Intestinal propulsion of a solid non-deformable bolus

A mathematical model of a segment of the gut with an enclosed pellet is constructed. The gut is represented as a thin deformable soft biological shell with the pellet modeled as a non-deformable solid. Mechanical properties of the gut wall were represented as longitudinal and circular smooth muscle layers embedded in stroma that satisfies the general type of nonlinear orthotropy. Deformations of the wall are finite. Bolus propulsion is numerically simulated by generation and propagation of an electromechanical wave along the syncytia. Pharmacological manipulation is applied to model 5-HT type 3 antagonist (Lotronex, GlaxoSmithKline) and 5-HT type 4 agonist (Zelnorm, Novartis, AB) drugs on the dynamics of bolus progression. The results lead to new quantitative insights into the complex spatio-temporal patterns of gastrointestinal transit. It is demonstrated that the reciprocal relationship in contraction of the longitudinal and circular smooth muscle syncytia is necessary to provide the "mixing" type of movements during the preparatory phase of propulsion. Strong simultaneous contractions of the both smooth muscle layers are required to expel the "mixed" pellet from the segment. The model is implemented as an interactive software system, Gut Discovery(www.aincompany.com), and accurately predicts the effects of drugs on gut motility.     

In vivo parameter identification in arteries considering multiple levels of smooth muscle activity

In this paper an existing in vivo parameter identification method for arteries is extended to account for smooth muscle activity. Within this method a continuum-mechanical model, whose parameters relate to the mechanical properties of the artery, is fit to clinical data by solving a minimization problem. Including smooth muscle activity in the model increases the number of parameters. This may lead to overparameterization, implying that several parameter combinations solve the minimization problem equally well and it is therefore not possible to determine which set of parameters represents the mechanical properties of the artery best. To prevent overparameterization the model is fit to clinical data measured at different levels of smooth muscle activity. Three conditions are considered for the human abdominal aorta: basal during rest; constricted, induced by lower-body negative pressure; and dilated, induced by physical exercise. By fitting the model to these three arterial conditions simultaneously a unique set of model parameters is identified and the model prediction agrees well with the clinical data.

     

A dynamic model of smooth muscle contraction

A dynamic model of smooth muscle contraction is presented and is compared with the mechanical properties of vascular smooth muscle in the rat portal vein. The model is based on the sliding filament theory and the assumption that force is produced by cross-bridges extending from the myosin to the actin filaments. Thus, the fundamental aspects of the model are also potentially applicable to skeletal muscle. The main concept of the model is that the transfer of energy via the cross-bridges can be described as a 'friction clutch' mechanism. It is shown that a mathematical formulation of this concept gives rise to a model that agrees well with experimental observations on smooth muscle mechanics under isotonic as well as isometric conditions. It is noted that the model, without any ad hoc assumptions, displays a nonhyperbolic force-velocity relationship in its high-force portion and that it is able to maintain isometric force in conditions of reduced maximum contraction velocity. Both these findings are consistent with new experimental observations on smooth muscle mechanics cannot be accounted for by the classical Hill model.     

Adaptation of active tone in the mouse descending thoracic aorta under acute changes in loading

Arteries can adapt to sustained changes in blood pressure and flow, and it is thought that these adaptive processes often begin with an altered smooth muscle cell activity that precedes any detectable changes in the passive wall components. Yet, due to the intrinsic coupling between the active and passive properties of the arterial wall, it has been difficult to delineate the adaptive contributions of active smooth muscle. To address this need, we used a novel experimental–computational approach to quantify adaptive functions of active smooth muscle in arterial rings excised from the proximal descending thoracic aorta of mice and subjected to short-term sustained circumferential stretches while stimulated with various agonists. A new mathematical model of the adaptive processes was derived and fit to data to describe and predict the effects of active tone adaptation. It was found that active tone was maintained when the artery was adapted close to the optimal stretch for maximal active force production, but it was reduced when adapted below the optimal stretch; there was no significant change in passive behavior in either case. Such active adaptations occurred only upon smooth muscle stimulation with phenylephrine, however, not stimulation with KCl or angiotensin II. Numerical simulations using the proposed model suggested further that active tone adaptation in vascular smooth muscle could play a stabilizing role for wall stress in large elastic arteries.     

