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l a t ~ l e t ~ R i c h PlasmaFrom Basic Science to Clinical pplicationsTimothy E. Foster,*t MD, Brian L Puskas,t MD, Bert R. Mandelbaum,+ MD,Michael B. Gerhardt,+ MD, and Scott A. Rodeo, MDFrom taoston University School of Medicine, Boston, Massachusetts,santa Monica Orthopaedic and Sports Medicine Group, Santa Monica,California, and the Hospital for Special Surgery, ew York ew York

Platelet-rich plasma PRP) has been utilized in surgery for 2 decades; there has been a recent interest in the use of PRP for the treatment of sports-related injuries. PRP contains growth factors and bioactive proteins that influence the healing of tendon, ligamentmuscle, and bone. This article examines the basic science of PRP, and it describes the current clinical applications in sports medicine.This study reviews and evaluates the human studies that have been published in the orthopaedic surgery and sports medicine literature. The use of PRP in amateur and professional sports is reviewed, and the regulation of PRP by antidoping agencies is discussedKeywords platelet-rich plasma PRP); growth factors

Research into the biology of bone, ligament, and tendonhealing has led to the development of a variety of productsdesigned to help stimulate biologic factors and promotehealing. The use of the autologous and recombinant products is a rapidly growing field of orthopaedics focusing onmanipulating growth factors and secretory proteins tomaximize the healing of bone and soft tissues. Despitetheir clinical use, many of these products have not beenstudied using rigorous scientific standards.

Platelet-rich plasma PRP) is an example of one suchautologous product that has been utilized and studiedsince the 1970s. Platelet-rich plasma has been used clinically in humans for its healing properties attributed to theincreased concentrations of autologous growth factors andsecretory proteins that may enhance the healing processon a cellular level. The hope is that PRP enhances therecruitment, proliferation, and differentiation of cellsinvolved in tissue regeneration. In the literature, PRPrelated products, also known as PRP, platelet-rich concentrate, platelet gel, preparation rich in growth factorsPRGF), and platelet releasate, have been studied with invitro and in vivo experiments in the fields of maxillofacialsurgery and general surgery.64 More recently, PRP s role inmuscle and tendon healing has been investigated withinthe orthopaedic literature and its use is becoming morefamiliar to the general public.5 A February 2009 article inThe ew York Times raised the public awareness ofPRP by

*Address correspondence to Timothy E Foster, MD, Co-Director,Sports Medicine, Boston University School of Medicine, 720 HarrisonAvenue, Suite 805, Boston, MA 02118 e-mail: [email protected]).No potential conflict of interest declared.The American Journal of Sports Medicine, Vol. 37, No. 11DOl: 10.1177/0363546509349921 2009 The Author s)

detailing the use of PRP to treat an injured PittsburghSteelers football player before the 2009 Superbowl. 79

Although there are numerous basic science studies, animal studies, and small case reports regarding PRP-relatedproducts, there are only a few controlled, clinical studiesthat provide a high level of medical evidence regarding thepotential benefits of PRP. The number of participants inthe studies is typically small, and the majority of studies areunderpowered. In sports medicine and orthopaedic surgerythe use of PRP and the studies examining its effects havenot used standardized techniques, and the majority areanecdotal studies based on small case series Level 4 evidence). Before adopting PRP into a sports medicine practiceit is important to assess the evidence in the literature thatsupports its safety and efficacy. This article will focus on thebasic science and clinical applications of PRP. t will alsoexamine the medical literature involving the use of PRP inorthopaedic surgery and other surgical specialties.

THE BASIC SCIENCE OF PRPDefinition of PRPPlatelets are small, nonnucleated bodies in peripherablood that are known primarily for their role in hemostasis. Platelets contain a number of proteins, cytokines, andother bioactive factors that initiate and regulate basicaspects of wound healing. Normal platelet counts in bloodrange from 150 000/f.lL to 350 000/f.lL. Plasma is the fluidportion of blood and contains clotting factors and otherproteins and ions. Platelet-rich plasma, with a plateleconcentration of at least 1 000 000 platelets/f.LL in 5 mL ofplasma, is associated with the enhancement of healing.61Platelet-rich plasma contains a 3- to 5-fold increase in growthfactor concentrations. Greater platelet concentrations have


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TABLE 1Qrovvth Factors Identified Within Platelet-Rich Plasma and Their Physiologic EffectaFactorPD-EGF

Target Cell/TissueBlood vessel cells, outer skin cellsFibroblasts, and many other cell types

FunctionCell growth, recruitmentDifferentiation, skin closureCytokine secretionPDGFA+ B Fibroblasts, smooth muscle cells, chondrocytes, osteoblasts,

mesenchymal stem cellsPotent cell growth, recruitmentBlood vessel growth, granulation

IGF-I, IIVEGF,ECGFbFGF

Blood vessel tissue, outer skin cellsFibroblasts,monocytesTGF gene family includes the BMPsOsteoblasts-highest levels of TGFBone, blood vessel, skin, other tissuesFibroblastsBlood vessel cellsBlood vessels, smooth muscle, skinFibroblasts, other cell types

Growth factor secretion; matrix formation with BMPs(collagen and bone)Blood vesse l (), collagen synthesisGrowth inhibition, apoptosis (cell death)Differentiation, activationCell growth, differentiation, recruitmentCollagen synthesis with PDGFCell growth, migration, new blood vessel growthAnti-apoptosis (anti-cell death)Cell growthCell migration, blood vessel growth

PD-EGF, platelet-derived epidermal growth factor; PDGF, platelet-derived growth factor; BMP, bone morphogenetic protein; TGF, transforming grmvih factor; lGF, insulin-like growth factor; VEGF, vascular endothelial growth factor; ECGF, endothelial cell growth factor; bFGF, basic fibroblast growth factor.

not been shown to further improve healing, although anumber of variables affect the biologic activity of variousPRP preparations.A number of terms have been loosely used to refer topreparations that isolate and concentrate platelets, such asplasma rich in platelets. The term platelet concentrate

has been used, but is inaccurate because this implies a solidcomposition of platelets without plasma, which would notclot. The term platelet gel has also been used, but this isalso incorrect because the gel does not contain the cell adhesion molecules present in clot. Platelet-rich plasma differsfrom fibrin glue because the clot in PRP contains only thesame concentrations of fibrin as a normal blood clot.

