Approximation of extracted features enabling 3D design tuning for reproducing the mechanical behaviour of biological soft tissues.

This article describes a new method, inspired by machine learning, to mimic the mechanical behaviour of target biological soft tissues with 3D printed materials. The principle is to optimise the structure of a 3D printed composite consisting of a geometrically tunable fibre embedded in a soft matrix. Physiological features are extracted from experimental stress-strain curves of several biological soft tissues. Then, using a cubic Bézier curve as the composite inner fibre, we optimised its geometric parameters, amplitude and height, to generate a specimen that exhibits a stress-strain curve in accordance with the extracted features of tensile tests. From this first phase, we created a database of specimen geometries that can be used to reproduce a wide variety of biological soft tissues. We applied this process to two soft tissues with very different behaviours: the mandibular periosteum and the calvarial periosteum. The results show that our method can successfully reproduce the mechanical behaviour of these tissues. This highlights the versatility of this approach and demonstrates that it can be extended to mimic various biological soft tissues.

A Step toward the Quantification of Noncovalent Interactions in Large Biological Systems: The Independent Gradient Model-Extremely Localized Molecular Orbital Approach.

The independent gradient model (IGM) is a recent electron density-based computational method that enables to detect and quantify covalent and noncovalent interactions. When applied to large systems, the original version of the technique still relies on promolecular electron densities given by the sum of spherically averaged atomic electron distributions, which leads to approximate evaluations of the inter- and intramolecular interactions occurring in systems of biological interest. To overcome this drawback and perform IGM analyses based on quantum mechanically rigorous electron densities also for macromolecular systems, we coupled the IGM approach with the recently constructed libraries of extremely localized molecular orbitals (ELMOs) that allow fast and reliable reconstructions of polypeptide and protein electron densities. The validation tests performed on small polypeptides and peptide dimers have shown that the novel IGM-ELMO strategy provides results that are systematically closer to the fully quantum mechanical ones and outperforms the IGM method based on the crude promolecular approximation, but still keeping a quite low computational cost. The results of the test calculations carried out on proteins have also confirmed the trends observed for the IGM analyses conducted on small systems. This makes us envisage the future application of the novel IGM-ELMO approach to unravel complicated noncovalent interaction networks (e.g., in protein-protein contacts) or to rationally design new drugs through molecular docking calculations and virtual high-throughput screenings.

Atomic Decomposition Scheme of Noncovalent Interactions Applied to Host-Guest Assemblies.

The design of novel stimuli-responsive supramolecular systems based on host-guest chemistry implies a thorough understanding of the noncovalent interactions involved. In this regard, some computational tools enabling the extraction of the noncovalent signatures from local descriptors based on the electron density have been previously proposed. Although very useful to detect the existence of such interactions, these analyses provide only a semi-quantitative description, which represents a limitation. In this work, we present a novel computational tool based on the local atomic descriptor IGM-δginter/At, which is able to decompose the fragment interaction into atomic contributions. Then, the role played by each atom in the formation of the host-guest assembly is quantified by an integrated Δginter/At score. Herein, we apply the IGM-Δginter/At approach to some challenging systems, including multimetallic arrays, buckycatchers, and organic assemblies. These systems exhibit unique structural features that make it difficult to determine the host/guest atoms that contribute the most to the guest encapsulation. Here, the Δginter/At score proves to be an appealing tool to shed light on the guest accommodation on a per-atom basis and could be useful in the rational design of more selective target agents. We strongly believe that this novel approach will be useful for experimental teams devoted to the synthesis of supramolecular systems based on host-guest chemistry.

New Way for Probing Bond Strength.

The covalent chemical bond is intimately linked to electron sharing between atoms. The recent independent gradient model (IGM) and its δg descriptor provide a way to quantify locally this electron density interpenetration from wavefunction calculations. Each bond has its own IGM-δgpair signature. The present work establishes for the first time a strong link between this bond signature and the physically grounded bond force constant concept. Analyzing a large set of compounds and bonds, the intrinsic bond strength index (IBSI) emerges from the IGM formulation. Our study shows that the IBSI does not belong to the class of conventional bond orders (like Mulliken, Wiberg, Mayer, delocalization index, or electron localization function-ELF), but is rather a new complementary index, related to the bond strength. A fundamental outcome of this research is a novel index allowing to range all two-center chemical bonds by their intrinsic strength in molecular situation. We believe that the IBSI is a powerful and robust tool for interpretation accessible to a wide community of chemists (organic, inorganic chemistry, including transition-metal complexes and reaction mechanisms).

