Here, we report results of our simulations studies on modeling the collagen-hydroxyapatite (HAP) interface in bone and influence of these interactions on mechanical behavior of collagen through molecular dynamics and steered molecular dynamics (SMD). Models of hexagonal HAP (10-10) and (0001) surface, and collagen with and without telopeptides were built to investigate the mechanical response of collagen in the proximity of mineral. The collagen molecule was pulled normal and parallel to the (0001) surface of hydroxyapatite. Water molecules were found have an important impact on deformation behavior of collagen in the proximity of HAP due to their large interaction energy with both collagen and HAP. Collagen appears stiffer at small displacement when pulled normal to HAP surface. At large displacement, collagen pulled parallel to HAP surface is stiffer. This difference in mechanical response of collagen pulled in parallel and perpendicular direction results from a difference in deformation mechanism of collagen. Further, the collagen molecule pulled in the proximity of HAP, parallel to surface, showed marked improvement in stiffness compared to absence of HAP. Furthermore, the deformation behavior of collagen not only depends on the presence or absence of HAP and direction of pulling, but also on the type of mineral surface in the proximity. The collagen pulled parallel to (10-10) and (0001) surfaces showed characteristically different type of load-displacement response. In addition, here we also report simulations on 300 nm length of collagen molecule indicating the role of length of model on the observed response in terms of both the magnitude of modulus obtained as well as the mechanisms of response of collagen to loading.

We employed passive particle-tracking microrheology to map the micromechanical structure of the hyaluronan-rich pericellular coat enveloping chondrocytes. Therefor we exploited the technique's position sensitivity to gain radial information on the coat. We observed a linear increase in viscoelasticity from the coat's rim towards the cell membrane. This gradient corresponds to hyaluronan concentration profiles observed in confocal fluorescent microscopy with small, specific hyaluronan markers. These results suggest that the structural basis of the pericellular coat is formed by grafted hyaluronan of different effective lengths stretched out by a homogenous decoration with hyaladherins such as aggrecan. The different effective lengths could be caused either by different lengths of the HA chains or by “side-on” attachments within the chain. Remarkably, the hyaluronan-rich coat increases the viscosity of the pericellular space only by about a factor of about two at 100 and at 20 Hz compared to pure media and an increasing elastic component is observed. Both the viscoelasticity as well as the hyaluronan concentration decrease linearly or slightly exponential from the cell membrane towards the PCC's rim. These observations could be obtained on living cells exploiting this unintrusive measurement techniques.

The chemical regeneration method of human enamel was improved for the probable clinical application: an oral medical device was designed to significantly reduce the necessary amount of remineralization liquid; the reactive liquid phase system was redesigned, thus the solution could be stored for long time.

Antler is an extraordinary bone tissue that displays significant overall toughness when compared to other bone materials. The origin of this toughness is due to the complex interaction between the nanoscale constituents as well as structural hierarchy in the antler material. Of particular interest is the mechanical performance of the interface between the collagen fibrils and considerably smaller volume of non-collagenous protein (NCP) between these fibrils. This paper directly examines the mechanical properties of isolated volumes of antler using combined in situ atomic force microscopy (AFM)-scanning electron microscopy (SEM) experiments. The antler material at the nanoscale is approximated to a fiber reinforced composite, with composite theory used to evaluate the interfacial shear stresses generated between the individual collagen fibrils and NCP during mechanical loading.

The mechanism of formation of hemozoin, a detoxification by-product of several blood-feeding organisms including malaria parasites, has been a subject of debate; however, recent studies suggest that neutral lipids may serve as a catalyst. In this study, a model system consisting of an emulsion of synthetic lipid bodies, resembling their in vivo counterpart in composition and size, was employed to investigate the formation of β-hematin, synthetic hemozoin, at the lipid-water interface. The introduction of heme (Fe(III)PPIX) to this synthetic neutral lipid bodies system under biomimetic conditions (37°C, pH 4.8) produced beta-hematin with apparent first order kinetics and an average half life of 0.5 min. TEM of monoglycerides (MPG) extruded through a 200 nm filter with heme produced beta-hematin crystals aligned and parallel to the lipid/water interface. TEM data suggests that beta-hematin crystallizes via epitaxial nucleation at the lipid-water interface through interaction of Fe(III)PPIX with the polar head group and elongation occurs parallel this interface.

We used high resolution micromechanical force sensors to study the in vivo mechanical response of embryonic Drosophila neurons. Our experiments show that Drosophila axons have a rest tension of a few nN and respond to mechanical forces in a manner characteristic of viscoelastic solids. In response to fast externally applied stretch they show a linear force-deformation response and when the applied stretch is held constant the force in the axons relaxes to a steady state value over time. More importantly, when the tension in the axons is suddenly reduced by releasing the external force the neurons actively restore the tension, sometimes close to their resting value. Along with the recent findings of Siechen et al (Proc. Natl. Acad. Sci. USA 106, 12611 (2009)) showing a link between mechanical tension and synaptic plasticity, our observation of active tension regulation in neurons suggest an important role for mechanical forces in the functioning of neurons in vivo.

