Donated, freeze-dried tendon grafts loaded with gene therapy may soon offer effective repair of injured tendons, a goal that has eluded surgeons to date. The new graft technique may provide the first effective framework around which flexor tendon tissue can reorganize as it heals. Such tissue-engineering approaches could significantly improve repair of anterior cruciate ligaments and rotator cuffs as well, researchers said. The study was in a mouse model designed to resemble hard-to-repair flexor tendons in human hands, and the results should provide an impetus for future clinical trials.
Tendons are elastic cords that anchor muscle to bone and enable flexing muscle to move limbs. Related injuries represent nearly half of 33 million U.S. orthopaedic injuries each year, and a frequent cause of emergency room visits. In many standard repair attempts, surgeons implant an autograft, a piece of tendon from elsewhere in the same patient. Along with requiring patients to sacrifice tendon, the problem with “live” autografts is that both the graft and the graft site “know” they have been injured. That signals immune cells and chemicals to rush into the graft site, seeking to fight infection. Unfortunately, those same processes cause inflammation and scarring, which in turn cause implanted tendon to stick to the joint. To work properly, the tendon must be free to glide across the joint. Tendon adhesions, a longstanding post-surgical problem, cause pain and permanently limit range of motion.
Researchers next experimented with allografts: tendons donated from one person to another. Clinically, this technique fared worse than autografts because patients’ bodies would recognize the donated tendon as foreign, attempt to wall it off with fibrous proteins, and in some cases reject the transplant. The field then looked at whether synthetic scaffolds made of gel or fiber mesh could serve as alternatives. Theoretically, such materials would guide damaged tissue as it reorganizes into healthy tendon without causing an immune reaction. They could be coated with anti-inflammatory drugs, growth factors, or gene therapy vectors to drive healing and reduce swelling. Unfortunately, artificial grafts too failed to yield useful tendon substitutes because they did not match the mechanical strength of human tissue.
A research team from the University of Rochester Medical Center explored yet another option: the implantation of allografts (donated, freeze-dried tendon) loaded with gene therapy. Their results in mice show that the allografts served as effective tissue-engineered scaffolds, with significantly fewer adhesions than seen with autografts. The allografts also sucked up, and delivered into the graft site, a solution of gene therapy vectors that directed the recipient’s cells to accept the graft and remodel it into living tissue.
“Orthopaedic surgeons have been searching for the perfect material to replace tendon, one with the right mix of strength and elasticity and would not cause adhesion,” said Hani Awad, Ph.D. (pictured), assistant professor of Biomedical Engineering and Orthopaedics within the Center for Musculoskeletal Research at the Medical Center. “We believe the only material to meet these strict requirements is non-living, but structurally intact tendon. We were surprised to find that no one had tried combining it with gene therapy or other drug delivery techniques to overcome its limitations,” said Awad.
“Tendon is very durable,” said Regis O’Keefe, M.D., Ph.D., chair of the Department of Orthopaedics and Rehabilitation at the University of Rochester Medical Center. “It could conceivably be freeze-dried, thawed, and then freeze-dried again without damaging it. It could be left on shelves at tissue banks indefinitely and then shipped long distances. To get it ready for surgery, you would thaw it in a solution containing growth factors, cut it to size on the spot, and implant it. While we acknowledge that this work is in mice, that there are differences between species and that more work needs to be done, we believe these results promise practical yet dramatic improvements in reconstructive surgery.”
Illustration: University of Rochester Medical Center.
Univeristy of Rochester Medical Center News Release (01/08/08)
Science Daily (01/10/08)
Medical News Today (01/09/08)
Abstract (Molecular Therapy, online publication, 8 January 2008)