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Can resilience be engineered?

Yale Medicine Magazine, 2014 - Autumn

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Of the many factors that influence the body’s ability to heal, age is perhaps the most critical. “The younger you are, the more resilience you have,” said Joseph A. Madri, M.D., Ph.D., professor of pathology and director of education. As researchers have noted for more than three decades, the womb is a good place to heal. “If you look at cases of in utero surgery you’d be hard pressed to find surgical scars,” said Madri, who directs the undergraduate course “Biological Reaction to Injury.”

In all likelihood, some combination of the growth factors, immune components, and stem cells in the uterus, plus the relative lack of biomechanical stress, allows not only the repair of fetal tissue but also its complete replacement. As a graduate student, Anjelica Gonzalez, Ph.D., an assistant professor of biomedical engineering, was intrigued by fetal regeneration and wondered how one might harness the regenerative capacity of fetal cells to promote healing.

Like her colleague Laura Niklason, M.D., Ph.D., professor of anesthesiology and of biomedical engineering, Gonzalez is looking closely at the elements involved in healing to find new ways to manipulate them in our favor. Her lab is investigating the chemical messengers that are active during fetal development for ideas that might lead to better treatment of severe burns in children. Niklason is pursuing a similar line of inquiry, with the aim of building better replacement blood vessels.

Gonzalez has focused much of her work on neutrophils, the immune system’s first responders to a burn injury. These white cells follow a trail of chemical signals through blood and tissue to arrive at the sites of inflammation. Once there, they ingest dead and dying cells within the damaged tissue, along with anything else—such as microbes looking for a way into the body—that may hinder healing. But if neutrophils remain at wound sites for too long, they can interfere with healing.

The amnion, the membrane that surrounds the fetus, contains natural proteins that recruit neutrophils and other leukocytes to the site of a wound and then block that recruitment once the white cells’ job is done. Gonzalez is trying to identify those amniotic signals that initiate and then terminate the inflammatory response and replicate them in an artificial scaffold—a structure that mimics the extracellular matrix and supports the three-dimensional growth of tissue. Gonzalez’s scaffolds would allow for inflammation but prevent it from becoming chronic, so that the regenerative programming in human cells can take over: cells divide, new tissue is born, and the wound heals. That inherent programming is also what allows Niklason to grow blood vessels in the lab.

Blood vessels are inherently resilient. They expand and contract with each heartbeat, roughly 100,000 times a day. Ironically, however, the same mechanisms meant to protect blood vessels from stress and damage can also lead to their failure.

When patients have high blood pressure, the blood vessel wall resists that force by growing thicker. But as the inside of the vessel narrows, the pressure and the risk of either rupture or blockage increase. Surgeons can bypass the damage to an artery with a vessel graft—a section of transplanted or prosthetic blood vessel that redirects blood flow around the damaged stretch of artery. Because veins are plentiful, they are a common source of grafts, but they aren’t built to withstand the same pressures as arteries. Synthetic grafts made of such plastics as Teflon are stronger, but they also fail over time.

Niklason is growing arteries from the body’s own smooth muscle cells instead. The cells are the seeds from which tissue will grow, but they need more than a Petri dish to grow into fully formed and functional vessels. Niklason harvests smooth muscle cells from donated tissue, seeds the cells on a biodegradable scaffold, and exposes them to mechanical and chemical cues that induce tissue growth. These are not the exact instructions that the cells would have received from a naturally occurring extracellular matrix, but they’re close enough. “The biological system for regeneration is robust enough that we don’t have to get it exactly perfect,” said Niklason.

As the muscle cells proliferate, the degradable polymer mesh that guided their growth disappears and is replaced by connective tissue—an extracellular matrix laid down by the cells themselves. Before the grafts are implanted, the cells, which contain the majority of the immunogenic cues, are removed, leaving behind a tube that will serve as a new artery.

Ideally, the graft will be repopulated by the host cells, which will produce their own mesh of protein-rich extracellular matrix. Over time the tissue will remodel until the graft that was implanted isn’t really there any longer: it has been completely replaced by host tissue. “That,” said Niklason, “is regeneration in the truest sense.”