Osteogenesis imperfecta (abbreviated as OI) is a genetic disorder in collagen characterized by mechanically weakened tendon, fragile bones, skeletal deformities and in severe cases prenatal death. Even though many studies have attempted to associate specific mutation types with phenotypic severity, the molecular and mesoscale mechanisms by which a single point mutation influences the mechanical behavior of tissues at multiple length-scales remain unknown. Here we review results of a hierarchy of full atomistic and mesoscale simulations that demonstrated that OI mutations severely compromise the mechanical properties of collagenous tissues at multiple scales, from single molecules to collagen fibrils. Notably, mutations that lead to the most severe OI phenotype correlate with the strongest effects, leading to weakened intermolecular adhesion, increased intermolecular spacing, reduced stiffness, as well as a reduced failure strength of collagen fibrils (Gautieri et al., Biophys. J., 2009). Our study explains how single point mutations can control the breakdown of tissue at much larger length-scales, a question of great relevance for a broad class of genetic diseases. Furthermore, by extending the MARTINI coarse-grained force field, we provide a new modeling tool to study collagen molecules and fibrils at much larger scales than accessible to existing full atomistic models, while incorporating key chemical and mechanical features and thereby presents a powerful approach to computational materiomics (Gautieri et al., Journal of Chemical Theory and Computation, 2010). We describe the coarse-graining approach and present preliminary findings based on this model in applying it to large-scale models of molecular assemblies into fibrils.

In this paper, we briefly report our recent work on multiscale modeling and simulations of soft elasticity and focal adhesion of stem cells. In particular, our work is focused on modeling and simulation of contact and adhesion of stem cells on substrates with different rigidities. In order to understand the precise mechanical influences on cell contact/adhesion and to explain the possible mechanotransduction mechanism, we have developed a three-dimensional soft-matter cell model that uses liquid-crystal gel or liquid-crystal elastomer gel to model the overall constitutive relations of the cell, and we have simulated the responses of the cell to extra-cellular stimulus. The discussion here is specifically focused on the following issues: (1) how to model the overall myosin responses at the early stage of differentiation process of the stem cell, (2) the effects of both the adhesive force due to ligand-receptor interaction or focal adhesion and the surface tension, and (3) possible cell conformation and configuration changes triggered by substrate's rigidity.

The animal cell cytoskeleton consists of three interconnected filament systems: actin containing microfilaments (MFs), microtubules (MTs), and intermediate filaments (IFs). Among these three filaments systems, IFs are the only one that show high extensibility at both the single filament and network levels. In this work, I am presenting a simple model of IFs extensibility based on the current structural knowledge of the filaments. The only extra information added to this model compared to previous ones is the fact that the unfolded N- and C-termini of IF proteins are sandwiched between adjacent coiled-coil rod domains within the filaments. Since we know the contour length and typical persistence length of these unfolded termini, it is possible to predict the persistence length of a single filament, its maximal extensibility and the onset of coiled-coil unfolding. The predictions of the model are in good agreement with experiments on single desmin IFs stretched on a surface by AFM and on vimentin and desmin networks probed by rheology.

In Type 1 and 2 diabetes tissue stiffening is evident from measurements of the gross mechanical properties of the vasculature. Elastic fibers play an important role in the mechanical function of vascular tissue, however, the effects of diabetes on individual elastic fiber components remains poorly defined. Fibrillin microfibrils, a key elastic fiber component, have a ‘beads-on-a-string’ structure with a periodicity of approximately 56 nm. We tested for possible disruption due to diabetes in fibrillin microfibrils isolated from rat aorta using an experimental model of Type 1 diabetes in rats. The isolated fibrillin microfibrils were imaged with atomic force microscopy (AFM) and image analysis techniques were used to characterise the microfibrils. Although there was no significant difference in mean microfibril length (control 23.2 repeats, SEM 6.2 repeats: diabetic 23.6 repeats, SEM 6.1 repeats: Mann Whitney U-test, p=0.391), mean periodicity was significantly reduced in microfibrils isolated from the diabetic rats (52.7 nm, SEM 0.4 nm) compared with age-matched controls (59.5 nm, SEM 0.4 nm) (p<0.001, Student's t-test). This study shows that diabetes leads to significant ultrastructural morphological changes in fibrillin microfibrils.

Bone is a complex material with structural features varying over many different length scales. Lamellae in bone are discrete units of collagen fibril arrays that are the dominant structural feature at length scales of a few microns. The mechanical properties of bone are importantly dependent on the synergy between the lamellae and structural features at other length scales. However, the mechanical properties at this micron level will be indicative of the bone material itself and ignores the structural and geometric organizations prevalent at larger length scales. The isolation of volumes of bone at the lamellar level requires precision cutting methodology and this paper exploits Focused Ion Beam (FIB) methods to mill small cantilever beams from bulk bone material. Importantly, FIB milling can only be performed in a relatively high vacuum environment. Atomic Force Microscopy (AFM) mechanical tests are therefore performed in two environments, high vacuum and air in order to assess the effects of vacuum on bone beam mechanical behaviour. Our results indicate that little difference in the bone beam elastic modulus is found from bending experiments at deflections up to 100nm in different environments.

