Help for young hearts

NIH pumps funds into Rice student’s work on replacement valves for children

BY MIKE WILLIAMS
Rice News staff

As a young student shadowing pediatric oncologists, Elizabeth Stephens realized just how hard it is to be around children who are ill.

Not too much later in her budding career, she decided to get to the heart of the matter.

	ELIZABETH STEPHENS

The San Diego native, working on combined medical and bioengineering doctorates at Rice and the Baylor School of Medicine, has received a fellowship from the National Institutes of Health (NIH) to pursue her research into congenital heart disease. Specifically, she’s working to design replacement heart valves for young patients that will grow as they do.

Currently, when a child is found to have a bad valve, it has to be replaced in one of two ways — with a bioprosthetic valve (harvested from a pig, for instance) or a mechanical device.

One problem is that mechanical valves, which work well in adults, require anticoagulant medicine to thin the blood — a very bad thing to give to an active child prone to cuts. And bioprosthetic valves, a relatively successful treatment in adults, rapidly calcify in children. However, there is a more basic problem with both these treatments: The replacement valves don’t grow with the child, so they have to be replaced every few years, requiring a childhood with repeated open-heart surgeries.

So Stephens, as principal investigator, has taken on the task of figuring out how to grow a new valve that can be implanted into a child, ideally using the youngster’s own cells as the source material.

Pathologists, she said, find it relatively easy to diagnose congenital valve disease, which is found in 1 percent of newborns. ”The valves are very disorganized,” she said. ”There are none of the layers, none of the properly aligned collagen — the connective tissue that gives it tensile strength — that you’d expect to find.”

The main challenge is to find a way to make replacement valves that can be implanted once and for all.

A healthy heart valve - actually a pig valve, which is similar in form and function to that of a human - that clearly shows organized layers of connective tissue, critical to proper function. Bottom, a diseased valve, with its layers in disarray.

For that, she’s calling on her own medical and bioengineering skills, and those of her advisers, Jane Grande-Allen, an associate professor of bioengineering, and Jennifer West, the Isabel C. Cameron Professor and chair of the Bioengineering Department.

”Libby’s proposal got the highest score I’ve ever seen from an NIH panel,” said Grande-Allen of Stephens’ winning application.

Grande-Allen said Stephens’ data will serve as a template for the process of building heart valves. ”People have been collecting information on valves for a long time, but not with the resolution Libby hopes to achieve,” she said. ”This fellowship gives her the opportunity to build upon the research she’s already done.”

Heart valves are complex connective tissues, Stephens explained, that evolve throughout a human’s life. Their compliance and stiffness, as well as their biology, change substantially with age and figuring out how to make a valve that’s appropriate for a patient of a particular age will be tricky.

”If cells from a given patient could be grown on a scaffold with the right signals, an implantable valve could be formed that could grow with the patient, making such repeated open-heart surgeries obsolete,” she wrote in her grant proposal.

Just how to go about that involves both biochemical engineering to create the valve and mechanical engineering to build the device that will be used to grow it. Stephens said the biochemical part involves using a polyethylene glycol hydrogel, a water-insoluble polymer that can be used as the scaffold in which target cells drawn from the patient are suspended. The design of this hydrogel is the component being addressed by her research.

The mechanical part, the bioreactor, would contain the scaffold. Several bioreactors are being designed by other graduate students in Grande-Allen’s lab. ”A bioreactor basically pumps media, the equivalent of blood, back and forth around the hydrogel while putting it through a bending motion,” said Stephens. ”The valve cells are very responsive to mechanical forces, so future graduate students could put these hydrogels into an environment where the cells experience a continuous stretch, so they will produce more collagen and extracellular matrix. In turn, that construct will get stronger and stronger, and then surgeons will be able to implant it.”

Stephens became interested in the mechanics of the heart while an undergraduate student at Yale and the University of California at San Diego, where she majored in chemistry. ”I love the heart. I like the mechanical aspect of it,” she said. ”I became interested in congenital heart disease because it’s a devastating problem, but we already have some powerful tools to fix it, and we’re rapidly acquiring more.”