"This is a first important step in showing that the ACL can heal if we give it the right conditions," Murray says. "That's an important shift from thinking that the ACL has to be completely replaced after an injury."
ACL injuries are notorious for not healing well. Epidemic among teenage girls – who are five times likelier than boys to tear the ligament – they typically occur during sports that involve jumping and pivoting, like soccer or basketball. ACLs are currently reconstructed by replacing the torn ligament with a tendon graft. This painful operation allows patients to return to sports after significant rehabilitation, but it does not fully restore knee mechanics, and does not prevent arthritis from developing years later.
Working with an animal model of a partial ACL tear, Murray's team inserted a collagen gel, mixed with platelet-rich blood plasma, into the wound. The gel provided a physical "bridge" between the torn ligament ends, while the platelets churned out a variety of growth factors. Compared with untreated knees, knees treated with the gel showed greater defect filling at 6 weeks (43 percent versus 23 percent). The gel-treated ACL defects also had a 40 percent increase in mechanical strength at 6 weeks, compared with just 14 percent for untreated defects.
Although she cautions that these results are preliminary and that more work needs to be done, Murray hopes to eventually extend her ACL regeneration technique to human patients, using platelets from their own blood plasma to create a less invasive ACL repair that would decrease recovery time and give athletes a knee with more normal function. With funding from the NIH, the National Football League, the Orthopedic Research and Education Foundation and the Center for Minimally Invasive Technology (Cambridge, Mass.), she is developing an arthroscopic approach that would squirt the gel into the wound via two small incisions in the knee. Her team is also trying to enhance the gel to speed the healing process.
Until the 1970s, surgeons tried to repair ACL tears by sewing the ligament ends back together, but the sutures nearly always failed. Murray, who became interested in ACL healing while pursuing a doctorate in materials science, wondered why this was so, and eventually went to medical school to pursue the problem. Ligaments should, in theory, heal easily--they're made of fibroblast cells, which are workhorses in the body and easy to grow.
Examining torn ACLs at the microscopic level, Murray and colleagues were surprised to find that the ligament tries valiantly to heal itself--cells migrate to the wound, growth factors are secreted and blood vessels grow to nourish the new tissue. But the ligament ends never join. What's missing, Murray realized, is something to bridge the gap.
In most torn ligaments, a blood clot forms and acts as a temporary scaffold or bridge. Cells migrate onto this bridge and begin fusing the ligament ends together. But in ACL injuries, fluid inside the knee joint dissolves the clot, so a bridge never forms. Most other ligaments, like the knee's medial collateral ligament (MCL), are outside the joint and don't have this problem.
"Even though ACL cells are happy to participate in the repair process, there's no place for them to do it," Murray says. "Our big finding was recognizing that the cells are fine--they just need a bridge that they like."
After trying various materials, her team found that the collagen hydrogel, mixed with platelet-rich blood plasma, was firm enough to be used as a bridge and wasn't readily dissolved by joint fluid.
In the future, Murray hopes to extend her technique to other injuries like meniscus and rotator-cuff tears. Her ultimate dream is cartilage regeneration to repair joints damaged by osteoarthritis. No one has yet been able to repair cartilage, but Murray has discovered that even in bad osteoarthritis, cartilage has active, proliferating cells. She hopes to find another scaffolding material that would coat the pitted surface of damaged cartilage and recreate a smooth, nearly friction-free surface--like filling in potholes in a road.
"The cells are trying to find structure, but they just don't have it," Murray says. "They need a thing to move into; a place to live."
The current study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Football League, the Orthopedic Research and Education Foundation and the Orthopaedic Foundation of Children's Hospital Boston.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, nine members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 347-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: http://www.childrenshospital.org/research/.
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