Can PRP effectively treat injured tendons?

Summary

PRP is widely used to treat tendon and other tissue injuries in orthopaedics and sports medicine; however, the efficacy of PRP treatment on injured tendons is highly controversial. In this commentary, I reason that there are many PRP- and patient-related factors that influence the outcomes of PRP treatment on injured tendons. Therefore, more basic science studies are needed to understand the mechanism of PRP on injured tendons. Finally, I suggest that better understanding of the PRP action mechanism will lead to better use of PRP for the effective treatment of tendon injuries in clinics.

Recent increases in the popularity of sports and the use of computers has created a rise in tendon injuries in both athletic and occupational settings. Tendon injuries, both acute and chronic (or tendinopathy), lower the quality of life of affected individuals and increase the costs of health care. Because injured tendons undergo a slow and incomplete healing process and often form scar tissue after healing, they are susceptible to re-injury1. Thus, restoring the normal structure and function to injured tendons remains one of the greatest challenges in orthopaedics and sports medicine.

In recent years, physicians in the orthopaedics and sports medicine field have adopted platelet-rich-plasma (PRP) to treat injured tendons and other tissues2. PRP is the plasma fraction of the blood; it contains concentrated platelets and, in many cases, white blood cells (WBCs). PRP is autologous and therefore considered to be inherently safe; it provides a natural conductive scaffold, and is a reservoir of many growth factors (e.g. PDGF, TGF-β, VEGF, and HGF), which can enhance healing of injured tissues including tendons3,4. However, no study has thus far demonstrated the exclusive role of PRP growth factors in enhancing tissue healing, and the role of other molecules should also be considered5.

PRP has been shown to effectively treat acute and chronic tendon injuries6–9; however, little or no effect was also reported by others when PRP was used to treat similar conditions10–12. The current controversy over PRP’s efficacy may be best addressed by basic science studies performed on cellular and animal models under well-controlled conditions. These models may include RNA silencing in vitro and gene knock-out or knock-down in mice in vivo to address specific functions of individual molecules contained in PRP. For example, a novel transgenic strategy has been recently developed to induce gene knock-down in platelets, which will allow characterization of genes involved in platelet production and the function of platelets in mice13.

In two of our recent studies, we investigated the effect of PRP on tendon stem/progenitor cells (TSCs) using a cell culture model14 and also determined the anti-inflammatory effects of PRP on tendon inflammation using both culture and animal models15. In the first study we aimed to test whether PRP treatment can promote tendon healing14. For this, we prepared PRP using methods that minimized the amounts of leukocytes and named it as the ‘PRP-releasate’. Our results showed that treating TSCs with PRP-releasate induced TSC differentiation into active tenocytes, which proliferated quickly and produced abundant collagen, indicating the potential of PRP to enhance the repair of injured tendons. Additionally, PRP did not induce non-tenocyte differentiation into chondrocytes, adipocytes, or osteocytes16, suggesting that PRP treatment does not increase the risk of nontendinous tissue formation in treated tendons.

In the second study15, we demonstrated that PRP’s anti-inflammatory function is mediated via HGF contained in PRP by suppressing the levels of prostaglandin biosynthetic pathway components (COX-1, COX-2, and mPGES-1 expression) and PGE₂ production. These results were corroborated by our animal model studies where PRP injections (which may contain small amounts of leukocytes due to difficulty in removing all these cells from a small volume) reduced COX-1 and COX-2 protein expression and lowered PGE₂ levels in the wounded Achilles tendons of mice. These results have clinical implications; high levels of PGE₂ are known to cause pain17–19, decrease cell proliferation and collagen production20, cause aberrant differentiation of TSCs into non-tenocytes21, and induce degenerative changes in rabbit tendons22. Therefore, PRP’s ability to reduce PGE₂ production is expected to benefit the healing of injured tendons. Additionally, growth factors contained in PRP can stimulate tendon healing and the fibrin gel in PRP can serve as a natural scaffold to attract cells, thus resulting in enhanced tendon healing.

Many conflicting results have been reported on the efficacy of PRP treatment, which are due in part, to the various factors that influence the outcome of treatments in clinical settings. The most important among them are PRP- and patient-associated factors. The PRP-related factors include: 1) type of preparation, which varies significantly (some PRP preparations contain WBCs, which release inflammatory agents, such as IL-1β and TNF-α and hence may cause catabolic effects on treated tissues); 2) platelet concentration, which determines the amount of growth factors present in PRP preparations; higher concentration of platelets in PRP may not be necessarily optimal at least for cell proliferation23; 3) use of activated or non-activated PRP; non-activated PRP may promote tissue healing more efficiently than activated PRP24; 4) method of PRP activation (the use of calcium or thrombin may yield differential results); 5) mode of application (whether injection or implantation of PRP gel); and 6) frequency of PRP applications during treatment.

The patient-associated factors include: 1) age (PRP is more effective in young patients, who have more and better-quality stem cells); 2) type of tendon injury (acute or chronic); 3) type of tissue injured (tendons or other soft tissues); 4) patient activity level; 5) treatment history; and 6) post-recovery plans (with or without rehabilitation)25. Whether patients are in rehabilitation or resume daily activities after PRP treatment could also be beneficial or detrimental. This is because moderate mechanical loading is known to suppress cellular inflammation26 and induce anabolic changes in tendon cells, but excessive mechanical loading worsens cellular inflammation by increasing PGE2 production21 and inducing aberrant differentiation of TSCs into non-tenocytes, which may lead to degenerative tendinopathy16.

In current clinical settings, PRP is prepared by centrifugation and a pre-determined dose is used for all types of tissue injuries. This “one-size-fits-all” approach is sub-optimal and, not surprisingly, skews the outcom e of PRP treatment. Recent studies have also shown that pro- and anti-angiogenic PRP components are segregated within granules and can be released selectively27, suggesting that the use of ‘total’ activated PRP to treat all types of tissue injuries may not be optimal. Therefore, selective release of specific molecular components within PRP preparations may improve healing outcomes.

Other varying factors frequently used in clinical studies are the various outcome measures of PRP treatment, including VAS (Visual Analog Scale), DASH (Disabilities of the Arm, Shoulder, and Hand), and VISA-A (Victorian Institute of Sport Assessment-Achilles) scale scores. While these scoring systems are necessary in patient PRP studies, they are based on patients’ own assessment of pain intensity and tendon function as well and thus unavoidably subjective and highly variable. To compensate such large variability, studies should include a large population of patients to assess the efficacy of PRP treatment. However, the sample sizes in a number of patient studies have been relatively small6,10,11. Indeed, patient studies with greater statistical power as well as adequate outcome measures have been called for28, 29.

As demonstrated by many previous studies and our own basic science research, PRP is likely a promising treatment to enhance the healing of injured tendons, but the factors mentioned above should be considered in current clinical practices and in the design of experimental research. This field would advance immensely with the optimization of PRP factors through additional basic science studies performed under well-controlled conditions30. We have linked at least one PRP component (HGF) to reduced inflammation and pain during tendon healing15. Additional studies that target various PRP components in vivo are needed to better understand their functions and enable the delivery of personalized PRP to patients. To ensure the efficacy of PRP treatment, guidelines for such treatment should be formulated based on the findings of basic science studies. It is anticipated that by optimizing PRP-associated factors and patient-related factors, we can effectively treat injured tendons in clinics.