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November 29, 2017

Fully Functioning Artificial Human Heart Muscle Developed

The final key that brought this discovery together was rocking the samples to bathe and splash them, improving nutrient delivery. [Duke University]

  • Duke University researchers say they have created an artificial human heart muscle large enough to patch over damage seen in patients who have suffered a heart attack. The advance takes a major step toward the end goal of repairing dead heart muscle in human patients, the team adds.

    The study (“Cardiopatch Platform Enables Maturation and Scale-Up of Human Pluripotent Stem Cell-Derived Engineered Heart Tissues”) appears online in Nature Communications.

    “Despite increased use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for drug development and disease modeling studies, methods to generate large, functional heart tissues for human therapy are lacking. Here we present a “Cardiopatch” platform for 3D culture and maturation of hiPSC-CMs that after 5 weeks of differentiation show robust electromechanical coupling, consistent H-zones, I-bands, and evidence for T-tubules and M-bands. Cardiopatch maturation markers and functional output increase during culture, approaching values of adult myocardium,” write the investigators. 

    “Cardiopatches can be scaled up to clinically relevant dimensions, while preserving spatially uniform properties with high conduction velocities and contractile stresses. Within window chambers in nude mice, cardiopatches undergo vascularization by host vessels and continue to fire Ca2+ transients. When implanted onto rat hearts, cardiopatches robustly engraft, maintain pre-implantation electrical function, and do not increase the incidence of arrhythmias. These studies provide enabling technology for future use of hiPSC-CM tissues in human heart repair.”

  • Duke engineers have engineered a heart patch large enough to cover most damage caused by heart attacks. These videos show the patch contracting on its own, a 3D visualization the patch's cells, and the rocking bath that proved critical to the heart patch's record-breaking size. [Nenad Bursac/Duke University]
  • "Right now, virtually all existing therapies are aimed at reducing the symptoms from the damage that's already been done to the heart, but no approaches have been able to replace the muscle that's lost, because once it's dead, it does not grow back on its own," said Ilya Shadrin, a biomedical engineering doctoral student at Duke University and first author on the study. "This is a way that we could replace lost muscle with tissue made outside the body."

    Unlike some human organs, the heart cannot regenerate itself after a heart attack. The dead muscle is often replaced by scar tissue that can no longer transmit electrical signals or contract, both of which are necessary for smooth and forceful heartbeats. 

    New therapies, such as the one being developed by Shadrin and his advisor Nenad Bursac, Ph.D., professor of biomedical engineering at Duke, are needed to prevent heart failure and its lethal complications.

    Current clinical trials are testing injection of stem cells derived from bone marrow, blood, or the heart itself directly into the affected site in an attempt to replenish some of the damaged muscle. While there do seem to be some positive effects from these treatments, their mechanisms are not fully understood. Fewer than 1% of the injected cells survive and remain in the heart, and even fewer become cardiac muscle cells.

    Heart patches, on the other hand, could conceivably be implanted over the dead muscle and remain active for a long time, providing more strength for contractions and a smooth path for the heart's electrical signals to travel through, notes Shadrin. These patches also secrete enzymes and growth factors that could help recovery of damaged tissue that hasn't yet died. 

    For this approach to work, however, a heart patch must be large enough to cover the affected tissue. It must also be just as strong and electrically active as the native heart tissue, or else the discrepancy could cause deadly arrhythmias.

    This is the first human heart patch to meet both criteria, says Dr. Bursac. "Creating individual cardiac muscle cells is pretty commonplace, but people have been focused on growing miniature tissues for drug development," he explains. "Scaling it up to this size is something that has never been done and it required a lot of engineering ingenuity."

    The cells for the heart patch are grown from human pluripotent stem cells. Dr. Bursac and Shadrin have successfully made patches using many different lines of human stem cells, including those derived from embryos and those artificially forced, or "induced," into their pluripotent state.

    Various types of heart cells can be grown from these stem cells: cardiomyocytes, fibroblasts, and endothelial and smooth muscle cells.  The researchers place these cells at specific ratios into a jelly-like substance where they self-organize and grow into functioning tissue.

    "It turns out that rocking the samples to bathe and splash them to improve nutrient delivery is extremely important," said Shadrin. "We obtained three to five times better results with the rocking cultures compared to our static samples."

    The results improved on the researchers' previous patches, which were 1 cm2  and 4 cm2. They successfully scaled up to 16 cm2 and five to eight cells thick. Tests show that the heart muscle in the patch is fully functional, with electrical, mechanical, and structural properties that resemble those of a normal, healthy adult heart. 

    "This is extremely difficult to do, as the larger the tissue that is grown, the harder it is to maintain the same properties throughout it," said Dr. Bursac. "Equally challenging has been making the tissues mature to adult strength on a fast timescale of five weeks while achieving properties that typically take years of normal human development." 

    Dr. Bursac and Shadrin have already shown that these cardiac patches survive, become vascularized, and maintain their function when implanted onto mouse and rat hearts. For a heart patch to ever actually replace the work of dead cardiac muscle in human patients, however, it would need to be much thicker than the tissue grown in this study. And for patches to be grown that thick, they need to be vascularized so that cells on the interior can receive enough oxygen and nutrients. Even then, researchers would have to figure out how to fully integrate the heart patch with the existing muscle.

    "Full integration like that is really important, not just to improve the heart's mechanical pumping, but to ensure the smooth spread of electrical waves and minimize the risk of arrhythmias," said Shadrin. 

    "We are actively working on that, as are others, but for now, we are thrilled to have the 'size matters' part figured out," added Bursac.

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