Platelet rich plasma (PRP) is widely used in orthopedics, but there is still fierce debate. Therefore, the German “Clinical Tissue Regeneration Working Group” of the German Orthopedics and Trauma Society conducted a survey to reach a consensus on the current therapeutic potential of PRP.
Therapeutic PRP applications are considered useful (89%) and may be more important in the future (90%). The most common indications are tendon disease (77%), osteoarthritis (OA) (68%), muscle injury (57%), and cartilage injury (51%). Consensus was reached in the statement of 16/31. The application of PRP in early knee osteoarthritis (Kellgren Lawrence II) is considered potentially useful, as well as for acute and chronic tendon diseases. For chronic lesions (cartilage, tendons), multiple injections (2-4) are more advisable than single injections. However, there is not enough data on the time interval between injections. It is strongly recommended to standardize the preparation, application, frequency, and determination of indications for PRP.
Platelet rich plasma (PRP) is widely used in regenerative medicine, especially in orthopedic sports medicine. Basic scientific research has shown that PRP has many positive effects on many musculoskeletal system cells, such as chondrocytes, tendon cells, or muscle cells, both in vitro and in vivo. However, the quality of existing literature is still limited, including basic science and clinical research. Therefore, in clinical research, the effect is not as good as basic scientific research.
There are many possible reasons. Firstly, multiple preparation methods (currently over 25 different commercially available systems) exist to obtain platelet derived growth factors, but the final PRP product is composed of their heterogeneous compositions and their painstaking efforts. For example, different PRP preparation methods exhibit different effects on joint chondrocytes. In addition, due to the fact that basic parameters such as blood composition (red blood cells, white blood cells, and platelets) have not yet been reported in every study, standardized reporting of these factors is urgently needed. The final PRP product also has significant individual differences. What complicates the problem is that the dosage, time, and quantity of PRP applications have not been standardized, and have not been fully studied in basic scientific research. In this regard, the demand for standardized formulations of platelet derived growth factor is evident, which will allow for standardized basic scientific testing of the effects of different parameters such as PRP formulation, PRP injection volume, and injection time. In addition, using classifications to better describe the PRP products used should be mandatory. Some authors have proposed different classification systems, including Mishra (platelet count, presence of white blood cells, activation) and Dohan Ellenfest (platelet count, white blood cell count, presence of fibrinogen), Delong (P latelet count, nail activation, w ^ Haide blood cell count; PAW classification) and Mautner (Platelet count, presence of large eukocyte, presence of R labeled blood cells, and use nail activation; PLRA classification) 。 Magalon et al. The proposed DEPA classification involves injection of platelet OSE, production efficiency, PRP’s security, and its activation. Harrison et al. Another comprehensive classification system was published, including activation methods used, total volume used, administration frequency and subcategories activated, platelet concentration and preparation techniques, as well as overall average counts and range (low high) white blood cell counts (neutrophils, lymphocytes, and monocytes) for platelets, red blood cells, and classifications. The latest classification comes from Kon et al. Based on expert consensus, the most important factors are described as platelet composition (platelet concentration and concentration ratio), purity (presence of red blood cells/white blood cells), and activation (endogenous/exogenous, calcium addition).
The use of many indicators for PRP has been widely discussed, such as the fact that the treatment of tendon disease has been described in clinical studies regarding various locations [with concurrent positive and negative results]. Therefore, it is often impossible to obtain conclusive evidence from literature. This also makes it difficult for PRP therapy to be included in various guidelines. Due to the many unresolved issues surrounding the use of PRP, the fundamental principle of this article is to showcase the views of experts from the German “Clinical Tissue Regeneration Working Group” of the German Orthopedics and Trauma Society (DGOU) on the use and future of PRP.