ioactive Factors in RPlatelet-rich plasma can potentially enhance healing by thedelivery of various growth factors and cytokines from thea-granules contained in platelets. The basic cytokines identified in platelets include transforming growth f a c t o r ~ (TGFplatelet-derived growth factor (PDGF), insulin-like growthfactor (IGF-I, IGF-II), fibroblast grovvth factor (FGF), epidermal growth factor, vascular endothel ial growth factor (VEGF),and endothel ial cell gro \i\ih factor. These cytokines play important roles in cell proliferation, chemotaxis, cell differentiation,and angiogenesis (Table 1). A particular value of PRP is thatthese native cytokines are all present in normal biologicratios. In contrast , exogenous cytokines such as bone morphogenic protein (BMP) are produced by recombinant technologyand are delivered in high doses using a carrier vehicle.Because healing is a highly complex process, there are distinctlimitations to the ability of single-factor therapy (ie, deliveryof an exogenous gro \i\ih factor) to improve tissue healing.Bioactive factors are also contained in the dense granulesin platelets. The dense granules contain serotonin, histamine,

dopamine, calcium, and adenosine. These non-growfactors have fundamental effects on the biologic aspecof wound healing. The 3 stages of healing are inflammatioproliferation, and remodeling. The inflammatory stagbegins vvith tissue injury; consequently, platelets are stimlated to aggregate and secrete growth factors, cytokineand hemostatic factors critical in the early stages of thintrinsic and extrinsic pathways of the clotting cascadHistamine and serotonin are released by platelets and bofunction to increase capillary permeability, which allowinflammatory cells greater access to the wound site anactivates macrophages.1056 Polymorphonuclear leukocytmigrate toward the area of inflammation and, soon thereater, cells begin to proliferate while fibroblasts help formground substance. Adenosine receptor activation modulatinflammation during wound healing (Tables 2 and 3).

The platelets in PRP are delivered in a clot, which cotains several cell adhesion molecules including fibronectifibrin, and vitronectin. These cell adhesion molecules pla role in cell migration, and thus also add to the potentibiologic activity of PRP. The clot itself can also play a roin wound healing by acting as conductive matrix or scafold upon which cells can adhere and begin the wounhealing process.Formulation o RPlatelet-rich plasma can only be made from anticoagulatblood. t cannot be made from clotted whole blood becauplatelets become part of the clot. Platelet-rich plasma alcannot be made from serum. Serum is the clear liquid paof the blood that remains after blood cells and clotting prteins have been removed; the serum contains very few platlets. Preparation of PRP begins by addition of citratewhole blood to bind the ionized calcium and inhibit th


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General ActivityCategoriesGrowth factors

Adhesive proteins

Clotting factorsFibrinolytic factors

Proteases andantiproteases

Basic proteins

Membrane glycoproteins

Platelet-Rich Plasma 226

TABLE 2Bioactive Molecules Found in the a-Granules of Plateletsa

T G F ~PDGF

Specific Molecules

IGF-I, IIFGFEGFVEGFECGFFibrinogenFibronectinVitronectinThrombospondin-1Factor V factor XI, protein S,

antithrombinPlasminogen

Biologic ActivitiesPromotes matrix synthesisChemoattraction, cell proliferationCell proliferation, maturation, bone matrix synthesisAngiogenesis, fibroblast proliferationCell proliferationAngiogenesisEndothelial cell proliferation, angiogenesisBlood clottin g cascade (fibrin clot formation)Binds to cell-surface integrins, affecting cell adhesion, cell growth,

migration, and differentiationCell adhesion, chemotaxisInhibition of angiogenesisAll play a role in thrombin activation and eventual fibrin clot formationPlasmin production (leads to fibrinolysis)

Plasminogen activator inhibitor Regulation of plasmin productiono:-2 antiplasmin Inactivation of plasminTIMP-4Metalloprotease-4o:1-antitrypsinPlatelet factor 4[ thromboglobulinEndostatinsCD40 ligand

P-selectin

Regulation of matrix degradationMatrix degradationInhibits a wide variety of proteases and enzymesInhibition of angiogenesisPlatelet activation, inhibition of angiogenesisInhibitors of endothelial cell migration and angiogenesisInflammation, synthesis of interleukins, and integrin production; platelet

endothelial cell adhesion, cell signaling, modulation of integr:in activation molecule-I (PECAM-1) on leukocytesVascular cell adhesion molecule, aids in binding and recruitment of leukocytes to inflamed tissue

TGF, transforming growth factor; PDGF, platelet-derived growth factor; IGF, insulin-like growth factor; FGF, fibroblast growth factor; EGF, epidermal growthfactor; VEGF, vascular endothelial growth factor; ECGF, endothelial cell growth factor; TIMP-4, tissue inhibitor ofmetalloprotease-4.

clotting cascade. This is followed by one or two centrifugation steps. The first centrifugation step separates the redand white blood cells from plasma and platelets. Red bloodcells (7 Jlm in diameter) and white blood cells (7-15 Jlm indiameter) are much larger than platelets (2 Jlm in diameter); these cells separate from the plasma and platelets.The second centrifugation step further concentrates theplatelets, producing the PRP separate from platelet-poorplasma.

The PRP must then be clotted to allow for delivery to thedesired site. Some commercially available systems usebovine thrombin to activate the clotting mechanism.n important point is that clotting leads to platelet activation, resulting in release of the growth factors from

the a-granules, otherwise known as degranulation.Approximately 70% of the stored growth factors arereleased within 10 minutes, and nearly 100% of the growthfactors are released within 1 hour.61 Small amounts of

growth factors may continue to be produced by the plateletduring the rest of its lifespan (8 to 10 days),

The use of bovine thrombin to activate the clottingmechanism and to induce platelet activation can lead tocomplications associated with formation of antibodiesagainst the bovine thrombin. This is a rare but potentiallyserious complication that can result in an immunemediated coagulopathy. Thrombin-activated clots alsodemonstrate significant retraction,

n alternative system to delay the release of grovirth factors is possible through the creation of a platelet-richfibrin matrix (PRFM, Cascade Platelet Rich PlasmaTherapy, MTF Sports Medicine, Edison, New Jersey).18This is done by addition of calcium chloride (CaCl9 ) to initiate the formation of autogenous thrombin from prothrombin. The CaC1 is added during the second centrifugationstep and results in formation of a dense fibrin matrix.Intact platelets are subsequently trapped in the fibrin


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TABLE 3Bioactive _lVIolecules Found in the DenseGranules of Plateletsa

Specific MoleculesSerotoninHistamineDopamineDP

ATP

Catecholamines

Biologic ActivitiesVasoconstriction, increased capillary per

meability, macrophage attractionIncreased capillary permeability, attractand activate macrophages

Regulation of heart rate and blood pressure, neurotransmitter

Promotes platelet aggregationParticipates in platelet response tocollagenCofactor for platelet aggregation andfibrin formationSympathomimetic hormones released by

the adrenal glands in response tostress

aADP, adenosine diphosphate; ATP adenosine triphosphate.

matrix. This system results in only a small amount ofthrombin and thus minimizes platelet activation. Theresult is that the platelets release growth factors slowlyover a 7-day period. The fibrin matrix itself may also contribute to healing by providing a conductive scaffold forcell migration and new matrix formation.

