In JoVE (1)

Other Publications (86)

Articles by Ellen Kuhl in JoVE

 JoVE Bioengineering

Quantification of Strain in a Porcine Model of Skin Expansion Using Multi-View Stereo and Isogeometric Kinematics

1Mechanical Engineering, Purdue University, 2Division of Plastic Surgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, 3Mechanical Engineering, Bioengineering, Cardiothoracic Surgery, Stanford University

JoVE 55052

Other articles by Ellen Kuhl on PubMed

Pharmacological Characterization of the Chronic Constriction Injury Model of Neuropathic Pain

European Journal of Pharmacology. May, 2004  |  Pubmed ID: 15140630

The chronic constriction injury model is a rat model of neuropathic pain based on a unilateral loose ligation of the sciatic nerve. The aim of the present study was to test its sensitivity to various clinically validated and experimental drugs. Mechanical allodynia and thermal hyperalgesia developed within one week post-surgery and were reliably present for at least 7 weeks. Mechanical allodynia was strongly attenuated by morphine (minimal effective dose in brackets: 8 mg/kg, p.o.) and the cannabinoids Delta9-tetrahydrocannabinol (3 mg/kg, p.o.) and (-)-cis-3-[2-hydroxy-4(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940; 0.05 mg/kg, i.p.), and weakly/moderately attenuated by the anticonvulsants gabapentin (50 mg/kg, i.p.) and carbamazepine (32 mg/kg, i.p.), the muscle relaxant baclofen (3 mg/kg, i.p.), and the adenosine kinase inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine (ABT-702; 30 mg/kg, i.p.). Thermal hyperalgesia was strongly attenuated by morphine (16 mg/kg, p.o.), Delta9-tetrahydrocannabinol (6 mg/kg, p.o.), CP 55,940 (0.025 mg/kg, i.p.), carbamazepine (32 mg/kg, i.p.) and the antidepressant amitriptyline (32 mg/kg, p.o.), and weakly/moderately attenuated by gabapentin (50 mg/kg, i.p.), the anti-inflammatory cyclooxygenase-2 inhibitor rofecoxib (30 mg/kg, i.p.) and the adenosine A1 receptor positive allosteric modulator 2-amino-4,5,6,7-tetrahydrobenzo(b)thiophen-3-yl 4-chlorophenylmethanone (T62; 30 mg/kg, i.p.). Both symptoms were hardly or not affected by the nonselective N-methyl-d-aspartate receptor antagonists ketamine and dizocilpine, and the N-methyl-d-aspartate receptor NR2B-selective antagonists ifenprodil and R-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenyl-methyl)-1-piperidine propranol (Ro 25-6981). The finding that mechanical allodynia and/or thermal hyperalgesia are attenuated by various established compounds further supports the validity of the chronic constriction injury model for the study of neuropathic pain and its use for the identification of novel treatments.

Visualization of Particle Interactions in Granular Media

IEEE Transactions on Visualization and Computer Graphics. Sep-Oct, 2008  |  Pubmed ID: 18599921

Interaction between particles in so-called granular media, such as soil and sand, plays an important role in the context of geomechanical phenomena and numerous industrial applications. A two scale homogenization approach based on a micro and a macro scale level is briefly introduced in this paper. Computation of granular material in such a way gives a deeper insight into the context of discontinuous materials and at the same time reduces the computational costs. However, the description and the understanding of the phenomena in granular materials are not yet satisfactory. A sophisticated problem-specific visualization technique would significantly help to illustrate failure phenomena on the microscopic level. As main contribution, we present a novel 2D approach for the visualization of simulation data, based on the above outlined homogenization technique. Our visualization tool supports visualization on micro scale level as well as on macro scale level. The tool shows both aspects closely arranged in form of multiple coordinated views to give users the possibility to analyze the particle behavior effectively. A novel type of interactive rose diagrams was developed to represent the dynamic contact networks on the micro scale level in a condensed and efficient way.

Material Properties of the Ovine Mitral Valve Anterior Leaflet in Vivo from Inverse Finite Element Analysis

American Journal of Physiology. Heart and Circulatory Physiology. Sep, 2008  |  Pubmed ID: 18621858

We measured leaflet displacements and used inverse finite-element analysis to define, for the first time, the material properties of mitral valve (MV) leaflets in vivo. Sixteen miniature radiopaque markers were sewn to the MV annulus, 16 to the anterior MV leaflet, and 1 on each papillary muscle tip in 17 sheep. Four-dimensional coordinates were obtained from biplane videofluoroscopic marker images (60 frames/s) during three complete cardiac cycles. A finite-element model of the anterior MV leaflet was developed using marker coordinates at the end of isovolumic relaxation (IVR; when the pressure difference across the valve is approximately 0), as the minimum stress reference state. Leaflet displacements were simulated during IVR using measured left ventricular and atrial pressures. The leaflet shear modulus (G(circ-rad)) and elastic moduli in both the commisure-commisure (E(circ)) and radial (E(rad)) directions were obtained using the method of feasible directions to minimize the difference between simulated and measured displacements. Group mean (+/-SD) values (17 animals, 3 heartbeats each, i.e., 51 cardiac cycles) were as follows: G(circ-rad) = 121 +/- 22 N/mm2, E(circ) = 43 +/- 18 N/mm2, and E(rad) = 11 +/- 3 N/mm2 (E(circ) > E(rad), P < 0.01). These values, much greater than those previously reported from in vitro studies, may result from activated neurally controlled contractile tissue within the leaflet that is inactive in excised tissues. This could have important implications, not only to our understanding of mitral valve physiology in the beating heart but for providing additional information to aid the development of more durable tissue-engineered bioprosthetic valves.

Special Issue on Computer Simulations of Mechanobiology. Preface

Computer Methods in Biomechanics and Biomedical Engineering. Oct, 2008  |  Pubmed ID: 18792830

Active Stiffening of Mitral Valve Leaflets in the Beating Heart

American Journal of Physiology. Heart and Circulatory Physiology. Jun, 2009  |  Pubmed ID: 19363135

The anterior leaflet of the mitral valve (MV), viewed traditionally as a passive membrane, is shown to be a highly active structure in the beating heart. Two types of leaflet contractile activity are demonstrated: 1) a brief twitch at the beginning of each beat (reflecting contraction of myocytes in the leaflet in communication with and excited by left atrial muscle) that is relaxed by midsystole and whose contractile activity is eliminated with beta-receptor blockade and 2) sustained tone during isovolumic relaxation, insensitive to beta-blockade, but doubled by stimulation of the neurally rich region of aortic-mitral continuity. These findings raise the possibility that these leaflets are neurally controlled tissues, with potentially adaptive capabilities to meet the changing physiological demands on the heart. They also provide a basis for a permanent paradigm shift from one viewing the leaflets as passive flaps to one viewing them as active tissues whose complex function and dysfunction must be taken into account when considering not only therapeutic approaches to MV disease, but even the definitions of MV disease itself.

Stress-strain Behavior of Mitral Valve Leaflets in the Beating Ovine Heart

Journal of Biomechanics. Aug, 2009  |  Pubmed ID: 19535081

Excised anterior mitral leaflets exhibit anisotropic, non-linear material behavior with pre-transitional stiffness ranging from 0.06 to 0.09 N/mm(2) and post-transitional stiffness from 2 to 9 N/mm(2). We used inverse finite element (FE) analysis to test, for the first time, whether the anterior mitral leaflet (AML), in vivo, exhibits similar non-linear behavior during isovolumic relaxation (IVR). Miniature radiopaque markers were sewn to the mitral annulus, AML, and papillary muscles in 8 sheep. Four-dimensional marker coordinates were obtained using biplane videofluoroscopic imaging during three consecutive cardiac cycles. A FE model of the AML was developed using marker coordinates at the end of isovolumic relaxation (when pressure difference across the valve is approximately zero), as the reference state. AML displacements were simulated during IVR using measured left ventricular and atrial pressures. AML elastic moduli in the radial and circumferential directions were obtained for each heartbeat by inverse FEA, minimizing the difference between simulated and measured displacements. Stress-strain curves for each beat were obtained from the FE model at incrementally increasing transmitral pressure intervals during IVR. Linear regression of 24 individual stress-strain curves (8 hearts, 3 beats each) yielded a mean (+/-SD) linear correlation coefficient (r(2)) of 0.994+/-0.003 for the circumferential direction and 0.995+/-0.003 for the radial direction. Thus, unlike isolated leaflets, the AML, in vivo, operates linearly over a physiologic range of pressures in the closed mitral valve.

Mechanics in Biology: Cells and Tissues

Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences. Sep, 2009  |  Pubmed ID: 19657002

Regional Stiffening of the Mitral Valve Anterior Leaflet in the Beating Ovine Heart

Journal of Biomechanics. Dec, 2009  |  Pubmed ID: 19766222

Left atrial muscle extends into the proximal third of the mitral valve (MV) anterior leaflet and transient tensing of this muscle has been proposed as a mechanism aiding valve closure. If such tensing occurs, regional stiffness in the proximal anterior mitral leaflet will be greater during isovolumic contraction (IVC) than isovolumic relaxation (IVR) and this regional stiffness difference will be selectively abolished by beta-receptor blockade. We tested this hypothesis in the beating ovine heart. Radiopaque markers were sewn around the MV annulus and on the anterior MV leaflet in 10 sheep hearts. Four-dimensional marker coordinates were obtained from biplane videofluoroscopy before (CRTL) and after administration of esmolol (ESML). Heterogeneous finite element models of each anterior leaflet were developed using marker coordinates over matched pressures during IVC and IVR for CRTL and ESML. Leaflet displacements were simulated using measured left ventricular and atrial pressures and a response function was computed as the difference between simulated and measured displacements. Circumferential and radial elastic moduli for ANNULAR, BELLY and EDGE leaflet regions were iteratively varied until the response function reached a minimum. The stiffness values at this minimum were interpreted as the in vivo regional material properties of the anterior leaflet. For all regions and all CTRL beats IVC stiffness was 40-58% greater than IVR stiffness. ESML reduced ANNULAR IVC stiffness to ANNULAR IVR stiffness values. These results strongly implicate transient tensing of leaflet atrial muscle during IVC as the basis of the ANNULAR IVC-IVR stiffness difference.

Anterior Mitral Leaflet Curvature in the Beating Ovine Heart: a Case Study Using Videofluoroscopic Markers and Subdivision Surfaces

Biomechanics and Modeling in Mechanobiology. Jun, 2010  |  Pubmed ID: 19890668

The implantation of annuloplasty rings is a common surgical treatment targeted to re-establish mitral valve competence in patients with mitral regurgitation. It is hypothesized that annuloplasty ring implantation influences leaflet curvature, which in turn may considerably impair repair durability. This research is driven by the vision to design repair devices that optimize leaflet curvature to reduce valvular stress. In pursuit of this goal, the objective of this manuscript is to quantify leaflet curvature in ovine models with and without annuloplasty ring using in vivo animal data from videofluoroscopic marker analysis. We represent the surface of the anterior mitral leaflet based on 23 radiopaque markers using subdivision surfaces techniques. Quartic box-spline functions are applied to determine leaflet curvature on overlapping subdivision patches. We illustrate the virtual reconstruction of the leaflet surface for both interpolating and approximating algorithms. Different scalar-valued metrics are introduced to quantify leaflet curvature in the beating heart using the approximating subdivision scheme. To explore the impact of annuloplasty ring implantation, we analyze ring-induced curvature changes at characteristic instances throughout the cardiac cycle. The presented results demonstrate that the fully automated subdivision surface procedure can successfully reconstruct a smooth representation of the anterior mitral valve from a limited number of markers at a high temporal resolution of approximately 60 frames per minute.

Characterization of Indentation Response and Stiffness Reduction of Bone Using a Continuum Damage Model

Journal of the Mechanical Behavior of Biomedical Materials. Feb, 2010  |  Pubmed ID: 20129418

Indentation tests can be used to characterize the mechanical properties of bone at small load/length scales offering the possibility of utilizing very small test specimens, which can be excised using minimally-invasive procedures. In addition, the need for mechanical property data from bone may be a requirement for fundamental multi-scale experiments, changes in nano- and micro-mechanical properties (e.g., as affected by changes in bone mineral density) due to drug therapies, and/or the development of computational models. Load vs. indentation depth data, however, is more complex than those obtained from typical macro-scale experiments, primarily due to the mixed state of stress, and thus interpretation of the data and extraction of mechanical properties is more challenging. Previous studies have shown that cortical bone exhibits a visco-elastic response combined with permanent deformation during indentation tests, and that the load vs. indentation depth response can be simulated using a visco-elastic/plastic material model. The model successfully captures the loading and creep displacement behavior, however, it does not adequately reproduce the unloading response near the end of the unloading cycle, where a pronounced decrease in contact stiffness is observed. It is proposed that the stiffness reduction observed in bone results from an increase in damage; therefore, a plastic-damage model was investigated and shown capable of simulating a typical bone indentation response through an axisymmetric finite element simulation. The plastic-damage model was able to reproduce the full indentation response, especially the reduced stiffness behavior exhibited during the latter stages of unloading. The results suggest that the plastic-damage model is suitable for describing the complex indentation response of bone and may provide further insight into the relationship between model parameters and mechanical/physical properties.