Relationship between transmural potential difference and smooth muscle slow waves and contractility in the rabbit small intestine in vitro

The relationship between transmural potential difference (PD) and smooth muscle electrical and mechanical activity was investigated in the rabbit ileum in vitro. Transmural PD was monitored using agar salt bridge electrodes connected via calomel half cells to an electrometer. Force displacement transducers recorded predominantly longitudinal smooth muscle activity. Concurrently, predominantly circular muscle activity was recorded at three sites using intraluminal pressure probes. At the same sites, suction electrodes monitored electrical activity of the smooth muscle. In all experiments, fluctuations in transmural PD were temporally linked to smooth muscle mechanical and electrical activity. The frequency of PD oscillations, electrical slow waves, and cyclic pressure changes were identical within each segment. Adrenaline abolished smooth muscle electrical spiking, all mechanical activity, and transmural fluctuations in PD. However, the slow waves were not abolished, though their frequency was increased. Phentolamine but not propranolol reversed the effects of adrenaline, thus slow wave frequency is influenced by alpha-adrenergic stimulation in the rabbit ileum. In conclusion, oscillations in transmural PD are unrelated to the ionic processes associated with the slow wave. However, they are in some way linked to smooth muscle contractile activity, possibly via an intrinsic neural mechanism as observed in the guinea pig.     

Viscoelastic properties of isolated rat colon smooth muscle cells

The measurement of the biomechanical properties of gastrointestinal smooth muscle cells is important for the basic understanding of digestive function and the interaction of muscle cells with the matrix. Externally applied forces will deform the cells depending upon their mechanical properties. Hence, the evoked response mediated through stretch-sensitive ion-channels in the smooth muscle cell membrane will depend upon membrane properties and the magnitude of the external force. The aim of this study was to test the hypothesis that gastrointestinal smooth muscle cells behave in a viscoelastic manner. Smooth muscle cells were dissociated from the muscle layers of the descending colon. The viscoelastic properties of the isolated cells were characterized by measuring the mechanical deflection response of the cell membrane to a negative pressure of 1cm H(2)O applied across the cell through a micropipette and fitting the response to a theoretical viscoelastic solid model. The viscoelastic mechanical constants of the isolated cells (N=9) were found to be as follows: k(1)=19.99+/-2.86 Pa, k(2)=7.19+/-1.21 Pa, mu=25.36+/-6.14 Pas and tau=4.84+/-0.95 s. This study represents, to the best of our knowledge, the first quantitative mechanical properties of isolated living smooth muscle cells from the gastrointestinal tract. The mechanical properties determined in this study will be of use in future analytical and numerical smooth muscle cell models to better predict the mechanism between the magnitude of mechanical stimuli, mechanosensitivity and the evoked afferent responses.     

Modeling the oscillation dynamics of activated airway smooth muscle strips

When strips of activated airway smooth muscle are stretched cyclically, they exhibit force-length loops that vary substantially in both position and shape with the amplitude and frequency of the stretch. This behavior has recently been ascribed to a dynamic interaction between the imposed stretch and the number of actin-myosin interactions in the muscle. However, it is well known that the passive rheological properties of smooth muscle have a major influence on its mechanical properties. We therefore hypothesized that these rheological properties play a significant role in the force-length dynamics of activated smooth muscle. To test the plausibility of this hypothesis, we developed a model of the smooth muscle strip consisting of a force generator in series with an elastic component. Realistic steady-state force-length loops are predicted by the model when the force generator obeys a hyperbolic force-velocity relationship, the series elastic component is highly nonlinear, and both elastic stiffness and force generation are adjusted so that peak loop force equals isometric force. We conclude that the dynamic behavior of airway smooth muscle can be ascribed in large part to an interaction between connective tissue rheology and the force-velocity behavior of contractile proteins.     