The Independent Gradient Model: A New Approach for Probing Strong and Weak Interactions in Molecules from Wave Function Calculations.

Extraction of the chemical interaction signature from local descriptors based on electron density (ED) is still a fruitful field of development in chemical interpretation. In a previous work that used promolecular ED (frozen ED), the new descriptor, δg , was defined. It represents the difference between a virtual upper limit of the ED gradient (∇ρIGM , IGM=independent gradient model) that represents a noninteracting system and the true ED gradient (∇ρ ). It can be seen as a measure of electron sharing brought by ED contragradience. A compelling feature of this model is to provide an automatic workflow that extracts the signature of interactions between selected groups of atoms. As with the noncovalent interaction (NCI) approach, it provides chemists with a visual understanding of the interactions present in chemical systems. ∇ρIGM is achieved simply by using absolute values upon summing the individual gradient contributions that make up the total ED gradient. Hereby, we extend this model to relaxed ED calculated from a wave function. To this end, we formulated gradient-based partitioning (GBP) to assess the contribution of each orbital to the total ED gradient. We highlight these new possibilities across two prototypical examples of organic chemistry: the unconventional hexamethylbenzene dication, with a hexa-coordinated carbon atom, and ß-thioaminoacrolein. It will be shown how a bond-by-bond picture can be obtained from a wave function, which opens the way to monitor specific interactions along reaction paths.

GPU accelerated implementation of NCI calculations using promolecular density.

The NCI approach is a modern tool to reveal chemical noncovalent interactions. It is particularly attractive to describe ligand-protein binding. A custom implementation for NCI using promolecular density is presented. It is designed to leverage the computational power of NVIDIA graphics processing unit (GPU) accelerators through the CUDA programming model. The code performances of three versions are examined on a test set of 144 systems. NCI calculations are particularly well suited to the GPU architecture, which reduces drastically the computational time. On a single compute node, the dual-GPU version leads to a 39-fold improvement for the biggest instance compared to the optimal OpenMP parallel run (C code, icc compiler) with 16 CPU cores. Energy consumption measurements carried out on both CPU and GPU NCI tests show that the GPU approach provides substantial energy savings. © 2017 Wiley Periodicals, Inc.

Accurately extracting the signature of intermolecular interactions present in the NCI plot of the reduced density gradient versus electron density.

An electron density (ED)-based methodology is developed for the automatic identification of intermolecular interactions using pro-molecular density. The expression of the ED gradient in terms of atomic components furnishes the basis for the Independent Gradient Model (IGM). This model leads to a density reference for non interacting atoms/fragments where the atomic densities are added whilst their interaction turns off. Founded on this ED reference function that features an exponential decay also in interference regions, IGM model provides a way to identify and quantify the net ED gradient attenuation due to interactions. Using an intra/inter uncoupling scheme, a descriptor (δginter) is then derived that uniquely defines intermolecular interaction regions. An attractive feature of the IGM methodology is to provide a workflow that automatically generates data composed solely of intermolecular interactions for drawing the corresponding 3D isosurface representations.

Development of the first model of a phosphorylated, ATP/Mg2+-containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design.

A model of phosphorylated and ATP-containing B-Raf protein kinase is needed as a tool for the structure-based design of new allosteric inhibitors, since no crystal structure of such a system has been resolved. Here, we present the development of such a model as well as a thorough analysis of its structural features. This model was prepared using a systematic molecular dynamics approach considering the presence or absence of both the phosphate group at the Thr599 site and the ATP molecule. Then, different structural features (i.e. DFG motif, Mg2+ binding loop, activation loop, phosphorylation site and αC-helix region) were analysed for each trajectory to validate the aimed 2pBRAF_ATP model. Moreover, the structure and activating interactions of this 2pBRAF_ATP model were found to be in agreement with previously reported information. Finally, the model was further validated by means of a molecular docking study with our previously developed lead compound I confirming that this ATP-containing, phosphorylated protein model is suitable for further structure-based design studies.

