Abstract
Platelet-rich plasma (PRP) is a versatile autologous blood product with regenerative, anti-inflammatory, and anti-microbial properties, derived from the growth factors and cytokines contained and released from platelets concentrated at supraphysiological levels. The basic science of PRP has demonstrated its regenerative and immunomodulatory properties via cell, tissue, and preclinical animal model studies, and clinical interest in translation of these properties has extended rapidly to regenerative medicine applications for musculoskeletal and spine disorders. However, randomized clinical trials of PRP therapy for osteoarthritis and chronic tendinopathy thus far have yielded often contradictory results. Therefore, efforts are underway to define both PRP composition and the underlying pathophysiology of specific disease processes, in order to elucidate the biological targets of PRP therapy and ultimately to improve clinical outcomes.
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Introduction
In 2001, Dr. Richard Marx, an oral and maxillofacial surgeon, defined platelet-rich plasma (PRP) as a “volume of autologous plasma that has a platelet concentration above baseline” [1]. However, surgical applications of platelets and clotting factors, fibrinogen and thrombin, emerged much earlier in the 1970s and 1980 to augment healing. Yet, it was not until Dr. Marx’s publication that a catalyst was in place for the development of PRP technology and commercialization.
By 2008, Hines Ward, then wide receiver for the Pittsburgh Steelers, reported to the media that he received PRP treatment for an acute grade 2 medial collateral ligament sprain, allowing him to return to play within 2 weeks, compared to the more typical 4–6-week recovery period [2]. The Steelers went on to win the Super Bowl that year. Ward’s injury, treatment, and response to PRP therapy represents a key event and impetus for growing clinical interest in PRP applications in sports medicine and musculoskeletal injuries.
In this chapter, we discuss the basic science underlying PRP and clinical applications for musculoskeletal pathology. We review the diverse classification schemes and preparation methods of PRP, which relate to observed variations in clinical outcomes and efficacy of treatment, and the advantages and disadvantages of PRP therapy. We examine the regulation of PRP technology and barriers to expanding Food and Drug Administration approval for additional musculoskeletal indications. Finally, we close with future directions for PRP applications to the field of nonoperative sports medicine and spine care.
Basic Science of PRP and Mechanism of Action
Clinical interest in PRP lies in its regenerative properties, as well as its anti-inflammatory, anti-microbial, and analgesic actions on the tissue of interest [3]. Platelets are anucleate cytoplasmic fragments of megakaryocytes from the bone marrow, containing upward of 50–80 α-granules per platelet [4]. Physiological levels of platelets range from 150,000 to 350,000/μL. Their lifespan is approximately 10 days in circulation [5], and platelet death occurs by an intrinsic program of apoptosis [6]. Platelet activation, adhesion, and aggregation are the initial steps of the wound repair process and inflammatory cascade (Fig. 5.1). After activation, α-granules within the platelets degranulate, releasing growth factors and cytokines involved in cell proliferation and tissue remodeling, which play key roles in wound healing and repair.
The three overlapping phases of wound healing : inflammation, proliferation, and remodeling. Following tissue injury, platelet adhesion, aggregation, and activation occur, along with initiation of the inflammatory cascade, occurring over the first few days of healing. This is followed by the cell proliferation and tissue synthesis phase, consisting of angiogenesis, collagen deposition, granulation tissue formation, epithelization, and wound contraction. Finally, the tissue remodeling phase occurs weeks to months after injury, involving collagen and extracellular matrix maturation. Time in days presented on a logarithmic scale. (Modified from Lee et al. [7])
The composition of PRP has been reported to contain over 300 growth factors and cytokines [8]. Growth factors present in PRP are promoters of mitogenesis and anabolism and have also been shown to suppress inflammation [9]. For example, PRP contains growth factors that have been shown to enhance chondrocyte proliferation, extracellular matrix (ECM) synthesis, and mesenchymal differentiation in laboratory studies [10, 11]. These growth factors include platelet-derived growth factors (PGDF-AA, PDGF-AB, PDGF-BB), transforming growth factors (TGF-β1, TGF-β2), insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor β (FGF-β) [1, 9]. PDGF in PRP has a role in early wound healing and stimulates fibroblast proliferation [12]. TGF-β1 increases collagen production by fibroblasts [13]. PRP also comprises cytokines with pro-inflammatory (interleukin 1, interleukin 6) and anti-inflammatory (interleukin 4, interleukin 10) functions . The function of major growth factors and cytokines of relevance to wound healing is summarized in Table 5.1.
PRP therapy allows for supraphysiological concentrations of these molecules to be delivered to a site of injury to optimize, accelerate, or reinitiate tissue healing, regeneration, and repair [43, 44]. Platelet activation leads to immediate secretion of growth factors, upward of 70% in the first 10 min, and over 95% of the growth factors within 1 h [1, 37]. However, an in vitro study of PRP activated by contact with collagenous tissue, explants did not demonstrate a decrease in TGF-β1 and PDGF-BB levels between 24 and 96 h (4 days) of culture [45], suggesting that platelets may continue to synthesize and secrete growth factors after initial activation. In the absence of activation, PDGF-AB release from PRP prepared by four different systems occurred steadily out to 120 h of in vitro storage at physiological temperature (37 °C) [46].
Applications of PRP leverage the function of platelets for remodeling, repair, and regeneration. Current musculoskeletal applications of PRP include treatment of tendinopathy, osteoarthritis, ligament and meniscus injury, muscle injury, and spine disorders. Although PRP has been promoted and publicized as a regenerative therapy, it is important to note that studies thus far have not demonstrated de facto tissue regeneration in clinical sports and spine applications.
Creation and Classification of PRP
The different forms and methods of preparing PRP are numerous, and its nomenclature reflects this variation. Platelet concentrate, platelet gel, platelet-rich fibrin matrix, platelet-rich in growth factors, and platelet-rich fibrin are names of products produced by various devices.
Protocols for deriving PRP involve a one- or more commonly two-step centrifugation procedure , which vary by time and speed. The first centrifugation step separates whole blood into platelet and cell fractions. The second centrifugation step, which is typically at higher speed, further refines the platelet fraction. The final volume of PRP produced from whole blood varies but is usually approximately 10% of the initial blood volume.
Preparation methods vary by platelet concentration, leukocyte concentration (leukocyte-rich versus leukocyte-poor), platelet activation, and use of anticoagulant. Platelet concentrations range from 2.5- to 8-fold compared to whole blood. Autologous conditioned plasma is a subclassification of PRP, which typically contains a lower fold increase in platelet concentration. Leukocyte concentration varies between leukocyte-rich (LR-PRP) and leukocyte-poor (LP-PRP) preparations . Tailoring PRP preparations to the treatment of specific clinical conditions is beginning to be evaluated more rigorously, with early data suggesting that LR-PRP is more effective for tendinopathy, while LP-PRP is superior for OA [47, 48].
Platelet activation serves as the first step in the inflammatory cascade. In the body, platelets are activated by agents such as thrombin, collagen, ADP, serotonin, and thromboxane A2. If desired during PRP preparation, exogenous platelet activation is typically achieved by the use of thrombin or calcium chloride. However, there remains no consensus on timing of activation, if exogenous activation is necessary at all prior to injection, or if activation should occur after injection, through interactions with collagen matrix in the native local environment. Due to the risk of life-threatening coagulopathy associated with bovine thrombin, secondary to antibodies to Factors V and XI and thrombin, recombinant human thrombin is available as an activation agent [49].
Finally, anticoagulants such as anticoagulant citrate dextrose-A (ACDA) or citrate phosphate dextrose are used to prevent blood clotting during PRP preparation.
More than 25 PRP preparation kits are currently available on the market [50]. A list summarizing representative kits, their underlying technology, and characteristics of the resulting PRP products is shown in Table 5.2. PRP systems can be categorized as plasma- or buffy coat-based . Plasma-based systems exclude leukocytes at the expense of some platelets, whereas buffy coat-based systems maximize platelet yield but also retain leukocytes and red blood cells (RBCs) [51].
There remains no universal classification for PRP. In 2009, Dohan Ehrenfest et al. published the first PRP classification system , based on the presence of leukocytes and fibrin architecture: leukocyte-poor or pure PRP/low-density fibrin network after activation (P-PRP), leukocyte-rich PRP/low-density fibrin network after activation (L-PRP), leukocyte-poor PRP/high-density fibrin network after activation (P-PRF), and leukocyte-rich PRP/high-density fibrin network after activation (L-PRF) [56].
In 2012, Mishra et al. added two additional classification components of platelet activation or non-activation and level of platelet enrichment [57], while Delong et al. proposed the PAW classification (P = absolute number of platelets, A = manner of platelet activation, W = presence or absence of leukocytes) [51]. The PLRA classification proposed in 2015 encompasses platelet count (P), leukocyte content (L), RBC content (R), and activation (A) [58]. The DEPA classification published by Magalon et al. encompasses four components: dose of injected platelets (D), efficiency of production (E), purity of PRP produced (P), and activation process (A) [59]. Finally, the MARSPILL classification was published in 2017, which comprises method (M; handmade or machine), activation (A; activated or not activated), red blood cells (R; rich or poor), spin (S; one or two spins), platelet number (P; folds basal), image guided (I; guided or not guided), leukocyte concentration (L; rich or poor), and light activation (L; activated or not activated) [60].