Imaging coronary artery microstructure using second-harmonic and two-photon fluorescence microscopy

The microstructural basis for the mechanical properties of blood vessels has not been directly determined because of the lack of a nondestructive method that yields a three-dimensional view of these vascular wall constituents. Here, we demonstrate that multiphoton microscopy can be used to visualize the microstructural basis of blood vessel mechanical properties, by combining mechanical testing (distension) of excised porcine coronary arteries with simultaneous two-photon excited fluorescence and second-harmonic generation microscopy. Our results show that second-harmonic generation signals derived from collagen can be spectrally isolated from elastin and smooth muscle cell two-photon fluorescence. Two-photon fluorescence signals can be further characterized by emission maxima at 495 nm and 520 nm, corresponding to elastin and cellular contributions, respectively. Two-dimensional reconstructions of spectrally fused images permit high-resolution visualization of collagen and elastin fibrils and smooth muscle cells from intima to adventitia. These structural features are confirmed by coregistration of multiphoton microscopy images with conventional histology. Significant changes in mean fibril thickness and overall wall dimension were observed when comparing no load (zero transmural pressure) and zero-stress conditions to 30 and 180 mmHg distension pressures. Overall, these data suggest that multiphoton microscopy is a highly sensitive and promising technique for studying the morphometric properties of the microstructure of the blood vessel wall.     

磁处理白术药液对消化功能影响的药效研究

目的 :研究磁处理白术药液对消化功能影响的药效作用。方法 :用碳末法比较生理盐水、磁处理白术药液与非磁处理白术药液对小鼠肠推进运动的影响 ;用对比法 ,比较磁处理白术药液与正常台氏液及与非磁处理白术药液对离体兔小肠平滑肌收缩运动的影响。结果 :小鼠肠碳末推进率 :与生理盐水组比较 ,磁处理白术药液有促进作用 (p <0 .0 1 ) ,磁处理白术药液与非磁处理白术药液相比差异不显著 ;离体兔小肠平滑肌收缩运动 :与正常台氏液相比 ,磁处理白术药液有促进作用 (p <0 .0 1 ) ,磁处理白术药液与非磁处理白术药液相比 ,有抑制作用。结论 :磁处理白术药液对小鼠肠推进运动功能及对离体兔小肠平滑肌收缩运动有明显作用。     

Extracellular matrix and airway smooth muscle interactions: a target for modulating airway wall remodelling and hyperresponsiveness?

The airway smooth muscle from asthmatic airways produces increased amounts and an altered composition of extracellular matrix proteins. The extracellular matrix can in turn influence the phenotype and function of airway smooth muscle cells, affecting the biochemical, geometric, and mechanical properties of the airway wall. This review provides a brief overview of the current understanding of the biology associated with airway smooth muscle interactions with the extracellular matrix. We present future directions needed for the study of cellular and molecular mechanisms that determine the outcomes of extracellular matrix - airway smooth muscle interactions, and discuss their possible importance as determinants of airway function in asthma.     

Effect of acute ischaemia on active and passive large deformation mechanics of canine carotid arteries

Large deformation mechanical properties of dog carotid arteries excised following 1 hour of ischaemia and 1 hour of reperfusion were compared to those of contralaterial normal arteries in vitro. Vascular smooth muscle was invariably activated by 0.5 microgram/ml noradrenaline. Relative reduction in the diameter of postischaemia arteries following noradrenaline administration was twice as large (max.: 13.2 +/- 2.0%) as that of normal controls (max.: 5.7 +/- 1.5%) in the pressure range of 0--220 mmHg. If the smooth muscle was totally relaxed there were no differences between the geometrical (wall-thickness, radius) and mechanical properties (stress, incremental elastic modulus, incremental distensibility, strain-energy density) of the arteries in the two series. It is concluded that the increased reactivity of postischaemic arteries is not caused by changes in geometric or mechanical properties of their passive wall elements.     

