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A constitutive model for a maturing fibrin network.

ABSTRACT: Blood clot formation is crucial to maintain normal physiological conditions but at the same time involved in many diseases. The mechanical properties of the blood clot are important for its functioning but complicated due to the many processes involved. The main structural component of the blood clot is fibrin, a fibrous network that forms within the blood clot, thereby increasing its mechanical rigidity. A constitutive model for the maturing fibrin network is developed that captures the evolving mechanical properties. The model describes the fibrin network as a network of fibers that become thicker in time. Model parameters are related to the structural properties of the network, being the fiber length, bending stiffness, and mass-length ratio. Results are compared with rheometry experiments in which the network maturation is followed in time for various loading frequencies and fibrinogen concentrations. Three parameters are used to capture the mechanical behavior including the mass-length ratio. This parameter agrees with values determined using turbidimetry experiments and is subsequently used to derive the number of protofibrils and fiber radius. The strength of the model is that it describes the mechanical properties of the maturing fibrin network based on it structural quantities. At the same time the model is relatively simple, which makes it suitable for advanced numerical simulations of blood clot formation during flow in blood vessels.

SUBMITTER: van Kempen THS

PROVIDER: S-EPMC4104056 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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A constitutive model for a maturing fibrin network.

van Kempen Thomas H S THS Bogaerds Arjen C B ACB Peters Gerrit W M GWM van de Vosse Frans N FN

Biophysical journal 20140701 2

Blood clot formation is crucial to maintain normal physiological conditions but at the same time involved in many diseases. The mechanical properties of the blood clot are important for its functioning but complicated due to the many processes involved. The main structural component of the blood clot is fibrin, a fibrous network that forms within the blood clot, thereby increasing its mechanical rigidity. A constitutive model for the maturing fibrin network is developed that captures the evolvin ...[more]

PMID: 25028892

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Project description:Hydrogels are effective platforms for use as artificial extracellular matrices, cell carriers, and to present bioactive cues. Two common natural polymers, fibrin and alginate, are broadly used to form hydrogels and have numerous advantages over synthetic materials. Fibrin is a provisional matrix containing native adhesion motifs for cell engagement, yet the interplay between mechanical properties, degradation, and gelation rate is difficult to decouple. Conversely, alginate is highly tunable yet bioinert and requires modification to present necessary adhesion ligands. To address these challenges, we developed a fibrin-alginate interpenetrating network (IPN) hydrogel to combine the desirable adhesion and stimulatory characteristics of fibrin with the tunable mechanical properties of alginate. We tested its efficacy by examining capillary network formation with entrapped co-cultures of mesenchymal stromal cells (MSCs) and endothelial cells (ECs). We manipulated thrombin concentration and alginate crosslinking density independently to modulate the fibrin structure, mesh size, degradation, and biomechanical properties of these constructs. In IPNs of lower stiffness, we observed a significant increase in total cell area (1.7 × 105 ± 7.9 × 104 µm2) and decrease in circularity (0.56 ± 0.03) compared to cells encapsulated in stiffer IPNs (4.0 × 104 ± 1.5 × 104 µm2 and 0.77 ± 0.09, respectively). Fibrinogen content did not influence capillary network formation. However, higher fibrinogen content led to greater retention of these networks confirmed via increased spreading and presence of F-actin at 7 days. This is an elegant platform to decouple cell adhesion and hydrogel bulk stiffness that will be broadly useful for cell instruction and delivery. STATEMENT OF SIGNIFICANCE: Hydrogels are widely used as drug and cell delivery vehicles and as artificial extracellular matrices to study cellular responses. However, there are limited opportunities to simultaneously control mechanical properties and degradation while mimicking the complex native adhesion motifs and ligands known to encourage cell engagement with the hydrogel. In this study, we describe a fibrin-alginate interpenetrating network (IPN) hydrogel designed to balance the compliance and provisional qualities of fibrin with the mechanical stability and tunability of alginate to interrogate these contributions on cell response. We used clinically relevant cell sources, a co-culture of endothelial cells and mesenchymal stromal cells, to test its efficacy in supporting capillary formation in vitro. These data demonstrate the promise of this IPN for use in tissue engineering.

Project description:Proper wound healing necessitates both coagulation (the formation of a blood clot) and fibrinolysis (the dissolution of a blood clot). A thrombus resistant to clot dissolution can obstruct blood flow, leading to vascular pathologies. This study seeks to understand the mechanisms by which individual fibrin fibers, the main structural component of blood clots, are cleared from a local volume during fibrinolysis. We observed 2-D fibrin networks during lysis by plasmin, recording the clearance of each individual fiber. We found that, in addition to transverse cleavage of fibers, there were multiple other pathways by which clot dissolution occurred, including fiber bundling, buckling, and collapsing. These processes are all influenced by the concentration of plasmin utilized in lysis. The network fiber density influenced the kinetics and distribution of these pathways. Individual cleavage events often resulted in large morphological changes in network structure, suggesting that the inherent tension in fibers played a role in fiber clearance. Using images before and after a cleavage event to measure fiber lengths, we estimated that fibers are strained ~23% beyond their equilibrium length during polymerization. To understand the role of fiber tension in fibrinolysis we modeled network clearance under differing amounts of fiber polymerized strain (prestrain). The comparison of experimental and model data indicated that fibrin tension enables 35% more network clearance due to network rearrangements after individual cleavage events than would occur if fibers polymerized in a non-tensed state. Our results highlight many characteristics and mechanisms of fibrin breakdown, which have implications on future fibrin studies, our understanding of the fibrinolytic process, and the development of thrombolytic therapies. STATEMENT OF SIGNIFICANCE: Fibrin fibers serve as the main structural element of blood clots. They polymerize under tension and have remarkable extensibility and elasticity. After the cessation of wound healing, fibrin must be cleared from the vasculature by the enzyme plasmin in order to resume normal blood flow: a process called fibrinolysis. In this study we investigate the mechanisms that regulate the clearance of individual fibrin fibers during fibrinolysis. We show that the inherent tension in fibers enhances the action of plasmin because every fiber cleavage event results in a redistribution of the network tension. This network re-equilibration causes fibers to buckle, bundle, and even collapse, leading to a more rapid fiber clearance than plasmin alone could provide.

Dataset Information

A constitutive model for a maturing fibrin network.

Publications

A constitutive model for a maturing fibrin network.

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