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Does Autologous Leukocyte-PlateleteRich Plasma ImproveTendon Healing in Arthroscopic Repair of Large or Massive

Rotator Cuff Tears?Christophe Charousset, M.D., Amine Zaoui, M.D., Laurence Bellaïche, M.D., and

Michel Piterman, M.D.

Y Purpose: To evaluate the clinical and magnetic resonance imaging (MRI) outcome of arthroscopic rotator cuff repair withthe use of leukocyte-plateleterich plasma (L-PRP) in patients with large or massive rotator cuff tears. Methods: Acomparative cohort of patients with large or massive rotator cuff tears undergoing arthroscopic repair was studied. Twoconsecutive groups of patients were included: rotator cuff repairs with L-PRP injection (group 1, n ¼ 35) and rotator cuffrepairs without L-PRP injection (group 2, n ¼ 35). A double-row cross-suture cuff repair was performed by a singlesurgeon with the same rehabilitation protocol. Patients were clinically evaluated with the Constant score; Simple ShoulderTest score; University of California, Los Angeles (UCLA) score; and strength measurements by use of a handheld dyna-mometer. Rotator cuff healing was evaluated by postoperative MRI using the Sugaya classification (type 1 to type 5).Results: We prospectively evaluated the 2 groups at a minimum 2-year follow-up. The results did not show differences incuff healing between the 2 groups (P ¼ .16). The size of recurrent tears (type 4 v type 5), however, was significantlysmaller in group 1 (P ¼ .008). There was no statistically significant difference in the recurrent tear rate (types 4 and 5)between the 2 groups (P ¼ .65). There was no significant difference between group 1 and group 2 in terms of University ofCalifornia, Los Angeles score (29.1 and 30.3, respectively; P ¼ .90); Simple Shoulder Test score (9.9 and 10.2, respectively;P ¼ .94); Constant score (77.3 and 78.1, respectively; P ¼ .82); and strength (7.5 and 7.0, respectively; P ¼ .51).Conclusions: In our study the use of autologous L-PRP did not improve the quality of tendon healing in patients un-dergoing arthroscopic repair of large or massive rotator cuff tears based on postoperative MRI evaluation. The only sig-nificant advantage was that the L-PRP patients had smaller iterative tears. However, the functional outcome was similar inthe 2 groups of patients. Level of Evidence: Level III, case-control study.PERSONAL C

OP

rthroscopic repair of massive rotator cuff tears is

Aassociated with less favorable clinical results and ahigher retear rate than repair of smaller tears, withstructural failure in up to 90% at 1 and 2 years post-operatively.1-4 One biological therapeutic approach toenhance healing of repaired cuff tears is the use ofautologous growth factors. The degranulation of theHOR

From Institut Osteo Articulaire Paris Courcelles (C.C.), Paris; the LaboratoryBio-engineering and Osteo-articular Biomaterial, University Denis Diderot.Z.), Paris; Centre d’Image Médicale Bachaumont (L.B.), Paris; and Labo-toire Parole et Langage, CNRS, Aix-Marseille Université (M.P.), Aix-en-rovence, France.The authors report that they have no conflicts of interest in the authorship

nd publication of this article.Received June 3, 2013; accepted December 31, 2013.Address correspondence to Christophe Charousset, M.D., Institut Osteorticulaire Paris Courcelles, 60 Rue de Courcelles 75008 Paris, France.-mail: dr.charousset@ioapc.fr� 2014 by the Arthroscopy Association of North America0749-8063/13368/$36.00http://dx.doi.org/10.1016/j.arthro.2013.12.018

28 Arthroscopy: The Journal of Arthroscopic and Related

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alpha granules in the platelets releases many differentgrowth factors.Therefore platelet-rich plasma (PRP) has gained

popularity in many fields, such as wound healing5 andsports medicine,6,7 especially to increase tendon heal-ing.8 The platelets release different growth factors:platelet-derived growth factor (PDGF), transforminggrowth factor b, vascular endothelial growth factor(VEGF), epithelial growth factor, hepatocyte growthfactor, and insulin-like growth factor. These growthfactors are believed to stimulate tendon healingthrough cell regeneration, collagen regeneration, andwell-ordered angiogenesis.8,9

Autologous growth factors are delivered locally in theform of PRP, and the ability of these growth factors toaugment cuff tear healing is currently under investi-gation. Barber et al.10 and Randelli et al.11 foundimproved healing of cuff tears augmented with PRP,whereas Chahal et al.12 stated in a systematic reviewthat PRP does not have an effect on the overall retearrate after arthroscopic rotator cuff repair.

