Strep throat is a common and treatable childhood disease in the United States, but in less wealthy countries, children afflicted with strep can develop rheumatic fever, in which runaway inflammation attacks the body’s tissues. Rheumatic fever often damages the valves of the heart, causing rheumatic heart disease that can lead to serious health problems, including heart failure.
Heart valves can be surgically replaced, but children whose bodies are still growing may need multiple, highly invasive surgeries to replace their valves with larger ones, putting them at risk. Kevin Kit Parker’s team at the Wyss Institute and Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS) vowed to fix this problem by creating an implantable heart valve that grows with a child, minimizing surgical complications and suffering.
They are now a big step closer to that goal, as described in a new paper published in Matter. Their next-generation synthetic heart valve, called FibraValve, can be manufactured in less than 10 minutes using a new method called focused rotary jet spinning (FRJS), which allows the researchers to customize the shape and properties of the valve’s delicate flaps down to the nanoscale. This new valve was readily colonized by living cells, both in vitro and in large animal model studies conducted by collaborators led by Wyss Associate Faculty member Simon Hoerstrup at the Wyss Zurich Translational Center in Zurich, Switzerland. This international collaboration was supported by Wyss Institute Project funding.
“This study illustrates FibraValves’ potential as a solution for children suffering from valve diseases. Our goal is for the patient’s native cells to use the device as a blueprint to regenerate their own living valve tissue, but FRJS also has potential as a platform to fabricate other medical devices in the future,” says Parker, PhD, who is an associate faculty member at the Wyss Institute as well as the Tarr Family Professor of Bioengineering and Applied Physics at SEAS.
From “Good” to “Great”
Parker and Hoerstrup’s quest to create a living, growing heart valve has been underway since 2014, and they produced their first synthetic heart valve, JetValve, in 2017. The JetValve is manufactured using a novel method called rotary jet spinning, in which a biocompatible synthetic polymer is extruded through a nozzle and spun into long nanofibers — similar to how a cotton candy machine spins sugar crystals into fluffy clouds. These nanofibers are collected on a heart-valve-shaped mandrel, producing biocompatible valves within minutes compared to the hours required for other manufacturing methods.
The JetValve was successfully implanted into a sheep’s heart using minimally invasive surgery, functioned properly, and recruited living cells to regenerate new tissue on the device. But the team knew they could do better. They re-visited multiple aspects of the JetValve — manufacturing, fiber material, and geometric design – and challenged themselves to improve them all.
For the manufacturing process, they added streams of focused air to the polymer-extruding stream to create focused rotary jet spinning (FRJS). This allowed them to improve the rate at which the polymer fibers were deposited onto the mandrel, and to easily adjust the resulting valve to the final desired shape. The polymer also produced networks of micro- and nanofibers that better mimicked the tissue structure of a human heart valve.
The team also used a new, custom polymer material to improve the infiltration of living cells once the FibraValve is implanted into the body. This material, called PLCL, is a combination of polycaprolactone (PCL) and polylactic acid (PLA). Previous studies had shown that PLCL lasts about six months when implanted into rats, is infiltrated by living cells and remodeled into functional tissue, and safely biodegrades.
The resulting PLCL FibraValves were softer and more elastic than JetValves. After four weeks of being cultured with cells isolated from the heart valves of sheep, the FibraValve enabled a more even distribution of cells throughout its scaffold than valves made of other polymers.
Finally, they worked on improving the geometry of the FibraValve — specifically, optimizing the shape of the valve’s inner leaflets to minimize leakage of blood backwards through the valve. They were able to reduce the amount of leakage from the ~30 percent seen with the JetValve to ~13 percent with their optimized design.
A New Hope for Human Patients
To test their FibraValve in a more realistic environment, Hoerstrup’s team implanted it into a living sheep’s heart using minimally invasive surgery. The FibraValve started to function immediately, its leaflets opening and closing to let blood flow through with every heartbeat. After just one hour, the scientists observed red and white blood cells infiltrating the valve’s porous scaffolding, as well as protein called fibrin being deposited on the outside of the valve. The valve displayed no damage or problems following implantation.
“It was very exciting to see the FibraValve functioning in vivo, especially since we were coordinating across an ocean with our colleagues in Zurich to make it happen,” says co-first author Michael Peters, a graduate student at the Wyss Institute and SEAS. “This approach to heart valve replacement might open the door towards customized medical implants that regenerate and grow with the patient, making children’s lives better.”
“From the clinical perspective, these first in-vivo results with FibraValve are promising and motivate us to initiate further pre-clinical evaluation,” says Hoerstrup, MD, PhD, who is an associate faculty at the Wyss Institute and founding co-director of the Wyss Zurich Translational Center at ETH Zurich and University of Zurich, chair and director at Institute for Regenerative Medicine, University of Zurich, Switzerland.
The team is looking forward to starting longer-term animal testing to evaluate the FibraValve’s performance and regenerative capabilities over weeks and months. They also anticipate that FRJS could be used to create a wider variety of implantable devices, including other valves, cardiac patches, and blood vessels.
“This team’s tenacity and refusal to rest on their laurels embodies the Wyss Institute’s innovative spirit and commitment to improving the lives of patients by making game-changing treatments faster, better, cheaper, and more accessible,” says Wyss founding director Donald Ingber, MD, PhD, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.
Additional authors of the paper include former Wyss Institute and SEAS members Sarah Motta, Christophe Chantre, Luca Cera, and Qihan Liu; current Wyss and SEAS member Huibin Chang; Elizabeth Cordoves from SEAS; Emanuela S. Fioretta and Polina Zaytseva from the Institute for Regenerative Medicine, University of Zurich; Nikola Cesarovic from the Deutsches Herzzentrum der Charite (DHZC) in Berlin and the ETH Zurich; and Maximilian Emmert from the Wyss Zurich, DHZC, and Charité Universitätsmedizin Berlin.
This work was supported by the Wyss Institute at Harvard University, Harvard SEAS, the Harvard Materials Research Science and Engineering Center, the European Union’s Horizon 2020 research and innovation program under grant agreement no. 852814 (TAVI4Life), the Swiss National Science Foundation under Spark grant no. CRSK-3_196717, and the Swiss National Science Foundation under grant no. PZ00P3_180138.