The German “Clinical Tissue Regeneration Working Group” is composed of 95 members, each specializing in orthopedic surgery and tissue regeneration (all medical doctors or doctors, no physical therapists or exercise scientists). A working group composed of 5 individuals (blind review) is responsible for promoting the investigation. After reviewing existing literature, the working group prepared potential information items that could be included in the first round of investigation. The first survey was conducted in April 2018, covering 13 questions and general aspects of the PRP application, including closed and open questions, and encouraging experts to propose further projects or modifications. Based on these answers, a second round of survey was developed and conducted in November 2018, with a total of 31 closed ended questions in 5 different categories: indications for cartilage injury and osteoarthritis (OA), indications for tendon pathology, indications for muscle injury, application of PRP, and future research areas.
Through an online survey (Survey Monkey, USA), an agreement was reached to allow respondents to rate whether the project should be included in the minimum reporting requirements, and to provide five possible response scales on Likert: ‘Very agree’; Agree; Neither agree nor oppose; Disagree or strongly disagree. The survey was piloted by three experts on face validity, understanding and acceptability, and the results were slightly modified. In the first round, a total of 65 experts participated, while in the second round, a total of 40 experts participated. For the second round of consensus, a priori definition states that if more than 75% of respondents agree, the project will be included in the final consensus document, and less than 20% of respondents do not agree. 75% of participants agree that it is the most commonly specified consensus decision, which was used in our study.
In the first round, 89% of people answered that PRP application is useful, and 90% of people believe that PRP will be more important in the future. Most members are familiar with basic science and clinical research, but only 58% of members use PRP in their daily practice. The most common reasons for not using PRP are the lack of a suitable environment, such as university hospitals (41%), expensive (19%), time-consuming (19%), or insufficient scientific evidence (33%). The most common indications for PRP use are tendon disease (77%), OA (68%), muscle injury (57%), and cartilage injury (51%), which is the basis for the second round of investigation. The indication for intraoperative use of PRP appears in conjunction with 18% cartilage repair and 32% tendon repair. Other indications are seen in 14%. Only 9% of people stated that PRP has no clinical use. PRP injection is sometimes used in combination with hyaluronic acid (11%). In addition to PRP, experts also injected local anesthetics (65%), cortisone (72%), hyaluronic acid (84%), and Traumel/Zeel (28%). In addition, experts overwhelmingly stated the need for more clinical research on the application of PRP (76%) and the need for better standardization (formulation 70%, indications 56%, timing 53%, injection frequency 53%). For detailed information on the first round, please refer to the appendix. Experts overwhelmingly stated that more clinical research is needed on the application of PRP (76%), and better standardization must be achieved (formulation 70%, indications 56%, timing 53%, injection frequency 53%). For detailed information on the first round, please refer to the appendix. Experts overwhelmingly stated that more clinical research is needed on the application of PRP (76%), and better standardization must be achieved (formulation 70%, indications 56%, timing 53%, injection frequency 53%).
Based on these answers, the second round focuses more on the topic of greatest interest. Consensus was reached in the statement of 16/31. It also shows areas where there is less consensus, especially in the field of indications. People generally agree (92%) that there are significant differences in the various indications of PRP application (such as OA, tendon disease, muscle injury, etc.).
[The stacked oblique bar chart represents the subdivision of the agreed level in the second round of survey (31 questions (Q1 - Q31)), which well shows the areas of disagreement.
The bar on the left side of the Y-axis indicates disagreement, while the bar on the right side indicates agreement. Most disagreements arise in the field of indications.]
Indications for cartilage injury and OA
There is general agreement (77.5%) that PRP can be used for early knee osteoarthritis [Kellgren Lawrence (KL) Level II]. For less severe cartilage injuries (KL Level I) and more severe stages (KL Level III and IV), there is no consensus yet on the use of PRP during or after cartilage regeneration surgery, although 67.5% of experts believe this is a promising field.
Indications for tendon lesions
In the survey, experts represented the vast majority (82.5% and 80%) that the use of PRP is useful in acute and chronic tendon diseases. In the case of rotator cuff repair, 50% of experts believe that intraoperative application of PRP may be useful, but 17.5% of experts hold the opposite opinion. A similar number of experts (57.5%) believe that PRP has a positive role in postoperative treatment after tendon repair.
Indication of muscle injury
But no consensus was found on the use of PRP for the treatment of acute or chronic muscle injury (such as over 75% consensus).
