Imagine this: You’re a college soccer player chasing after a pass when a defender misses the ball but inadvertently kicks your knee, taking you to the ground. A yellow card is called, but it is 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 a treatment could prevent this tissue damage from becoming a serious osteoarthritis case months, or even decades later? This is the challenge being tackled by researchers at Drexel’s School of Biomedical Engineering, Science and Health Systems, in conjunction with researchers at Villanova University, University of Delaware and Tulane University, recently published in ACS Nano.

Osteoarthritis – known as the “wear and tear” arthritis, due to the erosion of tissue cartilage inside joints – causes tissues to become brittle and less equipped to bend and absorb shock, leading to a greater likelihood of injury. Treatment focuses on pain management, using over-the-counter pain medicine, anti-inflammatory medications, or injections of hyaluronic acid to lubricate joints, but no treatments exist to slow or stop the progression of the disease and the damage it causes. Patients also may participate in rehabilitation activities, which has shown some success using strength exercises to reduce pain and stiffness at the site of the injury. But the benefit of physical therapy is woefully insufficient for the estimated 32.5 million osteoarthritis patients in the United States, treating the pain and dysfunction, but not able to reverse the damage done by osteoarthritis.

Now engineering researchers believe there may be a way to stop the progression of the disease, or perhaps even heal damage from osteoarthritis, in the form of an injection into the joint following injury.  If injected in those facing early cases of arthritis, the injection may prevent the advancement of the disease and eventual need for joint replacement.

In the study, the team created biomimetic proteoglycans – molecules that mimic traditional proteoglycans (sugar chain-decorated proteins that deliver hydration to tissues so they can handle compression from activities such as walking and jumping) – and introduced them into the cartilage tissue.

These biomimetic proteoglycans consist of chondroitin sulfate (one of the chemical building blocks of cartilage which is often taken by mouth with a supplement form of glucosamine by those suffering from arthritis), with a polymer molecule that makes it resistant to degrading once injected. These biomimetics mimic the “bottle-brush” structure of natural proteoglycans at nanoscale, and could partially replicate and restore the functions of these native ones to restore cartilage load-bearing and shock-absorption functions.

The result? An increased ability to bear compression and stimulated cells at the molecular level that may lead to further inhibition of tissue inflammation and alter the trajectory of the breakdown of cartilage — and even help repair already damaged tissue.

“This manufactured biomimetic proteoglycan mimics the structure and hydrating function of the natural proteoglycans that no longer function correctly in the site of an injury,” said co-senior author Lin Han, PhD, an associate professor in the School of Biomedical Engineering, Science and Health Systems. “The injection moves throughout the cartilage and attaches to the specialized molecules that surround cells in cartilage, known as the pericellular matrix.”

Han’s lab focuses on how these matrix molecules regulate the pathology of disease.

“Cells make matrix and the matrix regulates how cells sense their environment,” Han said.

First, a quick science lesson.

The pericellular matrix is tissue which surrounds the cells in cartilage that 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 start of the disease affecting a key cellular process known as mechanotransduction.

Kahle says earlier work by Han and colleagues shows that this pericellular microniche, or matrix, is damaged very early on after an injury. Post-traumatic osteoarthritis, that is, cases which start with a particular event (like a sports-related injury), can progress slowly over decades. The hope is that if someone gets an injury, they can get an injection of this molecule when experiencing this early degeneration to prevent a much more serious late-stage case of osteoarthritis. 

Han and study lead author Elizabeth Kahle, a fourth-year PhD candidate in Biomedical Engineering, Science, and Health Systems, take this suite 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’s College of Engineering, whose approach focuses on how engineers can make molecules that simulate the function of the proteoglycans in the body. Marcolongo’s materials lab aims to make biomaterials that have a similar structure as the healthy native molecules in the body.

“So we said, let’s see if these molecules could change how the cell responds and whether it has a direct role in the native environment,” said Han.

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

During the team’s mechanical testing, the injected molecules advanced into the site while researchers performed precise mechanical testing 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 test each group of cells and its larger matrix, and that’s where they found that delivery of these molecules to cartilage helped to recreate interactions between the network of molecules and metabolically active cells that may go on to stop the progression of tissue breakdown altogether.

Chondrocytes, the cells that are responsible for maintaining healthy cartilage, can be seen blinking like Christmas lights in a process known as calcium signaling. Changes in calcium concentration in cells corresponds to the observed “blinking” of these cells. These fluctuations help direct the metabolism of the cells and therefore direct the health of the overall tissue. Biomemetic proteoglycans are able to increase this calcium signaling which may help cartilage to repair itself.

“In mechanostransduction, the cells make changes to respond metabolically to changes in this network of molecules, known as the extracellular matrix,” said Kahle. “We’ve only begun to probe the complex mechanotransduction process, but this work reveals targets for future studies in the cartilage of healthy tissue and tissue from those suffering from osteoarthritis. We’re talking about nano-scale molecules – so we can simply inject them in a saline solution and let the molecules passively diffuse to the cells and do their job.”

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

“The work is an interdisciplinary collaboration of engineers across multiple universities and an orthopedic surgeon, which is the team it takes to make advances of this magnitude,” said Marcolongo, the Drosdick Endowed dean of Villanova’s College of Engineering. “I have been doing arthritis work for almost 30 years and have been interested in minimally invasive therapies. I don’t know of anyone who has been able to put a molecule into tissue and mechanically strengthen it. We’re trying to solve a disease with engineers and clinicians working together to come up with a solution that is clinically relevant.”

The authors suggest this work is indicative of a growing trend of bringing leaders together from a variety of engineering fields to innovate.

“Healthcare problems require such diverse expertise and they cannot be solved from one discipline,” said Han. “Success of modern biomedical research truly needs to build on the organic collaborations between scientists, engineers and clinicians from all different backgrounds.”

So how soon can patients get this treatment from their doctor?
“We’re working toward a course of treatment, conducting trials in humans, and the other steps needed to bring this treatment to the bedside,” said Kahle. “If the work continues to go as planned, Marcolongo believes this could be an FDA-approved therapy within 10 years.”

The authors note this early discovery could be the groundwork for therapies that dramatically improve the quality of life for millions of patients with osteoarthritis and other diseases where cells in tissues are under compression, such as the lower back injury known as intervertebral disc disease.

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