The optimal degree of fold change in platelet concentration has been debated. Early studies suggested that ideal platelet concentrations were only two- to threefold over baseline and that higher fold changes inhibited healing. These findings are in line with in vitro studies of platelet-rich plasma, where a dose-response relationship between growth factor concentrations and cell activity existed until an asymptotic level was reached, with some growth factors exerting an inhibitory effect at sufficiently high concentrations [61]. This has been clarified by follow-up studies, which suggested that fold changes in the range of five- to sevenfold were ideal and that inhibition did not occur until up to tenfold increase over baseline [62].
Buffy coat-based PRP systems that produce higher platelet concentrations tend to produce higher leukocyte and RBC concentrations as well [51]. The controversy over leukocyte concentration has revolved around neutrophils and their association with pro-inflammatory cytokines, interleukin 1 (IL-1) and tumor necrosis factor (TNF-α), which may exacerbate inflammation in osteoarthritis or acute muscle injuries. LR-PRP has been shown to cause synoviocyte cell death in culture and increase expression of inflammatory markers [47]. Likewise, the presence of RBCs in PRP is controversial, as RBCs have been documented to cause chondrocyte death [47, 63]. However, the leukocytes in PRP also contain monocytes, which differentiate into macrophages. While the primary function of macrophages was previously thought to be only for phagocytosis, it is now recognized that different types of activated macrophages exist, which have pro-inflammatory (M1) and anti-inflammatory (M2) roles. The M2 macrophage has specific functions in wound healing, which may assist tissue repair. A PRP formulation enriched with M2 macrophages may therefore be ideal for certain tissue pathologies. Newer PRP devices are able to achieve higher platelet concentrations while minimizing both WBC and RBC content through a two-spin suspension protocol.
Differences in PRP composition are related not only to variation in preparation methods but also to variation among patients, given the autologous nature of PRP. Both age and sex are known to influence PRP composition. A study of 39 healthy patients with no history of orthopedic problems and no current NSAID, antiplatelet, or aspirin use reported significant differences in composition of LP-PRP from male versus female subjects, with sex influencing growth factor and cytokine profile more than age [64]. In this study, substantial variability in PRP composition was found within groups of male and female subjects stratified by age (“young” group aged 18–30 years, “older” group aged 45–60 years). Nevertheless, PRP from male patients consistently contained significantly higher levels of growth factors and cytokines than PRP from female patients (TGF-β1, basic fibroblast growth factor, IL-1β, interleukin 1 receptor antagonist protein, TNF-α). Variation due to age was detected only in significantly lower IGF-1 levels in PRP from “older” versus “young” patients. Extrapolation of this data from healthy subjects to patients with musculoskeletal or spine disorders is difficult, as the latter group may have various medical co-morbidities or take medications that were excluded from this study. However, donor factors such as age and gender, and processing factors such as the time of day of platelet collection [65] are variables that are recognized to influence the growth factor and cytokine composition of PRP, in addition to other variables in PRP preparation previously discussed in this section.
Clinical Applications of PRP
Over 400 clinical trials of PRP are listed on ClinicalTrials.gov for various diseases and conditions [66]. In this section, we discuss clinical applications of PRP and the current level of evidence supporting its use for musculoskeletal and spine disorders.
Tendinopathy
Tendon injuries are common in both active and more sedentary people and may occur acutely or secondary to overuse [67]. Acute injuries are classified as tendinitis during the active, acute inflammation phase and tendinosis during the chronic, non-healing phase, characterized by a lack of inflammatory cells on histology in addition to evidence of aberrant tissue repair and thickening, collagen degeneration, and neovascularization [68]. Tendinopathy is a general term for tendon disorders, and chronic tendinopathy for conditions that remain refractory to conventional treatment. Sustained or repetitive injury over time may lead to chronic pathology, disability, and loss of function. Chronic tendinopathy is postulated to be a quiescent state along the spectrum of tendon pathology, an abnormal healing response or stage of stasis, in contrast to the inflammation and inflammatory cell infiltration present in early tendinopathy [69].
In this setting, the goal of biologic agents in the treatment of chronic tendinopathy is to restore or restart the healing process within the local tissue environment, rather than decreasing inflammation in more acute or subacute injuries. In laboratory and preclinical studies, PRP enhanced ECM synthesis of tenocytes and tendon explants in vitro [45, 70, 71] and promoted patellar tendon repair in a rat model [72].
Applications of PRP for chronic tendinopathy has been investigated in multiple clinical studies. The most current evidence from a systematic review and meta-analysis of 18 randomized controlled trials (RCTs) of PRP for treatment of tendinopathy supported the use of a single injection of LR-PRP using a peppering technique intratendinously under ultrasound guidance [48]. Here we discuss specific findings of PRP for lateral epicondylar (common extensor), patellar, and Achilles tendinopathy , although the clinical use of PRP applies to rotator cuff, gluteus medius, hamstring, and other sites of tendinopathy as well.
A RCT of 100 patients with chronic lateral epicondylar tendinopathy compared PRP with corticosteroid injection, which demonstrated a significant improvement in pain and function after follow-up out to 2 years [73, 74]. Krogh et al. recruited 60 patients with chronic lateral epicondylar tendinopathy for a RCT comparing treatment by PRP, saline, or glucocorticoid injections and found no difference in pain reduction at their primary end point of 3 months [75]. A double-blind RCT of 230 patients with chronic lateral epicondylar tendinopathy , treated by dry needling with or without leukocyte-rich PRP, yielded significant improvement in elbow tenderness and pain at 24 weeks post-intervention for the PRP treatment group [76]. Most recently, a systematic review of RCTs compared clinical outcomes of PRP, autologous blood, and corticosteroid injections for lateral epicondylar tendinopathy [77]. A network meta-analysis of 10 eligible studies out of 374 identified RCTs concluded that both PRP and autologous blood injections improved pain compared to corticosteroid, but autologous blood injections had a higher risk of complications than PRP.
LR-PRP treatment for patellar tendinopathy was studied in a double-blind RCT of 23 patients and was compared to dry needling alone [78]. Both groups underwent a standardized eccentric exercise program in addition to the intervention. Subjects that received PRP demonstrated greater clinical improvement at 12 weeks post-intervention, but this early improvement did not persist, as no significant difference was found between groups after 26 weeks. In contrast, in a RCT of 46 athletes with patellar tendinopathy , where subjects were randomized to two PRP injections over 2 weeks or 3 sessions of focused extracorporeal shockwave therapy , subjects who received PRP injections demonstrated improved pain and function at later time points of 6- and 12-month follow-up [79]. The most recent evidence from a systematic review and meta-analysis of studies of nonoperative management for patellar tendinopathy (PRP, extracorporeal shockwave therapy, eccentric exercise) suggests that multiple PRP injections (≥2) offer more satisfactory results in terms of pain and function at follow-up ≥6 months [80].
However, there was no difference in pain or activity level out to 24 weeks in a double-blind RCT of 54 patients with chronic Achilles tendinopathy randomized to PRP or a saline placebo treatment, followed by an eccentric exercise program [81]. More recently, a RCT of 24 patients with chronic Achilles tendinopathy treated with PRP or saline injections did not report any improvement in pain or function at 3 months, and the study itself was limited by large dropout rate [82]. Overall, the most recent data suggest that PRP is less effective for Achilles tendinopathy than other sites. Two separate meta-analyses of PRP versus placebo (saline) injection [83] and of autologous blood-derived products [84] including PRP compared to placebo (sham injection, no injection, or PT alone) reported that PRP injections were not more effective than placebo for Achilles tendinopathy .
Table 5.3 summarizes the results of selected clinical trials of PRP for chronic tendinopathy. Although the findings are promising and generally supportive of PRP for treatment of chronic tendinopathy, inconsistencies and variation in outcomes from these studies reflect variation in PRP preparation methods, choice of control intervention, post-intervention rehabilitation protocols, and anatomic sites of pathology.
Osteoarthritis
Osteoarthritis (OA) is a leading cause of pain and disability in adults and is multifactorial in etiology. However, to date, there remain no disease-modifying therapies for OA that can reverse or prevent the structural changes found in later stages of disease. Laboratory studies have observed that PRP enhances chondrogenic differentiation of mesenchymal stem cells, proliferation, and ECM synthesis, leading to multiple clinical trials to assess the utility of PRP for treatment of OA , most notably of the knee and hip [87].
A systematic review of PRP injections for knee OA yielded three meta-analyses that met criteria, which compared outcomes of intra-articular PRP versus control hyaluronic acid or placebo injections [88]. Campbell et al. reported that PRP treatment led to clinically relevant improvements in symptom relief and function as early as 2 months, peaking at 6 months, and persisting up to 12 months post-intervention. They note variation in protocol, including number (1–4) of and timing (1–3 weeks) between PRP injections, PRP volume injected, one- versus two-step centrifugation, and platelet activation, as well as variation in patient profile including age, duration of pain, and severity of OA . Their findings also suggested that PRP is more effective for patients with only evidence of early radiographic evidence of OA or lower Kellgren-Lawrence grade. They were unable to determine if multiple PRP injections were helpful, although multiple injections may increase the risk of local adverse reactions. The variability across the three meta-analyses precluded conclusions regarding other protocol parameters. They did conclude that higher-quality RCTs were necessary to persuade insurance providers to provide coverage for PRP for knee OA . Most recently, a meta-analysis of RCTs reported that intra-articular PRP injection provides more pain relief and functional improvement in patients with symptomatic knee OA at 1-year follow-up compared to HA and saline [89].
