Kappa Delta Lanier Award Goes to Constance R. Chu, MD, for Her Work Defining ‘Pre-osteoarthritis’

By: Terry Stanton

Constance R. Chu, MD, points to an experience early in her surgical career that may have launched her on a quest to solve the riddles and mysteries of osteoarthritis (OA)—more specifically, to visualize pre-OA. As a young knee surgeon at the University of Pittsburgh, she was tending to two patients: a 39-year-old man who was practically crippled with arthritis arising from an anterior cruciate ligament (ACL) tear—more so than many of her elderly patients—and a 15-year-old female with a fresh ACL tear.

“As I did the ACL surgery, I saw how beautifully normal her cartilage looked,” she recalled of the young patient. “I thought back to when I was a resident helping with research where rabbit ACLs were cut so they would develop OA. I said to myself, ‘My goodness, we have to figure out what happens between the time of injury and the development of clinical OA. What window of time do we have to intervene so there are fewer people coming into my office in their 30s and early 40s needing a joint replacement?’ Those were the clinical inspirations for my work.”

Constance R. Chu, MD

Over the next two decades, Dr. Chu would pursue a path of research in a quest to understand the progression from injury to arthritis and pain and disability, especially in the nascent phase of the disease process, when arthritic changes are not clinically or radiographically evident but are surely occurring.

Her research focused on the use of imaging technology to detect and define markers of pre-OA, culminating in cartilage mapping with MRI ultrashort echo time (UTE)-T2 star mapping (UTE-T2). Dr. Chu, now of Stanford University, is the 2019 recipient of the Kappa Delta Elizabeth Winston Lanier Award, which will be presented during today’s Your Academy 2019.

Her initial imaging work explored ways to diagnose OA in the early stages, following successful bench-to-bedside clinical translation of arthroscopic optical coherence tomography (OCT). The identification of a marker of potentially reversible early cartilage metabolic changes suggested a potential for articular cartilage to reverse early pathological changes and led to this “decade-long effort to conceptualize pre-OA and to define imaging markers of pre-OA suitable for clinical use,” she wrote.

Because in vivo OCT imaging of human articular cartilage is limited to in-depth assessment and requires an invasive procedure with a probe, Dr. Chu’s focus shifted to quantitative MRI.

Through a decade of National Institutes of Health R01 funding, she assembled an interdisciplinary research team to evaluate the potential of noninvasive MRI UTE imaging for improved visualization of cartilage deep tissue. They pioneered bench-to-bedside translation of cartilage MRI UTE-T2 mapping for that purpose. “In the last five years, we have shown important relationships between MRI UTE-T2 elevations and mechanical metrics known to predict poor clinical outcomes and OA progression,” she wrote.

Recently, Dr. Chu’s team has received substantial funding from the Department of Defense (DoD) and the Veterans Administration, employing MRI UTE-T2 for outcomes assessments in four clinical trials (three human and one equine) evaluating new strategies to delay or prevent the onset of disabling knee OA.

An officer and a clinician-scientist
Dr. Chu’s expertise in imaging and risk assessment arose from her prior military career. After graduating from West Point in 1983, in the class that can claim having the most orthopaedic surgeons, Dr. Chu entered the army as an officer and eventually commanded an imaging intelligence unit. “We used highly sophisticated imaging and imaging algorithms to identify things that were deliberately hidden from us,” she said. “That’s where the whole ‘what lies beneath’ theme that runs through my [Kappa Delta] paper and work comes from.”

When she went to medical school at Harvard University, she received a challenge from Henry Mankin, MD, chief of orthopaedics at Massachusetts General Hospital. “Dr. Mankin introduced me to this whole cartilage problem,” Dr. Chu said. “He told me, ‘We have one chance at a pristine articular surface because once the cartilage is damaged, it doesn’t heal.’ He challenged me to find a solution.” (Dr. Mankin died in December 2018 at the age of 90 years.) 

Dr. Chu said her military experience helped form and synergized with the multifactorial approach she and her colleagues took to solve the OA riddle. “There are mechanical and biologic factors, and, of course, the structural damage, that all need to be taken into account in determining the risk of OA,” she said. “The concept of pre-OA is to identify markers of risk prior to actual development of OA.”

Now, Dr. Chu and colleagues will seek new revelations as they embark on the DoD-sponsored trials. The horse study involves gene therapy. A human study will examine how to reduce abnormal loading when patients with ACL reconstruction walk. “We have shown in our gait studies that people start using their legs differently after ACL injury,” Dr Chu explained. “It’s not just the injured leg; over time, the other leg undergoes similar walking changes.”

“Some of these biomechanical markers are the same [seen] in people with late OA and in people as they age,” she said. “One of the DoD trials has patients go through a gait retraining program to try to normalize or reduce abnormal biomechanical loading. Another is a drug trial in which we will follow the patients over two years to see if the group taking the treatment has less pre-OA and improved joint health using the UTE imaging,” Dr. Chu said. “A third is a gene therapy trial in horses who also develop disabling OA after joint injuries. We also have mechanistic and induced pluripotent stem cell studies in the program. We will use the UTE imaging in all clinical trials to see if the interventions improve joint cartilage and meniscus properties after treatment.”

In another clinical trial funded by a Veterans Administration Merit Review grant, Dr. Chu and her team will also employ UTE-T2 mapping to evaluate the effect of platelet-rich plasma injections onto the articular cartilage of patients with early knee OA.

Dr. Chu said that among the main clinical takeaways her work has yielded so far is a suspicion that a longer recovery time might be important in preventing OA. “Just because patients feel great at six months to a year after their ACL surgery doesn’t mean that their joint is ready to go back to full sports,” she said.

“We are showing that about half of people likely aren’t ready at a year. In the sports medicine community, more top surgeons are moving toward one year for return to play instead of six months. In the near future, I anticipate having pretty strong justification for performing an MRI, including UTE imaging, to better assess joint tissue recovery and inform whether the patient needs some type of early intervention,” she added.

Dr. Chu speaks with infectious enthusiasm as she describes her work: “It’s exciting to be able to evaluate these treatments.” And, she is adamant in crediting numerous past mentors—including Dr. Mankin and ACL expert Freddie H. Fu, MD, of the University of Pittsburgh—her current and past research teams, and her Kappa Delta coauthors Ashley A. Williams, MS; Jennifer Erhart-Hledik, PhD; Matthew R. Titchenal, PhD; Yong Xian Qian, PhD; and Thomas P. Andriacchi, PhD. “This is a team effort,” Dr. Chu said.

Terry Stanton is senior science writer for AAOS Now. He can be reached at tstanton@aaos.org