A Multiscale Model for Eccentric and Concentric Cardiac Growth Through Sarcomerogenesis

Journal of Theoretical Biology. Aug, 2010  |  Pubmed ID: 20447409

We present a novel computational model for maladaptive cardiac growth in which kinematic changes of the cardiac chambers are attributed to alterations in cytoskeletal architecture and in cellular morphology. We adopt the concept of finite volume growth characterized through the multiplicative decomposition of the deformation gradient into an elastic part and a growth part. The functional form of its growth tensor is correlated to sarcomerogenesis, the creation and deposition of new sarcomere units. In response to chronic volume-overload, an increased diastolic wall strain leads to the addition of sarcomeres in series, resulting in a relative increase in cardiomyocyte length, associated with eccentric hypertrophy and ventricular dilation. In response to chronic pressure-overload, an increased systolic wall stress leads to the addition of sacromeres in parallel, resulting in a relative increase in myocyte cross sectional area, associated with concentric hypertrophy and ventricular wall thickening. The continuum equations for both forms of maladaptive growth are discretized in space using a nonlinear finite element approach, and discretized in time using the implicit Euler backward scheme. We explore a generic bi-ventricular heart model in response to volume- and pressure-overload to demonstrate how local changes in cellular morphology translate into global alterations in cardiac form and function.

Anterior Mitral Leaflet Curvature During the Cardiac Cycle in the Normal Ovine Heart

Circulation. Oct, 2010  |  Pubmed ID: 20937973

The dynamic changes of anterior mitral leaflet (AML) curvature are of primary importance for optimal left ventricular filling and emptying but are incompletely characterized.

In Vivo Dynamic Strains of the Ovine Anterior Mitral Valve Leaflet

Journal of Biomechanics. Apr, 2011  |  Pubmed ID: 21306716

Understanding the mechanics of the mitral valve is crucial in terms of designing and evaluating medical devices and techniques for mitral valve repair. In the current study we characterize the in vivo strains of the anterior mitral valve leaflet. On cardiopulmonary bypass, we sew miniature markers onto the leaflets of 57 sheep. During the cardiac cycle, the coordinates of these markers are recorded via biplane fluoroscopy. From the resulting four-dimensional data sets, we calculate areal, maximum principal, circumferential, and radial leaflet strains and display their profiles on the averaged leaflet geometry. Average peak areal strains are 13.8±6.3%, maximum principal strains are 13.0±4.7%, circumferential strains are 5.0±2.7%, and radial strains are 7.8±4.3%. Maximum principal strains are largest in the belly region, where they are aligned with the circumferential direction during diastole switching into the radial direction during systole. Circumferential strains are concentrated at the distal portion of the belly region close to the free edge of the leaflet, while radial strains are highest in the center of the leaflet, stretching from the posterior to the anterior commissure. In summary, leaflet strains display significant temporal, regional, and directional variations with largest values inside the belly region and toward the free edge. Characterizing strain distribution profiles might be of particular clinical significance when optimizing mitral valve repair techniques in terms of forces on suture lines and on medical devices.

Characterization of Mitral Valve Annular Dynamics in the Beating Heart

Annals of Biomedical Engineering. Jun, 2011  |  Pubmed ID: 21336803

The objective of this study is to establish a mathematical characterization of the mitral valve annulus that allows a precise qualitative and quantitative assessment of annular dynamics in the beating heart. We define annular geometry through 16 miniature markers sewn onto the annuli of 55 sheep. Using biplane videofluoroscopy, we record marker coordinates in vivo. By approximating these 16 marker coordinates through piecewise cubic splines, we generate a smooth mathematical representation of the 55 mitral annuli. We time-align these 55 annulus representations with respect to characteristic hemodynamic time points to generate an averaged baseline annulus representation. To characterize annular physiology, we extract classical clinical metrics of annular form and function throughout the cardiac cycle. To characterize annular dynamics, we calculate displacements, strains, and curvature from the discrete mathematical representations. To illustrate potential future applications of this approach, we create rapid prototypes of the averaged mitral annulus at characteristic hemodynamic time points. In summary, this study introduces a novel mathematical model that allows us to identify temporal, regional, and inter-subject variations of clinical and mechanical metrics that characterize mitral annular form and function. Ultimately, this model can serve as a valuable tool to optimize both surgical and interventional approaches that aim at restoring mitral valve competence.

Active Contraction of Cardiac Muscle: in Vivo Characterization of Mechanical Activation Sequences in the Beating Heart

Journal of the Mechanical Behavior of Biomedical Materials. Oct, 2011  |  Pubmed ID: 21783125

Progressive alterations in cardiac wall strains are a classic hallmark of chronic heart failure. Accordingly, the objectives of this study are to establish a baseline characterization of cardiac strains throughout the cardiac cycle, to quantify temporal, regional, and transmural variations of active fiber contraction, and to identify pathways of mechanical activation in the healthy beating heart. To this end, we insert two sets of twelve radiopaque beads into the heart muscle of nine sheep; one in the anterior-basal and one in the lateral-equatorial left ventricular wall. During three consecutive heartbeats, we record the bead coordinates via biplane videofluoroscopy. From the resulting four-dimensional data sets, we calculate the temporally and transmurally varying Green-Lagrange strains in the anterior and lateral wall. To quantify active contraction, we project the strains onto the local muscle fiber directions. We observe that mechanical activation is initiated at the endocardium slightly after end diastole and progresses transmurally outward, reaching the epicardium slightly before end systole. Accordingly, fibers near the outer wall are in contraction for approximately half of the cardiac cycle while fibers near the inner wall are in contraction almost throughout the entire cardiac cycle. In summary, cardiac wall strains display significant temporal, regional, and transmural variations. Quantifying wall strain profiles might be of particular clinical significance when characterizing stages of left ventricular remodeling, but also of engineering relevance when designing new biomaterials of similar structure and function.

A Novel Method for Quantifying the In-vivo Mechanical Effect of Material Injected into a Myocardial Infarction

The Annals of Thoracic Surgery. Sep, 2011  |  Pubmed ID: 21871280

Infarcted regions of myocardium exhibit functional impairment ranging in severity from hypokinesis to dyskinesis. We sought to quantify the effects of injecting a calcium hydroxyapatite-based tissue filler on the passive material response of infarcted left ventricles.

Rigid, Complete Annuloplasty Rings Increase Anterior Mitral Leaflet Strains in the Normal Beating Ovine Heart

Circulation. Sep, 2011  |  Pubmed ID: 21911823

Annuloplasty ring or band implantation during surgical mitral valve repair perturbs mitral annular dimensions, dynamics, and shape, which have been associated with changes in anterior mitral leaflet (AML) strain patterns and suboptimal long-term repair durability. We hypothesized that rigid rings with nonphysiological three-dimensional shapes, but not saddle-shaped rigid rings or flexible bands, increase AML strains.

Multiscale Computational Models for Optogenetic Control of Cardiac Function

Biophysical Journal. Sep, 2011  |  Pubmed ID: 21943413

The ability to stimulate mammalian cells with light has significantly changed our understanding of electrically excitable tissues in health and disease, paving the way toward various novel therapeutic applications. Here, we demonstrate the potential of optogenetic control in cardiac cells using a hybrid experimental/computational technique. Experimentally, we introduced channelrhodopsin-2 into undifferentiated human embryonic stem cells via a lentiviral vector, and sorted and expanded the genetically engineered cells. Via directed differentiation, we created channelrhodopsin-expressing cardiomyocytes, which we subjected to optical stimulation. To quantify the impact of photostimulation, we assessed electrical, biochemical, and mechanical signals using patch-clamping, multielectrode array recordings, and video microscopy. Computationally, we introduced channelrhodopsin-2 into a classic autorhythmic cardiac cell model via an additional photocurrent governed by a light-sensitive gating variable. Upon optical stimulation, the channel opens and allows sodium ions to enter the cell, inducing a fast upstroke of the transmembrane potential. We calibrated the channelrhodopsin-expressing cell model using single action potential readings for different photostimulation amplitudes, pulse widths, and frequencies. To illustrate the potential of the proposed approach, we virtually injected channelrhodopsin-expressing cells into different locations of a human heart, and explored its activation sequences upon optical stimulation. Our experimentally calibrated computational toolbox allows us to virtually probe landscapes of process parameters, and identify optimal photostimulation sequences toward pacing hearts with light.

Growing Skin: A Computational Model for Skin Expansion in Reconstructive Surgery

Journal of the Mechanics and Physics of Solids. Oct, 2011  |  Pubmed ID: 22081726

The goal of this manuscript is to establish a novel computational model for stretch-induced skin growth during tissue expansion. Tissue expansion is a common surgical procedure to grow extra skin for reconstructing birth defects, burn injuries, or cancerous breasts. To model skin growth within the framework of nonlinear continuum mechanics, we adopt the multiplicative decomposition of the deformation gradient into an elastic and a growth part. Within this concept, we characterize growth as an irreversible, stretch-driven, transversely isotropic process parameterized in terms of a single scalar-valued growth multiplier, the in-plane area growth. To discretize its evolution in time, we apply an unconditionally stable, implicit Euler backward scheme. To discretize it in space, we utilize the finite element method. For maximum algorithmic efficiency and optimal convergence, we suggest an inner Newton iteration to locally update the growth multiplier at each integration point. This iteration is embedded within an outer Newton iteration to globally update the deformation at each finite element node. To demonstrate the characteristic features of skin growth, we simulate the process of gradual tissue expander inflation. To visualize growth-induced residual stresses, we simulate a subsequent tissue expander deflation. In particular, we compare the spatio-temporal evolution of area growth, elastic strains, and residual stresses for four commonly available tissue expander geometries. We believe that predictive computational modeling can open new avenues in reconstructive surgery to rationalize and standardize clinical process parameters such as expander geometry, expander size, expander placement, and inflation timing.

A Fully Implicit Finite Element Method for Bidomain Models of Cardiac Electrophysiology

Computer Methods in Biomechanics and Biomedical Engineering. 2012  |  Pubmed ID: 21491253

This work introduces a novel, unconditionally stable and fully coupled finite element method for the bidomain system of equations of cardiac electrophysiology. The transmembrane potential Φ(i)-Φ(e) and the extracellular potential Φ(e) are treated as independent variables. To this end, the respective reaction-diffusion equations are recast into weak forms via a conventional isoparametric Galerkin approach. The resultant nonlinear set of residual equations is consistently linearised. The method results in a symmetric set of equations, which reduces the computational time significantly compared to the conventional solution algorithms. The proposed method is inherently modular and can be combined with phenomenological or ionic models across the cell membrane. The efficiency of the method and the comparison of its computational cost with respect to the simplified monodomain models are demonstrated through representative numerical examples.

Computational Modeling of Bone Density Profiles in Response to Gait: a Subject-specific Approach

Biomechanics and Modeling in Mechanobiology. Mar, 2012  |  Pubmed ID: 21604146

The goal of this study is to explore the potential of computational growth models to predict bone density profiles in the proximal tibia in response to gait-induced loading. From a modeling point of view, we design a finite element-based computational algorithm using the theory of open system thermodynamics. In this algorithm, the biological problem, the balance of mass, is solved locally on the integration point level, while the mechanical problem, the balance of linear momentum, is solved globally on the node point level. Specifically, the local bone mineral density is treated as an internal variable, which is allowed to change in response to mechanical loading. From an experimental point of view, we perform a subject-specific gait analysis to identify the relevant forces during walking using an inverse dynamics approach. These forces are directly applied as loads in the finite element simulation. To validate the model, we take a Dual-Energy X-ray Absorptiometry scan of the subject's right knee from which we create a geometric model of the proximal tibia. For qualitative validation, we compare the computationally predicted density profiles to the bone mineral density extracted from this scan. For quantitative validation, we adopt the region of interest method and determine the density values at fourteen discrete locations using standard and custom-designed image analysis tools. Qualitatively, our two- and three-dimensional density predictions are in excellent agreement with the experimental measurements. Quantitatively, errors are less than 3% for the two-dimensional analysis and less than 10% for the three-dimensional analysis. The proposed approach has the potential to ultimately improve the long-term success of possible treatment options for chronic diseases such as osteoarthritis on a patient-specific basis by accurately addressing the complex interactions between ambulatory loads and tissue changes.

