By Lindsay Brownell
Published by Wyss Institute at Harvard

(BOSTON) — Growing functional human organs outside the body is a long-sought “holy grail” of organ transplantation medicine that remains elusive. New research from Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Science (SEAS) brings that quest one big step closer to completion.

A team of scientists created a new method to 3D print vascular networks that consist of interconnected blood vessels possessing a distinct “shell” of smooth muscle cells and endothelial cells surrounding a hollow “core” through which fluid can flow, embedded inside a human cardiac tissue. This vascular architecture closely mimics that of naturally occurring blood vessels and represents significant progress toward being able to manufacture implantable human organs. The achievement is published in Advanced Materials.

“In prior work, we developed a new 3D bioprinting method, known as “sacrificial writing in functional tissue” (SWIFT), for patterning hollow channels within a living cellular matrix. Here, building on this method, we introduce coaxial SWIFT (co-SWIFT) that recapitulates the multilayer architecture found in native blood vessels, making it easier to form an interconnected endothelium and more robust to withstand the internal pressure of blood flow,” said first author Paul Stankey, a graduate student at SEAS in the lab of co-senior author and Wyss Core Faculty member Jennifer Lewis, Sc.D.

Finally, they were ready to test their method inside living human tissue. They constructed hundreds of thousands of cardiac organ building blocks (OBBs) – tiny spheres of beating human heart cells, which are compressed into a dense cellular matrix. Next, using co-SWIFT, they printed a biomimetic vessel network into the cardiac tissue. Finally, they removed the sacrificial core ink and seeded the inner surface of their SMC-laden vessels with ECs via perfusion and evaluated their performance.

Not only did these printed biomimetic vessels display the characteristic double-layer structure of human blood vessels, but after five days of perfusion with a blood-mimicking fluid, the cardiac OBBs started to beat synchronously – indicative of healthy and functional heart tissue. The tissues also responded to common cardiac drugs – isoproterenol caused them to beat faster, and blebbistatin stopped them from beating. The team even 3D-printed a model of the branching vasculature of a real patient’s left coronary artery into OBBs, demonstrating its potential for personalized medicine.

“We were able to successfully 3D-print a model of the vasculature of the left coronary artery based on data from a real patient, which demonstrates the potential utility of co-SWIFT for creating patient-specific, vascularized human organs,” said Lewis, who is also the Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.

In future work, Lewis’ team plans to generate self-assembled networks of capillaries and integrate them with their 3D-printed blood vessel networks to more fully replicate the structure of human blood vessels on the microscale and enhance the function of lab-grown tissues.

“To say that engineering functional living human tissues in the lab is difficult is an understatement. I’m proud of the determination and creativity this team showed in proving that they could indeed build better blood vessels within living, beating human cardiac tissues. I look forward to their continued success on their quest to one day implant lab-grown tissue into patients,” said Wyss Founding Director Donald Ingber, M.D., Ph.D. Ingber is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.

Additional authors of the paper include Katharina Kroll, Alexander Ainscough, Daniel Reynolds, Alexander Elamine, Ben Fichtenkort, and Sebastien Uzel. This work was supported by the Vannevar Bush Faculty Fellowship Program sponsored by the Basic Research Office of the Assistant Secretary of Defense for Research and Engineering through the Office of Naval Research Grant N00014-21-1-2958 and the National Science Foundation through CELL-MET ERC (#EEC-1647837).

Harvard’s Office of Technology Development worked with Professor Jennifer Lewis to protect the research group’s innovations, resulting in a robust patent portfolio for this technology platform. The Office of Technology Development is working with the research team to advance the innovations through existing and future commercialization opportunities.