Platelet rich plasma (PRP) is defined as an autologous. Platelet Rich Placebo?

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1 54 Bulletin of the Hospital for Joint Diseases 2013;71(1):54-9 Platelet Rich Placebo? Evidence for Platelet Rich Plasma in the Treatment of Tendinopathy and Augmentation of Tendon Repair Michael P. Hall, M.D., James P. Ward, M.D., and Dennis A. Cardone, D.O. Abstract Platelet rich plasma (PRP), an autologous sample of blood with a platelet concentration above baseline values, is hypothesized to augment soft tissue healing. Its use in sports medicine has risen dramatically, with common applications including the treatment of refractory tendinopathy and augmenting tendon repair. Many commercial preparation systems are available, but the optimal preparation remains unknown. Increasing numbers of clinical studies evaluating PRP have been reported and have provided both positive and negative evidence for its effectiveness. Well-designed, controlled studies are still lacking, but PRP may have a benefit for patients with tendinopathy that is refractory to other non-surgical treatments. Its use in tendon repair is currently not supported. Randomized, controlled studies with documentation of platelet, white blood cell, and growth factor concentration in the PRP preparation are necessary for future comparative research. Use of PRP should be approached judiciously until further evidence is available. Michael P. Hall, M.D., James P. Ward, M.D., and Dennis A. Cardone, D.O., are in the Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, New York. Correspondence: Dennis A. Cardone, D.O., Hospital for Joint Diseases. 301 East 17th Street, Suite 1402, New York, New York 10003: dennis.cardone@nyumc.org. Platelet rich plasma (PRP) is defined as an autologous sample of blood with platelet concentrations above baseline values. Platelets contain numerous growth factors and cytokines that are integral to complex tissue healing and repair. 1,2 The use of PRP was first popularized in maxillofacial surgery in the 1990s, and it was not until the early 2000s that its use in orthopaedic surgery began with attempts at augmenting spinal fusion. Clinical studies regarding its benefit in bone healing were mostly disappointing, but recent studies have provided strong in vitro evidence for a possible benefit in tendon and muscle repair. 3-7 After several reports of accelerated recovery in professional athletes treated with PRP, its use in sports medicine exploded. Although many reported applications exist, early research has primarily focused on the treatment of tendinopathy and the augmentation of tendon repair. Basic Science Tendon injuries are a growing problem in orthopaedics as an aging population stays more active with recreational activities. 8 Chronic injuries account for 30% to 50% of sporting injuries according to a recent report. 9 Tendons are devoid of neural elements; however, unmyelinated axons in the paratenon and endotenon modulate pain and immune responses. 10,11 Poor vascularity in tendon tissue seems to result in repair tissue that is functionally inferior to normal tendon and therefore is associated with an increased risk of further injury. 1,12,13 Tendon repair and regeneration appears to undergo four distinct phases. The first is an acute inflammatory phase in which there is hematoma formation, migration of hematopoetic cells into the injury site, and phagocytosis of necrotic tissue along with recruitment of fibroblasts. The second phase, termed the proliferative phase, is noted for fibroblast proliferation and type III collagen synthesis. The remodeling phase results in increased type I collagen synthesis with decreases in type III collagen and glycosaminoglycan synthesis. The consolidation phase marks the conversion of repair tissue to fibrous tissue and formation of scar-like tendon. 2,5,14-16 Histologically, the tissue demonstrates a fibroblastic response with vascular hyperplasia and disorganized collagen, without evidence of inflammation. These histologic findings combined with the clinical findings of pain, swelling, and decreased function defined the diagnosis of tendinopathy. Hall MP, Ward JP, Cardone DA. Platelet rich placebo? Evidence for platelet rich plasma in the treatment of tendinopathy and augmentation of tendon repair. Bull Hosp Jt Dis. 2013;71(1):54-9.

