Platelet-Poor Plasma for Muscle Injuries: A Review of Mechanisms and Clinical Perspectives

Abstract

Background:

Muscle injuries are a frequent challenge in professional sports, with hamstring injuries being particularly prevalent. Despite advances in rehabilitation protocols, recurrence rates remain high, and recovery timelines vary depending on injury location and severity.

Purpose:

To examine the roles of platelet-rich plasma (PRP) and platelet-poor plasma (PPP) in muscle injury treatment, highlighting their biological differences and potential clinical applications.

Study Design:

Narrative review.

Methods:

A comprehensive literature search was conducted, focusing on the biological properties of PRP and PPP, their effects on muscle regeneration, and clinical outcomes related to their use in muscle injury management.

Results:

PRP contains high concentrations of growth factors, including transforming growth factor–beta, myostatin, vascular endothelial growth factor, and platelet-derived growth factor, which promote cell proliferation and angiogenesis. However, its leukocyte content and associated pro-inflammatory cytokines may exacerbate inflammation, potentially increasing pain, delaying recovery, and raising the risk of heterotopic ossification. Conversely, PPP is rich in insulin-like growth factor–1 and hepatocyte growth factor, which modulate inflammation and fibrosis, promoting muscle regeneration. Basic science studies have demonstrated that PPP induces myoblast differentiation, whereas PRP primarily promotes myoblast proliferation, potentially favoring scar formation over true muscle tissue regeneration. Clinically, PPP has been explored as a treatment for muscle injuries, with some reports suggesting it may facilitate recovery and reduce reinjury risk. However, the limited availability of high-quality clinical trials prevents definitive conclusions about its efficacy compared with PRP.

Conclusion:

While both PRP and PPP offer biological advantages, PPP may present a favorable profile for muscle regeneration due to its ability to enhance differentiation while modulating inflammation. However, current clinical evidence remains limited, and further research is needed to establish definitive treatment guidelines.

Epidemiology and Risk Factors of Muscle Injuries

Muscle injuries are increasingly prevalent in professional sports. In men's professional soccer, hamstring injuries, the most commonly affected muscle group, now constitute 24% of all injuries, a significant increase from 12% over the past 2 decades. ¹⁰ This trend is consistent across various team sports, with hamstring injuries accounting for approximately 10% of all injuries. ¹⁵ The incidence of hamstring injuries is notably higher during matches compared with training sessions, and the risk of injury increases with the athlete's age. ²¹ Key risk factors for hamstring injuries include previous hamstring injuries and specific sports activities such as high-speed sprinting and kicking. ¹³ The recurrence rate of hamstring injuries remains high, ranging from 4% to 68%, depending on the injury definition and management strategies. ⁸

The prognosis of hamstring injuries varies based on several factors, including the injury location and severity. Injuries involving the proximal myotendinous junction or the intramuscular tendon are associated with longer return-to-play (RTP) times. ¹⁹ For instance, injuries with intramuscular tendon involvement can extend RTP to a mean of 78 days compared with 24 days for other types. ¹⁹ Higher-grade injuries are generally associated with longer recovery periods, making it essential to assess the extent of the injury accurately using either ultrasound or magnetic resonance imaging (MRI) to inform RTP predictions. ⁶ However, this remains a topic of debate in the literature. While some recent studies suggest that injury location significantly influences RTP, a prospective analysis by Ekstrand et al ¹¹ involving 255 hamstring injuries in elite soccer players found no correlation between injury location and RTP duration, suggesting that other factors, such as radiological grade and edema area, may play a more relevant role in determining recovery time.

Given the complexity of muscle healing and the ongoing search for optimal treatment strategies, this narrative review evaluates the role of platelet-poor plasma (PPP) compared with PRP in muscle injury management, analyzing their biological mechanisms and clinical applications.

Pathophysiology and Healing Mechanisms

Standard treatment for muscle injuries often relies on nonoperative measures such as rest, ice, compression, nonsteroidal anti-inflammatory drugs (NSAIDs), and a gradual rehabilitation plan. However, the cellular mechanisms involved in muscle healing—particularly the roles of intrinsic muscle cell populations including satellite cells (SCs) and fibroadipogenic precursors and immune cell subtypes (monocytes, macrophages, lymphocytes, platelets, and neutrophils)—are complex and remain incompletely understood. Inflammation is a fundamental aspect of the biological response to injury, and inflammatory mediators play a critical role in the initiation and regulation of tissue healing. Because inflammation is also associated with pain, NSAIDs are often used in the treatment of acute muscle injury. In the short term, studies have shown that NSAIDs can help reduce pain, strength loss, and inflammatory markers, as demonstrated in a meta-analysis including both human and animal studies. ²⁵ However, inflammation plays a crucial role in muscle regeneration by activating muscle progenitor cells and coordinating tissue repair.^4,9,36 Excessive suppression of this response, particularly with selective cyclooxygenase-2 inhibitors, has been associated with delayed regeneration and increased fibrosis. ³⁵ Given these concerns, the routine use of NSAIDs in the acute phase of muscle injury remains controversial and should be carefully evaluated.