While OA is traditionally described as a non-inflammatory arthritis, characterized by cartilage degeneration, it is now understood that OA affects all tissues within the joint and that inflammation plays a central role in both the onset and progression of disease. There has been much speculation that the role of PRP for clinical treatment of OA lies more in its anti-inflammatory and immunomodulatory effects for pain rather than its regenerative properties [52, 90]. In vitro studies have demonstrated that growth factors present in PRP can function in an anti-inflammatory role via the lipoxin LXA4 [9], which acts to resolve inflammatory processes, and that PRP modulates IL-1 production by macrophages [91].
Therefore, LP-PRP has been the preferred formulation for treatment of OA , given the concern for pro-inflammatory effects of neutrophils in LR-PRP preparations. Laboratory studies have demonstrated that LP-PRP decreased catabolism and increased tissue synthesis by chondrocytes [92]. A correlation was found between increasing leukocyte concentration and elevated inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8) [93]. Synoviocytes exhibited significant cell death and pro-inflammatory response with LR-PRP treatment, further supporting recommendations of LP-PRP preparations for intra-articular applications [47].
To this end, a meta-analysis of 6 RCTs and 3 prospective studies, totaling 1055 patients, compared outcomes and adverse effects of LP- and LR-PRP against control hyaluronic acid (HA) or placebo injections for knee OA [94]. Riboh et al. detected a small improvement in functional outcome scores in favor of LP-PRP versus LR-PRP compared with HA and placebo and did not detect any significant difference in safety profile between the two PRP formulations. Both LR- and LP-PRP were associated with a higher incidence of transient reactions such as local swelling and pain compared to HA. They again noted low-quality evidence due to variation in PRP preparation methods, even among LP- and LR-PRP formulations, and variation in severity of OA between treatment groups. Moreover, the analyzed studies skewed toward younger patients with milder OA .
Few studies have been published of PRP for hip OA , and two level I studies did not demonstrate long-term benefits of PRP versus HA at 1 year [95, 96]. A meta-analysis reported that patients with hip OA treated with PRP had improvements in pain and function at 2 months, but these changes were not sustainable, as there was no difference versus HA control at 6 and 12 months [97].
Table 5.4 lists the findings of selected clinical trials of PRP for OA . Overall, for knee OA, evidence suggests that LP-PRP improves pain and provides symptom relief for upward of 1 year following intervention. Selection of candidates with earlier stages of knee OA may prove more efficacious. In contrast, studies have not demonstrated a benefit of PRP over HA in treatment of symptomatic hip OA.
Ligament and Meniscus Injuries
PRP has been studied for treatment of ligament injuries , primarily in the context of enhancing surgical outcomes of anterior cruciate ligament (ACL) reconstruction, which is outside the scope of the nonoperative applications discussed in this chapter. In vitro studies have shown that PRP enhanced ACL cell viability and collagen production [104]. Overall, there is promising evidence that PRP can improve outcomes for ACL reconstruction [105, 106]. In addition, the ongoing Bridge-Enhanced ACL Repair (BEAR) Trial led by Murray et al. is investigating biologic augmentation of surgical ACL repair by PRP [107, 108].
Scant literature exists on the nonoperative treatment of ligament injuries by PRP. Laboratory studies have demonstrated that PRP stimulated DNA and collagen synthesis in human periodontal ligament cells [109, 110], and increased gene expression and synthesis of ECM proteins in equine suspensory ligament cells [45, 111]. Preclinical animal studies have utilized PRP to augment healing of medial collateral ligament (MCL) ruptures in a rabbit model and demonstrated greater mechanical strength of MCLs treated with PRP [112].
Case reports and series have been published for partial tears of the ulnar collateral ligament of the elbow in throwing athletes, suggesting a shorter return to play (RTP) following treatment with PRP [113, 114]. A small RCT of sixteen elite athletes with high ankle sprains (anterior inferior tibiofibular ligament tears) and dynamic syndesmosis instability randomized patients to receive ultrasound-guided PRP injections with rehabilitation versus rehabilitation only [115]. Subjects from both groups followed an identical rehabilitation protocol. In this small study, the PRP group demonstrated shorter RTP, syndesmosis re-stabilization, and decreased residual pain over time. However, further studies with higher levels of evidence are necessary to support the use of PRP for ligament injuries.
PRP has also been studied as a means to augment healing of meniscal tears in the avascular zone, which intrinsically do not heal and are typically surgically resected. Over time, loss of even a portion of the meniscus through arthroscopic partial meniscectomy predisposes to development of post-traumatic OA. To this end, preclinical and clinical studies have investigated the utility of PRP for meniscal repair and regeneration and for augmentation of surgical repair outcomes. In vitro, PRP increased rabbit meniscal cell proliferation and ECM synthesis compared to platelet-poor plasma (PRP) [116]. In vivo, PRP combined with gelatin hydrogel was implanted into meniscal defects in the avascular zone using a rabbit model. Compared to hydrogel without PRP, defects treated with PRP demonstrated greater cell numbers and ECM production, suggesting PRP can enhance the healing potential of the avascular zone of the meniscus.
In a case-control study of 34 patients undergoing open meniscal repair , the group that received PRP to augment repair demonstrated slight improvement at 1 year post-operatively [117]. In a separate study of surgeons performing 35 arthroscopic meniscus repairs with or without PRP augmentation, the addition of PRP was not found to influence reoperation rate [118]. To date, there have not been studies with higher levels of evidence published on the efficacy of PRP to guide nonoperative management of meniscal tears of traumatic or degenerative etiologies, although PRP is utilized for these applications in clinical practice. Therapeutic effects observed from PRP for degenerative meniscal tears in the setting of associated OA may result indirectly from treatment of the OA rather than the meniscal pathology itself.
Muscle Injuries
There is scant literature published on the use of PRP for muscle injuries . Hammond et al. completed a laboratory study using a rat model of an acute tibialis anterior muscle strain injury, treated with PRP, PPP, or no injection [119]. They demonstrated that PRP decreased recovery time in a small animal model and postulated that this was secondary to induction of myogenesis by growth factors present in PRP. A statistically significant decrease in recovery time was also reported in a RCT of 28 patients with acute hamstring injuries who were allocated to PRP with rehabilitation (26.7 ± 7.0 days) versus rehabilitation alone (42.5 ± 20.6 days), although there was substantial variance in the results [120]. In a double-blind, placebo-controlled RCT of 80 athletes with acute hamstring injuries, subjects were allocated to PRP or placebo saline injections, but did not demonstrate benefit of PRP in return to play or reinjury rate [121]. The most current meta-analysis of PRP for acute muscle injuries concluded with limited evidence that PRP may allow earlier return to play for patients with acute grade I or II muscle strains without a significant increase in risk of reinjury out to 6 months of follow-up [122].
Follow-up laboratory studies have suggested that depletion of platelets is more favorable for myocytes. Mazzocca et al. reported that a one-spin PRP protocol yielding lower platelet concentration increased myocyte proliferation [123]. Miroshnychenko et al. studied the effects of various PRP formulations on in vitro myogenic differentiation [124], and found that LR-PRP led to myoblast proliferation, but PPP and LR-PRP subjected to a second spin to remove platelets induced myoblast differentiation. It is clear that further clinical studies with higher levels of evidence must be performed, and may require consideration of tailoring PRP formulations specifically for treatment of muscle injuries .
Spine Disorders
Low back pain is among the most common outpatient complaints. Consequently, there is particular interest in PRP for treatment of disorders associated with low back pain, such as intervertebral disc (IVD) degeneration and facet joint osteoarthritis. In vitro laboratory studies have demonstrated that PRP stimulates proliferation and matrix synthesis by cells from both the nucleus pulposus (NP) and annulus fibrosus (AF) [125, 126]. PRP has also been shown to exhibit anti-inflammatory effects on NP cells exposed to pro-inflammatory cues [127]. A preclinical study utilized a rabbit model of IVD degeneration [128], injecting PRP in gelatin hydrogel microspheres into the NP, and comparing outcomes to control saline and sham groups. At 8 weeks, the authors noted suppression of degeneration with histologic evidence of ECM synthesis in animals injected with PRP. A follow-up study demonstrated greater IVD height on MRI and decreased apoptosis in the NP after PRP injection [129]. These findings were further verified in another rabbit study of IVD degeneration, comparing intradiscal PRP versus PPP injections [130].
In this setting, a few clinical studies of intradiscal PRP injections for low back pain have been performed with early but promising results. A prospective study of 22 patients who underwent intradiscal PRP injections (single-level to as many as five levels) demonstrated early improvement in pain and function out to 6 months [131]. A prospective, double-blind RCT of 47 patients with chronic discogenic low back pain received intradiscal PRP or contrast agent [132]. The 29 patients who received intradiscal PRP injections reported significant improvement in pain and function at 8 weeks through at least 2 years of follow-up [133].
