Lung Tissue Chip Enables Accurate Testing of Potential PF Therapies, Study Reports
A new in vitro lung tissue-on-a-chip system mimics tissue stiffening in pulmonary fibrosis (PF), and offers an accurate and rapid way to test treatment candidates, according to a new study.
The study, “Fibrotic microtissue array to predict anti-fibrosis drug efficacy,” was published in the journal Nature Communications.
Patients with idiopathic PF can currently be treated with two approved medications that help slow disease worsening — Esbriet (pirfenidone) marketed by Genentech, and Ofev (nintedanib), by Boehringer Ingelheim.
Advancing new treatments for lung fibrosis, or scarring, into clinical practice presents challenges such as the slow progression of the disease in animal models used in preclinical studies, and prolonged and expensive clinical trials in patients.
In vitro screening assays are, therefore, needed to collect early evidence of the effectiveness of potential therapies.
PF progression is characterized by tissue stiffening in the lungs’ alveoli, or tiny air sacs, caused by the buildup of a collagen-producing type of cell called myofibroblasts. Although various in vitro approaches have been developed to model PF, they have some drawbacks, such as a limited capacity to reproduce lung tissue mechanics.
To address these issues, bioengineers, from the University at Buffalo in New York and the University of Toronto in Canada, developed a 3D human lung tissue-on-a chip system. This type of high-throughput system mimics, to some extent, the structure and composition of human tissues, and enables testing treatment responses in conditions similar to those in the body, according to the scientists.
They used a technique called microlithography to print arrays of tiny squares, with micropillars as thin as a human hair placed around the edges of each square. The approach replicated the thin morphology of the alveoli of both healthy and fibrotic lungs, and enabled the stretching of lung tissue over the micropillars.
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The grown tissue is composed of a collagen matrix similar to the human extracellular matrix, which provides structural and biochemical support to cells and is implicated in fibrosis development. It allows for robust response to fibrosis induction and to potential therapies, the team noted.
Administration of TGF-beta — a molecule that controls diverse cellular mechanisms, including cell differentiation and growth — caused the tissue to contract and stiffen, bending the micropillars. This effect mimics the lung tissue stiffening that occurs in PF patients.
Proof-of-principle tests then showed that both Esbriet and Ofev eased the fibrotic bending of the micropillars, meaning they both inhibited tissue stiffening. This confirmed that the system reliably models PF and responds to treatment, while also contributing to the understanding of the therapies’ mode of action, the team noted.
“We expect our system to speed the translation of anti-fibrotic therapies from laboratories to the clinic,” Ruogang Zhao, PhD, the study’s senior author, said in a press release.
According to the team, the new system “represents a novel approach for drug screening with improved physiological relevance, accuracy and throughput,” and will “expedite the translation of anti-fibrotic therapies from the laboratories to the clinics.”
“We are now adapting the system to model the pathology of other membrane diseases such as fibrosis in the retina and intestinal fibrosis associated with Crohn’s disease,” said Zhao, who is an assistant professor in the Department of Biomedical Engineering at the University at Buffalo.
This study was funded by the National Institute of Biomedical Imaging and Bioengineering.
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