2022 Schmidt Science Fellow Hannah Zlotnick has pivoted from bioengineering to chemical engineering in her quest to find new treatments for osteoarthritis.

Although osteoarthritis may not emerge for years, the biological changes that drive it often begin in the immediate aftermath of a joint injury.

Published in PNAS this week, her ingenious 3D model provides a unique window on what happens inside the knee immediately after damage occurs.

“We can isolate cells non-invasively from patients with their consent, and use those cells to create three-dimensional (3D) tissue culture models of the knee joint,” Hannah explains.

“This allows us to study what happens to our joint tissues after an injury on a fundamental level, and also use these engineered tissues for drug screening applications.”

The pioneering work could open new therapeutic avenues for treating conditions such as osteoarthritis and help avoid the need for invasive joint replacement surgery.

Hannah’s interdisciplinary journey was partly inspired by injuries she sustained in the past.

Hannah playing soccer as a youth athlete, an experience that later inspired her interest in orthopedic research.

“As a youth athlete, I was acutely aware of the orthopedics office”, says Hannah with a wry smile.

She was a goalkeeper for the varsity women’s soccer team during her undergraduate years at MIT, and over the course of her soccer career, she broke her arm, wrist, and several fingers.

These painful experiences, along with witnessing teammates sustain season-ending ligament tears, sparked an enduring interest in orthopedic research.

Hannah is particularly interested in damage to the soft tissues in our joints, such as cartilage and synovium – the smooth, inner lining of the joint – which do not heal as well as bone.

“When cartilage heals, a fibrous, disorganized tissue takes its place, much unlike healthy cartilage.

“The unstructured repair cartilage is minimally functional, and it wears away more quickly as you move.

“This leaves little protection over the underlying bone,” she explains.

That degeneration leads to osteoarthritis, a painful, debilitating joint condition for which the only treatments available are steroid injections, over-the-counter painkillers or, joint replacement surgery.

Knee or hip replacement surgery is brutally invasive, and replacement joints have a limited lifespan.

That means a second surgery may be needed later on in a patient’s life to exchange the metal and plastic implants for new ones.

Hannah’s PhD at the University of Pennsylvania focused on finding new, less invasive treatment options for people with joint injuries.

Working in animal models, she developed techniques to recreate the cellular and mechanical structure of cartilage using magnetic fields to ultimately design longer-lasting cartilage repair tissue.

But her PhD also highlighted the importance of extending the clinical relevance of her work beyond animal models to better reflect what happens in people, motivating her pivot into in vitro models.

Hannah at a Global Meeting in Singapore, May 2023, during the first year of her Fellowship

The support she received as a Schmidt Science Fellow enabled her to pursue an interdisciplinary research pivot that involved moving from the Department of Bioengineering at the University of Pennsylvania to the University of Colorado Boulder’s Chemical and Biological Engineering department, where she now studies joint injuries using cells from human donors.

As part of this work, Hannah has created a miniature (less than 1mm across) 3D version of the tissue that lines the knee joint, called the synovium.

This is one of the few joint tissues to contain blood vessels, which transport inflammatory cells into the joint as part of the immune response to damage.

Decades later, this persistent inflammatory response can significantly contribute to osteoarthritis.

Hannah’s paper in PNAS details an exciting new discovery made with her so-called ‘acute injury-on-a-chip’ model.

This model included an engineered blood vessel surrounded by synovial fibroblasts; the most common type of cell found in the synovium.

Using this model system, Hannah discovered something unexpected: “It has been understood that synovial fibroblasts primarily promote disease.

However, at the time of injury, we observed that these ‘bad’ synovial fibroblasts were actually trying to maintain the healthy function of the blood vessels.”

This finding suggests that therapies designed to target receptors on these specific synovial cells could prevent joint injury from progressing to osteoarthritis.

The model provides a glimpse inside the joint at a critical moment in time that would be incredibly challenging to study inside the body.

Typically, researchers do not get access to a patient’s joint tissue until their surgery, several weeks after the initial injury.

Until now, it has been a mystery what happens inside patients’ cells in the hours immediately after an injury.

“This acute injury-on-a-chip model provides a unique lens into what happens immediately after an injury and how the cells respond. This information will guide therapeutic design to control cell behavior and hopefully prevent disease in the long term,” says Hannah.

“This acute injury-on-a-chip model provides a unique lens into what happens immediately after an injury and how the cells respond. This information will guide therapeutic design to control cell behavior and hopefully prevent disease in the long term”

There are broader applications for Hannah’s chip model, too. Osteoarthritis is fiendishly difficult to treat because it has multiple causes: injury, aging, metabolic imbalance, and more.

Patients with osteoarthritis may have any combination of these causes; they are all different.

“We can potentially incorporate cells from different patient populations into these 3D models to assess and predict how people will respond to certain therapies,” says Hannah.

In August, Hannah will begin a new position as Assistant Professor in the Department of Orthopaedic Surgery and Rehabilitation at Wake Forest University School of Medicine, where she plans to start her own lab to develop new materials to model and monitor joint health.

“I couldn’t have done any of this without the Schmidt Science Fellowship,” adds Hannah.

“The support has been phenomenal and not just the financial support, but also the community of fellows and staff, and all of the leadership development alongside.

“I’ve learned so much from all the other fellows in my cohort, from their research and career trajectories.

“And I’ve really enjoyed being part of the Program, not just during the first two years but also now being part of the Senior Fellow community.”