Modeling and Parameter Subset Selection for Fibrin Polymerization Kinetics with Applications to Wound Healing.

During the hemostatic phase of wound healing, vascular injury leads to endothelial cell damage, initiation of a coagulation cascade involving platelets, and formation of a fibrin-rich clot. As this cascade culminates, activation of the protease thrombin occurs and soluble fibrinogen is converted into an insoluble polymerized fibrin network. Fibrin polymerization is critical for bleeding cessation and subsequent stages of wound healing. We develop a cooperative enzyme kinetics model for in vitro fibrin matrix polymerization capturing dynamic interactions among fibrinogen, thrombin, fibrin, and intermediate complexes. A tailored parameter subset selection technique is also developed to evaluate parameter identifiability for a representative data curve for fibrin accumulation in a short-duration in vitro polymerization experiment. Our approach is based on systematic analysis of eigenvalues and eigenvectors of the classical information matrix for simulations of accumulating fibrin matrix via optimization based on a least squares objective function. Results demonstrate robustness of our approach in that a significant reduction in objective function cost is achieved relative to a more ad hoc curve-fitting procedure. Capabilities of this approach to integrate non-overlapping subsets of the data to enhance the evaluation of parameter identifiability are also demonstrated. Unidentifiable reaction rate parameters are screened to determine whether individual reactions can be eliminated from the overall system while preserving the low objective cost. These findings demonstrate the high degree of information within a single fibrin accumulation curve, and a tailored model and parameter subset selection approach for improving optimization and reducing model complexity in the context of polymerization experiments.

Application and reduction of a nonlinear hyperelastic wall model capturing ex vivo relationships between fluid pressure, area, and wall thickness in normal and hypertensive murine left pulmonary arteries.

Pulmonary hypertension is a cardiovascular disorder manifested by elevated mean arterial blood pressure (>20 mmHg) together with vessel wall stiffening and thickening due to alterations in collagen, elastin, and smooth muscle cells. Hypoxia-induced (type 3) pulmonary hypertension can be studied in animals exposed to a low oxygen environment for prolonged time periods leading to biomechanical alterations in vessel wall structure. This study introduces a novel approach to formulating a reduced order nonlinear elastic structural wall model for a large pulmonary artery. The model relating blood pressure and area is calibrated using ex vivo measurements of vessel diameter and wall thickness changes, under controlled pressure conditions, in left pulmonary arteries isolated from control and hypertensive mice. A two-layer, hyperelastic, and anisotropic model incorporating residual stresses is formulated using the Holzapfel-Gasser-Ogden model. Complex relations predicting vessel area and wall thickness with increasing blood pressure are derived and calibrated using the data. Sensitivity analysis, parameter estimation, subset selection, and physical plausibility arguments are used to systematically reduce the 16-parameter model to one in which a much smaller subset of identifiable parameters is estimated via solution of an inverse problem. Our final reduced one layer model includes a single set of three elastic moduli. Estimated ranges of these parameters demonstrate that nonlinear stiffening is dominated by elastin in the control animals and by collagen in the hypertensive animals. The pressure-area relation developed in this novel manner has potential impact on one-dimensional fluids network models of vessel wall remodeling in the presence of cardiovascular disease.