Distributed multi-scale muscle simulation in a hybrid MPI–CUDA computational environment

We present Mexie, an extensible and scalable software solution for distributed multi-scale muscle simulations in a hybrid MPI–CUDA environment. Since muscle contraction relies on the integration of physical and biochemical properties across multiple length and time scales, these models are highly processor and memory intensive. Existing parallelization efforts for accelerating multi-scale muscle simulations imply the usage of expensive large-scale computational resources, which produces overwhelming costs for the everyday practical application of such models. In order to improve the computational speed within a reasonable budget, we introduce the concept of distributed calculations of multi-scale muscle models in a mixed CPU–GPU environment. The concept is applied to a two-scale muscle model, in which a finite element macro model is coupled with the microscopic Huxley kinetics model. Finite element calculations of a continuum macroscopic model take place strictly on the CPU, while numerical solutions of the partial differential equations of Huxley’s cross-bridge kinetics are calculated on both CPUs and GPUs. We present a modular architecture of the solution, along with an internal organization and a specific load balancer that is aware of memory boundaries in such a heterogeneous environment. Solution was verified on both benchmark and real-world examples, showing high utilization of involved processing units, ensuring high scalability. Speed-up results show a boost of two orders of magnitude over any previously reported distributed multi-scale muscle models. This major improvement in computational feasibility of multi-scale muscle models paves the way for new discoveries in the field of muscle modeling and future clinical applications.Author's versio

On the microstructure of active cellular processes

Eukaryotic cells use a multitude of protein machines to regulate their own structure. In this thesis, we study how the geometrical arrangement of these interacting microscopic active elements sculpt the cell's own internal microstructure and its membrane enclosure.We first focus on the mechanisms generating actomyosin contractility, a crucial driver of cell motion and organization. We question the current position of highly organized, sarcomeric contractility as the only possible mechanism to drive contractility. We propose an alternative mechanism, and show that only it can account for the observed contractility of disordered actomyosin assemblies. It moreover yields qualitatively new effects in intracellular force transmission, including stress reversal and amplification, consistent with experimentally observations in fiber networks.We next elucidate some of the mechanisms through which the cell deforms and cuts its own membrane, thus enabling exchanges with the extracellular medium as well as between its internal compartments. We find that the function of the proteins responsible for this remodeling is strongly influenced by the mechanics of the membrane, and use these effects to elucidate the modes of operation of proteins clathrin and dynamin, as well as of protein complex ESCRT-III

Self-organized cyclic patterns in muscles and microscopic swimming

Living cells are self-sustained units of organisms. Within cells the complex interplay of a high amount of proteins and other molecules relies on information that is encoded in the dna. The self-organisation of cellular constituents might play an important role in cellular activity. There is evidence for self-organization in the cytoskeleton of cells where small numbers of interacting proteins create patterns of a higher order. The cytoskeleton of muscles has been shown to exhibit cyclic behaviour and wave patterns in absence of regulatory mechanisms. This thesis provides evidence that the experimental results can be accounted for by the self-organization of cytoskeletal filaments and motor proteins. A microscopic model exposes that the dynamics is excitable. Continuous descriptions of muscles reveal a non-hydrodynamic mode that accounts for wave generation. The phenomenological coefficients can directly be related to microscopic parameters. For this study, the principles that underly spontaneous muscle oscillations are used in a conceptual design of a simple self-driven swimmer at low Reynolds number. The swimmer\u27s motion can self-organize into directed movement by dynamically breaking the swimmer\u27s symmetries.Lebende Zellen sind selbständige Untereinheiten von Organismen. Innerhalb von Zellen beruht das komplexe Wechselspiel einer großen Menge verschiedener Proteinarten und anderer Moleküle auf Informationen die in der DNA kodiert sind. Dabei könnte die Selbstorganisation der Bestandteile von Zellen eine wichtige Rolle in der zellulären Aktivität spielen. Es gibt Hinweise auf selbstorganisierte Prozesse im Zytoskelett von Zellen wobei wenige verschiedenartige Proteine miteinander wechselwirken und Ordnungsstrukturen erzeugen. Im Zytoskelett von Muskeln werden oszillatorische Aktivitäten und Wellenmuster beobachtet, ohne regulatorische Mechanismen. Diese Arbeit findet Hinweise, dass die Selbstorganisation von Filamenten und Motorproteinen des Zytoskeletts die experimentellen Ergebnisse erklären kann. Ein mikroskopisches Model zeigt zudem die Anregbarkeit der Dynamik. In Beschreibungen von Muskeln als kontinuierliches Medium kann eine nicht hydrodynamische Mode identifiziert werden, die für die Wellenphänomene von essentieller Bedeutung ist. Dabei können phänomenologische Koeffizienten mikroskopischen Parametern zugeordnet werden. Die Prinzipien, die zu spontanen Muskeloszillationen führen, werden in einer Konzeptstudie eines einfachen Schwimmers bei kleinen Reynolds-Zahlen genutzt. Die Bewegung des Schwimmers kann sich von selbst in einen Zustand gerichteter Bewegung organisieren indem sie die Symmetrien des Schwimmers dynamisch bricht

