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Published 10/1/2009
Jay D. Lenn

Rotator cuff development: Lessons for healing in adults

OREF grants may help change the prognosis for rotator cuff injury patients

Rotator cuff tears are common injuries and a common cause of shoulder pain in adults. Unfortunately, surgical success in repairing rotator cuff tears is often limited by poor tendon-to-bone healing. With funding from the Orthopaedic Research and Education Foundation (OREF), two researchers are collaborating on projects that may improve surgical outcomes and healing.

Leesa M. Galatz, MD, received a 2007 OREF Career Development Award to study the effect of muscle load, or mechanical stress, on the development and healing of the tendon-to-bone insertion in the rotator cuff. Stavros Thomopoulos, PhD, was awarded a 2007 OREF Research Grant to study biofactors influencing the same process. Each researcher is serving as a co-investigator for the other’s project.

Organized vs. disorganized healing
The investigators propose that factors at work during normal development of tendon-to-bone integration may suggest strategies to enhance the healing process in adults. “The development of the rotator cuff follows a very ordered process,” said Dr. Thomopoulos. “You end up with tissue that’s very functional and a tendon-to-bone insertion that works extremely well.” In contrast, surgical repair often results in the development of disorganized scar tissue and no transitional tissue between the tendon and bone (
Fig. 1).

Drs. Galatz and Thomopoulos are using animal models to search for clues that may help them replicate the orderly process of development during the healing process. Mice are good models for studying the development of the supraspinatus tendon, the most commonly torn tendon in a rotator cuff tear. At birth, the mouse supraspinatus muscle is attached to the humeral head through an immature tendon, without any transitional tissue. This enables researchers to watch how the tendon-to-bone attachment develops and to identify key factors in the process.

In one line of investigation, the researchers are using botulinum toxin A (Botox) to immobilize the supraspinatus muscle of the left shoulder of mice at birth. By comparing the development of the left and right tendon-to-bone attachments in the Botox mice—as well as with a control group, Drs. Galatz and Thomopoulos have identified the role that muscle load, or mechanical factors, has on the process (Fig. 2).

At 2 weeks, they observed no differences in rotator cuff development. Subsequent observations, however, demonstrated that muscle load was essential for tendon-to-bone integration. A lack of muscle load delayed this process by inhibiting bone mineralization.

The next step is examining how well tendon-to-bone integration occurs when the Botox injections are discontinued and muscle load is resumed.

Optimal healing conditions
In related work with a rat model, Dr. Galatz and Dr. Thomopoulos are examining the role of muscle load on postoperative healing of the supraspinatus tendon. By comparing the healing process in rats with immobilized muscles and those with normal mobile muscles—a model for rest and rehabilitation in humans, respectively—the researchers hope to judge the impact of muscle load on healing.

Their laboratory work has potential application in the clinical setting. “The way we rehabilitate patients after rotator cuff repair is very controversial,” stated Dr. Galatz. “This investigation may suggest an optimal biomechanical environment for tendon healing and provide evidence that range-of-motion and strengthening exercises either enhance or deter healing.”

Mouse and rat models are also enabling Dr. Galatz and Dr. Thomopoulos to explore biologic factors influencing the development of tendon-to-bone attachments. Primary goals of the project supported by the 2007 OREF Research Grant are to ascertain the progression of cellular events that lead to a mature, functional tendon-to-bone attachment and to identify the growth factors that trigger this development. Understanding the timing and role of growth factors in this process may point to more effective therapeutic strategies.

Promoting better healing
The investigators have also used the mouse model to follow the development of the supraspinatus tendon from 2 weeks after conception to 3 weeks after birth. Their data have enabled them to determine when certain cellular events and extracellular structures—precursors to the mature, attached tendon—begin to form and when certain growth factors are active.

This analysis provides a foundation for developing and testing growth factor-based substances that may promote better healing after surgery. Dr. Thomopoulos is testing scaffolds that can be implanted during surgery and release growth factors on a controlled basis. By delivering a growth factor present during development—but not expressed in the adult—researchers hope to recreate the biologic environment necessary for establishing a stable tendon-to-bone connection.

Dr. Thomopoulos notes that the collaborative nature of their work expedites the transition from the laboratory to clinically useful applications.

“If we have the perfect release characteristics and everything works well, but the surgeon says the material is too difficult to handle in the operating room, we immediately need to consider other options. Even if we find an ideal solution from the basic science perspective, we always keep in mind the application and translation of it to patients,” he said.

Healing for all ages
Dr. Galatz adds that their work is addressing a significant clinical problem today. “Between age 60 and 65, the chances of successful healing of a rotator cuff tendon dramatically decrease. Biologic changes make healing much less predictable.”

As the baby boomer generation ages, orthopaedic surgeons are seeing an increasing number of rotator cuff tears. “People are interested in leading very active lifestyles,” said Dr. Galatz, “and rotator cuff disease is very disabling to their work and recreation.”

The collaborative research of Drs. Galatz and Thomopoulos may help change the prognosis of people undergoing surgery for rotator cuff injuries and contribute to our knowledge about tendon-to-bone healing, which can be applied in other anatomic areas. Both investigators credit OREF for making this work possible and for advancing the careers of people exploring novel ideas in orthopaedics.

“This money allows us to evaluate novel approaches for rotator cuff repair,” explained Dr. Thomopoulos. “We can then use the data to seek a larger grant from the National Institutes of Health, to expand our research program, and ultimately to translate our results to patients.”

Jay D. Lenn is a contributing writer for OREF and can be contacted at communications@oref.org