Mitral Valve Annuloplasty: a Quantitative Clinical and Mechanical Comparison of Different Annuloplasty Devices

Annals of Biomedical Engineering. Mar, 2012  |  Pubmed ID: 22037916

Mitral valve annuloplasty is a common surgical technique used in the repair of a leaking valve by implanting an annuloplasty device. To enhance repair durability, these devices are designed to increase leaflet coaptation, while preserving the native annular shape and motion; however, the precise impact of device implantation on annular deformation, strain, and curvature is unknown. In this article, we quantify how three frequently used devices significantly impair native annular dynamics. In controlled in vivo experiments, we surgically implanted 11 flexible-incomplete, 11 semi-rigid-complete, and 12 rigid-complete devices around the mitral annuli of 34 sheep, each tagged with 16 equally spaced tantalum markers. We recorded four-dimensional marker coordinates using biplane videofluoroscopy, first with device and then without, which were used to create mathematical models using piecewise cubic splines. Clinical metrics (characteristic anatomical distances) revealed significant global reduction in annular dynamics upon device implantation. Mechanical metrics (strain and curvature fields) explained this reduction via a local loss of anterior dilation and posterior contraction. Overall, all three devices unfavorably caused reduction in annular dynamics. The flexible-incomplete device, however, preserved native annular dynamics to a larger extent than the complete devices. Heterogeneous strain and curvature profiles suggest the need for heterogeneous support, which may spawn more rational design of annuloplasty devices using design concepts of functionally graded materials.

Growing Skin: Tissue Expansion in Pediatric Forehead Reconstruction

Biomechanics and Modeling in Mechanobiology. Jul, 2012  |  Pubmed ID: 22052000

Tissue expansion is a common surgical procedure to grow extra skin through controlled mechanical over-stretch. It creates skin that matches the color, texture, and thickness of the surrounding tissue, while minimizing scars and risk of rejection. Despite intense research in tissue expansion and skin growth, there is a clear knowledge gap between heuristic observation and mechanistic understanding of the key phenomena that drive the growth process. Here, we show that a continuum mechanics approach, embedded in a custom-designed finite element model, informed by medical imaging, provides valuable insight into the biomechanics of skin growth. In particular, we model skin growth using the concept of an incompatible growth configuration. We characterize its evolution in time using a second-order growth tensor parameterized in terms of a scalar-valued internal variable, the in-plane area growth. When stretched beyond the physiological level, new skin is created, and the in-plane area growth increases. For the first time, we simulate tissue expansion on a patient-specific geometric model, and predict stress, strain, and area gain at three expanded locations in a pediatric skull: in the scalp, in the forehead, and in the cheek. Our results may help the surgeon to prevent tissue over-stretch and make informed decisions about expander geometry, size, placement, and inflation. We anticipate our study to open new avenues in reconstructive surgery and enhance treatment for patients with birth defects, burn injuries, or breast tumor removal.

On the Biomechanics and Mechanobiology of Growing Skin

Journal of Theoretical Biology. Mar, 2012  |  Pubmed ID: 22227432

Skin displays an impressive functional plasticity, which allows it to adapt gradually to environmental changes. Tissue expansion takes advantage of this adaptation, and induces a controlled in situ skin growth for defect correction in plastic and reconstructive surgery. Stretches beyond the skin's physiological limit invoke several mechanotransduction pathways, which increase mitotic activity and collagen synthesis, ultimately resulting in a net gain in skin surface area. However, the interplay between mechanics and biology during tissue expansion remains unquantified. Here, we present a continuum model for skin growth that summarizes the underlying mechanotransduction pathways collectively in a single phenomenological variable, the strain-driven area growth. We illustrate the governing equations for growing biological membranes, and demonstrate their computational solution within a nonlinear finite element setting. In displacement-controlled equi-biaxial extension tests, the model accurately predicts the experimentally observed histological, mechanical, and structural features of growing skin, both qualitatively and quantitatively. Acute and chronic elastic uniaxial stretches are 25% and 10%, compared to 36% and 10% reported in the literature. Acute and chronic thickness changes are -28% and -12%, compared to -22% and -7% reported in the literature. Chronic fractional weight gain is 3.3, compared to 2.7 for wet weight and 3.3 for dry weight reported in the literature. In two clinical cases of skin expansion in pediatric forehead reconstruction, the model captures the clinically observed mechanical and structural responses, both acutely and chronically. Our results demonstrate that the field theories of continuum mechanics can reliably predict the mechanical manipulation of thin biological membranes by controlling their mechanotransduction pathways through mechanical overstretch. We anticipate that the proposed skin growth model can be generalized to arbitrary biological membranes, and that it can serve as a valuable tool to virtually manipulate living tissues, simply by means of changes in the mechanical environment.

Kinematics of Cardiac Growth: in Vivo Characterization of Growth Tensors and Strains

Journal of the Mechanical Behavior of Biomedical Materials. Apr, 2012  |  Pubmed ID: 22402163

Progressive growth and remodeling of the left ventricle are part of the natural history of chronic heart failure and strong clinical indicators for survival. Accompanied by changes in cardiac form and function, they manifest themselves in alterations of cardiac strains, fiber stretches, and muscle volume. Recent attempts to shed light on the mechanistic origin of heart failure utilize continuum theories of growth to predict the maladaptation of the heart in response to pressure or volume overload. However, despite a general consensus on the representation of growth through a second order tensor, the precise format of this growth tensor remains unknown. Here we show that infarct-induced cardiac dilation is associated with a chronic longitudinal growth, accompanied by a chronic thinning of the ventricular wall. In controlled in vivo experiments throughout a period of seven weeks, we found that the lateral left ventricular wall adjacent to the infarct grows longitudinally by more than 10%, thins by more than 25%, lengthens in fiber direction by more than 5%, and decreases its volume by more than 15%. Our results illustrate how a local loss of blood supply induces chronic alterations in structure and function in adjacent regions of the ventricular wall. We anticipate our findings to be the starting point for a series of in vivo studies to calibrate and validate constitutive models for cardiac growth. Ultimately, these models could be useful to guide the design of novel therapies, which allow us to control the progression of heart failure.

Computational Optogenetics: A Novel Continuum Framework for the Photoelectrochemistry of Living Systems

Journal of the Mechanics and Physics of Solids. Jun, 2012  |  Pubmed ID: 22773861

Electrical stimulation is currently the gold standard treatment for heart rhythm disorders. However, electrical pacing is associated with technical limitations and unavoidable potential complications. Recent developments now enable the stimulation of mammalian cells with light using a novel technology known as optogenetics. The optical stimulation of genetically engineered cells has significantly changed our understanding of electrically excitable tissues, paving the way towards controlling heart rhythm disorders by means of photostimulation. Controlling these disorders, in turn, restores coordinated force generation to avoid sudden cardiac death. Here, we report a novel continuum framework for the photoelectrochemistry of living systems that allows us to decipher the mechanisms by which this technology regulates the electrical and mechanical function of the heart. Using a modular multiscale approach, we introduce a non-selective cation channel, channelrhodopsin-2, into a conventional cardiac muscle cell model via an additional photocurrent governed by a light-sensitive gating variable. Upon optical stimulation, this channel opens and allows sodium ions to enter the cell, inducing electrical activation. In side-by-side comparisons with conventional heart muscle cells, we show that photostimulation directly increases the sodium concentration, which indirectly decreases the potassium concentration in the cell, while all other characteristics of the cell remain virtually unchanged. We integrate our model cells into a continuum model for excitable tissue using a nonlinear parabolic second order partial differential equation, which we discretize in time using finite differences and in space using finite elements. To illustrate the potential of this computational model, we virtually inject our photosensitive cells into different locations of a human heart, and explore its activation sequences upon photostimulation. Our computational optogenetics tool box allows us to virtually probe landscapes of process parameters, and to identify optimal photostimulation sequences with the goal to pace human hearts with light and, ultimately, to restore mechanical function.

Growth and Remodeling of the Left Ventricle: A Case Study of Myocardial Infarction and Surgical Ventricular Restoration

Mechanics Research Communications. Jun, 2012  |  Pubmed ID: 22778489

Cardiac growth and remodeling in the form of chamber dilation and wall thinning are typical hallmarks of infarct-induced heart failure. Over time, the infarct region stiffens, the remaining muscle takes over function, and the chamber weakens and dilates. Current therapies seek to attenuate these effects by removing the infarct region or by providing structural support to the ventricular wall. However, the underlying mechanisms of these therapies are unclear, and the results remain suboptimal. Here we show that myocardial infarction induces pronounced regional and transmural variations in cardiac form. We introduce a mechanistic growth model capable of predicting structural alterations in response to mechanical overload. Under a uniform loading, this model predicts non-uniform growth. Using this model, we simulate growth in a patient-specific left ventricle. We compare two cases, growth in an infarcted heart, pre-operative, and growth in the same heart, after the infarct was surgically excluded, post-operative. Our results suggest that removing the infarct and creating a left ventricle with homogeneous mechanical properties does not necessarily reduce the driving forces for growth and remodeling. These preliminary findings agree conceptually with clinical observations.

Frontiers in Growth and Remodeling

Mechanics Research Communications. Jun, 2012  |  Pubmed ID: 22919118

Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state-of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine.

How Do Annuloplasty Rings Affect Mitral Annular Strains in the Normal Beating Ovine Heart?

Circulation. Sep, 2012  |  Pubmed ID: 22965988

We hypothesized that annuloplasty ring implantation alters mitral annular strains in a normal beating ovine heart preparation.

Stretching Skeletal Muscle: Chronic Muscle Lengthening Through Sarcomerogenesis

PloS One. 2012  |  Pubmed ID: 23049683

Skeletal muscle responds to passive overstretch through sarcomerogenesis, the creation and serial deposition of new sarcomere units. Sarcomerogenesis is critical to muscle function: It gradually re-positions the muscle back into its optimal operating regime. Animal models of immobilization, limb lengthening, and tendon transfer have provided significant insight into muscle adaptation in vivo. Yet, to date, there is no mathematical model that allows us to predict how skeletal muscle adapts to mechanical stretch in silico. Here we propose a novel mechanistic model for chronic longitudinal muscle growth in response to passive mechanical stretch. We characterize growth through a single scalar-valued internal variable, the serial sarcomere number. Sarcomerogenesis, the evolution of this variable, is driven by the elastic mechanical stretch. To analyze realistic three-dimensional muscle geometries, we embed our model into a nonlinear finite element framework. In a chronic limb lengthening study with a muscle stretch of 1.14, the model predicts an acute sarcomere lengthening from 3.09[Formula: see text]m to 3.51[Formula: see text]m, and a chronic gradual return to the initial sarcomere length within two weeks. Compared to the experiment, the acute model error was 0.00% by design of the model; the chronic model error was 2.13%, which lies within the rage of the experimental standard deviation. Our model explains, from a mechanistic point of view, why gradual multi-step muscle lengthening is less invasive than single-step lengthening. It also explains regional variations in sarcomere length, shorter close to and longer away from the muscle-tendon interface. Once calibrated with a richer data set, our model may help surgeons to prevent muscle overstretch and make informed decisions about optimal stretch increments, stretch timing, and stretch amplitudes. We anticipate our study to open new avenues in orthopedic and reconstructive surgery and enhance treatment for patients with ill proportioned limbs, tendon lengthening, tendon transfer, tendon tear, and chronically retracted muscles.

Computational Modelling of Electrocardiograms: Repolarisation and T-wave Polarity in the Human Heart

Computer Methods in Biomechanics and Biomedical Engineering. Oct, 2012  |  Pubmed ID: 23113842

For more than a century, electrophysiologists, cardiologists and engineers have studied the electrical activity of the human heart to better understand rhythm disorders and possible treatment options. Although the depolarisation sequence of the heart is relatively well characterised, the repolarisation sequence remains a subject of great controversy. Here, we study regional and temporal variations in both depolarisation and repolarisation using a finite element approach. We discretise the governing equations in time using an unconditionally stable implicit Euler backward scheme and in space using a consistently linearised Newton-Raphson-based finite element solver. Through systematic parameter-sensitivity studies, we establish a direct relation between a normal positive T-wave and the non-uniform distribution of the controlling parameter, which we have termed refractoriness. To establish a healthy baseline model, we calibrate the refractoriness using clinically measured action potential durations at different locations in the human heart. We demonstrate the potential of our model by comparing the computationally predicted and clinically measured depolarisation and repolarisation profiles across the left ventricle. The proposed framework allows us to explore how local action potential durations on the microscopic scale translate into global repolarisation sequences on the macroscopic scale. We anticipate that our calibrated human heart model can be widely used to explore cardiac excitation in health and disease. For example, our model can serve to identify optimal pacing sites in patients with heart failure and to localise optimal ablation sites in patients with cardiac fibrillation.

