The Promising Future of Orthobiologics in ACL Surgery

Bert R. Mandelbaum, MD, DHL (Hon)

Disclosures

January 15, 2019

Surgeons often talk about repairing or reconstructing a torn anterior cruciate ligament (ACL), but those terms can be misleading. Fixing an ACL isn't like replacing a punctured car tire. The healing requires biological and biomechanical processes that we can influence but not control.

For this reason, I believe that orthobiologic interventions, such as platelet-rich plasma (PRP), will play an increasingly important role in treating these injuries.

Whether we take the torn edges of the ACL and sew them back together, or replace the damaged ligament with a graft, we are creating a scaffold. Stem and other cells gradually inhabit the tissue, regenerating collagen, blood vessels, and other components of a living tendon.

But along with the anabolic regeneration of the ligament, catabolic processes are taking place in the joint. They may help explain why 20% of people with ACL injuries suffer reinjury within 2 years.[1]

In this catabolic process, matrix metalloproteases and cytokines also cause degradation of cartilage. Long-term, between 60% and 90% of people with ACL injuries develop osteoarthritis of the knee, compared with 12% of the overall US population.[2]

That's why the ACL injury is not just a surgical problem, or biomechanical problem; it's a problem of facilitating homeostasis. There lies the opportunity for orthobiologics.

The Orthobiologic Advantage

Evidence for the opportunity to influence these biological processes even before surgery was provided in a randomized clinical trial by Christian Lattermann, MD, at the University of Kentucky, Lexington, and colleagues.[3] They found that increases in C-telopeptide of type II collagen, which is associated with collagen breakdown, were significantly greater in a placebo group than in groups that received injections of corticosteroids.[3]

The potential benefits of PRP are threefold. First, it may increase gene expression for growth factors. Second, it may enhance cell proliferation and angiogenesis. Third, it may summon the appropriate mesenchymal stem cells to the site of regeneration.[4] In this way, PRP may facilitate the early stages of graft remodeling, revascularization, and reenervation and maturation.

Most of the evidence for these changes comes from studies in animals. For example, in a porcine model of suture repair after ACL transaction, a scaffold was constructed of collagen hydrogel and PRP was added. The researchers documented significant improvements in joint stability and load at yield, and maximum load and linear stiffness at 4 weeks, compared with pigs that did not receive the PRP.[5]

The scaffold appears to play an essential role. In another study in pigs, suture repair after ACL transaction with PRP but no scaffold did not improve anterior-posterior knee laxity at 30° or 60°. Nor did it improve the maximum tensile load or linear stiffness or the ACL repairs.[6]

In a 2011 review, Martha Murray, MD, of Boston Children's Hospital in Boston, Massachusetts, found that PRP can be a favorable factor in terms of graft maturation and donor site morbidity.[7]

Other Avenues of Research

Whole blood might be as effective as PRP. In one of the few clinical trials of biologics for ACL injuries, Murray and colleagues[8] augmented a suture repair with a scaffold—the bridge-enhanced anterior cruciate ligament repair (BEAR)—placed between the torn ends of the ACL.

The BEAR scaffold is made of extracellular matrix proteins, including collagen, obtained from bovine tissue. (In animal studies, ACLs repaired with the BEAR scaffold have shown similar mechanical properties to bone-patellar tendon-bone allografts, and lower rates of osteoarthritis.) The researchers added 10 mm of autologous whole blood to the scaffold before wound closure.[8]

Patients treated this way didn't have any significant inflammation or infection, and MRI images showed a continuous ACL. Compared with patients grafted with hamstring, the patients treated with the repair and scaffold had significantly stronger hamstrings at 3 months.[8]

These studies don't provide enough evidence yet to demonstrate improved clinical outcome with orthobiologics for torn ACLs, but the work on this jigsaw puzzle is continuing. So far, the pieces all seem to fit; we just haven't gotten all of them out of the box.

Other orthobiologics are also showing promise in animal studies as well. In a rat model of an ACL injury, ACL-derived CD34+ cells were isolated from remnant human ACL tissues. They were virally transduced to express bone morphogenetic protein-2 and embedded within cell sheets wrapped around tendon autografts in the rats. This treatment improved histologic appearance, graft-bone interface biology, and tensile load to failure.[9] These significant biological effects in animals must be translated to human clinical evidence.

Personal Experience and Remaining Questions

In my own practice, we use PRP routinely and are studying its effects with MRI to assess the maturation of the graft as well as the clinical outcomes. So far, we find that at 3 months, over 90% of the grafts are mature. Without PRP, this process takes up to 12 months. We are now developing a randomized clinical trial to verify and elaborate on these preliminary findings.

But these are complex processes, and studies of PRP are challenging. They can't be organized like a traditional drug trial because of the tremendous variation from one case to another. Each patient receives PRP concentrated from their own blood. It differs from patient to patient with such factors as age, body mass index, diet, and use of nonsteroidal anti-inflammatory drugs.

Timing matters as well. In acute tendinopathies, there is a high concentration of white cells in the early phases of inflammation. Injecting PRP or stem cells too early may trigger undesired proinflammatory effects. Later injection may result in a desired immunosuppression and enhanced healing. On the other hand, the injection of these agents may also turn a chronic injury into an acute one, jump-starting the healing process.

Likewise, a study evaluating the use of bone marrow aspirate concentrate with MRI showed no change in the maturity of grafts.[10]

An Evolving Field

Which approach to ACL surgery will emerge as the best? Perhaps the best way to picture the future is by reflecting on the continual evolution of this field.

The first publication of an ACL repair dates back to 1902.[11] That year was a time of transition; photos from the period show streets with horses on one side and cars on the other. We were trying to figure out which was the best vehicle.

Now, 116 years later, we are evaluating whether gas, electric, or hybrid vehicles should predominate, just as we are assessing the merits and outcomes of ACL repair versus reconstruction in conjunction with PRP, whole blood, corticosteroids, and even stem cells.

I'm confident that these innovations will provide further harmonization and continued stepwise improvements in the prognoses of our patients. We must control the variables we can in order to adapt to the ones we cannot.

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