Most of the preclinical evidence supporting the benefit of PRP in tendinopathy is based on its supposed ability to stimulate tissue repair process. Cell cultures provide evidence that PRP is involved in the different phases of the repair process. In the inflammatory phase, the GF contained in PRP can mobilize circulating inflammatory cells into the wound.23 They also stimulate tenoviocytes to secrete collagen, VEGF and HGF, all of them reparative24 process accelerators. In the proliferative phase, PRP is capable of stimulating the proliferation and division of almost all types of mesenchymal cells (osteoblasts, fibroblasts, chondrocytes or tenoviocytes) and also multipotential25 stem cell.26 In the final phase of remodeling, PRP facilitates newly formed collagen maturation and apoptosis of excess cells.27 Taken together, all of these evidences involve PRP definitely in the tissue repair process, but do not clarify whether this involvement translates directly into acceleration, and even less when it favors faster and more efficient healing, as proposed by some authors. Some of these questions have been clarified by certain animal models. In murine models with partial section of the Achilles tendon, PRP has been shown to be associated with a faster consolidation of the tendon callus, which is also mechanically efficient.28,29 Part of this effect could be due to its ability to accumulate circulating proinflammatory cells in the tendon wound.23 In muscle, some models also have observed a benefit of PRP in the myofibrillar repair process. In a model of breaking-strain of the tibialis anterior in rats, PRP seems to significantly shorten recovery times in those lesions that require myogenesis for recovery, directly involving them in the process of muscular neoformation.30 None of these studies have yet determined the properties that each GF individually has in these two different microenvironments. The response to PRP in animal models of inflammatory tendinopathy31 has also been described, more in line with the reality of clinical rheumatologists.

Historically the first PRP therapeutic applications began in the field of dental surgery for compacting maxillofacial implants and bone32 sealant. These osteointegrating properties caught the attention of some orthopedic surgeons who saw PRP as the ideal adjuvant to shorten the recovery of certain surgeries.33 This osteoinductive and sealant effect is still controversial, but the most consistent and valuable for many of its advocates. The truth is that the composition of PRP's many factors individually has shown a potent bone anabolic effect. The osteoinductive potential of platelet derived growth has been confirmed in more than one study so some authors have speculated on its clinical use (especially the BB isoform) in osteoporosis and consolidation of fracture34 calluses. One of the best-known properties of the epidermal growth factor (EGF) is its ability to expand totipotent stem cell populations. EGF is also able to differentiate these cells to the osteoblast lineage, thereby favoring remarkable osteogenesis.35,36 The fibroblast growth factor (FGF) is a classic and very powerful stimulator of the differentiation and activation of osteoblasts and has bone anabolic potential which is due in large measure to the Wnt37 pathway activation. In rabbits, FGF has been used successfully for the treatment of hip osteonecrosis, avoiding collapse not only of the femoral head, but also the development of secondary38 coxarthrosis. In humans, FGF significantly accelerates the formation of bone callus, shortening tibial39 osteotomy patient's time to discharge. The transformative growth factor β (TGF β) is a GF widely involved in bone and chondral40 anabolism. However, the TGF β superfamily is a complex of factors and receptors which, under various circumstances, can be converted into powerful stimulators and also osteoclast determinants associated to, for example, myeloma bone aggressiveness and multiple skeletal41,42 metastases.

The set of all such evidence suggests that, by virtue of its composition, PRP meets the right qualities to play a powerful osteoinductive role, capable of accelerating consolidation or osteointegration of fractures quickly and efficiently43,44 as well as of different types of implants.45 However, the literature is not unanimous in weighing these hypothetical beneficial properties of PRP.46–48 The relative concentrations of each GF upon activation, the dosing schedule, the type of injury and the microenvironment are determinants that seem to alter the osteoinductive qualities of GF which may be translated into the real clinical benefits of PRP.

