Which axial and bending stiffnesses of posterior implants are required to design a flexible lumbar stabilization system?

Dynamic stabilization devices have been introduced to clinics as an alternative to rigid fixation. The stiffness of these devices varies widely, whereas the optimal stiffness, achieving a predefined stabilization of the spine, is unknown. This study was focused on the determination of stiffness values for posterior stabilization devices achieving a flexible, semi-flexible or rigid connection between two vertebrae.An extensively validated finite element model of a lumbar spinal segment L4-5 with an implanted posterior fixation device was used in this study. The model was exposed to pure moments of 7.5 and 20 Nm around the three principal anatomical directions, simulating flexion, extension, lateral bending and axial rotation. In parametrical studies, the influence of the axial and bending fixator stiffness on the spinal range of motion was investigated. In order to examine the validity of the computed results, an in-vitro study was carried out. In this, the influence of two posterior stabilization devices (DSS? and rigidly internal fixator) on the segmental stabilization was investigated.The finite element (FE)-model predicted that each load direction caused a pairing of stiffness relations between axial and bending stiffness. In flexion and extension, however, the bending stiffness had a neglectable effect on the segmental stabilization, compared to the axial stiffness. In contrast, lateral bending and axial rotation were influenced by both stiffness parameters. Except in axial rotation, the model predictions were in a good agreement with the determined in-vitro data. In axial rotation, the FE-model predicted a stiffer segmental behavior than it was determined in the in-vitro study.It is usually expected that high stiffness values are required for a posterior stabilization device to stiffen a spinal segment. We found that already small stiffness values were sufficient to cause a stiffening. Using these data, it may possible to develop implants for certain clinical indications.     

Mechano-sensing and cell migration: a 3D model approach

Cell migration is essential for tissue development in different physiological and pathological conditions. It is a complex process orchestrated by chemistry, biological factors, microstructure and surrounding mechanical properties. Focusing on the mechanical interactions, cells do not only exert forces on the matrix that surrounds them, but they also sense and react to mechanical cues in a process called mechano-sensing. Here, we hypothesize the involvement of mechano-sensing in the regulation of directional cell migration through a three-dimensional (3D) matrix. For this purpose, we develop a 3D numerical model of individual cell migration, which incorporates the mechano-sensing process of the cell as the main mechanism regulating its movement. Consistent with this hypothesis, we found that factors, such as substrate stiffness, boundary conditions and external forces, regulate specific and distinct cell movements.     

Adjustable Stiffness,External Fixator for the Rat Femur Osteotomy and Segmental Bone Defect Models

The mechanical environment around the healing of broken bone is very important as it determines the way the fracture will heal. Over the past decade there has been great clinical interest in improving bone healing by altering the mechanical environment through the fixation stability around the lesion. One constraint of preclinical animal research in this area is the lack of experimental control over the local mechanical environment within a large segmental defect as well as osteotomies as they heal. In this paper we report on the design and use of an external fixator to study the healing of large segmental bone defects or osteotomies. This device not only allows for controlled axial stiffness on the bone lesion as it heals, but it also enables the change of stiffness during the healing process in vivo. The conducted experiments have shown that the fixators were able to maintain a 5 mm femoral defect gap in rats in vivo during unrestricted cage activity for at least 8 weeks. Likewise, we observed no distortion or infections, including pin infections during the entire healing period. These results demonstrate that our newly developed external fixator was able to achieve reproducible and standardized stabilization, and the alteration of the mechanical environment of in vivo rat large bone defects and various size osteotomies. This confirms that the external fixation device is well suited for preclinical research investigations using a rat model in the field of bone regeneration and repair.     