Analogous to studies of PRP for OA at other anatomic sites, two studies on intra-articular PRP injections for lumbar facet joint syndrome were published by the same group of investigators. The first is a prospective study of 19 patients who received PRP injections, which demonstrated significant improvement in pain and function within a short-term study period of 3 months [134]. This group of investigators led by Wu et al. proceeded to a prospective RCT of 46 patients with lumbar facet joint syndrome, randomized to injections of PRP versus corticosteroid with local anesthetic (LA), with up to 6 months of follow-up [135]. Subjects who received corticosteroid/LA injections experienced initial improvement in pain and function, which decreased after 6 months. In contrast, subjects treated with PRP continued to experience improvement in pain and function out to 6 months.
For radicular pain, Centeno et al. has published the results of a case series of 470 patients who received lumbar epidural injections of platelet lysate, which consists of growth factors prepared by lysing platelets and removing cell debris [136]. Within the limitations of a case series, patients reported significant improvements in pain and function through 2 years of follow-up.
Although promising so far, more rigorous studies with higher levels of evidence must be performed to further investigate the utility of PRP for spine disorders.
Advantages of PRP
The primary advantage of PRP is the ability to offer more nonoperative treatment options for patients who have failed conventional treatment, who do not want surgery, or who are poor surgical candidates and for conditions with poor surgical outcomes, such as degenerative tendinopathies or meniscal tears.
Moreover, the autologous nature of PRP is thought to eliminate or at least minimize risk of immune rejection or disease transmission. Assuming sterility in preparation, the risk of contamination is low. Potential risks of PRP administration include adverse effects arising from the use of bovine thrombin used for platelet activation, which can rarely cause coagulopathy from antibody formation. Bovine thrombin is now avoided due to these risks, although earlier studies of PRP for non-musculoskeletal applications reported its use for platelet activation during oral and maxillofacial surgery [137,138,139,140] and wound care [29, 141,142,143,144,145].
Although there exists immense variation in PRP protocols, the procedure can be performed during the point of care in an office setting with access to phlebotomy services and a commercial PRP system. Although the cost of commercial PRP kits is not negligible, a standard hematology protocol for PRP preparation requires a little more than a centrifuge and basic laboratory supplies. This technology has been implemented in the global arena through the creation of a PRP injection program in Tanzania at the Bugando Medical Centre [146], via a collaboration with the local blood bank, providing proof of principle that access to PRP interventions can be achieved with minimal additional cost and resources.
Disadvantages of PRP
Disadvantages of PRP lie in the variability already well described in this chapter, including the lack of standardization in PRP preparation methods and reporting of PRP composition in literature, which limits comparisons between studies, coupled with the lack of one universally accepted classification scheme. High variability exists among patients, including donor factors such as age, gender, and comorbidities, and even among underlying patient conditions. Although clinical trials study PRP for specific pathologic conditions and utilize rigorous criteria for patient selection, there remains considerable heterogeneity among patients diagnosed with the same condition in terms of chronicity of symptoms and prior treatments such as oral medications, rehabilitation, and other injections. The durability of any intervention for musculoskeletal and spine disorders depends upon the quality of post-intervention rehabilitation and patient adherence to a home exercise program. Post-PRP rehabilitation protocols are not standardized for various conditions, and variability in therapy plays a significant role in the long-term outcomes of PRP intervention.
The success of a PRP intervention hinges on clinically significant improvement in standardized but subjective patient-reported outcomes of pain and function. The burden of proof for clinical efficacy of an intervention is all the more difficult to achieve when one considers that intra-articular saline placebo injections for knee OA have been reported to have both a statistically and clinically significant effect on pain and function out to 6-month follow-up [147]. Therefore, clinical investigators are now quantifying cytokine levels in the synovial fluid before and after PRP intervention for knee OA, in order to correlate clinical outcomes with the biological mechanisms of action of PRP [148].
Contraindications to PRP therapy include cancer (tumor or metastatic disease), active infections, thrombocytopenia, and pregnancy [149]. Growth factors such as isoforms of TGF-β and hepatocyte growth factor, found in PRP, have been associated with tumor growth [150], hence the relative contraindication in patients with cancer history . However, PRP has been utilized for patients with avascular necrosis of the mandible in cancer patients with a history of bisphosphonate use [151,152,153] and non-musculoskeletal applications in patients undergoing surgical tumor or complications related to active chemotherapy treatment [154, 155].
Finally, PRP therapy is not covered by insurances for the applications described in this chapter, which can pose a significant financial burden for patients. Wide variability in cost is present, to upward of $2000 or more per injection [2], based on many factors including the cost of the specific kit used for preparation and other local economic influences. The cost of PRP therapy is related to its off-label use for musculoskeletal and spine disorders, which do not have FDA approval.
Regulation of PRP
The clinical applications of PRP for musculoskeletal and spine disorders discussed in this chapter are considered off-label. PRP is a biologic and falls under the regulation of the FDA Center for Biologics Evaluation and Research (CBER). Under the Code of Federal Regulations (CFR) Title 21, PRP and other blood products are exempt from the FDA Regulation of Human Cells, Tissues, and Cellular and Tissue-based Products (HCT/Ps) [156]. Instead, the 510(k) application pathway has been used for clearance of PRP preparation systems that are considered “substantially equivalent” to other existing or predicate devices already available on the market. The first PRP preparation systems were reviewed by the Office of In Vitro Diagnostics and Radiological Health, received 510(k) clearance based upon predicate centrifuge devices, and were therefore classified as centrifuges.
The 510(k) pathway for clearance of PRP devices does not strictly require clinical data for FDA approval, as they are considered lower-risk devices and “substantially equivalent” to a previously cleared device [157]. The term “clearance” designates the limitations of use of the device, only to the indications of the predicate device that it has been determined to be “substantially equivalent .” This is in contrast to other regenerative therapies, which may receive “approval” through traditional FDA regulatory pathways as new drugs via new drug applications (NDA) or biologics license applications (BLA), which further require clinical data collected via investigational new drug (IND) or investigational device exemption (IDE) applications.
As early as February 2011, CBER granted 510(k) clearance to devices for mixing PRP with bone graft to improve its handling, for application to bony defects in the operative setting (“Platelet And Plasma Separator For Bone Graft Handling”) [158]. Injection or implantation of PRP without mixing with bone graft materials falls outside the intended use of these PRP systems and is considered off-label use. However, a clinician may still practice off-label use of PRP for musculoskeletal and spine disorders but may not market the use of the device for these off-label applications. CBER does not require an IND or IDE application to the FDA or institutional review board (IRB) approval for off-label use [159].
In 2007, the AutoloGel™ System (Cytomedix Inc., Gaithersburg, MD) received 510(k) clearance for topical application in the management of cutaneous wounds including chronic nonhealing diabetic, pressure, or venous wounds. Mixing PRP with bone graft for defects and topical application for chronic wounds remain the sole indications of use for PRP that have received FDA approval, although these treatments are considered experimental by insurance providers including the Centers for Medicare and Medicaid Services (CMS), with limited to no coverage at this time [160].
While PRP is not subject to FDA regulation of HCT/Ps under CFR Title 21, Part 1271, further activation of PRP by exogenous agents following centrifugation alone creates a potentially tricky situation in which PRP may be considered more than “minimally manipulated” and therefore subject to further regulation. Although no changes have yet occurred that impact off-label use of PRP, clinicians should remain up-to-date with the latest FDA regulatory stance on PRP.
Future Directions
Since its inception in the early 2000s, PRP therapy has rapidly entered the mainstream for applications as diverse as musculoskeletal and spine disorders to alopecia and aesthetics. The lack of conclusive scientific evidence of clinical efficacy, FDA approval, and insurance coverage has not significantly hindered the popularity of PRP therapy or patient interest.
Regulatory approval and insurance coverage decisions depend upon demonstrating higher-level supportive evidence of both safety and clinical efficacy of PRP therapy. This in turn requires a decrease in the variability found in prior PRP studies, which can be achieved in part by adoption of one universally accepted PRP classification scheme, and standardization in preparation methods, characterization, and reporting of PRP composition across clinical trials. Delivery of PRP must also be standardized, such as number and timing of injections and concurrently performed interventions such as percutaneous tenotomy, as well as post-procedural care with pathology-specific rehabilitation protocols. FDA approval for additional indications of PRP therapy requires a BLA or premarket approval (PMA) application, which involves larger-scale clinical studies that should be designed with close consideration of these variables in mind.
Although clinicians and patients have found success with PRP for the musculoskeletal and spine disorders described in this chapter, there remains a limited understanding of the precise pathophysiology that underlie these diseases. Without this knowledge, it is difficult to determine the precise targets of PRP therapy for each disease process and what relevant characteristics in PRP impact clinical response in patients. While current evidence suggests that LR-PRP is more suitable for tendinopathy and LP-PRP for OA, future work must continue to probe and define the growth factors and cytokine cocktails that are ideal for specific pathologies and develop novel methods of PRP preparation that yield these customized formulations.
Efforts are already underway in recently published studies of PRP for OA [148], in which investigators are measuring cytokine levels in synovial fluid to better understand the local effects of PRP, further refine its mechanism of action, and identify and validate biomarkers of disease. Since PRP is believed to improve pain and function for patients with OA through anti-inflammatory effects, the goal will be to demonstrate that decreasing inflammation will in turn slow progression of OA and ultimately, that PRP is a disease-modifying therapy for early-stage OA.
Although PRP is considered a regenerative therapy, based largely upon the effects of growth factors on cells and tissues in laboratory studies, convincing evidence of tissue regeneration has yet to be demonstrated in clinical studies. Demonstration of tissue regeneration is limited in part because clinical study results typically report standardized patient-reported outcomes without biological correlates or biomarkers that can support the potential efficacy of the intervention. Incorporation of OA biomarkers developed and validated for pain and disease progression [161] allows for a more objective measurement of pain improvement due to PRP and potential disease-modifying properties.
