The menisci are known to play a pivotal role during normal functioning of the knee joint. Their unique and complex chondral structure, as well as their biology, make treatment and repair very challenging. The menisci increase joint stability, distribute load, absorb shock and provide lubrication and nutrition to the remaining joint elements.
Meniscal tears are considered the most common orthopaedic diagnoses. For many years, arthroscopy was regarded as a “gold standard” in therapy with almost 4 million arthroscopies for meniscus pathologies performed annually all over the world, thus representing a serious socio-economic concern with relevant Health Care System costs [1
]. Interestingly, more than 50% of these surgeries are conducted in patients older than 45 years with degenerative meniscal lesions [2
]. This type of injury is a slowly progressing phenomenon, typically involving horizontal cleavage of the meniscal body with prevalence in the population reaching up to 56%. Interestingly, 61% of those tears have no clinical symptoms of meniscal pathology (pain, aching, stiffness or oedema) [2
]. These data provided the background for studies analysing the efficacy of arthroscopy in chronic meniscal lesion therapy. Several randomized clinical trials were performed and demonstrated no additional benefit of partial meniscectomy to sham surgery [3
]. These data introduced doubt into the current practice and resulted in making clinical decisions more challenging. Additionally, meniscectomy or partial meniscectomy results in rapid deterioration of articular cartilage and the development of arthritis [4
]. Despite the trend of meniscus tear repair and maintaining as much vital tissue as possible [5
] there is an inability amongst surgeons to restore anatomical and functional roles of the repaired meniscus. Simultaneously, osteoarthritis progressively develops. These rationales shifted the treatment protocols of chronic meniscal tears into the non-operative manner and motivated the search for new therapeutic strategies.
There are several clinical trials that have provided evidence for the use of blood or bone marrow derived products in the surgical treatment of meniscal pathology: the fibrin clot technique [6
], platelet-rich plasma (PRP) [8
] or the bone marrow venting procedure [10
]. There is, however, no data in the literature evaluating the effect of blood derived products on healing of chronic meniscal tears. Thus we designed a prospective, randomized, double-blind, parallel-group, placebo-controlled study to investigate the effectiveness and safety of minimally invasive (percutaneous) intrameniscal PRP application to complement repair of a symptomatic chronic meniscal lesion. We hypothesized that intrameniscal injection of PRP with concomitant meniscal trephination would result in both an improved healing rate and better functional outcomes.
Meniscal healing has always been a major challenge for orthopaedic surgeons. All types of meniscectomies can lead to an increase in the risk of osteoarthritis [15
] and evidence comparing the results of total and partial meniscectomy provide data on the beneficial effects of meniscus preservation [16
]. The rising problem in meniscal injury treatment is the substantial number of chronic meniscal lesions. Recent studies comparing non-operative and arthroscopic treatment showed no benefit of surgical treatment in large cohorts of patients [3
]. Data provided by the European Society of Sports Traumatology, Knee Surgery and Arthroscopy [18
] or the guidelines published in the British Medical Journal [19
] showed no or poor clinical benefit of arthroscopy in the case of degenerative meniscal lesions. In fact, arthroscopy was titled “the last resort” of treatment and applicable due to failure of conservative management.
The most significant finding of this study was that percutaneous trephination with or without a PRP boost induced the healing response of chronic meniscus tears. The process was augmented in the PRP – treated group. Interestingly, our results also demonstrated that no full meniscal integrity is necessary to obtain a clinically important difference in respect to PROMs. Additionally, we found that the functional outcomes (KOOS Symptoms) and pain levels (VAS) scored higher in patients treated with PRP-augmentation than in the control group.
