Getting Inside Osteoarthritis
Alan Grodzinsky studies osteoarthritis and other diseases of the musculoskeletal system. Osteoarthritis affects about half of all people older than 70, and as many as 600 million people worldwide.
Ever since hominids made the unusual shift to walking on two legs instead of four, our overloaded knees and hips have been paying the price. Osteoarthritis affects about half of all people older than 70, and as many as 600 million people worldwide. Longer lifespans, obesity, and sports injuries are adding to the count.
Osteoarthritis, which can affect the knee, hip, foot, ankle, shoulder, and back, also poses a financial burden due to lost productivity and costly joint replacement operations. In 2014, the American Academy of Orthopaedic Surgeons estimated that 4.7 million Americans have undergone total knee replacements (arthroplasty), and 2.5 million have undergone total hip arthroplasty. The operations are typically performed only after the cartilage is worn away, and after years of debilitating pain.
“Osteoarthritis presents a tremendous burden of pain and disability,” says MIT Department of Biological Engineering professor Alan Grodzinsky, whose lab focuses on osteoarthritis and other diseases of the musculoskeletal system. Grodzinsky Labs recently devised a novel technique for drug delivery into knee cartilage, and it’s also exploring various treatments that might someday stem or reverse the loss of tissue associated with the disease.
Osteoarthritis often derives from an impact event, although people born with slightly misaligned hips and knees are also susceptible. In addition, “Obesity adds to the problem by adding weight,” says Grodzinsky. “Fat tissue also has inflammatory cytokines called adipokines that can add to the disease’s effects.”
Osteoarthritis differs from rheumatoid arthritis in that mechanical and biological factors combine to affect joints, as compared to a systemic auto-immune disease. It also differs because it’s a focal disease. “If you injure one part of the knee you might get osteoarthritis there and nowhere else,” says Grodzinsky. “Rheumatoid arthritis is much more widespread,”
Impacts continue to be the biggest threat. “People think about osteoarthritis as an old age disease, but young people who injure their joints playing sports are also at risk,” says Grodzinsky. “Osteoarthritis is almost an epidemic among girls and women in high school and college who tear their ACL. The combination of injury and inflammation can lead to the osteoarthritis even by age 25.”
Despite decades of research, pain medication is still the only proven treatment for osteoarthritis. Like other researchers, Grodzinsky continues to search for new disease modifying drugs (DMOADs) that might halt or reverse the disease. Yet, his lab has recently focused on another important challenge: drug delivery.
Traditionally, DMOAD candidates have been administered as pills, an approach that suffers from being a systemic treatment for a local problem, says Grodzinsky. Some DMOAD trials have failed due to “systemic side effects that had nothing to do with the efficacy of the drugs in the regions of interest,” he adds. “So drug delivery is crucially important.”
Grodzinsky is focusing on delivery into cartilage, one of many types of tissues involved in osteoarthritis, and the last line of defense between bone grinding against bone. “There’s an extraordinarily difficult range of problems involved with getting drugs into this very dense tissue,” he says. “Cartilage has no blood supply or nerve supply, and the tissue has no lymph supply. Cartilage lives by diffusion and convection, with nutrients diffusing from the synovial fluid.”
Researchers have tried a range of approaches, including gene delivery. “If you can target a vector into a tissue of interest like cartilage, perhaps can you alter the way the cells and the cartilage are behaving by genetically modifying them to upregulate enzymes that are attacking the cellular matrix,” says Grodzinsky.
Another tactic is to use nanoparticles. “Nanoparticles might be delivered to the synovial fluid of the joint to deliver a drug that could diffuse to the target tissues,” says Grodzinsky. “The challenge is that any drug you intra-articularly inject into a joint is rapidly cleared by the capillaries and lymphatics in the synovium, so the molecules last no longer than several hours. You need extraordinarily large doses of the drug in the joint for long periods, which can cause unwanted side effects.”
Grodzinsky Labs has developed a similar approach, but one that involves highly charged nanoparticles. “We found out that charge and size are critically important for introducing a nanoparticle into cartilage from the synovial fluid,” says Grodzinsky, ascribing the discovery to one of his recent PhD students, Ambika Bajpayee. “The particle needs to be less than about 10 nanometers, and have a high positive charge.”
