Using “Synovium-on-a-Chip” To Study RA Treatment

By Vandana Suresh | March 25, 2024

Many people with rheumatoid arthritis (RA) get symptom relief and lower disease activity from one of the several types of medications available to treat it. But many patients still have joint symptoms despite different treatments, and do not achieve long-term remission. Thus, understanding the biological underpinnings of why some people with RA respond to treatment while others do not is an urgent clinical need.

To fill this knowledge gap, the Arthritis Foundation has awarded an RA Research Program award to Theresa Wampler Muskardin, MD, assistant professor of medicine and pediatrics at the Hospital for Special Surgery. With monetary support of $450,000 over three years, Dr. Wampler Muskardin’s team will leverage their expertise in “organ-on-a-chip” technology to understand the cellular and immune events in the synovium (tissue lining joints) that correlate with treatment responses in RA patients.

“The big gap now is trying to understand the biology of the RA patients that do not respond to treatments,” says Dr. Wampler Muskardin. “To answer that question, we will use our synovium-on-a-chip – the first vascularized, immunocompetent system that uses the patient’s own joint tissue – to test therapies that are already approved and ones that have not yet been tested for RA.”

The treatment options for RA have significantly expanded in the past decades. As the standard of care, patients are first prescribed conventional disease-modifying drugs (DMARDs) — for example, methotrexate — before moving on to biologic DMARDs (and their biosimilars), sometimes in combination with methotrexate. If the addition of biologics, typically TNF inhibitors, do not alleviate symptoms, Janus kinase (JAK) inhibitors may be started instead of biologics. Cycling through RA treatments in search of one that eventually works generally takes three to four months per drug, which can be very distressing for patients who do not respond to initial treatments.

“We know that remission at three months is the greatest predictor of long-term remission, and our goal is to help patients achieve remission at three months after diagnosis,” says Dr. Wampler Muskardin. “And yet, we have a mandated treatment approach where we know that most patients are not going to achieve low disease activity or remission at the end of three months.”

While the current approach is still the gold standard for treating RA, there is active research in predicting treatment responses so that patients are quickly matched to medications that will work for them. In that effort, Dr. Wampler Muskardin’s team will collect synovial tissue from RA patients and then assign them to study groups based on the tissue’s cellular composition. Then, Dr. Wampler Muskardin’ collaborator, Weiqiang Chen, PhD, associate professor of mechanical and aerospace engineering and biomedical engineering at New York University, will load the synovial tissue cells from each patient onto a microfluidic cell culture device – the synovium-on-a-chip.

This device recreates the complex environment of the joint. It contains different cell types and compartments found in the joint, bioengineered blood vessels and a central reservoir for loading immune cells isolated from RA patients’ bloodstream.

With this technology, the reservoir can be laden with white blood cells, particularly the monocytes (known to be pathogenic in RA), which can be studied as they transverse through the blood vessels into the synovial tissue. More importantly, the synovium-on-a-chip allows the team to study the effect of the synovial tissue signaling on monocytes, a process that could be altered in patients who are not responding to medication. In addition, this system will allow testing and comparing the effects of different therapies among patients who have been grouped by their synovium cellular content.

“I am grateful to the Arthritis Foundation for their support,” says Dr. Wampler Muskardin. “The award is critical to move this important research forward. I’m very thrilled about this opportunity.”

In addition to Drs. Wampler Muskardin and Chen, the team includes Timothy Niewold, MD, director of the Barbara Volcker Center for Women and Rheumatic Disease and vice chair for research in the Department of Medicine at the Hospital for Special Surgery.