n alternative method to activate the platelets is to usetype I collagen. Collagen has been found to be equallyeffective as thrombin in stimulating the release of PDGFand VEGF in a study that mixed soluble type I collagenwith PRP to create a collagen-PRP gel.34 Clots formedusing type I collagen also had significantly less P .003)retraction than clots formed using bovine thrombin.Further study is required to determine if tendon collagenin vivo can induce clotting of unactivated PRP and lead toplatelet activation. Relying on collagen to activate PRP invivo allows injection of unactivated PRP, which can bedone using a small-gauge needle.Effects of R on Soft TissuesConnective tissues, such as tendon, ligament, and muscle,heal through the 3 phases: inflammation, proliferation,and remodeling. Various cytokines are active during eachof these phases of wound healing. Cytokines play a fundamental role in wound healing by binding to transmembrane receptors on local and circulating cells, initiatingintracellular signaling that ultimately affects nuclear geneexpression. The result is the expression of proteins thatregulate cell proliferation, cell chemotaxis, angiogenesis,cellular differentiation, and extracellular matrix production. The cytokines and other bioactive factors releasedfrom PRP are known to affect these basic metabolic processes in soft tissues of the musculoskeletal system including tendon, ligament, and muscle.Effects of R on Tendon When considering the role ofPRP in tendon healing, it is important to distinguish treatment of acute tendon injury from chronic tendinosis. The

The American Journal of Sports Medic

biologic aspects of tendon healing and remodeling mayquite different between these 2 clinically distinct sittions. Several recent studies have clearly shown that Ppositively affects gene expression and matrix synthesistendon and tendon cells. Cell proliferation and total cogen production is increased in human tenoc;ytes cultuin PRP with slightly increased expression of matrdegrading enzymes matrix metalloproteinase MMPand MMP-3. 25 Equine flexor digitorum superficialis tendexplants cultured in PRP showed enhanced gene exprsion of type I collagen, type III collagen, and cartilaoligomeric matrix protein with no concomitant increasethe catabolic molecules MMP-3 and MMP-13.78 In vivoplatelet concentrate injected percutaneously intohematoma 6 hours after creation of defect in a rat Achitendon resulted in increased tendon callus strength astiffuess.7 A recent study showed that PRP injected intpatellar tendon injury site in a chimeric rat expressgreen fluorescent protein in circulating cells and bone mrow cells resulted in increased recruitment of circulatiderived cells to the injury site, with concomitant increacollagen production.45Effects of R on Muscle Several c:ytokines containedPRP have a positive effect on muscle healing. For exampbasic FGF bFGF) and IGF-I improved muscle healing igastrocnemius muscle laceration model in mice. Musctreated with IGF-I and bFGF showed improved healing asignificantly increased fast-twitch and tetanus strengtAutologous conditioned serum injected at 2, 24, or 48 hoafter injury in a mouse gastrocnemius contusion injmodel resulted in accelerated satellite cell activation aincreased diameter of regenerating myofibers.85

Basic Science Issues That Require Further StudyA number of important questions remain about the babiologic mechanisms ofPRP. Further information is requito examine the differential effects on acutely injured tdon versus degenerative tendon. The underlying celluand molecular processes are quite different between thtwo disparate clinical conditions. In the treatmentacutely injured soft tissue tendon, ligament, or muscthe best time to inject PRP must be determined. Thelogic milieu changes as healing progresses, and thus effects of cytokines may be very different at varying timafter injury. There may even be the potential to exacerbinflammation and thus pain) in the setting of acute injIn addition to determining the best time for PRP injectthe effect of serial injections should be explored. The kinics of cytokine release from various PRP preparatineeds further study, as this may ultimately determinebest time for injection for a given PRP formulation. Lasthe effect of local tissue pH on PRP activity needs furtstudy as there are some preliminary data that cytokrelease from PRP is pH-dependent.54

CURRENT CLINICAL APPLICATIONSThe literature is replete with studies documenting the sand efficacious use of PRP in a wide variety of fields


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number of animal studies, case reports, and small caseseries in the oral and maxillofacial surgery, otolaryngology,plastic s u r g e ~ y and general surgery literature have examined the role of PRP in various clinical settings. Theseinclude human case studies supporting the use of PRPrelated products, suggesting an overall improvement insoft tissue healing. Likewise, within the oral and maxillofacial surgery literature, there are other small human casereports that argue there is little benefit from using PRP topromote healing or osteogenesis.233372 In many cases, theterms autogenous platelet concentrate, platelet gel, andfibrin glue are used as synonyms for PRP; however, asdefined at the beginning of this article, they are distinctplatelet-related products.

Many of these studies claim excellent outcomes but are atbest limited case series; consequently, it is difficult to drawconclusions from these case reports that may or may nothave controls, have small sample sizes, and do not define astandardized preparation of PRP. This makes it hard tointerpret any of the results.6 Standardized dosing and composition of PRP is necessary in order to compare the datafrom different studies. Unfortunately, most of these humanclinical studies lack statistical significance because of smallsample sizes and a paucity of randomized controlled trials.Efforts are currently underway designing clinical studiesthat 'vill help further delineate the effects of PRP.Currently, the majority of orthopaedic applications forPRP can be grouped into 1 of 4 categories: chronic tendinopathies, acute ligamentous injuries, muscle injuries, andintraoperative augmentation. Historically, the focus hasbeen on intraoperative use, such as in the use of plateletderived products (fibrin sealants, platelet gels, etc) for sealing wounds following total knee replacement in an effort tominimize blood loss and promote wound healing.12'38 Plateletrich plasma has been used to induce a local healing responsein conditions such as lateral epicondylitis and plantar fasciitis.66 Most recently, orthopaedic surgeons have applied thistechnology to the treatment of acute ligamentous injuries inan effort to expedite healing and return t play.79 The application of a new technology in medicine is often met withsignificant enthusiasm.73 This may be especially true insports medicine when the patients are often elite athletes.The indications for the use of the technology often outpacethe basic science and clinical studies that validate the technology's efficacy.Recently published human clinical orthopaedic studiesof PRP are summarized in Table 4.Chronic Tendinopathy

Elbow Tendinopathy I Lateral Epicondylitis. A PRP injection can be used for patients with refractory lateral epicondylitis of the elbow who have failed conservative treatmentincluding physical therapy, a counter-force brace, andcorticosteroid injections. It is recommended that imagingstudies including either MRI or ultrasound should confirmextensor carpi radialis brevis tendinopathy. Postinjectionprotocol includes standard rehabilitation for eccentric

;;References 1 2 13 16 24 28 30 39 43 47 48 50 51 58 59 62 82.


strengthening and functional progressions with a gradualreturn to activities over to 8 weeks. It is not necessary toimmobilize the elbow after the injection. The criteria forreturn to sports may include painless full range of motionv1rith no localized pain or tenderness.

