Improving Human Health

Improving Human Health

UD’s Xinqiao Jia secures $4.85 million to advance vocal fold, salivary gland research

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.”

| Photo by Evan Krape

New Drug Carrier Systems

New Drug Carrier Systems

UD researchers advance drug delivery systems to treat connective tissue disorders

University of Delaware Professor Kristi Kiick is leading collaborative research to create new drug delivery systems with the potential to improve treatment for diseases that affect connective tissues, such as osteoarthritis or rheumatoid arthritis, which is an autoimmune disease.

The UD researchers have devised tiny cargo-carrying systems many times smaller than a human hair. These systems, or carriers, are made from molecules called peptides that help provide structure for cells and tissues.

The research team is working to program these nanoparticle carriers to selectively bind to degrading collagen in the body. Collagen is a protein that helps plump up or provide structure to connective tissue—everything from our skin to our bones, tendons and ligaments.

When collagen degrades, as a result of disease or injury, the nanoparticles designed by the Kiick lab can attach and remain at the injury site longer than many current treatment options. This allows for the possibility of delivering site-specific medicines over longer periods of time—from days to weeks.

In one collaborative project that involves this work, Kiick is trying to develop drug carriers that could be useful in treating osteoarthritis. Osteoarthritis is a degenerative joint disorder characterized by inflammation, pain and stiffness. According to the Centers for Disease Control and Prevention, it affects 32.5 million Americans.

Early studies with Christopher Price, an associate professor in biomedical engineering, suggests that these nanoparticles can be retained in tissue and knee joints. In other related studies, Kiick and her students have shown that drugs can be encapsulated and retained in the nanoparticles, until released by changes in temperature.

“We are interested in learning how to release drugs that can help not just with pain management, but also with slowing down disease progression,” said Kiick, Blue and Gold Distinguished Professor of Materials Science and Engineering. “It has been key that we have been able to collaborate with the Price laboratory in this type of work.”

For a long time, small molecule corticosteroids have been a standard of care for managing pain in osteoarthritic joints. Because the joint is full of thick, sticky fluid and is under constant mechanical stress and motion, these small-molecule drugs get expelled from the fluid around the knee pretty quickly, in minutes.

“We are hopeful that by controlling the nanoparticle composition and structure,” said Kiick, “we will be able to finely control, or tune, the drug delivery behavior to provide longer-lasting relief for people with inflammatory conditions, such as osteoarthritis.”

Kiick and colleagues reported advances on the nanoparticle design on Wednesday, Oct. 7, in a paper published in Science Advances, a peer-reviewed journal of the American Association for the Advancement of Science. Co-authors on the work include Jingya Qia, a graduate student in the Kiick lab, and Jennifer Sloppy, a senior microscopy specialist in UD’s Harker Interdisciplinary Science and Engineering Laboratory.

The paper’s key findings demonstrate the research team’s ability to control the shape of the nanoparticles, which will impact how well they can bind to tissue in the body and stay in a particular location. The research team also can precisely control the size of the nanoparticles, which has implications for how they might be retained at the injection site and also how they may be used by particular cells before being removed from the body. Finally, the paper describes some of the very fine details of how the specific building blocks inside these peptide molecules can affect the temperature at which those different shaped and sized nanoparticles can be disassembled to release a medicine.

The research builds on Kiick’s previous patented and patent-pending work in this area, but she said it is collaboration with others that is driving forward promising results. While the Kiick lab brings expertise in creating novel materials that can be used as delivery systems; Arthi Jayaraman, Centennial Term Professor for Excellence in Research and Education in the Department of Chemical and Biomolecular Engineering, is helping the team understand factors related to temperature sensitivity of the delivery vehicles and to develop computational tools that can help the research team characterize the vehicle’s shape.

Meanwhile, Price’s expertise in understanding post-traumatic osteoarthritis has been key to developing methods to use these nanoparticles to potentially treat disease. Price is exploring how particular drugs and cells interact, which may inform what specific classes of medicines are useful in treating osteoarthritis that develops following traumatic injury. The collaboration will help the Kiick lab tailor what types of nanoparticle devices can be used to deliver these different classes of medicines.

According to Kiick, thinking big, the team could imagine loading a custom cocktail of medicines into the drug-delivering nanoparticles capable of delivering relief over varying timescales and temperatures. The researchers already have the right material nanostructure that can allow this to happen; now they are exploring how to trigger the nanoparticles to release specific medications under particular conditions.

“You could imagine injecting these encapsulated medications at the knee,” she explained. “Then, when you want one medication to be released, the patient could ice their knee. If another drug is needed to provide relief over a longer time-period, heat could be applied.”

It could be a really simple way to help people manage chronic conditions that cause a lot of pain and reduce mobility. And because the treatment is local, it could reduce side effects that can occur when drugs have to be taken at high doses or over prolonged periods of time.

“If these delivery vehicles could reduce painful effects of osteoarthritis, or delay when osteoarthritis symptoms emerge, there could be important implications for improving quality of life for many people,” Kiick said.

 Graphic illustration by Jeffrey C. Chase