Nathaniel A. Dyment, PhD, Receives 2024 Kappa Delta Young Investigator Award

Nathaniel A. Dyment, PhD, was named the recipient of the 2024 Kappa Delta Young Investigator Award for his findings on biophysical and biochemical cues that direct the growth, development, homeostasis, and repair of tendons and ligaments. The award recognizes outstanding clinical research related to musculoskeletal disease or injury by investigators younger than 40 years.

Tendon and ligament disease and injuries affect more than 30 percent of adults in the United States and have poor healing outcomes due to the development of scar tissue, which often leads to retears. Tendon disease and injuries typically occur in two areas of the tendon: the tendon midsubstance (the middle level of the tendon) and the enthesis (the attachment site of tendon to bone). Unfortunately, clinicians and researchers lack biological benchmarks to assess the repairs of these tissues.

“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, assistant professor of orthopaedic surgery at the Perelman School of Medicine at the University of Pennsylvania. “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.”

Through the use of mechanobiology, the study of how mechanical factors affect cell behavior, Dr. Dyment and his colleagues explored 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.
• The loss of cellular tension in adult tendons leads to a robust catabolic response, regulated by the mechano-responsive Yap/Taz signaling pathway, which plays a role in cell growth and proliferation.

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 ACL 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 4 weeks after surgery, zonal tendon-to-bone attachments were seen in the bone tunnels. Although more disorganized, the zonal attachments shared common features with native entheses.
• Activating the Hedgehog (Hh) signaling pathway—a key regulator of enthesis formation during growth and development—increased the production of tendon-to-bone attachments following ACLR. This finding indicates that the Hh pathway could be a potential therapeutic target to improve tendon-to-bone repair.
• Dr. Dyment’s lab, in collaboration with his colleagues Andrew Kuntz, MD, and Robert Mauck, PhD, developed scaffold systems to localize delivery of Hh signaling drugs to the bone tunnels.

“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. The pathway is also a potent regulator of fibrocartilage production in the enthesis, and, excitingly, we found that it appears to have a similar role in tendon-to-bone integration in adults.”

Several of Dr. Dyment’s mentors and colleagues were instrumental to this research, including but not limited to: David Butler, David Rowe, Louis Soslowsky, Robert Mauck, Andrew 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.

Dr. Dyment will be honored at the Your Academy event Wednesday morning.

References

1. McCormick A, Charlton J, Fleming D: Assessing health needs in primary care. Morbidity study from general practice provides another source of information. BMJ 1995;310:1534.
2. Petty RE, Laxer RM, Lindsley CB, et al: Textbook of Pediatric Rheumatology (7th ed.). Philadelphia: Elsevier Health Sciences; 2015.
3. Gomes ME, Reis RL, Rodrigues, MT: Tendon Regeneration: Understanding Tissue Physiology and Development to Engineer Functional Substitutes (1st ed). Cambridge, Massachusetts: Academic Press; 2015.
4. Newell-Litwa KA, Horwitz R, Lamers ML: Non-muscle myosin II in disease: mechanisms and therapeutic opportunities. Dis Model Mech 2015;8(12):1495-515.