Microengineered alveolar array lung-on-chip with hydrogel membrane and simulated breathing mechanics for...

Area of Science:

• Biotechnology
• Biomaterials Engineering
• Respiratory Medicine

Background:

• Current in vitro models lack the biomechanical complexity of the human alveolar microenvironment.
• Replicating the native alveolar basement membrane's fragility and mechanical properties is challenging.
• Accurate, controlled micron-scale deflections are crucial for simulating breathing mechanics.

Purpose of the Study:

• To develop a lung-on-chip platform that accurately replicates the human alveolar microenvironment's biomechanical and structural features.
• To create a system for respiratory disease modeling and therapeutic evaluation.
• To enable preclinical testing of anti-fibrotic drugs.

Main Methods:

• Fabrication of a suspended hydrogel membrane (collagen and elastin) using precision injection molding.
• Co-culture of human alveolar epithelial cells and lung fibroblasts on the membrane.
• Application of cyclic mechanical stress mimicking respiratory movements and TGF-β1 stimulation.
• Pharmacological testing using the anti-fibrotic drug nintedanib.

Main Results:

• Cyclic stretching amplified fibrotic signaling, increasing extracellular matrix (ECM) component expression (collagen I, III, fibronectin) in the presence of TGF-β1.
• Nintedanib treatment reduced ECM protein and plasminogen activator inhibitor-1 (PAI-1) expression.
• The lung-on-chip system demonstrated reproducibility and facilitated medium-throughput operation.

Conclusions:

• The alveolar array-based lung-on-chip system effectively bridges the gap between conventional models and human lung physiology.
• This platform offers a robust tool for mechanistic studies of pulmonary fibrosis.
• It serves as a valuable system for preclinical evaluation of therapeutic interventions in respiratory diseases.