Structural Colors in a Heartbeat

Pharmaceutical developers must closely assess the potential side-effects of candidate drugs on heart rhythms, a shoal on which a number of high-profile drugs have crashed in the past. A research team in Japan and Hungary has developed an optical tool for making those assessments that leverages structural colors—the same technology that paints the wings of butterflies and the feathers of peacocks (RSC Adv., doi: 10.1039/c7ra06515a).

Searching for a beat

The pharmaceutical road is littered with drugs that have come to market, only to be subsequently pulled when their cardiotoxicity and arrhythmia side effects came to light. Some high-profile examples include clobutinol, a cough suppressant distributed by a number of international drug companies and yanked from distribution in 2007; and levacetylmethadol, a methadone-like opioid discontinued in the early 2000s when reports of life-threatening effects on heart rhythms began to crop up.

Those experiences have made pharma companies exceedingly cautious about cardiotoxicity of candidate drugs—and has prompted an ongoing quest for high-throughput methods to test drug impacts on heart-cell rhythms. A number of techniques exist, including dropping cardiac cells on quartz-crystal microbalances to read their beating signals; atomic-force microscopy; and traction-force microscopy, which involves attaching cardiac cells to a polymer substrate and measuring the substrate’s physical displacement as the cells beat. Many of these methods, however, are awkward or have practical limitations, and don’t provide the ability to view a drug candidate’s impact across a large canvas of cells.

A CD-R template

The team behind the new research, led by Easan Sivaniah of Kyoto University, Japan, looked for an optical approach to the problem—one that could be executed in the lab using an ordinary lab microscope, the best tool for large-scale observations of cells. The key to the researchers’ solution was to use changes in structural-color interference patterns as a visible meter for gauging changes in heart-cell beat rates.

To do so, the team first designed a thin-film diffraction grating made of polydimethylsiloxane (PDMS), cleverly using an ordinary optical CD-R disk as a template. (Yes, there is still a use for CDs.) The researchers placed a 2-cm² fragment of the blank CD—the patterning of which shows a familiar rainbow pattern under illumination—onto a PDMS gel surface, and then thermally set the material and peeled off the cured PDMS layer. The result was a PDMS surface layer that matched the diffraction pattern of the CD surface—a result that the team confirmed through optical measurements of both.

Catching the rhythm

The researchers next isolated a suspension of live cardiac cells from neonatal rats, and deposited them on the surface of the flexible polymer diffraction grating they had created. They then placed the cell-saturated grating under an ordinary stereo microscope. The scientists found that they could accurately count beat frequencies, synchronicity and strength by changes in light intensity and color contrast as the beating cells deformed the polymer substrate and changed its diffraction pattern. They also added a drug well known to affect heart rhythms—epinephrine, more familiarly known as adrenaline—to the mix, and could track its effect across the cell population under the microscope.

The team points out that the structural-color approach it’s devised requires no additional biomarkers, is simple to set up, and—in contrast to some other visual approaches to the problem—allows an assessment of a relatively large surface. This, the researchers suggest, could allow the measurements to tie easily into software tools that would allow rapid, high-throughput testing in the drug lab.

In addition to researchers from Kyoto University physics department, the team also included scientists from the university’s medical school and from Semmelweis University, Budapest, Hungary.