric swelling behavior. All properties were measured at several sites to elicit differences between sites of frequent and less frequent contact. Hydration was determined at each site and was compared with the material properties of cartilage from corresponding sites. There were extensive changes in all compressive, tensile, and swelling properties of cartilage after transection of the anterior cruciate ligament. Twelve weeks after surgery, the intrinsic moduli were reduced significantly in compression (approximately 24% of control values), tension (approximately 64%), and shear (approximately 24%), and the hydraulic permeability was elevated significantly (approximately 48%). Significant increases in hydration (approximately 9%) also were observed, as well as a strong correlation of hydration with hydraulic permeability. The pattern of these changes was not found to differ with site in the joint, but significant differences were observed in the magnitude of change for cartilage from the femoral groove and the femoral condyle. The pattern and extent of changes in the material properties following transection of the anterior cruciate ligament indicate that altered loading of the joint severely compromises the overall mechanical behavior of articular cartilage. The observed loss of matrix stiffness in compression, tension, and shear is associated with increases in the deformation of the solid matrix, a diminished ability to resist swelling, and the increase in hydration observed in this study. The increased swelling and elevated water content were related directly to the increase in hydraulic permeability; this suggests an associated loss of fluid pressurization as the load support mechanism in the degenerated cartilage. Without a successful mechanism for repair, damage to the solid matrix may progress and lead to further degenerative changes in the biochemistry, morphology, and mechanical behavior of articular cartilage.

Animals↗
PubMed1990

Human arm stiffness characteristics during the maintenance of posture.

When the hand is displaced from an equilibrium position, the muscles generate elastic forces to restore the original posture. In a previous study, Mussa-Ivaldi et al. (1985) have measured and characterized the field of elastic forces associated with hand posture in the horizontal plane. Hand stiffness which describes the relation between force and displacement vectors in the vicinity of equilibrium position was measured and graphically represented by an ellipse, characterized by its size, shape and orientation. The results indicated that the shape and orientation of the stiffness ellipse are strongly dependent on arm configuration. At any given hand position, however, the values of these parameters were found to remain invariant among subjects and over time. In this study we investigate the underlying causes for the observed spatial pattern of variation of the hand stiffness ellipse. Mathematically analyzing the relation between hand and joint stiffness matrices, we found that in order to produce the observed spatial variations of the stiffness ellipse, the shoulder stiffness must covary in the workspace with the stiffness component provided by the two-joint muscles. This condition was found to be satisfied by the measured joint stiffness components. Using anatomical data and considering the effects that muscle cross-sections and changes in muscle moment arms have on the joint stiffness matrix, we found that these anatomical factors are not sufficient to account for the observed pattern of variation of joint stiffness in the workspace. To examine whether the coupling between shoulder and two-joint stiffnesses results from the coactivation of muscles contributing to these stiffnesses, EMG signals were recorded from shoulder, elbow and two-joint muscles. Our results indicated that, while some muscle coactivation may indeed exist, it can be found for only some of the muscles and in only part of the workspace.

Arm↗
PubMed2003

Adaptive control of stiffness to stabilize hand position with large loads.

The goal of this work was to investigate stability in relation to the magnitude and direction of forces applied by the hand. The endpoint stiffness and joint stiffness of the arm were measured during a postural task in which subjects exerted up to 30% maximum voluntary force in each of four directions while controlling the position of the hand. All four coefficients of the joint stiffness matrix were found to vary linearly with both elbow and shoulder torque. This contrasts with the results of a previous study, which employed a force control task and concluded that the joint stiffness coefficients varied linearly with either shoulder or elbow torque but not both. Joint stiffness was transformed into endpoint stiffness to compare the effect on stability as endpoint force increased. When the joint stiffness coefficients were modeled as varying with the net torque at only one joint, as in the previous study, we found that hand position became unstable if endpoint force exceeded about 22 N in a specific direction. This did not occur when the joint stiffness coefficients were modeled as varying with the net torque at both joints, as in the present study. Rather, hand position became increasingly more stable as endpoint force increased for all directions of applied force. Our analysis suggests that co-contraction of biarticular muscles was primarily responsible for the increased stability. This clearly demonstrates how the central nervous system can selectively adapt the impedance of the arm in a specific direction to stabilize hand position when the force applied by the hand has a destabilizing effect in that direction.

Adaptation, Physiological↗
PubMed1998

A method to determine the 3-D stiffness of fracture fixation devices and its application to predict inter-fragmentary movement.