HLA Awareness in tissue decellularization: A paradigm shift for enhanced biocompatibility, studied on the model of the human fascia lata graft.

Last twenties, tissue engineering has rapidly advanced to address the shortage of organ donors. Decellularization techniques have been developed to mitigate immune rejection and alloresponse in transplantation. However, a clear definition of effective decellularization remains elusive. This study compares various decellularization protocols using the human fascia lata model. Morphological, structural and cytotoxicity/viability analyses indicated that all the five tested protocols were equivalent and met Crapo's criteria for successful decellularization. Interestingly, only the in vivo immunization test on rats revealed differences. Only one protocol exhibited Human Leucocyte Antigen (HLA) content below 1% residual threshold, the only criterion preventing rat immunization with an absence of rat anti-human IgG switch after one month (N=4 donors for each of the 7 groups, added by negative and positive controls, n=28). By respecting a refined set of criteria, i.e. lack of visible nuclear material, <50ng DNA/mg dry weight of extracellular matrix, and <1% residual HLA content, the potential for adverse host reactions can be drastically reduced. In conclusion, this study emphasizes the importance of considering not only nuclear components but also major histocompatibility complex in decellularization protocols and proposes new guidelines to promote safer clinical development and use of bioengineered scaffolds.

Decellularized vascularized bone grafts as therapeutic solution for bone reconstruction: A mechanical evaluation.

INTRODUCTION: Large bone defects are challenging for surgeons. Available reimplanted bone substitutes can't properly restore optimal function along and long term osteointegration of the bone graft. Bone substitute based on the perfusion-decellularization technique seem to be interesting in order to overcome these limitations. We present here an evaluation of the biomechanics of the bones thus obtained. MATERIAL AND METHODS: Two decellularization protocols were chosen for this study. One using Sodium Dodecyl Sulfate (SDS) (D1) and one using NaOH and H2O2 (D2). The decellularization was performed on porcine forearms. We then carried out compression, three-point bending, indentation and screw pull-out tests on each sample. Once these tests were completed, we compared the results obtained between the different decellularization protocols and with samples left native. RESULTS: The difference in the means was similar between the tests performed on bones decellularized with the SDS protocol and native bones for pull-out test: +1.4% (CI95% [-10.5%- 12.4%]) of mean differences when comparing Native vs D1, compression -14.9% (CI95% [-42.7%- 12.5%]), 3-point bending -5.7% (CI95% [-22.5%- 11.1%]) and indentation -10.8% (CI95% [-19.5%- 4.6%]). Bones decellularized with the NaOH protocol showed different results from those obtained with the SDS protocol or native bones during the pull-out screw +40.7% (CI95% [24.3%- 57%]) for Native vs D2 protocol and 3-point bending tests +39.2% (CI95% [13.7%- 64.6%]) for Native vs D2 protocol. The other tests, compression and indentation, gave similar results for all our samples. CONCLUSION: Vascularized decellularized grafts seem to be an interesting means for bone reconstruction. Our study shows that the decellularization method affects the mechanical results of our specimens. Some methods seem to limit these alterations and could be used in the future for bone decellularization.

Identification of a visco-hyperelastic model for mandibular periosteum.

In this paper, a visco-hyperelastic model representing the mechanical behavior of the human mandibular periosteum as an anisotropic and homogeneous material is identified. Different models, extracted from the literature, are tested and associated in order to describe the elastic and visco-elastic contributions of the cellular matrix on one hand and the collagen fibers on the other hand. The parameters of these models are determined using five human mandibular periosteum. Each harvested sample is cut and tested, at two different velocities, either longitudinally or transversely to collagen fibers main direction. The hyperelastic and visco-elastic contributions of the cellular matrix are extracted using tensile tests performed transversely. The hyperelastic and visco-elastic contributions of the collagen fibers are extracted using tensile tests performed longitudinally. In a second time, the identified combination of models is validated using twelve samples only tested longitudinally. The selected combination uses the simplified Rivlin's 2nd order law to model the hyper-elasticity of the cellular matrix, the Kulkarni's law to model its visco-elasticity contribution, and the Kulkarni's laws to model the whole contributions of collagen fibers.

