Platelet-Rich Plasma in Muscle Injuries: When and How It Can Be Used
Presenting a significant problem in clinical medicine, skeletal muscle regeneration (after injuries, in atrophic disorders, etc.) is limited by fibrous scar formation, slow healing time, and a high rate of injury recurrence. Unfortunately, not many alternatives exist to the generally accepted conservative RICE principle for treating muscle injuries. Local platelet-rich plasma (PRP) application is popular in the field of sports medicine as an autologous source of growth factors that are believed to have potential therapeutic implications. However, several concerns have been raised as to whether high concentrations of TGF-β contained in PRP itself may have a negative effect in regard to fibrosis and the lack of any preclinical data. Although it is believed to be already used by many sports physicians, there is no evidence-based protocol for using PRP in treating muscle injuries. This chapter explains the reason behind it and proposes the best time frame to use PRP in muscle injuries according to physiological healing processes.
KeywordsSatellite Cell Platelet Rich Plasma Muscle Injury Muscle Regeneration Satellite Cell Activation
Nonsteroidal anti-inflammatory drug
Rest, ice, compression, elevation
Transforming growth factor beta
World Anti-Doping Agency
Musculoskeletal injuries that result in the necrosis of muscle fibers are encountered frequently in clinical and sports medicine (Li et al. 2004). Injured skeletal muscle can undergo repair spontaneously via regeneration; however, this process is often incomplete because overgrowth of extracellular matrix and deposition of collagen lead to significant fibrous scarring (Huard et al. 2002; Li and Huard 2002). Muscle injuries therefore frequently result in significant morbidity, including early functional and structural deficits, contraction injury, muscle atrophy, contracture, and pain.
By neutralizing pro-fibrotic processes in injured skeletal muscle, it is possible to prevent fibrosis and enhance muscle regeneration, thereby improving the functional recovery of the injured muscle (Huard et al. 2002). Platelet-rich plasma (PRP)-based therapy is widely accepted for treating ligamentous and tendinous injuries; however, this does not apply in case of muscle tissue. This chapter aims to answer the question why this is so, to provide the molecular background of muscle regeneration and to suggest the most appropriate ways to use PRP in muscle injuries accordingly.
Why in the Era of PRP -Based Therapy Muscle Tissue Has Been Left Out?
Muscle injuries which are one of the most commonly encountered injuries in sports account for 10–55 % of all sports injuries (Garrett 1996). Clinical experience reveals a high recurrence rate of skeletal muscle strain injuries, nearly 30 % in some professional-level athletes (Woods et al. 2004). Still no established therapeutic alternative exists to conservative R.I.C.E. (rest, ice, compression, elevation) principle. On the other hand, PRP-based therapy for ligaments in tendinous injuries has gained on popularity in recent years due to its relative simplicity, low cost, and low risk. The reason why no or only few reports about its use in muscle injuries is present is because the therapy was initially designed for relative vascular tissues. Cartilage, tendons, and ligaments all have a low regeneratory potential as growth factors and cells involved in healing process only poorly physically reach the site of the injury, especially if located in deep layers. On the other hand, skeletal muscle, which is a tissue rich in blood vessels, regenerates much faster after injury and did not until recently as such represent a relevant target for PRP therapy.
Further, PRP contains TGF-β, a cytokine closely associated with skeletal muscle fibrosis, as it plays a significant role in both initiation of fibrosis and induction of myofibroblastic differentiation of myogenic cells in injured skeletal muscle (Li and Huard 2002; Li et al. 2004). Many reports indicate that the overproduction of TGF-β in response to injury and disease is a major cause of tissue fibrosis both in animals and humans (Border and Noble 1994; Li et al. 2004). As TGF-β is a cytokine, which is present in PRP as well, doubts have arisen concerning its use. Due to the application of exogenous TGF-β into the tissue, which has been proven to be highly responsible for tissue scarring, some experts do not favor this therapeutic option. However, in a recent in vitro study using human myoblast cell line, it was shown that on one hand PRP-derived growth factors promote satellite and muscle cell proliferation; on the other hand they inhibit fibrotic differentiation, mainly on account of down-expression of TGF-β, presumably due to the synergistic action of various PRP-derived growth factors (Kelc et al. 2011).
As a source of autologous growth factors, PRP is speculated to be used by many sports physicians for treating muscle injuries. The use of platelet-derived preparations was prohibited by the World Anti-Doping Agency (WADA) until 2011 but was removed from the list after considering the lack of evidence concerning the use of the method for the purposes of performance enhancement as current studies did not reveal a potential for performance enhancement beyond a therapeutic effect (Official WADA Website 2012). To date, there are no randomized control studies confirming the real role of PRP in treating muscle injuries (Mishra et al. 2009), neither was any sample in clinical studies large enough to represent relevant statistical data (Foster et al. 2009). However, the preclinical data seems to be promising for the clinical studies to take place.
Physiological Molecular Mechanisms as a Background for PRP Therapy After Muscle Injury
Hemostasis: This stage usually starts with the formation of a blood clot and is followed by the local degranulation of platelets, which release several growth factors.