Inter-fragmentary movement considerably influences the fracture healing process. Large shear movement delays while moderate axial movement stimulates the healing process. To be able to control the mechanical situation at a fracture site and to achieve optimal bony healing it is essential to understand the relationship between inter-fragmentary movement, bony loading and fixation stiffness. A 6 x 6 stiffness matrix is introduced which completely describes the linear relationship between the 6 inter-fragmentary movements and the resulting bony loading (3 forces and 3 moments). Further, it is illustrated that even in relatively stiff external fixateur constructs simple axial loading of the bony fragments leads to complex inter-fragmentary movement. When the 3-D stiffness description is multiplied by the load state in sheep tibiae, movements similar to those measured in vivo are calculated. The relationship between axial compression and medio-lateral or dorso-ventral shear varies depending on the mounting plane of the external fixateur. The authors conclude that a single value is not sufficient to describe the mechanical relationship between inter-fragmentary movement and bony loading. Only a complete description of fixation stiffness allows prediction of inter-fragmentary movement and differentiation between various configurations of fixation devices and their potential for mechanically promoting bony healing.

Animals↗
PubMed2005

Differential degradation of matrix proteoglycans and edema development in rabbit lung.

The specific role of solid extracellular matrix components in opposing development of pulmonary interstitial edema was studied in adult anesthetized rabbits by challenging the lung parenchyma with an intravenous injection of a bolus of collagenase or heparanase. In 10 rabbits, pulmonary interstitial pressure (Pip) was measured by micropuncture in control and up to 3 h after collagenase or heparanase intravenous injection. With respect to control (Pip= -9.3 +/- 1.5 cmH2O, n = 10), both treatments caused a significant increase of Pip and of the wet weight-to-dry weight lung ratio. However, while tissue matrix stiffness was maintained after 60 min of collagenase, as indicated by the attainment of a positive Pip peak (Pip= 4.5 +/- 0.3 cmH2O, n = 5), this mechanical response was lost with heparanase (Pip= -0.6 +/- 1.3 cmH2O, n = 5). Biochemical analysis performed on a separate rabbit group (n = 15) showed an increased extraction of uronic acid with both enzymes, indicating a progressive matrix fragmentation. Gel chromatography analysis of the proteoglycan (PG) families showed that 60 min of both enzymatic treatments left the large-molecular-weight PGs (versican) essentially unaffected. However, the heparan-sulfate PG fraction was significantly cleaved, as indicated by a significant increase of the smaller PG fragments with heparanase, but not with collagenase. Hence, present data suggest that the integrity of the heparan-sulfate PGs is required to maintain the three-dimensional architecture of the pulmonary tissue matrix and in turn to counteract tissue fluid accumulation in situations of increased fluid filtration.

Animals↗
PubMed2004

History-dependent sorption in humic acids and a lignite in the context of a polymer model for natural organic matter.

We examined sorption of two apolar compounds in three samples of macromolecular natural organic matter (NOM) in order to test whether history-dependent ("irreversible") behaviors, including sorption hysteresis and the conditioning effect, agree with a pore deformation/creation hypothesis applicable to the glassy organic solid state as proposed in the polymer literature. The compounds are 1,2,4-trichlorobenzene (TCB) and naphthalene (Naph). The NOM samples are a soil humic acid (H-HA), an Al3+-exchanged form of the same humic acid (Al-HA), and a low-rank coal (Beulah-Zap lignite, BZL). The HAs, at least, are believed free of environmental black carbon. The degree of nonlinearity in the isotherm and the ratio of hole-filling to solid-phase dissolution increased in the order of hardness (stiffness) of the solid: H-HA < Al-HA < BZL. Independent of solid, solutes show a 14-18 kJ/mol preference for hole "sites" as compared to dissolution "sites", which we attribute to the free energy needed in the dissolution domain to create a cavity to accommodate the solute. All solids exhibited hysteresis and the conditioning effect, which refers to enhanced re-sorption after pretreatment with a conditioning agent (in this case, chlorobenzene). Conditioning the sample results in increased sorption and increased contribution of hole-filling relative to dissolution. The effects of original hole population, matrix stiffness, and solute concentration on the hysteresis index and on the magnitude of the conditioning effect are consistent with a pore-deformation mechanism as the underlying cause of sorption irreversibility. This mechanism involves concurrent processes of irreversible hole expansion and the creation of new holes by the incoming sorbate (or conditioning agent). The results show that nonlinear and irreversible behavior may be expected for macromolecular forms of NOM that are in a glassy state and emphasize the case that NOM is not a passive sorbent but may be physically altered by the sorbate.

Adsorption↗
PubMed1992

A theoretical model of the knee and ACL: theory and experimental verification.