The use of PRP in joints is relatively recent and has scant preclinical literature. Regarding degenerative arthropathy, there is only one work that analyzes the effect of PRP in knee osteoarthritis in rabbits. In this study, the authors histologically examined knees of rabbits treated with PRP-impregnated microspheres, observing a reduction in the progression of osteoarthritis with respect to controls. Using complementary cell cultures, the authors concluded that this effect was due to the metabolic stimulation of chondral matrix synthesis through glucosaminglycans.49 Regarding inflammatory arthritis, a paper has just recently been released, of particular interest to rheumatologists, which analyzes the effect of PRP in a porcine model of antigen-induced rheumatoid arthritis. In this study, intra-articular treatment with PRP of arthritic knees resulted, histologically and immunohistochemically, in a significant attenuation of the inflammatory changes characteristic of the disease, both at the synovial and50 cartilage levels. These results contrast to some extent, with the recently proinflammatory effect attributed to platelets in rheumatoid arthritis and other inflammatory arthropathies.51

The use of the PRP in the subacromial syndrome and all variants lacks, to date, studies that evaluate it as a single treatment. The only evidence mentions its use as an adjuvant in decompressive and reconstructive surgery of the rotator cuff. In this type of surgery, PRP improves the results of conventional reconstructive surgery and shortens recuperation time.52,53

Epicondylitis is a limiting tendinopathy, with a clear tendency to become chronic, which has a random, often partial response to glucocorticoid infiltrations and physiotherapy. Some authors have investigated the effectiveness of PRP in this disease because of the potential remedial effect observed in animal models. The pioneering essay that analyzes for the first time the effect of PRP on epicondylitis dates from 2006. This is a pilot, local anesthetic-controlled study, performed on 19 patients with refractory epicondylitis9 who were proposed surgery. In this study, the effect of a single injection of PRP on pain (Visual Analog Pain Scale [VAS]) and functional capacity (Mayo Elbow Score modified) was analyzed. At 8 weeks, patients referred an improvement of 60% (16% in controls), which after two years ended up being 93%. No adverse effects were reported. More recently, an open study with 30 patients also analyzed the role of PRP as salvage therapy in epicondylitis.54 As in previous studies, a single dose of PRP was administered and its effect was evaluated annually on pain (VAS) and functional capacity (American Shoulder & Elbow Surgeons outcome instrument). It reported a 25% improvement in VAS in ≥90% of patients, finding no adverse effects. The findings of the two studies ponder the clinical utility of PRP in patients with refractory epicondylitis. Remember that the design of both had some biases that limit the value of their findings. The main limitation lies in the small number of patients treated in both cases, to which the lack of randomization and blinding in a randomized controlled retrospective manner must be added. At the beginning of 2010 the first quality clinical trial was published, leading to less vulnerable conclusions on the role of PRP in patients with epicondylitis.55 It was a comparative clinical trial, controlled with corticosteroids, randomized, double-blind study on 100 patients with chronic epicondylitis who were followed one year. It analyzed the effect of a single injection of PRP in pain and improvement of functional capacity of the elbow, using corticosteroid infiltration as control. A VAS decreased in the Disabilities of the Arm, Shoulder and Hand score (DASH) more than 25% was considered as a measure of response to treatment. In the PRP group, it was reported by 73% of respondents, while in the group of patients who received corticosteroids only 50% reported the outcome. In this study no adverse effect was reported. The authors concluded that PRP significantly exceeded the clinical benefit obtained by corticosteroids. However, the clinical benefit achieved by corticosteroids in this work is directly influenced by the fact that all the patients included in the trial must have had evidence of pre refractoriness to local injections of corticosteroids. This bias prevents a true comparative analysis as it greatly favors PRP in comparison with steroids. Additionally, the results of this study support the concept reported in the previous 2, on the analgesic properties of the PRP in the treatment of epicondylitis, without presenting clinically significant adverse effects.

Plantar fasciitis is another common problem in rheumatology and, like the rest of tendinopathy, also tends to chronicity. The only evidence that analyzes the effect of PRP on plantar fasciitis dates from 2004 and is the first study that applies PRP to any type of tendinopathy. It is a series of 9 patients, followed for a year, with plantar fasciitis refractory to NSAIDs, immobilization, physical therapy and corticosteroid infiltration, given a single ultrasound-guided injection of PRP in the central and medial calcaneal fascicles. It evaluated the improvement in pain and ultrasound pattern changes. At follow-up, 8 of the 9 patients were asymptomatic but one of them required a second dose. The ultrasound thickness decreased at 3 months (on average) 1.2mm in the central and 2.3mm in the medial bundles. The evidence provided by this work seems worthy of further study, but it is still anecdotal given the small number of patients treated and the biases inherent in a retrospective design and open design.

