Jason Ford

Smooth muscle mimic to advance asthma drug testing

News

A Harvard University team has developed a human airway muscle-on-a-chip that could be used to test new asthma drugs.

The device is said to accurately mimic the way smooth muscle contracts in the human airway, under normal circumstances and when exposed to asthma triggers. It is also said to offer a window into the cellular and subcellular responses within the tissue during an asthmatic event.

As reported in Lab on a Chip, the chip - a soft polymer well that is mounted on a glass substrate - contains a planar array of microscale, engineered human airway muscles designed to mimic the laminar structure of the muscular layers of the human airway.

The team mimicked an asthmatic airway on their airway muscle-on-a-chip by first introducing Interleukin-13 (IL-13), a natural protein often found in the airway of asthmatic patients. Then they used a neurotransmitter called acetylcholine to trigger the sm
The team mimicked an asthmatic airway on their airway muscle-on-a-chip by first introducing Interleukin-13 (IL-13), a natural protein often found in the airway of asthmatic patients. Then they used a neurotransmitter called acetylcholine to trigger the smooth muscle to hypercontract, and a bronchodilator used in inhalers called a β-agonist to elicit muscle relaxation

To mimic a typical allergic asthma response, the team first introduced interleukin-13 (IL-13) to the chip. IL-13 is a natural protein often found in the airway of asthmatic patients that mediates the response of smooth muscle to an allergen.

Then they introduced acetylcholine, a neurotransmitter that causes smooth muscle to contract. The airway muscle on the chip hypercontracted – and the soft chip curled up – in response to higher doses of the neurotransmitter.

They achieved the reverse effect as well and triggered the muscle to relax using drugs called β-agonists, which are used in inhalers.

They were also able to measure the contractile stress of the muscle tissue as it responded to varying doses of the drugs, said lead author Alexander Peyton Nesmith, a Ph.D./M.D. student at Harvard SEAS and the University of Alabama at Birmingham.

‘Our chip offers a simple, reliable and direct way to measure human responses to an asthma trigger,’ he said in a statement.

The team then investigated what happened on a cellular level in response to the IL-13 and confirmed, for example, that the smooth muscle cells grew larger in the presence of IL-13 over time – a structural hallmark of the airways in asthma patients as well. They also documented an increased alignment of actin fibres within smooth muscle cells, which is consistent with the muscle in the airway of asthma patients. Actin fibres are super-thin cellular components involved in muscle contraction.

Next they observed how IL-13 changes the expression of contractile proteins called RhoA proteins, which have been implicated in the asthmatic response, although the details of their activation and signalling have remained elusive.

To do this they introduced HA1077, a drug that is not currently used to treat asthmatic patients but targets the RhoA pathway. The drug made the asthmatic tissue on the chip less sensitive to the asthma trigger – and preliminary tests indicated that using a combined therapy of HA1077 plus a currently approved asthma drug worked better than the single drug alone.

‘Asthma is one of the top reasons for trips to the emergency room – particularly for children, and a large segment of the asthmatic population doesn’t respond to currently available treatments,’ said Wyss Institute Founding Director Don Ingber, M.D., Ph.D. ‘The airway muscle-on-a-chip provides an important and exciting new tool for discovering new therapeutic agents.’