Sophie Rausch

Material model of lung parenchyma based on living precision-cut lung slice testing

We describe a novel constitutive model of lung parenchyma, which can be used for continuum mechanics based predictive simulations. To develop this model, we experimentally determined the nonlinear material behavior of rat lung parenchyma. This was achieved via uni-axial tension tests on living precision-cut rat lung slices. The resulting force-displacement curves were then used as inputs for an inverse analysis. The Levenberg-Marquardt algorithm was utilized to optimize the material parameters of combinations and recombinations of established strain-energy density functions (SEFs). Comparing the best-fits of the tested SEFs we found Wpar = 4.1 kPa(I1-3)2 + 20.7 kPa(I1 - 3)3 + 4.1 kPa(-2 ln J + J2 - 1) to be the optimal constitutive model. This SEF consists of three summands: the first can be interpreted as the contribution of the elastin fibers and the ground substance, the second as the contribution of the collagen fibers while the third controls the volumetric change. The presented approach will help to model the behavior of the pulmonary parenchyma and to quantify the strains and stresses during ventilation.

Local Strain Distribution in Real Three-Dimensional Alveolar Geometries

Mechanical ventilation is not only a life saving treatment but can also cause negative side effects. One of the main complications is inflammation caused by overstretching of the alveolar tissue. Previously, studies investigated either global strains or looked into which states lead to inflammatory reactions in cell cultures. However, the connection between the global deformation, of a tissue strip or the whole organ, and the strains reaching the single cells lining the alveolar walls is unknown and respective studies are still missing. The main reason for this is most likely the complex, sponge-like alveolar geometry, whose three-dimensional details have been unknown until recently. Utilizing synchrotron-based X-ray tomographic microscopy, we were able to generate real and detailed three-dimensional alveolar geometries on which we have performed finite-element simulations. This allowed us to determine, for the first time, a three-dimensional strain state within the alveolar wall. Briefly, precision-cut lung slices, prepared from isolated rat lungs, were scanned and segmented to provide a three-dimensional geometry. This was then discretized using newly developed tetrahedral elements. The main conclusions of this study are that the local strain in the alveolar wall can reach a multiple of the value of the global strain, for our simulations up to four times as high and that thin structures obviously cause hotspots that are especially at risk of overstretching.

Characteristics of highly flexible PDMS membranes for long-term mechanostimulation of biological tissue.

Measurement of mechanical properties of soft biological tissue remains a challenging task in mechanobiology. Recently, we presented a bioreactor for simultaneous mechanostimulation and analysis of the mechanical properties of soft biological tissue samples. In this bioreactor, the sample is stretched via deflection of a flexible membrane. It was found that the use of highly compliant membranes increases accuracy of measurements. Here, we describe the production process and characteristics of thin and flexible membranes of polydimethylsiloxane (PDMS) designed to improve the signal-to-noise ratio of our bioreactor. By a spin-coating process, PDMS membranes were built by polymerization of a two component elastomer. The influence of resin components proportion, rotation duration, and speed of the spinning were related to the membrane mechanics. Membranes of 22 mm inner diameter and 33 to 36 microm thickness at homogeneous profiles were produced. Isolated rat diaphragms served as biological tissue samples. Mechanical properties of the membranes remained constant during 24 h of mechanostimulation. In contrast, time- and strain-dependent mechanical properties of the diaphragms were found.