Evidence of Adaptive Mitral Leaflet Growth

Journal of the Mechanical Behavior of Biomedical Materials. Nov, 2012  |  Pubmed ID: 23159489

Ischemic mitral regurgitation is mitral insufficiency caused by myocardial infarction. Recent studies suggest that mitral leaflets have the potential to grow and reduce the degree of regurgitation. Leaflet growth has been associated with papillary muscle displacement, but role of annular dilation in leaflet growth is unclear. We tested the hypothesis that chronic leaflet stretch, induced by papillary muscle tethering and annular dilation, triggers chronic leaflet growth. To decipher the mechanisms that drive the growth process, we further quantified regional and directional variations of growth. Five adult sheep underwent coronary snare and marker placement on the left ventricle, papillary muscles, mitral annulus, and mitral leaflet. After eight days, we tightened the snares to create inferior myocardial infarction. We recorded marker coordinates at baseline, acutely (immediately post-infarction), and chronically (five weeks post-infarction). From these coordinates, we calculated acute and chronic changes in ventricular, papillary muscle, and annular geometry along with acute and chronic leaflet strains. Chronic left ventricular dilation of 17.15% (p<0.001) induced chronic posterior papillary muscle displacement of 13.49 mm (p=0.07). Chronic mitral annular area, commissural and septal-lateral distances increased by 32.50% (p=0.010), 14.11% (p=0.007), and 10.84% (p=0.010). Chronic area, circumferential, and radial growth were 15.57%, 5.91%, and 3.58%, with non-significant regional variations (p=0.868). Our study demonstrates that mechanical stretch, induced by annular dilation and papillary muscle tethering, triggers mitral leaflet growth. Understanding the mechanisms of leaflet adaptation may open new avenues to pharmacologically or surgically manipulate mechanotransduction pathways to augment mitral leaflet area and reduce the degree of regurgitation.

Stretching Skin: The Physiological Limit and Beyond

International Journal of Non-linear Mechanics. Oct, 2012  |  Pubmed ID: 23459410

The goal of this manuscript is to establish a novel computational model for skin to characterize its constitutive behavior when stretched within and beyond its physiological limits. Within the physiological regime, skin displays a reversible, highly nonlinear, stretch locking, and anisotropic behavior. We model these characteristics using a transversely isotropic chain network model composed of eight wormlike chains. Beyond the physiological limit, skin undergoes an irreversible area growth triggered through mechanical stretch. We model skin growth as a transversely isotropic process characterized through a single internal variable, the scalar-valued growth multiplier. To discretize the evolution of growth in time, we apply an unconditionally stable, implicit Euler backward scheme. To discretize it in space, we utilize the finite element method. For maximum algorithmic efficiency and optimal convergence, we suggest an inner Newton iteration to locally update the growth multiplier at each integration point. This iteration is embedded within an outer Newton iteration to globally update the deformation at each finite element node. To illustrate the characteristic features of skin growth, we first compare the two simple model problems of displacement- and force-driven growth. Then, we model the process of stretch-induced skin growth during tissue expansion. In particular, we compare the spatio-temporal evolution of stress, strain, and area gain for four commonly available tissue expander geometries. We believe that the proposed model has the potential to open new avenues in reconstructive surgery and rationalize critical process parameters in tissue expansion, such as expander geometry, expander size, expander placement, and inflation timing.

Characterisation of Electrophysiological Conduction in Cardiomyocyte Co-cultures Using Co-occurrence Analysis

Computer Methods in Biomechanics and Biomedical Engineering. 2013  |  Pubmed ID: 21970595

Cardiac arrhythmias are disturbances of the electrical conduction pattern in the heart with severe clinical implications. The damage of existing cells or the transplantation of foreign cells may disturb functional conduction pathways and may increase the risk of arrhythmias. Although these conduction disturbances are easily accessible with the human eye, there is no algorithmic method to extract quantitative features that quickly portray the conduction pattern. Here, we show that co-occurrence analysis, a well-established method for feature recognition in texture analysis, provides insightful quantitative information about the uniformity and the homogeneity of an excitation wave. As a first proof-of-principle, we illustrate the potential of co-occurrence analysis by means of conduction patterns of cardiomyocyte-fibroblast co-cultures, generated both in vitro and in silico. To characterise signal propagation in vitro, we perform a conduction analysis of co-cultured murine HL-1 cardiomyocytes and murine 3T3 fibroblasts using microelectrode arrays. To characterise signal propagation in silico, we establish a conduction analysis of co-cultured electrically active, conductive cardiomyocytes and non-conductive fibroblasts using the finite element method. Our results demonstrate that co-occurrence analysis is a powerful tool to create purity-conduction relationships and to quickly quantify conduction patterns in terms of co-occurrence energy and contrast. We anticipate this first preliminary study to be a starting point for more sophisticated analyses of different co-culture systems. In particular, in view of stem cell therapies, we expect co-occurrence analysis to provide valuable quantitative insight into the integration of foreign cells into a functional host system.

A Three-constituent Damage Model for Arterial Clamping in Computer-assisted Surgery

Biomechanics and Modeling in Mechanobiology. Jan, 2013  |  Pubmed ID: 22446834

Robotic surgery is an attractive, minimally invasive and high precision alternative to conventional surgical procedures. However, it lacks the natural touch and force feedback that allows the surgeon to control safe tissue manipulation. This is an important problem in standard surgical procedures such as clamping, which might induce severe tissue damage. In complex, heterogeneous, large deformation scenarios, the limits of the safe loading regime beyond which tissue damage occurs are unknown. Here, we show that a continuum damage model for arteries, implemented in a finite element setting, can help to predict arterial stiffness degradation and to identify critical loading regimes. The model consists of the main mechanical constituents of arterial tissue: extracellular matrix, collagen fibres and smooth muscle cells. All constituents are allowed to degrade independently in response to mechanical overload. To demonstrate the modularity and portability of the proposed model, we implement it in a commercial finite element programme, which allows to keep track of damage progression via internal variables. The loading history during arterial clamping is simulated through four successive steps, incorporating residual strains. The results of our first prototype simulation demonstrate significant regional variations in smooth muscle cell damage. In three additional steps, this damage is evaluated by simulating an isometric contraction experiment. The entire finite element simulation is finally compared with actual in vivo experiments. In the short term, our computational simulation tool can be useful to optimise surgical tools with the goal to minimise tissue damage. In the long term, it can potentially be used to inform computer-assisted surgery and identify safe loading regimes, in real time, to minimise tissue damage during robotic tissue manipulation.

Mathematical Modeling of Collagen Turnover in Biological Tissue

Journal of Mathematical Biology. Dec, 2013  |  Pubmed ID: 23129392

We present a theoretical and computational model for collagen turnover in soft biological tissues. Driven by alterations in the mechanical environment, collagen fiber bundles may undergo important chronic changes, characterized primarily by alterations in collagen synthesis and degradation rates. In particular, hypertension triggers an increase in tropocollagen synthesis and a decrease in collagen degradation, which lead to the well-documented overall increase in collagen content. These changes are the result of a cascade of events, initiated mainly by the endothelial and smooth muscle cells. Here, we represent these events collectively in terms of two internal variables, the concentration of growth factor TGF-β and tissue inhibitors of metalloproteinases TIMP. The upregulation of TGF-β increases the collagen density. The upregulation of TIMP also increases the collagen density through decreasing matrix metalloproteinase MMP. We establish a mathematical theory for mechanically-induced collagen turnover and introduce a computational algorithm for its robust and efficient solution. We demonstrate that our model can accurately predict the experimentally observed collagen increase in response to hypertension reported in literature. Ultimately, the model can serve as a valuable tool to predict the chronic adaptation of collagen content to restore the homeostatic equilibrium state in vessels with arbitrary micro-structure and geometry.

A Fully Implicit Finite Element Method for Bidomain Models of Cardiac Electromechanics

Computer Methods in Applied Mechanics and Engineering. Jan, 2013  |  Pubmed ID: 23175588

We propose a novel, monolithic, and unconditionally stable finite element algorithm for the bidomain-based approach to cardiac electromechanics. We introduce the transmembrane potential, the extracellular potential, and the displacement field as independent variables, and extend the common two-field bidomain formulation of electrophysiology to a three-field formulation of electromechanics. The intrinsic coupling arises from both excitation-induced contraction of cardiac cells and the deformation-induced generation of intra-cellular currents. The coupled reaction-diffusion equations of the electrical problem and the momentum balance of the mechanical problem are recast into their weak forms through a conventional isoparametric Galerkin approach. As a novel aspect, we propose a monolithic approach to solve the governing equations of excitation-contraction coupling in a fully coupled, implicit sense. We demonstrate the consistent linearization of the resulting set of non-linear residual equations. To assess the algorithmic performance, we illustrate characteristic features by means of representative three-dimensional initial-boundary value problems. The proposed algorithm may open new avenues to patient specific therapy design by circumventing stability and convergence issues inherent to conventional staggered solution schemes.

Mechanics of the Mitral Valve: a Critical Review, an in Vivo Parameter Identification, and the Effect of Prestrain

Biomechanics and Modeling in Mechanobiology. Oct, 2013  |  Pubmed ID: 23263365

Alterations in mitral valve mechanics are classical indicators of valvular heart disease, such as mitral valve prolapse, mitral regurgitation, and mitral stenosis. Computational modeling is a powerful technique to quantify these alterations, to explore mitral valve physiology and pathology, and to classify the impact of novel treatment strategies. The selection of the appropriate constitutive model and the choice of its material parameters are paramount to the success of these models. However, the in vivo parameters values for these models are unknown. Here, we identify the in vivo material parameters for three common hyperelastic models for mitral valve tissue, an isotropic one and two anisotropic ones, using an inverse finite element approach. We demonstrate that the two anisotropic models provide an excellent fit to the in vivo data, with local displacement errors in the sub-millimeter range. In a complementary sensitivity analysis, we show that the identified parameter values are highly sensitive to prestrain, with some parameters varying up to four orders of magnitude. For the coupled anisotropic model, the stiffness varied from 119,021 kPa at 0 % prestrain via 36 kPa at 30 % prestrain to 9 kPa at 60 % prestrain. These results may, at least in part, explain the discrepancy between previously reported ex vivo and in vivo measurements of mitral leaflet stiffness. We believe that our study provides valuable guidelines for modeling mitral valve mechanics, selecting appropriate constitutive models, and choosing physiologically meaningful parameter values. Future studies will be necessary to experimentally and computationally investigate prestrain, to verify its existence, to quantify its magnitude, and to clarify its role in mitral valve mechanics.

Systems-based Approaches Toward Wound Healing

Pediatric Research. Apr, 2013  |  Pubmed ID: 23314298

Wound healing in the pediatric patient is of utmost clinical and social importance because hypertrophic scarring can have aesthetic and psychological sequelae, from early childhood to late adolescence. Wound healing is a well-orchestrated reparative response affecting the damaged tissue at the cellular, tissue, organ, and system scales. Although tremendous progress has been made toward understanding wound healing at the individual temporal and spatial scales, its effects across the scales remain severely understudied and poorly understood. Here, we discuss the critical need for systems-based computational modeling of wound healing across the scales, from short-term to long-term and from small to large. We illustrate the state of the art in systems modeling by means of three key signaling mechanisms: oxygen tension-regulating angiogenesis and revascularization; transforming growth factor-β (TGF-β) kinetics controlling collagen deposition; and mechanical stretch stimulating cellular mitosis and extracellular matrix (ECM) remodeling. The complex network of biochemical and biomechanical signaling mechanisms and the multiscale character of the healing process make systems modeling an integral tool in exploring personalized strategies for wound repair. A better mechanistic understanding of wound healing in the pediatric patient could open new avenues in treating children with skin disorders such as birth defects, skin cancer, wounds, and burn injuries.

On the Mechanics of Continua with Boundary Energies and Growing Surfaces

Journal of the Mechanics and Physics of Solids. Jun, 2013  |  Pubmed ID: 23606760

Many biological systems are coated by thin films for protection, selective absorption, or transmembrane transport. A typical example is the mucous membrane covering the airways, the esophagus, and the intestine. Biological surfaces typically display a distinct mechanical behavior from the bulk; in particular, they may grow at different rates. Growth, morphological instabilities, and buckling of biological surfaces have been studied intensely by approximating the surface as a layer of finite thickness; however, growth has never been attributed to the surface itself. Here, we establish a theory of continua with boundary energies and growing surfaces of zero thickness in which the surface is equipped with its own potential energy and is allowed to grow independently of the bulk. In complete analogy to the kinematic equations, the balance equations, and the constitutive equations of a growing solid body, we derive the governing equations for a growing surface. We illustrate their spatial discretization using the finite element method, and discuss their consistent algorithmic linearization. To demonstrate the conceptual differences between volume and surface growth, we simulate the constrained growth of the inner layer of a cylindrical tube. Our novel approach towards continua with growing surfaces is capable of predicting extreme growth of the inner cylindrical surface, which more than doubles its initial area. The underlying algorithmic framework is robust and stable; it allows to predict morphological changes due to surface growth during the onset of buckling and beyond. The modeling of surface growth has immediate biomedical applications in the diagnosis and treatment of asthma, gastritis, obstructive sleep apnoea, and tumor invasion. Beyond biomedical applications, the scientific understanding of growth-induced morphological instabilities and surface wrinkling has important implications in material sciences, manufacturing, and microfabrication, with applications in soft lithography, metrology, and flexible electronics.

