by Jackie Swift
If you’ve ever had a tendon injury, you know how debilitating that can be and how long it takes to heal. In fact, although you may have eventually gone back to your usual physical activity, the injury site is probably still weak. “Once a tendon is injured, it almost never fully recovers,” says Nelly Andarawis-Puri, Sibley School of Mechanical and Aerospace Engineering. “You’re likely more prone to injury forever. Tendons are very soft tissues that regularly transmit very large forces to allow us to achieve basic motion. They insert into stiff bone, which is a huge property mismatch. That interface is very complex.”
Andarawis-Puri studies tendon injuries in an attempt to understand how wear and tear develops in the tendon and how to successfully heal the damage. “It’s a very real problem. Thirty percent of all people will have a tendon injury, and the risk is higher in women,” she says.
Tendons are prone to injuries caused by overuse. Athletes, factory workers, military personnel, and others who engage in repetitive motion are at greater risk of experiencing a torn or ruptured tendon. “Any biological attempt your tendon exhibits to try to repair this induced damage is far outpaced by your capacity to accumulate further damage,” Andarawis-Puri explains. “As you injure your tendon, you’re going to accumulate more and more injury before any sort of repair happens, which is how you eventually end up with a rupture.”
With funding from the National Institutes of Health, Andarawis-Puri and her lab are carrying out a number of projects investigating the mechanisms behind tendon damage and healing. In one line of research, they are using animal models to understand the role played in healing by loading, which is representative of physical therapy (PT). PT is often prescribed as a clinical treatment for tendon injuries, but it can sometimes aid in healing while at other times it can subject the damaged tendon to an increased risk of further injury. Recently Andarawis-Puri and her colleagues made an important discovery: the timing of the start of physical exercise is crucial to whether the injury heals or becomes worse. “If you initiate exercise one day after the onset of injury, you further exacerbate it,” she says. “You get further degeneration. But if you start the exercise two weeks after the injury, you get repair of the damage.”
Tendons are a band of fibrous material primarily made up of collagen, which forms a hierarchical extracellular matrix (ECM) that provides structural and biochemical support to cells. When tendons are injured, their structure changes. Instead of straight lines, their collagen becomes kinked. “We found that you end up with a lot more of these kinks if you start exercising one day after injury,” Andarawis-Puri says. “There are many other changes in the tissue as well. There are certain proteins indicative of tendinopathy — the disease state that results from accumulation of sub-rupture damage — which are increased, too. On the other hand, many of the proteins are modulated back to naive levels when you start exercise two weeks later. This tells us that something about how the ECM regulates the cells that live within it differs one day after injury versus two weeks after.”
“As you injure your tendon, you’re going to accumulate more and more injury before any sort of repair happens, which is how you eventually end up with a rupture.”
Why good or bad outcomes are tied to the timing of the start of exercise is still unknown, but Andarawis-Puri does know that exercise begun two weeks after injury decreases cell death in the ECM and increases the population of myofibroblasts, a cell type known to help with wound healing. “Myofibroblasts can apply tension to the ECM and that contracts a wound and causes it to close up,” she says. “We’ve shown that there is an increase in myofibroblasts in this entirely different context — when you have remodeling of the tendon from exercise. That potentially explains what happens to our kinks. It’s possible the myofibroblasts physically straighten them out.”
In another line of research, the Andarawis-Puri Lab is investigating how to promote the scarless healing of tendons. “For a tissue that plays such an important role in the governing mechanics of the body, scarring is a horrible thing,” Andarawis-Puri says. “Once it is scarred, tendon tissue doesn’t have the mechanical properties it once had. It can’t bear the same types of loads. The mismatch of properties between tendons and bone really becomes a problem because the tendon doesn’t have the native structure any more. It’s very much prone to re-rupture.”
Using a strain of inbred mouse model that naturally exhibits regenerative abilities known as the Murphy Roths Large (MRL) mouse, the researchers are trying to understand and promote scarless healing in ruptured tendons. MRL mice models are a mystery. Scientists don’t know why these mice models as adults are able to regenerate certain tissues that other strains of mice models can’t. One hypothesis is that the healing ability is tied to the systemic environment, that is, the entire body plays a part in the process. Andarawis-Puri and her collaborators have a counter hypothesis. They hypothesize that each individual tissue with regenerative abilities within the mouse model — including tendon tissue — has the ability to regenerate regardless of the systemic environment. To investigate this, they have initiated a series of projects. In one, they have organ-cultured MRL tendons in the lab to see how the tendons filled missing sections. “They filled in the collagen differently than would tendons from a normal healer mouse strain,” Andarawis-Puri says. “They filled in more completely and more aligned outside of any systemic environment. That tells us there’s a blueprint in the tissue that tells these cells how to lay down their ECM and how to heal in this more aligned fashion. More aligned means there’s no scar.”
Investigating More Ways of Repair
In another project, Andarawis-Puri and her colleagues are swapping injured tendons between regular healer and MRL mice models to see how the tendons heal when they are in the different systemic environments. In yet another, they are seeding cells from the tendons of normal healer mice models onto decellularized tendons from MRL mice models to see if the tendon matrix from the MRL tendon can reprogram the cells from the normal healer and prompt them to lay down matrix in a regenerative manner. If so, this may be a key step to advancing tissue engineering approaches for humans.
“The question is, when tendon injuries do occur, can we promote some sort of effective repair?” Andarawis-Puri says. “That could be in conjunction with surgery to improve patient outcomes, or it could be instead of surgery. It would be great if we could just inject something — say, a cocktail of growth factors — that would actually tell your cells how to lay down good matrix to ultimately produce scarless healing.”