Managing tendinopathies and tendon tears: Nanoscale mesh scaffolding promotes biological healing response

Tendinopathy is a common clinical syndrome that can affect any tendon. Patients present across an age and activity spectrum with pain, swelling and impaired function. Previously described by the diagnostic terms "tendinitis" or "tendinosis," the clinical condition is now more accurately referred to as tendinopathy. Chronic tendinopathies can weaken tendons and cause overt tendon tears.

"When patients have a tendinopathy, it represents a failure of the body's normal repair mechanisms. Although there is some evidence that it may begin as an inflammatory condition, the pathology is better characterized as a degenerative condition," explains Mark E. Morrey, M.D., an orthopedic surgeon at Mayo Clinic's campus in Rochester, Minnesota.

As a specialist in tendinopathies and soft tissue healing conditions, Dr. Morrey also conducts research focused on using novel scaffolds to direct growth in different types of soft tissues, utilizing rotator cuff injuries as a model. Adds colleague John W. Sperling, M.D., of Mayo Clinic in Rochester: "The clinical potential of this approach is significant because it promises, for the first time, to enable the physician to restore high-quality tendon tissue needed for optimal function."

Role of inflammation

Clinical symptoms of tendinopathies are still often treated with corticosteroids. "This approach has been utilized for decades and appeared to have some benefit for our patients. Unfortunately, well-designed randomized controlled long-term studies have shown that although this treatment has worked in the short term, it can lead to more recurrences and poor tendon health in the long term," Dr. Morrey says. "When considering an injection of corticosteroids for tendinopathies, physicians should look very carefully at emerging data regarding tendon quality and potential long-term risks and benefits to patients."

Dr. Morrey's research seeks to characterize the underlying molecular and biological causes of failed healing in rotator cuff tear models. The goal is to correct them so the tendon can recover its natural healing ability. His results suggest a major factor contributing to failure to heal is the absence of requisite mechanical cues such as tension and extracellular architecture. These cues direct tendon cells to regenerate.

Cellular confusion

Lacking these cues within the cellular microenvironment, ruptured tendon cells fail to elongate, a morphological deficit that impairs the cells' function to produce the normal proteins needed for healthy tendon. Explains Dr. Morrey: "In healthy tendon, as cells are dividing, they change their shape and they become more elongated as a direct response to the extracellular architecture." Injured cells take on a rounder shape, resembling cartilage cells, a condition known as chondroid metaplasia.

"This is what we are seeing at the histologic level," Dr. Morrey explains. "These cells don't know what to become — they're confused, in a sense, because they lack the appropriate inputs to guide healthy growth. As a result, they resemble cartilage cells and produce a cartilage-like extracellular matrix instead of a tendon-like matrix."

Researchers at Mayo and England's Oxford University are collaborating to apply these insights to promote tendon healing. By restoring the necessary conditions within the matrix to cue the proper growth of tendon cells, they aim to regenerate tendon structure.

Guiding growth

To create conditions that favor the growth of new tendon cells, Dr. Morrey and Oxford colleagues are developing a synthetic, degradable mesh patch to provide a scaffold for tendon regeneration. "A scaffold is a means of re-creating those mechanical cues so the cells can recover their natural architecture and hopefully promote normal healing," Dr. Morrey explains.

When placed over a traditional surgical rotator cuff repair, the patch can augment healing by providing the cues that guide the regenerating cells to grow into a tendon-like structure. Once that is achieved, the scaffold degrades and leaves behind normal, healthy, tendon tissue. "The cells are initially told what to become because of the architecture of the patch," Dr. Morrey says. "It is partially a mechanical signal to guide tendon cell elongation that has to do with the alignment and fiber size of the patch components."

Researchers have known for years that the extracellular architecture impacts tendon cell growth. But they had not realized the extent to which these cues determine growth and differentiation of tendon cells. Now, with the patch, they can evaluate the role of many growth variables to one day devise an optimal therapy that cues the body's own production of new tendon cells to heal an injury.

Biocompatibility issues

Fiber size

In designing any biological implant, it is important that the materials used do not promote an unwanted immune response. "We know the body responds differently to different materials. This includes varied responses to the chemical degradation products of these materials, and to the sizes of fibers utilized in these patches," Dr. Morrey says.

As the fiber size of the patch changes, the immune system responds differently to it from a biocompatibility standpoint: It may reject and wall off the material, rather than incorporate it. "To be successful, you have to get the right mixture of fiber size and chemical structure to tell the cells what to do."

Injury response

In addition to mechanical changes, injury prompts powerful biochemical changes within the cell. When injury occurs, the cellular response begins with neutrophils, which release reactive oxygen species. These damage the tissue further and also recruit other cells, including the first responders in a healing situation, macrophages.

Macrophages: Heal or harm?

Biomaterials, such as scaffolds that are implanted to aid healing during the injury response, may alter the healing response. Depending on biomaterial features such as fiber size and the types and level of degradation products, macrophages recruited to the area of injury can heal or harm.

If given the right cues, they can help promote healing in a regenerative, tissue-responsive macrophage form that basically accepts the material as its own. But if a macrophage takes the form of a foreign-body giant cell, it may become harmful as it tries to deal with the byproducts of injury. This can lead to excessive fibrosis and encapsulation.

An important focus of Dr. Morrey's research is directed at controlling signals to macrophages with the goal of downplaying the rejection response and promoting a healing response. Says Dr. Morrey: "We need better approaches to treating tendinopathies and tendon tears. With biologic approaches utilizing scaffolds, I believe we are one step closer to developing them."

Jun. 10, 2014