Predicting and understanding collagen remodeling in human native heart valves during early development.

The hemodynamic functionality of heart valves strongly depends on the distribution of collagen fibers, which are their main load-bearing constituents. It is known that collagen networks remodel in response to mechanical stimuli. Yet, the complex interplay between external load and collagen remodeling is poorly understood. In this study, we adopted a computational approach to simulate collagen remodeling occurring in native fetal and pediatric heart valves. The computational model accounted for several biological phenomena: cellular (re)orientation in response to both mechanical stimuli and topographical cues provided by collagen fibers; collagen deposition and traction forces along the main cellular direction; collagen degradation decreasing with stretch; and cell-mediated collagen prestretch. Importantly, the computational results were well in agreement with previous experimental data for all simulated heart valves. Simulations performed by varying some of the computational parameters suggest that cellular forces and (re)orientation in response to mechanical stimuli may be fundamental mechanisms for the emergence of the circumferential collagen alignment usually observed in native heart valves. On the other hand, the tendency of cells to coalign with collagen fibers is essential to maintain and reinforce that circumferential alignment during development. STATEMENT OF SIGNIFICANCE: The hemodynamic functionality of heart valves is strongly influenced by the alignment of load-bearing collagen fibers. Currently, the mechanisms that are responsible for the development of the circumferential collagen alignment in native heart valves are not fully understood. In the present study, cell-mediated remodeling of native human heart valves during early development was computationally simulated to understand the impact of individual mechanisms on collagen alignment. Our simulations successfully predicted the degree of collagen alignment observed in native fetal and pediatric semilunar valves. The computational results suggest that the circumferential collagen alignment arises from cell traction and cellular (re)orientation in response to mechanical stimuli, and with increasing age is reinforced by the tendency of cells to co-align with pre-existing collagen fibers.

Strain mediated enzymatic degradation of arterial tissue: Insights into the role of the non-collagenous tissue matrix and collagen crimp.

Collagen fibre remodelling is a strain dependent process which is stimulated by the degradation of existing collagen. To date, literature has focussed on strain dependent degradation of pure collagen or structurally simple collagenous tissues, often overlooking degradation within more complex, heterogenous soft tissues. The aim of this study is to identify, for the first time, the strain dependent degradation behaviour and mechanical factors influencing collagen degradation in arterial tissue using a combined experimental and numerical approach. To achieve this, structural analysis was carried out using small angle light scattering to determine the fibre level response due to strain induced degradation. Next, strain dependent degradation rates were determined from stress relaxation experiments in the presence of crude and purified collagenase to determine the tissue level degradation response. Finally, a 1D theoretical model was developed, incorporating matrix stiffness and a gradient of collagen fibre crimp to decouple the mechanism behind strain dependent arterial degradation. SALS structural analysis identified a strain mediated degradation response in arterial tissue at the fibre level not dissimilar to that found in literature for pure collagen. Interestingly, two distinctly different strain mediated degradation responses were identified experimentally at the tissue level, not seen in other collagenous tissues. Our model was able to accurately predict these experimental findings, but only once the load bearing matrix, its degradation response and the gradient of collagen fibre crimp across the arterial wall were incorporated. These findings highlight the critical role that the various tissue constituents play in the degradation response of arterial tissue. STATEMENT OF SIGNIFICANCE: Collagen fibre architecture is the dominant load bearing component of arterial tissue. Remodelling of this architecture is a strain dependent process stimulated by the degradation of existing collagen. Despite this, degradation of arterial tissue and in particular, arterial collagen, is not fully understood or studied. In the current study, we identified for the first time, the strain dependent degradation response of arterial tissue, which has not been observed in other collagenous tissues in literature. We hypothesised that this unique degradation response was due to the complex structure observed in arterial tissue. Based on this hypothesis, we developed a novel numerical model capable of explaining this unique degradation response which may provide critical insights into disease development and aid in the design of interventional medical devices.

Modelling The Combined Effects Of Collagen and Cyclic Strain On Cellular Orientation In Collagenous Tissues.

