From Root Cause to Remedy: Can Microgravity Help Prevent Post-Traumatic Osteoarthritis?

April 23, 2024 • By Stephenie Livingston, Staff Writer

Alan Grodzinsky sees things differently. When he uses fluorescent dyes to test cell viability in the cartilage tissue he studies, dead cells are supposed to light up red in a field of green live cells. But when he looks at them through a microscope, the colorblind biologist only sees green. These hindrances mean he relies on and gets to know his students more than some professors. It was among them that he saw an unexpected and growing “epidemic” firsthand: early-onset osteoarthritis.

“It’s an epidemic among young women playing sports like soccer in high school and college,” he said. “Totally normal knee, and all of a sudden, you have a joint injury, and within 5 or 10 or 15 years, you develop full-blown osteoarthritis.”

Grodzinsky, a biological engineering professor at the Massachusetts Institute of Technology (MIT), studies the lasting effects of traumatic injuries on human joints, the cartilage and tissue structures that connect our bones and enable our movement. He’s most interested in post-traumatic osteoarthritis (PTOA), a common condition that affects around 20 percent of the 650 million people worldwide with osteoarthritis. However, no U.S. Food and Drug Administration-approved drugs exist to treat osteoarthritis. While osteoarthritis research and treatment usually focus on older people, Grodzinsky’s research is inspired by young people who begin to develop PTOA after injuries, such as ACL and meniscus tears in the knee.

The initiation of PTOA is difficult to study, and delivering medications to cartilage is notoriously tricky. So, doctors only treat the symptoms rather than the underlying causes that drive the disease to prevent long-term joint damage. But Grodzinsky sees a different path toward prevention: addressing its trigger.

When a joint is injured, inflammatory proteins called cytokines are immediately released from a connective soft-tissue membrane called the synovium. When the inflammation dies down, the cytokines stick around and continue to wreak havoc in the cartilage, tendons, and other tissues. Even if the initial injury heals, too often, the tissue is never the same.

To better understand this process, Grodzinsky and his team turned to space. They thought it might simulate osteoarthritis characteristics quicker, with past research demonstrating accelerated bone loss in microgravityThe condition of perceived weightlessness created when an object is in free fall, for example when an object is in orbital motion. Microgravity alters many observable phenomena within the physical and life sciences, allowing scientists to study things in ways not possible on Earth. The International Space Station provides access to a persistent microgravity environment.. Grodzinsky said it was also an opportunity to understand how spaceflight might affect the initiation of osteoarthritis in astronauts.

The team’s International Space Station (ISSInternational Space Station) National Laboratory®-sponsored experiment, funded by the National Institutes of Health, developed a microphysiological system—also called a tissue chip—capable of mimicking the earliest events of PTOA’s initiation and providing an in vitro platform for testing drugs that may hinder or even block its progression. The tissue chips, created using human tissues in a small plastic dish, mime the cartilage, bone, and synovium (CBS) in certain joints. CBS joints, like knees and hips, are the most common sites of osteoarthritis.

The results, published in Frontiers in Space in March 2024, were striking. The researchers found that their tissue chipA tissue chip, or organ-on-a-chip or microphysiological system, is a small engineered device containing human cells and growth media to model the structure and function of human tissues and/or organs. Using tissue chips in microgravity, researchers can study the mechanisms behind disease and test new treatments for patients on Earth. The National Institutes of Health (NIH) has a multiyear partnership with the ISS National Laboratory® to fund tissue chip research on the space station. model successfully reproduced a physiologically relevant joint model with viable and reproducible human CBS cocultures that generated a baseline for PTOA disease and treatment conditions. Specifically, the device could accurately simulate the progression of PTOA and treatment effects with drugs commonly used to treat inflammation and pain in osteoarthritis patients, as well as a drug for tissue growth shown to stimulate cartilage repair. These findings provide valuable insights into the disease process and potential therapeutic strategies.

“This opens up new possibilities for testing drugs and interventions for osteoarthritis and other joint disorders,” says Grodzinsky. “It could also aid in developing preventative treatments.”

The Long Road From Boston to the Space Station

Grodzinsky anxiously watched the night sky in the early morning hours. After a string of scrubbed launch attempts during the spring of 2019, this time—he hoped—his experiment would travel to the ISS on SpaceX’s 17th Commercial Resupply Services (CRS) mission, contracted by NASANational Aeronautics and Space Administration.

Months earlier, the team decided to use donated human tissue for the study to jumpstart the type of data collection that can lead to human trials and avoid animal trials. Before turning to human donors for his spaceflight investigations, Grodzinsky’s lab experimented using cow cartilage, typically used to tackle everything from joint disease to bone cancer. As you walk into his office at MIT, a painting of a cow greets you, and dozens of cow figurines line the shelves.

But when it came time to launch the investigation, transporting live human tissue from a lab in Boston to the space station was a “logistical nightmare,” said Lisa Flaman, a former staff research specialist in Grodzinsky’s lab. Scrubbed launches worsened the situation, resulting in a need for last-minute tissues.

Grodzinsky added, “Along the way, there were daily and nightly heart attacks as we tried to make sure we could get new donor tissues from donor banks about a week before the rocket went up. When the rocket goes up, you’ve got to be on it, and you just never know when you’ll get a donor.”

Finally, at 2:48 a.m., launching against a pitch-black sky, Grodzinsky could clearly see the rocket exhaust plume and the Falcon 9’s flame light up the night as it carried his experiment to space. If he missed any colors, he couldn’t tell. Flaman remembers the instant relief she felt watching the rocket carrying her project leave Earth.

