Using a Novel Microfabricated Model of the Alveolar-Capillary Barrier to Investigate the Effect of Matrix Structure on Atelectrauma

Abstract

The alveolar-capillary barrier is composed of epithelial and endothelial cells interacting across a fibrous extracelluar matrix (ECM). Although remodeling of the ECM occurs during several lung disorders, it is not known how fiber structure and mechanics influences cell injury during cyclic airway reopening as occurs during mechanical ventilation (atelectrauma). We have developed a novel in vitro platform that mimics the micro/nano-scale architecture of the alveolar microenvironment and have used this system to investigate how ECM microstructural properties influence epithelial cell injury during airway reopening. In addition to epithelial-endothelial interactions, our platform accounts for the fibrous topography of the basal membrane and allows for easy modulation of fiber size/diameter, density and stiffness. Results indicate that fiber stiffness and topography significantly influence epithelial/endothelial barrier function where increased fiber stiffness/density resulted in altered cytoskeletal structure, increased tight junction (TJ) formation and reduced barrier permeability. However, cells on rigid/dense fibers were also more susceptible to injury during airway reopening. These results indicate that changes in the mechanics and architecture of the lung microenvironment can significantly alter cell function and injury and demonstrate the importance of implementing in vitro models that more closely resemble the natural conditions of the lung microenvironment.

Polymer- and Hybrid-Based Biomaterials for Interstitial, Connective, Vascular, Nerve, Visceral and Musculoskeletal Tissue Engineering

“…As a result, it was found that the stiffness of hybrid matrices significantly affects the barrier function of the epithelium/endothelium. An increase in the rigidity or density of the matrix led to a change in the structure of the cytoskeleton and a change in cell permeability [178]. Reprinted from [173] with permission from Nature Publishing Group, © 2017.…”

“…Adherence of NCI-H292 cells; tuning mechanical properties of materials [177,178,248] bFGF and AA2P based PGA/PLA Improving cells adhesion and stimulates cells proliferation and differentiation [249] Kidney (Section 6.2) Mg(OH) 2 and acellular ECM PLGA Neutralization of the effects induced by degradation of PLGA products, suppression of inflammatory reactions [186] l-DOPA and collagen IV PCL Improving cells adhesion and proliferation [250] Liver (Section 6.3) ECM-molecules PLA Microenvironment manipulation; changes of gene expression, protein contents, and cell adherence [251] PCL [252] HGF based Gelatin Controlled release for enhancement of the in vivo therapeutic effects RGD and YIGSR based PCL and PLA Improved hepatocyte adhesion [196] Cardiac muscles (Section 7.1) bFGF based PLGA Neovascular formation [253] Laminin based PU Improving cells adhesion [254] Skeletal muscles (Section 7.2)…”

Mechanosensitive activation of mTORC1 mediates ventilator induced lung injury during the acute respiratory distress syndrome

“…An in vitro model of atelectrauma was used as previously described. (28,78) Briefly, polyacrylamide gels containing 10% w/w acrylamide (Bio-Rad) and 0.25% w/w bisacrylamide (Bio-Rad) were fabricated on 40 mm glass slides (20 kPa, 200 µm thickness).…”

Laminin-driven Epac/Rap1 regulation of epithelial barriers on decellularized matrix

“…Matrix proteins such as collagens, elastin, laminin, fibronectin, and glycosaminoglycans (GAGs) are preserved through the decellularization process, but there are reports of up to a 50% loss of most of these components compared to native ECM [32,33]. Variations in ECM composition and stiffness can have a profound effect on cell phenotype, as well as cell attachment and barrier function [34][35][36]. High collagen and fibronectin content promote cell attachment at the expense of suboptimal barriers, indicative of metastasis and fibrosis [37][38][39][40].…”