In summary, PRP is a promising therapy that offers a nonsurgical approach to treatment of musculoskeletal and spine disorders, for patients who have failed conventional therapy or with conditions that have poor surgical outcomes. However, there remains much to elucidate in the basic science and underlying mechanism of action of PRP, in order to accelerate regulatory approval and insurance coverage and expand access to PRP treatment for patients of all socioeconomic background. In the future, PRP therapy will require a personalized approach, tailoring PRP formulations for both patient-specific and condition-specific characteristics.
References
Marx RE. Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant Dent. 2001;10:225–8.
Schwarz A. A promising treatment for athletes, in blood. New York Times. 2009.
McCarrel TM, Mall NA, Lee AS, Cole BJ, Butty DC, Fortier LA. Considerations for the use of platelet-rich plasma in orthopedics. Sports Med. 2014;44:1025–36.
Harrison P, Cramer EM. Platelet alpha-granules. Blood Rev. 1993;7:52–62.
Leeksma CHW, Cohen JA. Determination of the life span of human blood platelets using labelled diisopropylfluorophosphonate. J Clin Invest. 1956;35:964–9.
Mason KD, Carpinelli MR, Fletcher JI, et al. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128:1173–86.
Lee KS, Wilson JJ, Rabago DP, Baer GS, Jacobson JA, Borrero CG. Musculoskeletal applications of platelet-rich plasma: fad or future? Am J Roentgenol. 2011;196:628–36.
Coppinger JA, Cagney G, Toomey S, Kislinger T, Belton O, McRedmond JP, Cahill DJ, Emili A, Fitzgerald DJ, Maguire PB. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood. 2004;103:2096–104.
El-Sharkawy H, Kantarci A, Deady J, Hasturk H, Liu H, Alshahat M, Van Dyke TE. Platelet-rich plasma: growth factors and pro- and anti-inflammatory properties. J Periodontol. 2007;78:661–9.
Akeda K, An HS, Okuma M, Attawia M, Miyamoto K, Thonar EJ-MA, Lenz ME, Sah RL, Masuda K. Platelet-rich plasma stimulates porcine articular chondrocyte proliferation and matrix biosynthesis. Osteoarthr Cartil. 2006;14:1272–80.
Vogel JP, Szalay K, Geiger F, Kramer M, Richter W, Kasten P. Platelet-rich plasma improves expansion of human mesenchymal stem cells and retains differentiation capacity and in vivo bone formation in calcium phosphate ceramics. Platelets. 2006;17:462–9.
Liu Y, Kalén A, Risto O, Wahlström O. Fibroblast proliferation due to exposure to a platelet concentrate in vitro is pH dependent. Wound Repair Regen. 2002;10:336–40.
Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79:1283–316.
LaPrade RF, Geeslin AG, Murray IR, Musahl V, Zlotnicki JP, Petrigliano F, Mann BJ. Biologic treatments for sports injuries II think tank – current concepts, future research, and barriers to advancement, part 1. Am J Sports Med. 2016;44:3270–83.
Scholz A, Plate KH, Reiss Y. Angiopoietin-2: a multifaceted cytokine that functions in both angiogenesis and inflammation. Ann N Y Acad Sci. 2015;1347:45–51.
Tanoue H, Morinaga J, Yoshizawa T, et al. Angiopoietin-like protein 2 promotes chondrogenic differentiation during bone growth as a cartilage matrix factor. Osteoarthr Cartil. 2018;26:108–17.
Yang X, Chen Z, Meng X, Sun C, Li M, Shu L, Fan D, Fan T, Huang AY, Zhang C. Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway. PLoS One. 2018;13:e0209300.
Fréchette J, Martineau I, Gagnon G. Platelet-rich plasmas: growth factor content and roles in wound healing. J Dent Res. 2005;84(5):434–9.
Tamama K, Fan VH, Griffith LG, Blair HC, Wells A. Epidermal growth factor as a candidate for ex vivo expansion of bone marrow-derived mesenchymal stem cells. Stem Cells. 2006;24:686–95.
Sibilia M, Wagner B, Hoebertz A, Elliott C, Marino S, Jochum W, Wagner EF. Mice humanised for the EGF receptor display hypomorphic phenotypes in skin, bone and heart. Development. 2003;130:4515–25.
Mazzucco L, Balbo V, Cattana E, Guaschino R, Borzini P. Not every PRP-gel is born equal. Evaluation of growth factor availability for tissues through four PRP-gel preparations: Fibrinet, RegenPRP-Kit, Plateltex and one manual procedure. Vox Sang. 2009;97:110–8.
Eppley BL, Woodell JE, Ph D, Higgins J. Experimental platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing. Plast Reconstructive Surg. 2003;114(6):1502–8.
Mazzocca AD, McCarthy MB, Chowaniec DM, Cote MP, Romeo AA, Bradley JP, Arciero RA, Beitzel K. Platelet-rich plasma differs according to preparation method and human variability. JBJS. 2012;94:308–16.
Hutley L, Shurety W, Newell F, McGeary R, Pelton N, Grant J, Herington A, Cameron D, Whitehead J, Prins J. Fibroblast growth factor 1: a key regulator of human adipogenesis. Diabetes. 2004;53:3097–106.
Javerzat S, Auguste P, Bikfalvi A. The role of fibroblast growth factors in vascular development. Trends Mol Med. 2002;8:483–9.
Nomi M, Miyake H, Sugita Y, Fujisawa M, Soker S. Role of growth factors and endothelial cells in therapeutic angiogenesis and tissue engineering. Curr Stem Cell Res Ther. 2006;1:333–43.
Haider HK, Jiang S, Idris NM, Ashraf M. IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circ Res. 2008;103:1300–8.
Longobardi L, O’Rear L, Aakula S, Johnstone B, Shimer K, Chytil A, Horton WA, Moses HL, Spagnoli A. Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling. J Bone Miner Res. 2006;21:626–36.
Everts PAM, Devilee RJJ, Brown Mahoney C, Eeftinck-Schattenkerk M, Box HAM, Knape JTA, van Zundert A. Platelet gel and fibrin sealant reduce allogeneic blood transfusions in total knee arthroplasty. Acta Anaesthesiol Scand. 2006;50:593–9.
Weibrich G, Kleis WKG, Hafner G, Hitzler WE. Growth factor levels in platelet-rich plasma and correlations with donor age, sex, and platelet count. J Craniomaxillofac Surg. 2002;30:97–102.
Sumanasinghe RD, Pfeiler TW, Monteiro-Riviere NA, Loboa EG. Expression of proinflammatory cytokines by human mesenchymal stem cells in response to cyclic tensile strain. J Cell Physiol. 2009;219:77–83.
Sundman EA, Cole BJ, Fortier LA. Growth factor and catabolic cytokine concentrations are influenced by the cellular composition of platelet-rich plasma. Am J Sports Med. 2011;39:2135–40.
Gothard D, Smith E, Kanczler J, Rashidi H, Qutachi O, Henstock J, Rotherham M, El Haj A, Shakesheff K, Oreffo R. Tissue engineered bone using select growth factors: a comprehensive review of animal studies and clinical translation studies in man. Eur Cell Mater. 2014;28:166–208.
Tokunaga A, Oya T, Ishii Y, et al. PDGF receptor beta is a potent regulator of mesenchymal stromal cell function. J Bone Miner Res. 2008;23:1519–28.
Ng F, Boucher S, Koh S, et al. PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood. 2008;112:295–307.
Castillo TN, Pouliot MA, Kim HJ, Dragoo JL, Kim HJ, Dragoo JL. Comparison of growth factor and platelet concentration from commercial platelet-rich plasma separation systems. Am J Sports Med. 2011;39:266–71.
Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg. 2004;62:489–96.
Paiva KBS, Granjeiro JM. Bone tissue remodeling and development: focus on matrix metalloproteinase functions. Arch Biochem Biophys. 2014;561:74–87.
Ogawa T, Akazawa T, Tabata Y. In vitro proliferation and chondrogenic differentiation of rat bone marrow stem cells cultured with gelatin hydrogel microspheres for TGF-beta1 release. J Biomater Sci Polym Ed. 2010;21:609–21.
Nöth U, Osyczka AM, Tuli R, Hickok NJ, Danielson KG, Tuan RS. Multilineage mesenchymal differentiation potential of human trabecular bone-derived cells. J Orthop Res. 2002;20:1060–9.
Joyce ME, Jingushi S, Bolander ME. Transforming growth factor-beta in the regulation of fracture repair. Orthop Clin North Am. 1990;21:199–209.
Grosskreutz CL, Anand-Apte B, Dupláa C, Quinn TP, Terman BI, Zetter B, D’Amore PA. Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro. Microvasc Res. 1999;58:128–36.
Anitua E, Sánchez M, Nurden AT, Zalduendo MM, De la Fuente M, Azofra J, Andía I. Platelet-released growth factors enhance the secretion of hyaluronic acid and induce hepatocyte growth factor production by synovial fibroblasts from arthritic patients. Rheumatology. 2007;46:1769–72.