Surgery, Vol 30, No 4 (April), 2014: pp 428-435

Fig 1. Final arthroscopic view of repaired cuff tear.

LEUKO-PRP IN ROTATOR CUFF REPAIR 429

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The purpose of this study was to evaluate the clinicaland magnetic resonance imaging (MRI) results ofarthroscopic rotator cuff repair with the use ofleukocyte-plateleterich plasma (L-PRP) in patientswith large or massive posterosuperior rotator cuff tears.Our hypothesis was that the injection of L-PRP duringlarge or massive cuff tear repair would result inimproved tendon healing and better clinical outcomes.

MethodsThe inclusion criteria were as follows: the presence of a

reparable large ormassive full-thickness posterosuperiorrotator cuff tear according to the Codman classification,with no previous surgery on the shoulder in question, nodegenerative arthritis of the glenohumeral joint, noautoimmune or rheumatologic disease, and no sign ofadhesive capsulitis or shoulder instability.We excluded patients with a partial-thickness tear, a

small tomedium full-thickness tear, an irreparable tear, ora full-thickness tear with extension anteriorly to includemore than the subscapularis tendon. Patients withthrombocytopenia or blood dyscrasia were also excluded.Seventy patients who presented to our hospital from

June 2008 through June 2010 to undergo arthroscopicrepair of large or massive rotator cuff tears met ourinclusion criteria and were prospectively enrolled in ourstudy. All were diagnosed with full-thickness rotatorcuff tears based on both physical examination andpreoperative MRI. MRI scans were performed at amedian of 19 days (range, 9 to 40 days) before thepatients’ inclusion. Fatty degeneration of the rotatorcuff muscles was documented on MRI and classified asdescribed by Goutallier et al.13 and Fuchs et al.14 (grade0, no fatty infiltration; grade 1, some fatty streaks; grade2, more muscle than fat; grade 3, as much muscle as fat;or grade 4, less muscle than fat).The patients were divided into 2 consecutive groups:

35 patients in whom repairs were augmented withautologous L-PRP injection (group 1) and 35 patientswithout L-PRP injection (group 2). The patients werenot blinded. The PRP group was treated first, and weexplained to these patients that they would be includedin a study to evaluate the effect of PRP augmentationon cuff tear repair. We explained to the patients in thesecond group that they would receive the conventionaltreatment for cuff tears.Each patient’s suitability for inclusion was confirmed

once the dimension of the rotator cuff tear had beenverified at the time of arthroscopy. The institutionalreview board of our center approved the study, andeach patient signed a detailed informed-consent form.

Surgical ProcedureThe surgical procedure was performed with the pa-

tient under general anesthesia with an interscaleneblock.

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PRP PreparationAutologous L-PRP Preparation. L-PRP was obtained byuse of the GPS III Platelet Concentration System (Bio-met Biologics, Warsaw, IN) per the instructions for use.With the patient under anesthesia, 54 mL of blood wasobtained from a venous puncture and mixed with 6 mLof anticoagulant citrate dextrose formula A. The 60 mLof anticoagulated blood was put into a speciallydesigned disposable and centrifuged for 15 minutes at3,220 rpm in a dedicated centrifuge (model 755VES230V; The Drucker Company, Philipsburg, PA). Aftercentrifugation, the concentrated platelets, in betweenthe 2 buoys, were resuspended to form 6 mL of L-PRP,which was stored in a dedicated sterile syringe until use.

