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          Roundtable on Innovative Treatments for Enthesis Repair


Roundtable


Roundtable on Innovative Treatments for Enthesis Repair *May 22, 2017*
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    Background

Rotator cuff or Achilles tendon “tears” often refer to an injury to the region where a tendon inserts into bone. This interface is called the enthesis. Such injuries have one of three causes: an acute massive overload that tears a healthy tendon at the insertion site, an acute massive overload that tears an enthesis that was already weakened by degeneration, or overall degeneration that gradually leads to failure. Repairing degenerated and torn entheses can be challenging. The field of regenerative medicine has enlisted artificial scaffolds, stem cells, and growth factors to address this challenge by re-establishing the bone-tendon interface. Despite the many scientific advances in this area, translation of these discoveries into clinical care of enthesis injuries is limited. This is particularly true for the shoulder.

In 2017, NIAMS brought together basic, translational, and clinical investigators to identify research gaps and emerging technologies that could lead to better strategies for repairing the bone-tendon enthesis. The meeting was organized around the following questions:

How are failures and limitations of the current treatment approaches to tendon injuries pointing to gaps in our understanding of the mechanism of action?
	What are the most promising research areas for enthesis repair? What are the most immediate clinical needs and how can the gaps be addressed?
	What needs to happen to enable robust translational and clinical studies of these potential treatments/therapies?Written input collected by participants from their research communities guided the discussion. The NIAMS greatly appreciates the community’s input.

Highlights from the group’s discussion of the cellular and molecular research opportunities, animal models that could answer biologic questions and accelerate the development of clinical interventions, and opportunities to advance clinical research and patient care are described below.

Basic cellular and molecular research needs

Interventions that move an injured or degenerated enthesis to a healthier state could be useful pre-treatments that “prime” an injured tendon so that it is more likely to heal following surgical repair. The following areas were mentioned as understudied areas from which such strategies may emerge.

Enthesis development, maintenance, and degeneration

Studies of enthesis progenitor cells and the mechanisms by which they form the tendon-bone junction hold promise, as does research into the cells and molecules that are produced by surrounding tissues such as the bone marrow, tendon, muscle, and bursa. Such cells and molecules are likely to contribute to enthesis health and could be harnessed as potential treatments. The role of mechanical stress on cell behavior also must be considered when studying the enthesis.

Likewise, the biologic mechanisms that influence enthesis degeneration are ripe for exploration. Degeneration is an active process that involves mechanisms that could be targeted therapeutically. Participants discussed using systems-biology approaches to examine the molecules that contribute to or protect against degeneration.

Inflammation and the immune response

While inflammation promotes tendon/enthesis healing, it also contributes to degeneration. As with many other conditions, therapies targeting inflammatory responses could be more useful if researchers had a better understanding of inflammation’s positive and negative effects, the types and concentrations of cells and molecules involved, and the timing and duration of their appearance at the site of injury. Additional research opportunities involve the role of mechanical stress (during and after injury) in stimulating positive and negative inflammatory responses in other musculoskeletal tissues such as skeletal muscle and synovium.

Biological basis of cellular therapies

Beneficial cells or secreted factors could be therapeutically valuable if researchers could direct them to the damaged tissue. Platelet-rich plasma and related approaches using cells isolated from patients are being implemented in clinical settings with little understanding of the mechanisms of success or failure and which signaling factors influence outcomes. Techniques differ, clinical results of these procedures are uneven, and much of the observed variation is attributed to differences in the composition of the materials being reinjected into patient. If the specific cells and factors involved in healing were identified, scaffolds could be developed that would recruit and secure these beneficial components into an injured enthesis to accelerate repair.

Mechanical influences on tissue repair

Repair is a multi-scale problem that ranges from the gross tissue properties to the load that is placed on individual cells and influences their behavior. Recognizing that biologic mechanisms and mechanical stresses are interrelated, participants discussed the relative value of attempting to understand and recapitulate biological processes and of taking an engineering approach toward dissipating the mechanical stress that concentrates when connecting two materials (i.e., tendon and bone). Participants noted that the field would benefit from micron-scale imaging tools that provide information about an enthesis’ responses to loading.

