Research continues into possible use of PRP, tissue engineering
Surgical repair of anterior cruciate ligament (ACL) tears has a high rate of poor outcomes and failures—with a nonunion rate of 90 percent. For this reason, ACL reconstruction, using a patellar tendon or hamstring graft, is the standard treatment.
But why is the ACL such a poor healer? Certain other ligaments, including the medial collateral ligament (MCL), heal uneventfully without surgery. Could the difference have to do with biologic factors in the joint?
In a torn MCL, a blood clot forms at the tear site, leading to a proliferation phase of collagen production that results in remodeling and restoration of strength and function (Fig. 1). In the torn ACL, clot formation never initiates, and subsequent healing does not occur, so that repair procedures are ineffective.
According to researcher Martha M. Murray, MD, of Children’s Hospital Boston and Harvard Medical School, management of ACL injury by repair rather than reconstruction would, if successful, have the theoretical advantages of preserving anatomy, physiology (eg, nerves and intrinsic cells), and some biomechanics.
Dr. Murray and colleagues have conducted experiments to determine why the healing response is so different in intra- and extra-articular ligaments, and they are applying their findings as they test the effects of tissue-focused therapies and agents, such as platelet-rich plasma (PRP) and collagen. She shared the results of their research during an instructional course lecture at the 2010 AAOS Annual Meeting.
A needed bridge
Scaffold failure in a torn ACL seems to be the product of the joint environment. As far back as the 1960s, researchers found that blood clots dissolve in synovial fluid. Dr. Murray notes that both genetics and evolution may be contributing factors.
Because synovial fluid prevents the formation of a fibrin-platelet clot in the wound site, today’s researchers and surgeons are faced with the challenge of achieving healing in the joint. Finding a substitute clot could be the answer to enhanced ACL healing.
One option might be collagen-fibrin scaffolds, made by combining the patient’s blood with a collagen scaffold. The fibrin in the blood plasma and the added collagen could form a copolymer that cannot be broken down quickly by the normal enzymes in the synovial fluid. Collagen also activates platelets, which early in wound healing release growth factors that engage the healing process, Dr. Murray says (Fig. 2).
A sticky issue
Although PRP has shown effectiveness when used for certain conditions, its liquid consistency makes it difficult to use in anatomic locations without natural compartments.
“Being liquid is helpful if the PRP is injected into a closed space, as for lateral epicondylitis, where the concentrate is in a small area and will remain there. In the knee joint, a liquid may not stay where it is needed,” Dr. Murray says. Adding thrombin to PRP results in a stickier mass, so researchers have studied a mixture of thrombin, PRP gel, and collagen. In vitro results were so poor, however, that the investigators did not even try the mixture in animals.
It may be some time before a formulation involving PRP and collagen can be used to heal, rather than replace, ruptured ACLs in humans, Dr. Murray says. Meanwhile, in vivo testing is continuing. In large-animal (pig) models, she says, collagen-platelet scaffolding has promising 3-month data. Longer-term studies in large animals will begin this summer and yield results in about 2 years.
Dr. Murray acknowledges that efficacy “can be difficult to show, especially with the ACL, where the early results of reconstruction look very good. Going to repairs is a pretty big jump, and we would really need to show that tissue-engineered primary repairs are as good as—if not better than—reconstruction before we can recommend that transition for patients. We are constantly trying to develop the best suturing techniques—what kind of suture to use, where to put the suture—and to improve the scaffolding. We are making progress and working to be better.”
Although the eventual clinical verdict is uncertain, Dr. Murray believes in pursuing therapy options arising from both a tissue- and cell-based approach.
“I’m ever hopeful,” she says. “Some day we’re going to look back and say, ‘People tore their ACL and we did what? We took out the ACL, then took out their hamstring tendons and put those through bone tunnels to replace the whole ACL? Why didn’t we just make the broken part of the ligament heal with tissue engineering like we do with everything else now?’
“I think the future is in regeneration and repair for a lot of things, not just the ACL. Hopefully, as the science for repair and regeneration advances in a variety of wound healing areas, we as orthopaedists will be able to take advantage of that new knowledge and apply it to some of our toughest problems—rotator cuff repair, meniscus repair, and cartilage repair,” she says.
A mixed record of success
PRP is being used clinically in a number of practices, with a mixed record of success to go with the publicity it has garnered.
