Biology subjects

Szafron, J. M.

Publications and source records attributed to Szafron, J. M..

7 recordsLinked to original sources

bioRxiv2026

Inherent Biomechanical Properties of the Lung: In vivo-Ex vivo Comparisons in Mice

Mammalian lungs operate within a thoracic "cage" composed of parietal pleura, rib cage, skeletal muscle, and diaphragm, yet clinical ventilator metrics largely reflect the combined mechanics of lung and surrounding structures and the thoracic cage. We hypothesized that thoracic boundary conditions selectively alter measured lung biomechanics. We performed paired pulmonary function testing (FlexiVent) in C57BL6 mice of both sexes spanning development through adulthood, measuring quasi-static pressure-volume behavior and dynamic forced-oscillation parameters in vivo (supine, mechanically ventilated) and again ex vivo in the same lungs. In a subset, we additionally compared in vivo and ex vivo {micro}CT-derived lung volumes, including a pressure-fixed ex vivo protocol using snap freezing at controlled inflation pressure. Quasi-static pressure-volume curves were similar between conditions, with near-identity at higher pressures and only modest divergence at low pressures, consistent with thoracic structures primarily modulating recruitment/de-recruitment rather than intrinsic elastic recoil. Maximal volume at 30 cmH2O showed strong in vivo-ex vivo correlation and minimal bias, and static compliance and PV-loop hysteresis exhibited small biases relative to reported disease-model effect sizes. In contrast, dynamic mechanics demonstrated a clear in vivo elevation of tissue damping (G) with only modest change in tissue elastance (H) and little change in Newtonian resistance (Rn), producing a meaningful increase in hysteresivity ( = G/H). This dissociation implicates frequency-dependent mechanical heterogeneity (e.g., time-constant mismatch/pendelluft) imposed or amplified by nonuniform thoracic loading. Ex vivo {micro}CT enabled reliable whole-lung segmentation and correlated with ex vivo PFT volumes at matched pressures, whereas in vivo volumetry showed weaker agreement. These results indicate that thoracic structures contribute modest restriction but disproportionately increase dynamic dissipation and heterogeneity, suggesting that ex vivo functional testing and oscillometry-like metrics may better detect biomechanical changes inherent to lung parenchyma.

physiology↗

bioRxiv2025

Development of an Open-source Low-cost Pressure Myography and Cardiac Flow Simulator, HemoLens, for Mechanical Characterization of Native and Engineered Blood Vessels

Pressure myography, the standard for assessing vascular mechanics and vasoreactivity, is costly ($40,000+), has low throughput, and is limited to static fluid flow. Here, we developed HemoLens, an open-source 3D-printed pressure myography system for [~]$700. HemoLens features compact micromanipulators, incremental in-line pressure control, physiological temperature regulation, and modular pulse pressure control between normotensive and hypertensive levels. HemoLens efficacy was demonstrated by delineation of physiological reactivity and pathological mechanical phenotypes using native mouse arteries and bioprinted acellular scaffolds. Wildtype vessels show greater distention (124.3 vs. 43.07 {micro}m) and increased dynamic compliance compared to diseased vessels. Small diameter (450 {micro}m) collagen-based artery-like scaffolds are FRESH bioprinted to mimic hypertensive vascular stiffening. Engineered hypertensive vessels demonstrate increased burst pressure (464 mmHg) and reduced dynamic compliance reminiscent of diseased arteries. Together, HemoLens lowers the barrier to entry in pressure myography research by serving as a comprehensive low-cost system for native and engineered vessel characterization. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/651300v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@6b87d0org.highwire.dtl.DTLVardef@1a17b5eorg.highwire.dtl.DTLVardef@aa6056org.highwire.dtl.DTLVardef@19ac816_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Hypoxia-Induced Cardiopulmonary Remodeling and Recovery: Critical Roles of the Proximal Pulmonary Artery, Macrophages, and Exercise

