Organ Model: Respiratory System

Organ Model: Lung (Alveolus)

Applications: AAV

Abstract: Enhanced vascular permeability in the lungs can lead to pulmonary edema, impaired gas exchange, and ultimately respiratory failure. While oxygen delivery, mechanical ventilation, and pressure-reducing medications help alleviate these symptoms, they do not treat the underlying disease. Mechanical activation of transient receptor potential vanilloid 4 (TRPV4) ion channels contributes to the development of pulmonary vascular disease, and overexpression of the high homology (HH) domain of the TRPV4-associated transmembrane protein CD98 has been shown to inhibit this pathway. Here, we describe the development of an adeno-associated virus (AAV) vector encoding the CD98 HH domain in which the AAV serotypes and promoters have been optimized for efficient and specific delivery to pulmonary cells. AAV-mediated gene delivery of the CD98 HH domain inhibited TRPV4 mechanotransduction in a specific manner and protected against pulmonary vascular leakage in a human lung Alveolus-on-a-Chip model. As AAV has been used clinically to deliver other gene therapies, these data raise the possibility of using this type of targeted approach to develop mechanotherapeutics.

Organ Model: Lung (Alveolus)

Application: Immunology & Inflammation

Abstract: Here, we describe a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of the human lung. This bioinspired microdevice reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into the alveolar space. In nanotoxicology studies, this lung mimic revealed that cyclic mechanical strain accentuates toxic and inflammatory responses of the lung to silica nanoparticles. Mechanical strain also enhances epithelial and endothelial uptake of nanoparticulates and stimulates their transport into the underlying microvascular channel. Similar effects of physiological breathing on nanoparticle absorption are observed in whole mouse lung. Mechanically active “organ-on-a-chip” microdevices that reconstitute tissue-tissue interfaces critical to organ function may therefore expand the capabilities of cell culture models and provide low-cost alternatives to animal and clinical studies for drug screening and toxicology applications.