2 Bulletin of the Hospital for Joint Diseases 2013;71(1): There are several theoretical benefits of platelet infusion into areas of tendon injury. Platelets contain numerous growth factors that are released from alpha granules upon contact with collagen at the site of injury. Growth factors released include platelet derived growth factor (PDGF), transforming growth factor beta (TGF-β), fibroblast growth factor (FGF), endothelial growth factor (EGF), and vascular endothelial growth factor (VEGF). 17,18 Other cytokines released include interleukin 8 (IL-8), angiopoietin, and metalloproteases (MMP) 1, 2, and Although the exact function of many growth factors is still unclear, PDGF seems to play a central role in the healing process via chemotaxis, fibroblast proliferation, collagen synthesis, and stimulation of VEGF and TGF-β. 20 In a cell culture study by de Mos and colleagues, a significant increase in collagen production was seen in cells treated with or without PRP compared with baseline; however, only the PRP group had a significant increase in the concentration of VEGF at all tested time points. TGF-β was significantly higher in the PRP group and is thought to play a role in the initial inflammatory modulation and have a positive effect on collagen production. 6 In another human cell culture study, Anitua and colleagues found that only the PRP group had a significant increase in levels of VEGF and HGF when compared to cells exposed to platelet poor plasma (PPP) or supernatant released from a PPP clot. This led to a significant enhancement in cell proliferation in the PRP group, and it was theorized that VEGF and HGF may be part of the intrinsic mechanism of local tissue repair and for inducing angiogenesis. 7 Platelet Rich Plasma Preparation Controversy exists in the literature as to what is the optimal platelet concentration, the use of activators, the presence of white blood cells (WBC), and the timing or number of injections. Marx believed a minimum of 1 million platelets was necessary to create PRP, and Weibrich and colleagues reported a concentration of four to six times normal serum levels was optimal for dental peri-implant bone regeneration. 21,22 However, efficacy of PRP has been demonstrated at significantly lower platelet concentrations for sports medicine applications. 23,24 White blood cells are important in acute inflammation and have also been found to have antimicrobial effects against methicillin sensitive Staphylococcus aureus (MSSA) and methicillin resistant Staphylococcus aureus (MRSA) in a PRP preparation. 25 Recent reports, however, have demonstrated that inclusion of white blood cells appears to have a deleterious effect on the efficacy of PRP. Anitua and coworkers determined that the presence of MMP-8 and 9 from polymorphonuclear cells (PMN s) decreased the effectiveness of PRP injection, as these matrix-degrading enzymes release reactive oxygen species that destroy all surrounding cells, whether injured or healthy. 26 Tidball and colleagues also found an increase in muscle tissue damage due to PMN s. This was attributed to the release of excessive amounts of reactive oxygen species during the inflammatory phase of injury. 27 There are numerous PRP centrifugation systems commercially available with different yields of platelet concentration and processing time. There is also minimal comparative clinical data between varying centrifugation systems. Castillo and colleagues compared the growth factor and platelet concentration in five patients using three commercially available systems; the Cascade (MTF Sports Medicine, Edison, NJ), Magellan (Arteriocyte Inc., Cleveland, OH), and the GPS III (Biomet, Warsaw, IN). 28 They found no significant difference in the mean platelet, red blood cell, TGF-β, or fibrinogen concentrations between the systems. The MTF Cascade preparation was found to have the lowest WBC concentration, and Magellan system was found to have a significantly higher concentration of PDGF-αβ. Given the possible differences between preparation systems, and even patients, it will be vital for future comparative research to report platelet and growth factor concentrations in the PRP product studied. Laboratory Evidence There have been several animal studies evaluating the use of PRP to augment tendon repair. Kajikawa and associates injected PRP into a surgically created patellar tendon injury in a rat model. They evaluated the tendons histologically and concluded that the number of circulation-derived cells that infiltrated the wounded area was significantly increased in the PRP group on day 3 and day 7. This, they argued, confirmed the value of PRP as an activator of circulation-derived cells in the early phases of tendon healing. 29 In a similar rat tendon injury model, Lyras and coworkers compared application of insulin like growth factor 1 (IGF- 1) to a PRP gel. IGF-1 is a known stimulator of collagen production and a potent stimulator of cell proliferation. 