Energy cost of balance control during walking decreases with external stabilizer stiffness independent of walking speed

Human walking requires active neuromuscular control to ensure stability in the lateral direction, which inflicts a certain metabolic load. The magnitude of this metabolic load has previously been investigated by means of passive external lateral stabilization via spring-like cords. In the present study, we applied this method to test two hypotheses: (1) the effect of external stabilization on energy cost depends on the stiffness of the stabilizing springs, and (2) the energy cost for balance control, and consequently the effect of external stabilization on energy cost, depends on walking speed. Fourteen healthy young adults walked on a motor driven treadmill without stabilization and with stabilization with four different spring stiffnesses (between 760 and 1820 N m⁻¹) at three walking speeds (70%, 100%, and 130% of preferred speed). Energy cost was calculated from breath-by-breath oxygen consumption. Gait parameters (mean and variability of step width and stride length, and variability of trunk accelerations) were calculated from kinematic data. On average external stabilization led to a decrease in energy cost of 6% (p<0.005) as well as a decrease in step width (24%; p<0.001), step width variability (41%; p<0.001) and variability of medio-lateral trunk acceleration (12.5%; p<0.005). Increasing stabilizer stiffness increased the effects on both energy cost and medio-lateral gait parameters up to a stiffness of 1260 N m⁻¹. Contrary to expectations, the effect of stabilization was independent of walking speed (p=0.111). These results show that active lateral stabilization during walking involves an energetic cost, which is independent of walking speed.     

Analysis of the effects of medicinal leech on arterial function in elderly volunteers by means of photoplethysmography with Angioscan-01

The state of the arterial wall in elderly patients after the application of medicinal leech was analyzed using an Angioscan-01 diagnostic device. The effect of one medicinal leech on the endothelial vasomotor function of small resistance arteries and medium-sized muscular arteries was estimated. Arterial wall rigidity was assessed by measuring the arterial stiffness index and the augmentation index during stress testing in the form of brachial artery occlusion. It has been shown that the application of one medicinal leech has not only local, but also system effect on arterial endothelium by improving its vasomotor function through normalization of arterial wall stiffness. This process is supposed to involve the salivary cell secretion of medicinal leech, which is able to raise the NO level both in cells and in extracellular fluid and to activate e-NOS and n-NOS, as it has been shown recently in the culture of human vascular endothelial cells (HUVEC).     

A new approach to the human muscle model

Hill's (1938) two component muscle model is used as basis for digital computer simulation of human muscular contraction by means of an iterative process. The contractile (CC) and series elastic (SEC) components are lumped components of structures which produce and transmit torque to the external environment. The CC is described in angular terms along four dimensions as a series of non-planar torque-angle-angular velocity surfaces stacked on top of each other, each surface being appropriate to a given level of muscular activation. The SEC is described similarly along dimensions of torque, angular stretch, overall muscle angular displacement and activation. The iterative process introduces negligible error and allows the mechanical outcome of a variety of normal muscular contractions to be evaluated parsimoniously. The model allows analysis of many aspects of muscle behaviour as well as optimization studies. Definition of relevant relations should also allow reproduction and prediction of the outcome of contractions in individuals.     

On the mechanism and functional significance of the ADP/ATP carrier (AAC) dimerization

According to previous studies, ADP/ATP carrier (AAC) can possibly exist as a monomer or in a dimer state in the inner mitochondrial membrane; however, the question on its functional oligomeric state is still open. The aim of the present work is to establish the external factors that could control the functional oligomeric state of AAC (i.e., monomer or dimer). The study is based on the results of our previous work, which revealed that the volume regulation system of mitochondria (MVRS) affects the oxidative phosphorylation (OXPHOS) system: MVRS could transfer OXPHOS system functioning in a state of supercomplex. Consequently, one may expect that the volume regulation system could also control the functional state of AAC during phosphorylation. Here, on rat liver mitochondria we show that, depending on the incubation medium tonicity, AAC functions in two different ways: either as a monomer (in hypotonic and isotonic media) or as a dimer (in a hypertonic medium). Thus, the transition between the monomeric and dimeric forms of AAC is regulated by MVRS, as well as by functioning of OXPHOS. We conclude that the structural reorganization of AAC is associated with the entire OXPHOS reorganization into a supercomplex. It was also found that dimerization of AAC can occur not only due to the action of MVRS (in hypotonic media) but also under hypoxic conditions.     