Mishra and Pavelko66 evaluated a series of 140 patientswith chronic lateral epicondylar elbow pain. Of thosepatients, 20 met the inclusion criteria and were offeredPRP injection as an alternative to surgery. Fifteen patientsunderwent PRP injection and 5 patients served as controlsby undergoing local anesthetic inject ion only. The patientsundergoing PRP therapy were noted to have 60 improvement at 8 weeks, 81 at months, and 93 at finalfollow-up (range, 12-38 months). At 8 weeks, 3 of the 5patients in the control group sought treatment outside thestudy or formally withdrew from the study and limitingcomparisons. Therefore, the final outcome data reflectsonly the patients who were treated with PRP. At the finalfollow-up of these patients (rall1{e 12-38 months), 93 werecompletely satisfied with t h ~ treatment, 94 (range90-100 ) of PRP-treated patients were able to return towork and sports, and 99 were able to return to activitiesof daily living. No adverse events or complications werereported. This study has significant design flaws; thesample size is small and the attrition rate approaches 60 .However, it is one of the few studies performed in a prospective fashion and includes a control group.

In 2003, Edwards and Calandruccio26 reported a 79success rate in treating a group of patients with refractorychronic epicondylitis. Twenty-two of the 28 patients werereported to be pain-free follo\ving autologous blood injection therapy. Edwards and Calandruccio injected wholeblood that had not been centrifuged, which is differentthan the preparation for PRP. No adverse events and norecurrences were reported. However, the authors do notcomment on the discomfort level at the site of injection ina large portion of their patients in the immediate periodfollowing the autologous blood injection. This is a Level 4study with a small sample size and no control group; consequently, it is difficult to draw definitive conclusions.Achilles Tendinopathy. The theoretical explanation fortendon injuries suggests a continuum of events, includinghypovascularity and repetitive microtrauma, resulting inlocalized tendon degeneration and weakness. The ultimateresult may be rupture if it is continually subjected to loadsthat exceed the tendon s physiologic capacity. Based on thismodel, the introduction of PRP is hypothesized to reversethe effects of tendinopathy by stimulating revascularization and enhancing healing at a microscopic level.4 It isimportant to recognize that Achilles tendinopathy mayhave different clinical manifestations and may requirevarying treatments. Achilles tendon pathology can be classified into 3 different categories: paratendinitis, paratendinitis with tendinosis, and pure tendinosis. 4

Paratendinitis involves inflammation only in thepara enon, regardless of whether it is lined by synovium.The paratenon thickens, and adhesions may form betweenthe paratenon and the tendon. Platelet-rich plasma injection for this disorder has not been described. However,patients will rarely present with isolated paratendinitis


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TABLE 4Published Human Clinical Orthopaedic PRP Studiesa

Authors


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mucoid degeneration, lipomatous infiltration, and calcifYing tendinopa;thy have been noted at the time of surgicalrepair. Platelet-rich plasma has been advocated for usein chronic Achilles tendinopathy. Based on the gross andhistologic properties of Achilles tendinosis, an opportunitytheoretically exists for improvement by injecting PRP inan effort to stimulate angiogenic infiltration and remodeling by tenoc:ytes. illtimately, the use ofPRP may lead to animprovement in symptoms and increased function in thegroup of patients suffering from tendinosis ' ith or withoutparatendinitis.

Patients with refractory Achilles tendinopathy who havefailed physical therapy and multiple modalities of conservative treatment are candidates for PRP injection. Thephysical examination findings should confirm the presenceof Achilles tendinopathy and be corroborated with imagingstudies. Some clinicians have advocated the use of ultrasound guidance for needle localization and confirmation ofthe PRP aliquot directly into the affected area.

Immediately after the injection, the patient is protectedwith a brace and is removed from athletic activity. oenhance tendon healing, an immediate protocol of activeand active-assisted range of motion strictly in the plantarflexion-dorsiflexion plane is initiated. The patient gradually progresses with a standard protocol for strength andfunctional recovery. In our opinion, a gradual return toactivities over 6 to 8 weeks is recommended depending onthe size and severity of the lesion.

Plantar Fasciitis. The use of PRP in the foot has onlybeen studied for the treatment of chronic refractory plantar fasciitis. Barrett and Erredge8 reported on a smallseries of patients with chronic plantar fasciitis. The diagnosis was confirmed by ultrasound, and the study participants underwent a washout period for 90 days prior toPRP injection in which brace wear, nonsteroidal antiinflammatory drugs (NSAIDs), and corticosteroid injectionwere prohibited. The PRP injection was administered intothe medial plantar fascia with ultrasound guidance. Six of9 patients achieved complete symptomatic relief after 2months. After 2 months, the failure group was offered theoption of a second PRP injection. One of the 3 unsuccessfulpatients eventually achieved complete resolution of symptoms after the second PRP injection. Overall, 77.9 ofpatients had complete resolution s.ymptoms at 1 year. Thisstudy was limited by its small sample size and lack of acontrol group.

Patients with refractory plantar fasciitis who have failedphysical therapy and multiple conservative modalitiesincluding orthoses, NSAIDs, and corticosteroid injectionsmay be candidates for PRP injections. n MRI or ultrasound study may confirm the diagnosis; however, imagingstudies are of uncertain value in the diagnosis of plantarfasciitis. It is unknown whether PRP is beneficial forpatients with tears of the plantar fascia because there areno data on this specific problem at the time of this publication. The postinjection protocol should include immediateweightbearing and a standard rehabilitation program forstrength and functional progress. A gradual return toactivities over 6 to 8 weeks is recommended, with a moregradual modified training schedule for running athletes.

Patellar Tendinopathy. Patellar tendinopathy is distinguished from other patellar tendon ailments by the


presence of intrasubstance changes demonstrated onultrasound or MRI.27'32 Patellar tendinosis most commonlyinvolves the .proximal bone-tendon junction. The intrasubstance changes within the tendon histologically aredescribed as angiofibroblastic hyperplasia.31' 70 The originof patellar tendinosis is thought to be due to extrinsic factors such as intensity and duration of training, trainingsurfaces, footwear, and equipment. More recent studiesfocus on intrinsic factors such as patellar impingement,malalignment, and muscle imbalance, which may predispose a jumping athlete to patellar tendinosis. 52

Chronic patellar tendinopathy, also commonly referredto as jumper's knee, represents a significan t problem in theathlete. There are very few modalities t h a ~ h a v e beenshown to expedite healing time; the current treatmentrelies on physical therapy and relative rest from sportsparticipation. Platelet-rich plasma therapy is thought to bean adjunctive solution in an effort to accelerate healing inthis chronic disorder.Taylor et al83 conducted an animal study in an effort todemonstrate the safety of autologous blood injections. nautologous whole blood product, without centrifugation asis performed with PRP, was injected into the patellar tendon of New Zealand White rabbits. A histologic analysiswas performed at 6 and 12 weeks after injection; theresults suggest a robust angiogenic response and no abnormal histologic markers. There were no adverse events andit was concluded that autologous blood product injectioninto the patellar tendon posed little if any risk both locallyand systemically.

Kajikawa et al45 more recently examined the effects ofPRP injection into the patellar tendon of rats and concluded that this is a safe and potentially effective treatment modality for tendon healing. Histologic analysis ofthe tendon after injection demonstrated increased levels oftypes I and III collagen and macrophages, which is consistent with repair and remodeling of the tendon. There wereno local adverse events noted.