30 The PRP treated group was found to have a denser appearance and fewer elastic fibers remaining with better tenocyte orientation at 3 weeks. 31 The same investigators evaluated the angiogenic effect of PRP in a rabbit patellar tendon model. They found an initial increase in the vascularity in the PRP treated tendons followed by a decrease by 4 weeks. The PRP treated tendons also had improved tenocyte orientation compared with the more immature tissue seen in the control group. 32 Aspenberg and colleagues evaluated the load to failure of rat Achilles tendons after PRP treatment. They determined that tendons treated with PRP reached 84% of the load to failure when compared with unoperated tendons at day 21. This was compared to a control group that reached 63% and 70% of load to failure by day 21 and 28, respectively. An improved tendon callus maturity was also noted in the PRP treated tendons by day Virchenko and colleagues demonstrated that post-operative exercise is necessary to realize the full effect of the PRP treatment. In a rat model,

3 56 Bulletin of the Hospital for Joint Diseases 2013;71(1):54-9 the investigators examined the effect of exercise by dividing the rats into groups treated with PRP only or PRP and botulinum toxin to abolish the rat s ability to perform exercise. The botulinum treatment was found to abolish the benefit of the PRP injection in terms of load to failure. 34 Clinical Evidence Elbow Tendinopathy The treatment of lateral epicondylosis, or tennis elbow, has been of particular controversy in recent literature. Steroid injections have been reported to lead to intratendinous degeneration with permanent adverse changes in the ultrastructure of the tendon itself. 35 These findings have led several investigators to evaluate the use of PRP as a potentially effective non-operative modality for lateral epicondylosis. Mishra and Pavelko performed an unblinded cohort study comparing the efficacy of a single injection of PRP (GPS II, Biomet, Warsaw IN) to an injection of bupivacaine in 15 patients (14 lateral, 1 medial epicondylosis). 36 All patients had failed physical therapy and other non-operative measures for a minimum of 3 months. Injections were given via a peppering technique, and the average platelet concentration in PRP was five times normal serum levels on average. At 8 weeks follow-up, the PRP group had a significant reduction in Visual Analog Score (VAS) and a significant improvement in the Mayo elbow score compared to bupivicaine. Three of five patients in the bupivacaine group dropped out after 8 weeks, preventing meaningful longer term comparisons. Patients in the PRP group continued to improve, and at a mean of 25 months, 93% were completely satisfied with their treatment and 94% were able to resume their work and sporting activities. In a randomized, double-blind study by Peerbooms and coworkers, 100 consecutive patients were randomized to receive an injection of PRP (Recover, Biomet, Warsaw, IN) or corticosteroid (triamcinolone 40 mg) for refractory lateral epicondylosis. All patients had failed physical therapy and other non-operative measures for a minimum of 6 months. At the 4 and 8 week follow-up visits, the steroid group had a greater reduction in both the VAS and Disability of the Arm, Shoulder, and Hand (DASH) scores compared with the PRP group, though these results were not statistically significant. However, at 6 months, 1 year, and 2 years the PRP group had a significantly greater reduction in both VAS and DASH scores compared to the steroid group. 37,38 This led the investigators to conclude that PRP is a superior form of treatment for refractory lateral epicondylosis. The limitation of this study is the lack of true control group, as the limited efficacy of steroid injections and possible detrimental longterm effects have been previously reported. 39 Hechtman and associates further evaluated the effect of PRP (Cascade, MTF, Edison, NJ) in lateral and medial epicondylosis in a prospective cohort of 31 elbows that had failed non-operative treatment, including steroid injection. Ninety percent of patients achieved greater than 25% reduction in VAS scores and achieved the majority of their pain relief in the first month. Only two patients went on to require surgical treatment. 40 Blood treatment around the elbow is not a new technique, however. In the past decade, autologous blood injections (ABI) have been used for lateral and medial epicondylosis with reports of up to 85% success in several case series. 41,42 Creaney and colleagues recently published a randomized, double-blind controlled trial of ABI compared to PRP for 150 patients with refractory symptoms for a minimum of 6 months. 