Decellularized vascularized bone grafts: A preliminary in vitro porcine model for bioengineered transplantable bone shafts.

Introduction: Durable reconstruction of critical size bone defects is still a surgical challenge despite the availability of numerous autologous and substitute bone options. In this paper, we have investigated the possibility of creating a living bone allograft, using the perfusion/decellularization/recellularization (PDR) technique, which was applied to an original model of vascularized porcine bone graft. Materials and Methods: 11 porcine bone forelimbs, including radius and ulna, were harvested along with their vasculature including the interosseous artery and then decellularized using a sequential detergent perfusion protocol. Cellular clearance, vasculature, extracellular matrix (ECM), and preservation of biomechanical properties were evaluated. The cytocompatibility and in vitro osteoinductive potential of acellular extracellular matrix were studied by static seeding of NIH-3T3 cells and porcine adipose mesenchymal stem cells (pAMSC), respectively. Results: The vascularized bone grafts were successfully decellularized, with an excellent preservation of the 3D morphology and ECM microarchitecture. Measurements of DNA and ECM components revealed complete cellular clearance and preservation of ECM's major proteins. Bone mineral density (BMD) acquisitions revealed a slight, yet non-significant, decrease after decellularization, while biomechanical testing was unmodified. Cone beam computed tomography (CBCT) acquisitions after vascular injection of barium sulphate confirmed the preservation of the vascular network throughout the whole graft. The non-toxicity of the scaffold was proven by the very low amount of residual sodium dodecyl sulfate (SDS) in the ECM and confirmed by the high live/dead ratio of fibroblasts seeded on periosteum and bone ECM-grafts after 3, 7, and 16 days of culture. Moreover, cell proliferation tests showed a significant multiplication of seeded cell populations at the same endpoints. Lastly, the differentiation study using pAMSC confirmed the ECM graft's potential to promote osteogenic differentiation. An osteoid-like deposition occurred when pAMSC were cultured on bone ECM in both proliferative and osteogenic differentiation media. Conclusion: Fully decellularized bone grafts can be obtained by perfusion decellularization, thereby preserving ECM architecture and their vascular network, while promoting cell growth and differentiation. These vascularized decellularized bone shaft allografts thus present a true potential for future in vivo reimplantation. Therefore, they may offer new perspectives for repairing large bone defects and for bone tissue engineering.

Periosteum and fascia lata: Are they so different?

Introduction: The human fascia lata (HFL) is used widely in reconstructive surgery in indications other than fracture repair. The goal of this study was to compare microscopic, molecular, and mechanical properties of HFL and periosteum (HP) from a bone tissue engineering perspective. Material and Methods: Cadaveric HP and HFL (N = 4 each) microscopic morphology was characterized using histology and immunohistochemistry (IHC), and the extracellular matrix (ECM) ultrastructure assessed by means of scanning electron microscopy (SEM). DNA, collagen, elastin, glycosaminoglycans, major histocompatibility complex Type 1, and bone morphogenetic protein (BMP) contents were quantified. HP (N = 6) and HFL (N = 11) were submitted to stretch tests. Results: Histology and IHC highlighted similarities (Type I collagen fibers and two-layer organization) but also differences (fiber thickness and compaction and cell type) between both tissues, as confirmed using SEM. The collagen content was statistically higher in HFL than HP (735 vs. 160.2 µg/mg dry weight, respectively, p < 0.0001). On the contrary, DNA content was lower in HFL than HP (404.75 vs. 1,102.2 µg/mg dry weight, respectively, p = 0.0032), as was the immunogenic potential (p = 0.0033). BMP-2 and BMP-7 contents did not differ between both tissues (p = 0.132 and p = 0.699, respectively). HFL supported a significantly higher tension stress than HP. Conclusion: HP and HFL display morphological differences, despite their similar molecular ECM components. The stronger stretching resistance of HFL can specifically be explained by its higher collagen content. However, HFL contains many fewer cells and is less immunogenic than HP, as latter is rich in periosteal stem cells. In conclusion, HFL is likely suitable to replace HP architecture to confer a guide for bone consolidation, with an absence of osteogenicity. This study could pave the way to a bio-engineered periosteum built from HFL.