The application of PRP to treat osteoarthritis of the knee can be considered a relatively new therapeutic indication that focuses undoubtedly on the most current clinical research. This new indication has led to multiple studies in the past 3 years, both controlled and open. Among them, one highlight is a retrospective study of 60 patients with osteoarthritis of the knees, followed for 5 weeks.14 This study compared the therapeutic effect of PRP with high molecular weight hyaluronic acid (HMWHA). The authors treated 30 patients with an infiltration weekly (for 3 weeks) of activated PRP and a similar number with a single dose of HMWHA. Respondents were considered those who decreased the WOMAC pain score ≥40% from baseline. The authors found 33% responders with PRP and 10% with hyaluronic acid at the end of follow-up. Such a low percentage of responders to viscosupplementation is surprising, documented in the literature with much higher response rates than those in this trial.56 Undoubtedly, a very poor response from the control group favors PRP in the comparative analysis. Probably, this analysis would have been more truthful and more clinically relevant if the patients had been tracked longer in order to fully develop the potential HMWHA accredited analgesic efficacy.57 In favor of the results of this study it should be noted that it was the first to specify the relative concentrations of GF contained in the infiltrated plasma, and also it is the only paper published that explicitly uses leukocyte free PRP, a very important fact for some authors.58 Very recently a new study, with a larger number of patients, again compares the effect of PRP with hyaluronic acid. This is a new comparative trial on 150 patients with osteoarthritis of the knees, followed for 6 months. It establishes three treatment arms with 50 patients each: activated PRP (infiltration every 21 days), HMWHA (single dose) and low molecular weight hyaluronic acid (LMWHA) (single dose). It analyzed the effect on the visual analogue scale of quality of life related to health status (EQ VAS) and knee function using the International Knee Documentation Committee index (IKDC). At follow-up, the authors reported better response rates in PRP-treated patients than in those treated with AHAPM or AHBPM (P<.005). In all groups, the response was better in younger patients and in those who had a more recent onset osteoarthritis. As in previous studies, a comparative analysis was not entirely fair and in this case, the AHBPM comparison was not clear. The use of infra treatment therapeutic dose control, as in this case, for AHBPM,59 favors the intervention to be analyzed (PRP). Besides this bias, lack of randomization and blinding lack credibility and, on the other hand, employs rare outcome measures and doubtful discriminative ability for osteoarthritis of the knee, such as IKDC, for example, as it is an index originally designed for the analysis of knee60 ligamentous instability.

Some series of patients with osteoarthritis of the knees, successfully treated with PRP have also been reported in recent years. The largest number belongs to a Spanish group that included 261 patients treated with three injections of activated PRP every 15 days (infiltrated volume not detailed), which was followed for 6 months.61 VAS, WOMAC (pain, stiffness and functional class), and SF-36 Lequesme (baseline and 6 months) were assessed. In their results, the authors reported improvement in all outcome measures, with percentages (relative to baseline) ranging from 8.4 in SF-36 and 30.7 in the WOMAC pain subscale. Another series with a longer follow-up, included 100 patients with osteoarthritis of the knee treated and followed for a year.15 In this work, which also employed 3 doses of activated PRP administered every three weeks, the authors found a significant improvement in VAS and EQ IKDC that, although more marked in the first 6 months, remained for a year. As in other studies of the same group, patients with the most benefit were young and had a less evolved osteoarthritis. Finally, one last article is worth mentioning that evaluates the effect of PRP in 14 patients with refractory prosthetic gonarthrosis62 proposed for replacement. It included patients with osteoarthritis of the knee refractory to conservative treatment (NSAIDs, rehabilitation, acupuncture, corrective splints, injections of corticosteroids or hyaluronic acid) that were treated with 3 doses of activated PRP (one per month). An effect was observed one year after infiltration on the VAS and the Knee Injury & Osteoartrhitis Outcome measure. The authors observed a linear improvement of VAS and Knee Injury & Osteoartrhitis Outcome in 60% of patients at follow-up. Although 40% of patients did not improve, none had to undergo surgery during the study.

Significant adverse effects were not reported in the five above mentioned studies, except for local postpuncture pain.