Autologous Thrombin Preparation. Autologous thrombinwas prepared by use of the Clotalyst Autologous Clot-ting Factor System (Biomet Biologics). Eleven millilitersof the patient’s blood was obtained by venipuncture atthe same time as the blood for the L-PRP and wasmixed with 1 mL of anticoagulant citrate dextrose for-mula A. Four milliliters of the Clotalyst reagent (Ther-mogenesis, Rancho Cordova, CA) was put into theClotalyst disposable, followed by 12 mL of the anti-coagulated blood. The Clotalyst disposable was incu-bated in the Clotalyst heater (Biomet Biologics) at 25�Cfor 20 to 25 minutes. The Clotalyst disposable was thencentrifuged for 5 minutes at 3,200 rpm in a dedicatedcentrifuge (model 755VES 230V). After centrifugation,the autologous thrombin was aspirated and stored in adedicated sterile syringe until use (Fig 1).

Surgical TechniqueCuff repairwas conductedwith the patient in the beach-

chair position with the usual arthroscopic materials (knotpusher, cuff-penetrating graspers) and with BioZip bio-absorbable anchors double loaded with Force Fiberultrahighemolecular weight polyethyleneecontainingsutures (Stryker, Kalamazoo, MI).

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Fig 3. Arthroscopic view of position of applicator throughrepair site.

430 C. CHAROUSSET ET AL.

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The surgeon measured the tear size in the ante-roposterior dimension using a calibrated probe intro-duced through the posterior portal while viewing fromthe lateral portal. An arthroscopic double-row cross-suture rotator cuff repair was performed in all cases bythe same surgeon according to a previously describedtechnique.15,16 In brief, this technique consists of a“cross” and “bridge” fixation using standard sutureanchors. For the lateral row, we used two 6.5-mmanchors placed 2 cm below the edge of the greater tu-berosity, with a 2-cm distance between the anchors. Forthe medial-row anchors, we used two 5-mm anchorsplaced just lateral to the bone-cartilage junction inalignment with the 6.5-mm lateral anchors. Four an-chors were used in all cases.Arthroscopic acromioplasty was carried out in every

patient, and the distal clavicle was resected if the patienthad a symptomatic, degenerative acromioclavicularjoint preoperatively. Biceps tears and instability weretreated with either tenodesis or tenotomy.The repair was completed in all cases. Regarding the

cuff tear size, a tear measuring greater than 5 cm wasfound in 8 patients in group 1 and 6 patients in group 2,without a significant difference between the groups(P ¼ .73).

Surgical Application of PRPAt the end of the arthroscopic procedure, the inflow

cannula was closed and the arthroscopic fluid carefullyaspirated through the outflow cannula, producing a drysubacromial space. A final L-PRP volume of 6 mL wasobtained by the adopted protocol. By use of the lateralportal, the spray applicator kit loaded with syringesof L-PRP and autologous thrombin was positionedthrough the repaired rotator cuff (Figs 2 and 3). Theblood products were then slowly injected and uni-formly applied. A dry arthroscopic check was per-formed to evaluate clot formation (Fig 4).R P

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Fig 2. External view of L-PRP being applied to repair sitethrough working arthroscopic portal.

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In the non-PRP patients, dry arthroscopy was per-formed in the same manner, without any injection.

Postoperative Rehabilitation ProtocolAll patients followed the same postoperative protocol.

They were supported in a sling, and pendulum exer-cises and relaxation of the muscles around the shouldergirdle were initiated on the day after surgery with theassistance of a physical therapist. Passive shouldermotion was initiated 5 days after surgery. The sling wasremoved 3 weeks postoperatively, and active-assistedmotion was started at that time. Full active shouldermotion was allowed at 6 to 8 weeks postoperatively,and strengthening exercises were initiated at 3 months.Full return to sports and heavy labor was allowed at6 months according to the individual’s functionalrecovery.

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Fig 4. Checking of clot formation.

Table 1. Baseline Characteristics for Matched Study Groups

Group 1 (L-PRP) (n ¼ 35) Group 2 (Control) (n ¼ 35)

P ValueNo. of Patients Mean Range SD No. of Patients Mean Range SD

Age 63.9 yr 48-78 yr 6.9 yr 61.4 yr 45-80 yr 5.9 yr .3248Male 19 20 .4067Dominance 26 23 >.99Duration >12 mo 9 11 .6489Upper limb worker 13 16 .6098Fatty infiltration 1.5 0-3 0.5 1.6 0-3 0.6 .9053SST score 3.1 0-8 1.5 2.9 1-8 1.1 .98Pain rating 3.7 0-10 2.5 4.8 0-10 1.2 .9894Constant score 47.9 32-65 6.9 48.3 36-64 5.7 .7474UCLA score 11.1 8-13 1.1 12.2 8-14 1.3 .7794Initial strength 2.8 kg 0-8 kg 1.7 kg 2.8 kg 0-9 kg 1.4 kg .7843Tear size >5 cm 8 6 .7371

NOTE. For ordinal data, results are expressed as mean, range, and standard deviation; for categorical data, results are expressed as number ofoccurrences.SST, Simple Shoulder Test; UCLA, University of California, Los Angeles.