Preclinical and translational models

Although animal models have significant limitations, they also have important roles to play in the testing of biological mechanisms and the safety of potential treatments.

Enthesis development

While mouse models provide insights into the fundamental mechanisms of tendon and enthesis development and growth, the relevance of these mechanisms to enthesis repair is unclear. Zebrafish is another model that has been used to study enthesis formation.

Overuse injuries

Most animal models mimic acute trauma to healthy tissues, rather than other types of injuries. However, mouse and rat models of overuse exist and can add value to mechanistic studies. Dogs that train for agility events and horses naturally develop acute and chronic overuse injuries, which also can provide useful information regarding treatments and prevention strategies.

Surgical repair of the rotator cuff

While rat shoulder anatomy resembles that of other quadrupeds, the tendon fibers connecting the upper limb to the torso align in a pattern that resembles human shoulder tendons. Despite this similarity, a rat’s small size places different mechanical stresses on a repair site. Sheep and dogs can serve as large-animal models for medial collateral ligament, patellar tendon, and Achilles tendon injuries, but their shoulders differ from humans with respect to anatomy, pathogenesis, biomechanical loading, and re-tear rates following surgery. The tree kangaroo shoulder most closely mimics primate anatomy, but that animal is not studied in biomedical research.

Safety and proof-of-concept studies

Mice and rats can be appropriate for studies of cell, biologic, and scaffold therapies. Rabbits were mentioned as potentially serving as a bridge between rodent and large animal models. The National Center for Advancing Translational Sciences (NCATS) Tissue Chip Program was mentioned as another source of models that could be harnessed for preclinical testing of drugs, biologics, and cell-based interventions. At the time of the roundtable, NIH was preparing to make awards in response to RFA-TR-16-017, Microphysiological Systems (MPS) for Disease Modeling and Efficacy Testing (UG3/UH3).

Opportunities to advance clinical research and patient care

Meaningful studies of surgical repair and rehabilitation strategies must address outcomes that matter to patients. While many clinical studies focus on factors that influence healing, restoration of function and reduction in pain also are important.

Standardized outcomes for studies of surgical repair and rehabilitation of rotator cuff tears

Clinical studies could be more rigorous if researchers had reproducible and sensitive methods of assessing outcomes (e.g., active range of motion measures, passive range of motion measures, isometric muscle strength). While there was general agreement that clinical studies should be powered to detect clinically relevant changes in pain, function, and the repair’s structural integrity, many of the tools to reliably measure such changes still need to be developed, refined, and validated. One participant articulated the need as “a gait analysis for the upper extremities.” Similarly, measures of patient-reported outcomes for arms and shoulders were described as less specific than those that had been developed for the lower extremities.

Imaging tools to improve the diagnosis and staging of rotator cuff injuries

High resolution magnetic resonance imaging sequences and ultrasound approaches are being developed to monitor healing, scarring, and inflammation in other tissues or joints (e.g., torn anterior cruciate ligaments, osteoarthritic knees). Similar noninvasive imaging tools that could better quantify rotator cuff tear size, tear location, and tissue quality would improve the care that patients with shoulder injuries receive today. If the tools were sensitive enough to detect small changes, they also could be used to prospectively monitor post-operative healing, which in turn would contribute to the body of knowledge regarding the effectiveness of different repair approaches.

Imaging modalities and algorithms that accurately assess enthesis health and predict repair outcomes also could enable efficient clinical trials of new repair strategies. Participants noted that different tissues require different imaging approaches (e.g., enthesis vs. full tendon vs. entire shoulder). In addition to better imaging approaches to examine tissue structure, the field would benefit from imaging tools that provide insights into the tissue’s functional properties.

Sources of shoulder pain

As with many orthopaedic conditions (e.g., herniated discs, spinal stenosis, knee osteoarthritis), rotator cuff damage that is detected through imaging tests does not always correlate with pain or impaired function. Little is known about the factors that prompt a degenerating enthesis to cause pain. Muscle behavior (e.g., spasticity) in response to injury was mentioned as a potentially overlooked pain source.

