The 2021 Kappa Delta Young Investigator Award was given to Lin Han, PhD, for his research on the structure and function of cartilage extracellular matrix (ECM) and its impact on tissue regeneration and disease evolution in osteoarthritis (OA).
The Young Investigator Award recognizes outstanding clinical research related to musculoskeletal disease or injury conducted by investigators younger than 40 years.
With this research, Dr. Han and his colleagues provided a new understanding about how to improve cartilage regeneration and disease intervention. Using nanomechanical tools, which measure molecules at a very minute scale, they found new molecular activities that govern the proper functioning of healthy cartilage ECM and the degeneration of ECM that occurs in OA.
“Cartilage is one of the simplest tissues in the human body, yet the more we discover, the more we become aware of the unknowns,” said Dr. Han, associate professor in the School of Biomedical Engineering, Science and Health Systems at Drexel University in Philadelphia.
“Even after decades of research on cartilage tissue engineering and regeneration, we still cannot find a way to fully restore the function of native cartilage. When cartilage is damaged by injury, overuse, or inflammation, patients may go through a period where they cannot continue life as normal,” he added.
Understanding cartilage ECM
Articular cartilage covers the ends of bones and provides functions critical for joint motion, including load-bearing, energy dissipation, and lubrication; however, it has poor self-healing capabilities. The major trademark of OA is the irreversible breakdown of cartilage ECM, but the limited understanding of how ECM works in healthy and disease states has hindered its treatment.
Aggrecan, a component of ECM that plays an important role in the proper functioning of articular cartilage, is a key indicator of cartilage health and disease. When a patient has OA, aggrecan fragmentation is one of the earliest molecular events.
Dr. Han and colleagues used atomic force microscopy–based tools to evaluate the nanomechanics of aggrecan under various loading modalities, such as compression, which allowed the researchers to understand the biometric assembly of aggrecan.
The outcomes suggested the existence of new methods of molecular interactions that strengthen the assembly of aggrecan networks. This work was the first to study the dynamic mechanical behaviors of cartilage on such a minute level, setting the path for several follow-up studies.
Collagens and other proteins in the ECM
Dr. Han and his research colleagues also studied the interactions between aggrecan and the fibrillar network collagen II, one of the primary connective tissues of the body. The researchers found that aggrecan and collagen undergo molecular adhesion when compressed, contributing to several biophysical factors that help aggrecan and collagen II evolve. These results demonstrated that the interactions between aggrecan and collagen II could play an important role in the reliability of ECM.
Further studies discovered that decorin plays an essential role in regulating the integrity of cartilage ECM, functioning as a “physical linker” to strengthen the integration of the aggrecan network and delaying the loss of fragmented aggrecan from degenerative cartilage.
“Aggrecan is the molecule that determines the shock absorption and the load-bearing function,” Dr. Han said. “Knowing this, we can potentially design new strategies that use decorin to promote the regeneration of articular cartilage, which could lead to new treatment strategies.”
ECM in post-traumatic osteoarthritis
Post-traumatic osteoarthritis (PTOA) is the most widespread form of OA in young adults, resulting in a decreased quality of life over the long term. Early diagnosis and effective intervention are difficult due to limited understanding of the initiation of PTOA.
Utilizing mice injury models, Dr. Han found that cartilage modulus begins to weaken as early as one week after surgery and continues until 12 weeks, preceding historical signs of cartilage damage at four to eight weeks. Administering a small-molecule inhibitor can reduce the modulus reduction.
For the first time, the researchers were able to quantify the biomechanical changes of cartilage in the initiation of PTOA, demonstrating how highly sensitive cartilage is when OA begins.
Further studies showed that the impairment of cartilage matrix, as a result of aggrecan degrading, is a leading event in PTOA initiation.
Ongoing studies are testing the potential of improving cartilage regeneration or OA intervention by regulating the activities of particular molecules through the use of collagen II and native decorin.
“The findings will eventually help guide surgeons in designing more specific strategies for patients,” Dr. Han said. “For example, hypothetically, there may be a type of mechanical load that would be more advantageous for us to stimulate cartilage cells and, in turn, strengthen the articular cartilage tissue. Physical therapists and surgeons can then understand what exercises are going to benefit particular patients,” he added.
Dr. Han will receive his award Thursday at Your Academy 2021, 9:30 a.m. to 11:30 a.m., in Ballroom 20B.