Multiscale computer muscle model based on finite element macromodel and Huxley's micromodel : doctoral dissertation

Izučavanje ponašanja mišića na osnovu precizno definisanih računarskih modela predstavlja jedan od najvećih izazova u oblasti primenjene nauke i inženjerstva. Promene u strukturalnim i funkcionalnim karakteristikama mišića usled nekih bolesti ili poremećaja u radu mišića, zahtevaju modelovanje biofizičkih procesa na više prostornih i vremenskih skala. Višeskalni modeli mišića mogu implementirati različite fenomenološke ili biofizičke modele mišića u okviru mikroskale. Implementacija fenomenoloških mikromodela doprinosi manjoj složenosti višeskalnog modela, ali takvi modeli nisu u stanju da precizno predvide prelazna ponašanja mišića pri neizometrijskim uslovima. Da bi se poboljšali ovi nedostaci, u okviru disertacije razvijen je višeskalni model mišića zasnovan na makromodelu konačnih elemenata i Hakslijevom mikromodelu (KEHaksli). Metod konačnih elemenata (MKE) integriše aktivne i pasivne materijalne karakteristike mišića u mehaniku kontinuuma na makroskali, dok se na mikroskali koristi modifikovana verzija Hakslijevog modela poprečnih mostova kako bi se izračunao aktivni napon i trenutna krutost u mišićnim vlaknima. Sva predviđanja dobijena KE-Haksli višeskalnim modelom su verifikovana poređenjem sa eksperimentalnim rezultatima i sa rezultatima dobijenim prostorno eksplicitnim simulacijama molekularnog modela (MUSICO). Mogućnosti korišćenja KE-Haksli modela u simulacijama složenih mišića, prikazane su na 2D modelu ljudskog jezika. Takođe, prikazana je upotreba KE-Haksli modela i u simulacijama određenih bolesti mišića. Zahvaljujući Mexie platformi za paralelna izvršavanja simulacija višeskalnih modela mišića, računski zahtevne simulacije KE-Haksli modela se izvode u razumnom vremenskom okviru, što model čini upotrebljivim za razne istraživačke i kliničke primene.The study of the muscle behavior based on precisely defined computer models is one of the greatest challenges in the field of applied science and engineering. Changes in the structural and functional characteristics of muscles during some diseases or disorders, require modeling of biophysical processes on several spatial and temporal scales. Multiscale muscle models can implement different phenomenological or biophysical muscle models within a microscale. The implementation of phenomenological micromodels contributes to the lower complexity of the multiscale model, but such models are not able to accurately predict transient muscle behavior under non-isometric conditions. To improve these shortcomings, a multiscale muscle model based on the finite element macromodel and the Huxley micromodel was developed as part of the thesis. The finite element method (FEM) integrates the active and passive material characteristics of the muscles into a continuum mechanics on the macroscale, while a modified Huxley’s cross-bridge model is used to calculate active muscle tension and instantaneous stiffnessin muscle fibers on the microscale. All predictions generated by the FE-Huxley multiscale model were verified by comparison with experimental results and with simulation results obtained by spatially explicit molecular model (MUSICO). The possibilities of using the FE-Huxley model in simulations of complex muscles are presented on a 2D model of the human tongue. Also, the use of the FE-Huxley model in simulations of certain muscle diseases is presented. Thanks to the Mexie platform for parallel execution simulations of multiscale muscle models, computationally demanding simulations of the FE-Huxley model are performed in a reasonable time frame, which makes the model usable for a variety of research and clinical applications