Variability in susceptibility to injury and response to treatment

Human variation regarding susceptibility to injury and response to treatment underscores the importance of studying people to improve clinical outcomes. Little is known about the biological factors (e.g., genes, genetic variants) that protect against rotator cuff injury and degeneration and that facilitate healing. As noted under the imaging section above, improved strategies for classifying patients would enable rigorous studies into whether an intervention works and for which types of injuries.

Variability also can be caused by factors such as a patient’s age, sex, overall health, behavior, and environment. Age clearly influences injury susceptibility and recovery. Studies of cell-based therapies such as platelet-rich plasma indicate that younger people are more likely to have substances in their blood that promote healing; older people produce substances that yield opposite results. Older women are most susceptible to rotator cuff tears, suggesting hormonal influences. As with treatments for other musculoskeletal conditions, smoking impairs recovery following rotator cuff surgery.

Postoperative rehabilitation is another source of variability. Differences in rehabilitation protocols, the ways the protocols are administered, and patient adherence influence outcomes. Moreover, cell-based/regenerative medicine approaches may require a substantially different rehabilitation regimen than is required following a suture repair.

Biochemical markers to predict and measure healing

The identification of biomarkers that are indicative of disease progression or healing could suggest possible therapeutic targets that could prevent the need for surgery or could enhance post-surgical recovery. Those that yield information about the mechanisms underlying tissue degeneration also could be used to stratify patients for clinical studies, similar to the imaging tools described above.

Large cohort studies that might be leveraged to answer research questions

Participants discussed existing cohort studies that researchers may be able to leverage to address some of the research opportunities and needs described above.  These include the

NIH Common Fund’s Health Care Systems Research Collaboratory, which focuses on access to electronic health data from large healthcare systems.
	Department of Veterans Affairs’ Million Veteran Program, a database containing genomic data and health information from former members of the U.S. military.
	Osteoarthritis Initiative, which has knee MRIs that could be used for studies of the patellar tendon attachment.
	Precision Medicine Initiative’s *All of Us*Research Program, a goal of which is to identify biological markers that signal increased or decreased risk of developing common diseases.Extramural Participants

ALMAN, Benjamin A., M.D., Duke University
ANDARAWIS-PURI, Nelly, Ph.D., Cornell University
CHU, Constance R., M.D., Stanford University
DERWIN, Kathleen A., Ph.D., Cleveland Clinic
GALATZ, Leesa, M.D., Icahn School of Medicine at Mount Sinai (co-chair)
HUANG, Alice, Ph.D., Icahn School of Medicine at Mount Sinai
LU, Helen H., Ph.D., Columbia University
MENDIAS, Christopher, Ph.D., A.T.C., University of Michigan Medical School
RATCLIFFE, Anthony, Ph.D., Synthasome, Inc. (co-chair)
SCHWEITZER, Ronen, Ph.D., Oregon Health and Science University
SPINDLER, Kurt, M.D., Cleveland Clinic Sports Health Center
TEMENOFF, Johnna S., Ph.D., Georgia Institute of Technology and Emory University
THOMOPOULOS, Stavros, Ph.D., Columbia University

NIH

ALEKEL, D. Lee, Ph.D.
BURROWS, Stephanie, Ph.D.Carter, Robert, M.D.
CAUGHMAN, Cindy, M.P.H.Cernich, Alison, Ph.D.
CHEEVER, Thomas, Ph.D.
DRUGAN, Jonelle K., Ph.D., M.P.H.Katz, Stephen I., M.D., Ph.D. (co-chair)Lester, Gayle, Ph.D.

LINDE, Anita M., M.P.P.McGowan, Joan A., Ph.D.
NICKS, Kristy, Ph.D.
REUSS, Reaya, M.S.
SERRATE-SZTEIN, Susana A., M.D.Tyree, Bernadette, Ph.D.Wang, Fei, Ph.D.
WANG, Xibin, Ph.D.Washabaugh, Charles H., Ph.D. 
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