Current Treatment Approaches for Muscle Injuries

There is no universal consensus on the optimal rehabilitation protocol for muscle injuries in professional athletes, but key principles guide treatment. Rehabilitation should be individualized, considering the sport, affected muscles, and injury severity. ²⁷ In early recovery, avoiding high strain loads is crucial, with progression based on symptoms and functional capacity. Eccentric exercises, particularly Nordic hamstring exercises, have been shown to reduce RTP times and reinjury risks, with systematic reviews indicating a potential 51% reduction in hamstring injury rates when properly implemented.^1,39

While nonoperative approaches, including physical therapy, often yield favorable outcomes, persistent cases may require adjunct therapies. Hematoma aspiration, especially when combined with platelet-rich plasma (PRP), has shown promise in accelerating recovery and reducing recurrence rates in specific cases. ³⁸ Low-level laser therapy has also been explored, although its clinical efficacy remains inconsistent. ¹

Given the high recurrence rate of hamstring injuries, preventive strategies are essential. Strength-based interventions, including resistance training, plyometrics, and blood flow–restricted exercises, can enhance muscle resilience. Addressing hamstring-to-quadriceps imbalances, incorporating flexibility training, and utilizing proprioceptive techniques such as neurodynamic sliding and vibration therapy may further reduce injury susceptibility. ³³

Surgical Treatment of Muscle Strains

Surgical intervention is typically reserved for severe muscle injuries, such as tendon avulsions or high-grade intramuscular tendon injuries, particularly when nonoperative treatment fails. Various surgical techniques have been described in the literature, including anchor fixation, tenodesis, tenectomy, and suture repair, with the choice of procedure depending on injury severity and anatomic location.^22,28 For distal hamstring tendon injuries that typically involve the tibial insertion of the semitendinosus and gracilis tendons, studies indicate that surgery results in a higher return-to-sport (RTS) rate compared with nonoperative management, with a mean return time of approximately 4.2 months. ²² Additionally, surgical repair of high-grade intramuscular hamstring tendon injuries in athletes has been associated with predictable recovery and a low risk of reinjury, allowing RTP at a mean of 3.1 months after repair. ² These findings suggest that, while nonoperative management remains the first-line approach, surgery may play a critical role in select cases, particularly for athletes requiring optimal functional recovery.

RTS Criteria After Muscle Strains

The decision to RTS after a muscle strain should be based on objective criteria that assess functional recovery and minimize reinjury risk. Pain perception remains a key consideration, as persistent discomfort may indicate ongoing tissue remodeling or compensatory movement patterns that increase reinjury risk. Strength testing, particularly using isokinetic dynamometry, is commonly used to evaluate muscle strength and detect residual deficits, with guidelines often emphasizing the need for near-complete strength recovery before clearance.^16,17 Neuromuscular control assessments, including agility drills and eccentric strengthening exercises, are essential to ensure the muscle can withstand sport-specific demands. ¹⁷ Imaging, such as MRI, can help detect residual edema or incomplete healing, which may indicate a higher risk of recurrence if RTS is premature. ¹⁶

For surgically treated injuries, such as proximal hamstring avulsions, RTS criteria incorporate functional milestones alongside objective measures. Meta-analyses report superior postsurgical strength (85.01% vs 63.95%) and satisfaction (90.81% vs 52.94%) compared with nonoperative treatment, with RTS requiring a minimum of 4 months after repair in athletes. ³

Muscle Regeneration and the Role of SCs

To better understand how various treatment options affect muscle healing, it is essential to consider the body's natural regenerative capacity. Skeletal muscle has the remarkable ability to regenerate after injury, largely driven by SCs—a distinct group of resident myogenic precursors. These cells are located around the periphery of skeletal myofibers, near capillaries and neuromuscular junctions, where they participate in intercellular communication and cellular cross-talk that activates them after injury, initiating tissue repair. SCs are pivotal in orchestrating muscle regeneration, and understanding this natural process is crucial for evaluating how therapeutic interventions can support or enhance recovery. ⁵

