TECHNOLOGY

Looking for a place to cure osteoarthritis


In 1976, Alan Grodzinski ’71, SCD’74, was feeling somewhat disappointed.

He spent two years teaching a basic course in semiconductor physics and circuits at MIT’s Department of Electrical Engineering and Computer Science, as well as learning the components of the fast-moving field. This left him no time for research. Then a golden opportunity was created.

With the help of the late Irving London, founder of the Harvard-MIT program in health sciences and technology, Grodzinski won a subtitle at Boston Children’s Hospital on the advice of the late Mel Glimcher, head of orthopedic surgery and pioneer researcher in biology. Of human bones and collagen.

Glimmer wanted to start a research project on cartilage, the solid matrix of fibers that line the joints, and osteoarthritis, a chronic, painful disease that breaks down that cartilage.

This was appropriate for 29-year-old Grodjinski, who achieved his 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 followed: trying to find effective treatments for osteoarthritis, the leading cause of chronic pain and disability worldwide. It affects more than 30 million Americans and a few million worldwide.

“It’s a huge financial burden and a burden of disability. And while it’s not deadly, it certainly contributes to a decline in quality of life, “said Joseph Buckwalter, an Iowa-based orthopedic surgeon and osteoarthritis specialist who has known Grodzinski for decades. “The cost of total joint replacement, mainly the knee and buttocks, is one of our major health expenses.”

There is no plan for pain

The U.S. Food and Drug Administration has not approved any disease-modifying drugs for osteoarthritis ওষুধ drugs that treat the underlying condition rather than just the symptoms. Grodzinski said most sufferers can expect painkillers like Matrin, 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.

Although the elderly are most susceptible to osteoarthritis, Grodzinski has focused most of his research on younger people, especially female athletes, who often develop the condition after a knee injury.

Every year thousands of young women are injured in the anterior cruciate ligament of their knee. “When I teach my course at MIT on biomechanics,” Grodzinski says, “I ask about ACL injuries and still raise my hand as much as in the past. I recently taught a course at Harvard Medical School, and four out of 20 students in the class cry Was suffering and one was in his third surgery. “

Doctors can fix these tears, he said, but both men and women with joint injuries are at higher risk of developing osteoarthritis in later years. And while knee replacement can counteract the effects of osteoarthritis, doctors are reluctant to perform this type of surgery on young people because it may need to be repeated after the first prosthetic joint is removed.

A knee implant can last year after year, Buckwalter says, but “I have nightmares about doing it in someone under the age of 40, because the adversity is almost irresistible that they will need another.”

Nanoparticle Rx

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

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

Six days after being treated with nanoparticles containing insulin-like growth factor 1 (blue) in rheumatic knees, the particles have entered through the cartilage of the knee joint.

Brett Geiger and Jeff Wickoff

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

This negatively charged tissue matrix also provides a way to deliver drugs directly to the tissue: loading them into positively charged nanoparticles. Grodzinsky’s team has been able to show in the knee cartilage of human corpses that such particles can resist damage due to primary inflammation and injury.

Early nanoparticle work was started several years ago by Grodjinski’s former doctoral student Ambika Vajpayee, MNG ’07, PhD ’15, who is now a professor at Northeastern University. Vajpayee then collaborated with Paula Hammond, head of MIT’s Department of Chemical Engineering, who was a pioneer in the use of nanoparticles to deliver drugs to cancer tumors.

In Grodzinsky’s lab, medicated nanoparticles are injected into animal joints, just as they would in human patients, he said, and “once they are inside, if they are used at the right concentration, they can stay inside for many weeks.” Nest.

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

One is the anti-inflammatory dexamethasone, which has been used successfully in some hospitalized Covid-19 patients to treat asthma. The other is insulin-like growth factor 1 (IGF-1), a hormone that stimulates bone and cartilage tissue growth and is used in babies born younger than normal.

Dexamethasone reduces cartilage rupture after an injury, Grodzinski says, while IGF-1 may promote tissue repair.