Growth on Demand: Reviewing the Mechanobiology of Stretched Skin

Journal of the Mechanical Behavior of Biomedical Materials. Dec, 2013  |  Pubmed ID: 23623569

Skin is a highly dynamic, autoregulated, living system that responds to mechanical stretch through a net gain in skin surface area. Tissue expansion uses the concept of controlled overstretch to grow extra skin for defect repair in situ. While the short-term mechanics of stretched skin have been studied intensely by testing explanted tissue samples ex vivo, we know very little about the long-term biomechanics and mechanobiology of living skin in vivo. Here we explore the long-term effects of mechanical stretch on the characteristics of living skin using a mathematical model for skin growth. We review the molecular mechanisms by which skin responds to mechanical loading and model their effects collectively in a single scalar-valued internal variable, the surface area growth. This allows us to adopt a continuum model for growing skin based on the multiplicative decomposition of the deformation gradient into a reversible elastic and an irreversible growth part. To demonstrate the inherent modularity of this approach, we implement growth as a user-defined constitutive subroutine into the general purpose implicit finite element program Abaqus/Standard. To illustrate the features of the model, we simulate the controlled area growth of skin in response to tissue expansion with multiple filling points in time. Our results demonstrate that the field theories of continuum mechanics can reliably predict the manipulation of thin biological membranes through mechanical overstretch. Our model could serve as a valuable tool to rationalize clinical process parameters such as expander geometry, expander size, filling volume, filling pressure, and inflation timing to minimize tissue necrosis and maximize patient comfort in plastic and reconstructive surgery. While initially developed for growing skin, our model can easily be generalized to arbitrary biological structures to explore the physiology and pathology of stretch-induced growth of other living systems such as hearts, arteries, bladders, intestines, ureters, muscles, and nerves.

Mechanics of the Mitral Annulus in Chronic Ischemic Cardiomyopathy

Annals of Biomedical Engineering. Oct, 2013  |  Pubmed ID: 23636575

Approximately one third of all patients undergoing open-heart surgery for repair of ischemic mitral regurgitation present with residual and recurrent mitral valve leakage upon follow up. A fundamental quantitative understanding of mitral valve remodeling following myocardial infarction may hold the key to improved medical devices and better treatment outcomes. Here we quantify mitral annular strains and curvature in nine sheep 5 ± 1 weeks after controlled inferior myocardial infarction of the left ventricle. We complement our marker-based mechanical analysis of the remodeling mitral valve by common clinical measures of annular geometry before and after the infarct. After 5 ± 1 weeks, the mitral annulus dilated in septal-lateral direction by 15.2% (p = 0.003) and in commissure-commissure direction by 14.2% (p < 0.001). The septal annulus dilated by 10.4% (p = 0.013) and the lateral annulus dilated by 18.4% (p < 0.001). Remarkably, in animals with large degree of mitral regurgitation and annular remodeling, the annulus dilated asymmetrically with larger distortions toward the lateral-posterior segment. Strain analysis revealed average tensile strains of 25% over most of the annulus with exception for the lateral-posterior segment, where tensile strains were 50% and higher. Annular dilation and peak strains were closely correlated to the degree of mitral regurgitation. A complementary relative curvature analysis revealed a homogenous curvature decrease associated with significant annular circularization. All curvature profiles displayed distinct points of peak curvature disturbing the overall homogenous pattern. These hinge points may be the mechanistic origin for the asymmetric annular deformation following inferior myocardial infarction. In the future, this new insight into the mechanism of asymmetric annular dilation may support improved device designs and possibly aid surgeons in reconstructing healthy annular geometry during mitral valve repair.

On the Effect of Prestrain and Residual Stress in Thin Biological Membranes

Journal of the Mechanics and Physics of Solids. Sep, 2013  |  Pubmed ID: 23976792

Understanding the difference between ex vivo and in vivo measurements is critical to interpret the load carrying mechanisms of living biological systems. For the past four decades, the ex vivo stiffness of thin biological membranes has been characterized using uniaxial and biaxial tests with remarkably consistent stiffness parameters, even across different species. Recently, the in vivo stiffness was characterized using combined imaging techniques and inverse finite element analyses. Surprisingly, ex vivo and in vivo stiffness values differed by up to three orders of magnitude. Here, for the first time, we explain this tremendous discrepancy using the concept of prestrain. We illustrate the mathematical modeling of prestrain in nonlinear continuum mechanics through the multiplicative decomposition of the total elastic deformation into prestrain-induced and load-induced parts. Using in vivo measured membrane kinematics and associated pressure recordings, we perform an inverse finite element analysis for different prestrain levels and show that the resulting membrane stiffness may indeed differ by four orders of magnitude depending on the prestrain level. Our study motivates the hypothesis that prestrain is important to position thin biological membranes in vivo into their optimal operating range, right at the transition point of the stiffening regime. Understanding the effect of prestrain has direct clinical implications in regenerative medicine, medical device design, and and tissue engineering of replacement constructs for thin biological membranes.

Generating Fibre Orientation Maps in Human Heart Models Using Poisson Interpolation

Computer Methods in Biomechanics and Biomedical Engineering. 2014  |  Pubmed ID: 23210529

Smoothly varying muscle fibre orientations in the heart are critical to its electrical and mechanical function. From detailed histological studies and diffusion tensor imaging, we now know that fibre orientations in humans vary gradually from approximately -70° in the outer wall to +80° in the inner wall. However, the creation of fibre orientation maps for computational analyses remains one of the most challenging problems in cardiac electrophysiology and cardiac mechanics. Here, we show that Poisson interpolation generates smoothly varying vector fields that satisfy a set of user-defined constraints in arbitrary domains. Specifically, we enforce the Poisson interpolation in the weak sense using a standard linear finite element algorithm for scalar-valued second-order boundary value problems and introduce the feature to be interpolated as a global unknown. User-defined constraints are then simply enforced in the strong sense as Dirichlet boundary conditions. We demonstrate that the proposed concept is capable of generating smoothly varying fibre orientations, quickly, efficiently and robustly, both in a generic bi-ventricular model and in a patient-specific human heart. Sensitivity analyses demonstrate that the underlying algorithm is conceptually able to handle both arbitrarily and uniformly distributed user-defined constraints; however, the quality of the interpolation is best for uniformly distributed constraints. We anticipate our algorithm to be immediately transformative to experimental and clinical settings, in which it will allow us to quickly and reliably create smooth interpolations of arbitrary fields from data-sets, which are sparse but uniformly distributed.

Growing Matter: a Review of Growth in Living Systems

Journal of the Mechanical Behavior of Biomedical Materials. Jan, 2014  |  Pubmed ID: 24239171

Living systems can grow, develop, adapt, and evolve. These phenomena are non-intuitive to traditional engineers and often difficult to understand. Yet, classical engineering tools can provide valuable insight into the mechanisms of growth in health and disease. Within the past decade, the concept of incompatible configurations has evolved as a powerful tool to model growing systems within the framework of nonlinear continuum mechanics. However, there is still a substantial disconnect between the individual disciplines, which explore the phenomenon of growth from different angles. Here we show that the nonlinear field theories of mechanics provide a unified concept to model finite growth by means of a single tensorial internal variable, the second order growth tensor. We review the literature and categorize existing growth models by means of two criteria: the microstructural appearance of growth, either isotropic or anisotropic; and the microenvironmental cues that drive the growth process, either chemical or mechanical. We demonstrate that this generic concept is applicable to a broad range of phenomena such as growing arteries, growing tumors, growing skin, growing airway walls, growing heart valve leaflets, growing skeletal muscle, growing plant stems, growing heart valve annuli, and growing cardiac muscle. The proposed approach has important biological and clinical applications in atherosclerosis, in-stent restenosis, tumor invasion, tissue expansion, chronic bronchitis, mitral regurgitation, limb lengthening, tendon tear, plant physiology, dilated and hypertrophic cardiomyopathy, and heart failure. Understanding the mechanisms of growth in these chronic conditions may open new avenues in medical device design and personalized medicine to surgically or pharmacologically manipulate development and alter, control, or revert disease progression.

On the Mechanics of Growing Thin Biological Membranes

Journal of the Mechanics and Physics of Solids. Feb, 2014  |  Pubmed ID: 24563551

Despite their seemingly delicate appearance, thin biological membranes fulfill various crucial roles in the human body and can sustain substantial mechanical loads. Unlike engineering structures, biological membranes are able to grow and adapt to changes in their mechanical environment. Finite element modeling of biological growth holds the potential to better understand the interplay of membrane form and function and to reliably predict the effects of disease or medical intervention. However, standard continuum elements typically fail to represent thin biological membranes efficiently, accurately, and robustly. Moreover, continuum models are typically cumbersome to generate from surface-based medical imaging data. Here we propose a computational model for finite membrane growth using a classical midsurface representation compatible with standard shell elements. By assuming elastic incompressibility and membrane-only growth, the model a priori satisfies the zero-normal stress condition. To demonstrate its modular nature, we implement the membrane growth model into the general-purpose non-linear finite element package Abaqus/Standard using the concept of user subroutines. To probe efficiently and robustness, we simulate selected benchmark examples of growing biological membranes under different loading conditions. To demonstrate the clinical potential, we simulate the functional adaptation of a heart valve leaflet in ischemic cardiomyopathy. We believe that our novel approach will be widely applicable to simulate the adaptive chronic growth of thin biological structures including skin membranes, mucous membranes, fetal membranes, tympanic membranes, corneoscleral membranes, and heart valve membranes. Ultimately, our model can be used to identify diseased states, predict disease evolution, and guide the design of interventional or pharmaceutic therapies to arrest or revert disease progression.

Application of Finite Element Modeling to Optimize Flap Design with Tissue Expansion

Plastic and Reconstructive Surgery. Oct, 2014  |  Pubmed ID: 24945952

Tissue expansion is a widely used technique to create skin flaps for the correction of sizable defects in reconstructive plastic surgery. Major complications following the inset of expanded flaps include breakdown and uncontrolled scarring secondary to excessive tissue tension. Although it is recognized that mechanical forces may significantly impact the success of defect repair with tissue expansion, a mechanical analysis of tissue stresses has not previously been attempted. Such analyses have the potential to optimize flap design preoperatively.

A Mechanical Model Predicts Morphological Abnormalities in the Developing Human Brain

Scientific Reports. Jul, 2014  |  Pubmed ID: 25008163

The developing human brain remains one of the few unsolved mysteries of science. Advancements in developmental biology, neuroscience, and medical imaging have brought us closer than ever to understand brain development in health and disease. However, the precise role of mechanics throughout this process remains underestimated and poorly understood. Here we show that mechanical stretch plays a crucial role in brain development. Using the nonlinear field theories of mechanics supplemented by the theory of finite growth, we model the human brain as a living system with a morphogenetically growing outer surface and a stretch-driven growing inner core. This approach seamlessly integrates the two popular but competing hypotheses for cortical folding: axonal tension and differential growth. We calibrate our model using magnetic resonance images from very preterm neonates. Our model predicts that deviations in cortical growth and thickness induce morphological abnormalities. Using the gyrification index, the ratio between the total and exposed surface area, we demonstrate that these abnormalities agree with the classical pathologies of lissencephaly and polymicrogyria. Understanding the mechanisms of cortical folding in the developing human brain has direct implications in the diagnostics and treatment of neurological disorders, including epilepsy, schizophrenia, and autism.

Characterization of Living Skin Using Multi-view Stereo and Isogeometric Analysis

Acta Biomaterialia. Nov, 2014  |  Pubmed ID: 25016279

Skin is our interface with the outside world. In its natural environment, it displays unique mechanical characteristics, such as prestretch and growth. While there is a general agreement on the physiological importance of these features, they remain poorly characterized, mainly because they are difficult to access with standard laboratory techniques. Here we present a new, inexpensive technique to characterize living skin using multi-view stereo and isogeometric analysis. Based on easy-to-create hand-held camera images, we quantify prestretch, deformation and growth in a controlled porcine model of chronic skin expansion. Over a period of 5 weeks, we gradually inflate an implanted tissue expander, take weekly photographs of the experimental scene, reconstruct the geometry from a tattooed surface grid and create parametric representations of the skin surface. After 5 weeks of expansion, our method reveals an average area prestretch of 1.44, an average area stretch of 1.87 and an average area growth of 2.25. Area prestretch is maximal in the ventral region with a value of 2.37, whereas area stretch and area growth are maximal above the center of the expander, with values of 4.05 and 4.81, respectively. Our study has immediate impact on understanding living skin to optimize treatment planning and decision making in plastic and reconstructive surgery. Beyond these direct implications, our experimental design has broad applications in clinical research and basic sciences: it serves as a simple, robust, low cost, easy-to-use tool to reconstruct living membranes, which are difficult to characterize in a conventional laboratory setup.