For this study we used leukocyte- and platelet-rich plasma (L-PRP). Its fluid like state enables delivery to the target site by needle injection. Once activated, L-PRP forms a gel and releases most of the growth factors in the first few hours post injection until fully dissolved within 3 days [20
]. It supports growth factors to act as an assembly of platelets and leukocytes in a complex matrix. Although leukocyte and platelet rich fibrin (L-PRF), was shown to slowly release growth factors over a period of about 7 days [21
] providing optimal kinetics of a release, it forms a 3D matrix that cannot be delivered via a minimally invasive way (e.g., intra-articular injection)
PRP has been shown to influence not only the process of meniscal healing in vitro and in vivo [22
] but also the treatment of other musculoskeletal injuries [24
]. Some evidence has been provided for the use of PRP in meniscal repair [8
]. The authors found that clinical outcomes and healing rates were better with the introduction of PRP into the lesion at the end of surgery. Griffin et al. performed a retrospective chart review with a minimum of 2 year follow-up and failed to show any benefit of PRP augmentation [26
]. However, the study was underpowered for the primary and secondary outcomes. Another Study by Strümper, R. et al. demonstrated that intra-articular autologous conditioned serum injection might be an effective treatment option for knee pain associated with meniscal lesions [27
]. The authors showed that surgery was avoided during the 6-month observation period and the Oxford Knee Score improved significantly from 29.1–44.3 in 83% of patients. Interestingly, the structural findings on MRI, measured by Boston Leeds Osteoarthritis Knee Score, also showed significant improvement. The limitations of the study were its retrospective character and lack of control group analysis. We believe that an additional weak point of this study was connected to not addressing perimeniscal capillary plexus (PCP) while performing the joint injection. Trephination is a known technique usually employed during arthroscopy [28
]. It involves the formation of vascular access channels from the meniscus periphery (PCP) to the tear. This process initiates bleeding into the meniscal lesion and subsequent tissue repair response. This simple technique was showed to increase the meniscal healing rate while applied during a surgical procedure [30
], most probably by providing the injury site with both growth factors and mesenchymal stem cells.
The results of experimental studies support the hypothesis that PRP may improve meniscal healing through activation of fibrochondrocytes present within the meniscus [31
]. The process also involves the activity of mesenchymal stem cells, which seem to be necessary for the repair of meniscal lesions [23
]. The PRP itself releases the “cytokine cocktail” of the healing cascade [25
]. The main growth factors are: platelet derived growth factor, platelet derived endothelial growth factor, vascular endothelial growth factor, insulin like growth factor, platelet derived angiogenesis factor, transforming growth factor-b, hepatocyte growth factor and others [32
]. This release initiates the chemotaxis of immunocompetent cells, inflammation, angiogenesis and as a consequence the process of synthesis of the extracellular matrix and tissue remodelling. The PRP works at various levels for joint homeostasis. Studies have shown that PRP application decreases catabolism while increasing anabolic activity and observations have been made that catabolic activity in meniscus chondral tissue helps identify patients who are at risk for progression of osteoarthritis [33
]. Other processes, such as chondral remodelling is promoted by PRP administration. Higher production of collagen II, matrix molecules and prostaglandin has been observed in hyaline cartilage [34
]. On the contrary, Lee et al. showed on a rabbit model of a circular meniscal defect that PRP treatment failed to enhance the production of meniscus cartilage. Additionally, it accelerated fibrosis and increased catabolic processes [36
]. However, findings from in vivo and in vitro studies cannot be directly translated to clinical practice.
Increasing data provide evidence for the necessity of mesenchymal stem cells in delivering the positive effect of PRP on healing of meniscal and hyaline cartilage defects [23
] and the process of chondrocyte differentiation [38
]. PRP has been shown to enhance proliferation of stromal stem cells [39
] as well as their adhesion and migration [40
]. This phenomenon is probably dependent on the release of a growth factor cocktail and triggering of synovial tissue to create a more balanced intra-articular environment. Recent studies link the synovium-derived stem cells to chondral regeneration, as they possess chondrogenic potential and encouraging results have been shown for cartilage repair purposes in experimental studies [41
We hypothesize, that trephination, by creating multiple wounds and inducing intrameniscal bleeding, starts the process of tissue repair with activation of synovial and blood derived stem cells, which—in our study—are stimulated by addition of PRP. The combination of those two processes allows for efficient meniscal tissue regeneration.
This is the first study to employ percutaneous trephination of a chronic meniscal lesion with or without PRP augmentation. The second strength is the study design itself, the randomized and blinded nature of this study and being adequately powered to detect differences in healing rates. Lastly, independent evaluators were used for assessing of the outcomes.
We acknowledge some limitations in this study. The study group was small, increasing the risk of type II error. Additionally, some patients refused MRI arthrography due to its interventional character, still their comfort of life improved significantly. Also, calculation of the primary outcome might have been influenced by factors that could affect MRI images and their interpretation. There is also the issue of heterogeneity within groups. Localization of the tear in medial or lateral compartments may influence the primary outcome, as the biology of those menisci might differ. We find no statistically significant differences between these groups but in the literature the results are mixed [42
]. Additionally, PROMs data have partially overlapping 95% confidence intervals, increasing the risk of type II error. Moreover, it is still unknown which of the factors are solely responsible for the improved outcomes in the PRP group. The rehabilitation protocol was uniform in all patients but we could not control those differences that might have occurred in patients being treated in multiple outpatient centres. Lastly, the observation period in this study allowed only for a short-term analysis.