Animal research using IGF-1 has been done in collaboration with Hammond, and Grodzinsky’s lab has also extended this experimental treatment to human tissues based on dead human samples. So far, the lab has been able to obtain fragments of knee bone, cartilage and synovial joint capsules from 45 donors, said Garima Dwivedi, a postdoctoral researcher at the lab.

Dwivedi and his colleagues kept samples of wells made on plastic plates and kept them metabolically active. They then apply a mechanical effect that mimics what happens in a knee injury. It releases inflammatory molecules known as cytokines and initiates a process similar to osteoarthritis.

Space

In this work, the researchers placed nanoparticles through cultures that bathed tissue samples – a technique they could also 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 Earth orbits than in Earth, although the causes are somewhat mysterious. One analysis estimated that atrophy of muscles and bones in astronauts is 10 times faster at microgravity.

Determining how joint damage can be repaired can be important for future long-term space missions.

With funding from NIH and NASA, Grodzinsky’s lab sent knee cartilage-sister plugs and synovial tissue samples to the ISS in 2019 and 2020. They hoped to determine if osteoarthritis could be started to mimic what might happen. In humans after a knee injury – to explore and eliminate mechanical processes in the workplace using the microgravity environment – and to try to treat it with dexamethasone and IGF-1.

Preliminary results have been encouraging, he says. On a recent trip to the ISS, the lab found that both drugs reduced the damage to many cartilage samples.

“Since most researchers nowadays insist that there probably won’t be a single magic bullet, we believe that the ability to test a combination of drugs in vitro is an important step forward,” Grodzinski said.

The work of microgravity could also pay dividends for future space missions, Dwivedi said. Astronauts who exercise intensively in space to prevent atrophies, which tend to suffer from muscle and bone weightlessness, are three times more likely to be injured than humans on Earth, he said, so determining how to repair joint damage can be important. For future long-term space missions.

Sympathetic mentorship

Grodzinsky always seemed lucky to find a home at MIT.

Growing up in Long Island, where he attended public school in the post-war suburb of East Meadow, he occasionally met his older brother, Stephen Grodzinski, at ’65 Burton House, SM ’67. She remembers, “It feels great to me.”

He went to get his SCD under the late James Melcher, director of the school’s laboratory for electromagnetic and electronic systems. But a recession soon struck, and the only position he was offered was a postdock in Saskatchewan on ice and an assistant professor of music and engineering in Brazil. His mentors – including Ioannis Ianas, best known for inventing artificial skin – encouraged him to stick around, offering him teaching positions in electrical engineering. He has been at the institute ever since.

In 1995, MIT set up the Biomedical Engineering Center, which was then a new field to carry out research. Three years later, Grodzinski was named director in his current position. At that time, with the joint appointment in EECS and Mechanical Engineering, the affiliation of his faculty changed to the newly formed Department of Biological Engineering.

Grodjinski believes that the success of any research he has achieved is “extraordinary PhD students and the direct results of postdox that we have been able to get at MIT.” They have instead prospered under his merciful counsel.

“It’s a pleasure to work with him, primarily because he gives you so much freedom to develop your own ideas,” says Postdoc Dwivedi. “And no matter who you are or what stage of your career you are in, he listens to you with the utmost attention and respect.”

Professor Gropodzinski and wife Gayle
Grodjinski and his wife, Gayle, now a pediatric neuropsychologist at Boston Children’s Hospital, met with Chamber Music Players.

Web Chapel

He appreciated his personal support. When her parents contracted Kovid in India in April, she “gave me completely free time to take care of them,” she says.

Grodzinski himself has been able to avoid osteoarthritis, although, at age 74, he is in the main risk category for the disease.

Maybe, he thinks, because his publicity as a musician has kept him unsettled. After years of piano lessons at the Third Street Music School Settlement in New York, he became the lead violist of the MIT Symphony Orchestra as a graduate. He also played in the freelance string quartet after finishing his SCD and met his wife Gayle while playing chamber music.

After officially setting foot on 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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