Inflation instability in the lung: an analytical model of a thick-walled alveolus with wavy fibres under large deformations.

Inflation of hollow elastic structures can become unstable and exhibit a runaway phenomenon if the tension in their walls does not rise rapidly enough with increasing volume. Biological systems avoid such inflation instability for reasons that remain poorly understood. This is best exemplified by the lung, which inflates over its functional volume range without instability. The goal of this study was to determine how the constituents of lung parenchyma determine tissue stresses that protect alveoli from instability-related overdistension during inflation. We present an analytical model of a thick-walled alveolus composed of wavy elastic fibres, and investigate its pressure-volume behaviour under large deformations. Using second-harmonic generation imaging, we found that collagen waviness follows a beta distribution. Using this distribution to fit human pressure-volume curves, we estimated collagen and elastin effective stiffnesses to be 1247 kPa and 18.3 kPa, respectively. Furthermore, we demonstrate that linearly elastic but wavy collagen fibres are sufficient to achieve inflation stability within the physiological pressure range if the alveolar thickness-to-radius ratio is greater than 0.05. Our model thus identifies the constraints on alveolar geometry and collagen waviness required for inflation stability and provides a multiscale link between alveolar pressure and stresses on fibres in healthy and diseased lungs.

Breath Hold Facilitates Targeted Deposition of Aerosolized Droplets in a 3D Printed Bifurcating Airway Tree.

The lungs have long been considered a desired route for drug delivery but, there is still a lack of strategies to rationally target delivery sites especially in the presence of heterogeneous airway disease. Furthermore, no standardized system has been proposed to rapidly test different ventilation strategies and how they alter the overall and regional deposition pattern in the airways. In this study, a 3D printed symmetric bifurcating tree model mimicking part of the human airway tree was developed that can be used to quantify the regional deposition patterns of different delivery methodologies. The model is constructed in a novel way that allows for repeated measurements of regional deposition using reusable parts. During ventilation, nebulized ~3-micron-sized fluid droplets were delivered into the model. Regional delivery, quantified by precision weighing individual airways, was highly reproducible. A successful strategy to control regional deposition was achieved by combining an inspiratory wave form with a "breath hold" pause after each inspiration. Specifically, the second generation of the tree was successfully targeted, and deposition was increased by up to four times in generation 2 when compared to a ventilation without the breath hold (p < 0.0001). Breath hold was also demonstrated to facilitate deposition into blocked regions of the model, which mimic airway closure during an asthma that receive no flow during inhalation. Additionally, visualization experiments demonstrated that in the absence of fluid flow, the deposition of 3-micron water droplets is dominated by gravity, which, to our knowledge, has not been confirmed under standard laboratory conditions.

Blood pressure-induced physiological strain variability modulates wall structure and function in aorta rings.

Vascular smooth muscle cells respond to mechanical stretch by reorganizing their cytoskeletal and contractile elements. Recently, we showed that contractile forces in rat aorta rings were maintained when the rings were exposed to 4 h of physiological variability in cycle-by-cycle strain, called variable stretch (VS), mimicking beat-to-beat blood pressure variability. Contractility, however, was reduced when the aorta was exposed to monotonous stretch (MS) with an amplitude equal to the mean peak strain of VS. OBJECTIVE: Here we reanalyzed the data to obtain wall stiffness as well as added new histologic and inhibitor studies to test the effects of VS on the extracellular matrix. MAIN RESULTS: The results demonstrate that while the stiffness of the aorta did not change during 4 h MS or VS, nonlinearity in mechanical behavior was slightly stronger following MS. The inhibitor studies also showed that mitochondrial energy production and cytoskeletal organization were involved in this fluctuation-driven mechanotransduction. Reorganization of ß-actin in the smooth muscle layer quantified from immunohistochemically labeled images correlated with contractile forces during contraction. Histologic analysis of wall structure provided evidence of reorganization of elastin and collagen fibers following MS but less so following VS. The results suggested that the loss of muscle contraction in MS was compensated by reorganization of fiber structure leading to similar wall stiffness as in VS. SIGNIFICANCE: We conclude that muscle tone modulated by variability in stretch plays a role in maintaining aortic wall structural and mechanical homeostasis with implications for vascular conditions characterized by a loss or an increase in blood pressure variability.

Design and nonlinear modeling of a sensitive sensor for the measurement of flow in mice.

OBJECTIVE: While many studies rely on flow and pressure measurements in small animal models of respiratory disease, such measurements can however be inaccurate and difficult to obtain. Thus, the goal of this study was to design and implement an easy-to-manufacture and accurate sensor capable of monitoring flow. APPROACH: We designed and 3D printed a flowmeter and utilized parametric (resistance and inertance) and nonparametric (polynomial and Volterra series) system identification to characterize the device. The sensor was tested in a closed system for apparent flow using the common mode rejection ratio (CMRR). The sensor properly measured tidal volumes and respiratory rates in spontaneously breathing mice. The device was used to evaluate a ventilator's ability to deliver a prescribed volume before and after lung injury. MAIN RESULTS: The parametric and polynomial models provided a reasonable prediction of the independently measured flow (Adjusted coefficient of determination [Formula: see text] = 0.9591 and 0.9147 respectively), but the Volterra series of the 1st, 2nd, and 3rd order with a memory of six time points provided better fits ([Formula: see text] = 0.9775, 0.9787, and 0.9954, respectively). At and below the mouse breathing frequency (1-5 Hz), CMRR was higher than 40 dB. Following lung injury, the sensor revealed a significant drop in delivered tidal volume. SIGNIFICANCE: We demonstrate that the application of nonparametric nonlinear Volterra series modeling in combination with 3D printing technology allows the inexpensive and rapid fabrication of an accurate flow sensor for continuously measuring small flows in various physiological conditions.