University of Delaware materials scientist Xinqiao Jia has received a combined $4.85 million in funding from the National Institutes of Health (NIH) for research aimed at improving human health through new approaches in tissue engineering.

Tissue engineering is an interdisciplinary field that focuses on developing methods to repair or replace biological tissues that have been damaged or degraded over time. 

Jia and colleagues will explore ways to regenerate salivary glands that have been damaged by radiation therapy for head and neck cancers. She also will focus on understanding what causes damage or scarring to vocal folds, the pliable tissue that enables our ability to talk. 

Faster than a hummingbird’s wings

Vocal folds produce sound by vibrating more than 100 times per second as air from the lungs passes through the paired tissues. In other words, our vocal folds do the heavy lifting when we speak. 

For comparison, this movement is nearly two times faster than the average North American hummingbird, which flaps its wings about 53 times per second in flight.

Each vocal fold consists of a soft connective tissue, known as the lamina propria (LP), sandwiched between a muscle and a flat, protective layer called the epithelium (EP). It’s a delicate structure, and little is known about the molecular and cellular processes that can lead to chronic vocal fold scarring, leaving millions of affected Americans with limited treatment options. 

Armed with $2.49 million in NIH funding, Jia, professor of materials science and engineering in the College of Engineering, will spend the next five years working to understand how vocal folds regenerate after damage — or don’t — and why. 

“If you have a scar or scab on your skin, eventually it just falls off. But on a vocal fold this scarring persists and doesn’t go away. With scarred vocal folds, your ability to speak is severely compromised,” she said. 

Jia is particularly interested in whether vocal fold damage results from chemical (i.e., smoking) or mechanical causes to drive development and testing of new treatment options.

Building on previous research, she plans to create a vocal-fold-on-a-chip model with embedded sensor technology to monitor the development of the vocal fold tissue in real time with help from several interdisciplinary colleagues. UD collaborators include Joe Fox, a pioneer in developing highly efficient chemical reactions for making tissue-mimicking hydrogels used to grow the vocal folds, and materials scientist Charles Dhong, who specializes in measuring mechanical forces at biological interfaces. Susan Thiebault, who has expertise in vocal fold physiology and biology at University of Wisconsin, Madison, also will contribute to the project.

The model will include built-in airflow to stimulate speech, allowing the device to reflect the human anatomy and physiology more closely than current models. The researchers also plan to introduce cigarette smoke into the chip model to explore whether smoking plays a role in the damage that can cause vocal-fold tissue to become stiff and fibrotic. 

“Once our model is validated, we can begin testing medications for repairing the tissue,” Jia said.

Help for dry-mouth syndrome 

Meanwhile, in a second project with $2.36 million in NIH funding over five years, Jia and colleagues will investigate methods to restore function in salivary glands that have been damaged by radiation therapy for head and neck cancers.

The human body contains three major salivary glands. When these salivary glands become damaged, they no longer secrete the saliva needed for digestion and for keeping the mouth free of bacteria. This can lead to a condition called dry-mouth syndrome, or xerostomia, a permanent and painful side effect of radiation therapy that affects about 50,000 head and neck cancer patients annually in the United States.

Jia explained that it is acinar cells that are responsible for creating saliva, which is collected in the ducts and channeled to the mouth. While the acinar cells become damaged after radiation treatment, the channels remain largely intact. Interestingly, within these salivary gland channels are progenitor cells that have the potential to become different cell types and restore the salivary gland. 

In previous work, Jia and colleagues including Dr. Robert Witt, director of the head and neck oncology clinic at ChristianaCare’s Helen F. Graham Cancer Center, showed that it was possible to isolate progenitor cells from salivary gland tissue samples taken prior to radiation therapy and grow them in hydrogels in the lab into multicellular structures that mimic the structure of acini that secrete saliva. While this advance is hopeful and exciting, the hard part has been figuring out ways to reintegrate the tissue in the body.

For the new arc of this work, Jia enlisted several researchers with expertise in needed areas to join the team, including Fox and Jason Gleghorn, a biomedical engineer. Gleghorn’s background in the biological processes that cause organs, such as the lungs, to develop a branched architecture and in developing artificial blood vessels will be useful in the context of salivary gland regeneration, Jia said. In the meantime, Fox’s chemistry expertise can help provide the cells with the proper environment so that they organize and orient correctly to do their job. Kenneth Yamada, a biologist with the National Institutes of Dental and Craniofacial Research with extensive background in the developmental biology of salivary glands, rounds out the team.

“One thing we’ve learned from literature and our previous study is that the salivary gland doesn’t develop if there is no nerve or blood vessel,” said Jia. “In this new work, we plan to reconstitute blood vessels alongside the growing salivary gland in hopes the vasculature will provide the right signal and architecture to guide the development of the salivary gland. It’s going to be very difficult, but you have to start somewhere.”