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Matters of the heart - How chip mass production promotes safer drugs

Interventions & Care

Flexible and stretchable – they’re not qualities you’d normally ascribe to the regular printed circuit board. And yet flexibility and stretchability are key aspects of organs-on-a-chip designed to simulate the heart during effort. Such organs-on-a-chip are vital to the development of safer new drugs. LUMC is providing the proper cell structures for heart simulation, while TU Delft and Philips are working on the chips.

In drug discovery, many candidates fail because it turns out that the active substance negatively affects the heartbeat. In other cases, new drugs may make it through clinical trials, even though they are cardiotoxic to a small category of users. The number of patients at risk is so low, that the pattern of this risk only becomes apparent from big data, i.e., after years of use by a large user base. To get around this problem, and as testing on live heart tissue is impossible, the alternative is to test on human heart-cell arrays on a chip. The problem is that this does not at present allow testing for the most relevant situation: the performance of the heart muscle under effort. “Christine Mummery and Robert Passier from the LUMC therefore had a clear question for us,” says Professor Ronald Dekker of Philips and TU Delft. He and his group are active in flexible and stretchable chips. “The question was: can you develop a chip on which human heart cells are exposed to drug candidates during the simulation of effort?”

Closer to real life

Mummery and Passier themselves are able to produce the necessary patient-specific heart cells on the basis of Induced Pluripotent Stem cells (IPSs). “Some years ago, we were able to grow IPS into ‘beating’ heart muscle cells,” says Professor Robert Passier, cardiac stem-cell researcher at LUMC and UTwente. “However, this success required optimisation, as the result was a heterogeneous, random mix of cardiac cells, including ventricular and atrial and pacemaker cells. The study of specific heart afflictions requires research into particular types of cells.”

The researchers now have a better understanding of that process, and they are getting better and better at growing the specific cell types they need for their research (although further improvement is still needed). The next step is to, once again, grow a heterogeneous mix of heart cells, but this time in such a coordinated way, that it results in exactly the right amounts and structures to build actual pieces of heart tissue. This once again opens new windows for research. “When we manage to grow more complex tissue structures with the right stimuli, such as stretching, that should result in better maturation of the tissue, allowing for closer to real-life condition testing. “In turn,” says Passier, “this will lead to better predictions – to the benefit of the patient.”

In due time, it will become possible to test it on larger series of relatively cheap, mass-produced mini-hearts, aimed at very specifically defined groups who are sensitive to certain heart diseases or (for instance) orphan diseases in general.

Safer drug development

With an electrical pulse the right heart cells are induced to stretch. This, of course, requires a chip that stretches along with the cells. Dekker and his team succeeded in finding one. Cytostretch will enable even safer drug development. “In due time, it will become possible to test it on larger series of relatively cheap, mass-produced mini-hearts, aimed at very specifically defined groups who are sensitive to certain heart diseases or (for instance) orphan diseases in general.”

The key to success, say Dekker and Passier, was the willingness and ability of completely different disciplines to collaborate with mutual understanding and patience. Passier: “It’s not easy to achieve an approach integrating, for instance, stem-cell biology, biomaterials, microfluidics and nanotechnology. It requires a lot of communication to learn to better understand each other.” The most difficult part for Dekker was becoming familiar with each other’s totally different professional vocabulary. Over the last half decade, we've managed to learn from each other and respect our differences. This gives us a head-start over others.”

“In the Netherlands, we have all the necessary disciplines together within a relatively limited radius,” says Dekker. “For instance, the micro-manufacturing knowledge from TU Delft combined with the IPS-capabilities at the LUMC. The Institute for human Organ and Disease Model technologies (hDMT) is the first institute of its kind worldwide to unite all these disciplines.” Passier agrees: “With Delft, Leiden and also Twente, we have the required complementary technologies in place. Over the last few years, we've grown accustomed to multidisciplinary collaboration. This allows for the even closer collaboration that could lead to more results, attained even quicker.”

Industrialisation

There were – and still are – plenty of challenges until the mass-produced end-product will become available. “On the basis of the principles we've proven, we’re presently working on industrialisation,” says Dekker. “It might take up to a decade to bring the technology to the market – a process that’s often underestimated. We aim to develop the Cytostretch chips as a generic platform. Disrespectfully, you might call it a standard ‘pizza flat bread’. Depending on the specific application, all kinds of ‘toppings’ could be added such as sensors, grooves to align the heart tissue or holes. Academic or pharmaceutical researchers could subsequently add their cells and carry out their research.”

It should be possible to produce the Cytostretch chips in a regular micro-manufacturing plant. The technology for this is being developed as part of the European ECSEL project InForMed, in which Philips Innovation Services, Pluriomics and Multichannel Systems, for example, participate. “We’re happy with the progress we’re making,” Dekker concludes. “Eventual commercialisation of the chip platform will be in the hands of the start-up, bIOnd, Dekker announces, “with Philips Innovation Services in a supplying role.”

Interview by: Leendert van der Ent