Haemodynamics and wall remodelling of a growing cerebral aneurysm: a computational model

We have developed a computational simulation model for investigating an often postulated hypothesis connected with aneurysm growth. This hypothesis involves a combination of two parallel and interconnected mechanisms: according to the first mechanism, an endothelium-originating and wall shear stress-driven apoptotic behavior of smooth muscle cells, leading to loss of vascular tone is believed to be important to the aneurysm behavior. Vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All resistance and capacitance vessels under basal conditions exhibit some degree of smooth muscle contraction that determines the diameter, and hence tone, of the vessel. The second mechanism is connected to the arterial wall remodeling. Remodeling of the arterial wall under constant tension is a biomechanical process of rupture, degradation and reconstruction of the medial elastin and collagen fibers. In order to investigate these two mechanisms within a computationally tractable framework, we devise mechanical analogues that involve three-dimensional haemodynamics, yielding estimates of the wall shear stress and pressure fields and a quasi-steady approach for the apoptosis and remodeling of the wall. These analogues are guided by experimental information for the connection of stimuli to responses at a cellular level, properly averaged over volumes or surfaces. The model predicts aneurysm growth and can attribute specific roles to the two mechanisms involved: the smooth muscle cell-related loss of tone is important to the initiation of aneurysm growth, but cannot account alone for the formation of fully grown sacks; the fiber-related remodeling is pivotal for the latter.     

Mucosal folding in biologic vessels

A two-layer model is used to simulate the mechanical behavior of an airway or other biological vessel under external compressive stress or smooth muscle constriction sufficient to cause longitudinal mucosal buckling. Analytic andfinite element numerical methods are used to examine the onset of buckling. Post-buckling solutions are obtained by finite element analysis, then verified with large-scale physical model experiments. The two-layer model provides insight into how the stiffness of a vessel wall changes due to changes in the geometry and intrinsic material stiffnesses of the wall components. Specifically, it predicts that the number of mucosal folds in the buckled state is diminished most by increased thickness of the inner collagen-rich layer, and relatively little by increased thickness of the outer submucosal layer. An increase in the ratio of the inner to outer material stiffnesses causes an intermediate reduction in the number of folds. Results are cast in a simple form that can easily be used to predict buckling in a variety of vessels. The model quantitatively confirms that an increase in the thickness of the inner layer leads to a reduction in the number of mucosal folds, and further, that this can lead to increased vessel collapse at high levels of smooth muscle constriction.     

Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs.

Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0-20 cmH(2)O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls (P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi (P < 0.01) and smooth muscle strips (P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.     

Peristaltic transport of a solid bolus

An analysis of the peristaltic propulsion of a solid spherical bolus enclosed in a contractile membrane is presented. The model is based on in vitro preparations of intestinal segments, and utilizes a simplified representation of the mechanical properties of the muscular coats of the wall. The sequence of deformed configurations of the membrane and the displacement of the bolus are obtained by numerical solution of the model equations. The analysis presented in this paper could be useful for other studies in biomechanics (e.g. uterine contraction and motion of red blood cells in narrow capillaries).     

Carotid artery mechanical properties and stresses quantified using in vivo data from normotensive and hypertensive humans

The goal of this study was to model the in vivo non-linear mechanical behavior of human common carotid arteries (CCAs) and then to compare wall stresses and associated contributions of micro-constituents in normotensive (NT) and treated hypertensive (HT) subjects. We used an established theoretical model of 3D arterial mechanics that assumes a hyperelastic, anisotropic, active–passive, and residually stressed wall. In vivo data were obtained non-invasively from CCAs in 16 NT (21–64 years old) and 25 treated HT (44–69 years old) subjects. The associated quasi-static boundary value problem was solved semi-analytically over a cardiac cycle while accounting for surrounding perivascular tissue. Best-fit values of model parameters, including those describing contributions by intramural elastin, fibrillar collagen, and vascular smooth muscle, were estimated by a non-linear least-squares method. The model (1) captured temporal changes in intraluminal pressure, (2) estimated wall stress fields that appeared to reflect the presence or absence of age and disease, and (3) suggested changes in mechanical characteristics of wall micro-constituents despite medical treatment of hypertension. For example, age was positively correlated with residual stresses and altered fibrillar collagen in NT subjects, which indirectly validated the modeling, and HT subjects had higher levels of stresses, increased smooth muscle tone, and a stiffer elastin-dominated matrix despite treatment. These results are consistent with prior reports on effects of age and hypertension, but provide increased insight into evolving contributions of cell and matrix mechanics to arterial behavior in vivo.     