Creaney L, Hamilton B. Growth factor delivery methods in the management of sports injuries: the state of play. Br J Sports Med. 2008;42:314–20.
McCarrel T, Fortier L. Temporal growth factor release from platelet-rich plasma, trehalose lyophilized platelets, and bone marrow aspirate and their effect on tendon and ligament gene expression. J Orthop Res. 2009;27:1033–42.
Leitner GC, Gruber R, Neumüller J, Wagner A, Kloimstein P, Höcker P, Körmöczi GF, Buchta C. Platelet content and growth factor release in platelet-rich plasma: a comparison of four different systems. Vox Sang. 2006;91:135–9.
Braun HJ, Kim HJ, Chu CR, Dragoo JL. The effect of platelet-rich plasma formulations and blood products on human synoviocytes. Am J Sports Med. 2014;42:1204–10.
Fitzpatrick J, Bulsara M, Zheng MH. The effectiveness of platelet-rich plasma in the treatment of tendinopathy. Am J Sports Med. 2017;45:226–33.
Zehnder JL, Leung LL. Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin. Blood. 1990;76:2011–6.
Chahla J, Cinque ME, Piuzzi NS, Mannava S, Geeslin AG, Murray IR, Dornan GJ, Muschler GF, LaPrade RF. A call for standardization in platelet-rich plasma preparation protocols and composition reporting. JBJS. 2017;99:1769–79.
DeLong JM, Russell RP, Mazzocca AD. Platelet-rich plasma: the PAW classification system. Arthrosc J Arthrosc Relat Surg. 2012;28:998–1009.
Andia I, Maffulli N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat Rev Rheumatol. 2013;9:721–30.
Redler LH, Thompson SA, Hsu SH, Ahmad CS, Levine WN. Platelet-rich plasma therapy: a systematic literature review and evidence for clinical use. Phys Sportsmed. 2011;39:42–51.
Lopez-Vidriero E, Goulding KA, Simon DA, Sanchez M, Johnson DH. The use of platelet-rich plasma in arthroscopy and sports medicine: optimizing the healing environment. Arthrosc J Arthrosc Relat Surg. 2010;26:269–78.
Engebretsen L, Steffen K, Alsousou J, et al. IOC consensus paper on the use of platelet-rich plasma in sports medicine. Br J Sports Med. 2010;44:1072–81.
Ehrenfest DM, Rasmusson L, Albrektsson T. Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends Biotechnol. 2009;27:158–67.
Mishra A, Harmon K, Woodall J, Vieira A. Sports medicine applications of platelet rich plasma. Curr Pharm Biotechnol. 2012;13:1185–95.
Mautner K, Malanga GA, Smith J, Shiple B, Ibrahim V, Sampson S, Bowen JE. A call for a standard classification system for future biologic research: the rationale for new PRP nomenclature. PM R. 2015;7:S53–9.
Magalon J, Chateau AL, Bertrand B, Louis ML, Silvestre A, Giraudo L, Veran J, Sabatier F. DEPA classification: a proposal for standardising PRP use and a retrospective application of available devices. BMJ Open Sport Exerc Med. 2016;2:e000060.
Lana JF, Purita J, Paulus C, et al. Contributions for classification of platelet rich plasma – proposal of a new classification: MARSPILL. Regen Med. 2017;12:565–74.
Mooren RE, Hendriks EJ, van den Beucken JJ, Merkx MA, Meijer GJ, Jansen JA, Stoelinga PJW. The effect of platelet-rich plasma in vitro on primary cells: rat osteoblast-like cells and human endothelial cells. Tissue Eng Part A. 2010;16:3159–72.
Giusti I, Rughetti A, D’Ascenzo S, Millimaggi D, Pavan A, Dell’Orso L, Dolo V. Identification of an optimal concentration of platelet gel for promoting angiogenesis in human endothelial cells. Transfusion. 2009;49:771–8.
Roosendaal G, Vianen ME, Marx JJM, Van Den Berg HM, Lafeber FPJG, Bijlsma JWJ. Blood-induced joint damage: a human in vitro study. Arthritis Rheum. 1999;42:1025–32.
Xiong G, Lingampalli N, Koltsov JCB, Leung LL, Bhutani N, Robinson WH, Chu CR. Men and women differ in the biochemical composition of platelet-rich plasma. Am J Sports Med. 2018;46:409–19.
Hartley PS. The diurnal tick-tockery of platelet biology. Platelets. 2012;23:157–60.
Medicine USNL of search of: platelet rich plasma – List Results 2019 ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=&term=platelet+rich+plasma&cntry=&state=&city=&dist=. Accessed 27 Jan 2019.
Maffulli N, Wong J, Almekinders LC. Types and epidemiology of tendinopathy. Clin Sports Med. 2003;22:675–92.
Pingel J, Lu Y, Starborg T, Fredberg U, Langberg H, Nedergaard A, Weis M, Eyre D, Kjaer M, Kadler KE. 3-D ultrastructure and collagen composition of healthy and overloaded human tendon: evidence of tenocyte and matrix buckling. J Anat. 2014;224:548–55.
Millar NL, Hueber AJ, Reilly JH, Xu Y, Fazzi UG, Murrell GAC, McInnes IB. Inflammation is present in early human tendinopathy. Am J Sports Med. 2010;38:2085–91.
Schnabel LV, Mohammed HO, Miller BJ, McDermott WG, Jacobson MS, Santangelo KS, Fortier LA. Platelet rich plasma (PRP) enhances anabolic gene expression patterns in flexor digitorum superficialis tendons. J Orthop Res. 2007;25:230–40.
de Mos M, van der Windt AE, Jahr H, van Schie HT, Weinans H, Verhaar JAN, van Osch GJ. Can platelet-rich plasma enhance tendon repair? A cell culture study. Am J Sports Med. 2008;36:1171–8.
Aspenberg P, Virchenko O. Platelet concentrate injection improves Achilles tendon repair in rats. Acta Orthop Scand. 2004;75:93–9.
Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial. Am J Sports Med. 2010;38:255–62.
Gosens T, Peerbooms JC, Van Laar W, Den Oudsten BL. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. Am J Sports Med. 2011;39:1200–8.
Krogh TP, Fredberg U, Stengaard-Pedersen K, Christensen R, Jensen P, Ellingsen T. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med. 2013;41:625–35.
Mishra AK, Skrepnik NV, Edwards SG, Jones GL, Sampson S, Vermillion DA, Ramsey ML, Karli DC, Rettig AC. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med. 2014;42:463–71.
Arirachakaran A, Sukthuayat A, Sisayanarane T, Laoratanavoraphong S, Kanchanatawan W, Kongtharvonskul J. Platelet-rich plasma versus autologous blood versus steroid injection in lateral epicondylitis: systematic review and network meta-analysis. J Orthop Traumatol. 2016;17:101–12.
Dragoo JL, Wasterlain AS, Braun HJ, Nead KT. Platelet-rich plasma as a treatment for patellar tendinopathy: a double-blind, randomized controlled trial. Am J Sports Med. 2014;42:610–8.
Vetrano M, Castorina A, Vulpiani MC, Baldini R, Pavan A, Ferretti A. Platelet-rich plasma versus focused shock waves in the treatment of jumper’s knee in athletes. Am J Sports Med. 2013;41:795–803.
Andriolo L, Altamura SA, Reale D, Candrian C, Zaffagnini S, Filardo G. Nonsurgical treatments of patellar tendinopathy: multiple injections of platelet-rich plasma are a suitable option: a systematic review and meta-analysis. Am J Sports Med. 2019;47(4):1001–18.
de Vos RJ, Weir A, van Schie HTM, Bierma-Zeinstra SMA, Verhaar JAN, Weinans H, Tol JL. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA. 2010;303:144–9.
Krogh TP, Ellingsen T, Christensen R, Jensen P, Fredberg U. Ultrasound-guided injection therapy of achilles tendinopathy with platelet-rich plasma or saline: a randomized, blinded, placebo-controlled trial. Am J Sports Med. 2016;44:1990–7.
Lin M-T, Chiang C-F, Wu C-H, Hsu H-H, Tu Y-K. Meta-analysis comparing autologous blood-derived products (including platelet-rich plasma) injection versus placebo in patients with Achilles tendinopathy. Arthroscopy. 2018;34:1966–75.
Zhang Y-J, Xu S-Z, Gu P-C, Du J-Y, Cai Y-Z, Zhang C, Lin X-J. Is platelet-rich plasma injection effective for chronic Achilles tendinopathy? A meta-analysis. Clin Orthop Relat Res. 2018;476:1633–41.
de Vos RJ, Weir A, van Schie HTM, Bierma-Zeinstra SMA, Verhaar JAN, Weinans H, Tol JL. Platelet rich plasma injection for chronic Achilles tendinopathy. JAMA. 2010;303:144–9.
De Jonge S, De Vos RJ, Weir A, Van Schie HTM, Bierma-Zeinstra SMA, Verhaar JAN, Weinans H, Tol JL. One-year follow-up of platelet-rich plasma treatment in chronic achilles tendinopathy: a double-blind randomized placebo-controlled trial. Am J Sports Med. 2011;39:1623–9.
Spreafico A, Chellini F, Frediani B, et al. Biochemical investigation of the effects of human platelet releasates on human articular chondrocytes. J Cell Biochem. 2009;108:1153–65.