The Role of Mechanics During Brain Development

Journal of the Mechanics and Physics of Solids. Dec, 2014  |  Pubmed ID: 25202162

Convolutions are a classical hallmark of most mammalian brains. Brain surface morphology is often associated with intelligence and closely correlated to neurological dysfunction. Yet, we know surprisingly little about the underlying mechanisms of cortical folding. Here we identify the role of the key anatomic players during the folding process: cortical thickness, stiffness, and growth. To establish estimates for the critical time, pressure, and the wavelength at the onset of folding, we derive an analytical model using the Föppl-von-Kármán theory. Analytical modeling provides a quick first insight into the critical conditions at the onset of folding, yet it fails to predict the evolution of complex instability patterns in the post-critical regime. To predict realistic surface morphologies, we establish a computational model using the continuum theory of finite growth. Computational modeling not only confirms our analytical estimates, but is also capable of predicting the formation of complex surface morphologies with asymmetric patterns and secondary folds. Taken together, our analytical and computational models explain why larger mammalian brains tend to be more convoluted than smaller brains. Both models provide mechanistic interpretations of the classical malformations of lissencephaly and polymicrogyria. Understanding the process of cortical folding in the mammalian brain has direct implications on the diagnostics of neurological disorders including severe retardation, epilepsy, schizophrenia, and autism.

The Generalized Hill Model: A Kinematic Approach Towards Active Muscle Contraction

Journal of the Mechanics and Physics of Solids. Dec, 2014  |  Pubmed ID: 25221354

Excitation-contraction coupling is the physiological process of converting an electrical stimulus into a mechanical response. In muscle, the electrical stimulus is an action potential and the mechanical response is active contraction. The classical Hill model characterizes muscle contraction though one contractile element, activated by electrical excitation, and two non-linear springs, one in series and one in parallel. This rheology translates into an additive decomposition of the total stress into a passive and an active part. Here we supplement this additive decomposition of the stress by a multiplicative decomposition of the deformation gradient into a passive and an active part. We generalize the one-dimensional Hill model to the three-dimensional setting and constitutively define the passive stress as a function of the total deformation gradient and the active stress as a function of both the total deformation gradient and its active part. We show that this novel approach combines the features of both the classical stress-based Hill model and the recent active-strain models. While the notion of active stress is rather phenomenological in nature, active strain is micro-structurally motivated, physically measurable, and straightforward to calibrate. We demonstrate that our model is capable of simulating excitation-contraction coupling in cardiac muscle with its characteristic features of wall thickening, apical lift, and ventricular torsion.

Computational Modeling of Skin: Using Stress Profiles As Predictor for Tissue Necrosis in Reconstructive Surgery

Computers & Structures. Sep, 2014  |  Pubmed ID: 25225454

Local skin flaps have revolutionized reconstructive surgery. Mechanical loading is critical for flap survival: Excessive tissue tension reduces blood supply and induces tissue necrosis. However, skin flaps have never been analyzed mechanically. Here we explore the stress profiles of two common flap designs, direct advancement flaps and double back-cut flaps. Our simulations predict a direct correlation between regions of maximum stress and tissue necrosis. This suggests that elevated stress could serve as predictor for flap failure. Our model is a promising step towards computer-guided reconstructive surgery with the goal to minimize stress, accelerate healing, minimize scarring, and optimize tissue use.

The Living Heart Project: A Robust and Integrative Simulator for Human Heart Function

European Journal of Mechanics. A, Solids. Nov, 2014  |  Pubmed ID: 25267880

The heart is not only our most vital, but also our most complex organ: Precisely controlled by the interplay of electrical and mechanical fields, it consists of four chambers and four valves, which act in concert to regulate its filling, ejection, and overall pump function. While numerous computational models exist to study either the electrical or the mechanical response of its individual chambers, the integrative electro-mechanical response of the whole heart remains poorly understood. Here we present a proof-of-concept simulator for a four-chamber human heart model created from computer topography and magnetic resonance images. We illustrate the governing equations of excitation-contraction coupling and discretize them using a single, unified finite element environment. To illustrate the basic features of our model, we visualize the electrical potential and the mechanical deformation across the human heart throughout its cardiac cycle. To compare our simulation against common metrics of cardiac function, we extract the pressure-volume relationship and show that it agrees well with clinical observations. Our prototype model allows us to explore and understand the key features, physics, and technologies to create an integrative, predictive model of the living human heart. Ultimately, our simulator will open opportunities to probe landscapes of clinical parameters, and guide device design and treatment planning in cardiac diseases such as stenosis, regurgitation, or prolapse of the aortic, pulmonary, tricuspid, or mitral valve.

Modeling and Simulation of Viscous Electro-Active Polymers

European Journal of Mechanics. A, Solids. Nov, 2014  |  Pubmed ID: 25267881

Electro-active materials are capable of undergoing large deformation when stimulated by an electric field. They can be divided into electronic and ionic electro-active polymers (EAPs) depending on their actuation mechanism based on their composition. We consider electronic EAPs, for which attractive Coulomb forces or local re-orientation of polar groups cause a bulk deformation. Many of these materials exhibit pronounced visco-elastic behavior. Here we show the development and implementation of a constitutive model, which captures the influence of the electric field on the visco-elastic response within a geometrically non-linear finite element framework. The electric field affects not only the equilibrium part of the strain energy function, but also the viscous part. To adopt the familiar additive split of the strain from the small strain setting, we formulate the governing equations in the logarithmic strain space and additively decompose the logarithmic strain into elastic and viscous parts. We show that the incorporation of the electric field in the viscous response significantly alters the relaxation and hysteresis behavior of the model. Our parametric study demonstrates that the model is sensitive to the choice of the electro-viscous coupling parameters. We simulate several actuator structures to illustrate the performance of the method in typical relaxation and creep scenarios. Our model could serve as a design tool for micro-electro-mechanical systems, microfluidic devices, and stimuli-responsive gels such as artificial skin, tactile displays, or artificial muscle.

Computational Modeling of Hypertensive Growth in the Human Carotid Artery

Computational Mechanics. Jun, 2014  |  Pubmed ID: 25342868

Arterial hypertension is a chronic medical condition associated with an elevated blood pressure. Chronic arterial hypertension initiates a series of events, which are known to collectively initiate arterial wall thickening. However, the correlation between macrostructural mechanical loading, microstructural cellular changes, and macrostructural adaptation remains unclear. Here, we present a microstructurally motivated computational model for chronic arterial hypertension through smooth muscle cell growth. To model growth, we adopt a classical concept based on the multiplicative decomposition of the deformation gradient into an elastic part and a growth part. Motivated by clinical observations, we assume that the driving force for growth is the stretch sensed by the smooth muscle cells. We embed our model into a finite element framework, where growth is stored locally as an internal variable. First, to demonstrate the features of our model, we investigate the effects of hypertensive growth in a real human carotid artery. Our results agree nicely with experimental data reported in the literature both qualitatively and quantitatively.

Human Pluripotent Stem Cell Tools for Cardiac Optogenetics

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference. 2014  |  Pubmed ID: 25571406

It is likely that arrhythmias should be avoided for therapies based on human pluripotent stem cell (hPSC)-derived cardiomyocytes (CM) to be effective. Towards achieving this goal, we introduced light-activated channelrhodopsin-2 (ChR2), a cation channel activated with 480 nm light, into human embryonic stem cells (hESC). By using in vitro approaches, hESC-CM are able to be activated with light. ChR2 is stably transduced into undifferentiated hESC via a lentiviral vector. Via directed differentiation, hESC(ChR2)-CM are produced and subjected to optical stimulation. hESC(ChR2)-CM respond to traditional electrical stimulation and produce similar contractility features as their wild-type counterparts but only hESC(ChR2)-CM can be activated by optical stimulation. Here it is shown that a light sensitive protein can enable in vitro optical control of hESC-CM and that this activation occurs optimally above specific light stimulation intensity and pulse width thresholds. For future therapy, in vivo optical stimulation along with optical inhibition could allow for acute synchronization of implanted hPSC-CM with patient cardiac rhythms.

The Emergence of Extracellular Matrix Mechanics and Cell Traction Forces As Important Regulators of Cellular Self-organization

Biomechanics and Modeling in Mechanobiology. Jan, 2015  |  Pubmed ID: 24718853

Physical cues play a fundamental role in a wide range of biological processes, such as embryogenesis, wound healing, tumour invasion and connective tissue morphogenesis. Although it is well known that during these processes, cells continuously interact with the local extracellular matrix (ECM) through cell traction forces, the role of these mechanical interactions on large scale cellular and matrix organization remains largely unknown. In this study, we use a simple theoretical model to investigate cellular and matrix organization as a result of mechanical feedback signals between cells and the surrounding ECM. The model includes bi-directional coupling through cellular traction forces to deform the ECM and through matrix deformation to trigger cellular migration. In addition, we incorporate the mechanical contribution of matrix fibres and their reorganization by the cells. We show that a group of contractile cells will self-polarize at a large scale, even in homogeneous environments. In addition, our simulations mimic the experimentally observed alignment of cells in the direction of maximum stiffness and the building up of tension as a consequence of cell and fibre reorganization. Moreover, we demonstrate that cellular organization is tightly linked to the mechanical feedback loop between cells and matrix. Cells with a preference for stiff environments have a tendency to form chains, while cells with a tendency for soft environments tend to form clusters. The model presented here illustrates the potential of simple physical cues and their impact on cellular self-organization. It can be used in applications where cell-matrix interactions play a key role, such as in the design of tissue engineering scaffolds and to gain a basic understanding of pattern formation in organogenesis or tissue regeneration.

Use It or Lose It: Multiscale Skeletal Muscle Adaptation to Mechanical Stimuli

Biomechanics and Modeling in Mechanobiology. Apr, 2015  |  Pubmed ID: 25199941

Skeletal muscle undergoes continuous turnover to adapt to changes in its mechanical environment. Overload increases muscle mass, whereas underload decreases muscle mass. These changes are correlated with, and enabled by, structural alterations across the molecular, subcellular, cellular, tissue, and organ scales. Despite extensive research on muscle adaptation at the individual scales, the interaction of the underlying mechanisms across the scales remains poorly understood. Here, we present a thorough review and a broad classification of multiscale muscle adaptation in response to a variety of mechanical stimuli. From this classification, we suggest that a mathematical model for skeletal muscle adaptation should include the four major stimuli, overstretch, understretch, overload, and underload, and the five key players in skeletal muscle adaptation, myosin heavy chain isoform, serial sarcomere number, parallel sarcomere number, pennation angle, and extracellular matrix composition. Including this information in multiscale computational models of muscle will shape our understanding of the interacting mechanisms of skeletal muscle adaptation across the scales. Ultimately, this will allow us to rationalize the design of exercise and rehabilitation programs, and improve the long-term success of interventional treatment in musculoskeletal disease.

On High Heels and Short Muscles: a Multiscale Model for Sarcomere Loss in the Gastrocnemius Muscle

Journal of Theoretical Biology. Jan, 2015  |  Pubmed ID: 25451524

High heels are a major source of chronic lower limb pain. Yet, more than one third of all women compromise health for looks and wear high heels on a daily basis. Changing from flat footwear to high heels induces chronic muscle shortening associated with discomfort, fatigue, reduced shock absorption, and increased injury risk. However, the long-term effects of high-heeled footwear on the musculoskeletal kinematics of the lower extremities remain poorly understood. Here we create a multiscale computational model for chronic muscle adaptation to characterize the acute and chronic effects of global muscle shortening on local sarcomere lengths. We perform a case study of a healthy female subject and show that raising the heel by 13cm shortens the gastrocnemius muscle by 5% while the Achilles tendon remains virtually unaffected. Our computational simulation indicates that muscle shortening displays significant regional variations with extreme values of 22% in the central gastrocnemius. Our model suggests that the muscle gradually adjusts to its new functional length by a chronic loss of sarcomeres in series. Sarcomere loss varies significantly across the muscle with an average loss of 9%, virtually no loss at the proximal and distal ends, and a maximum loss of 39% in the central region. These changes reposition the remaining sarcomeres back into their optimal operating regime. Computational modeling of chronic muscle shortening provides a valuable tool to shape our understanding of the underlying mechanisms of muscle adaptation. Our study could open new avenues in orthopedic surgery and enhance treatment for patients with muscle contracture caused by other conditions than high heel wear such as paralysis, muscular atrophy, and muscular dystrophy.