Cartilage is an extremely negatively charged tissue composed of a dense extracellular matrix that includes Aggrecan, which helps resist compressive and sheer loads. “A negatively charged particle wouldn’t last long, but a positively charged nanoparticle might be accelerated into cartilage due to electrostatic interactions,” says Grodzinsky. “The idea is that you can functionalize a particular drug of choice, have the nanoparticle carry the drug into the cartilage, let it reside for weeks or months, and then deliver it without fighting clearance.”
Grodzinsky’s technique uses Avidin, a natural protein just barely small enough to make it into the synovial fluid, but so positively charged that it causes partitioning. “A positively charged particle will partition upwards into the tissue, providing a nice steep concentration gradient that helps to accentuate diffusion,” he says.
At Grodzinsky Labs, Bajpayee demonstrated a drug delivery system using cartilage in vitro in culture. Her approach used Avidin functionalized to a glucocorticoid drug called Dexamethasone. The experiment simulated a challenge from inflammatory cytokine typical in an ACL injury. “Avidin carried the glucocorticoid directly into the cartilage, and helped suppress the cytokine challenge and maintain homeostasis for several weeks,” says Grodzinsky.
An important side benefit is that the drug can be delivered in low dosages, thereby presumably limiting side effects. The research is now moving to animal studies.
While the Avidin/Dexamethasone combination looks promising, it is only halting the degradation, not reversing it. It would also require frequent injections. Grodzinsky is now exploring other nanoparticles/peptide combos that might achieve more. “It may be possible to induce cells to regrow and repopulate the tissue with new matrix molecules,” he says. “One possibility is anabolic growth factor, which can be used in extremely low concentrations. We have been experimenting with IGF-1, which induces the chondrocytes in the extracellular matrix to synthesize and lay out new matrix. We may be able to functionalize a nanoparticle with a drug combination like IGF-1 with Dexamethasone, which could suppress catabolic and degradation events. The IGF-1 could upregulate anabolic growth of tissue.” In addition to exploring protein-peptide nanoparticles, the lab has recently begun collaborating with the Paula Hammond lab of MIT’s Koch Institute to explore the use of synthetic nanoparticles coupled to IGF-1.
To simulate knee cartilage without using animal models, Grodzinsky’s researchers have removed cartilage from animals or human donor joints, and simulated different types of injuries and repetitive compressive forces with various high impact or repetitious low-impact loads. The damaged tissues are placed in culture along with a range of inflammatory cytokines typical of the joint environment, and then monitored.
“Ultimately you need animal models, but for drug discovery, this lets you more easily study the degradation and the ability of drugs to halt it and eventually rebuild,” says Grodzinsky.
Grodzinsky Lab is also looking into tissue regeneration to address a complete loss of cartilage, known as a focal defect. Typical re-generation techniques using marrow progenitor cells result in a fibrous wound repair tissue that wears away in 5 to 10 years. To generate longer-lasting cartilage, researchers are trying out various scaffolds and hydrogels.
“One scaffold is pre-seeded with the cell in an incubator,” says Grodzinsky. “The whole tissue is implanted, with the hope that marrow progenitor cells will migrate in. We’re also trying a particular hydrogel self-assembling peptide scaffold that does not require pre-seeding. The process uses various growth factors to stimulate migration of stem cells into the scaffold.”
The results have been promising, but many challenges await. “No matter how beautiful your construct looks in the incubator, if it doesn’t integrate with the native tissue, it’s not going to last,” says Grodzinsky. “Mechanical loads placed over two materials with very different mechanical properties can induce fractures.”
Grodzinsky believes researchers may eventually develop polymers for joint replacements that last longer than the current 10 to 20 years. “In 50 years, we might have wonderful polymeric materials that are better than metal and plastic and won’t need to be nailed into place,” he says.
It will be difficult to mimic all the qualities of cartilage. “Cartilage is a self-stiffening material, so when you stand on it, it resists compression, and when you run on it, it gets stiffer as the applied load and pace increase,” says Grodzinsky. “So far we haven’t been able to make materials that simulate that. I continue to marvel at the intricacy and beauty of cartilage.”