Water reorientation dynamics in the first hydration shells of F- and I-.

Molecular dynamics and analytic theory results are presented for the reorientation dynamics of first hydration shell water molecules around fluoride and iodide anions. These ions represent the extremes of the (normal) halide series in terms of their size and conventional structure-making and -breaking categorizations. The simulated reorientation times are consistent with NMR and ultrafast IR experimental results. They are also in good agreement with the theoretical predictions of the analytic Extended Jump Model. Analysis through this model shows that while sudden, large amplitude jumps (in which the reorienting water exchanges hydrogen-bond partners) are the dominant reorientation pathway for the I(-) case, they are comparatively less important for the F(-) case. In particular, the diffusive reorientation of an intact F(-)···H(2)O hydrogen-bonded pair is found to be most important for the reorientation time, a feature related to the greater hydrogen-bond strength for the F(-)···H(2)O pair. The dominance of this effect for e.g. multiply charged ions is suggested.

Vibrational symmetry breaking of NO3- in aqueous solution: NO asymmetric stretch frequency distribution and mean splitting.

We apply a solute-solvent approach to a theoretical study of vibrational symmetry breaking in aqueous NO(3)(-) solution. Experimental infrared and Raman spectra have shown that the NO asymmetric stretches, which are degenerate for the isolated anion, are split by 35-60 cm(-1) in dilute solution. As an initial step to calculating the spectra, we have computed the distribution of energies, or the "static spectrum", and the resulting mean splitting of the two NO asymmetric stretch eigenstates in an aqueous milieu. These have been obtained in a two-mode treatment that considers only the NO asymmetric stretch mode pair as well as a full six-mode treatment. In both sets of calculations, six eigenstates, namely, the ground state, the two NO asymmetric stretch fundamentals, and its three overtones, were determined to suffice for converged energy distributions and mean splittings. The couplings between these six states are driven by the solvent forces on the anion's modes, which were extracted from molecular dynamics simulations. The solvent forces on the two central modes were found to give rise to a majority of the computed mean splitting of 21.7 cm(-1). The distribution of NO asymmmetric stretch excitation energies with these two modes alone was found to have a Maxwell-Boltzmann shape. The solvent forces on the in-plane bends were found to modestly reduce the splitting size and slightly alter the width of the parent distribution. The symmetric stretch force was found to have no effect on the splitting but instead resulted in a widening on the distribution shape. The force gradients were found to have a weak effect on both the eigenvalue distribution and the mean splitting.

Modeling of the human mandibular periosteum material properties and comparison with the calvarial periosteum.

Knowledge of mandibular periosteum mechanical properties is fundamental for understanding its role in craniofacial growth, in trauma and bone regeneration. There is a lack in the literature regarding mechanical behavior of the human periosteum, including both experimental and modeling aspects. The proposed study involves tensile tests of periosteum samples from different locations including two locations of human mandibular periosteum: lingual and vestibular, compared with samples from various locations of the calvarial periosteum. We propose to analyze the tensile response of the mandibular periosteum using a model, initially applied on the skin, and based on a structural approach involving the mechanical properties of the corrugation of the collagen. Two different approaches for the model parameters' identification are proposed: (1) identification from experimental curve fitting and (2) identification from histological study. This approach allows us to compare parameters extracted from the traction test fitting to structural parameters measured on periosteum histological slices. Concerning experimental aspects, we showed significant differences, in terms of stiffness, between calvarial and mandibular periostea. (The mean final stiffness is [Formula: see text] for the mandible versus [Formula: see text] for the calvaria.) About modeling, we succeed to capture the correct mechanical behavior for the periosteum, and the statistical analysis showed that certain parameters from the geometric data and traction data are significantly comparable (e.g., [Formula: see text] for [Formula: see text]). However, we also observed a discrepancy between these two approaches for the elongation at which the fibril has become straight ([Formula: see text]).

Contribution of the periosteum to mandibular distraction.