Hypoxemia impairs cardiopulmonary function. We investigated pulmonary artery remodeling in mice exposed to chronic hypoxia for up to five weeks and quantified associated changes in cardiac and lung function, without or with subsequent normoxic recovery in the absence or presence of exercise or pharmacological intervention. Hypoxia-induced stiffening of the proximal pulmonary artery stemmed primarily from remodeling of the adventitial collagen, which resulted in part from altered inter-cellular signaling associated with phenotypic changes in the mural smooth muscle cells and macrophages. Such stiffening appeared to precede and associate with both right ventricular and lung dysfunction, with changes emerging to similar degrees regardless of the age of onset of hypoxia during postnatal development. Key homeostatic target values of the wall mechanics were recovered by the pulmonary arteries with normoxic recovery while other values recovered only partially. Overall cardiopulmonary dysfunction due to hypoxia was similarly only partially reversible. Remodeling of the cardiopulmonary system due to hypoxia is a complex, multi-scale process that involves maladaptations of the proximal pulmonary artery.

physiology↗

bioRxiv2024

High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension

Pathological high shear stress (HSS, 100 dyn/cm2) is generated in distal pulmonary arteries (PA) (100-500 m) in congenital heart defects and in progressive PA hypertension (PAH) with inward remodeling and luminal narrowing. Human PA endothelial cells (PAEC) were subjected to HSS versus physiologic laminar shear stress (LSS, 15 dyn/cm2). Endothelial-mesenchymal transition (EndMT), a feature of PAH not previously attributed to HSS, was observed. H3K27ac peaks containing motifs for an ETS-family transcription factor (ERG) were reduced, as was ERG-Kruppel-like factors (KLF)2/4 interaction and ERG expression. Reducing ERG by siRNA in PAEC during LSS caused EndMT; transfection of ERG in PAEC under HSS prevented EndMT. An aorto-caval shunt was preformed in mice to induce HSS and progressive PAH. Elevated PA pressure, EndMT and vascular remodeling were reduced by an adeno-associated vector that selectively replenished ERG in PAEC. Agents maintaining ERG in PAEC should overcome the adverse effect of HSS on progressive PAH.

cell biology↗

bioRxiv2023

Instability in computational models of vascular smooth muscle cell contraction

PurposeThrough their contractile and synthetic capacity, vascular smooth muscle cells play a key role in regulating the stiffness and resistance of the circulation. To model the contraction of blood vessels, an active stress component can be added to the (passive) Cauchy stress tensor. Different constitutive formulations have been proposed to describe this active stress component. Notably, however, the ex vivo measurement of the biomechanical behaviour of contacted blood vessels presents several experimental challenges, which complicate the acquisition of comprehensive data sets to inform complex active stress models. In this work, we examine formulations for use with limited experimental contraction data as well as those developed to capture more comprehensive data sets. MethodsWe prove analytically that a subset of these formulations exhibits unstable behaviours (i.e., a non-unique diameter solution for a given pressure) in certain parameter ranges, particularly when contractile deformations are large. Furthermore, using experimental literature data, we present two case studies where these active stress models are used to capture the contractile response of vascular smooth muscle cells in the presence of 1) limited and 2) extensive contraction data. ResultsOur work shows how limited contraction data complicates the selection of an appropriate active stress model for vascular applications, potentially resulting in unrealistic modelled behaviours. ConclusionAs such, the data presented herein provide a useful reference for the selection of an active stress model which balances the trade-off between accuracy and the available biomechanical information.

biophysics↗

bioRxiv2023

A Computational Growth and Remodeling Framework for Adaptive and Maladaptive Pulmonary Arterial Hemodynamics

Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step towards predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.

bioengineering↗

bioRxiv2020

Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth

The umbilical artery lumen occludes rapidly at birth, preventing blood loss, whereas the umbilical vein remains patent, providing the newborn with a placental infusion. Here, we identify differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. We show that the umbilical artery, unlike the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism elicited by biomechanical and computational analysis. Vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown in umbilical vessels. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrated their opposing roles in umbilical cord arterial-venous dimorphism and contrasting effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that their differential proteoglycan dynamics were a positive selection step in mammalian evolution.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