In our experience, patellar tendinosis in humans oftenresolves with prolonged conservative treatment thatfocuses on quadriceps stretching, achieving quadricepshamstring muscle balance, ice, cross-friction massage, andlocal modalities. However, it is not uncommon for patientsto continue to exhibit pain and disability despite a prolonged course of conservative care. In the athlete, when thedisability affects the ability to train and/or play at the levelof desired performance, other options are considered.Traditionally, surgical intervention is the next step in thetreatment algorithm. Surgical debridement of the mucinoid degeneration may improve the functional capacity ofthe patient; however, the surgical procedure is invasiveand associated with several months of rehabilitation in ourexperience. Before surgical intervention, PRP offers analternative treatment option in the patient who has failedconservative measures.

When considering PRP intervention, it is critical to distinguish patellar tendinosis from other common causes of anterior knee pain, particularly in the adolescent athlete. Thereare currently no prospective, randomized studies to helpguide treatment of patellar tendinopathy with PRP. The clinician must distinguish between patellar tendinopathy andother clinical entities such as Sinding-Larsen-Johansson


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disease or Osgood-Schlatter disease, which typically resolvewith skeletal maturi.ty.14'63 t is our opinion that PRP is notindicated for these diagnoses. However, a PRP injection canbe considered in a skeletally mature adolescent patient withchronic, refractory patellar tendinosis.

Despite the lack of any prospective randomized data toguide our decisions regarding PRP, our clinical indicationsfor PRP treatment for patellar tendinosis are as follows: 1)severe symptoms present for more than 3 months that areunresponsive to physical therapy, (2) clinical findings corroborated by changes on MRI or ultrasound, and (3) theathlete has had a washout period from NSAIDs for atleast 1 week before PRP injection. 73 Additionally, patientsare instructed to avoid NSAID use for 3 to 4 weeks afterintervention to avoid any interference with muscle healing.80 The postinjection protocol includes standard rehabilitation for strength and functional progressions andgradual return to activities over 6 to 8 weeks. Frequentand liberal use of ice, particularly in the early stages, hasbeen helpful in controlling the discomfort that can occur asa result of the injection. Criteria for return to sport includepainless full range of motion and ability to tolerate goingup and down stairs without discomfort.Bone HealingA number of studies have focused on how PRP affectsosteoblasts, osteoclasts, and mesenchyma l osteoprogenitorstem cells. As mentioned above, it is hypothesized thatplatelets can act as an exogogenous source of growth factors that could potentially stimulate bone formation.15Gruber et al41 showed that platelets can stimulate the formation of osteoclast-like cells, which can help with bonegrowth and remodeling. Gandhi et al37 investigated thepercutaneous application of PRP in a diabetic femur fracture model, suggesting that PRP can upregulate cellularproliferation and improve mechanical strength of the healing bone. Similarly, Sanchez et al 76 applied PRP to clinicalnonunions and reported on their retrospective case seriesof 16 aseptic supracondylar and diaphyseal atrophic nonunions after failed surgical fixation 21 months previously.Some of these patients were treated \vith surgical bonegrafting augmented by PRP (13 patients) and percutaneous injection of PRP (3 patients). Mixed results werereported and therefore no definitive conclusions could bedrawn. The study was further limited by the lack of a control group.76 Han et al42 recently published an articledescribing an in vitro and in vivo experiment to test theeffects of PRP as an adjuvant to bone grafting. This studywas based on the use of PRP as an autologous source ofgrowth factors that can enhance the quality and quantityof osteogenesis.

The use ofPRP to help restore soft tissue or bone defectsin different surgical settings, including orthopaedic surgery, maxillofacial surgery, and plastic surgery, has beenstudied. The use of isolated cells with a biocompatiblematrix in combination with PRP maximizes the effects ofgrowth factors on these cells.57 The advantage of PRP as amatrix for cells is that PRP is autologous and nontoxic.Therefore, it makes an ideal matrix for cell incubation (eg,mesenchymal cells). Yamada et al87 demonstrated in acanine model that the combination of mesenchvmal stem

The American Journal of Sports Medici

cells with PRP resulted in neovascularization and a highmaturation of bone when compared to the control subjecSimilarly, Kitoh et al49 reported on a case series with dtraction osteogenesis in which 17 patients were treatwith PRP while 29 patients did not receive PRP treatmenThe authors concluded that in the PRP group there was delay in consolidation and there were fewer complicationThe role of PRP in bone healing remains an area for fertiresearch.

Osteoarthritis Clinical trials are currently underwexamining the effects of PRP injection for osteoarthritisthe knee. Kon et al (unpublished data, submitted for pulication) have investigated 40 patients with osteoarthriof the knee who were treated with intra-articular PRinjection. A total of 3 separate injections were adminftered. Clinical outcome measures revealed significaimprovements in visual analog pain scale, InternationKnee Documentation Committee scores and subjectievaluations at 6-month follow-up P < .05). Specificalpatients under 60 years of age demonstrated 85 satisfation as opposed to those older than 60 years, who weshown to have 33 satisfaction.

Sanchez et al 7 also studied the effectiveness of intrarticular injections of PRGF for osteoarthritis of the kneand performed an observational, retrospective, cohostudy using hyaluronan injections for a control grouEach group included 30 patients with osteoarthritis of tknee, matched according to age, sex, body mass index, aradiographic severity. The treatments were based ontotal of 3 injections performed over a 3-week period. Tobserved success rates by week 5 for the pain subscareached 33.4 for the PRGF group and 10 for thyaluronan group P = .004). No adverse events wereported.

The interaction of PRP with chondrocytes and growfactors may enable orthopaedic surgeons to improve tcurrent treatment of articular cartilage lesions. The castudies in the literature suggest that there is promisethe treatment of cartilage lesions with PRP or PRP cobined with a biomatrix; however, to date, there arerandomized, long-term studies providing reliable medievidence that supports this claim.Acute Ligamentous InjuriesRecently, the use ofPRP in the treatment of acute ligameinjuries in athletes has gained in popularity among spomedicine specialists. Mter a ligament injury, the medicare of an elite athlete is focused on the safe and expetious return of the athlete to competition. Medial collateligament injuries (of the knee) are a common problemsports such as soccer and American football. Two of tauthors (B.R.M. and M.B.G.) recently completed an unpulished study evaluating a group of professional soccer plaers with grade II acute medial collateral ligament injurwho were treated with a single PRP injection and wecompared to a control group treated with standard rand rehabilitation. The PRP injections were administerin the intervention group within 72 hours of injury. Treturn-to-play time was shortened by 27 compared to tcontrol group. This study is limited by its retrospectdesign and limited number of study participants (n = 22


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Acute Muscle Injuriesn injury to mi.Iscle tissue can be due to a direct blow, orfrom tearing of the muscle fibers because of eccentric load

while the muscle is contracting. These mechanisms cancause a spectrum of injury ranging from contusion to significant muscle tear (strain). Acute muscle strains arecommon injuries that account for the majority of misseddays of practice and games in the elite athlete. 44 The mostcommonly injured muscle groups in the athlete include thehamstrings, gastrocnemius, and quadriceps. These injuriescan take several weeks to heal and it is not uncommon foran athlete to miss a significant part of the season depending upon the severity of the injury.Muscle healing follows the stages of inflammation, proliferation, and remodeling that are coordinated by cellularinteractions. As in other parts of the body, healing is dependent upon the vascularity of the tissue.88 The speed ofrecovery depends on the severity of the injury, the postinjury treatment, and the patient s inherent ability to healsoft tissue injuries. The usual recommendation for a muscular injury is rest, ice, compressive dressings, and elevation of the affected extremity. Several techniques have beenemployed in an effort to shorten return to play intervals.