The role of branched muscle fibres and ACTN3 polymorphism as a genetic disease modifier in Duchenne nuscular dystrophy

Duchenne muscular dystrophy (DMD) is the second most common fatal genetic disease in humans, with an incidence of 1 in 3300 live male births. DMD is characterized by progressive cycles of skeletal muscle necrosis/regeneration triggered by the absence of the protein dystrophin from the inner surface of the sarcolemma. In DMD and dystrophin-negative mdx mice, regenerated skeletal muscle fibres are branched and deterioration of muscle contractile function with age is correlated with an increase in both the number and complexity of branched fibres. In this thesis, I present four papers in support of my hypothesis, that when the number and complexity of branched fibres in dystrophin-negative muscles reaches a critical threshold, termed ‘tipping point’, the branches in and of themselves, mechanically weaken the muscle and are susceptible to rupturing when subjected to high forces such as those experienced during eccentric/lengthening contractions. Methodologically, the papers utilise a combination of isolated muscle function contractile measurements coupled with single fibre imaging and confocal microscopy of cleared whole muscles. All experiments use intact muscles isolated from the dystrophic mdx mouse, double knockout (dk)Actn3KO/mdx (dKO) mouse and littermate controls. In conclusion, I propose a two-phase model to explain the aetiology of DMD. Phase-one involves the absence of dystrophin triggering a pathological increase in [Ca2+]in resulting in skeletal muscle fibre necrosis followed immediately by regeneration. The process proceeds cyclically, increasing the number of abnormally branched regenerated dystrophin-deficient muscle fibres. Once the number and complexity of branched fibres passes a level I term ‘tipping point’, phase-two occurs; now eccentric contractions cause force deficits as a consequence of branches rupturing. In the final stage, phase-two will tend to have a positive feedback component, as breaking branches will no longer support the eccentrically contracting muscle, placing additional stress on the remaining branches during the contraction. It is important to note that depending on the complexity of branching and forces experienced by the muscle, phase-one and phase-two are not mutually exclusive and will occur simultaneously

Enabling Detailed, Biophysics-Based Skeletal Muscle Models on HPC Systems

Realistic simulations of detailed, biophysics-based, multi-scale models often require very high resolution and, thus, large-scale compute facilities. Existing simulation environments, especially for biomedical applications, are typically designed to allow for high flexibility and generality in model development. Flexibility and model development, however, are often a limiting factor for large-scale simulations. Therefore, new models are typically tested and run on small-scale compute facilities. By using a detailed biophysics-based, chemo-electromechanical skeletal muscle model and the international open-source software library OpenCMISS as an example, we present an approach to upgrade an existing muscle simulation framework from a moderately parallel version toward a massively parallel one that scales both in terms of problem size and in terms of the number of parallel processes. For this purpose, we investigate different modeling, algorithmic and implementational aspects. We present improvements addressing both numerical and parallel scalability. In addition, our approach includes a novel visualization environment which is based on the MegaMol framework and is capable of handling large amounts of simulated data. We present the results of a number of scaling studies at the Tier-1 supercomputer HazelHen at the High Performance Computing Center Stuttgart (HLRS). We improve the overall runtime by a factor of up to 2.6 and achieve good scalability on up to 768 cores

Architectural control of ice-templated collagen scaffolds for cardiac regeneration

