WINSTON-SALEM, N.C., Oct. 23, 2026 —Researchers at Wake Forest University School of Medicine have demonstrated a natural mechanism that helps protect the important structural and functional tissue molecule hyaluronan from damage caused by inflammation.
The findings, published recently in the journal Proceedings of the National Academy of Sciences (PNAS), could help researchers better understand how the body maintains tissue during inflammation — whether it’s due to injury, infection, or a chronic condition — and potentially inform future approaches to treat diseases like cancer and osteoarthritis.
Hyaluronan, also called hyaluronic acid, is a common ingredient in skincare goods, but it is also found naturally throughout the body where it provides tissues with critical structure, hydration, and cell signaling.
During inflammation, a byproduct of the body’s natural defenses is the production of molecules called reactive oxygen species, or ROS, that can interact with biomolecules and cause extensive damage at elevated levels. Hyaluronan is particularly vulnerable to ROS damage, which can break large hyaluronan molecules into smaller fragments and interfere with their normal functions.
In the new study, researchers found that the attachment of proteins known as “heavy chains” to hyaluronan can provide substantial protection against this destructive process. In this naturally occurring modification, existing hyaluronan molecules are decorated with heavy chains by another enzyme found in the body. While it is observed commonly in inflammation, the biological function of the modification has not been fully understood.
“Our findings suggest that heavy chain modifications may be one of the ways the body responds to oxidative stress to help preserve hyaluronan structure and the tissues it supports,” said Adam R. Hall, Ph.D., corresponding author of the study and Professor of Biomedical Engineering at Wake Forest University School of Medicine.
“Understanding how this protective process works could give us new insights, not only into inflammation and how to treat it, but also into other processes that produce ROS, such as environmental and radiation exposures.”
Using solid-state nanopore technology developed at the School of Medicine, researchers were able to measure the size of hyaluronan molecules both with and without the protective heavy-chain modification. The team then exposed both types of molecule to ROS in laboratory experiments and found that unmodified hyaluronan fragmented rapidly, declining in size by 64% in one experiment. However, heavy chain-modified hyaluronan changed by only about 2% under the same conditions, within experimental error of untreated molecules.
Researchers also found that simply having the heavy-chain proteins nearby was not enough to provide protection: the heavy chains needed to be chemically attached to the hyaluronan molecule to be effective. Experiments where hyaluronan was simply mixed with other proteins or with unattached heavy chains did not prevent fragmentation, indicating that the direct, covalent connection between the heavy chain and hyaluronan is critical to the protective effect.
“That gives us an important clue about the mechanism involved and helps us better understand why this modification occurs during inflammation,” Hall said.
The researchers also tested whether this protective effect could be observed in a more biologically complex system. They examined joint fluid affected by advanced osteoarthritis and compared it to fluid from a healthy joint. Osteoarthritic samples had significantly more heavy chain-modified hyaluronan due to their inflammatory disease, and consequently their hyaluronan showed less fragmentation following laboratory exposure to the ROS than the hyaluronan from healthy joints.
The researchers noted that the modification did not completely protect naturally occurring hyaluronan from breakdown associated with chronic exposure. However, the findings provide evidence that heavy-chain modification serves as a strategy for making hyaluronan in the body more resilient to damage.
The work could eventually have implications for understanding inflammatory and tissue-degenerative conditions and how to treat them.
“This is a fundamental discovery about how hyaluronan can be protected in the inflammatory environment that the body often finds itself in,” Hall said. “The next steps are to understand how this protection happens and determine how that knowledge could ultimately be used to address diseases in which inflammation and tissue damage play an important role.”
Hall collaborated with other researchers at Wake Forest University School of Medicine, along with Cornell University, University of California, Davis, the University of Manchester and the University of Oklahoma Health Campus. The solid-state nanopore technology used to measure the hyaluronan was developed by faculty inventors at Wake Forest University School of Medicine and may financially benefit from future development of the technology, as disclosed in the publication.
The research was supported by National Institutes of Health grants 5R01GM134226-06 and P41EB020594, as well as Arthritis UK and the Wellcome Trust, also noted in the publication.
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About Wake Forest University School of Medicine
Wake Forest University School of Medicine is the academic core of Charlotte, North Carolina-based Advocate Health and a recognized leader in experiential medical education and groundbreaking research. It directs the education of nearly 1,900 students and fellows, including physicians, basic scientists and allied clinical professionals. The school of medicine also strategically investigates opportunities that will expand basic and clinical research, resulting in nationally and internationally recognized excellence in biomedical research. The school has two campuses, each co-located with leading-edge innovation districts, The Pearl, in Charlotte, and Innovation Quarter, in Winston-Salem, North Carolina. These affiliated life-sciences innovation districts focus on advancing health care through new medical technologies and biomedical discovery.
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Headquartered in Charlotte, North Carolina, Advocate Health is the third-largest nonprofit, integrated health system in the United States. A preeminent academic health system at the forefront of clinical excellence, innovation and research, it delivers care under the names Advocate Health Care in Illinois; Atrium Health in the Carolinas, Georgia and Alabama; and Aurora Health Care in Wisconsin and Michigan, and Wake Forest University School of Medicine is its academic core. Nationally recognized for expertise in heart and vascular, neurosciences, oncology, pediatrics and rehabilitation, Advocate Health is also a pioneer in the delivery of virtual health care. It is accelerating discovery by making research participation part of the standard-of-care through its one-of-a-kind National Center for Clinical Trials, plus two affiliated life-sciences-focused innovation districts and one of the nation’s largest graduate medical education programs. With more than 165,000 teammates serving patients at 69 hospitals and over 1,000 care locations across eight states, Advocate Health reinvests over $6 billion each year to improve community health, making it one of the nation’s largest providers of community benefit.