Practical Aspects of PRP Application
There are three statements that can be agreed upon:
(1) Chronic lesions require more than one injection of PRP
(2) Insufficient information on the optimal time interval between injections (no consensus found on weekly intervals)
(3) The variability of different PRP formulations may play an important role in their biological effects
Future Research Areas
PRP production must be better standardized (95% consistency) and its clinical application (such as injection frequency, application time, clinical indications). Even in areas such as OA treatment where there is reportedly good clinical data, expert members believe that there is still a great need for more basic scientific and clinical research. This also applies to other indications.
The research results indicate that there is still widespread debate on the application of PRP in orthopedics, even in national expert groups. Out of 31 speeches, only 16 reached a common consensus. There is the greatest consensus in the field of future research, indicating a strong need to generate expanded evidence through conducting many different future studies. In this regard, the critical assessment of available evidence by expert working groups is a way to enhance medical knowledge.
Indications for OA and cartilage injury
According to current literature, PRP may be suitable for early and moderate OA. Recent evidence suggests that intra-articular injection of PRP may improve patient symptoms regardless of the degree of cartilage damage, but there is usually a lack of good subgroup analysis based on Kellgren and Lawrence classification. In this regard, due to insufficient available data, experts currently do not recommend using PRP for KL level 4. PRP also has the potential to improve knee joint function, possibly by reducing inflammatory reactions and slowing down the degenerative remodeling process of joint cartilage. PRP typically achieves better results in male, young, patients with lower levels of cartilage damage and body mass index (BMI).
When interpreting published clinical data, the composition of PRP seems to be a key parameter. Due to the demonstrated cytotoxic effect of plasma rich in white blood cells on synovial cells in vitro, LP-PRP is mainly recommended for intra articular application. In a recent basic scientific study, the effects of poor white blood cell (LP) and rich white blood cell (LR) PRP on the development of OA were compared in a mouse model after meniscectomy. LP-PRP showed superior performance in preserving cartilage volume compared to LR-PRP. A recent meta-analysis of randomized controlled trials found that PRP had better results compared to hyaluronic acid (HA), and subgroup analysis showed that LP-PRP had better results than LR-PRP. However, there was no direct comparison between LR – and LP-PRP, making further research necessary. In fact, the largest study comparing LR-PRP with HA shows that LR-PRP has no adverse effects. In addition, a clinical study comparing LR-PRP and LP-PRP directly showed no clinical differences in results after 12 months. LR-PRP contains more pro-inflammatory molecules and higher concentrations of growth factors, but also contains higher concentrations of anti-inflammatory cytokines, such as interleukin-1 receptor antagonists (IL1-Ra). Recent studies have described the “inflammatory regeneration” process of white blood cells secreting pro-inflammatory and anti-inflammatory cytokines, demonstrating a positive impact on tissue regeneration. Additional clinical studies with prospective randomized design are necessary to determine the optimal production or PRP formulation composition and ideal application protocol in OA.
Therefore, some suggest that HA and PRP may be superior treatment methods for patients with mild OA and low BMI. Recent systematic evaluations have shown that PRP has a better therapeutic effect compared to HA. However, the unanimously proposed open points include the need for standardized PRP preparation, application rates, and the need for further randomized clinical trials with high water quality. Therefore, currently official recommendations and guidelines are often inconclusive in supporting or opposing the use of knee osteoarthritis. In summary, based on current evidence, different preparation schemes limit high methodological variability, and PRP may lead to pain improvement in mild to moderate OA. The expert group does not recommend using PRP in severe OA situations. More recent studies have shown that PRP also contributes to the placebo effect, especially in the treatment of OA or lateral Epicondylitis. PRP injection may only be part of the overall treatment strategy to address the biological issues of OA. In addition to other important factors such as weight loss, correcting dislocations, muscle training, and knee pads, it may help alleviate pain and bring better results to patients.
