Biologics are becoming increasingly popular in the field of orthopaedics for nonsurgical management or as an adjunct to surgical treatments. Media attention to platelet-rich plasma (PRP)—an autologous blood derivative that isolates high concentrations of platelets and is rich in multiple growth factors and cytokines—has given this treatment a starring role.

But does the evidence support the multiple touted uses for PRP? This two-part series will identify and objectively present the current evidence in determining the most appropriate roles for PRP in today's orthopaedic armamentarium. This article will focus on the composition of PRP and its application to the treatment of osteoarthritis, fractures and anterior cruciate ligament (ACL) reconstruction; the second article will examine its use in treating cartilage, muscle and tendon injuries.

Background
Separately, the growth factors and cytokines in PRP play important roles in hemostasis, construction of new connective tissue, revascularization, cellular recruitment, and inflammation modulation. The most significant of these factors include the following:

• platelet-derived growth factor (PDGF)
• transforming growth factor beta (TGF-β)
• fibroblast growth factor (FGF)
• insulin-like growth factor 1 (IGF-1)
• connective tissue growth factor (CTGF)
• epidermal growth factor (EGF)
• vascular endothelial growth factor (VEGF)

After injury, these factors are released in a span of time from within minutes up to days. In addition, the fibrin, fibronectin, vitronectin, and thrombospondin found in PRP can attract other cells—including osteoblasts, fibroblasts, and epithelial cells—that are active in the healing process.

The optimal platelet concentration, in a therapeutic PRP formulation, is thought to be between three and five times that of whole blood. A higher concentration of platelets has been found to inhibit healing.

In addition to the platelets in the solution, the amount of leukocytes in the solution has also been reported to influence its activity. Additionally, in vitro analyses have found increased growth factor availability, specifically TGF-β1, in platelet-rich fibrin constructs as compared to naturally occurring clots.

The proposed function of PRP is to promote tissue healing by increasing extracellular matrix deposition, reducing pro-apoptotic signals, and minimizing joint inflammation. PRP is an attractive therapeutic option because it is readily available, versatile, safe, and is permitted for use in athletes; however, numerous questions revolve around its clinical applications and efficacy.

Despite an expanding body of literature on appropriate uses of this novel therapy, high quality investigations sufficiently powered to illustrate long-term clinical benefits of PRP are scarce, and studies often report conflicting results. Furthermore, when comparing these studies, the preparation, activation, delivery, and dosing schedule of PRP are not uniform.

PRP may be prepared by one or a combination of processes, including gravitational (centrifuge), filters, and/or cell separation devices. Each method has its advantages and yields a different concentration of PRP. As a result, great variability can be found in the final concentration of platelets and bioactive molecules delivered, and no consensus exists on which method produces the best product for a specific clinical use. The differences also influence the overall regenerative potential of the PRP used in various investigations, making direct comparison difficult. Finally, the direct concentration of PRP cannot always be quantified or determined due to the biologic variation among individuals.

The use of PRP has been studied in osteochondritis dissecans of the knee and talus, osteoarthritis, delayed union and nonunion fracture care, ACL reconstruction, rotator cuff repair (RCR), various tendinopathies, as augmentation to microfracture procedures and in the form of intra-articular injections. Despite these numerous investigations, comparative clinical trials and meta-analyses, the appropriate clinical applications of PRP have yet to be determined.

In 2011, AAOS Now hosted a forum attended by 50 of the most experienced clinicians and scientists in the field, recognizing that PRP has rapidly become an important topic and application in modern orthopaedic practice. The World Anti-Doping Agency does not prohibit the use of PRP in the treatment of world-class athletes, stating that "platelet-derived preparations were removed from the Prohibited List as current studies on PRP do not demonstrate any potential for performance enhancement beyond a potential therapeutic effect."

Osteoarthritis
Osteoarthritis (OA) accounts for nearly one-quarter of all outpatient primary care visits and 50 percent of all NSAID prescriptions, affecting nearly 27 million people in the United States. In 2011, it was the second most expensive condition seen in U.S. hospital stays with an aggregate cost of nearly $15 billion, making it a highly desirable area for clinical research and a focus of biologic administration.

In evaluating the head-to-head comparison of intra-articular PRP injection versus hyaluronic acid (HA) viscosupplementation at 12 months, clear benefit has been identified in younger patients' subjective pain and clinical outcome scores. However, the results were not as convincing in the older patient population with moderate-to-severe OA. When Rodriguez-Merchan et al identified 20 studies of intra-articular injections of PRP for knee OA, in contradistinction to previous suggestions of efficacy in prevention of OA progression, they concluded that "presently there is no clear evidence from well-designed clinical trials that intra-articular injections of PRP are efficacious in osteoarthritis."