Platelet-rich plasma has been suggested as a potentialintervention for athletes with acute muscular injuries. Onein vitro study suggests that growth factors may influencemuscle regeneration after injury.46 Platelet-rich plasmatreatment after an acute muscular injury may benefit theathlete by decreasing the time to recovery; however, thereare no randomized controlled human studies regarding theuse of PRP for muscle injuries.

Cugat et al presented an unpublished case series of 14professional athletes with acute muscle injuries at the 2005International Society of Arthroscopy, Knee Surgery, andOrthopaedic Sports Medicine meeting in Florida. Thisgroup of athletes included 8 soccer players and 6 basketballplayers, accounting for a total of 16 muscular injuries. Allinjuries occurred from direct mechanical trauma and injuries were assigned a grade based on the Rodineau andDurey classification of muscle injuries (grades 1-4, with ahigher score corresponding to greater muscle damage).29 nautologous PRP preparation was injected directly into thetear under direct ultrasonic guidance after aspiration of thehematoma. The return-to-play interval was diminished ineach group according to severity, and in the less severeinjuries (grades 1 and 2), a greater than 50 reduction inreturn to play was reported. At regular intervals, follow-upincluded clinical assessment as well as ultrasonic imaging,which confirmed progressive healing of the injured muscle.They concluded that PRP can be helpful in returning athletes to sport, with a shorter time of restoration and rehabilitation. However, the results need to be considered inlight of the retrospective nature of the study design. Also,no control group was used. Comparisons were based onpreviously published expected return-to-play data according to the muscle involved and the injury severity.

Despite the reported success in expediting return to playafter muscular injury in the athlete, other researchershave investigated the theoretical concerns that PRP derivatives could induce a fibrotic healing response in muscletissues. 19 This theoretical deleterious side effect of PRP is


based on the elevation of G F ~ levels after its injectioninto muscle. Basic science studies have demonstrated thatplatelet granules can release TGF-B when stimulated(Table 1). Transforming growth factor-P has also beenshown to stimulate fibrosis in in vitro muscle tissue studies. It is hypothesized that fibrotic healing following muscular injury can lead to an increased incidence of rein ury.Therefore, some researchers have advocated caution whenconsidering PRP injections for athletes with muscularinjury. The same group of researchers who raised concernsregarding PRP argue that the introduction of n t i T G F ~agents such as suramin, decorin, y-interferon, and relaxinmay be helpful in reducing fibrosis and thus expeditingmuscle healing.68'69

Intraoperative Uses of PRPTotal Knee Arthroplasty. The earliest of use of PRP in

orthopaedic surgery involved total knee arthroplasty(TKA). The primary indication in this setting is to promotewound healing and to decrease blood loss. Berghoff et al

12re-viewed a large series of patients in an attempt to limitblood loss in patients undergoing TKA. The study designincluded a control group (n = 66) and an interventiongroup (n = 71). In the intervention group, an autologousPRP fibrin sealant was sprayed in the knee just prior toclosure. The PRP was mixed with bovine thrombin andCaCl2 in an effort to activate the platelets and stimulatethe clotting cascade. The intervention group demonstratedhigher postoperative hemoglobin levels, lower incidence ofpostoperative transfusion, and shorter hospital stays.Additionally, at the 6-week follow-up appointment, theintervention group had a significantly greater knee rangeof motion (110.2 9.77) compared with the control group(105.3 12.1) P .05).Gardner et ae8 conducted a similar study in a series ofpatients undergoing TKA. In the intervention group, theincision was treated intraoperatively with a platelet gelprior to closure. The authors reported lower blood loss(measured by comparison of preoperative hemoglobin levels to postoperative day 3 hemoglobin), improved earlyrange ofmotion, and fewer narcotic requirements. However,this was a retrospective chart review, which exposes thestudy to significant bias.38Anterior Cruciate igament Reconstruction. A series ofstudies have been performed to evaluate the role of a collagen scaffold containing PRP in anterior cruciate ligament (ACL) healing. There is ineffective healing of ACLtears because of the lack of a bridging scaffold joining thetorn ends of the ligament, and due in part to intra-articular fibrinolysates that inhibit formation of a bridging fibrinclot. Application of a collagen hydrogel scaffold containingPRP has been found to improve primary healing of theACL in several animal models. For instance, in a porcinemodel of suture repair after ACL transection, ligamentstreated with a collagen-PRP hydrogel at the ACL transection site had significant improvement in load at yield,maximum load, and linear stiffness at 4 weeks comparedwith untreated repairs.67 The authors also argue that thecollagen-PRP hydrogel improves the healing of direct ACLrepair with sutures. In a goat model, the application of acollae-en-olatelet composite around a patellar tendon


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autograft ACL reconstruction resulted in improvements inknee laxity compared to grafts treated with a collagen scaffold alone. There were also significant correlations betweenserum platelet concentration and anteroposterior laxity2 . 2r = .643; = .009), mrunmm:p load r = .691; = .006),and graft stiffness r2 = .840; < .001).81 Presently thereare no in vivo human studies that support the use of PRPwith ACL repair or reconstruction.cute chilles Tendon Repair Sanchez et al75 examinedthe intraoperative use of PRP in athletes undergoingAchilles tendon repair. Platelet-rich plasma was used toaugment the primary repair of the Achilles in patients whowere compared with age-matched controls. A PRP supernatant was extracted from each patient and then treatedin 2 differen t ways. A CaCl2 additive was added to 4 mL ofPRP and allowed to sit for 30 minutes allowing the formation of a fibrin type of scaffold. This scaffold was directlyincorporated into the Achilles repair. The remaining 4 mLof PRP was treated with CaCl2 and then immediatelysprayed on the repair site just before closure. Follow-upincluded physical examination and ultrasonic imaging atregular intervals up to a year. The results showed that theintervention group had earlier range of motion, no woundcomplications, and patients were able to resume gentlerunning sooner than the control group.