Mechanical behavior of human embryonic stem cell pellet under unconfined compression

As a prelude to the understanding of mechanotransduction in human embryonic stem cell (hESC) differentiation, the mechanical behavior of hESCs in the form of cell pellet is studied. The pellets were tested after 3 or 5 weeks of cell culture in order to demonstrate the effect of the duration of cell culture on the mechanical properties of the pellets. A micromechanical tester was used to conduct unconfined compression on hESC pellet, and experimental, numerical, and analytical methods were combined to determine the mechanical properties of hESC pellet. It is assumed that the mechanical behavior of hESC pellets can be described by an isotropic, linear viscoelastic model consisting of a spring and two Maxwell units in parallel, and the Poisson’s ratio of the hESC pellet is constant based on pellet deformation in the direction perpendicular to the compression direction. Finite element method (FEM) simulation was adopted to determine the values of Poisson’s ratio and the five parameters contained in the viscoelastic model. The variations of Poisson’s ratio and the initial elastic modulus are found to be larger compared with those of the four other parameters. Results show that longer duration of cell culture leads to higher modulus of hESC pellet. The effect of pellet size error on the values of mechanical parameters determined is studied using FEM simulation, and it is found that the effect of size error on Poisson’s ratio and initial elastic modulus is much larger than that on the other parameters.     

Viscoelastic influence on wall and baroreceptors of rabbit carotid sinus.

This study examined multifiber baroreceptor nerve activity (BNA) as a function of carotid sinus wall distension in 19 rabbits. Analysis estimated mechanical or viscoelastic properties of the sinus wall and their influence on BNA. In six sinuses, properties were altered by treatment with the enzyme protease to remove the endothelium and with nifedipine to passively relax smooth muscle. Properties were estimated from dynamic and steady state wall response to a 45 mm Hg step increase and decrease in intrasinus pressure (ISP) of 20 min. Control wall response had fast and slow (creep) portions with a viscosity increase from 1,370 N(s)/m to 17,864 N(s)/m during step-up in ISP. Wall elasticity averaged 77 N/m; which estimated the relationship of force and change in steady state response. Control BNA response also had fast and slow (resetting) portions. A BNA and wall response relationship (BNA/m) was defined as transduction-gain (T-G) with proportional and dynamic components. In the subgroup, wall creep and baroreceptor resetting were abolished by protease treatment, suggesting an endothelial mediator which influenced sinus smooth muscle. Histology data indicated enzyme damage was limited to tunica intima tissues, and nifedipine did not block Ca2+ channels on neural structures. By comparison of responses before and after treatments the proportional component of T-G was equated to an elastic influence (1/E), with E = 7.5 x 10(-6) m/BNA, while the dynamic component was equated to a viscous influence (1/V), with V = 1.53 x 10(-4) m(s)/BNA. A simple but fundamental relationship for baroreceptor-tissue linkages was estimated by BNA/m = 1/(Vs + E), a first-order transfer function.     

Calcium dependence of electrical and mechanical activity in rat ileum examined by the sucrose-gap technique

1. Single sucrose gap recordings showed that spontaneous action potentials of rat ileal smooth muscle consisted of slow waves and superimposed spikes which generated rhythmic contractions. As external potassium was raised, the resting potential progressively depolarized.2. Calcium-free salines inhibited spontaneous mechanical activity and inhibited the plateau phase of the action potential, but spontaneous spike depolarizations persisted.3. Verapamil, nifedipine and diltiazem all inhibited spontaneous mechanical activity and the plateau phase of the action potential, while in addition diltiazem augmented spike amplitude.4. Mn ions also inhibited mechanical activity and the action potential plateau, without affecting spike activity while the calcium ionophore A23187 enhanced both mechanical and electrical activity with a pronounced effect on spike amplitude.5. These results are consistent with the view that the plateau phase of the ileal smooth muscle action potential is dependent upon an influx of extracellular calcium possibly through voltage dependent slow calcium channels.