Catharine Paddock PhD
Drug development is a costly and lengthy business, not helped by the fact there is a high failure rate in drug testing due to the reliance on animal models. Animal biology is not an ideal substitute for human biology, but until something better comes along, it is all we have. Now, a new study suggests the organ-on-a-chip method may offer a more ideal model.
Study leader Kevin Healy, a bioengineering professor at the University of California-Berkeley, says:
"It takes about $5 billion on average to develop a drug, and 60% 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."
As around one third of the candidate drugs that are ditched are those that seem to have a bad effect on the heart, Prof. Healy and colleagues decided to design a model based on the human heart.
They conclude that their work is a major step forward in the development of faster, more accurate ways of testing drug safety. Prof. Healy believes that:
"Ultimately, these chips could replace the use of animals to screen drugs for safety and efficacy."
In their study, they describe how they devised the model and tested it with cardiovascular medications.
'Heart-on-a-chip' contains a network of pulsating cardiac muscle cells
The human heart model that Prof. Healy and colleagues devised is a "heart-on-a-chip" comprising an inch-long silicone device with a thin network of pulsating cardiac muscle cells.
In the journal Scientific Reports, the team says their heart-on-a-chip - which they call a "cardiac microphysiological system (MPS)" - is an ideal tool for testing toxic side effects of new drugs on the human heart because it ticks four important boxes:
- It uses cells that have human genes
- The cells are aligned in a way that reflects the structure of human heart tissue
- It mimics the dynamics of blood flow in heart tissue
- It can be used for biological, electrophysiological and physiological analysis.
The authors note that using animal models to predict human reactions to drugs often fail because of fundamental differences in biology between species. For example, the ion channels that conduct the electrical pulses that heart cells send out can vary in number and type between animals and humans.
"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," Prof. Healy explains.
Device is populated with heart cells made from human-induced pluripotent stem cells
The heart-on-a-chip is made of heart cells generated from human-induced pluripotent stem cells - the adult stem cells that can be coaxed to differentiate into various types of tissue.
The heart-on-a-chip has a 3D geometry and spacing that is comparable to that of connective tissue fiber in a human heart. The researchers then populated this with layers of differentiated heart cells, which in the confined geometry were forced to align in one direction.
Microfluidic channels on either side of the cell-populated area perform like blood vessels and mimic the same dynamics of nutrients and drugs diffusing from blood vessels into human tissue.
Such a setup could also serve as a model of how the cells get rid of their waste products, note the authors.
Lead author Dr. Anurag Mathur, a postdoctoral scholar in Healy's lab and a fellow of the California Institute for Regenerative Medicine, explains:
"This system is not a simple cell culture where tissue is being bathed in a static bath of liquid. We designed this system so that it is dynamic; it replicates how tissue in our bodies actually gets exposed to nutrients and drugs."
Heart-on-a-chip tested with four drugs and reacted as expected
The authors explain how within 24 hours of populating the device with heart cells, the engineered heart tissue was beating on its own at the normal rate of 55-80 beats per minute.
The team tested four well-known cardiovascular drugs on the device: isoproterenol, E-4031, verapamil and metoprolol. They used changes in the pulse rate of the tissue to measure the response to the drugs.
The changes in pulse rate were as expected for the drugs. For example, after half an hour of being exposed to isoproterenol - a drug used to treat slow heart rate, or bradycardia - the pulse rate of the heart-on-a-chip increased from 55 to 124 beats per minute.
Multi-organ testing devices could have hundreds of microphysiological cell systems
The engineered tissue remained viable and worked for several weeks. Such a timescale is sufficient for testing several different drugs, Prof. Healy says.
He and his colleagues are now investigating whether the method can be used to model multi-organ interactions. Prof. Healy notes:
"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."
The team anticipates the "widespread adoption" of organ-on-a-chip for drug screening and disease modeling and foresee devices containing hundreds of microphysiological cell systems.
The project is funded through the Tissue Chip for Drug Screening Initiative, which is sponsored by the National Institutes of Health.
In October 2014, Medical News Today learned how the University of Kansas is leading the development of a lab-on-a-chip that promises to detect lung cancer - and possibly other deadly cancers - much earlier. That method, which only uses a small drop of a patient's blood, is also based on microfluid technology. It analyzes the contents of exosomes - tiny bags of molecules that cells release now and again.