By MITZI BAKER

Advances in total joint replacement no longer mean that an arthritic or damaged joint will inevitably lead to loss of mobility. Many joint replacements last decades, but a significant number – about 10 percent – fail within 15 to 20 years, which is becoming a problem as younger patients take advantage of the technology.

Noah Epstein, a third-year School of Medicine student working in the lab of orthopedic surgery professors Stuart Goodman, MD, PhD, and R. Lane Smith, PhD, has been looking at why joint replacements fail. He has developed a mouse model that can start unraveling the complicated process.

“One of the challenges with this kind of clinical problem is that there is a 20-year outcome, so it’s hard to replicate,” said Epstein, who presented his findings at the Orthopedic Research Society’s 50th annual meeting Monday in San Francisco.

“It’s helpful to see what’s happening, so we wanted to create a model that replicated what is seen clinically.” To accomplish this goal, he relied upon studies that can be easily and cost-effectively done with a mouse over weeks and months rather than the years it takes in humans.

When an arthritic or damaged joint is removed, it is replaced with a prosthesis – an artificial joint typically made of a metal piece such as various alloys that fit closely into a sturdy plastic segment.

But these materials gradually erode through wear and tear, releasing tiny metal and plastic particles that enter the joint space. Some artificial joint recipients experience chronic inflammation as a result, leading to pain and loosening of the joint, which may require another replacement.

The inflammatory response results when the body senses a foreign intruder. One of the ways the immune system tries to eliminate the intruder is by calling in cells to fight. This response, while necessary, can backfire in the case of organ transplants and joint replacements, attacking a beneficial intruder and causing it to function improperly.

Everyone who receives a new joint has an inflammatory response, Epstein said, and everybody sheds tiny particles of the device into the joint space. What remains a mystery, however, is why some people develop loosening while others do not.

A key player in the inflammatory response is interleukin-1, or IL-1, which is one of a number of molecules called cytokines that acts as a signaling network for the immune system. The researchers thought it was logical to start by looking at the role IL-1 plays in response to an artificial joint.

To explore the role of IL-1 in joint replacement failure, Epstein looked at implants in normal mice and in mice that lacked the receptor for IL-1, which makes them unresponsive to the molecule’s effects.

The team implanted tiny stainless steel wires into both thighbones of each mouse in the study. In one leg of each mouse, they injected titanium particles to simulate particles released as an artificial joint erodes.

In the IL-1 deficient mice, they saw some reduction of the level of other cytokines known to play a role in inflammation, indicating a protective effect.

However, they also saw less bone growth around the implants in those mice. Bone growth around the artificial joint assists in integrating the device into its new environment which helps it function as close to a normal joint as possible.

Epstein noted that inflammation is a complicated process. Many other factors come into play in addition to IL-1, such that the elimination of one cytokine wouldn't be expected to fully protect the mice from an inflammatory onslaught.

Epstein said it will be valuable to use their model to look at whether the recovery process following the single injection of particles is different in the mice without IL-1.

He emphasized they were at an early stage of understanding the process. He is now working on a mouse model that could simulate a continuous flow of particles to more closely mimic the human situation of constant exposure.

In the future, the researchers hope to develop methods that modulate the joint replacement process with drugs that could alter human immune responses at the appropriate times.