The acute inflammatory phase: This stage is characterized by peripheral muscle fiber contraction, formation of edema, and cell damage and death.
The remodeling phase: This stage lasts from 24 to 48 h up to 6 weeks. Anatomic structures are restored, and tissue regeneration occurs. Several cell types are involved; particularly fibroblasts start to synthesize scar tissue.
Debris is being removed by macrophages that secrete growth factors and activate the satellite cells. These are regenerative mononucleated stem cells of muscle tissue that normally lie between the basal lamina and plasma membrane of the muscle fiber (Mauro 1961). First, they form myoblasts which then begin to produce muscle-specific proteins and finally mature into muscle fibers with peripherally located nuclei (Carlson and Faulkner 1983).
PRP Alone or a Combination with TGF-β Inhibition ?
In recent years, numerous therapeutic agents have been described in the muscle regeneration researches to have a significant antifibrotic effect in patients with a heart or kidney disease and systemic sclerosis. Consequently, researchers are testing these agents also for muscle healing, as therapeutic targets are the same. It has been shown in in vitro and in vivo studies that drugs with antifibrotic properties that can prevent or minimize scar formation have potential as stand-alone or adjuvant therapies. Decorin (Fukushima et al. 2001), follistatin (Lee and McPherron 2001; Gilson et al. 2009), relaxin (Mu et al. 2010), suramin (Chan et al. 2005), and certain others have been reported to have significant beneficial effect on muscle healing after injury.
Fibrotic scar formation seems to be the main problem in the muscle regeneration process as the scar represents a nonfunctional tissue as well as the weakest spot for the injury to recur. Therefore, all the efforts should be made to avoid it. Although PRP itself seems to downregulate TGF-β expression in skeletal muscle in vitro, this can be further decreased by the simultaneous use of a TGF-β antagonist. When combined with PRP in vitro, decorin was shown to decrease not only in TGF-β but also MSTN expression (Kelc and Vogrin 2013).
Although WADA prohibits any use of myostatin inhibitors in athletes, their potential to act only therapeutically at the site of injury without any performance enhancement may play an important role in the therapy of muscle injuries in the future.
Therapy of Muscle Injuries Should Consist of at Least Three Stages
During the first 24/48 h, hematoma appears together with inflammatory response, macrophage, and neutrophil stimulation. The first measures in this stage are adequate immobilization and local cryotherapy several times during the day. At the end of this stage, which begins after initial 24 h, the activation of muscle progenitor satellite cells is at the highest level as it is influenced by cytokine expression during the inflammatory process as well as by growth factors, released from the platelets. Therefore, the second day after injury could be the first appropriate moment for local PRP application to give the regeneratory process an “extra boost.” Because satellite cell activation and differentiation is strongly regulated by TGF-β and MSTN, a combination therapy with their inhibitor should be considered. During this and further stages, nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided as they interfere with the regeneratory process and promote fibrotic remodeling (Shen et al. 2005).
During the days following the injury, muscle structures are restored, and tissue regeneration occurs. In particular, myofibroblasts differentiate, and fibroblasts start to synthesize scar tissue having a wound contracture as a consequence. In this stage, which usually lasts 2–10 days, regular isometric strength exercises should be performed inside the pain-free range. At the beginning without and then with continuous loading, followed by concentric exercises as soon as the subject has achieved a full range of pain-free motion. Additional continuous local application of PRP and antifibrotic agents is advisable around the fifth and ninth day after injury due to a highly potential washout effect.
This stage is characterized by collagen remodeling that leads to an increase in functional capabilities of the injured tissue. In order to achieve as full as possible restoration of muscle tissue without a scar, stretching and eccentric exercises should be performed. Another PRP application would be appropriate 14–20 days after the injury, and the use of antifibrotic agent is again to be considered. Athletes should carefully return to sports-specific exercises under special surveillance of both coach and team physician. Tensiomyography or similar testing is advisable to monitor the athlete’s performance and determine the right moment for return to play.
Although no evidence-based protocol for PRP use in muscle injuries exists, the described treatment regimen consists of the combination of accepted conservative treatment options and the targeted therapy according to molecular mechanisms after injury. However, more prospective randomized control studies will have to take place in order to show the true value of PRP and antifibrotic therapy of muscle injuries.
Also extra caution needs to be taken, as the use of TGF-β and MSTN inhibitors is so far still prohibited by WADA.
The therapy of an injured muscle should be carried out according to the physiological phases of regeneration. In the first stage, all the physical means should be used (R.I.C.E.) to control the hematoma and swelling. At the end of this stage and the beginning of the next, satellite cell activation and myogenic differentiation support through PRP is potentially of great importance. Simultaneously, this moment could also be appropriate for the local application of antifibrotic agents; however, this has not yet been adequately tested, and more studies are required to recommend the adoption of this approach. Furthermore, such interventions are advised twice again in the next 10 days while performing isometric and concentric exercises and repeated between 14 and 20 days after injury as eccentric and sports-specific exercises shall take place. Return-to-play time should be considered carefully and based on different modalities of physical testing.
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