The role of PRP in regenerative cartilage surgery is another widely debated area. Although basic scientific research has shown a positive impact on chondrocytes, clinical evidence for the use of PRP during surgery, cartilage regeneration surgery, or rehabilitation stages is still insufficient, reflecting our findings. In addition, the optimal timing for postoperative PRP treatment is still uncertain. But most experts agree that PRP may help promote biological cartilage regeneration. In summary, the current results of critical judgment suggest that further evaluation of the potential role of PRP in regenerative cartilage surgery is necessary.
Indications for tendon lesions
The use of PRP for the treatment of tendinosis is a controversial topic in the literature. A review of basic scientific research indicates that PRP has positive effects in vitro (such as increasing tendon cell proliferation, promoting anabolic effects, such as increasing collagen production) and in vivo (increasing tendon healing). In clinical practice, many studies have shown that PRP treatment has both positive and no effects on various acute and chronic tendon diseases. For example, a recent systematic review emphasized the controversial results of PRP application in different tendon lesions, mainly having a positive impact on lateral elbow tendon lesions and patellar tendon lesions, but not on Achilles tendon or rotator cuff lesions. The vast majority of surgical RCT records lack beneficial effects, and there is still no conclusive evidence of its conservative application in rotator cuff diseases. For external Epicondylitis, the current meta-analysis shows that corticosteroids have a short-term positive effect, but the long-term effect of PRP is superior. Based on current evidence, patellar and lateral elbow tendinosis have shown improvement after PRP treatment, while the Achilles tendon and rotator cuff do not seem to benefit from PRP application. Therefore, a recent consensus by the ESSKA Basic Science Committee concluded that there is currently no consensus on the use of PRP for the treatment of tendinosis. Despite controversy in the literature, as shown by recent research and systematic evaluations, PRP has a positive role in treating tendon diseases from both basic scientific and clinical perspectives. Especially considering the potential side effects of corticosteroids when using tendon diseases. The results of this survey indicate that Germany’s current view is that PRP can be used to treat acute and chronic tendon diseases.
Indication of muscle injury
More controversial is the use of PRP to treat muscle injuries, which is one of the most common injuries in professional sports, resulting in approximately 30% of off field days. PRP provides the possibility of improving biological healing and accelerating recovery exercise rates, which has received increasing attention in the past few years. Although 57% of the answers given in the first round listed muscle injury as the most common indication for PRP use, there is still a lack of solid scientific background. Several in vitro studies have observed the potential benefits of PRP in muscle injury. The acceleration of satellite cell activity, increase in regenerated fibril diameter, stimulation of myogenesis, and increased activity of MyoD and myostatin have all been well tested. Further information about Mazoka et al. An increase in the concentration of growth factors such as HGF, FGF, and EGF was observed in PRP-LP. Tsai et al. emphasized these findings. In addition to proving the increased protein expression of cyclin A2, cyclin B1, cdk2 and PCNA, it is proved that the skeletal muscle cell vitality and cell proliferation are increased by transferring cells from G1 phase to S1 and G2&M phases. A recent systematic review summarized the current scientific background as follows: (1) In most studies, PRP treatment increased muscle cell proliferation, growth factor expression (such as PDGF-A/B and VEGF), white blood cell recruitment, and angiogenesis in muscle compared to the control group model; (2) The PRP preparation technology is still inconsistent in the research of basic scientific literature; (3) Evidence from basic scientific research in vitro and in vivo suggests that PRP may serve as an effective treatment method that can accelerate the healing process of muscle lesions compared to the control group, based on the observed effects at the cellular and tissue levels in the treatment group.
