The growing number of biological structures being grown on chips in various laboratories around the world is rapidly replicating the entire gamut of major human organs. Now one of the most important of all – a viable functioning heart – has been added to that list by researchers at the University of California at Berkeley (UC Berkeley) who have taken adult stem cells and grown a lattice of pulsing human heart tissue on a silicon device.
Sourced from human-induced pluripotent stem cells able to be persuaded into forming many different types of tissue, the human heart device cells are not simply separate groups of cells existing in a petri dish, but a connected series of living cells molded into a structure that is able to beat and react just like the real thing.
"This system is not a simple cell culture where tissue is being bathed in a static bath of liquid," said study lead author Anurag Mathur, a postdoctoral researcher at UC Berkeley. "We designed this system so that it is dynamic; it replicates how tissue in our bodies actually gets exposed to nutrients and drugs."
Touted as a possible replacement for living animal hearts in drug-safety screening, the ability to easily access and rapidly analyze a heart equivalent in experiments presents appealing advantages.
"Ultimately, these chips could replace the use of animals to screen drugs for safety and efficacy," said professor of bioengineering at UC Berkeley, and leader of the research team, Kevin Healy.
The cardiac microphysiological system, as the team calls its heart-on-a-chip, has been designed so that its silicon support structure is equivalent to the arrangement and positioning of conjoining tissue filaments in a human heart. To this supporting arrangement, the researchers loaded the engineered human heart cells into the priming tube, whose cone-shaped funnel assisted in aligning the cells in a number of layers and in one direction.
In this setup, the team created microfluidic channels on each side of the cell holding region to replicate blood vessels to imitate the interchange of nutrients and drugs by diffusion in human tissue. The researchers believe that this arrangement may also one day provide the ability to view and gauge the expulsion of metabolic waste from the cells in future experiments.
"Many cardiovascular drugs target those channels, so these differences often result in inefficient and costly experiments that do not provide accurate answers about the toxicity of a drug in humans," said Professor Healy. "It takes about US$5 billion on average to develop a drug, and 60 percent of that figure comes from upfront costs in the research and development phase. Using a well-designed model of a human organ could significantly cut the cost and time of bringing a new drug to market."
The use of animal organs to forecast human reactions to new drugs is problematic, the UC Berkeley researchers note, citing the fundamental differences between species as being responsible for high failure rates in using these models. One aspect responsible for this failure is to be found in the difference in the ion channel structure between human and other animals where heart cells conduct electrical currents at different rates and intensities. It is the standardized nature of using actual human heart cells that the team sees as the heart-on-a-chip's distinct advantage over animal models.
The UC Berkeley device is certainly not the first replication of an organ-on-a-chip, but potentially one of the first successful ones to integrate living cells and artificial structures in a single functioning unit. Harvard's spleen-on-a-chip, for example, replicates the operation of the spleen, but does so by using a set of circulatory tubes containing magnetic nanobeads.
The gut-on-a-chip and the lung-on-a-chip devices also both developed by Harvard do use certain biological aspects – gut cells and lung cells, respectively – but do not act as functioning conglomerations of cells that make up an entire functioning organ, as the UC Berkeley heart device does.
The closest version of a heart-on-a-chip to the UC Berkeley one is, yet again, a Harvard invention: functioning human heart tissue with a cardiovascular disease. In this case, it similarly uses pluropotent stem cells grown into heart cells, but ones that are only able to beat weakly, and act as a model of Barth syndrome for use in research into that malady.
The defining aspect of the UC Berkeley model, however, is that the connected and associated human heart cells in the unit form a viable whole that spontaneously beats without assistance within 24 hours of being amassed in the device's collection chamber, and within a normal physiological range of about 55 to 80 beats per minute.
To test that the conglomerate of beating cells was more than just a collection of cells that appeared to behave like a single organ, the researchers monitored the responses of the heart cells to a range of common cardiovascular drugs. These included isoproterenol, E-4031, verapamil and metoprolol, which the team individually applied to the cells and observed any alterations in the beating rate to measure the response of the heart cells to the applied drugs.
The researchers discovered that the cells predictably altered in a fashion consistent with known effects after exposure to the cardiovascular drugs. As an example, 30 minutes of subjection to a drug used for the treatment of bradycardia (slow heart rate), the beating rate of the tissue rose from 55 to 124 beats per minute.
In light of this and other proof of the viability and efficacy of the heart-on-a-chip device, the researchers have also suggested that future iterations could be modified to replicate human genetic diseases or even to use an individual’s own stem cells to create a bespoke tissue culture capable of gauging exact reactions to various substances. The team is also investigating if the heart-on-a-chip system may be employed in the replication of individually modeled multi-organ interactions. In this vein, the researchers believe that a normal-sized culture platter could possibly support many hundreds of such microphysiological cell culture systems.
“Linking heart and liver tissue would allow us to determine whether a drug that initially works fine in the heart might later be metabolized by the liver in a way that would be toxic,” said Professor Healy.
The video below shows the modified cells contained on the heart-on-a-chip functioning as a single beating organ.
The research was recently published in the journal Scientific Reports.
Source: UC Berkeley