Young Investigator Award recognizes tissue engineering studies

Stavros Thomopoulos, PhD, winner of the 2009 Kappa Delta Young Investigator Award, took on that challenge. His award-winning paper—“Structure, Biomechanics, and Mechano­biology in the Attachment of Tendon to Bone”—details his efforts to understand how cells at the insertion point of tendon and bone respond to changes in their mechanical environment (their “mechanobiology”). His results, he hopes, will “provide guidance and a theoretical framework for efforts to apply tissue engineering strategies to improve healing and surgical repair of the tendon-to-bone insertion.” It’s a goal he anticipates will be achieved within his lifetime.

Like rope and cement
If bone is hard and porous, like cement, tendons are soft and stringy, like a rope. “The attachment of a compliant material like tendon to a relatively stiff material like bone is a fundamental engineering challenge,” said Dr. Thomopoulos. As the tendon approaches the insertion site, its composition and mechanical properties change. This “graded morphology” is “presumed to aid in the efficient transfer of load between the two materials.”

He began his research by developing models to examine the role of mechanobiology at the tendon-to-bone insertion site. His data support a new description of con­tinuous gradation in biomechanical, compositional, and structural properties from tendon to bone, rather than discrete zones of different cell­ular compositions and properties.

“The tendon-to-bone insertion site varies dramatically along its length in collagen structure, extracellular matrix composition, mineral content, geometry, and viscoelastic properties [which] distribute the forces more effectively across the transition from a flexible to a rigid material,” he wrote.

Load or no load?
One series of studies examined the impact of loading on the development and healing of tendon-to-bone insertion. Using botulinum toxin in a mouse model, Dr. Thomopoulos mimicked the clinical condition of neonatal brachial plexus palsy. “Reduced loading during development impairs mineral deposition at the insertion …[and] fibrocartilage formation …[and] leads to disorganized fiber distribution and inferior mechanical properties in tendon at the insertion,” he found.

After seeing the critical role that mechanical loading played during tendon-to-bone insertion development, Dr. Thomopoulos went on to examine the impact of loading during healing. To his surprise, he found that “cast immobilization is beneficial to tendon-to-bone healing compared to exercise.” Immobil­izing the tissue enabled the healing tissue to approach the structural properties of normal uninjured tissue by 8 weeks postinjury.

But a follow-up study found that “complete removal of load is detrimental to tendon-to-bone healing.” Using both rat and canine models, he found that “complete removal of load resulted in repairs with less range of motion and lower biomechanical properties compared to repairs in which the muscle-tendon-bone unit was left intact.”

As a result, he stated, “mechanical loading is necessary for collagen alignment and anisotropic mechanical properties… [and] influences extracellular matrix production.”

Three conclusions
In his paper, Dr. Thomopoulos came to three conclusions. First, “effective attachment of tendon to bone depends on the formation of a functionally graded insertion.” Because the grading occurs at both microscopic and nanoscopic levels, the poor outcomes seen in tendon-to-bone healing may be due to high levels of stress concentrated at the interface between the two dissimilar materials.

To address this issue, his second conclusion notes that “a tissue-engineered tendon-to-bone graft would have significant clinical impact for the repair of tendon to bone. … A functionally graded material implanted at the time of surgical repair may provide mechanical stability and guide the repair process, leading to a successful attachment of tendon to bone.”

His final conclusion—“mechanobiology can play a role in clinical management of tendon-to-bone pathologies”—has direct clinical applications, particularly in treating rotator cuff repairs and in designing treatments for neonatal brachial plexus palsy. In postoperative treatment of rotator cuff repairs, for example, muscle paralysis induced through the use of botulinum toxin may be more effective than sling immobilization because it does not require patient compliance.

Dr. Thomopoulos reports no conflicts of interest with industry. His research is supported by grants from the National Institutes of Health, the Orthopaedic Research and Education Foundation, and the Department of Orthopaedic Surgery of Washington University, St. Louis.