In addition to SCs, the extracellular matrix (ECM) plays a vital role in muscle healing, forming a reciprocal relationship with SCs that is essential for muscle homeostasis and regeneration. Beyond providing structural support, the ECM in the SC niche actively regulates SC behavior. Key ECM components, such as laminins, collagens, and proteoglycans, deliver biochemical signals that control SC quiescence, activation, and differentiation. This dynamic remodeling supports SC expansion and self-renewal, creating an optimal environment for muscle repair. Disruptions in ECM integrity or signaling pathways, such as integrins, can impair these processes, highlighting the ECM's critical role in effective muscle healing. ³⁷

Autologous Blood Products in Muscle Healing: PRP Versus PPP

Given the treatment modalities that aim to influence or enhance the body's innate regenerative processes, autologous blood products, such as PRP and more recently PPP, have been explored for their potential. However, they have produced mixed results,^14,15 with some studies showing no significant improvements in RTP or reinjury rates. Nonetheless, these therapies continue to be pursued to enhance recovery, particularly in more complex or resistant injuries for which nonoperative methods alone may be insufficient.^1,38

Proteomic analysis comparing PRP and PPP revealed that these blood product formulations shared a 50% overlap in identified proteins. These proteins represented >100 distinct pathways, with a substantial focus on regulating the inflammatory response, indicating that these mediators could potentially contribute to muscle repair and regeneration. ²³ However, the variability in PRP preparation methods presents a significant challenge in clinical research and application. Differences in centrifugation protocols, platelet concentrations, leukocyte content, and activation methods can lead to substantial heterogeneity in PRP formulations, making direct comparisons between studies difficult.

The lack of standardized reporting on PRP characteristics further complicates the interpretation of clinical outcomes, as variations in preparation may influence growth factor composition, inflammatory response, and therapeutic efficacy. This inconsistency raises concerns about the reproducibility of results and underscores the need for standardized protocols and detailed characterization of PRP formulations in future research to ensure more reliable and clinically relevant findings. ²⁶

Experimental and Preclinical Evidence

In experimental models, platelet-derived products have been demonstrated to facilitate muscle regeneration through several mechanisms, including modulating the inflammatory response by enhancing M2 macrophage recruitment, inducing a myogenic response through SC activation, upregulating myogenic regulatory factors, modulating muscle-specific microRNAs, activating signaling pathways driving myofiber formation, mitigating mitochondrial dysfunction in myocytes caused by muscle injury while augmenting their endogenous antioxidant activity, and inhibiting apoptosis in muscle cells. ⁵

While PRP contains a higher concentration of growth factors overall, PPP is specifically rich in extra-platelet factors such as insulin-like growth factor–1, hepatocyte growth factor, and many plasma proteins. These growth factors are known to inhibit inflammation and fibrosis, and they promote tissue repair and wound healing. ⁵ In contrast, PRP contains higher concentrations of growth factors like transforming growth factor–beta (TGF-β), vascular endothelial growth factor, and platelet-derived growth factor, which are more associated with cell proliferation and angiogenesis. ⁷ Besides the cytokines, the presence of leukocytes in PRP can also exacerbate inflammation, potentially increasing pain and delaying recovery. ³²

Lastly, apart from the platelets, there are also numerous signaling molecules and soluble mediators in the plasma portion. ²³

The biologically plausible superiority of PPP over PRP in influencing myogenesis was assessed in a basic science study. Miroshnychenko et al ²⁴ reported on the differential effects of PPP and PRP on muscle regeneration at the cellular level, comparing the biological effects of PPP and PRP on human skeletal muscle myoblast differentiation, focusing on the influence of cytokines and the effect of a second centrifugation step. In addition to that, they also assessed the effect of using specific antibodies against TGF-β and myostatin (MSTN) to further evaluate their role in modulating myoblast differentiation and muscle regeneration. ²⁴

The study found that PRP, which is rich in growth factors such as TGF-β and MSTN, primarily promoted myoblast proliferation without inducing differentiation. In contrast, PPP, which has lower concentrations of these factors, significantly induced myoblast differentiation. This differentiation was evidenced by increased multinucleated myotubule formation and myosin heavy chain expression, indicating a shift toward muscle regeneration rather than mere cell proliferation and potential scar formation. ²⁴

Additionally, the second centrifugation step, which further reduced the platelet concentration in PRP, resulted in a decreased proliferation rate and a significant induction of myoblast differentiation. This finding suggests that the reduction in platelet concentration and associated cytokines, such as TGF-β and MSTN, plays a crucial role in promoting myoblast differentiation. The removal of TGF-β and MSTN from PRP using antibody-coated beads also mildly enhanced myoblast differentiation, but the most pronounced differentiation was seen with PPP and PRP subjected to a second-stage spin. ²⁴

Clinical Evidence of PRP and PPP in Muscle Injuries

In a clinical context, Hamilton et al ¹⁵ conducted a randomized controlled trial comparing PRP, PPP, and no injection in athletes with acute hamstring injuries, with all groups undergoing standard rehabilitation. They found no significant benefit of PRP over PPP or no injection in terms of time to RTP or reinjury rates, suggesting that intensive rehabilitation remains the cornerstone of treatment. However, it is important to note that the study by Hamilton et al ¹⁵ did not utilize ultrasound-guided (USG) injections, which may represent a significant source of bias. Accurate needle placement under USG guidance could influence the efficacy of the injected therapies, potentially explaining the lack of observed benefits.

