A microfluidic potassium ion-sensing chip platform incorporating PulmoForge X, a UV-cured biomimetic airway construct based on functionalized human 3D COPD spheroids, for GPCR-targeted natural product screening and efficacy evaluation

Chronic obstructive pulmonary disease (COPD) represents a major public health challenge. G protein-coupled receptors (GPCRs) represent a promising yet underexploited class of therapeutic targets for COPD. However, the lack of robust biological models and high-throughput screening tools capable of rapidly evaluating drug-induced GPCR activity has substantially hindered the development of GPCR-targeted therapies. Here, we report an integrated microphysiological platform for rapid and functionally relevant screening of GPCR-targeting therapeutics for COPD. Human COPD-derived cells were cultured into functional three-dimensional (3D) spheroids and used to engineer a novel biomimetic COPD airway model, designated PulmoForge X. PulmoForge X was subsequently incorporated into a microfluidic chip integrated with potassium-selective screen-printed electrodes and wireless electrochemical sensors, establishing the PulmoForge X-EC Chip System. By leveraging extracellular potassium (K⁺) dynamics as a real-time electrophysiological readout, this system sensitively captures integrated functional outcomes of drug-induced GPCR modulation, reflecting alterations in downstream GPCR signaling pathways and associated membrane potential changes. The PulmoForge X-EC Chip System enables ultra-rapid GPCR activity screening. Notably, the PulmoForge X-EC Chip System provides a human-relevant, animal substitution alternative for COPD drug discovery that aligns with the initiatives of the FDA Modernization Act 2.0.