We propose a strategy to simulate the dynamics of molecular assemblies over long times, provided they have a hierarchical and modular nature. In the scheme, fast fluctuations are averaged into a set of effective potentials (fluctuation softened potentials or FSPs), and the remaining slower dynamics are propagated in a drastically reduced configuration space (coupled energy landscapes or CEL). As a preliminary validation of the FSPs we compute the free energy of binding of a protein complex (RNase:barstar) for different relative positionings of the proteins. As a demonstration of CEL, we simulate the dynamics of microtubule unraveling upon hydrolysis of bound nucleotides. The method should allow the use of time steps hundreds to thousands of times longer than in conventional molecular dynamics, so that with only atomic structures and interactions as input, motions over human time scales (>ms) could be simulated.

Discrete volumes of material in the form of a beam have been isolated from a parent limpet tooth using Focused Ion Beam (FIB) techniques. Mechanical bending tests of individual beams are performed using atomic force microscopy (AFM). The relatively small volumes tested in this beam-bending configuration allow approximation of the limpet tooth structure to a uniaxial short fibre composite. This mechanical testing technique is superior to conventional micro-hardness indentation as a defined stress condition within a locally defined volume is examined. Composite theory is shown to be valid for describing the mechanical properties of limpet teeth at sub-micron lengths scales and used to determine the synergy between the nanomaterial constituents.

The practical adhesion of equine pericardium membranes bonded with surgical glue has been measured by the bulge-and-blister technique under injection of pressurized distilled water. The value of the interfacial crack propagation energy can be estimated from the critical debonding pressure. The measured practical adhesion energies are weak with regards to those of engineering structural adhesives, but they are reliable enough to allow a comparison between different surgical glues and a study of the influence of the bonding experimental conditions.

Polypeptide sequences have an inherent tendency to self-assemble into filamentous nanostructures commonly known as amyloid fibrils. Such self-assembly is used in nature to generate a variety of functional materials ranging from protective coatings in bacteria to catalytic scaffolds in mammals. The aberrant self-assembly of misfolded peptides and proteins is also, however, implicated in a range of disease states including neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. It is increasingly evident that the intrinsic material properties of these structures are crucial for understanding the thermodynamics and kinetics of the pathological deposition of proteins, particularly as the mechanical fragmentation of aggregates enhances the rate of protein deposition by exposing new fibril ends which can promote further growth. We discuss here recent advances in physical techniques that are able to characterise the hierarchical self-assembly of misfolded protein molecules and define their properties.

Shape memory polymers (SMPs) are increasingly being considered for use in minimally invasive medical devices. For safe deployment of implanted devices it is important to be able to precisely control the actuation temperature of the device. In this study we report the effect of varying monomer composition on the glass transitions/actuation temperatures (Tg) of novel low density shape memory foams. The foams were based on hexamethylenediisocyanate (HDI), triethanolamine (TEA) and tetrakis (2-hydroxyl propyl) ethylenediamine (HPED), and were produced via a combination of chemical and physical blowing process. The process for post-foaming cleaning was also varied. Foams were characterized by DSC, DMA, and for shape memory. No clear trends were observed for foam samples without cleaning, and this was attributed to process chemicals acting as plasticizers. In foams cleaned via washing and/or sonication, the Tg was observed to decrease for compositions that were higher in the TEA content. Also, no change in shape memory behavior was observed for varying compositions. This work demonstrates the ability to tailor actuation transition temperature while maintaining shape memory behavior for low density foams suitable for aneurysm treatment.

Humidity can lower the stiffness of beta keratin, which is the main component of spatula pads terminated at the bottom of a gecko's toe. To see if this softening can influence gecko adhesion, numerical simulation of the vertical peeling of a spatula pad adhered on a rough surface is performed, which shows that the reduction in material stiffness indeed leads to substantial increases in the pull-off force ″(Chen, B. and Gao, H. International Journal of Applied Mechanics, 2010). This work provides an alternative explanation of experimental observations on the capillary effect in gecko adhesion.

We have proposed a new model for microcrack detection by osteocytes in bone. According to this model, cell signalling is initiated by the cutting of cellular processes which span the crack. We show that shear displacements of the crack faces are needed to rupture these processes, in an action similar to that of a pair of scissors. Current work involves a combination of cell biology experiments, theoretical and experimental fracture mechanics and system modelling using control theory approaches. The approach will be useful for understanding effects of extreme loading, aging, disease states and drug treatments on bone damage and repair; the present paper presents recent results from experiments and simulations as part of current, ongoing research.