Fracture mechanics analysis of fibrin fibers using mesoscale and continuum level methods.

Computational models for simulating and predicting fibrin fiber fracture are important tools for studying bulk mechanical properties and mechanobiological response of fibrin networks in physiological conditions. In this work, we employed a new strategy to model the mechanical response of a single fibrin fiber using a collection of bundled protofibrils and modeled the time-dependent properties using discrete particle simulations. Using a systematic characterization of the parameters, this model can be used to mimic the elastic behavior of fibrin fibers accurately and also to simulate fibrin fiber fracture.

Multiscale Network Modeling of Fibrin Fibers and Fibrin Clots with Protofibril Binding Mechanics.

The multiscale mechanical behavior of individual fibrin fibers and fibrin clots wasmodeled by coupling atomistic simulation data and microscopic experimental data. We propose anew protofibril element composed of a nonlinear spring network, and constructed this based onmolecular simulations and atomic force microscopy results to simulate the force extension behaviorof fibrin fibers. This new network model also accounts for the complex interaction of protofibrilswith one another, the effects of the presence of a solvent, Coulombic attraction, and other bindingforces.

Recent advances in computational modeling of fibrin clot formation: A review.

The field of thrombosis and hemostasis is crucial for understanding and developing new therapies for pathologies such as deep vein thrombosis, diabetes related strokes, pulmonary embolisms, and hemorrhaging related diseases. In the last two decades, an exponential growth in studies related to fibrin clot formation using computational tools has been observed. Despite this growth, the complete mechanism behind thrombus formation and hemostasis has been long and rife with obstacles; however, significant progress has been made in the present century.

Physiochemical Effects of Nanoparticles on Cell Nuclear Complex Pore Transport: A Coarse-Grained Computational Model.

Understanding and controlling the interaction between nanoparticles and cell nuclei is critical to the development of the biomedical applications such as gene delivery, cellular imaging, and tumor therapy. Recent years have witnessed growing evidence that the size, shape, and the grafting density of the karyopherins ligands of nanoparticles provide a significant influence on the uptake mechanism of nanoparticles into cells; however, there is a lack of investigation into how these physical factors play a role in cellular nuclear uptake and how the nanoparticle enters the nucleus. Here, we build a computational framework to parametrically evaluate the effects of the size, shape, and the grafting density of the karyopherins ligands of designed nanoparticles on their transport through the nuclear pore complex of a cell nucleus so as to provide a novel scheme for nanoparticle design and precise nucleus-targeted therapy.

Flow plate separation of cells based on elastic properties: a computational study.

Medical studies have consistently shown that the best defense against cancer is early detection. Due to this, many efforts have been made to develop methods of screening patient blood quickly and cheaply. These methods range from separation via differences in size, electrostatic potential, chemical potential, antibody-binding affinity, among others.

Glucose Concentration Affects Fibrin Clot Structure and Morphology as Evidenced by Fluorescence Imaging and Molecular Simulations.

Although in vivo studies have been conducted in the past to determine hyperglycemic effects and influence on clotting risk in patients with diabetes, the true extent of hyperglycemia on unstable and spontaneous clot formation remains highly debated. Factors such as increased glycation, elevated fibrinogen concentration, elevated prothrombin levels, and decreased plasminogen are known to influence fibrin conversion, clot morphology, and thrombus formation in these individuals. In this regard, the isolated effects of hyperglycemia on irregular fibrin clot formation were investigated in a controlled fibrinogen system.

Human cathepsins K, L, and S: Related proteases, but unique fibrinolytic activity.

Background: Fibrin formation and dissolution are attributed to cascades of protease activation concluding with thrombin activation, and plasmin proteolysis for fibrin breakdown. Cysteine cathepsins are powerful proteases secreted by endothelial cells and others during cardiovascular disease and diabetes. Their fibrinolytic activity and putative role in hemostasis has not been well described.

Fibrin polymerization simulation using a reactive dissipative particle dynamics method.

The study on the polymerization of fibrinogen molecules into fibrin monomers and eventually a stable, mechanically robust fibrin clot is a persistent and enduring topic in the field of thrombosis and hemostasis. Despite many research advances in fibrin polymerization, the change in the structure of fibrin clots and its influence on the formation of a fibrous protein network are still poorly understood. In this paper, we develop a new computational method to simulate fibrin clot polymerization using dissipative particle dynamics simulations.

Molecular insights into the irreversible mechanical behavior of sickle hemoglobin.

Sickle cell disease is caused by the amino acid substitution of glutamic acid to valine, which leads to the polymerization of deoxygenated sickle hemoglobin (HbS) into long strands. These strands are responsible for the sickling of red blood cells (RBCs), making blood hyper-coagulable leading to an increased chance of vaso-occlusive crisis. The conformational changes in sickled RBCs traveling through narrow blood vessels in a highly viscous fluid are critical in understanding; however, there are few studies that investigate the origins of the molecular mechanical behavior of sickled RBCs.

ELECTROMAGNETICALLY INDUCED DISTORTION OF A FIBRIN MATRIX WITH EMBEDDED MICROPARTICLES.

Blood clots occur in the human body when they are required to prevent bleeding. In pathological states such as diabetes and sickle cell disease, blood clots can also form undesirably due to hypercoagulable plasma conditions. With the continued effort in developing fibrin therapies for potential life-saving solutions, more mechanical modeling is needed to understand the properties of fibrin structures with inclusions.

