Picture this: you are a college football player chasing a pass when a defender misses the ball but accidentally kicks your knee, knocking you down. A yellow card is issued, but it’s insufficient justice – your seemingly minor knee pain from the incident leads to a much bigger problem decades later: you need knee replacement therapy for your osteoarthritis.

But what if treatment could prevent that tissue damage from becoming a serious case of osteoarthritis months or even decades later? The researchers at Drexel’s are facing up to this challenge School of Biomedical Engineering, Science and Health Systemsin collaboration with researchers from Villanova University, the University of Delaware, and Tulane University, recently published in ACS nano.

Osteoarthritis – known as the “wear and tear” arthritis, due to erosion of tissue cartilage in joints – causes tissue to become brittle and less able to flex and absorb shock, leading to a higher likelihood of injury. Treatment focuses on managing pain with over-the-counter pain relievers, anti-inflammatory drugs, or hyaluronic acid injections to lubricate the joints, but there are no treatments to slow or stop the progression of the disease and the damage it causes. Patients can also participate in rehabilitation activities, which have shown some success with strength exercises to reduce pain and stiffness at the injury site. But the benefit of physical therapy falls woefully short of the estimates 32.5 million osteoarthritis patients in the United States treating pain and dysfunction but unable to reverse the damage caused by osteoarthritis.

Now engineering researchers believe there may be a way to stop the disease from progressing, or perhaps even heal damage caused by osteoarthritis, in the form of an injection into the joint after an injury. When injected into patients with early cases of arthritis, the injection can prevent the disease from progressing and the eventual need for joint replacement.

In the study, the team created biomimetic proteoglycans – molecules that mimic traditional ones proteoglycans (proteins decorated with sugar chains that add moisture to tissues so they can withstand compression from activities like walking and jumping) – and introduced them into cartilage tissue.

These biomimetic proteoglycans are made up of chondroitin sulfate (one of the chemical building blocks of cartilage, which arthritis sufferers often take by mouth along with a supplement form of glucosamine) with a polymer molecule that makes it resistant to degradation after injection. These biomimetics mimic the nanoscale “bottlebrush” structure of natural proteoglycans and could partially replicate and restore the functions of these native ones to restore the load-bearing and shock-absorbing functions of cartilage.

The result? An increased ability to endure compression and stimulated cells at the molecular level, which can lead to further inhibition of tissue inflammation and alter the course of cartilage degradation – and can even help repair already damaged tissue.

“This engineered biomimetic proteoglycan mimics the structure and hydrating function of natural proteoglycans that stop functioning properly at the site of injury,” said the co-senior author Lin Han, PhD, Associate Professor in the School of Biomedical Engineering, Science and Health Systems. “The injection moves through the cartilage and attaches to the specialized molecules that surround the cells in the cartilage known as the pericellular matrix.”

Hans Labor focuses on how these matrix molecules regulate the pathology of diseases.

“Cells form a matrix, and the matrix regulates how cells perceive their environment,” Han said.

First a short science lesson.

The pericellular matrix is ​​tissue that surrounds the cartilage cells, which support things like collagen, proteoglycans, proteins, and other parts of macromolecules in cells and tissues. In early osteoarthritis cases, the pericellular matrix breaks down and leads to the onset of the disease, which affects an important cellular process known as mechanotransduction.

According to Kahle, previous work by Han and colleagues shows that this pericellular microniche, or matrix, is one damaged very early after an injury. Post-traumatic osteoarthritis, ie cases that begin with a specific event (e.g. a sports injury), can progress slowly over decades. The hope is that someone who sustains an injury can inject this molecule when they experience this early degeneration to prevent a much more serious late-stage case of osteoarthritis.

Han and lead author of the study Elizabeth Bald, a fourth-year PhD candidate in Biomedical Engineering, Science, and Health Systems, take this set of biomimetic proteoglycans and study how they can influence cells to respond to their environment, to colleague, co-senior author Michele Marcolongo, PhD, Dean of Villanova College of Engineering, whose approach focuses on how engineers can create molecules that simulate the function of proteoglycans in the body. Marcolongo’s materials laboratory aims to produce biomaterials that have a structure similar to the healthy natural molecules found in the body.

“So we said, let’s see if these molecules could change how the cell responds and if they play a direct role in the natural environment,” Han said.

Han and Marcolongo’s teams took these biomimetic proteoglycans and diffused them into cartilage harvested from an adult cow knee, where the cartilage is still alive, so the cells are still responding to and producing their natural matrix.

During the team’s mechanical tests, the injected molecules advanced into the site while the researchers performed precise mechanical tests on the cells and surrounding cartilage. They used fluorescent imaging to observe different matrix molecules in different regions of the cartilage and specific markers to probe each cell group and its larger matrix, and there they found that delivery of these molecules to the cartilage helped determine interactions between the network of molecules to mimic and metabolically active cells that can halt the progression of tissue degradation altogether.

Chondrocytes, the cells responsible for maintaining healthy cartilage, blink like Christmas lights in a process known as calcium signaling. Changes in calcium concentration in cells correspond to the observed “blinking” of those cells. These fluctuations help direct the metabolism of the cells, thereby directing the health of all tissues. Biomemetic proteoglycans are able to amplify this calcium signaling, which can help cartilage repair itself.

“During mechanotransduction, the cells make changes in order to react metabolically to changes in this network of molecules, the so-called extracellular matrix,” says Kahle. “We have only just begun to study the complex mechanotransduction process, but this work indicates targets for future studies in cartilage from healthy tissues and tissues from patients suffering from osteoarthritis. We’re talking about nanoscale molecules – so we can just inject them into a saline solution and passively let the molecules diffuse into the cells and do their job.”

This is a perfect integration of Hans’ knowledge of matrix biology and biomechanics and Marcolongo’s work in the field of biomaterials.

“The work is an interdisciplinary collaboration of engineers from multiple universities and an orthopedic surgeon, the team needed to achieve advances of this magnitude,” said Marcolongo, dean of the Drosdick Foundation at Villanova College of Engineering. “I have worked with arthritis for almost 30 years and am interested in minimally invasive therapies. I don’t know anyone who has managed to insert a molecule into tissue and strengthen it mechanically. We try to solve a disease by having engineers and clinicians working together to find a clinically relevant solution.”

The authors suggest that this work indicates a growing trend of bringing together leaders from a variety of technical fields to innovate.

“Health problems require such a diverse range of expertise, and they can’t be solved by one discipline,” Han said. “The success of modern biomedical research really needs to be built on the organic collaboration between scientists, engineers and clinicians from different backgrounds.”

How quickly can patients receive this treatment from their doctor?
“We’re working on a course of treatment, doing human trials and the other steps that are needed to bring this treatment to the bedside,” Kahle said. “If work proceeds as planned, Marcolongo believes this could be an FDA-approved therapy within 10 years.”

The authors state that this early discovery could be the basis for therapies that improve the quality of life for millions of patients with osteoarthritis and other diseases in which cells in tissues are under pressure, such as arthritis. such as the lower back injury known as disc disease.


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