Rotator Cuff Repair The literature reveals that despitethe technical expertise of the surgeon a significant failurerate can be expected after rotator cuff repair. The biologicalmilieu at the rotator cuff footprint and the inherent poorhealing potential of the distal rotator cuff tendon create anenvironment that is not optimal for healing of the tendonto bone. Augmentation of the rotator cuff repair vvith PRPcould hypothetically optimize the biologic environment atthe repair site and allow for a more robust healingresponse at the osseous-tendon interface. The intraoperative use ofPRP augmentation of the rotator cuffrepair hasbeen gaining in popularity among shoulder surgeons.Gamradt et al 36 have reviewed the basic science regardingthe use of autogenous platelets and growth factors used toenhance the healing of the repaired rotator cuff Plateletrich plasma augmentation of rotator cuff repair at thetendon-bone interface is described in this review. Thissame group of researchers is currently conducting a randomized clinical trial assessing the efficacy of theirdescribed technique.

cute rticular Cartilage Repair Articular cartilageinjuries and degenerative joint disease represent one ofthe most challenging and one of the most activelyresearched topics in all of orthopaedic surgery and sportsmedicine. Bennett and Schultz10 showed good results usingPRP in treating articular carilage lesions. Platelet-richplasma increased total glycosaminoglycosides and type IIcollagen synthesis with decreased cartilage degradation.Platelet-rich plasma also induced chondrogenesis frommesenchymal stem cells and promoted chondrocyte proliferation differentiation and adhesion.10 Evidence that supports that PRP stimulates mesenchymal stem cells isimportant because Barry et al9 demonstrated that mesenchymal stem cells cultured with T G F ~ produced significantly more proteoglycans and type II collagen. Similarly,Fukumoto et al35 found that IGF-I has a synergisticeffect with T G F ~ in promoting mesenchymal stem cell

The American Journal of Sports Medicine

chondrogenesis. In addition, Wilke et al84 showed earlyenhanced chondrogenesis in cartilage defects in an equinemodel and concluded that mesenchymal stem cellarthroscopic implantation in horses improved cartilagehealing response.

Cugat et al2 described the use of plasma rich in growthfactors to treat chondral defects in athletes and reportedgood results demonstrating that this plasma in physiological concentrations is effective for the recovery of articularcartilage; furthermore Cugat et al concluded that localtreatment is safe and does not alter the systemic concen-. rations of these proteins. Anitua et al6 demonstrated thatplatelet-released growth factors induced secretion of hyaluronic acid that may provide a homeostatic environment /for tissue repair inside the joint. These studies suggest -that PRP may play an important role in cartilage regeneration by regulating cells, protein synthesis and growthfactors.

Akeda et ae showed in a porcine model that PRP playsa role in the upregulation of chondrocytes and cartilagematrix derivatives. Based on their data clinical researchers have attempted to apply these principles in the clinicalsetting. For example, Wu et al86 suggest that PRP can beused as a chondrocyte carrier for the treatment of acutearticular cartilage lesions of the knee. A thrombin-PRP clotserved as a scaffold for transferring chondrocytes tothe lesion. This concept is offered as a hypothesis, butthere are no data regarding outcomes utilizing this technique. Interestingly, Gobbi et al have studied the adjunctive use of PRP and bone marrow cells in the treatment ofarticular cartilage defects, and gave an oral presentationon these unpublished data at the 2009 InternationalCartilage Repair Society meeting in Miami. In the presentation Gobbi desc ribed the treatment of 20 patients since2006 using autologous thrombin and PRP to produce asticky clot material that is pasted into the defect and thencovered with a collagen membrane. The preliminary clinical results are encouraging, with mean International KneeDocumentation Committee subjective scores improvingfrom 48.27 preoperatively to 68.58 at 20-month follow-up.The final mean Tegner score of 5.75 was similar to thepreinjury score of 6.50, and 92.57 was the final Lysholmscore. Within 1 year of the PRP clot placement a secondlook arthroscopy and biopsy was performed. The defectsites were filled with good cartilage-like material that wasfirm to palpation and a biopsy showed hyaline-like tissue\\ith good integration to the surrounding cartilage.

AUTHORS CLINICAL EXPERIENCE WITH PRPPREPARATIONCentrifugation SystemsVarious plasma separation devices are in active clinicaluse, and each device has slightly different preparationsteps. In general the process is very straightforwardregardless of the manufacturer of the device. The main differences among the current systems include the volume ofblood required and the technical handling of the specimenduring the centrifugation and separation process. Thecritical difference among the various systems is in the


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Figure 1. Preparation of platelet rich layer

platelet concentration yield. The ideal concentration factorfor the platelets is currently unknown, and therefore theredoes not appear to be any clear-cut superiority of one system over the other at this time.Harvesting o CellsThe patient's blood is typ ically drawn from the antecubitalregion using aseptic technique. It is recommended that an18-gauge needle be used in an effort to reduce irritationand trauma to the platelets such that they remain in arelative inactive state. The blood sample is then transferred to the centrifuge and the spinning process begins.Depending on the system being used, the centrifugationprocess will ultimately yield between 3 and 6 mL of plateletrich aggregate (Figure 1) and 30 to 60 mL of whole blood,respectively, may need to be harvested to produce theseyields.Procedure for Soft Tissue InjectionThe area of injury is identified and the zone of injury isclearly marked based on physical examination, imagingstudies, and area of maximal tenderness. Some cliniciansare utilizingdynamic musculoskeletal ultrasound to betteridentifY the area to be injected with PRP. We recommendthe use of an ultrasound-guided injection for the treatmentof chronic patellar tendinopathy and Achilles tendinopathybecause the ultrasound guidance allows for the accurateplacement of PRP into the pathologic region of the tendon.There are no data to support the use of ultrasound; however, ultrasound permits the physician to control the depthof the needle and to accurately deliver the PRP into thetendon substance. The use of local anesthetic before injection or with the injection of PRP may be controversial; theanesthetic may change the pH of the tissue and decreasethe effectiveness of the injection. This has not been documented clinically, but PRP is sensitive to changes in pH


and local anesthetics may change the tissue environment.A local anesthetic may be delivered prior to injection; theexact timing of the subsequent PRP injection has not beendetermined. Platelet-rich plasma is delivered via standardinjection technique using an 18-gauge needle. Dependingon the indication, some clinicians prefer to buffer the PRPvvith CaC12 and thrombin, or the pure sample of PRP canbe used. A multiplanar injection technique (peppering thetendon) is recommended in an effort to deliver the platelets to a wider surface area and thus potentially enhancethe healing process. Some patients will mount a fairly dramatic inflammatory response after PRP injection, whichmanifests with discomfort at the injection site. For thisreason, we recommend observation for 15 to 20 minutesafter injection to make sure the pain is under control andthat patients can safely ambulate and function after theprocedure. They are instructed to ice the injected area ifneeded for pain control in addition to elevation of the limband activity modification for 24 to 48 hours depending onthe severity of the injury. Acetaminophen with or withoutnarcotic medication can be taken after the injection forpain control. However, it is important that NSAIDs not beused in the first 2 weeks after injection; they may inhibitthe prostaglandin pathway and may inhibit the beneficialeffects stimulated by the PRP injection. 80 There is no current clinical evidence in humans for this practice, but theeffect of PRP depends on the inflammatory healing cascade which theoretically could be inhibited by NSAIDs.