Principles of Physiological Regulation of the Body Functions in Incomplete Adaptation

The main condition of completing the process of adaptation of the body to the effect of an external factor is the return of the homeostatic system parameters to their initial levels or their stabilization at a new level. The article considers the state of incomplete adaptation (IA) based on the process of the stabilization of systemic reactions (respiration and blood circulation) on repeated exposure to extreme environmental factors (hypoxia and cold) associated with the excitation of the central regulatory mechanisms of the respiratory center system performing a compensatory–protective function. It is postulated that a change in the afferent information flows (the thresholds of excitation and reactivity of the peripheral receptor systems) forms the basis of IA. The IA state is supposed to persist for an indefinitely long period of time due to insufficient functional reserves and to be the cause of psychosomatic pathology.     

Effect of sensory-motor latencies and active muscular stiffness on stability for an ankle-hip model of balance on a balance board

To achieve human upright posture (UP) and avoid falls, the central nervous system processes visual, vestibular, and proprioceptive information to activate the appropriate muscles to accelerate or decelerate the body’s center of mass. In this process, sensory-motor (SM) latencies and muscular deficits, even in healthy older adults, may cause falls. This condition is worse for people with chronic neuromuscular deficits (stroke survivors, patients with multiple sclerosis or Parkinson’s disease). One therapeutic approach is to recover or improve quiet UP by utilizing a balance board (BB) (a rotating surface with a tunable stiffness and time delay), where a patient attempts to maintain UP while task difficulty is manipulated. While BBs are commonly used, it is unclear how UP is maintained or how changes in system parameters such as SM latencies and BB time delay affect UP stability. To understand these questions, it is important that mathematical models be developed with enough degrees-of-freedom to capture the many responses evoked during the maintenance of UP on a BB. This paper presents an ankle-hip model of balance on a BB, which is used to study the combined effect of SM latencies and active muscular stiffness of the ankle and hip joints, and the BB stiffness and time delay on UP stability. The analysis predicts that people with proprioceptive, visual, vestibular loss, or increased SM latencies may show either leaning postures or larger body-sway. The results show that the BB time delay and the visual and vestibular feedback have the largest impact on UP stability.     

Sit-to-stand motor strategies investigated in able-bodied young and elderly subjects

For the execution of a certain motor task, a motor strategy is chosen by each individual among those that are consistent with the structural and functional constraints of his/her locomotor system, and that tends to maximise the effectiveness of the motor act. The identification of this strategy allows for the assessment of the individual's functional status. This study aimed at identifying the motor strategies adopted for the execution of the sit-to-stand motor task, at different speeds and initial postures, in a sample of 35 community-dwelling elders and in a sample of 16 young able-bodied individuals. This was done using a method, least perceivable to the test subject and "economical" for the experimenter, which entailed the recording of external forces only. A musculo-skeletal system model, based on a telescopic inverted-pendulum (TIP) moved by a linear and two rotational muscle-equivalent actuators, was then used. Parameters describing the kinematics and dynamics of these actuators were extracted and submitted to statistical analysis. Different motor strategies were identified in the two age groups, as well as associated with both a different initial posture (ankle dorsiflexion angle) and speed of execution of the motor task. In particular, the elder group, as compared with the young group, prior to seat-off tended to flex the trunk more, thus bringing the CM closer to the base of support, and at a higher velocity, thus gaining a higher momentum. After seat-off, elders rotated the body forward and, only after having brought their CM over the base of support, effectively started elevation. Both global muscular effort and coordination effort associated with the achievement of balance and raising were lower. However, maximal speed was also lower. The above results indicated that the elders could count on a lower functional reserve than the young individuals and, from the methodological viewpoint, that the TIP approach is a good candidate for subject-specific functional evaluation in a clinical context.     

