Looking for a space to treat osteoarthritis


In 1976, Alan Grodzinski ’71, ScD ’74, felt a little disappointed.

He had spent two years teaching a basic course in semiconductor physics and circuits in the Department of Electrical Engineering and Computer Science at the Massachusetts Institute of Technology, studying the material in the fast-growing field while continuing. This left him no time for research. Then a golden opportunity arose.

With the help of the late Irving London, founder of the Harvard-MIT Health Science and Technology Program, Grodzinski won a leave of absence at Boston Children’s Hospital under the late Mel Glimcher, head of orthopedic surgery and a pioneering biology researcher. of human bones and collagen.

Glimcher wanted to start a research project on cartilage, the healthy matrix of fibers that covers the joints, and on osteoarthritis, the chronic, painful disease that destroys that cartilage.

It was ideal for 29-year-old Grodzinski, who had won ScD by studying the electrical properties of collagen, one of the components of cartilage. By the end of the year, he was on the path he had followed since: trying to find effective treatments for osteoarthritis, the leading cause of chronic pain and disability worldwide. It affects more than 30 million Americans and hundreds of millions worldwide.

“It’s a huge financial burden and a burden of disability. And while it’s not fatal, it certainly contributes to a loss of quality of life, “said Joseph Buckwolter, an Iowa-based orthopedic surgeon and osteoarthritis expert who has known Grodzinski for decades. “The cost of a total joint replacement, mainly of the knees and hips, is one of our main healthcare costs.

There is no plan for pain

The US Food and Drug Administration has not approved any disease-modifying drugs for osteoarthritis – drugs that treat the underlying condition, not just the symptoms. Most sufferers can hope for, Grodzinski says, are painkillers like Motrin, occasional steroid injections, and eventually joint replacement surgery. More than one million knee and hip replacements are performed in the United States each year, and the number is expected to increase as the population ages.

While older people are most susceptible to osteoarthritis, Grodzinski has focused much of his research on younger people, especially female athletes, who often develop the condition after knee injuries.

Every year, tens of thousands of young women receive injuries to the anterior cruciate ligaments of their knees. “When I teach my course at the Massachusetts Institute of Technology in biomechanics,” says Grodzinski, “I ask about ACL injuries, and just as many hands are raised today as they were in the past. I recently taught a course at Harvard Medical School, and of the 20 students in the class, four women had suffered an ACL rupture and one was in her third operation.

Doctors can fix those tears, he says, but both men and women who suffer from joint injuries are still at high risk of developing osteoarthritis in the coming years. And while knee replacement may counteract the effects of osteoarthritis, doctors are reluctant to perform such surgery on younger people because it will probably have to be repeated after the first artificial joint wears out.

A knee implant can last for years, Buckwalter says, but “I would have nightmares doing it to someone under 40 because the chances are almost high that he will need another one.”

Rx nanoparticles

Researchers have identified existing drugs that can alleviate osteoarthritis, but they are hampered by the fact that cartilage does not have a natural blood supply, Grodzinski said. When doctors inject a steroid into the knee joint to reduce inflammation, the body clears most of the medicine before it can enter the cartilage.

To address this problem, his lab has pioneered research involving nanoparticles, the knees of a human corpse, and even missions to the International Space Station.

image for knee examination
Six days after treatment of an arthritic knee with nanoparticles containing insulin-like growth factor 1 (blue), the particles penetrated the cartilage of the knee joint.

BRETT GEIGER AND JEFF WEIKOFF

Starting with this leave more than four decades ago, Grodzinski learned an important fact about cartilage. While the tissue fibers themselves provide some of the support for our joints, much of their strength comes from its electrostatic properties. “It turns out that about half of the mechanical compressive hardness of our cartilage is due to electrostatic repulsive interactions between negatively charged sugar chains,” he says.

This negatively charged tissue matrix also offers a way to deliver drugs directly into the tissue: by loading them into positively charged nanoparticles. Grodzinski’s team was able to show the cartilage in the knee of a human corpse that such particles could counteract early inflammation and damage caused by injuries.

The initial work with nanoparticles was started a few years ago by Grodzinski’s former doctoral student Ambika Bajpaye, MNG ’07, PhD ’15, now a professor at Northeastern University. Bajpayee then collaborated with Paula Hammond, head of MIT’s chemical engineering department, who pioneered the use of nanoparticles to deliver drugs to cancerous tumors.

In Grodzinsky’s laboratory, drug-containing nanoparticles are injected into the joints of animals, just as they would in patients, he says, and “once inside, if used in the right concentration, they can stay inside for many weeks. ”Huddled in the fibrous matrix.

The group has focused on supplying two drugs that are already approved for human use.

