BioTechniques News
Maddy Chapman
A novel ‘asthma-on-a-chip’ platform breathes new life into study of the condition, offering hope for future treatments.
University of Pennsylvania (PA, USA) engineers have developed a human lung-on-a-chip technology that can recreate the mechanical stresses experienced by the respiratory tract during an asthma attack, enabling them to study the condition in ways that are not currently possible in patients.
In asthmatic lungs, airway flexibility is gradually lost as walls thicken and stiffen due to collagen build-up. These stiff, narrow airways – a hallmark of severe, persistent asthma – are less responsive to medication, leading to further complications with the disease. Until recently, this process was thought to be caused solely by chronic inflammation, and so therapies tend toward targeting it – but it’s becoming increasingly obvious that this isn’t the whole story.
“One thing we know for certain is that the airways in asthmatic lungs constrict frequently. Yet we understand surprisingly little about how this defining mechanical feature affects the pathophysiology of the disease,” explained researcher Dan Huh.
Studying this process in detail in patients isn’t really possible, and, unfortunately, preclinical investigation also remains a challenge, which is where engineered human airway tissues come to the fore.
Drawing on their experience in cell biology and soft robotics, Huh and colleagues created a clinically relevant model of asthmatic human lungs that combines patient-derived airway epithelial cells and fibroblasts in a hydrogel device fitted with pneumatically driven soft actuators. When the actuators contract, the tissues are squeezed in a way that emulates airway constriction in asthmatic lungs.
The team applied controlled compression to their lung-on-chip devices to mimic airway constriction during an asthma attack, and found that doing so induced fibrotic airway remodeling in diseased tissue, but not in healthy tissue.
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Another frequently observed feature of asthmatic lungs is abnormally dense vascularization of the airways. To investigate this characteristic, the team used the chips to generate vascularized airway constructs – engineered vascularized tissues with a functional respiratory epithelium – using them to demonstrate, for the first time, that the compressive force also induces vascular remodeling in the asthmatic airway and that this process is driven, in large, by the same fibrosis that contributes to the stiffening of the airways.
This “[links] a physical event to two of the disease’s defining structural changes and [points] to how repeated constriction could progressively worsen the disease over time,” Huh commented.
To pinpoint the molecular mediators of this process, the team conducted proteomics analysis on the fluid released by compressed cells in their novel system, identifying proteins already known to play a part in asthma, as well as those that weren’t, which may make potential new therapeutic targets. They even tested some pharmacological interventions known to modulate these pathways, highlighting how the ‘asthma-on-a-chip’ devices may help contribute to future drug discovery.
“This work shows how bioengineered human tissue models can be used to advance our mechanistic understanding of disease pathophysiology and to discover and test new drugs,” added Huh.
“We’re raising the bar,” he said of his broader work evolving organ-on-a-chip technologies. “Real tissues don’t exist and function in isolation, so we don’t study them that way. We are developing new ways to recreate how different tissues live and work together, and then to watch what happens when we put them under the kinds of stress that drive disease.”
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