A three-dimensional mathematical model of the human knee joint was developed to examine the role of single ligaments, such as an anterior cruciate ligament (ACL) graft in ACL reconstruction, on joint motion and tissue forces. The model is linear and valid for small motions about an equilibrium position. The knee joint is modeled as two rigid bodies (the femur and the tibia) interconnected by deformable structures, including the ACL or ACL graft, the cartilage layer, and the remainder of the knee tissues (modeled as a single element). The model was demonstrated for the equilibrium condition of the knee in extension with an anterior tibial force, causing anterior drawer and hyperextension. The knee stiffness matrix for this condition was measured for a human right knee in vitro. Predicted model response was compared with experimental observations. Qualitative agreement was found between model and experiment, validating the model and its assumptions. The model was then used to predict the change in graft and cartilage forces and joint motion of the knee due to an increment of load in the normal joint both after ACL removal and with various altered states simulating ACL reconstructions. Results illustrate the interdependence between loads in the ACL graft, other knee structures, and contact force. Stiffer grafts and smaller maximum unloaded length of the ligament lead to higher graft and contact forces. Changes in cartilage stiffness alter load sharing between ACL graft and other joint tissues.

Anterior Cruciate Ligament↗
PubMed1996

A method for determination of the anisotropic properties of biomembranes.

A methodology was developed for potential determination of the anisotropic properties of biomembranes. This method is based on the theoretical discretization of a continuous membrane used for finite element analysis and the simultaneous measurement of the displacement of nodes on the surface of a membrane. From the given loads and measured nodal displacements, one can assemble the resulting stiffness matrix and approximate the material properties associated with the membrane. Mathematical estimations and computer simulations were performed to determine the perturbation of load and displacement errors on the resulting material properties. The results indicated that the material properties are particularly sensitive to displacement errors. The displacement measurements may require an accuracy of 20 microns for a 4 x 4 cm2 specimen. Significant inaccuracies occur close to the points of load application.

Anisotropy↗
PubMed2006

Hydrogels as artificial matrices for human embryonic stem cell self-renewal.

Human embryonic stem cells (hESCs) have the potential to differentiate into all cell types in the body and hold great promise for regenerative medicine; however, large-scale expansion of undifferentiated hESCs remains a major challenge. Self-renewal of hESCs requires culturing these cells on either mouse or human fibroblast cells (i.e., a feeder layer of cells), or on artificial extracellular matrices (ECMs) while supplementing the media with soluble growth factors. Here we report a completely synthetic ECM system composed of a semi-interpenetrating polymer network (sIPN), a polymer hydrogel, which was designed to allow the independent manipulation of cell adhesion ligand presentation and matrix stiffness. In the short term, hESCs that were cultured on the sIPN adhered to the surface, remained viable, maintained the morphology, and expressed the markers of undifferentiated hESCs. This was the first demonstration that a completely synthetic ECM can support short-term self-renewal of hESCs.

Biocompatible Materials↗
PubMed2005

Finite element implementation of a generalized Fung-elastic constitutive model for planar soft tissues.

Numerical simulations of the anisotropic mechanical properties of soft tissues and tissue-derived biomaterials using accurate constitutive models remain an important and challenging research area in biomechanics. While most constitutive modeling efforts have focused on the characterization of experimental data, only limited studies are available on the feasibility of utilizing those models in complex computational applications. An example is the widely utilized exponential constitutive model proposed by Fung. Although present in the biomechanics literature for several decades, implementation of this model into finite element (FE) simulations has been limited. A major reason for limited numerical implementations are problems associated with inherent numerical instability and convergence. To address this issue, we developed and applied two restrictions for a generalized Fung-elastic constitutive model necessary to achieve numerical stability. These are (1) convexity of the strain energy function, and (2) the condition number of material stiffness matrix set lower than a prescribed value. These constraints were implemented in the nonlinear regression used for constitutive model parameter estimation to the experimental biaxial mechanical data. We then implemented the generalized Fung-elastic model into a commercial FE code (ABAQUS, Pawtucket, RI, USA). Single element and multi-element planar biaxial test simulations were conducted to verify the accuracy and robustness of the implementation. Results indicated that numerical convergence and accurate FE implementation were consistently obtained. The present study thus presents an integrated framework for accurate and robust implementation of pseudo-elastic constitutive models for planar soft tissues. Moreover, since our approach is formulated within a general FE code, it can be straightforwardly adopted across multiple software platforms.

Anisotropy↗
PubMed2004

The tension mounts: mechanics meets morphogenesis and malignancy.

