Beating “Heart-on-a-Chip” May Revolutionize In Vitro Cardiac Studies

Much of what we know about organ physiology can be traced back to in vitro studies of cells in a cultured environment. For example, we know about ion channels and how they control the contractions of the heart because of early “patch-clamp” studies on cardiomyocytes, grown in the lab. This enabled early pharmacological studies through which drugs and compounds, like dobutamine or epinephrine, could be tested prior to animal and clinical trials.

A significant limitation of these studies, however, is that they often do not reflect the complexity and emergent properties present in 3D tissues. Researchers have circumvented this by growing cells in more intricate environments more representative of in vivo tissue. Despite this, a remaining challenge for cardiac research is the difficulty in measuring both the electrophysiological and contractile properties of heart tissue in vitro.

Researchers at the Harvard School of Engineering and Applied Science have developed a “heart-on-a-chip” consisting of eight muscular thin filaments (MTFs) that can be measured simultaneously. According to the paper in this month’s Lab on a Chip, their platform offers “several key advances in screening technology, including the ability to measure contractile stress as a function of time, AP [action potential] propagation, and inter- and intracellular architecture.”  The team bases these claims off of contractility, dose-response, and optical mapping experiments, leading them to the following conclusion:

We reported the development of a novel chip design for in vitro cardiac contractility and pharmacological studies. Previous technologies are capable of providing correlations between single myocyte electrophysiological and contraction properties, but they cannot be used to garner tissue scale data. This need is addressed by the ‘‘heart on the chip’’ technology, which is used in conjunction with cell culture techniques that can recapitulate healthy, diseased, and developing cardiac tissues. Our technology is ideal to study the two factors that can contribute to the force produced by in vitro cardiac tissues: the alignment of the contractile apparatus and the gene expression profile, which is affected by the shape and deformation of cellular structures.48 In sum, we have demonstrated the chip to be a platform for quantification of stress, electrophysiology, and cellular architecture.

We corresponded with senior author on the study, Professor Kit Parker, to get more details on the current status of the “heart-on-a-chip:”
 
Shiv Gaglani, Medgadget: The paper mentions the limitation of maintaining cardiomyocyte viability while transferring the chip from one system to another. It then discusses the potential of building a microscope to circumvent this problem and collect contractility and electrophysiological data simultaneously. Can you comment on plans for enhancing the system in this, or another, way?                                                                                                                              
Dr. Parker: We are working on that now. Part of the issue is that the contractility assay can be viewed with the naked eye, but must be done from the top down. The electrophysiology (EP) experiments are generally done at higher magnification with either a fast, fluorescent CCD camera. Voltage sensitive dyes are generally cell-toxic, so we do the contractility experiments without them, then load for the EP studies. We could do a simultaneous contractility and EP study if we compromised fidelity on the EP studies and did a pseudo ECG along with the contractility study. However, that would be a generalized signal averaged over all the tissues…..not necessarily what we want.

 
Medgadget: What are the next steps for the heart-on-a-chip (e.g. additional research, commercialization, etc)?

Dr. Parker:  We are working with other materials for the polymer thin film, we have increased the number of films and put the whole system in a microfluidic system, and we are trying a variety of commercially available iPS or ES derived human cardiac myocytes. We have incorporated a new company, BioDais, that will use these, and other proprietary assays from my group, do assess candidate molecules and do safety pharmacology, as a CRO, in a variety of microtissues built to replicate the function of muscular organs….so now we are working on vascular, airway, gut, skeletal and soon bladder and uterine smooth muscle.

Additionally, we are working on a valve on a chip that will allow us to look at the toxicity of drugs like Phen-Phen or Parkinson’s Disease drugs….so we are developing an array of assays that exploit our ability to build tissues that replicate organ microenvironments (both in function and gene expression), use human cells, get lots of high quality data fast and cheaper than in tissues isolated from animals.

Also, check out this video of the Heart-on-a-Chip from The New Scientist:

Lab on a Chip paper: Ensembles of engineered cardiac tissues for physiological and pharmacological study: Heart on a chip

Flashback from same research team: Real Muscles for Artificial Machines