Regarding PPP, several case reports have documented its use for muscle injuries, showing promising outcomes in athletes. The first documented case involved a Division I football kicker with a grade 2 quadriceps injury who returned to play within 1 month, with MRI confirming injury resolution. ¹⁸ Other cases include a professional baseball pitcher with a latissimus dorsi strain, a collegiate outfielder with multiple oblique muscle tears, a collegiate pitcher with an internal oblique tear, and a collegiate baseball player with a grade 2 hamstring strain—all of whom returned to sport sooner than typical recovery timelines. ³¹ Although only limited conclusions can be drawn from such simple case reports, these cases highlight the potential of PPP to accelerate recovery in complex muscle injuries.

In a study with higher methodological rigor, Kruse et al ²⁰ conducted a quasi-experimental investigation into the efficacy of PPP in a controlled setting. They found that PPP resulted in a faster RTS compared with leukocyte-rich PRP for acute thigh muscle injuries (included but not limited to hamstring, quadriceps, and adductor), with no significant difference in reinjury rates. After adjusting for injury grade, athletes in the PPP group returned to unrestricted play a mean of 22.89 days (95% CI, 15.72-30.06 days) sooner than those in the PRP group. These findings suggest that PPP may be a viable option for expediting recovery in muscle injuries without increasing reinjury risk. ²⁰

Additionally, systematic reviews and meta-analyses, such as those by Seow et al ³⁴ and Grassi et al, ¹² have generally shown that PRP does not significantly improve outcomes compared with standard rehabilitation alone for muscle injuries. These findings suggest the need to explore other autologous blood formulations such as PPP in the treatment of muscle injury, with rigorous comparison to conventional rehabilitation protocols.

Potential Risks and Limitations of PRP and PPP

Moreover, a potential side effect of PRP treatment for muscle injuries is the risk of heterotopic ossification (HO). PRP contains high levels of growth factors, particularly bone morphogenetic proteins, which may inadvertently promote the osteogenic differentiation of progenitor cells. This process is further influenced by local tissue conditions, such as oxygen tension, pH, and mechanical stimuli. ³⁰ For example, a recent cohort study by Poor et al ²⁹ reported a higher incidence of HO in patients with core muscle injuries (CMIs) treated with PRP. Among 3642 patients with new CMIs, 68 (1.9%) developed HO; of these, 44 of 108 (40.7%) had received PRP, compared with only 24 of 3534 (0.7%) without previous PRP treatment. Despite the potential selection bias in this referral setting, which may overrepresent patients with unfavorable outcomes requiring further treatment, the data suggest a significant association, particularly in athletes. ²⁹ In contrast, limited evidence links PPP to HO, as most research focuses on PRP.

Conclusion and Future Directions

PPP has demonstrated potential as a treatment for muscle injuries, including hamstring strains, with some limited evidence suggesting a faster RTS compared with PRP. However, current clinical research remains limited, and no definitive conclusions can be drawn regarding its superiority in facilitating RTS. No current evidence confirms that PPP is superior to either PRP or rehabilitation protocols alone in facilitating RTS. Intensive rehabilitation continues to be the cornerstone of treatment, and further high-quality clinical studies are essential to establish the efficacy, safety, and optimal role of PPP in sports medicine.

This review contributes to the growing body of literature on PPP by providing a detailed exploration of its biological mechanisms and clinical applications. While previous studies have highlighted the potential benefits of PPP, important questions remain regarding its mechanisms of action, clinical efficacy, and role in rehabilitation protocols. By integrating basic science findings with current clinical evidence and rehabilitation perspectives, this review aimed to offer a more comprehensive understanding of PPP's therapeutic potential. As research in this area continues to evolve, further investigations will be crucial to refine its clinical applications and optimize its use in the management of muscle injuries in sports medicine. Similarly, although PRP remains widely used and supported by preclinical data, its clinical results remain inconsistent, and concerns regarding its pro-inflammatory profile warrant continued investigation.