Lung-on-a-Chip: The Future of Personalized Cystic Fibrosis Drug Development

Cystic fibrosis (CF) is a devastating hereditary disease that causes persistent lung infections, which limit a patient’s ability to breathe over time. While recent therapeutic breakthroughs improve patient life expectancy, many ultimately succumb to CF because available therapies fail to protect against respiratory infections. Researchers have struggled to develop better treatments because few preclinical models replicate key CF features and enable rigorous drug testing, but hope is on the horizon.1 

Don Ingber engineered cystic fibrosis airway chips that recapitulate patient symptoms.

Don Ingber’s team engineered cystic fibrosis airway chips that recapitulate patient symptoms.

WYSS INSTITUTE AT HARVARD UNIVERSITY

In a recent study published in the Journal of Cystic Fibrosis, Don Ingber and his group at the Wyss Institute of Biologically Inspired Engineering presented the CF airway chip—a new in vitro model engineered with patient cells.2 This chip, which mimics the pathological hallmarks of the disease, will allow scientists to better understand CF pathogenesis and screen for more effective drugs to treat the disorder in patients with diverse genetic backgrounds and comorbidities.

Ingber has spent a large part of his career developing better tools and technologies to study organ physiology. In 2010, his team created the first lung-on-a-chip, a small in vitro model that recreates the cellular interactions that take place within the lung and exposes these tissues to the same biomechanical forces they face in the organ, including fluid flow and breathing.3,4 “The fluid flow through the vascular channel and the breathing motions are critical for the functionality of these tissues and organs. This is true for all organs, but especially for the lung,” Ingber said. 

To create a clinically relevant CF model that mimics key patient symptoms, he recently modified his lung-on-a-chip model and lined it with patient cells to create the CF airway chip.2,3,4 

Ingber’s chip contains two separate channels that mimic an airway and a blood vessel. These are separated by a thin membrane, so scientists can add microbes to the air and immune cells to the medium to study a tissue’s immune responses to infection. Ingber’s team only had access to patient lung epithelial cells, so they built a chimeric CF airway chip in which mutant airway cells interact with healthy vascular tissues and immune cells. 

Using CF airway chips, researchers study how bacteria infect CF lung epithelial cells, the type of immune response they induce, and which drugs better protect CF airways.

Using CF airway chips, researchers study how bacteria infect CF lung epithelial cells, the type of immune response they induce, and which drugs better protect CF airways.

Wyss Institute at Harvard University

“We’re building this organ up from scratch, so we started with [patient] lung lining cells and asked how this mimicked the body’s response. If it doesn’t, something’s missing and we can add [patient-derived] blood vessel cells, or connective tissue, or immune cells,” Ingber said. In the case of the CF airway chip, Ingber found that the epithelium was the major driver of CF lung pathology. 

Like patient lungs, CF chips have more ciliated epithelial cells that secrete thicker mucus and have more inflammation compared to chips made from healthy cells. “It’s amazing. These cells—even though they’re cultured for weeks, under air, in this little device—really exhibit the properties of cystic fibrosis in many ways,” Ingber said. 

The CF airway chip is also more susceptible to bacterial infection, similar to patients. To test this, Ingber’s team added Pseudomonas aeruginosa, a bacterium that thrives in CF patient airways, to the air flow. Compared to healthy chips, the bacteria grew to a much greater extent in the CF ones.2 “This is the first [system] that uses lung cells to really model what’s going on in the patients and it replicates what’s been seen in CF patients,” said Brigitte Gomperts, a professor of pediatrics and pulmonary medicine at UCLA, who was not involved in the study.

In vitro systems made from patient cells, such as the CF airway chip, hold great promise for developing precision medicine approaches for CF.“You can now develop personalized chips and test drugs for a particular group of patients that have the same genetic makeup, or the same comorbidities, things that are very hard to tease out in clinical trials. Organ chips allow you to effectively begin to approach human experimentation in vitro, which is, I think, really exciting” Ingber said.

References

  1. C. Sen et al., “Three-dimensional models of the lung: past, present and future: a mini-review,” Biochem Soc Trans, 50(2):1045-56, 2022.
  2. R. Plebani et al., “Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip: Cystic fibrosis airway chip,” J Cyst Fibros, S1569-1993(21)02106-8, 2021.
  3. D. Huh et al., “Reconstituting organ-level lung functions on a chip,” Science, 328(5986):1662-8, 2010.
  4. “Preventing the Next Pandemic with Organ Chips,” The Scientist, The Scientist Speaks, March 2022, https://viewonline.the-scientist.com/preventing-the-next-pandemic-with-organ-chips, accessed on May 3, 2022. 
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Source: the-scientist.com

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