Summary:
UCLA researchers in the Department of Medicine and Environmental Health Sciences have developed a ventilated human lung system for laboratory testing of inhaled substances.
Background:
Measuring the toxicology of inhaled air, aerosols and other substances is challenging due to the complexity of human studies and limitations in existing testing methods. Additionally, individual differences in genetics, behavior, and/or environment make it difficult to detect early responses to inhalation exposures, often requiring decades of observation across large populations. While animal studies have historically played a key role, fundamental differences in respiratory physiology, exposure conditions, and regenerative properties limit their relevance to human outcomes. Additionally, ethical concerns further drive the need for alternative approaches. Recent advances in testing systems, such as organotypic air-liquid-interface (ALI) airway cultures derived from human airway progenitors, offer a promising approach for studying exposure toxicity in lung tissues in more physiologically relevant conditions. However, these models often fail to capture key dynamic features such as region-specific aerosol exposure and deposition patterns, breathing-induced pressure changes, and the impact of the unique lung environment (warm, humid, high CO2) on aerosol transformation. Additionally, serial dilution and clearance mechanisms that occur with each breath are rarely considered. To address these gaps, there is a critical need for artificial testing systems that accurately simulate region-specific intrapulmonary exposures conditions.
Innovation:
UCLA researchers have developed an artificial lung system to bridge the critical gaps in inhalation toxicology testing. This system mimics the size and anatomical shape of human lungs and incorporates 3D-printed models of the respiratory tract extending from the mouth to multiple airway branches to replicate region-specific airflow and exposure patterns. A programmable ventilation system that integrates customized gas sources along with heating and humidification allows the user to simulate a broad range of realistic breathing patterns, airflow patterns and lung environmental conditions that can be operated under either positive or negative pressure conditions. Mechanisms for regulating chamber compliance replicate the cyclical pressure changes that lung tissues are exposed to in vivo. The exposure system can be readily adapted to inhale from a generated exposure environment or to integrate puffs of a generated aerosol (to simulate drug exposure, smoking, vaping, etc.) that are inhaled with a breath. A variety of monitoring ports and equipment can be adapted to provide real-time measures of the exposure conditions occurring at different regions within the system. Each component can be individually controlled, altered, and monitored to understand its impact on inhalational biology and exposures. The exposure system can operate in an exposure assessment mode (non-sterile) or a lung tissue exposure mode (sterile) in which ALI cultures or lung tissue sections can be repeatedly exposed within the simulated lung over time. Validation studies using e-cigarette aerosols and artificial microparticles have demonstrated its ability to measure deposition patterns and detect subtle biological responses in human airway cultures. This system provides a significant and novel advancement in the ability to recreate and test intrapulmonary exposure conditions and toxicology of the lung.
Potential Applications:
• Inhalation toxicology research for pollutants, vaping, industrial chemicals, etc.
• Drug delivery testing for aerosolized medicines
• Development of safer consumer products
• Biomedical research on lung diseases and respiratory therapies
Advantages:
• Realistic simulator of human lung anatomy and function that integrates ongoing breathing with controlled inhalation exposures
• Controlled and reproducible intrapulmonary exposure conditions
• Integrated monitoring systems in various locations of the pathway
• Ability to assess biological response in human airway cultures, including specific components of the airway pathway
• Reduces reliance on animal testing and human clinical trials
• Adaptable for various inhalation studies and future advancements
Development-To-Date:
Two abstracts describing the features and performance have been presented at the American Association for Aerosol Research and two related peer-reviewed publications are available.
Related Papers and Patents:
1. Li, L., Chen, H., Zhu, Y. Harui, A, Roth, M.D. (2024). Ventilation and features of the lung environment dynamically alter modeled intrapulmonary aerosol exposure from inhaled electronic cigarettes. Sci Rep 14 (1):31683. https://doi.org/10.1038/s41598-024-81066-x
2. Chen, H., Harui, A., Feng, Y., Li, L., Patel, S., Schmidt, J., Roth, M. D., & Zhu, Y. (2024). A ventilated three-dimensional artificial lung system for human inhalation exposure studies. Environmental Science & Technology, 58(52):22919-22929. doi: 10.1021/acs.est.4c08315
3. Chen H, Harui A, Feng Y, Roth MD, Zhu Y. An artificial lung model for characterizing deposition of e-cigarette aerosols in human tracheobronchial airways. American Association for Aerosol Research (AAAR), Raleigh, North Carolina, October 3-7, 2022 (Abstract only)
4. Li L, Chen H, Harui A, Roth MD, Zhu Y. Development of a ventilated artificial lung model for characterizing the physicochemical properties of inhaled e-cigarette aerosols. American Association of Aerosol Research (AAAR). Albuquerque, New Mexico, October 18-22, 2021 (Abstract only)
Reference:
UCLA Case No. 2023-306