Multi-view Stereo Analysis Reveals Anisotropy of Prestrain, Deformation, and Growth in Living Skin

Biomechanics and Modeling in Mechanobiology. Oct, 2015  |  Pubmed ID: 25634600

Skin expansion delivers newly grown skin that maintains histological and mechanical features of the original tissue. Although it is the gold standard for cutaneous defect correction today, the underlying mechanisms remain poorly understood. Here we present a novel technique to quantify anisotropic prestrain, deformation, and growth in a porcine skin expansion model. Building on our recently proposed method, we combine two novel technologies, multi-view stereo and isogeometric analysis, to characterize skin kinematics: Upon explantation, a unit square retracts ex vivo to a square of average dimensions of [Formula: see text]. Upon expansion, the unit square deforms in vivo into a rectangle of average dimensions of [Formula: see text]. Deformations are larger parallel than perpendicular to the dorsal midline suggesting that skin responds anisotropically with smaller deformations along the skin tension lines. Upon expansion, the patch grows in vivo by [Formula: see text] with respect to the explanted, unexpanded state. Growth is larger parallel than perpendicular to the midline, suggesting that elevated stretch activates mechanotransduction pathways to stimulate tissue growth. The proposed method provides a powerful tool to characterize the kinematics of living skin. Our results shed light on the mechanobiology of skin and help us to better understand and optimize clinically relevant procedures in plastic and reconstructive surgery.

Mechanics of the Brain: Perspectives, Challenges, and Opportunities

Biomechanics and Modeling in Mechanobiology. Oct, 2015  |  Pubmed ID: 25716305

The human brain is the continuous subject of extensive investigation aimed at understanding its behavior and function. Despite a clear evidence that mechanical factors play an important role in regulating brain activity, current research efforts focus mainly on the biochemical or electrophysiological activity of the brain. Here, we show that classical mechanical concepts including deformations, stretch, strain, strain rate, pressure, and stress play a crucial role in modulating both brain form and brain function. This opinion piece synthesizes expertise in applied mathematics, solid and fluid mechanics, biomechanics, experimentation, material sciences, neuropathology, and neurosurgery to address today's open questions at the forefront of neuromechanics. We critically review the current literature and discuss challenges related to neurodevelopment, cerebral edema, lissencephaly, polymicrogyria, hydrocephaly, craniectomy, spinal cord injury, tumor growth, traumatic brain injury, and shaken baby syndrome. The multi-disciplinary analysis of these various phenomena and pathologies presents new opportunities and suggests that mechanical modeling is a central tool to bridge the scales by synthesizing information from the molecular via the cellular and tissue all the way to the organ level.

Mechanical Properties of Gray and White Matter Brain Tissue by Indentation

Journal of the Mechanical Behavior of Biomedical Materials. Jun, 2015  |  Pubmed ID: 25819199

The mammalian brain is composed of an outer layer of gray matter, consisting of cell bodies, dendrites, and unmyelinated axons, and an inner core of white matter, consisting primarily of myelinated axons. Recent evidence suggests that microstructural differences between gray and white matter play an important role during neurodevelopment. While brain tissue as a whole is rheologically well characterized, the individual features of gray and white matter remain poorly understood. Here we quantify the mechanical properties of gray and white matter using a robust, reliable, and repeatable method, flat-punch indentation. To systematically characterize gray and white matter moduli for varying indenter diameters, loading rates, holding times, post-mortem times, and locations we performed a series of n=192 indentation tests. We found that indenting thick, intact coronal slices eliminates the common challenges associated with small specimens: it naturally minimizes boundary effects, dehydration, swelling, and structural degradation. When kept intact and hydrated, brain slices maintained their mechanical characteristics with standard deviations as low as 5% throughout the entire testing period of five days post mortem. White matter, with an average modulus of 1.89 5kPa ± 0.592 kPa, was on average 39% stiffer than gray matter, p<0.01, with an average modulus of 1.389 kPa ± 0.289 kPa, and displayed larger regional variations. It was also more viscous than gray matter and responded less rapidly to mechanical loading. Understanding the rheological differences between gray and white matter may have direct implications on diagnosing and understanding the mechanical environment in neurodevelopment and neurological disorders.

Patient-Specific Airway Wall Remodeling in Chronic Lung Disease

Annals of Biomedical Engineering. Oct, 2015  |  Pubmed ID: 25821112

Chronic lung disease affects more than a quarter of the adult population; yet, the mechanics of the airways are poorly understood. The pathophysiology of chronic lung disease is commonly characterized by mucosal growth and smooth muscle contraction of the airways, which initiate an inward folding of the mucosal layer and progressive airflow obstruction. Since the degree of obstruction is closely correlated with the number of folds, mucosal folding has been extensively studied in idealized circular cross sections. However, airflow obstruction has never been studied in real airway geometries; the behavior of imperfect, non-cylindrical, continuously branching airways remains unknown. Here we model the effects of chronic lung disease using the nonlinear field theories of mechanics supplemented by the theory of finite growth. We perform finite element analysis of patient-specific Y-branch segments created from magnetic resonance images. We demonstrate that the mucosal folding pattern is insensitive to the specific airway geometry, but that it critically depends on the mucosal and submucosal stiffness, thickness, and loading mechanism. Our results suggests that patient-specific airway models with inherent geometric imperfections are more sensitive to obstruction than idealized circular models. Our models help to explain the pathophysiology of airway obstruction in chronic lung disease and hold promise to improve the diagnostics and treatment of asthma, bronchitis, chronic obstructive pulmonary disease, and respiratory failure.

Emerging Brain Morphologies from Axonal Elongation

Annals of Biomedical Engineering. Jul, 2015  |  Pubmed ID: 25824370

Understanding the characteristic morphology of our brain remains a challenging, yet important task in human evolution, developmental biology, and neurosciences. Mathematical modeling shapes our understanding of cortical folding and provides functional relations between cortical wavelength, thickness, and stiffness. Yet, current mathematical models are phenomenologically isotropic and typically predict non-physiological, periodic folding patterns. Here we establish a mechanistic model for cortical folding, in which macroscopic changes in white matter volume are a natural consequence of microscopic axonal growth. To calibrate our model, we consult axon elongation experiments in chick sensory neurons. We demonstrate that a single parameter, the axonal growth rate, explains a wide variety of in vitro conditions including immediate axonal thinning and gradual thickness restoration. We embed our axonal growth model into a continuum model for brain development using axonal orientation distributions motivated by diffusion spectrum imaging. Our simulations suggest that white matter anisotropy-as an emergent property from directional axonal growth-intrinsically induces symmetry breaking, and predicts more physiological, less regular morphologies with regionally varying gyral wavelengths and sulcal depths. Mechanistic modeling of brain development could establish valuable relationships between brain connectivity, brain anatomy, and brain function.

Segmental Aortic Stiffening Contributes to Experimental Abdominal Aortic Aneurysm Development

Circulation. May, 2015  |  Pubmed ID: 25904646

Stiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined.

Human Cardiac Function Simulator for the Optimal Design of a Novel Annuloplasty Ring with a Sub-valvular Element for Correction of Ischemic Mitral Regurgitation

Cardiovascular Engineering and Technology. Jun, 2015  |  Pubmed ID: 25984248

Ischemic mitral regurgitation is associated with substantial risk of death. We sought to: (1) detail significant recent improvements to the Dassault Systèmes human cardiac function simulator (HCFS); (2) use the HCFS to simulate normal cardiac function as well as pathologic function in the setting of posterior left ventricular (LV) papillary muscle infarction; and (3) debut our novel device for correction of ischemic mitral regurgitation. We synthesized two recent studies of human myocardial mechanics. The first study presented the robust and integrative finite element HCFS. Its primary limitation was its poor diastolic performance with an LV ejection fraction below 20% caused by overly stiff ex vivo porcine tissue parameters. The second study derived improved diastolic myocardial material parameters using in vivo MRI data from five normal human subjects. We combined these models to simulate ischemic mitral regurgitation by computationally infarcting an LV region including the posterior papillary muscle. Contact between our novel device and the mitral valve apparatus was simulated using Dassault Systèmes SIMULIA software. Incorporating improved cardiac geometry and diastolic myocardial material properties in the HCFS resulted in a realistic LV ejection fraction of 55%. Simulating infarction of posterior papillary muscle caused regurgitant mitral valve mechanics. Implementation of our novel device corrected valve dysfunction. Improvements in the current study to the HCFS permit increasingly accurate study of myocardial mechanics. The first application of this simulator to abnormal human cardiac function suggests that our novel annuloplasty ring with a sub-valvular element will correct ischemic mitral regurgitation.

Physical Biology of Human Brain Development

Frontiers in Cellular Neuroscience. 2015  |  Pubmed ID: 26217183

Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view toward surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular events associated with extreme radial and tangential expansion. We demonstrate how computational modeling of differential growth can bridge the scales-from phenomena on the cellular level toward form and function on the organ level-to make quantitative, personalized predictions. Physics-based models can quantify cortical stresses, identify critical folding conditions, rationalize pattern selection, and predict gyral wavelengths and gyrification indices. We illustrate that physical forces can explain cortical malformations as emergent properties of developmental disorders. Combining biology and physics holds promise to advance our understanding of human brain development and enable early diagnostics of cortical malformations with the ultimate goal to improve treatment of neurodevelopmental disorders including epilepsy, autism spectrum disorders, and schizophrenia.

Isogeometric Kirchhoff-Love Shell Formulations for Biological Membranes

Computer Methods in Applied Mechanics and Engineering. Aug, 2015  |  Pubmed ID: 26251556

Computational modeling of thin biological membranes can aid the design of better medical devices. Remarkable biological membranes include skin, alveoli, blood vessels, and heart valves. Isogeometric analysis is ideally suited for biological membranes since it inherently satisfies the C(1)-requirement for Kirchhoff-Love kinematics. Yet, current isogeometric shell formulations are mainly focused on linear isotropic materials, while biological tissues are characterized by a nonlinear anisotropic stress-strain response. Here we present a thin shell formulation for thin biological membranes. We derive the equilibrium equations using curvilinear convective coordinates on NURBS tensor product surface patches. We linearize the weak form of the generic linear momentum balance without a particular choice of a constitutive law. We then incorporate the constitutive equations that have been designed specifically for collagenous tissues. We explore three common anisotropic material models: Mooney-Rivlin, May Newmann-Yin, and Gasser-Ogden-Holzapfel. Our work will allow scientists in biomechanics and mechanobiology to adopt the constitutive equations that have been developed for solid three-dimensional soft tissues within the framework of isogeometric thin shell analysis.

Systems Biology and Mechanics of Growth

Wiley Interdisciplinary Reviews. Systems Biology and Medicine. Nov-Dec, 2015  |  Pubmed ID: 26352286

In contrast to inert systems, living biological systems have the advantage to adapt to their environment through growth and evolution. This transfiguration is evident during embryonic development, when the predisposed need to grow allows form to follow function. Alterations in the equilibrium state of biological systems breed disease and mutation in response to environmental triggers. The need to characterize the growth of biological systems to better understand these phenomena has motivated the continuum theory of growth and stimulated the development of computational tools in systems biology. Biological growth in development and disease is increasingly studied using the framework of morphoelasticity. Here, we demonstrate the potential for morphoelastic simulations through examples of volume, area, and length growth, inspired by tumor expansion, chronic bronchitis, brain development, intestine formation, plant shape, and myopia. We review the systems biology of living systems in light of biochemical and optical stimuli and classify different types of growth to facilitate the design of growth models for various biological systems within this generic framework. Exploring the systems biology of growth introduces a new venue to control and manipulate embryonic development, disease progression, and clinical intervention.

Modeling Tissue Expansion with Isogeometric Analysis: Distinguishing True Skin Growth from Elastic Skin Stretch

Plastic and Reconstructive Surgery. Oct, 2015  |  Pubmed ID: 26397523

Secondary Instabilities Modulate Cortical Complexity in the Mammalian Brain

Philosophical Magazine (Abingdon, England). 2015  |  Pubmed ID: 26523123

Disclosing the origin of convolutions in the mammalian brain remains a scientific challenge. Primary folds form before we are born: they are static, well defined, and highly preserved across individuals. Secondary folds occur and disappear throughout our entire life time: they are dynamic, irregular, and highly variable among individuals. While extensive research has improved our understanding of primary folding in the mammalian brain, secondary folding remains understudied and poorly understood. Here, we show that secondary instabilities can explain the increasing complexity of our brain surface as we age. Using the nonlinear field theories of mechanics supplemented by the theory of finite growth, we explore the critical conditions for secondary instabilities. We show that with continuing growth, our brain surface continues to bifurcate into increasingly complex morphologies. Our results suggest that even small geometric variations can have a significant impact on surface morphogenesis. Secondary bifurcations, and with them morphological changes during childhood and adolescence, are closely associated with the formation and loss of neuronal connections. Understanding the correlation between neuronal connectivity, cortical thickness, surface morphology, and ultimately behavior, could have important implications on the diagnostics, classification, and treatment of neurological disorders.