Mandibular distraction is a surgical process that progressively lengthens bone. To improve the distraction procedure and devices, the load of distraction and the mechanical strain of soft tissues during the process must be determined. We tested the assumption that it could be the periosteum primarily opposing distraction. Therefore we assessed the mechanical properties of the human mandibular periosteum and compared the stress-strain data with the torque measured on the activator during a cadaveric mandibular distraction. A 20 mm horizontal mandibular distraction was performed in 7 cadavers using standard distractors. Torque was measured with a torquemeter placed on the activation rods of the devices, providing a load (Lt) for each millimeter of distraction. In parallel, 18 periosteum samples were harvested from 9 cadaver mandibles. Uniaxial tensile tests were performed on the specimens and an estimated load (Lc) was calculated using periosteal stress-strain data and mandibular dimensions. During the distraction process, we observed an increase of the load Lt from 11.6 to 50.6 N. The periosteum exhibited a nonlinear viscoelastic stress-strain relationship, typical of biological tissues composed of collagen and elastin. The median Lc and Lt were not significantly different for the first millimeter of distraction. We demonstrated the periosteum is primarily responsible for opposing the distraction load.

Influence of a stormwater sediment deposit on microbial and biogeochemical processes in infiltration porous media.

The purpose of this study was to test the relative influence of organic matter quantity and quality and the pollutant content of a stormwater sediment deposit on mineralization processes, microbial characteristics, and the release of solutes in infiltration sediment systems. In microcosm experiments, two other natural sediment deposits (one low and one rich particulate organic matter deposits) were studied to compare their effects with those of the stormwater deposit. The results showed that the biogeochemical processes (aerobic respiration, denitrification, fermentative processes), the microbial metabolism (enzymatic activities), and the releases of several solutes (NH(4)(+) and DOC) were stimulated in presence of the stormwater deposit and the natural particulate organic matter (POM)-rich deposit because of the quantity of the POM in these deposits. In the stormwater deposit, the high availability of the POM (indicated by its low C/N ratio and its high P content) produced a higher stimulation of the microbial metabolism than in presence of the POM-rich deposit (with a high C/N ratio). Pollutant (hydrocarbon and heavy metal) contents of the stormwater deposit did not have a significant effect on microbial processes. Thus, main effects of the stormwater sedimentary deposit on infiltration system were due to its organic matter characteristics (quantity and quality). Such organic matter characteristics need to be considered in future studies to determine the contamination potential of stormwater management practices.

Do tubificid worms influence organic matter processing and fate of pollutants in stormwater sediments deposited at the surface of infiltration systems?

The purpose of this study was to quantify the influences of tubificid worms on the biogeochemical functioning of an infiltration system impacted by a stormwater sediment deposit. Effects of worms with stormwater sediment deposit were compared with effects of worms with two other natural sediment deposits (one low and one rich-particulate organic matter deposits). We measured the effects of invertebrates on sediment reworking, organic matter processing, solute fluxes, microbial characteristics, and pollutant release from stormwater deposit to water. Our results showed that tubificid worms had slight effects on microbial activities in presence of the stormwater deposit whereas they significantly stimulated microbial activities in columns impacted by the other two deposits. High contents of labile organic matter contained in stormwater sediments probably led to very strong microbial activities that could not be easily stimulated by worm activities. In our experimental conditions, no significant influence of tubificid worms on the fate of pollutants (heavy metals and PAHs) contained in the stormwater deposit was measured. In conclusion, our study demonstrated that the organic matter characteristics of the stormwater sediments limited the efficiency of tubificid worms to stimulate organic matter mineralization in infiltration systems.

Dynamo efficiency controlled by hydrodynamic bistability.

Hydrodynamic and magnetic behaviors in a modified experimental setup of the von Kármán sodium flow-where one disk has been replaced by a propeller-are investigated. When the rotation frequencies of the disk and the propeller are different, we show that the fully turbulent hydrodynamic flow undergoes a global bifurcation between two configurations. The bistability of these flow configurations is associated with the dynamics of the central shear layer. The bistable flows are shown to have different dynamo efficiencies; thus for a given rotation rate of the soft-iron disk, two distinct magnetic behaviors are observed depending on the flow configuration. The hydrodynamic transition controls the magnetic field behavior, and bifurcations between high and low magnetic field branches are investigated.