43 Using a lateral epicondylosis outcome score, both groups showed improvement at 6 months with 72% and 66% in the ABI and PRP groups, respectively. There was no statistical difference between groups that leads one to question if the additional growth factors in PRP are necessary. Achilles Tendinopathy The body of evidence examining the use of PRP in Achilles tendinopathy has grown. The pathologic site of Achilles tendinopathy most commonly occurs in the mid-portion of the tendon, approximately 2 cm to 6 cm proximal to the enthesis and occurs only rarely at the calcaneal insertion. 44 In a similar manner to other tendinopathies, an inflammatory lesion is rarely seen within the body of the tendon. 45 Recent studies have established that eccentric exercise is necessary for improved collagen synthesis, decreased pain, and optimal recovery This, however, does not obviate the need to evaluate emerging treatment modalities to more effectively treat Achilles tendinopathy. In a randomized, double-blind, placebo-controlled trial, de Vos and colleagues evaluated the use of PRP injection in conjunction with eccentric exercises for the treatment of Achilles tendinopathy. They randomized 54 eccentric exercise naïve patients to either PRP or saline injection with a needling technique. At 6 months, improvement was observed in both the PRP and saline group in Victorian Institute of Sports Assessment Achilles (VISA-A) scores by 20 points, yet no significant difference was found. The investigators recently reported one year outcomes and continued to find no statistical difference between groups. 49,50 This study is limited, however, by a possible therapeutic effect of the rehabilitation program as eccentric exercise has been shown to improve VISA-A scores by 20 points alone. 48 The investigators further evaluated this same patient group in regards to the ultrasonographic tendon structure and neovascularization of the tendon after PRP injection. 51 They were unable to find a significant difference in the change in neovascularization score from baseline to 6 or 24 weeks in either group. Given these results, the investigators argue against the use of PRP injections for the treatment of Achilles tendinopathy. Gaweda and colleagues published encouraging results from a prospective cohort of 15 subjects treated with PRP injection after failure of other non-operative measures. 52 Patients experienced a significant improvement in both American Orthopaedic Foot and Ankle Society (AOFAS)

4 Bulletin of the Hospital for Joint Diseases 2013;71(1): and VISA-A scores beginning at 6 weeks and at all-time points until conclusion of the study at 18 months. After only 3 months, they also found decreased tendon thickening on ultrasound evaluation in 11 of 15 patients. Patellar Tendinopathy Patellar tendinopathy can be a particularly vexing condition with an average duration of symptoms of 3 years with 53% of patients reporting that they quit their sporting career due to the condition at 15 year follow-up. 53,54 Kon and coworkers evaluated the use of PRP in 20 consecutive patients with jumper s knee of at least 3 months duration with persistent patellar tendinopathy and magenetic resonance imaging (MRI) or ultrasound findings consistent with degenerative changes in the tendon. 55 Patients received three injections every 15 days with an average 600% increase in platelet concentration compared with normal serum levels. At 6 months follow-up, they found a significant improvement in VAS, Short Form -36 (SF-36) and Tegner scores with 80% of patients satisfied with their treatment. Given this improvement, the investigators supported PRP use in refractory cases of patellar tendinopathy. A study from the same institution compared 15 patients with a similar PRP treatment and rehab protocol to a matched historical cohort who received a standardized physical therapy program alone. 56 Both groups improved in VAS and Tegner scores at 6 months with 86.7% satisfaction in the PRP group compared to 68.8% in the control. However, no statistical differences were found between groups. Tendon Repair Sanchez and colleagues reported a case control study on the use of PRP (PRGF System II, BTI, Vitoria-Gasteiz, Spain) to augment surgical repair of complete Achilles tendon ruptures, comparing six athletes to a matched control group. 24 Patients in the PRP group had a significantly faster return of range of motion and required less time to resume gentle running or training activities. They returned to their sporting activity at a mean 14 weeks compared to 22 weeks in the control group. The possible benefit of PRP for a Achilles repair has been challenged by a randomized, single-blind, controlled trial of 30 patients performed by Schepull and coworkers. 