Ankle intrinsic stiffness changes with postural sway

In standing, the human body is inherently unstable and its stabilization requires constant regulation of ankle torque, generated by a combination of ankle intrinsic properties, peripheral reflexes, and central contributions. Ankle intrinsic stiffness, which quantifies the joint intrinsic properties, has been usually assumed constant in standing; however, there is strong evidence that it is highly dependent on the joint torque, which changes significantly with sway in stance. In this study, we examined how ankle intrinsic stiffness changes with postural sway during standing. Ten subjects stood on a standing apparatus, while subjected to pulse perturbations of ankle position. The mean torque of a short period before the start of each pulse was used as a measure of background torque. Responses with similar background torques were grouped together and used to estimate the parameters of an intrinsic stiffness model. Stiffness estimates were normalized to the critical stiffness and the background torque was transformed to the center of pressure location. We found that in most subjects, the normalized stiffness increased linearly with the movement of center of pressure towards the toes, with an average slope of 2.11 ± 0.80 1/m·rad. This modulation of ankle intrinsic stiffness seems functionally appropriate, since the intrinsic stiffness increases quickly, as the center of pressure moves toward the toes and the limits of stability. These large changes of ankle intrinsic stiffness with postural sway must be incorporated in any model of stance control.     

Functional and structural impact of pirfenidone on the alterations of cardiac disease and diabetes mellitus

A synthetic compound, termed pirfenidone (PFD), is considered promising for the treatment of cardiac disease. It leads to beneficial effects in animal models of diabetes mellitus (DM); as well as in heart attack, atrial fibrillation, muscular dystrophy, and diabetic cardiomyopathy (DC). The latter is a result of alterations linked to metabolic syndrome as they promote cardiac hypertrophy, fibrosis and contractile dysfunction. Although reduced level of fibrosis and stiffness represent an essential step in the mechanism of PFD action, a wide range of functional effects might also contribute to the therapeutic benefits. For example, PFD stimulates L-type voltage-gated Ca²⁺ channels (LTCCs), which are pivotal for a process known as excitation–contraction coupling (ECC). Recent evidence suggests that these two types of actions – namely structural and functional – aid in treating both cardiac disease and DM. This view is supported by the fact that in DC, for example, systolic dysfunction arises from both cardiac stiffness linked to fibrosis and down-regulation of ECC. Thus, not surprisingly, clinical trials have been conducted with PFD in the settings of DM, for treating not only cardiac but also renal disease. This review presents all these concepts, along with the possible mechanisms and pathophysiological consequences.     

Impedance characteristics of a neuromusculoskeletal model of the human arm I. Posture control

The mechanical impedance of neuromusculoskeletal models of the human arm is studied in this paper. The model analysis provides a better understanding of the contributions of possible intrinsic and reflexive components of arm impedance, makes clear the limitations of second-order mass-viscosity-stiffness models and reveals possible task effects on the impedance. The musculoskeletal model describes planar movements of the upper arm and forearm, which are moved by six lumped muscles with nonlinear dynamics. The motor control system is represented by a neural network which combines feedforward and feedback control. It is optimized for the control of movements or for posture control in the presence of external forces. The achieved impedance characteristics depend on the conditions during the learning process. In particular, the impedance is adapted in a suitable way to the frequency content and direction of external forces acting on the hand during an isometric task. The impedance characteristics of a model, which is optimized for movement control, are similar to experimental data in the literature. The achieved stiffness is, to a large extent, reflexively determined whereas the approximated viscosity is primarily due to intrinsic attributes. It is argued that usually applied Hill-type muscle models do not properly represent intrinsic muscle stiffness. Received: 14 October 1997 / Accepted in revised form: 18 May 1999     