A range of biomaterials and fabrication methods have been explored to produce biomimetic scaffolds to facilitate cardiac tissue regeneration. Ice-templated collagen scaffolds have demonstrated translational success in other clinical applications. The ice templating technique utilizes phase separation dynamics during solidification and subsequent sublimation of ice to produce scaffolds with interconnected porosity. Although composition has been found to be key to determining cellular response, both nano-scale and micro-scale surface features of ice templated collagen scaffolds have also been found to encourage cellular ingrowth and attachment. Previous research has introduced techniques to control pore size and anisotropy. To date, however, ice-templating has not been shown to allow control of architecture to the extent that it is possible to replicate the structure of more complex tissue morphologies such as the myocardium. In this thesis, the underpinning physics of ice formation is leveraged to determine the final architecture of ice-templated collagen scaffolds. A controllable directional freezing apparatus was designed and built to enable fine control of the thermal environment during solidification. A relationship between the set thermal parameters and final pore architecture was established. This relationship enabled the production of structures with controlled pore alignment and size. The direct control and monitoring capabilities of the freezing apparatus enabled observations of intrinsic freezing kinetics. This insight allowed the solidification processes of anisotropic and isotropic ice-templating to be compared, and a link between the previously distinct fields was hypothesized. A novel thermal control technique was developed that dictated ice growth directions and achieved complex lamellar orientation of ice-templated collagen scaffolds. A new mould design was produced, with a heat-sink at the base and heat sources in the mould walls, which afforded three-dimensional thermal control during the solidification process. Ultimately, this created complex lamellar orientation of ice-templated collagen scaffolds. The technique is presented alongside a finite element model, developed as a predictive tool for the design of final lamellar orientation. Heat source moulds were used to introduce controlled thermal gradients during the solidification phase of the ice-templating process. Various heat source profiles were implemented and simulated. It was found that by introducing controlled complex thermal gradients during solidification, scaffolds with multidirectional pore orientations were produced, and the finite element simulation was found to accurately predict lamellar orientation. Taken together, the model and heat source freezing technique provide the opportunity for design and production of regenerative collagen scaffolds with tailored architectural morphologies. After establishing a control protocol for producing structures with tailored local lamellar architecture, patches were tested by observing the effects of scaffold architecture on cellular behaviour and mechanical conformation to the dynamic movements of the heart. Cardiomyocytes (H9 hESCs) were seeded onto scaffolds with aligned and isotropic pore structures and the cell signalling patterns were then compared. It was determined that the biomimetic accuracy of the aligned scaffold improved the uniformity of calcium signalling in cardiomyocytes when compared with those on isotropic structures. These results indicate that myocardial function is enhanced by defined scaffold orientation. The application of an ex vivo ovine cardiac perfusion model enabled direct observation of the native myocardial movement during the cardiac cycle. Through direct optical imaging and digital image correlation, collagen scaffolds were tested to assess their response to native myocardial deformation patterns. The strain dynamics of aligned and isotropic scaffold architectures were compared, and the efficacy of both glue and suture fixation methods were explored. It was determined that aligned scaffolds adhered with suture fixation complied with the native physio-mechanical environment. Similarly adhered isotropic scaffolds and patches adhered with glue, however, resulted in reduced deformation relative to the native myocardium. The work in this thesis has established a novel freeze casting technique to afford specific three dimensional control of collagen scaffold alignment. The resulting scaffolds with directionally aligned pore architectures were found to enhance cellular and mechanical dynamics to better replicate the native behaviour of myocardial tissue.British Heart Foundation, Gates Cambridge Foundatio

