Bioengineered Heart Chambers Created
Kevin Costa and Eun Jung Lee
Biomedical Engineering Associate Professor Kevin Costa and his doctoral student, Eun Jung (Alice) Lee, have developed the first functional 3D engineered simplified heart chambers that exhibit key characteristics of the heart’s pumping action. “We have engineered fully biological, living heart chambers, or organoids, that spontaneously beat and respond to external stimuli,” said Professor Costa.
Unlike traditional engineered cardiac tissue patches, these hollow spherical cardiac organoids offer the unique ability to regulate wall stress, which is a key factor influencing normal and pathological cardiac function, and to measure the resulting pressure-volume relationships that cardiologists use to define the pumping capacity of the heart. By providing a controllable biomimetic cardiac environment, research using cardiac organoids can help to elucidate the mechanisms involved in complex processes such as stem cell differentiation, facilitating the translation of such therapies to clinical practice, and may eventually reduce the need to use experimental animals for such studies.
Up until now, to study the effects of various interventions on how the heart pumps, without the complication of neural regulation, immune responses, and other complexities present in the body, researchers have relied on the so-called Langendorff-isolated working heart preparation. This century-old technique involves surgically removing the heart from a laboratory animal and using electrical stimulators and plumbing to keep the heart beating and pumping fluid outside of the body. However, a major limitation is that the natural heart can only stay alive in the laboratory under these conditions for a few hours, making it difficult to study important processes such as development, growth, and repair, which take much longer to occur.
To help solve the problem of controlled long-term study, one approach used by Costa and other biomedical engineers has been to develop highly sophisticated computer models that attempt to incorporate the detailed complexities of the natural heart and predict how it would behave under various conditions. However, Costa points out, “validating the results of computer models remains a difficult issue.” So, he and Lee hypothesized that an alternative approach might be to engineer idealized model tissues that retain essential physiologic characteristics of the natural heart, but allow simpler theoretical analysis. “Rather than making the equations more complicated,” Costa said, “we wondered if we could make the heart less complicated.”
Costa and Lee used tissue engineering techniques and a custom inflatable mold to create a thin-walled spherical cardiac pump composed of specialized heart muscle cells embedded in a 3-D collagen extracellular matrix material. The process is “kind of like making Jell-O,” says Costa, “except it’s alive!” The resulting organoid chamber beats on its own, develops pressure, ejects fluid, contains wall stress, and performs other traditional heart functions. It also avoids much of the complexity and complications of working with natural hearts, such as the need to maintain a circulatory system to supply oxygen and nutrients. To see a video of the beating organoid, click here.
Currently, the organoids generate about 5% of the pressure that can be developed by a similarly organized embryonic heart. When Costa first presented their preliminary results at the annual international meeting of the American Heart Association in 2005, he was concerned that the audience would focus on the sub-physiologic level of function. “I was surprised when members of the audience started asking about how we got it to work so well,” he said.
Costa and his team have also adapted a cryo-injury method to rapidly freeze a targeted portion of the tissue, essentially giving the organoid a heart attack. The ability to create a well-defined injury zone, and to then monitor how the healing process evolves and how that affects the pump function of the chamber in a well-controlled environment, offers a very powerful experimental tool for studying heart disease. Importantly, by providing an active 3-D cell culture environment, cardiac organoids may yield new biological insights that are not possible using traditional hard, flat Petri dishes.
In summary, these cardiac organoids represent a major breakthrough toward the development of surrogate engineered hearts for a wide range of experimental investigation and high-throughput screening applications where the effects on cardiac pump function are a primary concern. Moreover, by extending such approaches to applications other than the heart, Costa suggests that similar engineered tissue models of injury and disease could represent an exciting new frontier for the field of tissue engineering, which has been primarily focused on creating healthy replacements for diseased or damaged tissue.
Lee and Costa’s cardiac organoid experiments were published in the February, 2008, issue of Tissue Engineering, in a paper entitled “Engineered Cardiac Organoid Chambers: Toward a Functional Biological Model Ventricle.” In addition to Costa and Lee, who is currently with the Department of Anesthesiology at Yale, other researchers on the project were Do Eun Kim and Evren U. Azeloglu of SEAS’s Department of Biomedical Engineering. The research was funded by the Whitaker Foundation, a private organization supporting Biomedical Engineering research and education, as well as the National Heart Lung and Blood Institute of the NIH.
