Harvard University researchers have developed an organ on a chip that recapitulates genetic, morphological and functional markers of failing myocardium.1 The system could help identify therapeutic candidates that slow or reverse heart failure with better reliability than current in vitro culture systems.

Traditional in vitro models of heart failure involve exposing cultured cardiomyocytes to chemical or mechanical stimuli that induce pathological gene expression, hypertrophy and remodeling.2-4

A Harvard team led by Kevin Kit Parker has been developing heart-on-a-chip systems that also recapitulate contractile function, which is considered a better proxy of cardiac output than changes in gene expression and electrophysiological properties. Parker is a professor of bioengineering and applied physics at Harvard and core member of the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Parker's team previously used neonatal rat ventricular myocytes and its own muscular, thin-film technology to engineer an organ-on-a-chip microsystem that recapitulates the healthy myocardium.5 The system could be used to screen compounds for cardiotoxicity but not for the ability to correct a disease phenotype.

Now, the same group has engineered a microsystem that recapitulates the failing myocardium. The new chip consists of neonatal rat ventricular myocytes seeded on a fibronectin-patterned flexible silicone membrane. The chip further incorporates a custom-built multiwell system that allows the user to subject the engineered myocardium to uniaxial and cyclical stretch.

Cyclic stretching of myocardium recreated pathological heart failure-associated changes to myocyte shape, sarcomere alignment, calcium cycling and gene expression. Importantly, the stretched myocardium showed lower contractile functionality than unstretched myocardium.

Results were published in the Proceedings of the National Academy of Sciences.

"The results in the current study are exciting for heart failure because until now, there has not been a way to scale down a system that replicates the major parameters of the failing myocardium to one that could be easily used by bench scientists at pharmaceutical companies," said Paul August, director and U.S. head of the Early to Candidate Unit at Sanofi. "This system could help move the relevant disease models more upstream in the drug discovery process and could improve our ability to interrogate the effects of compounds before we reach animal models."

"What the Parker group has achieved in the current study is an extension of their earlier heart-on-a-chip system," said David Giegel, founder and president of TissueNetix Inc. "This new system will now allow scientists to set up specific assays to test compounds for their ability to ameliorate the disease phenotype."

TissueNetix is developing a cardiac cell conduction array to assess compounds for potential cardiotoxicity during the drug discovery process. The assay consists of normal human cardiomyocytes that are electrically coupled and beat in a manner similar to the heart. Giegel said TissueNetix's assay should be more reliable at detecting cardiotoxicity than cellular assays currently used in industry.

Looking at more with less

The new system's ability to recapitulate more aspects of heart failure than conventional cellular models should yield more reliable and sensitive detection of compounds that affect disease phenotype.

"When cells are taken out of the body and grown in culture, they usually won't behave as they would in the body," which decreases the reliability of the observed results, said Shuichi Takayama, a professor in the Department of Biomedical Engineering at the University of Michigan. "The special format system developed by this group allows cultured cardiomyocytes to behave as they would in the body. The hope is that such a system will have better correlation to the disease and allow users to more reliably link their observations to disease mechanisms."

"One of the compelling advantages of the described model is that this system permits quantitative analysis of the contractility of engineered cardiac muscle in vitro during electrical and pharmacological simulation," added Dongeun Huh, an assistant professor in the Department of Bioengineering at the University of Pennsylvania.

"The fact that this system allows for concurrent measurements of genetic, structural and functional phenotypes in a single device in an array format makes this microengineered disease model a unique, robust platform for quantitative analysis of integrated cardiac responses to various external stimuli such as therapeutic agents, pathogens, chemicals, environmental toxins and cosmetics," added Huh.

Megan McCain, a postdoctoral fellow at Harvard and the Wyss Institute and lead author on the paper, added that conventional in vitro models miss subtle effects that compounds could have on the heart. She said enabling concurrent assessment of multiple model parameters could improve the consistency and overall quality of data collected from experiments using the chips.

Parker noted that the chips are easier to use and are less costly than animal models and that the manufacturing process is fast and reproducible.

McCain added that the group can create ready-to-use chips in five days.

Adapting for industry use

Parker said the group is trying to build its current failing myocardium-on-a-chip system using human cardiomyocytes derived from induced pluripotent stem (iPS) cells, standardize the fabrication process and adapt the chips for use with high throughput screening systems.

In addition to using human cardiomyocytes, Huh said it would be important to incorporate other cells of the myocardium into the chip system as well to help recapitulate interactions between different cell types known to be crucial to the onset and exacerbation of various heart diseases.

"This will eventually lead to more realistic and complete disease models that enable one to probe and understand complex and diverse disease processes in ways that have not been possible using conventional cell culture and animal models," Huh told SciBX.

McCain said that other research directions pursued by the group include creating chips that use iPS cell-derived cardiomyocytes taken from patients for personalized disease modeling applications and creating chips that could recapitulate interactions between different organs.

Giegel said it would be important for the Harvard researchers to do proof-of-concept studies showing that the system can screen for compounds that correct the disease phenotype.

August wanted to see the Harvard group's chip tested with well-characterized molecules that affect the physiology of the heart.

"Basically, I want to see this technology evaluated against agents that have known effects on cardiovascular function in vivo, such as those that modulate cytoskeletal architecture or contractile activity, and see if these chips could recapitulate those effects," he told SciBX.

August added that his group also is working collaboratively with Parker on another organ-on-a-chip system to model skeletal muscle function in rare diseases.

Takayama added that it would be important to demonstrate cases in which the human myocardium-on-a-chip system accurately predicts the effects of the compound in humans but the traditional human cell culture systems and animal models do not.

Harvard has multiple issued and pending patents covering the myocardium-on-a-chip systems. The technology is available for licensing.

Lou, K.-J. SciBX 6(25); doi:10.1038/scibx.2013.617 Published online June 27, 2013


1.   McCain, M.L. et al. Proc. Natl. Acad. Sci. USA; published online May 28, 2013; doi:10.1073/pnas.1304913110 Contact: Kevin Kit Parker, Harvard University, Cambridge, Mass. e-mail: kkparker@seas.harvard.edu

2.   Frank, D. et al. Hypertension 51, 309-318 (2008)

3.   Kelso, E.J. et al. Mol. Cell. Biochem. 157, 149-155 (1996)

4.   Blaauw, E. et al. Am. J. Physiol. Heart Circ. Physiol. 299, H780-H787 (2010)

5.   Grosberg, A. et al. Lab Chip 11, 4165-4173 (2011)


      Harvard University, Cambridge, Mass.

      Sanofi (Euronext:SAN; NYSE:SNY), Paris, France

      TissueNetix Inc., San Diego, Calif.

      University of Michigan, Ann Arbor, Mich.

      University of Pennsylvania, Philadelphia, Pa.

      Wyss Institute for Biologically Inspired Engineering at Harvard University, Cambridge, Mass.