The tissue microenvironment regulates mammary gland development and tissue homeostasis through soluble, insoluble and cellular cues that operate within the three dimensional architecture of the gland. Disruption of these critical cues and loss of tissue architecture characterize breast tumors. The developing and lactating mammary gland are also subject to a plethora of tensional forces that shape the morphology of the gland and orchestrate its functionally differentiated state. Moreover, malignant transformation of the breast is associated with dramatic changes in gland tension that include elevated compression forces, high tensional resistance stresses and increased extracellular matrix stiffness. Chronically increased mammary gland tension may influence tumor growth, perturb tissue morphogenesis, facilitate tumor invasion, and alter tumor survival and treatment responsiveness. Because mammary tissue differentiation is compromised by high mechanical force and transformed cells exhibit altered mechanoresponsiveness, malignant transformation of the breast may be functionally linked to perturbed tensional-homeostasis. Accordingly, it will be important to define the role of tensional force in mammary gland development and tumorigenesis. Additionally, it will be critical to identify the key molecular elements regulating tensional-homeostasis of the mammary gland and thereafter to characterize their associated mechanotransduction pathways.

Animals↗
PubMed2026

Rewiring Cellular Context as A Central Mechanism Governing Cancer Stem Cell Survival: Insights from ESC Comparisons.

Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance, yet their remarkable persistence remains poorly understood. While CSCs share stemness attributes with embryonic stem cells (ESCs), including self-renewal, transcriptional plasticity, and permissive chromatin, they exhibit a fundamentally divergent regulatory logic that prioritizes survival over developmental fidelity. ESCs maintain globally open chromatin that supports transcriptional hyperactivity but predisposes them to apoptosis under genotoxic stress, whereas CSCs maintain dynamically inducible, permissive chromatin at survival loci while repressing differentiation programs, enabling adaptive stress responses. We advance the hypothesis that CSC persistence emerges not from any single factor, but from the integrative rewiring of signaling cascades (Wnt/&#x3b2;-catenin, Notch, Hedgehog, PI3K/AKT/mTOR), stress-responsive transcription factors (HIFs, NF-&#x3ba;B, STAT3), and core pluripotency networks (OCT4, SOX2, NANOG) within a survival-centric context, reinforced by dynamic chromatin remodeling, inducible super-enhancer landscapes, and microenvironmental cues (hypoxia, inflammation, matrix stiffness). Within this framework, the E2F family serves as a key contextual integrator: in ESCs, constitutive E2F activity triggers p53-mediated apoptosis upon DNA damage, preserving genomic integrity; in CSCs, deregulated E2F activity redirects transcription toward DNA repair, antioxidant defenses, and anti-apoptotic programs. This functional divergence underscores that phenotypic outcome is determined by the broader cellular and epigenetic landscape rather than any single factor. We conclude that CSC persistence is an emergent property of this integrated, survival-centric program, fundamentally distinct from the developmental imperative of ESCs. Effective therapeutic strategies must therefore move beyond targeting individual pathways to dismantle the interconnected regulatory networks that define the CSC survival context, offering a more robust approach to overcome therapy resistance and prevent tumor relapse.

Cancer Stem Cells (CSCs)↗
PubMed1987

Response of a human head/neck/upper-torso replica to dynamic loading--II. Analytical/numerical model.

A three-dimensional lumped-parameter model of the human head/neck/upper-torso was developed to predict its motion for any specified initial conditions and that could also be used to compare with the results of other investigators. This model consists of ten rigid bodies representing the head, cervical vertebrae C1-C7, T1 and T2 combined with the rest of the torso. These rigid bodies were connected by intervertebral joints described by a stiffness matrix relating the force (moment) and translation (rotation). Fifteen pairs of muscles were incorporated in the model, represented by three-point linear elements with nonlinear constitutive relationships obtained from cadaver test results. The calculated response compared favorably with human volunteer data for both flexion and lateral whiplash. However, tests on an inanimate replica of a human indicated greater flexibility than predicted by the corresponding numerical model. The difference is believed to be due to insufficient mass of the muscles incorporated in the structure.

Acceleration↗
PubMed1992

Application of the finite-element method to simulation of damage to the human skull as a consequence of missile impact on a multi-layered composite crash helmet.