One is the anti-inflammatory dexamethasone, which has also been used successfully to treat breathing problems in some hospitalized patients with covid-19. The other is insulin-like growth factor 1 (IGF-1), a hormone that promotes the growth of bone and cartilage tissue and is used in children born smaller than normal.

Dexamethasone reduces cartilage degradation after injury, Grodzinski said, while IGF-1 can promote tissue repair.

Studies on animals using IGF-1 were done in collaboration with Hammond, and Grodzinsky’s laboratory extended this experimental treatment to human tissues, relying on samples from dead people. So far, the lab has been able to obtain pieces of knee bone, cartilage and a synovial joint capsule from 45 donors, said Garima Dvivedi, a doctoral student at the lab.

Dwivedi and her colleagues place the samples in wells embedded in plastic plates and keep them metabolically active. They then apply a mechanical action that mimics what happens when a knee is injured. This releases inflammatory molecules known as cytokines and begins a process similar to that of osteoarthritis.

Outer space

In this work, researchers place nanoparticles in a culture medium that bathes tissue samples, a technique they could use in future experiments on the space station, which has become a magnet for researchers studying aging diseases.

Scientists have known for years that human tissues age faster in low orbit on Earth than on Earth, although the reasons are somewhat mysterious. One analysis found that astronauts’ muscles and bones atrophied 10 times faster under microgravity.

Thinking about how to repair joint damage can be crucial for future long-term space missions.

With funding from the NIH and NASA, Grodzinski’s lab sent samples of knee cartilage and synovial tissue to the ISS in 2019 and 2020. They hoped to determine if a disease similar to osteoarthritis could be initiated “on a plate.” to simulate what happens to people after a knee injury – using the medium of microgravity to study and eliminate mechanical processes at work – and to try to treat it with dexamethasone and IGF-1.

Preliminary results are encouraging, he said. On a recent trip to the ISS, the lab found that both drugs reduced damage to many of the cartilage samples.

“Since most researchers today emphasize that there will probably be no magic bullet, we believe that the ability to test drug combinations in vitro is an important step forward,” Grodzinski said.

Working in microgravity could also pay dividends for future space missions, Duvedi said. Astronauts who train intensely in space to counteract the atrophy that muscles and bones suffer from weightlessness are three times more likely to get hit injuries than humans on Earth, she says, so figuring out how to repair the damage of joints can be crucial for future long-term space missions.

Compassionate mentoring

Grodzinski always seemed destined to find a home at the Massachusetts Institute of Technology.

Growing up on Long Island, where he attended public schools in the thriving postwar suburb of East Meadow, he sometimes attended his older brother Stephen Grodzinski ’65, SM ’67, at Burton House. He remembers thinking, “That looks great to me.”

He went on to receive a doctorate from the late James Melcher, director of the school’s laboratory for electromagnetic and electronic systems. But the recession soon struck, and the only positions offered were a postdock in icy Saskatchewan and an assistant music and engineering assistant in Brazil. His mentors – including Ioannis Janas, best known for inventing artificial leather – encouraged him to stay around, offering him a teaching position in electrical engineering. He has been at the institute ever since.

In 1995, the Massachusetts Institute of Technology established the Center for Biomedical Engineering to advance research in the then new field. Three years later, Grodzinski was appointed to his current post as its director. At that time, his faculty membership changed to the newly formed Department of Biological Engineering, with joint appointments in EECS and mechanical engineering.

Grodzinski believes that every research success he has achieved is a direct result of “the huge doctoral students and doctoral students we have been able to get at MIT.” They, in turn, prospered under his compassionate mentorship.

“It was a pleasure working with him, above all because he gives you a lot of independence to develop your own ideas,” says Postdock Dwivedi. “And no matter who you are or what stage of your career you are in, he listens to you with great attention and respect.

Professor Gropdzinski and his wife Gale
Grodzinski and his wife, Gail, now a pediatric neuropsychologist at Boston Children’s Hospital, met while playing chamber music.

WEBB CHAPPELL

She also appreciates his personal support. When her parents in India became infected with covid in April, he “gave me complete free time to help take care of them,” she said.

Grodzinski himself managed to avoid osteoarthritis, although at the age of 74 he was in the main risk category for the disease.

Maybe, he thinks, it’s because his passion as a musician kept him flexible. After years of piano lessons at the Third Street Music School Settlement in New York, he became principal violist of the MIT Symphony Orchestra as a student. He also plays as a freelance string quartet after graduating from ScD and meeting his wife, Gail, who plays chamber music.

After officially entering campus as a student at the age of 18, he said with a smile, “Somehow I never found a way to leave.”



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