Advanced Multi-scale Modelling of the Respiratory System

This chapter is concerned with computational modelling of the respiratory system against the background of acute lung diseases and mechanical ventilation. Conceptually, we divide the lung into two major subsystems, namely the conducting airways and the respiratory zone. Due to their respective complexity, both parts are out of range for a simulation resolving all relevant length scales. Therefore, we develop novel multi-scale approaches taking into account the unresolved parts appropriately. In the respiratory zone, an alveolar ensemble is modelled considering not only tissue behaviour but also the influence of the covering surfactant film. On the global scale, a homogenised parenchyma model is derived from experiments on living lung tissue. At certain hotspots, novel nested multi-scale procedures are utilised to simulate the dynamic behaviour of lung parenchyma as a whole while still resolving alveolar scales locally. In the tracheo-bronchial region, CT-based geometries are employed in fluid-structure interaction simulations. Physiological outflow boundary conditions are derived by considering the impedance of the unresolved parts of the lung in a fully coupled 3D-0D procedure. Finally, a novel coupling approach enables the connection of 3D parenchyma and airway models into one overall lung model for the first time.

Computational Modelling of the Respiratory System for Improvement of Mechanical Ventilation Strategies

This paper is concerned with a brief outline of our computational models of the respiratory system against the background of acute lung diseases and mechanical ventilation. We divide the lung into two major subsystems, namely the conducting airways and the respiratory zone represented by lung parenchyma. Due to their respective complexity, both parts are themselves out of range for a direct numerical simulation resolving all relevant length scales. Therefore, we develop detailed individual models for parts of the subsystems as a basis for novel multi-scale approaches taking into account the unresolved parts appropriately. In the tracheo-bronchial region, CT-based geometries up to a maximum of approximately seven generations are employed in fluid-structure interaction simulations, considering not only airway wall deformability but also the influence of surrounding lung tissue. Physiological outflow boundary conditions are derived by considering the impedance of the unresolved parts of the lung in a fully coupled 3D-1D approach. In the respiratory zone, an ensemble of alveoli representing a single ventilatory unit is modeled considering not only soft tissue behavior but also the influence of the covering surfactant film. Novel nested multi-scale procedures are then employed to simulate the dynamic behavior of lung parenchyma as a whole and local alveolar ensembles simultaneously without resolving the alveolar micro-structure completely.

Coupled and Multi-Scale Building Blocks for a Comprehensive Computational Lung Model

Mechanical ventilation is a vital supportive therapy for critical care patients suffering from Acute Respiratory Distress syndrome (ARDS) or Acute Lung Injury (ALI) in view of oxygen supply. However, a number of associated complications often occur, which are collectively termed ventilator induced lung injuries (VILI) [1]. Biologically, these diseases manifest themselves at the alveolar level and are characterized by inflammation of the lung parenchyma following local overdistension or high shear stresses induced by frequent alveolar recruitment and derecruitment. Despite the more recent adoption of protective ventilation strategies based on the application of lower tidal volumes and a positive end-expiratory pressure (PEEP), patient mortality rates are with approximately 40% still very high. Understanding the reason why the lungs still become damaged or inflamed during mechanical ventilation is a key question sought by the medical community. In this contribution, an overview on recently developed building blocks of a comprehensive lung model will be given, with a main focus on lower airways.Copyright

MECHANICAL TESTING AND INVERSE ANALYSIS FOR DEVELOPING A MATERIAL MODEL OF LUNG PARENCHYMA

The mechanical ventilation of patients with Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI) is a life saving treatment. However, insufficient understanding of lung mechanics can cause overstraining of the parenchymal tissue resulting in additional inflammatory injuries. These ventilation induced lung injuries (VILI) are mainly occurring in the alveolar tissue. The goal of our research is to improve mechanical ventilation, and thus to reduce the frequency and severity of VILI. Our research focuses on the development of different computational models that should serve a better understanding of the lung [Wiechert, 2007]. We are working on different projects concerning this complex multiscale problem. Since VILI occur mainly in the alveolar tissue, this work concentrates on a better understanding and modeling of this tissue. Our aim is to come up with accurate material models of parenchymal lung tissue. Currently our work is based on two material models for soft biological tissue that are already implemented in our research code [Holzapfel, 2001], [Itskov, 2006]. By mechanically testing tissue slices we will be able to determine appropriate material parameters of alveolar tissue more precisely and use these in our model development.