Campbell KA, Saltzman BM, Mascarenhas R, Khair MM, Verma NN, Bach BR, Cole BJ. Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? A systematic review of overlapping meta-analyses. Arthroscopy. 2015;31:2213–21.
Dai W-L, Zhou A-G, Zhang H, Zhang J. Efficacy of platelet-rich plasma in the treatment of knee osteoarthritis: a meta-analysis of randomized controlled trials. Arthrosc J Arthrosc Relat Surg. 2017;33:659–70.
Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: a systematic review. Arthrosc J Arthrosc Relat Surg. 2016;32:495–505.
Woodall J, Tucci M, Mishra A, Benghuzzi H. Cellular effects of platelet rich plasma: a study on HL-60 macrophage-like cells. Biomed Sci Instrum. 2007;43:266–71.
Sundman EA, Cole BJ, Karas V, Della Valle C, Tetreault MW, Mohammed HO, Fortier LA. The anti-inflammatory and matrix restorative mechanisms of platelet-rich plasma in osteoarthritis. Am J Sports Med. 2014;42:35–41.
McCarrel TM, Minas T, Fortier LA. Optimization of leukocyte concentration in platelet-rich plasma for the treatment of tendinopathy. J Bone Joint Surg Am. 2012;94:e143.
Riboh JC, Saltzman BM, Yanke AB, Fortier L, Cole BJ. Effect of leukocyte concentration on the efficacy of platelet-rich plasma in the treatment of knee osteoarthritis. Am J Sports Med. 2016;44:792–800.
Di Sante L, Villani C, Santilli V, Valeo M, Bologna E, Imparato L, Paoloni M, Iagnocco A. Intra-articular hyaluronic acid vs platelet-rich plasma in the treatment of hip osteoarthritis. Med Ultrason. 2016;18:463–8.
Battaglia M, Guaraldi F, Vannini F, Rossi G, Timoncini A, Buda R, Giannini S. Efficacy of ultrasound-guided intra-articular injections of platelet-rich plasma versus hyaluronic acid for hip osteoarthritis. Orthopedics. 2013;36:e1501–8.
Ye Y, Zhou X, Mao S, Zhang J, Lin B. Platelet rich plasma versus hyaluronic acid in patients with hip osteoarthritis: a meta-analysis of randomized controlled trials. Int J Surg. 2018;53:279–87.
Filardo G, Di Matteo B, Di Martino A, Merli ML, Cenacchi A, Fornasari P, Marcacci M, Kon E. Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med. 2015;43:1575–82.
Di Martino A, Di Matteo B, Papio T, Tentoni F, Selleri F, Cenacchi A, Kon E, Filardo G. Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med. 2018;47(2):347–54.
Smith PA. Intra-articular autologous conditioned plasma injections provide safe and efficacious treatment for knee osteoarthritis: An FDA-sanctioned, randomized, double-blind, placebo-controlled clinical trial. Am J Sports Med. 2016;44:884–91.
Cole BJ, Karas V, Hussey K, Merkow DB, Pilz K, Fortier LA. Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med. 2017;45:339–46.
Duymus TM, Mutlu S, Dernek B, Komur B, Aydogmus S, Kesiktas FN. Choice of intra-articular injection in treatment of knee osteoarthritis: platelet-rich plasma, hyaluronic acid or ozone options. Knee Surgery Sport Traumatol Arthrosc. 2017;25:485–92.
Görmeli G, Görmeli CA, Ataoglu B, Çolak C, Aslantürk O, Ertem K. Multiple PRP injections are more effective than single injections and hyaluronic acid in knees with early osteoarthritis: a randomized, double-blind, placebo-controlled trial. Knee Surgery Sport Traumatol Arthrosc. 2017;25:958–65.
Fallouh L, Nakagawa K, Sasho T, Arai M, Kitahara S, Wada Y, Moriya H, Takahashi K. Effects of autologous platelet-rich plasma on cell viability and collagen synthesis in injured human anterior cruciate ligament. J Bone Joint Surg Am. 2010;92:2909–16.
Orrego M, Larrain C, Rosales J, Valenzuela L, Matas J, Durruty J, Sudy H, Mardones R. Effects of platelet concentrate and a bone plug on the healing of hamstring tendons in a bone tunnel. Arthroscopy. 2008;24:1373–80.
Radice F, Yánez R, Gutiérrez V, Rosales J, Pinedo M, Coda S. Comparison of magnetic resonance imaging findings in anterior cruciate ligament grafts with and without autologous platelet-derived growth factors. Arthroscopy. 2010;26:50–7.
Murray MM, Flutie BM, Kalish LA, Ecklund K, Fleming BC, Proffen BL, Micheli LJ. The bridge-enhanced anterior cruciate ligament repair (BEAR) procedure: an early feasibility cohort study. Orthop J Sport Med. 2016;4:2325967116672176.
Perrone GS, Proffen BL, Kiapour AM, Sieker JT, Fleming BC, Murray MM. Bench-to-bedside: bridge-enhanced anterior cruciate ligament repair. J Orthop Res. 2017;35:2606–12.
Okuda K, Kawase T, Momose M, Murata M, Saito Y, Suzuki H, Wolff LF, Yoshie H. Platelet-rich plasma contains high levels of platelet-derived growth factor and transforming growth factor-β and modulates the proliferation of periodontally related cells in vitro. J Periodontol. 2003;74:849–57.
Kawase T, Okuda K, Wolff LF, Yoshie H. Platelet-rich plasma-derived fibrin clot formation stimulates collagen synthesis in periodontal ligament and osteoblastic cells in vitro. J Periodontol. 2003;74:858–64.
Smith JJ, Ross MW, Smith RKW. Anabolic effects of acellular bone marrow, platelet rich plasma, and serum on equine suspensory ligament fibroblasts in vitro. Vet Comp Orthop Traumatol. 2006;19:43–7.
Yoshioka T, Kanamori A, Washio T, Aoto K, Uemura K, Sakane M, Ochiai N. The effects of plasma rich in growth factors (PRGF-Endoret) on healing of medial collateral ligament of the knee. Knee Surg Sports Traumatol Arthrosc. 2013;21:1763–9.
Podesta L, Crow SA, Volkmer D, Bert T, Yocum LA. Treatment of partial ulnar collateral ligament tears in the elbow with platelet-rich plasma. Am J Sports Med. 2013;41:1689–94.
Dines JS, Williams PN, ElAttrache N, Conte S, Tomczyk T, Osbahr DC, Dines DM, Bradley J, Ahmad CS. Platelet-rich plasma can be used to successfully treat elbow ulnar collateral ligament insufficiency in high-level throwers. Am J Orthop (Belle Mead NJ). 2016;45:296–300.
Laver L, Carmont MR, McConkey MO, Palmanovich E, Yaacobi E, Mann G, Nyska M, Kots E, Mei-Dan O. Plasma rich in growth factors (PRGF) as a treatment for high ankle sprain in elite athletes: a randomized control trial. Knee Surgery Sport Traumatol Arthrosc. 2015;23:3383–92.
Ishida K, Kuroda R, Miwa M, Tabata Y, Hokugo A, Kawamoto T, Sasaki K, Doita M, Kurosaka M. The regenerative effects of platelet-rich plasma on meniscal cells in vitro and its in vivo application with biodegradable gelatin hydrogel. Tissue Eng. 2007;13:1103–12.
Pujol N, De Chou ES, Boisrenoult P, Beaufils P. Platelet-rich plasma for open meniscal repair in young patients: any benefit? Knee Surgery Sport Traumatol Arthrosc. 2015;23:51–8.
Griffin JW, Hadeed MM, Werner BC, Diduch DR, Carson EW, Miller MD. Platelet-rich plasma in meniscal repair: does augmentation improve surgical outcomes? Clin Orthop Relat Res. 2015;473:1665–72.
Hammond JW, Hinton RY, Curl LA, Muriel JM, Lovering RM. Use of autologous platelet-rich plasma to treat muscle strain injuries. Am J Sports Med. 2009;37:1135–42.
A Hamid MS, Mohamed Ali MR, Yusof A, George J, LPC L. Platelet-rich plasma injections for the treatment of hamstring injuries. Am J Sports Med. 2014;42:2410–8.
Reurink G, Goudswaard GJ, Moen MH, Weir A, Verhaar JAN, Bierma-Zeinstra SMA, Maas M, Tol JL. Platelet-rich plasma injections in acute muscle injury. N Engl J Med. 2014;370:2546–7.
Sheth U, Dwyer T, Smith I, Wasserstein D, Theodoropoulos J, Takhar S, Chahal J. Does platelet-rich plasma Lead to earlier return to sport when compared with conservative treatment in acute muscle injuries? A systematic review and meta-analysis. Arthrosc – J Arthrosc Relat Surg. 2018;34:281–8.
Mazzocca AD, McCarthy MBR, Chowaniec DM, Dugdale EM, Hansen D, Cote MP, Bradley JP, Romeo AA, Arciero RA, Beitzel K. The positive effects of different platelet-rich plasma methods on human muscle, bone, and tendon cells. Am J Sports Med. 2012;40:1742–9.
Miroshnychenko O, Chang WT, Dragoo JL. The use of platelet-rich and platelet-poor plasma to enhance differentiation of skeletal myoblasts: implications for the use of autologous blood products for muscle regeneration. Am J Sports Med. 2017;45:945–53.