“We were drinking espresso just to stay awake, and, thankfully, it went off,” she said. “It was beautiful—the greatest thing ever. Life-changing. I still watch my little videos from the launch.”

Once on station, for several weeks, the automated tissue chips were cocultured inside specialized incubators designed by ISS National Lab Commercial Service ProviderImplementation Partners that own and operate commercial facilities for the support of research on the ISS or are developing future facilities. Techshot, which is now part of Redwire Corporation. The effects of microgravity on cartilage, bone, and inflammatory cells were monitored using quantitative experimental and computational analyses. Back at MIT, pressure was applied to the cartilage just before launch, providing a realistic PTOA model.

In other words, the experiment took “a hammer” to the cartilage affixed to the bone to simulate an injury. Then, the tissue was put into a culture medium to see if the injured synovium released inflammatory cytokines into the synovial fluid-like media that bathes the cartilage. Next, the platform’s microfluidic system delivered nutrients, and in some cases drugs, to the cells, allowing the researchers to test the tissues with and without disease-modifying medications.

When Grodzinsky’s experiment applied a mechanical injury to the cartilage layer, the injured cartilage showed signs of exposure to inflammatory cytokines secreted from the synovium, mimicking the early stages of PTOA. The team was optimistic—the objective, after all, was to develop a system where researchers could detect the earliest events that occur at the initiation of the disease. “So, we thought we were on the right track,” said Grodzinsky.

However, problems with the microfluidics system hindered drug delivery in that first experiment. So Grodzinsky’s team geared up to relaunch the experiment on NASA’s SpaceX CRS-21 in December 2020 with an improved microfluidic system.

With the onset of the COVID-19 pandemic that year, Grodzinsky feared his work would stall. He received special permission from MIT to continue preparing for the launch. With Boston and his institution in shutdown, his team went to Logan Airport in Boston to pick up cadaver knee joints, then drove them back to MIT to do the tissue harvest at his lab before shipping the tissue down to Florida for launch.

“We were racing to get the experiment 250 miles from ground to the space station, but the first 1,500 miles is getting the tissues from Boston to Florida intact,” added Grodzinsky.

Despite “lots of ulcers,” the second experiment was successfully executed. Over a four- to five-year stretch, the team used tissue from 88 knees from 55 donors between ages 23 and 88 for two launches, two experiments in space, and dozens of control experiments on Earth.

Flaman said that, in the end, it’s all about helping patients. “My aunt is a scientist, and looking up to her inspired a lot of my interest in science, and now she has osteoarthritis,” she said. “There really aren’t enough treatment options for people like her, and that’s upsetting because the number of people with this condition is growing every year. It’s an unmet need.”

A Joint Effort to Treat Post-Traumatic Osteoarthritis 

Translating the results from these space-based experiments to real-world applications on Earth requires a collaborative approach to tackle the most difficult challenges. For example, according to Chris Evans, a cell and molecular biologist with the Mayo Clinic whose team develops genetic therapies to treat joint diseases, injecting medication into cartilage is “a bit like trying to get a drug into a piece of rubber.”

Evans, who advised Grodzinsky’s experiments and his students’ post-ISS research, says cartilage is dense and hard to penetrate, but his and Grodzinsky’s labs have figured out some ways to do it. Evans’ experiments use viruses to deliver drugs to cartilage, while Grodzinsky has pioneered the use of drugs with a very specialized positively charged chemistry that can penetrate the negatively charged cartilage.

For Grodzinsky’s second space station experiment, the team tested the drug dexamethasone (Dex), among others, for its potential to inhibit the cytokines that damage cartilage and joints. However, Evans said the drug has “a bad rap” due to evidence that shows it might inhibit tissue repair.

“But we’ve shown that with the right dose, you can have the good effect of stopping these bad molecules from being made without damaging the good ones, so the results are encouraging along those lines,” Evans said.

Grodzinsky’s team found that the space-tested drugs could “mollify or ameliorate cell death caused by the cytokines,” meaning the drugs hindered their blow. The postflight analysis also showed that the space environment enhanced certain inflammatory responses in the tissues under all test conditions. Not just the injury model but even the control.

Was it microgravity? The small amount of radiation? Or is it something that depends on donor variability, a factor that “came out in spades” when the experiment was repeated on Earth with dozens of knee samples, Grodzinsky said.

Grodzinsky wonders if the findings were a “luck of the draw.” Did the tissue from two donor knees used in the tissue chips sent to space happen to have this response, or would this happen to anyone’s tissue?

But unlike experiments on Earth, “you can’t just go back up to the space station a week or two later,” he said. So, while the findings are an exciting and promising start, he said further testing in space is needed.

Evans added, “These sorts of experiments had never been done before in this way. Just the opportunity to see what these cells do under reduced gravity is tremendously appealing. It feels like you’re working at a new frontier, which is rare.”

Evans says this research also opens doors for engineering cartilage in space and better understanding the impact of long-term space travel on human joints. “I mean, there are many interesting possibilities,” he said. More directly, the research could result in an off-the-shelf injectable drug to treat damaged cartilage in patients on Earth.

“We’ve just finished a clinical trial for an osteoarthritis gene therapy, so we’re in the groove,” said Evans. “And anything that comes out of Al’s work, I would certainly elbow my way to the front of the queue to give it a shot in a carefully planned clinical trial.”