A 3D computational simulation of fracture callus formation: influence of the stiffness of the external fixator

The stiffness of the external fixation highly influences the fracture healing pattern. In this work we study this aspect by means of a finite element model of a simple transverse mid-diaphyseal fracture of an ovine metatarsus fixed with a bilateral external fixator. In order to simulate the regenerative process, a previously developed mechanobiological model of bone fracture healing was implemented in three dimensions. This model is able to simulate tissue differentiation, bone regeneration, and callus growth. A physiological load of 500 N was applied and three different stiffnesses of the external fixator were simulated (2300, 1725, and 1150 N/mm). The interfragmentary strain and load sharing mechanism between bone and the external fixator were compared to those recorded in previous experimental works. The effects of the stiffness on the callus shape and tissue distributions in the fracture site were also analyzed. We predicted that a lower stiffness of the fixator delays fracture healing and causes a larger callus, in correspondence to well-documented clinical observations.     

Dynamic stiffness and crossbridge action in muscle

Small sinusoidal vibrations at 300 HZ were applied to frog sartorius muscle to measure the dynamic stiffness (Young's modulus) throughout the course of tetanus. For a peak-to-peak amplitude of 0.4% the dynamic Young's modulus increased from 1.5 X 10(5) Nm-2 in the resting state to 2 X 10(7) Nm-2 in tetanus. After correction for the external connective tissue, the dynamic Young's modulus of the muscle was almost directly proportional to the tension throughout the development of tetanus. The ratio of dynamic Young's modulus to tensile stress thus remained constant (with a value at 300 Hz of approximately 100), consistently with Huxley and Simmon's identification of the crossbridges as the source of both tension and stiffness. For a single crossbridge the ratio of stiffness to tension was 8.2 X 10(7) m-1 at 300 Hz; it is deduced from literature data that the limiting value at high frequencies is about 1.6 X 10(8) m-1. This ratio is interpreted on Harrington's (1971) model to show that crossbridge action can be explained by a helix-coil transition of about 80 out of the 260 residues in each S-2 myosin strand. It is also shown that a helix-coil model can account for the observed rapid relaxation of muscle without invoking any complex behaviour of the crossbridge head.     

Identifying responsive modules by mathematical programming: an application to budding yeast cell cycle

High-throughput biological data offer an unprecedented opportunity to fully characterize biological processes. However, how to extract meaningful biological information from these datasets is a significant challenge. Recently, pathway-based analysis has gained much progress in identifying biomarkers for some phenotypes. Nevertheless, these so-called pathway-based methods are mainly individual-gene-based or molecule-complex-based analyses. In this paper, we developed a novel module-based method to reveal causal or dependent relations between network modules and biological phenotypes by integrating both gene expression data and protein-protein interaction network. Specifically, we first formulated the identification problem of the responsive modules underlying biological phenotypes as a mathematical programming model by exploiting phenotype difference, which can also be viewed as a multi-classification problem. Then, we applied it to study cell-cycle process of budding yeast from microarray data based on our biological experiments, and identified important phenotype- and transition-based responsive modules for different stages of cell-cycle process. The resulting responsive modules provide new insight into the regulation mechanisms of cell-cycle process from a network viewpoint. Moreover, the identification of transition modules provides a new way to study dynamical processes at a functional module level. In particular, we found that the dysfunction of a well-known module and two new modules may directly result in cell cycle arresting at S phase. In addition to our biological experiments, the identified responsive modules were also validated by two independent datasets on budding yeast cell cycle.     