A recent comprehensive systematic review by Khoshbin et al evaluated six Level 1 and II studies. There were four randomized controlled trials (RCT) and two prospective nonrandomized studies evaluating intra-articular PRP injection as compared to HA and normal saline (NS). The analysis was well-powered, with 577 patients with mean age of 56.1 years (PRP) and 57.1 (HA and NS) years. At 6-month follow-up, both objective outcome measures of the Western Ontario and McMaster Universities Arthritis Index scale and the International Knee Documentation Committee scores favored PRP to HA and NS as a treatment modality for symptomatic knee OA. However, they found no significant differences in the patients' visual analog scale (VAS) or overall satisfaction scores.

The evidence
The current literature suggests that intra-articular PRP injections may have beneficial effects in the treatment of adult patients with mild-to-moderate knee OA as well as in younger patients with mild OA as compared to HA or NS. Due to a lack of consensus in evidence and the paucity of studies reporting on long-term follow-up, however, the determination of efficacy of PRP requires further investigation to allow for more appropriate treatment recommendations.

Fracture care and fusion
Although PRP has shown promising osteogenic properties in various in vitro studies, the jury is still out regarding its clinical efficacy in promoting fracture or fusion healing. One Level III study by Tsai et al and a retrospective study of 76 patients by Carreon et al evaluating PRP in lumbar fusion found no difference in nonunion rates.

Additionally, the role of thrombin as an adjunct to PRP therapy has become an interesting topic of debate given thrombin's observed effect of inducing platelet secretion of various growth factors. And yet, some data suggest that PRP-thrombin therapy may actually be detrimental to osteo-inductivity and bone formation. Historically, Weiner and Walker demonstrated that the use of autologous growth factors from PRP decreased fusion rates compared to isolated iliac crest bone graft for single-level lumbar fusions.

The evidence
Limited evidence exists demonstrating efficacy for bone formation, with some studies suggesting detrimental effects.

ACL reconstruction
Most biomechanical and clinical studies of ACL repair have focused on tunnel placement, graft selection, single versus double-bundle, graft-tunnel fixation, etc. The biologic environment must also be taken into account. The ACL has poor vascularity and its largely intra-articular location subject it to synovial fluid proteases. Together, these factors create a less than favorable environment for tissue healing.

A number of studies have attempted to use magnetic resonance imaging (MRI) to evaluate ACL grafts with and without PRP augmentation. A prospective single-blind study and one RCT reported faster ACL graft maturation in grafts augmented with PRP, as signified by lower intensity signal on MRI. Additionally, a comprehensive systematic review of eight RCTs reported a 20 percent to 30 percent acceleration in graft maturation.

Recent data from the Multicenter Orthopaedic Outcomes Network (MOON) cohort study does not support the use of PRP in allograft reconstruction, as the researchers reported no difference in patient-reported outcomes at 2-year follow-up. Although much of the biologic study has focused on autograft and allograft augmentation via PRP to support ligamentization and bone-graft interface healing, some early reports suggest improved patient-reported outcomes and MRI evaluation with PRP application directly into the patellar and tibial bone plug harvest sites following ACL reconstruction using bone-patellar tendon-bone autograft. Cervellin at al reported higher Victorian Institute of Sport Assessment questionnaire scores at 12-month follow-up in patients treated with PRP. An additional randomized study by de Almeida et al reported improved postoperative VAS scores and a decreased patellar tendon gap area via MRI analysis at 6 months following patellar-tendon graft harvest.

The evidence
The literature does not support a clear benefit for the use of PRP with regard to ligamentization, graft maturation, and patient-reported outcomes, as there is conflicting Level-1 evidence regarding its efficacy. Current evidence does, however, suggest that direct application of PRP into the patellar and tibial plug donor sites is linked to improved patient-reported outcomes of knee function and decreased patellar tendon gap. Further study is needed to evaluate larger RCT cohorts with longer term follow-up and uniform application of PRP.

Robert L. Parisien, MD, is an orthopaedic surgical resident at Boston University Medical Center in Boston, MA. He can be reached at robert.l.parisien@gmail.com

David P. Trofa, MD, is an orthopaedic surgical resident at Columbia University Medical Center in New York, NY. Jesse Dashe, MD, is an orthopaedic surgical resident at Boston University Medical Center. Scott F.M. Duncan, MD, MPH, MBA, is chairman of the Department of Orthopaedic Surgery at Boston University Medical Center and a member of the AAOS Now editorial board.

Bottom Line

• The proposed function of PRP is to promote tissue healing by increasing extracellular matrix deposition, reducing pro-apoptotic signals, and minimizing joint inflammation.
• Intra-articular PRP injections may benefit adult patients with mild-to-moderate knee OA as well as younger patients with mild OA, but more study is needed.
• Limited evidence demonstrates efficacy of PRP for bone formation, with some literature suggesting detrimental effects.
• The literature does not support a clear benefit for the use of PRP with regard to ligamentization, graft maturation, and subjective patient-reported outcomes in ACL surgery.
• Current evidence suggests direct application of PRP into the patellar and tibial plug donor sites in ACL reconstruction is linked to improved patient-reported outcomes of knee function and decreased patellar tendon gap.

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