Coarse-grained molecular dynamics simulations of fibrin polymerization: effects of thrombin concentration on fibrin clot structure.

Studies suggest that patients with deep vein thrombosis and diabetes often have hypercoagulable blood plasma, leading to a higher risk of thromboembolism formation through the rupture of blood clots, which may lead to stroke and death. Despite many advances in the field of blood clot formation and thrombosis, the influence of mechanical properties of fibrin in the formation of thromboembolisms in platelet-poor plasma is poorly understood. In this paper, we combine the concepts of reactive molecular dynamics and coarse-grained molecular modeling to predict the complex network formation of fibrin clots and the branching of fibrin monomers.

Computational predictions of cysteine cathepsin-mediated fibrinogen proteolysis.

Fibrin clot formation is a proteolytic cascade of events with thrombin and plasmin identified as the main proteases cleaving fibrinogen precursor, and the fibrin polymer, respectively. Other proteases may be involved directly in fibrin(ogen) cleavage, clot formation, and resolution, or in the degradation of fibrin-based scaffolds emerging as useful tools for tissue engineered constructs. Here, cysteine cathepsins are investigated for their putative ability to hydrolyze fibrinogen, since they are potent proteases, first identified in lysosomal protein degradation and known to participate in extracellular proteolysis.

Molecular dynamics simulations indicate that deoxyhemoglobin, oxyhemoglobin, carboxyhemoglobin, and glycated hemoglobin under compression and shear exhibit an anisotropic mechanical behavior.

We developed a new mechanical model for determining the compression and shear mechanical behavior of four different hemoglobin structures. Previous studies on hemoglobin structures have focused primarily on overall mechanical behavior; however, this study investigates the mechanical behavior of hemoglobin, a major constituent of red blood cells, using steered molecular dynamics (SMD) simulations to obtain anisotropic mechanical behavior under compression and shear loading conditions. Four different configurations of hemoglobin molecules were considered: deoxyhemoglobin (deoxyHb), oxyhemoglobin (HbO), carboxyhemoglobin (HbCO), and glycated hemoglobin (HbA).

Computational imaging analysis of glycated fibrin gels reveals aggregated and anisotropic structures.

In this article, a computational imaging analysis method is presented for the evaluation of aggregation and anisotropy in both native (unglycated) and glycated fibrin matrix structures. The imaging analysis was used to test the hypothesis that glycated fibrin structures are more aggregated and anisotropic than unglycated (native) fibrin structures. Glycation of fibrinogen, and subsequently fibrin, occurs under normal physiological conditions; however, excess glycation due to disease states such as diabetes can disrupt the fibrin matrix and cause an abnormal structure and function.

Computational imaging analysis of fibrin matrices with the inclusion of erythrocytes from homozygous SS blood reveals agglomerated and amorphous structures.

Sickle cell disease is a single point mutation disease that is known to alter the coagulation system, leading to hypercoagulable plasma conditions. These hypercoagulable conditions can lead to complications in the vasculature, caused by fibrin clots that form undesirably. There is a need to understand the morphology and structure of fibrin clots from patients with sickle cell disease, as this could lead to further discovery of treatments and life-saving therapies.

Experimental and imaging techniques for examining fibrin clot structures in normal and diseased states.

Fibrin is an extracellular matrix protein that is responsible for maintaining the structural integrity of blood clots. Much research has been done on fibrin in the past years to include the investigation of synthesis, structure-function, and lysis of clots. However, there is still much unknown about the morphological and structural features of clots that ensue from patients with disease.

Experimental mechanics of magnetic microparticle-induced strain on fibrin clots.

In this study, a novel technique was developed in which magnetic microparticles (MMPs) and quantum dots (QDs) were successfully incorporated into fibrin clots. The MMPs were added at concentrations of 0.1 and 1 wt % of the fibrin content in an effort to determine if a magnetic field could be used to mechanically stretch the fibrin network, simulating how cells may invade a network.

Fatigue Response and Constitutive Behavior Modeling of Poly(ethylene terephthalate) Unreinforced and Nanocomposite Fibers Using Genetic Neural Networks.

The constitutive behavior of poly(ethylene terephthalate) (PET) unreinforced (control) and PET fibers reinforced with 5 wt% vapor-grown carbon nanofibers (VGCNFs) under uniaxial tension and subsequent to fatigue loading has been evaluated utilizing various analytical models. Two types of fatigue tests were performed: (1) Long cycle fatigue at 50 Hz (glassy fatigue) to evaluate fatigue resistance and (2) fatigue at 5 Hz (rubbery fatigue) to evaluate residual strength performance. The long cycle fatigue results at 50 Hz indicated that the PET-VGCNF sample exhibited an increased fatigue resistance of almost two orders of magnitude when compared to the PET unreinforced filament.

A modular fibrinogen model that captures the stress-strain behavior of fibrin fibers.

We tested what to our knowledge is a new computational model for fibrin fiber mechanical behavior. The model is composed of three distinct elements: the folded fibrinogen core as seen in the crystal structure, the unstructured α-C connector, and the partially folded α-C domain. Previous studies have highlighted the importance of all three regions and how they may contribute to fibrin fiber stress-strain behavior.