57 Sixteen patients enrolled in the PRP group were injected (ABX Diagnostics, Montpellier, France) with an average platelet concentration 17 times greater than that found in normal whole blood. The investigators were unable to find a difference in mechanical strain or ultrasound characteristics between groups at any time point. Furthermore, they found a decrease in the Achilles Tendon Total Rupture Score at 12 months, suggesting a possible deleterious effect of the PRP injection. Improving tendon healing in rotator cuff repair has been another focus of PRP therapy. Castricini and colleagues performed a randomized, controlled trial to evaluate the efficacy of PRP (Cascade Platelet Rich Fibrin Matrix, MTF, Edison, NJ) placed at the site of repair. Eighty-eight patients with isolated small to medium sized supraspinatus tears were followed for a minimum of 16 months. All patients had a double row suture repair and completed a standardized rehab protocol. Both groups enjoyed a significant improvement in Constant scores compared with baseline; however, there was no statistically significant difference between groups. There was also no statistically significant difference in tendon thickness or footprint coverage observed on follow up MRI. The PRP group demonstrated significantly less tendon signal intensity, but the clinical significance of this is unknown. The investigators concluded that they were unable to recommend the use of PRP for repair of small or medium-sized supraspinatus tears. 58 Summary The use of platelet rich plasma has expanded in large part due to media reports of professional athletes making remarkable recoveries after injections. However, little clinical evidence demonstrating an effect greater than placebo currently exists. At present, the evidence in support of PRP seems to be strongest for refractory cases of lateral epicondylosis. No high quality evidence exists for a benefit of PRP in tendon repair. Future research must include platelet, white blood cell and growth factor concentrations in PRP preparations delivered in order for effective comparisons to be made. Well-designed studies will be vital in determining what conditions, if any, PRP is best suited to treat. Disclosure Statement None of the authors have a financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony. References 1. Molloy T, Wang Y, Murrell G. The roles of growth factors in tendon and ligament healing. Sports Med. 2003;33(5): Sharma P, Maffulli N. Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg Am Jan;87(1): Griffin XL, Smith CM, Costa ML. The clinical use of plateletrich plasma in the promotion of bone healing: a systematic review. Injury Feb;40(2): Ranly DM, Lohmann CH, Andreacchio D, et al. Plateletrich plasma inhibits demineralized bone matrix-induced bone formation in nude mice. J Bone Joint Surg Am Jan;89(1): Aspenberg P. Stimulation of tendon repair: mechanical loading, GDFs and platelets. A mini-review. 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6 Bulletin of the Hospital for Joint Diseases 2013;71(1): Sep;45(12): doi: /bjsm Epub 2011 Mar Puddu G, Ippolito E, Postacchini F. A classification of Achilles tendon disease. Am J Sports Med Jul-Aug;4(4): Leach RE, James S, Wasilewski S. Achilles tendinitis. Am J Sports Med Mar-Apr;9(2): Rees JD, Maffulli N, Cook J. Management of tendinopathy. Am J Sports Med Sep;37(9): de Vos RJ, Weir A, Visser RJ, et al. The additional value of a night splint to eccentric exercises in chronic midportion Achilles tendinopathy: a randomised controlled trial. Br J Sports Med Jul;41(7):e Rompe JD, Nafe B, Furia JP, Maffulli N. Eccentric loading, shock-wave treatment, or a wait-and-see policy for tendinopathy of the main body of tendo Achillis: a randomized controlled trial. Am J Sports Med Mar;35(3): de Vos RJ, Weir A, van Schie HT, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA Jan 13;303(2): de Jonge S, de Vos RJ, Van Schie HT, et al. One-year follow-up of a randomised controlled trial on added splinting to eccentric exercises in chronic midportion Achilles tendinopathy. Br J Sports Med Jul;44(9): de Vos RJ, Weir A, Tol JL, et al. No effects of PRP on ultrasonographic tendon structure and neovascularisation in chronic midportion Achilles tendinopathy. Br J Sports Med Apr;45(5): doi: /bjsm Epub 2010 Nov Gaweda K, Tarczynska M, Krzyzanowski W. Treatment of Achilles tendinopathy with platelet-rich plasma. Int J Sports Med Aug;31(8): Lian OB, Engebretsen L, Bahr R. Prevalence of jumper s knee among elite athletes from different sports: a cross-sectional study. Am J Sports Med Apr;33(4): Kettunen JA, Kvist M, Alanen E, Kujala UM. Long-term prognosis for jumper s knee in male athletes. A prospective followup study. Am J Sports Med Sep-Oct;30(5): Kon E, Filardo G, Delcogliano M, et al. Platelet-rich plasma: new clinical application: a pilot study for treatment of jumper s knee. Injury Jun;40(6): Filardo G, Kon E, Della Villa S, et al. Use of platelet-rich plasma for the treatment of refractory jumper s knee. Int Orthop Aug;34(6): Schepull T, Kvist J, Norrman H, et al. Autologous platelets have no effect on the healing of human achilles tendon ruptures: a randomized single-blind study. Am J Sports Med Jan;39(1): Castricini R, Longo UG, De Benedetto M, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med Feb;39(2):