Pirvu TN, Schroeder JE, Peroglio M, Verrier S, Kaplan L, Richards RG, Alini M, Grad S. Platelet-rich plasma induces annulus fibrosus cell proliferation and matrix production. Eur Spine J. 2014;23:745–53.
Akeda K, An HS, Pichika R, Attawia M, Eugene JM, Lenz ME, Uchida A, Masuda K. Platelet-rich plasma (PRP) stimulates the extracellular matrix metabolism of porcine nucleus pulposus and anulus fibrosus cells cultured in alginate beads. Spine (Phila Pa 1976). 2006;31:959–66.
Kim H-J, Yeom JS, Koh Y-G, Yeo J-E, Kang K-T, Kang Y-M, Chang B-S, Lee C-K. Anti-inflammatory effect of platelet-rich plasma on nucleus pulposus cells with response of TNF-α and IL-1. J Orthop Res. 2014;32:551–6.
Nagae M, Ikeda T, Mikami Y, Hase H, Ozawa H, Matsuda K-I, Sakamoto H, Tabata Y, Kawata M, Kubo T. Intervertebral disc regeneration using platelet-rich plasma and biodegradable gelatin hydrogel microspheres. Tissue Eng. 2007;13:147–58.
Sawamura K, Ikeda T, Nagae M, et al. Characterization of in vivo effects of platelet-rich plasma and biodegradable gelatin hydrogel microspheres on degenerated intervertebral discs. Tissue Eng Part A. 2009;15:3719–27.
Obata S, Akeda K, Imanishi T, Masuda K, Bae W, Morimoto R, Asanuma Y, Kasai Y, Uchida A, Sudo A. Effect of autologous platelet-rich plasma-releasate on intervertebral disc degeneration in the rabbit anular puncture model: a preclinical study. Arthritis Res Ther. 2012;14:R241.
Levi D, Horn S, Tyszko S, Levin J, Hecht-Leavitt C, Walko E. Intradiscal platelet-rich plasma injection for chronic discogenic low back pain: preliminary results from a prospective trial. Pain Med. 2016;17:1010–22.
Tuakli-Wosornu YA, Terry A, Boachie-Adjei K, Harrison JR, Gribbin CK, LaSalle EE, Nguyen JT, Solomon JL, Lutz GE. Lumbar intradiskal platelet-rich plasma (PRP) injections: a prospective, double-blind, randomized controlled study. PM&R. 2016;8:1–10.
Monfett M, Harrison J, Boachie-Adjei K, Lutz G. Intradiscal platelet-rich plasma (PRP) injections for discogenic low back pain: an update. Int Orthop. 2016;40:1321–8.
Wu J, Du Z, Lv Y, Zhang J, Xiong W, Wang R, Liu R, Zhang G, Liu QA. New technique for the treatment of lumbar facet joint syndrome using intra-articular injection with autologous platelet rich plasma. Pain Phys. 2016;19:617–25.
Wu J, Zhou J, Liu C, Zhang J, Xiong W, Lv Y, Liu R, Wang R, Du Z, Zhang G, Liu Q. A prospective study comparing platelet-rich plasma and local anesthetic (LA)/corticosteroid in intra-articular injection for the treatment of lumbar facet joint syndrome. Pain Pract. 2017;17:914–24.
Centeno C, Markle J, Dodson E, Stemper I, Hyzy M, Williams C, Freeman M. The use of lumbar epidural injection of platelet lysate for treatment of radicular pain. J Exp Orthop. 2017;4:38.
Marx RE, Carlson ER, Eichstaedt RM, Schimmele SR, Strauss JE, Georgeff KR. Platelet-rich plasma: growth factor enhancement for bone grafts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;85:638–46.
Kassolis JD, Rosen PS, Reynolds MA. Alveolar ridge and sinus augmentation utilizing platelet-rich plasma in combination with freeze-dried bone allograft: case series. J Periodontol. 2000;71:1654–61.
Whitman DH, Berry RL, Green DM. Platelet gel: an autologous alternative to fibrin glue with applications in oral and maxillofacial surgery. J Oral Maxillofac Surg. 1997;55:1294–9.
Froum SJ, Wallace SS, Tarnow DP, Cho S-C. Effect of platelet-rich plasma on bone growth and osseointegration in human maxillary sinus grafts: three bilateral case reports. Int J Periodontics Restorative Dent. 2002;22:45–53.
Vang SN, Brady CP, Christensen KA, Allen KR, Anderson JE, Isler JR, Holt DW, Smith LM. Autologous platelet gel in coronary artery bypass grafting: effects on surgical wound healing. J Extra Corpor Technol. 2007;39:31–8.
Trowbridge CC, Stammers AH, Woods E, Yen BR, Klayman M, Gilbert C. Use of platelet gel and its effects on infection in cardiac surgery. J Extra Corpor Technol. 2005;37:381–6.
Khalafi RS, Bradford DW, Wilson MG. Topical application of autologous blood products during surgical closure following a coronary artery bypass graft. Eur J Cardiothorac Surg. 2008;34:360–4.
Driver VR, Hanft J, Fylling CP, Beriou JM, Autologel Diabetic Foot Ulcer Study Group. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage. 2006;52:68–70.
Carter MJ, Fylling CP, Li WW, de Leon J, Driver VR, Serena TE, Wilson J. Analysis of run-in and treatment data in a wound outcomes registry: clinical impact of topical platelet-rich plasma gel on healing trajectory. Int Wound J. 2011;8:638–50.
Kim AE. Dr. Alfred Gellhorn and Dr. Christopher Visco present NewYork-Presbyterian’s efforts in Tanzania at the United Nations | Department of Rehabilitation Medicine 2017. https://rehabmed.weill.cornell.edu/dr-alfred-gellhorn-and-dr-christopher-visco-present-newyork-presbyterians-efforts-tanzania-united. Accessed 27 Jan 2019.
Saltzman BM, Leroux T, Meyer MA, Basques BA, Chahal J, Bach BR, Yanke AB, Cole BJ. The therapeutic effect of intra-articular normal saline injections for knee osteoarthritis: a meta-analysis of evidence level 1 studies. Am J Sports Med. 2017;45:2647–53.
Cole BJ, Karas V, Hussey K, Pilz K, Fortier LA. Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med. 2017;45:339–46.
Bava ED, Barber FA. Platelet-rich plasma products in sports medicine. Phys Sportsmed. 2011;39:94–9.
Pollard JW. Tumour-stromal interactions. Transforming growth factor-beta isoforms and hepatocyte growth factor/scatter factor in mammary gland ductal morphogenesis. Breast Cancer Res. 2001;3:230–7.
Curi MM, Cossolin GSI, Koga DH, Araújo SR, Feher O, dos Santos MO, Zardetto C. Treatment of avascular osteonecrosis of the mandible in cancer patients with a history of bisphosphonate therapy by combining bone resection and autologous platelet-rich plasma: report of 3 cases. J Oral Maxillofac Surg. 2007;65:349–55.
Mozzati M, Gallesio G, Arata V, Pol R, Scoletta M. Platelet-rich therapies in the treatment of intravenous bisphosphonate-related osteonecrosis of the jaw: a report of 32 cases. Oral Oncol. 2012;48:469–74.
Martins MAT, Martins MD, Lascala CA, Curi MM, Migliorati CA, Tenis CA, Marques MM. Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: a preliminary study. Oral Oncol. 2012;48:79–84.
Aielli F, Giusti R, Rughetti A, Dell’Orso L, Ficorella C, Porzio G. Rapid resolution of refractory chemotherapy-induced oral mucositis with platelet gel-released supernatant in a pediatric cancer patient: a case report. J Pain Symptom Manag. 2014;48:e2–4.
Di Costanzo G, Loquercio G, Marcacci G, Iervolino V, Mori S, Petruzziello A, Barra P, Cacciapuoti C. Use of allogeneic platelet gel in the management of chemotherapy extravasation injuries: a case report. Onco Targets Ther. 2015;8:401–4.
U.S. Department of Health and Human Services. Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use 2017. https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm585403.pdf. Accessed 20 Jan 2019.
Beitzel K, Allen D, Apostolakos J, Russell R, McCarthy M, Gallo G, Cote M, Mazzocca A. US definitions, current use, and FDA stance on use of platelet-rich plasma in sports medicine. J Knee Surg. 2014;28:029–34.
U.S. Food and Drug Administration. 510(k) premarket notification 2019. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm?ID=BK100058. Accessed 20 Jan 2019.
U.S. Food and Drug Administration. “Off-label” and investigational use of marketed drugs, biologics, and medical devices – Information Sheet 2018. https://www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm. Accessed 20 Jan 2019.
U.S. Centers for Medicare & Medicaid Services. Autologous platelet-rich plasma – Centers for Medicare & Medicaid Services 2015. https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development/Autologous-Platelet-rich-Plasma.html. Accessed 20 Jan 2019.
Kraus VB, Collins JE, Hargrove D, Losina E, Nevitt M, Katz JN, Wang SX, Sandell LJ, Hoffmann SC, Hunter DJ. Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA biomarkers consortium. Ann Rheum Dis. 2017;76:186–95.
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Yuan, X.(., Gellhorn, A.C. (2020). Platelet-Rich Plasma. In: Cooper, G., Herrera, J., Kirkbride, J., Perlman, Z. (eds) Regenerative Medicine for Spine and Joint Pain. Springer, Cham. https://doi.org/10.1007/978-3-030-42771-9_5
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