Dr. Murray, who does not use PRP in her knee-focused practice, notes that for an injury such as an acute tear of the Achilles’ tendon, some studies have not found PRP to be very helpful “because there are already platelets at the injury site.”
In the more common chronic lateral epicondylitis resulting from an old injury, however, PRP may be quite beneficial. “There’s no inflammation, nothing to get the healing process going. In that tendinosis type of picture, platelets may be helpful because they may restart the wound healing cascade in a place where it’s been burnt out,” says Dr. Murray.
With a stabilizing carrier like collagen, she says, PRP may even be useful in the management and prevention of osteoarthritis. The treatment challenge is similar to that of ACL tears in terms of mechanism.
“With OA, we think what happens is that the cartilage cracks over time,” she says. “The cracks don’t heal because the cartilage cells can’t bridge and close them. I hope we could someday resurface the cartilage with biologic scaffolds, providing a place for the surrounding cells to invade and produce new cartilage.
“We know the cartilage cells are active, even in bad osteoarthritis,” she continues. “For example, a piece of osteoarthritic cartilage cultured in a Petri dish will give rise to millions of cells within a couple of weeks. If we could give those cells a bridge across a defect to remodel, I think we could get improved cartilage regeneration.”
The use of PRP in ACL reconstruction has been controversial. A recent Chilean study found that applying PRP to both the bone tunnels and graft reduced the time to obtain a completely homogeneous intra-articular magnetic resonance image (MRI) result to less than half that required for the non-PRP group.
Another Chilean study, presented at the 2010 AAOS Annual Meeting, detected no clinical or functional benefit from the use of PRP in ACL reconstruction, although it did report possibly better maturation.
According to Dr. Murray, “We don’t have a good idea of what a very functional graft looks like on MRI. A really dark area may be either a functioning ligament or just dead collagen. A light area may be vascularity showing a living, remodeling ligament or fluid due to impingement and inflammation. Some studies may indicate healing on MRI, but we don’t yet know what MRI changes mean in terms of graft strength or function.”
As for other challenging applications, Dr. Murray notes that for the rotator cuff, when PRP was used on the joint side and exposed to synovial fluid, results were poor. When it was used on the bursal side, results were better. A number of factors determine effectiveness, she says.
“It’s very complicated in the joint because for tissues like meniscus, rotator cuff, and ACL, not only do we have to look at the PRP characteristics—platelet count, white blood cell count, activator choice—we also need to consider if the material will be exposed to synovial fluid and subject to premature dissolution after it is applied,” she explains. “In that case, such as in a study of PRP laid over an ACL reconstruction, a reported lack of any effect may be due to early loss of the PRP clot.”
In conclusion, she says, “I would be cautious about using PRP to treat injuries inside of joints. It may be more useful when you can combine it with a carrier to stabilize it in the synovial environment.”
She advises orthopaedic surgeons to ask for data on the specific PRP product they are using, or a product with similar platelet cell concentration, white cell concentration, and activator.
“Clinicians can help our understanding of these new biologics by studying the outcomes in their patients for the procedures they are performing,” she says. “That is where clinicians can truly help advance this emerging field.”
Disclosure information for Dr. Murray—Connective Orthopaedics.
Terry Stanton is senior science writer for AAOS Now. He can be reached at firstname.lastname@example.org
- Injured intra-articular tissues such as the ACL do not heal because of a lack of wound site bridging. Synovial fluid in the joint dissolves the fibrin-platelet clot and prevents bridging.
- Combining PRP with a collagen scaffold enables the fibrin in the blood plasma and the added collagen to form a copolymer that the normal enzymes in the synovial fluid can’t quickly break down.
- PRP has demonstrated efficacy and benefits when applied for chronic conditions such as chronic lateral epicondylitis.
- The benefit of PRP applied in ACL reconstruction has not been demonstrated.
Radice F, Yánez R, Gutiérrez V, Rasales J, Pinedo M, Coda S: Comparison of magnetic resonance imaging findings in anterior cruciate ligament grafts with and without autologous platelet-derived growth factors. Arthroscopy 2010;26:50-57.
Figueroa D, Meleán P, Calvo R, Vaisman A: Effects of platelet rich plasma in hamstring anterior cruciate ligament reconstruction. Presented at the American Academy of Orthopaedic Surgeons Annual Meeting, New Orleans, March 9-13, 2010.