Finite-element analysis is a powerful technique which could be applicable to the study of a wide range of circumstances where the frame and/or the vital organs of the body are subjected to extreme loading conditions. This paper reports the results of an exploratory investigation in which the performance of a crash helmet in protecting the skull from an impacting load is modelled. The immediate objective is to show how a typical crash helmet design of glass-reinforced plastic (GRP) outer casing with quasi-foam-like liner can, with a suitable choice of material properties, attenuate the transfer of energy from the impacting mass such that the damage intensity to the skull is minimized. A simplified structure for both helmet and skull shape is adopted and the skull is modelled as being supported on an elastic foundation. The material properties used are representative rather than being accurately matched to experimentally determined ones. Several aspects of the modelling technique are worthy of particular note: the simulation of material anisotropy by means of multiple reinforcement layers with varying orientation, the use of dashpot elements for energy attenuation and the incorporation of multipoint constraint between the skull and the helmet lining to ensure integrity of the model with correct stiffness matrix values and allowing independent monitoring of all stress levels at the mating interface region. The results of the modelling show that the specific limited objectives can be met but also indicate how vitally important information could be obtained from similar but more detailed studies which included representative modelling of the body organs and skeleton.

Anisotropy↗
PubMed2004

The use of temperature-composition combinatorial libraries to study the effects of biodegradable polymer blend surfaces on vascular cells.

Controlling cellular and physiological responses such as adhesion, proliferation and migration is a highly desirable feature of engineered scaffolds. One important application would be the design of tissue engineered vascular grafts that regulate cell adhesion and growth. We utilized temperature-composition combinatorial polymer libraries to investigate the effects of surfaces of blended poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(epsilon-caprolactone) (PCL) on murine vascular smooth muscle cells (SMC). In this manner, SMCs were exposed to approximately 1000 distinguishable surfaces in a single experiment, allowing the discovery of optimal polymer compositions and processing conditions. SMC adhesion, aggregation, proliferation, and protein production were highest in regions with mid- to high-PCL concentrations and high annealing temperatures. These regions exhibited increased surface roughness, increased microscale PLGA-rich matrix stiffness, and significant change of bulk PCL-rich crystallinity relative to other library regions. This study revealed a previously unknown processing temperature and blending composition for two well-known polymers that optimized SMC interactions.

Animals↗
PubMed2005

A large-strain finite element formulation for biological tissues with application to mitral valve leaflet tissue mechanics.

This paper presents a finite element formulation suitable for large-strain modeling of biological tissues and uses this formulation to implement an accurate finite element model for mitral valve leaflet tissue. First, an experimentally derived strain energy function is obtained from literature. This function is implemented in finite elements using the mixed pressure-displacement formulation. A modification is made to aid in maintaining positive definiteness of the stiffness matrix at low strains. The numerical implementation is shown to be accurate in representing the analytical model of material behavior. The mixed formulation is useful for modeling of soft biological tissues in general, and the model presented here is applicable to finite element simulation of mitral valve mechanics.

Animals↗
PubMed2005

Repair of porcine articular cartilage defect with autologous chondrocyte transplantation.

Articular cartilage is known to have poor healing capacity after injury. Autologous chondral grafting remains the mainstay to treat well-defined, full-thickness, symptomatic cartilage defects. We demonstrated the utilization of gelatin microbeads to deliver autologous chondrocytes for in vivo cartilage generation. Chondrocytes were harvested from the left forelimbs of 12 Lee-Sung pigs. The cells were expanded in monolayer culture and then seeded onto gelatin microbeads or left in monolayer. Shortly before implantation, the cell-laden beads were mixed with collagen type I gel, while the cells in monolayer culture were collected and re-suspended in culture medium. Full-thickness cartilage defects were surgically created in the weight-bearing surface of the femoral condyles of both knees, covered by periosteal patches taken from proximal tibia, and sealed with a porcine fibrin glue. In total, 48 condyles were equally allotted to experimental, control, and null groups that were filled beneath the patch with chondrocyte-laden beads in gel, chondrocytes in plain medium solution, or nothing, respectively. The repair was examined 6 months post-surgery on the basis of macroscopic appearance, histological scores based on the International Cartilage Repair Society Scale, and the proportion of characteristic chondrocytes. Tensile stress-relaxation behavior was determined from uniaxial indentation tests. The experimental group scored higher than the control group in the categories of matrix nature, cell distribution pattern, and absence of mineralization, with similar surface smoothness. Both the experimental and control groups were superior to the null group in the above-mentioned categories. Viable cell populations were equal in all groups, but the proportion of characteristic chondrocytes was highest in the experimental group. Matrix stiffness was ranked as null > native cartilage > control > experimental group. Transplanted autologous chondrocytes survive and could yield hyaline-like cartilage. The application of beads and gel for transplantation helped to retain the transferred cells in situ and maintain a better chondrocyte phenotype.

Animals↗