April 2006
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Research
Growth-factor-rich gel regenerates torn ACLs
Children's Hospital Boston orthopedic surgeon Martha Murray, MD, may have found a better fix for tears to the anterior cruciate ligament (ACL). These poorly healing knee injuries are epidemic among girls who play jumping/pivoting sports like soccer and basketball. Treatment currently involves replacing the torn ACL with a tendon graft, but this painful operation does not fully restore knee mechanics. In the April Journal of Orthopaedic Research, Murray and colleagues report that an enriched collagen gel can stimulate natural ACL healing.
Examining ACL tears at the microscopic level, Murray was surprised to find a vigorous healing effort—cells migrated to the wound, growth factors were secreted and blood vessels grew. Yet the ligament ends never joined. Then Murray noticed that after most ligament tears, a blood clot forms, providing a temporary bridge that cells can crawl onto to begin the healing process. But in ACL injuries, fluid inside the knee joint dissolves the clot, so this bridge never forms. "The ACL cells are happy to participate in the repair process, but there's no place for them to do it," Murray explains.
So Murray's team developed a bridging material that isn't readily dissolved: a mixture of collagen hydrogel and platelet-rich blood plasma. Working with animals, they inserted this gel into the site of the ACL tear. Platelets in the gel churned out growth factors, and at six weeks, knees treated with the gel showed more tissue healing (43 percent vs. 23 percent) and a greater increase in ligament strength (40 percent vs. 14 percent when compared with untreated knees.
Murray hopes to eventually take her regeneration technique to the clinic. With funding from the NIH, the National Football League and the Center for Minimally Invasive Technology, she is developing an arthroscopic approach that would squirt the gel into the wound via two small incisions in the knee. If all goes well, the result will be a less invasive ACL repair, decreasing recovery time and giving athletes a knee with more normal function.
David Zurakowski, PhD, in Children's Department of Orthopedic Surgery, was senior author of the study.
New view of asthma may offer a better treatment target
Dale Umetsu, MD, PhD, and Omid Akbari, PhD. A newly recognized type of cell may play an important role in asthma, perhaps explaining why current therapies sometimes fail, report Dale Umetsu, MD, PhD, and Omid Akbari, PhD, in Children's Hospital Boston's Division of Immunology. A study in asthma patients, published in the March 16 New England Journal of Medicine, provides the latest evidence that immune cells, known as natural-killer T (NKT) cells, are key in asthma's development.
Previously, conventional CD4+ T lymphocytes—specifically, type 2 helper (Th2) cells—were believed to cause the inflammatory process that is central to asthma. Th2 cells are the target of corticosteroids, the mainstay of asthma therapy, but these drugs don't always work.
In 2003, while at Stanford University, Umetsu and Akbari showed that in mice, asthma development requires the activation of NKT cells: animals without NKT cells did not develop airway hyperreactivity, a cardinal feature of asthma. In February 2006, Umetsu and Stanford graduate student Everett Meyer further showed that NKT-cell activation can cause asthma in mice even when Th2 cells are completely absent.
Intrigued, Umetsu and Akbari decided to study human patients. They examined lung specimens from 14 adults with moderate-to-severe bronchial asthma, and found that, on average, at least two-thirds of the patients' pulmonary T cells were NKT cells, not conventional Th2 cells. In contrast, NKT cells were virtually absent in six healthy controls and in five patients with sarcoidosis (a respiratory inflammatory disease marked by high lung levels of CD4+ T cells).
"Conventional Th2 cells may not be as important in causing asthma as was thought," Umetsu says. "If we can specifically eliminate NKT cells, we should be able to treat asthma more effectively."
Interestingly, NKT cells produce the same chemical messengers as Th2 cells, but induce asthma more rapidly and directly. They also seem to be triggered by a unique class of antigens known as glycolipids, whose origins are still unknown.¬Ý"Most of the focus in asthma has been on protein antigens," Umetsu says. "This finding opens a whole new area of research."
Rosemarie DeKruyff, PhD, also from Immunology, collaborated on the study.