Adherent cells are generally able to reorient in response to cyclic strain. In three-dimensional tissues, however, extracellular collagen can affect this cellular response. In this study, a computational model able to predict the combined effects of mechanical stimuli and collagen on cellular (re)orientation was developed. In particular, a recently proposed computational model (which only accounts for mechanical stimuli) was extended by considering two hypotheses on how collagen influences cellular (re)orientation: collagen contributes to cell alignment by providing topographical cues (contact guidance); or collagen causes a spatial obstruction for cellular reorientation (steric hindrance). In addition, we developed an evolution law to predict cell-induced collagen realignment. The hypotheses were tested by simulating bi- or uniaxially constrained cell-populated collagen gels with different collagen densities, subjected to immediate or delayed uniaxial cyclic strain with varying strain amplitudes. The simulation outcomes are in agreement with previous experimental reports. Taken together, our computational approach is a promising tool to understand and predict the remodeling of collagenous tissues, such as native or tissue-engineered arteries and heart valves.

Efficient computational simulation of actin stress fiber remodeling.

Understanding collagen and stress fiber remodeling is essential for the development of engineered tissues with good functionality. These processes are complex, highly interrelated, and occur over different time scales. As a result, excessive computational costs are required to computationally predict the final organization of these fibers in response to dynamic mechanical conditions. In this study, an analytical approximation of a stress fiber remodeling evolution law was derived. A comparison of the developed technique with the direct numerical integration of the evolution law showed relatively small differences in results, and the proposed method is one to two orders of magnitude faster.

Mercury assessment and evaluation of its impact on fish in the Cecina river basin (Tuscany, Italy).

This paper reports the results of mercury contamination monitoring in the Cecina river basin (Tuscany, Italy). Mercury was measured in the waters, sediments and fish species of the river and its most important tributaries. In fish specimens the organic form was also determined. The results showed high mercury levels in most of the samples analysed. Particularly high concentrations were found in the sediments of the S. Marta canal flowing into the Cecina, where a chlor-alkali plant discharges its wastes, and high levels were still detectable 31 km downstream from the confluence. Near the S. Marta confluence many fish specimens were very contaminated and a study on Leuciscus cephalus cabeda growth suggested that at this site mercury accumulation occurs in these organisms since they are very young.

Lichen (Xanthoria parietina) biomonitoring of trace element contamination and air quality assessment in Pisa Province (Tuscany, Italy).

In the northern part of Pisa Province (Tuscany, Italy), the use of lichens as both airborne trace element biomonitors and air quality bioindicators is described. The following elements were analysed in Xanthoria parietina: As, Cd, Cr, Ni, Pb, V, Zn and Hg, and the results are compared with those we previously obtained in Livorno Province (Tuscany) using the same lichen species. The results identify spots of different environmental metal contamination and air quality. Median values of Pb, V and Ni concentrations were much lower than those of Livorno Province, with maximum values even nine times lower. Arsenic contamination was also lower, while Cd, Hg and Zn levels were similar in the two areas. In Pisa Province, the highest levels of contamination were recorded for Zn, Pb, Cr and Ni, and a degree of agreement was found between air quality and metal concentrations in lichens. The air quality in Pisa Province is better than in Livorno Province, even if the different climatic and orographic features of the two areas may influence the presence of lichen species and thus an assessment of air quality.

Assessment of water pollution and suitability to fish life in six Italian rivers.

This paper reports the results of a monitoring programme of six rivers (Serchio, Cecina, Cascina, ERa, Elsa and Pavone) that drain north-west Tuscany (Italy). In this area, agricultural, industrial and urbanization pressures affect water quality, also in terms of suitability for the survival of aquatic organisms. The river waters were monitored for several physico-chemical parameters (temperature, dissolved oxygen, suspended solids, total ammonia, nitrites, Cu, Cd, Cr, Ni and Pb) in order to assess the anthropogenic impact on the environmental conditions of these watercourses and their suitability for fish life. Statistical data handling was performed for each river and the percentage of physico-chemical parameters that, according to the E.C. law, were over the limits that must not be exceeded to protect fish life, was calculated and a classification was made of the six rivers in this sense. Concerning the metals, inter-element relationships (between chromium and nichel, lead and copper, nichel and lead and copper, copper and lead) were found which allow some remarks on the origins of the anthropogenic impacts, and comparisons were made with two metal-polluted watercourses in northern Italy, the Po and Lambro rivers. From the comparison, the Tuscan rivers showed generally lower metal contamination, especially with respect to the Lambro.

Mercury levels in agricultural products of Mt. Amiata (Tuscany, Italy).

This work assesses mercury in agricultural products of Mt. Amiata (central Italy), an area characterized by the presence of important HgS deposits, and by intense mercury mining and smelting activities in the past. The results show that at some sampling stations the Hg contents in vegetables, meat, and other products were high. The relations between agricultural products, soil and air mercury concentrations are discussed, and consideration is given to possible dangers to human health for residents of the Mt. Amiata area.