February 21, 2024

Researchers have built a lung in the lab that mimics the human lung more accurately than conventional models, opening the door to fast-track drug discovery and development and reducing our reliance on animals for testing.

Lung disease is the leading cause of death worldwide. According to the World Health Organization (WHO), chronic obstructive pulmonary disease (COPD) will become the third leading cause of death by 2030 due to worsening air quality and the aftermath of COVID-19.

COPD is an incurable disease that blocks the small airways in the lungs, making breathing difficult, with smoking and air pollution being the most common causes. Current treatments cannot reverse the damage done to lung tissue. While newer treatments, such as stem cell-based drugs, have shown the ability to repair or prevent lung deterioration, there is a notable lack of new therapies approved to treat lung disease.

Traditionally, animal models have been required to develop and test new drugs for COPD. The problem with using animals for testing is that some aspects of their anatomy and physiology differ from humans, and many animal models do not allow aerosol drug testing.

Recently, progress has been made in developing alternatives to animal models. Organ-on-a-chip, organoids — 3D structures grown from human cells that mimic real organs — and 3D-printed organs are good examples. But they also have drawbacks, often related to their small size, limited cell numbers and lack of similarity to the complex structures and processes of the human lung. But now, a team led by researchers at the University of Sydney has created lungs that more accurately mimic human lungs.

“In traditional cell culture, you put cells in a dish and grow them under static conditions, which is a far cry from what happens in humans,” said Thanh Huyen Phan, lead author of the study. “What we’re doing is creating environmental conditions similar to those that exist in the human body.”

The researchers took the cells directly from the patient and arranged them in layers, just as they appeared in the body.

“We take the cells directly from the patient and we build them in layers because they exist in the body,” said Wojciech Chrzanowski, corresponding author of the study. “So, first you have epithelial cells, then you have fibroblasts— — we’re actually creating a simulated organ that closely resembles real human lungs.”

The lung model is kept under the same environmental conditions as the real lung, with air on one side and liquid on the other. The interface is combined with microcirculation to simulate the circulatory system of the human body. The researchers created two lung models for different purposes.

“We decided to create two different lung models, one of which mimics a phase 1 clinical trial; a healthy lung to study the safety of new drugs,” Chrzanowski said. “Another trial that mimics a phase 2; a diseased lung that, in our case, mirrored COPD, allowing us to study the therapeutic effect or advantage of the drug.”

But lung models can be used for more than just drug testing.

“These miniature lung organoid models can also be used to test toxicity,” Chrzanowski said. “For example, silica dust or air pollutants such as particles produced during bushfires.”

And, more importantly, they can be personalized.

“Because we can take cells directly from individual patients, we can create models of the patients themselves to test the effectiveness of drugs on them,” Chrzanowski said.

In addition to offering an alternative to animal testing, the strengths of their lab-made lungs lie in their reproducibility, reliability, and ability to conduct large-scale studies in a cost-effective manner, the researchers say.

“They speed up the discovery process and shorten the transition to the clinic, but also greatly increase our confidence in the molecules we create before going into clinical trials,” Chrzanowski said. “The normal timeline for clinical translation of drugs is about 10 to 10 15 years, but when you use organoid models, you can dramatically reduce that time.”

The study was published in the journal Biomaterials Research.

source: University of Sydney