Role of knee ligaments in proprioception and regulation of muscle stiffness

Physiologic evidence for the sensory role of the knee joint ligaments are reviewed. The cruciate and collateral ligaments accomodate morphologically different sensory nerve endings with different capabilities of providing the central nervous system (CNS) with information not only about noxious and chemical stimuli but also about mechanical events, e.g., movement- and position-related stretches of the ligaments. Available data show that low-threshold joint/ligament receptor (i.e., mechanoreceptor) afferents evoke only weak and rare effects in skeletomotor neurons (α-motoneurons), whereas they frequently and powerfully influence fusimotor neurons (γ-motoneurons). The effects on the γ-muscle-spindle system in the muscles around the knee are so potent that even stretches of the cruciate ligaments at relatively moderate loads (not noxious) may induce major changes in responses of the muscle spindle afferents. As the activity in the primary muscle spindle afferents modifies stiffness in the muscles, the cruciate ligament receptors may, through the γ-muscle-spindle system, participate in regulation and preparatory adjustment of the stiffness of the muscles around the knee joint and thereby of knee joint stiffness. Thus, the sensory system of the cruciate ligaments is able to contribute significantly to the functional stability of the knee joint. The possible role of (ligamentous) joint receptors in genesis and spread of muscular tension in occupational muscle pain and in chronic musculoskeletal pain syndromes is also discussed.     

The type III secretion chaperone LcrH co-operates with YopD to establish a negative, regulatory loop for control of Yop synthesis in Yersinia pseudotuberculosis

The enteropathogen Yersinia pseudotuberculosis is a model system used to study the molecular mechanisms by which Gram-negative pathogens secrete and subsequently translocate antihost effector proteins into target eukaryotic cells by a common type III secretion system (TTSS). In this process, YopD (Yersinia outer protein D) is essential to establish regulatory control of Yop synthesis and the ensuing translocation process. YopD function depends upon the non-secreted TTSS chaperone LcrH (low-calcium response H), which is required for presecretory stabilization of YopD. However, as a new role for TTSS chaperones in virulence gene regulation has been proposed recently, we undertook a detailed analysis of LcrH. A lcrH null mutant constitutively produced Yops, even when this strain was engineered to produce wild-type levels of YopD. Furthermore, the YopD-LcrH interaction was necessary to regain the negative regulation of virulence associated genes yops). This finding was used to investigate the biological significance of several LcrH mutants with varied YopD binding potential. Mutated LcrH alleles were introduced in trans into a lcrH null mutant to assess their impact on yop regulation and the subsequent translocation of YopE, a Rho-GTPase activating protein, across the plasma membrane of eukaryotic cells. Two mutants, LcrHK20E, E30G, I31V, M99V, D136G and LcrHE30G lost all regulatory control, even though YopD binding and secretion and the subsequent translocation of YopE was indistinguishable from wild type. Moreover, these regulatory deficient mutants showed a reduced ability to bind YscY in the two-hybrid assay. Collectively, these findings confirm that LcrH plays an active role in yop regulation that might be mediated via an interaction with the Ysc secretion apparatus. This chaperone-substrate interaction presents an innovative means to establish a regulatory hierarchy in Yersinia infections. It also raises the question as to whether or not LcrH is a true chaperone involved in stabilization and secretion of YopD or a regulatory protein responsible for co-ordinating synthesis of Yersinia virulence determinants. We suggest that LcrH can exhibit both of these activities.     

A proprioception based regulation model to estimate the trunk muscle forces

Evaluation of loads acting on the spine requires the knowledge of the muscular forces acting on it, but muscles redundancy necessitates developing a muscle forces attribution strategy. Optimisation, EMG, or hybrid models allow evaluating muscle force patterns, yielding a unique muscular arrangement or/and requiring EMG data collection. This paper presents a regulation model of the trunk muscles based on a proprioception hypothesis, which searches to avoid the spinal joint overloading. The model is also compared to other existing models for evaluation. Compared to an optimisation model, the proposed alternative muscle pattern yielded a significant spine postero-anterior shear decrease. Compared to a model based on combination of optimisation criteria, present model better fits muscle activation observed using EMG (38% improvement). Such results suggest that the proposed model, based on regulation of all spinal components, may be more relevant from a physiologic point of view.