Tau-ism: The Yin and Yang of Microtubule Sliding, Detachment, and Rupture

Biophysical Journal. Dec, 2015  |  Pubmed ID: 26636932

Period-doubling and Period-tripling in Growing Bilayered Systems

Philosophical Magazine (Abingdon, England). 2015  |  Pubmed ID: 26752977

Growing layers on elastic substrates are capable of creating a wide variety of surface morphologies. Moderate growth generates a regular pattern of sinusoidal wrinkles with a homogeneous energy distribution. While the critical conditions for periodic wrinkling have been extensively studied, the rich pattern formation beyond this first instability point remains poorly understood. Here we show that upon continuing growth, the energy progressively localizes and new complex morphologies emerge. Previous studies have often overlooked these secondary bifurcations; they have focused on large stiffness ratios between layer and substrate, where primary instabilities occur early, long before secondary instabilities emerge. We demonstrate that secondary bifurcations are particularly critical in the low stiffness ratio regime, where the critical conditions for primary and secondary instabilities move closer together. Amongst all possible secondary bifurcations, the mode of period-doubling plays a central role - it is energetically favorable over all other modes. Yet, we can numerically suppress period-doubling, by choosing boundary conditions, which favor alternative higher order modes. Our results suggest that in the low stiffness regime, pattern formation is highly sensitive to small imperfections: surface morphologies emerge rapidly, change spontaneously, and quickly become immensely complex. This is a common paradigm in developmental biology. Our results have significantly applications in the morphogenesis of living systems where growth is progressive and stiffness ratios are low.

The Incompatibility of Living Systems: Characterizing Growth-Induced Incompatibilities in Expanded Skin

Annals of Biomedical Engineering. May, 2016  |  Pubmed ID: 26416721

Skin expansion is a common surgical technique to correct large cutaneous defects. Selecting a successful expansion protocol is solely based on the experience and personal preference of the operating surgeon. Skin expansion could be improved by predictive computational simulations. Towards this goal, we model skin expansion using the continuum framework of finite growth. This approach crucially relies on the concept of incompatible configurations. However, aside from the classical opening angle experiment, our current understanding of growth-induced incompatibilities remains rather vague. Here we visualize and characterize incompatibilities in living systems using skin expansion in a porcine model: We implanted and inflated two expanders, crescent, and spherical, and filled them to 225 cc throughout a period of 21 days. To quantify the residual strains developed during this period, we excised the expanded skin patches and subdivided them into smaller pieces. Skin growth averaged 1.17 times the original area for the spherical and 1.10 for the crescent expander, and displayed significant regional variations. When subdivided into smaller pieces, the grown skin patches retracted heterogeneously and confirmed the existence of incompatibilities. Understanding skin growth through mechanical stretch will allow surgeons to improve-and ultimately personalize-preoperative treatment planning in plastic and reconstructive surgery.

Response to Letters Regarding Article, "Segmental Aortic Stiffening Contributes to Experimental Abdominal Aortic Aneurysm Development"

Circulation. Jan, 2016  |  Pubmed ID: 26719393

Generating Purkinje Networks in the Human Heart

Journal of Biomechanics. Aug, 2016  |  Pubmed ID: 26748729

The Purkinje network is an integral part of the excitation system in the human heart. Yet, to date, there is no in vivo imaging technique to accurately reconstruct its geometry and structure. Computational modeling of the Purkinje network is increasingly recognized as an alternative strategy to visualize, simulate, and understand the role of the Purkinje system. However, most computational models either have to be generated manually, or fail to smoothly cover the irregular surfaces inside the left and right ventricles. Here we present a new algorithm to reliably create robust Purkinje networks within the human heart. We made the source code of this algorithm freely available online. Using Monte Carlo simulations, we demonstrate that the fractal tree algorithm with our new projection method generates denser and more compact Purkinje networks than previous approaches on irregular surfaces. Under similar conditions, our algorithm generates a network with 1219±61 branches, three times more than a conventional algorithm with 419±107 branches. With a coverage of 11±3mm, the surface density of our new Purkije network is twice as dense as the conventional network with 22±7mm. To demonstrate the importance of a dense Purkinje network in cardiac electrophysiology, we simulated three cases of excitation: with our new Purkinje network, with left-sided Purkinje network, and without Purkinje network. Simulations with our new Purkinje network predicted more realistic activation sequences and activation times than simulations without. Six-lead electrocardiograms of the three case studies agreed with the clinical electrocardiograms under physiological conditions, under pathological conditions of right bundle branch block, and under pathological conditions of trifascicular block. Taken together, our results underpin the importance of the Purkinje network in realistic human heart simulations. Human heart modeling has the potential to support the design of personalized strategies for single- or bi-ventricular pacing, radiofrequency ablation, and cardiac defibrillation with the common goal to restore a normal heart rhythm.

Using 3D Printing to Create Personalized Brain Models for Neurosurgical Training and Preoperative Planning

World Neurosurgery. Jun, 2016  |  Pubmed ID: 26924117

Three-dimensional (3D) printing holds promise for a wide variety of biomedical applications, from surgical planning, practicing, and teaching to creating implantable devices. The growth of this cheap and easy additive manufacturing technology in orthopedic, plastic, and vascular surgery has been explosive; however, its potential in the field of neurosurgery remains underexplored. A major limitation is that current technologies are unable to directly print ultrasoft materials like human brain tissue.

Multiphysics and Multiscale Modelling, Data-model Fusion and Integration of Organ Physiology in the Clinic: Ventricular Cardiac Mechanics

Interface Focus. Apr, 2016  |  Pubmed ID: 27051509

With heart and cardiovascular diseases continually challenging healthcare systems worldwide, translating basic research on cardiac (patho)physiology into clinical care is essential. Exacerbating this already extensive challenge is the complexity of the heart, relying on its hierarchical structure and function to maintain cardiovascular flow. Computational modelling has been proposed and actively pursued as a tool for accelerating research and translation. Allowing exploration of the relationships between physics, multiscale mechanisms and function, computational modelling provides a platform for improving our understanding of the heart. Further integration of experimental and clinical data through data assimilation and parameter estimation techniques is bringing computational models closer to use in routine clinical practice. This article reviews developments in computational cardiac modelling and how their integration with medical imaging data is providing new pathways for translational cardiac modelling.

A Finite Element Model for Mixed Porohyperelasticity with Transport, Swelling, and Growth

PloS One. 2016  |  Pubmed ID: 27078495

The purpose of this manuscript is to establish a unified theory of porohyperelasticity with transport and growth and to demonstrate the capability of this theory using a finite element model developed in MATLAB. We combine the theories of volumetric growth and mixed porohyperelasticity with transport and swelling (MPHETS) to derive a new method that models growth of biological soft tissues. The conservation equations and constitutive equations are developed for both solid-only growth and solid/fluid growth. An axisymmetric finite element framework is introduced for the new theory of growing MPHETS (GMPHETS). To illustrate the capabilities of this model, several example finite element test problems are considered using model geometry and material parameters based on experimental data from a porcine coronary artery. Multiple growth laws are considered, including time-driven, concentration-driven, and stress-driven growth. Time-driven growth is compared against an exact analytical solution to validate the model. For concentration-dependent growth, changing the diffusivity (representing a change in drug) fundamentally changes growth behavior. We further demonstrate that for stress-dependent, solid-only growth of an artery, growth of an MPHETS model results in a more uniform hoop stress than growth in a hyperelastic model for the same amount of growth time using the same growth law. This may have implications in the context of developing residual stresses in soft tissues under intraluminal pressure. To our knowledge, this manuscript provides the first full description of an MPHETS model with growth. The developed computational framework can be used in concert with novel in-vitro and in-vivo experimental approaches to identify the governing growth laws for various soft tissues.

Elastosis During Airway Wall Remodeling Explains Multiple Co-existing Instability Patterns

Journal of Theoretical Biology. Aug, 2016  |  Pubmed ID: 27211101

Living structures can undergo morphological changes in response to growth and alterations in microstructural properties in response to remodeling. From a biological perspective, airway wall inflammation and airway elastosis are classical hallmarks of growth and remodeling during chronic lung disease. From a mechanical point of view, growth and remodeling trigger mechanical instabilities that result in inward folding and airway obstruction. While previous analytical and computational studies have focused on identifying the critical parameters at the onset of folding, few have considered the post-buckling behavior. All prior studies assume constant microstructural properties during the folding process; yet, clinical studies now reveal progressive airway elastosis, the degeneration of elastic fibers associated with a gradual stiffening of the inner layer. Here, we explore the influence of temporally evolving material properties on the post-bifurcation behavior of the airway wall. We show that a growing and stiffening inner layer triggers an additional subsequent bifurcation after the first instability occurs. Evolving material stiffnesses provoke failure modes with multiple co-existing wavelengths, associated with the superposition of larger folds evolving on top of the initial smaller folds. This phenomenon is exclusive to material stiffening and conceptually different from the phenomenon of period doubling observed in constant-stiffness growth. Our study suggests that the clinically observed multiple wavelengths in diseased airways are a result of gradual airway wall stiffening. While our evolving material properties are inspired by the clinical phenomenon of airway elastosis, the underlying concept is broadly applicable to other types of remodeling including aneurysm formation or brain folding.

Tri-layer Wrinkling As a Mechanism for Anchoring Center Initiation in the Developing Cerebellum

Soft Matter. Jul, 2016  |  Pubmed ID: 27252048

During cerebellar development, anchoring centers form at the base of each fissure and remain fixed in place while the rest of the cerebellum grows outward. Cerebellar foliation has been extensively studied; yet, the mechanisms that control anchoring center initiation and position remain insufficiently understood. Here we show that a tri-layer model can predict surface wrinkling as a potential mechanism to explain anchoring center initiation and position. Motivated by the cerebellar microstructure, we model the developing cerebellum as a tri-layer system with an external molecular layer and an internal granular layer of similar stiffness and a significantly softer intermediate Purkinje cell layer. Including a weak intermediate layer proves key to predicting surface morphogenesis, even at low stiffness contrasts between the top and bottom layers. The proposed tri-layer model provides insight into the hierarchical formation of anchoring centers and establishes an essential missing link between gene expression and evolution of shape.

Terminating Atrial Fibrillation by Cooling the Heart

Heart Rhythm. Nov, 2016  |  Pubmed ID: 27435588

Partial LVAD Restores Ventricular Outputs and Normalizes LV but Not RV Stress Distributions in the Acutely Failing Heart in Silico

The International Journal of Artificial Organs. Oct, 2016  |  Pubmed ID: 27646633

Heart failure is a worldwide epidemic that is unlikely to change as the population ages and life expectancy increases. We sought to detail significant recent improvements to the Dassault Systèmes Living Heart Model (LHM) and use the LHM to compute left ventricular (LV) and right ventricular (RV) myofiber stress distributions under the following 4 conditions: (1) normal cardiac function; (2) acute left heart failure (ALHF); (3) ALHF treated using an LV assist device (LVAD) flow rate of 2 L/min; and (4) ALHF treated using an LVAD flow rate of 4.5 L/min.

Stress Singularities in Swelling Soft Solids

Physical Review Letters. Sep, 2016  |  Pubmed ID: 27715096

When a swelling soft solid is rigidly constrained on all sides except for a circular opening, it will bulge out to expand as observed during decompressive craniectomy, a surgical procedure used to reduce stresses in swollen brains. While the elastic energy of the solid decreases throughout this process, large stresses develop close to the opening. At the point of contact, the stresses exhibit a singularity similar to the ones found in the classic punch indentation problem. Here, we study the stresses generated by swelling and the evolution of the bulging shape associated with this process. We also consider the possibility of damage triggered by zones of either high shear stresses or high fiber stretches.

The Pursuit of Engineering the Ideal Heart Valve Replacement or Repair: A Special Issue of the Annals of Biomedical Engineering

Annals of Biomedical Engineering. Feb, 2017  |  Pubmed ID: 28150054

Wrinkling Instabilities in Soft Bilayered Systems

Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences. May, 2017  |  Pubmed ID: 28373385

Wrinkling phenomena control the surface morphology of many technical and biological systems. While primary wrinkling has been extensively studied, experimentally, analytically and computationally, higher-order instabilities remain insufficiently understood, especially in systems with stiffness contrasts well below 100. Here, we use the model system of an elastomeric bilayer to experimentally characterize primary and secondary wrinkling at moderate stiffness contrasts. We systematically vary the film thickness and substrate prestretch to explore which parameters modulate the emergence of secondary instabilities, including period-doubling, period-tripling and wrinkle-to-fold transitions. Our experiments suggest that period-doubling is the favourable secondary instability mode and that period-tripling can emerge under disturbed boundary conditions. High substrate prestretch can suppress period-doubling and primary wrinkles immediately transform into folds. We combine analytical models with computational simulations to predict the onset of primary wrinkling, the post-buckling behaviour, secondary bifurcations and the wrinkle-to-fold transition. Understanding the mechanisms of pattern selection and identifying the critical control parameters of wrinkling will allow us to fabricate smart surfaces with tunable properties and to control undesired surface patterns like in the asthmatic airway.This article is part of the themed issue 'Patterning through instabilities in complex media: theory and applications.'

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