Traditional osteoarthritis (OA) treatment depends on the patient’s ailment and what information they report. Usually, it begins with seeing an orthopedic surgeon to address pain, where they run tests and do scans that can detect the level of OA present in the cartilage. Common problems include cartilage degradation and bone formation, but sometimes these do not show up on the tests. Depending on the severity of the condition, the patient can take anti-inflammatories, do physical therapy or have surgery. The gold standard of treatment is total joint replacement; however, this isn’t ideal for younger patients who would require multiple replacements throughout their life. One of the first options for surgical treatment is microfracture surgery, during which holes are drilled into the underlying bone below cartilage to get the stem cells in the bone to try to infiltrate the cartilage. However, this forms fibrotic tissue instead of the articular cartilage that is present on joints, and therefore actually leads to more cartilage degradation over time .
At the Washington University School of Medicine in St. Louis, senior investigator Farshid Guliak, PhD, is working on developments in the new field of mechanogenetics, which considers mechanical processes in genetic engineering techniques. This is relevant to osteoarthritis, as walking is a simple mechanical process that involves cellular activity, which can be manipulated in a lab setting. With no therapies actually preventing joint damage in osteoarthritis, Guliak was inspired to engineer cartilage cells that would respond to the mechanical loading of a joint. When the cartilage cells are under stress, such as every time someone takes a step, they produce an anti-inflammatory drug that can limit the damage due to arthritis .
Lara Pferdehirt, a graduate research assistant in Guliak’s lab, explains that their process began with experimenting on pig cartilage cells to determine which cellular pathways respond to mechanical stress. They were also able to identify cartilage gene circuits, which are made of components of interacting genes and proteins to perform diverse cellular properties . From this, they developed a mechanically responsive bioartificial tissue that releases a drug called Anakinra. It’s normally used to treat rheumatoid arthritis, but relatively ineffective in osteoarthritis patients when injected into one joint at a time. Anakinra only seems to work if it’s delivered continuously for years to relieve the stress during mechanical loading. Initially, it was thought this was because not enough of the drug was reaching the joint due to its short half-life, however another underlying problem was its ability to integrate with the cartilage. Essentially, constant injections of anakinra would be required to have any effect. These engineered cells release the drug wherever it’s needed, acting as a solution for both localized drug delivery and cartilage integration. This also helps avoid possible side effects from long-term delivery of an anti-inflammatory drug, such as stomach pain, diarrhea, fatigue and hair loss.
Pferdehirt described the different conditions created for the cells, such as making them responsive to mechanical loading and inflammation or just to mechanical loading, to test the upregulation of various inflammatory pathways. To test their designs, they observed three aspects of mechanical loading. Compressive loading is what the joints actually feel, which was experimentally determined using a machine that applies different stresses to cartilage disks. When mechanical loading happens, fluid leaves the joint space and laterflows back in, causing the cells to experience a change in osmolarity, thereby causing osmotic loading. Lastly, they resembled the key pathways by building ion channels that would activate the processes and allow for testing. By looking at luminescence and ion concentrations, they were able to conclude the efficacy of the engineered cells and relevance of mechanogenetics to regenerative medicine.
They are planning on testing in animal models, specifically pigs, as the cells are originally derived from them and mice are not good loading models. There are hurdles in getting to clinical trials and implanting tissue-engineered constructs, as they are fairly uncommon to insert, particularly into joints.
As for future steps, other genetic circuits can be manipulated to release drugs. Whether looking at other aspects of osteoarthritis or pain management in general, using other ion channels and drugs is promising for a variety of treatments in any type of mobility. Some genetic circuits are activated with every step in walking, while others respond to an overload of traumatic injury. There’s potential for this technology to immediately release an anti-inflammatory upon a traumatic event, reducing the risk for osteoarthritis and expediting the healing process.
While cartilage and osteoarthritis provide an ideal model for mechanical loading, there are a plethora of applications outside of joint pain. Pferdehirt expands on this with “There’s a lot of other tissues in your body that experience a mechanical load and nobody’s ever thought to actually have mechanics be the driver of a genetic circuit before. I’m hopeful that this will not only be able to be applied in your cartilage but also in your heart and be tailored to heart disease.”
For now, these tissue-engineered cells can help those suffering from osteoarthritis pain, especially as a more attractive option for younger patients. Mechanogenetics acts as a stepping stone to a variety of scientific advancements in how diseases can be both managed and prevented.
Edited by: Shamika Bhandarkar
Illustrated by: Shanthi Deivanayagam