DISCUSSIONPlatelet-rich plasma has emerged as a promising, but notproven, treatment option for joint, tendon, ligament, andmuscle injuries. In vitro basic science studies and in vivoanimal studies have helped elucidate some of the effectsPRP has on a cellular level to improve tissue repair.Platelet-rich plasma is autologous and able to be administered in a simple fashion, and has an excellent safetyprofile. Well-designed prospective randomized trials arenecessary to better understand the clinical results of PRPtreatment.Regulation o PRP in SportsThe use of PRP in amateur and professional athletesis controversial under the current rules of the antidopingagencies. For instance, an International Olympic CommitteeMedical Commission Consensus Statement welcomes further research into the area of PRP to understand its therapeutic effects for patient safety.55 A 2008 article from theBritish Journal o Sports Medicine commented specificallyon the injection of autogenous growth factors that can befound in PRP, and states that World Anti-Doping Agency(WADA) rules prohibit the use of growth hormone, IGF-I,and mechano growth factor (MGF).20 Recently, on September19, 2009, the WADA Executive Committee addressed thetopic of PRP use and decided that platelet-derived preparations will be prohibited when administered by an intramuscular route, and that other routes of administration willrequire a declaration of use that is in compliance with the


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International Standard for Therapeutic Use Exemptions(TUEs). This d e i s i o ~ regarding the 2010 ProhibitedSubstances arid Method List will be posted on their officialWeb site on October 1, 2009, and will take effect on January1 2010. Additionally, the US Anti-doping Agency (USADA)has an April 2009 athlete's advisory on its official Web sitestating that the organization considers a PRP injectionequivalent to an injection of growth factors. Consequently,PRP is prohibited under S2 Hormones and RelatedSubstances and an athlete needs a TUE if a medical professional determines that a PRP injection is necessary for anathlete. USADA's posit ion affects all athletes that competein sports governed by the USADA Protocol for OlympicMovement Testing. t s known that serum IGF-I levels varygreatly among individuals and change depending on apatient s genetics, nutritional status, and how recently theyexercised.11 Overall, basic science research supports thebelief that PRP is unlikely to provide a potent athleticadvantage because unbound IGF-I has too short a half-life(10 minutes to 16 hours) to provide a performance advantage. Isoform IGF-IEa found in PRP is not the isoformresponsible for skeletal muscle hypertrophy (IGF-IEc/MGF),and the dose ofiGF-I in PRP is subtherapeutic to produce asystemic anabolic effect.20Olympic-affiliated and international antidoping governing bodies do not have jurisdiction over the professionalsports leagues in the United States. Professional baseball,football, soccer, hockey, and basketball are not specificallygoverned by WADA rules but instead by agreements governed by the provisions of the leagues and unions undertheir respective collective bargaining agreements. Althoughthese various leagues have a list of banned substances, PRPis not specifically addressed. What remains unclear iswhether using PRP, and hence an athlete s own IGF-I, violates antidoping rules, as would the use of an athlete sautologous red blood cells to gain an advantage (blood doping). Throughout the literature, there is no suggestion thatPRP has a systemic effect or provides a performance advantage. Additionally, there are only anecdotal reports suggesting that PRP accelerates the repair of an injured area aspopularized by the use of PRP to treat the PittsburghSteeler Hines Ward's injury before the Super Bowl.79

Potential Advantages and Limitations o PRPIf well-controlled clinical trials demonstrate that PRPaccelerates the rate of soft tissue injury healing, there areseveral potential advantages. First, there is a low chanceof rejection because the injection is from the patient sautologous blood. Second, PRP can be prepared at the timeof care in a simple and relatively inexpensive mannerrather than the more complicated process of gatheringstem cells.

There are limitations associated with the use of PRP. Anoptimal dose range of PRP has yet to be defined. Althoughapplication of the PRP may enhance mesenchymal stemcell migration and proliferation, overexposure of cells toPRP may also limit differentiation of those cells into theappropriate cell lines.60 Thus, there are theoretical concerns that after an injection of PRP, there could be a systemic increase in growth factors and a possible cancer-likeeffect; but there are no data to support this hvnothesis.

The merican Journal of Sports Medicine

Marx60 has been critical of this viewpoint as PRP is primarily a patient s own platelets simply administered backto the patient in a more concentrated dose.A review ofthe literature reveals a rampant lack of standardization in the preparation of PRP; consequently, it isproblematic when attempting to extrapolate data from 1study to the next. The lack of standardized protocol toproduce and evaluate PRP in the literature can helpexplain the inconsistent clinical and experimental results.Grageda 0 proposed that in addition to a uniform protocol,future studies should quantifY platelet yield both in wholeblood and in the PRP used in experiments, and the use ofcommercial assays to quantifY growth factor concentration. To avoid problems in the future, it is imperative tostandardize PRP production followed up by a randomizedcontrolled trial to study the effects of PRP on wound healing and promotion of soft tissue and bone healing.

CONCLUSIONt is clear that PRP and PRP-related products have been

applied to a diversity of tissues in a variety of surgicalfields. The overall goal of PRP is to deliver a high concentration of platelet growth factors to enhance healing. Thiscurrent review suggests that PRP may be advantageous insports medicine, but there are little data aside from smallcase series to support these claims despite PRP s widespread use in the fields of maxillofacial surgery, plasticsurgery, and orthopaedic surgery. The use of PRP doeshave some controversial implications with internationalantidoping regulations for professional athletes and eliteamateur athletes. Multiple basic science, in vivo animal,and small human case series agree that PRP has a role inthe stimulation of the healing cascade.The majority of human studies that have been performedhave a small number of participants and controls. Thestudies do not have enough statistical power to documenta true statistical difference between the controls and treatment groups. There is a need for prospective, randomized,controlled, double-blind studies that meet the requirements for properly powered studies. The studies need tofocus on the use of PRP in the treatment of acute andchronic injuries. The application of PRP in different tissuestructures (ligament, tendon, muscle, and articular cartilage) needs to be studied using standardized methods. Theappropriate host tissue environment requires furtherstudy, and the mechanism of action and clinical effect foreach tissue type should be defined.

There remains a significant amount of basic sciencestudy and clinical evaluation that is required to define theoptimal concentration of PRP, the optimal timing of theinjection after an acute injury, and the optimal physiologicenvironment.A degree of caution should be exercised with the development of novel technologies. The discovery and subsequentdevelopment and use of BMP within orthopaedic surgeryalso was met with significant optimism regarding itspotential clinical application. Thomas A Einhorn, MD, athought leader in bone biology and metabolic bone disease,recently said, The development of BMP definitely rode awave of optimism that this was the growth factor that was


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going to solve all of our bone healing problems. That expec-tation was not met , . . personal communication, TAEinhorn MD, August 2009). The role of PRP in sportsmedicine may signal the dawn of a new era in which ath-letic injuries are treated with. cell lines, growth factors, andbioactive proteins, but there remains a significant amountof work before this becomes the standard of care.REFERENCES

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