Nathaniel A. Dyment, Ph.D., assistant professor of orthopedic surgery, Perelman School of Medicine, University of Pennsylvania, has won the American Academy of Orthopaedic Surgeons (AAOS) 2024 Kappa Delta Young Investigator Award.
The award recognizes outstanding clinical research related directly to musculoskeletal disease or injury. Dr. Dyment won his award for his clinical research regarding the biophysical and biochemical cues that direct the growth and development, homeostasis and repair of tendons and ligaments.
“We don’t have specific markers that delineate between immature and mature tendon cells and don’t fully understand the biological and mechanical inputs that control tendon cell behavior,” said Dr. Dyment.
“Therefore, the development of treatments to successfully repair or regenerate tendons is very difficult. Often, a tendon tears near the bone at the enthesis and can frequently be a chronic tear. The degeneration that is happening in tendons can take decades to develop, making successful treatment of these injuries a big challenge. One strategy is to understand the disease process better so we can try to intervene earlier.”
Using mechanobiology, Dr. Dyment and his colleagues focused on tendon tensional homeostasis, which is critical to maintaining tendon tissue properties. Tensional homeostasis is the result of extrinsic (applied) loads, such as those from activities of daily living, and intrinsic (internal) loads, often generated by structural proteins inside the cell. The researchers explored how mechanical forces affect tendons during the various stages of embryonic development, postnatal growth, and homeostasis.
The major findings included:
- Muscle contraction is critical to postnatal growth of the Achilles tendon and can impair growth if reduced.
- Non-muscle myosin II motor proteins, which contribute to cellular organization and regulation and help drive cell tension, are required to maintain the tendon matrix into adulthood.
When torn tendons are sutured back to the bone, these repairs often lead to the formation of scar tissue and don’t produce an organized enthesis structure at the attachment site. The research team set out to understand the specific cell populations that participate in the healing response, which can help promote enthesis formation following an injury. Dr. Dyment and his team used the anterior cruciate ligament reconstruction (ACLR) surgical model as a test platform to manipulate specific cell populations during the tendon-to-bone integration process that occurs between the tendon graft and adjacent bone following surgery.
Their findings showed:
- At four weeks post-surgery, zonal tendon-to-bone attachments were seen in the bone tunnels. While more disorganized, the zonal attachments shared common features with native entheses.
- Activating the Hedgehog signaling pathway—a key regulator of enthesis formation during growth and development—increased the production of tendon-to-bone attachments following ACLR. This indicates that the Hedgehog pathway could be a therapeutic target to improve tendon-to-bone repair.
“Using developmental studies—how the tissue originally forms—we determined the elements that are absolutely critical to the establishment of this tissue,” said Dr. Dyment. “The Hedgehog pathway was specifically expressed by cells where the tendon inserts into bone that produce fibrocartilage in this area.”
Dr. Dyment explained the role of the Hedgehog pathway to OTW, “During my graduate studies, we found that cells in the tendon-to-bone insertion site (i.e., enthesis) expressed genes within the Hedgehog signaling pathway.”
“We later discovered that these cells would go on to make fibrocartilage within the enthesis, which is critical to the mechanical function of this tissue. In fact, this pathway is critical for the production and maturation of enthesis fibrocartilage.”
“We later investigated whether this pathway was active during tendon-to-bone integration following ACL reconstruction. Indeed, it was expressed by cells that produce the fibrocartilage in the tendon-to-bone attachments, similar to the expression patterns found during enthesis growth and development. We next found that by stimulating the pathway in our ACL reconstruction model, we could improve the tunnel integration process.”
“This pathway offers a novel target to potentially improve tunnel integration following ACL reconstruction and could also be more broadly applicable to tendon-to-bone repair in other contexts.”
“Growing up playing sports and experiencing injuries, both first and second hand, sparked my interest in sports medicine,” stated Dr. Dyment to OTW. “I started studying tendons and ligaments as a Ph.D. student in Dr. Dave Butler’s Functional Tissue Engineering Laboratory at the University of Cincinnati. Many of the research questions that my lab has today were shaped by the studies and findings we had as a group during my graduate and postdoctoral studies.”
“This work would not be possible without the contributions of my excellent mentors, colleagues, and trainees that I’ve had the pleasure of working with over the years. These people include, but are not limited to, Dave Butler, David Rowe, Lou Soslowsky, Rob Mauck, Andy Kuntz, Joel Boerckel, Lin Han, Eiki Koyama, Catherine Bautista, Mary Kate Evans, Natalie Fogarty, Keitaro Fujino, Yusuke Hagiwara, Xi Jiang, Talayah Johnson, Dakota Jones, Tim Kamalitdinov, Jonathan Marcelin, Rashad Madi and Tonia Tsinman.”