Although a retrospective study described complete healing and considered that off-site time did not have a significant advantage, Bubnov et al. In a cohort study of 30 athletes, it was observed that pain was reduced and the speed of recovery from competition was significantly accelerated. Hamid et al. In a randomized controlled trial (RCT) comparing PRP infiltration with conservative treatment regimens, significantly faster recovery from competition was described. The only double blind multicenter RCT included hamstring injury in athletes (n=80), and no significant placebo infiltration was observed compared to PRP. The promising biological principles, positive preclinical findings, and successful early clinical experience with PRP injection mentioned above have not been confirmed by recent high-level RCT. The current consensus among GOTS members has evaluated conservative therapies for muscle injury and concluded that there is currently no clear evidence that intramuscular injection can be used to treat muscle injury. This is consistent with our results, and there is no consensus on the use of PRP in the treatment of muscle injury. Further research is urgently needed on the dose, time, and frequency of PRP in muscle injury. Compared to cartilage injury, in muscle injury, the use of treatment algorithms, especially PRP, may be related to the level and duration of the injury, distinguishing between the involvement of injured muscle diameter and possible tendon injury or avulsion injury.
The application field of PRP is one of the most frequently discussed areas, and the lack of standardization is currently one of the main issues in clinical trials. Most experts have not seen any increase in the use of PRP, however, some studies have shown that the additional use of hyaluronic acid can be compared to the single use of PRP for OA. The consensus is that multiple injections should be given for chronic diseases, and the OA field supports this suggestion, where multiple injections are more effective than single injections. Basic scientific research is exploring the dose-effect relationship of PRP, but these results still need to be transferred to clinical research. The optimal concentration of PRP has not been determined yet, and research has shown that higher concentrations may have negative effects. Similarly, the impact of white blood cells depends on the indication, and some indications require PRP with poor white blood cells. The variability of individual PRP composition plays an important role in the impact of PRP.
Future Research Areas
It is unanimously agreed that according to recent publications, more research on PRP is necessary in the future. One of the main issues is that PRP formulations must be better standardized (with 95% consistency). One possible aspect of achieving this goal may be the aggregation of platelets to achieve larger volumes, which is more standardized. In addition, various parameters for clinical application are unknown, such as how many injections should be used, the time between injections, and the dosage of PRP. Only in this way can it be possible to conduct high-level research and evaluate which indications are most suitable for using PRP, making basic scientific and clinical research, preferably randomized controlled studies, necessary. Although consensus has been reached that PRP may play an important role in the future, it seems that more experimental and clinical research is needed now.
One possible limitation of this survey’s attempt to address the widely debated topic of PRP application is its ethnic characteristics. The availability of PRP and country differences in reimbursement may affect outcomes and regulatory aspects. Furthermore, consensus is not multidisciplinary and only includes the opinions of orthopedic doctors. However, this may also be seen as an advantage as it is the only group actively implementing and supervising PRP injection therapy. In addition, the survey conducted has a different methodological quality compared to the strictly executed Delphi process. The advantage is a consensus formed by a group of professional orthopedic doctors with extensive professional knowledge in their respective fields from the perspectives of basic science and clinical practice.
Based on the consensus of at least 75% of participating experts, reach a consensus on the following points:
OA and cartilage injury: The application of mild knee osteoarthritis (KL II grade) may be useful
Tendon pathology: The application of acute and chronic tendon diseases may be useful
Practical suggestion: For chronic lesions (cartilage, tendons), multiple injections (2-4) at intervals are more advisable than a single injection.
However, there is insufficient data on the time interval between single injections.
Future research: It is strongly recommended to standardize the production, preparation, application, frequency, and indication range of PRP. Further basic and clinical research is necessary.
The general consensus is that there are differences in the various indications of PRP application, and there is still significant uncertainty in the standardization of the PRP program itself, especially for different indications. The application of PRP in early knee osteoarthritis (KL grade II) and acute and chronic tendon diseases may be useful. For chronic (cartilage and tendon) lesions, interval multiple injections (2-4) is more advisable than single injections, but there is insufficient data on the time interval between single injections. A major issue is the variability of individual PRP composition, which plays an important role in the role of PRP. Therefore, the production of PRP must be better standardized, as well as clinical parameters such as injection frequency, and the time between injection and accurate indications. Even for OA, which currently represents the best research field for PRP application, more basic scientific and clinical research is needed, as well as other proposed indications.
（The contents of this article are reprinted, and we do not provide any express or implied guarantee for the accuracy, reliability or completeness of the contents contained in this article, and are not responsible for the opinions of this article, please understand.）
Post time: May-24-2023