A finite element approach to study skeletal muscle tissue

This dissertation investigates force generation in muscle using a finite element (FE) approach to model electrical activity and mechanical force production within skeletal muscle. The work proposes new FE models design/formulations to answer specific research questions related to skeletal muscle properties. The focus is on two specific determinants of skeletal muscle force: the activation and the connective tissue. A FE model was created and designed to study the impact of the dielectric and geometric (pennation) properties of the muscle tissues on the electric activation signal detected on the skin surface by bipolar electrodes (surface electromyography, sEMG). The model shows that when considering parallel muscle fibres the tissue, attenuated mainly frequencies in the physiological range (92-542 Hz). This study revealed a strong impact of the muscle fibres pennation angle, on the detected signal (low pass filtering effect); suggesting that the low pass filtering behaviour observed in experimental data is due to the geometry (curvature or pennation) rather than the dielectric properties. The model informed recommendations for sEMG experimental protocol to increase the inter-electrodes distance when measuring sEMG of pennated muscles. A micromechanical model of the muscle tissue was created to explore the influence of the connective tissue properties (endomysium) on the total muscle force production. The constitutive model was used to study the mechanical consequence of clustering of fibres due to the remodelling of the motor units, which occurs with ageing. An FE model with a bundle of 19 fibres was designed and simulated activating 21% and 37% of the fibres in a distributed and clustered pattern. Results showed for both activation levels that the pattern of the strain distribution changed with an increased deformation toward the centre of the bundle. This could lead to excessive unbalanced stresses if higher deformations are involved. The micromechanical model can be used to study muscle force determinants at a fascicle level. It showed the importance of the fibre distribution during the muscle activation and the consequences of age related alterations on force production

Biofunctional hydrogels for skeletal muscle constructs

Skeletal muscle tissue damage costs the US government hundreds of billions of dollars annually. Meanwhile, there is great potential to use skeletal muscle as a scalable actuator system, covering wide length scales, frequencies, and force regimes. Hence, the interest in soft robotics and regenerative medicine methods to engineer skeletal muscle has increased in recent years. The challenges to generate a functional muscle strip are typical to those of tissue engineering, where common issues such as cell source, material scaffold, bioreactor method or configuration play key roles. Specifically, it is important to translate the existing body of myogenesis knowledge into engineering muscle constructs by examining the impact of the cell microenvironment on growth, alignment, fusion, and differentiation of skeletal muscle cells. The main motivation behind this thesis was to generate a contractile 3D skeletal muscle construct utilizing organized biochemical and physical cues to guide muscle cell differentiation and maturation. Such a construct is expected to play an important role in medical applications and the development of soft robotics. To do this, 3D, swollen hydrogels were chosen to provide tailorable platforms that support cellular activities to similar extents as native matrices. For this work, we utilized an engineered bio-functionalized poly(ethylene glycol)-(PEG)-hydrogel with maleimide (MAL) cross-linking reaction chemistry that gels rapidly with high reaction efficiency under cytocompatible reaction conditions. PEG alone has been shown to have low protein adsorption, a minimal inflammatory profile, well established chemistry, and a long history of safety in vivo. The PEG-MAL system in particular allows “plug-and-play” design variation, control over polymerization time, and small degradation products. To develop an effective soft biomaterial for the development of an aligned, functional muscle construct, we (i) screened hydrogel properties for differentiation, (ii) recreated alignment of skeletal muscle cells, (iii) determined effective generated force upon action of an external agonist. The impact of this study in generating a controllable force actuator will be significant in the construction of biological machines. Concomitantly, this study will provide a unique regenerative solution for skeletal muscle tissue repair and regeneration.Ph.D

Muscular activity and its relationship to biomechanics and human performance

The purpose of this manuscript is to address the issue of muscular activity, human motion, fitness, and exercise. Human activity is reviewed from the historical perspective as well as from the basics of muscular contraction, nervous system controls, mechanics, and biomechanical considerations. In addition, attention has been given to some of the principles involved in developing muscular adaptations through strength development. Brief descriptions and findings from a few studies are included. These experiments were conducted in order to investigate muscular adaptation to various exercise regimens. Different theories of strength development were studied and correlated to daily human movements. All measurement tools used represent state of the art exercise equipment and movement analysis. The information presented here is only a small attempt to understand the effects of exercise and conditioning on Earth with the objective of leading to greater knowledge concerning human responses during spaceflight. What makes life from nonliving objects is movement which is generated and controlled by biochemical substances. In mammals. the controlled activators are skeletal muscles and this muscular action is an integral process composed of mechanical, chemical, and neurological processes resulting in voluntary and involuntary motions. The scope of this discussion is limited to voluntary motion