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Updated: Jan 10, 2026
Generation of Human Nasal Epithelial Cell Spheroids for Individualized Cystic Fibrosis Transmembrane Conductance Regulator Study
Published on: April 11, 2018
Airway-to-Go: An Ex Vivo Cystic Fibrosis Airway Model and Bioreactor System for High Throughput Gene Therapy
Maria R Hudock1,2, Griffin W Daly1, Daniel Rivas1
1Department of Biomedical Engineering, Columbia University, New York, New York 10032, United States.
Abstract:
Despite three decades of progress since the cystic fibrosis transmembrane conductance regulator (CFTR) gene was discovered, there is still no gene therapeutic cure for the lethal pulmonary component of cystic fibrosis (CF). Existing CF models fall short of capturing all aspects of CF lung disease: animal models either develop gastrointestinal-only disease or are prohibitively expensive for large-scale experiments, while cell culture models lack both 3D tissue context and the thick inflammatory exudate barrier to airway-side delivery. To maximize translational potential, CF gene therapeutics must be tested on a model that captures all genotypic and phenotypic aspects of CF lung disease. Here, we combine three key innovations─(i) a grab-and-go, real-time, imaging-enabled bioreactor, (ii) an optimized tissue culture protocol for human and porcine airway explants, and (iii) a biophysical-bioelectrical barrier model of CF─to build the Airway-to-Go, a platform uniquely suited to high-throughput screening of candidate gene therapies for CF. Our air-liquid interface bioreactor design provides an even distribution of nebulized material and interfaces with a range of nondestructive monitoring technologies, including bioluminescence imaging, bioimpedance monitoring, and fluorescence microscopy in two planes. A Pneumacult-based tissue culture method enabled by new tissue holders supports both porcine and human CF airway explant structure and function for as long as 10 weeks. Disease model components that mimic the bioelectrical (via CFTR inhibition) and biophysical (via bioartificial mucus addition) barriers to gene delivery influence tissue inflammatory state and gene uptake, without causing toxicity. When these components were combined for a demonstrative gene delivery study using viral vectors, nondestructive readouts of gene delivery success revealed differences in gene uptake and expression due to CF-mimetic biophysical and bioelectrical barriers. This work establishes a built-for-purpose platform to accelerate translation of CF gene therapeutics, using porcine and human tissue explants as a steppingstone to clinical trials.
Insights
Researchers developed the Airway-to-Go platform to test cystic fibrosis (CF) gene therapies. This novel bioreactor system uses airway explants to better model CF lung disease for high-throughput screening of potential cures.
Area of Science:
- Biomedical Engineering
- Pulmonary Medicine
- Gene Therapy
Background:
- Cystic Fibrosis (CF) remains a lethal pulmonary disease without a gene therapeutic cure, despite decades of research.
- Current CF models (animal and cell culture) inadequately replicate the complex lung environment, hindering therapeutic development.
- Effective CF gene therapeutics require testing on models that fully capture genotypic and phenotypic aspects of the disease.
Purpose of the Study:
- To develop and validate a novel platform, Airway-to-Go, for high-throughput screening of cystic fibrosis gene therapeutics.
- To create a model that integrates key CF lung disease features, including 3D tissue context and biophysical/bioelectrical barriers.
- To accelerate the translation of CF gene therapies towards clinical trials.
Main Methods:
- Development of an imaging-enabled, air-liquid interface bioreactor for uniform nebulized material distribution.
- Optimization of a tissue culture protocol for human and porcine airway explants, maintaining structure and function for up to 10 weeks.
- Integration of disease model components mimicking CF's bioelectrical (CFTR inhibition) and biophysical (bioartificial mucus) barriers to gene delivery.
Main Results:
- The Airway-to-Go platform successfully supported human and porcine airway explants for extended periods.
- The integrated disease model components mimicked CF barriers without causing toxicity, influencing inflammatory state and gene uptake.
- Demonstrative gene delivery studies using viral vectors showed differential gene uptake and expression influenced by CF-mimetic barriers, validated by non-destructive imaging and bioimpedance.
Conclusions:
- The Airway-to-Go platform is a purpose-built system uniquely suited for high-throughput screening of CF gene therapeutics.
- This model advances CF research by providing a more accurate preclinical testing environment using human and porcine tissue explants.
- The platform represents a significant step towards accelerating the development and clinical translation of effective CF gene therapies.
