Novel bioreactor to repair vocal chords

Damaged or diseased vocal cords can forever change and even silence the voices we love, from a family member's to a famous personality's.

Julie Andrews, who starred in such classics as The Sound of Music, is among the professional singers who have undergone surgery to remove callus-like growths that can form from overuse of these two small, stretchy bands of tissue housed in the larynx, or voice box. Sadly, Andrews may never fully recover her singing voice after surgery on her vocal cords in 1997.

Engineering pliable, new vocal cord tissue to replace scarred, rigid tissue in these petite, yet powerful organs is the goal of a new University of Delaware research project. It is funded by a five-year, $1.8 million grant from the National Institutes of Health's National Institute on Deafness and Other Communication Disorders.

Xinqiao Jia, UD assistant professor of materials science and engineering, is leading the project. Jia's research focuses on developing intelligent biomaterials that closely mimic the molecular composition, mechanical responsiveness and nanoscale organization of natural extracellular matrices--the structural materials that serve as scaffolding for cells. These novel biomaterials, combined with defined biophysical cues and biological factors, are being used for functional tissue regeneration.

Randall Duncan, associate professor of biological sciences and mechanical engineering at UD and an expert in cellular biomechanics and signal transduction, is a co-investigator on the project. He will assist the interdisciplinary research team in determining how vocal cord cells respond to mechanical forces, which is the first step in engineering functional vocal cord tissue. Duncan is actively involved in Jia's career development as her senior mentor at UD.

Rodney Clifton, professor of engineering at Brown University and a member of the National Academy of Engineering, is providing the project with a unique testing capability, using a device he invented that can measure the mechanical properties, or elasticity, of tissue samples at human speech frequencies. Jia began working with Clifton a few years ago when she was a postdoctoral researcher and he was a visiting scientist at the Massachusetts Institute of Technology.

Also collaborating on the project is Dr. Robert Witt, a head and neck oncologist at Christiana Care Health System, in Newark, Del. Witt will provide clinical expertise in vocal cord pathology. The research partnership was established through the Center for Translational Cancer Research, which is directed by Mary C. Farach-Carson, professor of biological sciences and material sciences at UD.

According to Jia, the vocal cords are more accurately defined as "vocal folds." Each vocal fold is a laminated structure consisting of a pliable vibratory layer of connective tissue, known as the lamina propria, sandwiched between a membrane (epithelium) and a muscle. These flexible folds of tissue, coated in mucous to keep them moist, operate like an elevator door and must come together to produce a sound.

When you talk or sing, the folds may vibrate more than 100 times a second from the air that is forced up from the lungs through the trachea. However, excessive use or abuse of the voice can lead to scarring of the vocal fold lamina propria, which disrupts their natural pliability, resulting in hoarseness and other symptoms of vocal dysfunction.

"The reduction of vocal-fold scarring remains a significant therapeutic challenge," Jia said.

Jia and her colleagues want to explore two parallel tissue-engineering approaches to regenerate the lamina propria. One method focuses on injecting gelatin-like materials, composed of soft, strong and long-lasting hydrogels, into damaged tissue to improve its pliability and prevent scar formation.

In the second approach, the scientists want to form functional tissue from a combination of vocal fold connective tissue cells (fibroblasts), artificial extracellular matrix, and biological cues and mechanical stimuli that capture the mechanical and biological characteristics of the natural organs.

"In order to grow a functional tissue in vitro, you need to provide the cells with a biological and physical environment that is as close to that of the natural tissue as possible," Jia said.

To mimic the complex and rigorous movement experienced by vocal fold tissue, the researchers have constructed a bioreactor capable of delivering well-defined vibrational and tensile stresses.

The device, which Jia designed, simulates the demanding, high-frequency environment in which vocal fold cells live, vibrating back and forth at up to 100 hertz (100 times a second). Not only do the vocal folds collide as they open and close, driven by air from the lungs, they also must be able to elongate as the pitch of the voice changes, a movement that occurs at a much slower frequency of 1-2 hertz (1-2 times a second), according to Jia.

"The combination of vocal fold fibroblasts, elastic and bioactive artificial extracellular matrices, and a dynamic bioreactor offers an exciting opportunity for in vitro tissue engineering of vocal fold lamina propria," Jia noted.

Earlier this year, Jia received the National Science Foundation's Faculty Early Career Development Award. The highly competitive award is bestowed on those scientists deemed most likely to become the academic leaders of the 21st century.

Jia received her bachelor's degree in applied chemistry and master's degree in polymer chemistry and physics from Fudan University in Shanghai, China, and a doctoral degree in polymer science and engineering from the University of Massachusetts at Amherst.

Before joining the UD faculty in 2005, Jia worked as a postdoctoral researcher with Robert Langer, a pioneer in tissue engineering at the Massachusetts Institute of Technology. Langer recently was awarded the National Medal of Science, the nation's highest honor for science and technology.