LEUKO-PRP IN ROTATOR CUFF REPAIR 431

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The clinical postoperative follow-up was performed at

3 weeks and 3, 6, 12, and 24 months. The integrity ofthe repair was evaluated with MRI.

MRI Evaluation of Cuff IntegrityThe primary outcome was tendon healing evaluated

by MRI (1.5 T) in all patients. MRI scans were acquired6 months after repair. All MRI studies were evaluatedby 1 independent musculoskeletal radiologist withextensive experience in interpretation of shoulder MRIstudies. He was blinded to the patient’s treatmentassignment and not involved in the clinical evaluation.The images were used for structural and qualitativeassessment of the rotator cuff, and repair integrity wasdetermined according to the classification of Sugayaet al.17 This classification distinguishes 5 repair cate-gories with the use of oblique coronal, oblique sagittal,and transverse T2-weighted images. Type 1 indicates arepaired rotator cuff that has sufficient thickness withhomogeneously low intensity on each image; type 2,sufficient thickness with a partial high-intensity area;type 3, insufficient thickness without discontinuity;type 4, presence of a minor discontinuity in more than1 slice of each image, suggestive of a small tear; andtype 5, presence of a major discontinuity on each im-age, suggestive of a large tear.

Clinical OutcomeSecondary outcomes included the Constant score;

Simple Shoulder Test score; University of California,Los Angeles score; and strength measurements by useof a handheld dynamometer. We measured strength ofelevation in the scapular plane. Clinical evaluationswere performed by a blinded study nurse.

A Priori Power AnalysisAn a priori power analysis was performed for the

primary outcome measure (proportion of retears of

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repaired cuffs). On the basis of our experience, as wellas previous studies, the retear rate for the repaired cuffis approximately 50%.18 Given the timeframe allowedfor our study, we expected to treat 35 patients in eachgroup. We chose the traditional values a ¼ .05 andb ¼ .20, implying a power of 0.80. With these values,the probability to see a significant decrease in the retearrate in a comparison test of 2 proportions will be at least80% if the retear rate decrease is at least 26%dthat is,if the retear rate in the L-PRP group is lower than 14%and the retear rate of the control group is at least40%.19

Statistical AnalysisTwo-sided unpaired Mann-Whitney tests were used

to compare the 2 groups. Exact P values could not becomputed because there were ties in the data. P valueswere therefore estimated by normal approximations.Significance was set at P ¼ .05. Statistical analyses wereperformed with the use of the software R, version2.14.1-1.

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ResultsAt 2 years’ follow-up, there were no intraoperative

or postoperative complications. Both groups were ho-mogeneous, with no significant differences regardingdemographic characteristics, fatty degeneration, preop-erative functional scores, and follow-up (mean, 28.6months; range, 24 to 34 months) (Table 1).

Cuff IntegrityGroup 1 (L-PRP group) included 31 patients (4 pa-

tients were lost to follow-up at 6 months), and group 2(control group) included 30 patients (5 patients werelost to follow-up at 6 months). Table 2 shows thenumber and proportion of patients in each Sugayacategory for the 2 groups. The general tendency

Table 2. Comparison of Structural Integrity of Cuff Repair Assessed by MRI

Repair Integrity(Sugaya Category17) Group 1 (L-Prp) Group 2 (Control)

P Value

Statistical Test 1* Statistical Test 2y Statistical Test 3z

Type 1 11 (35.5%) 5 (16.7%) .16Type 2 5 (16.1%) 10 (33.3%)Type 3 4 (12.9%) 3 (10.0%)Type 4 9 (29.0%) 3 (10.0%) .65 .008Type 5 2 (6.5%) 9 (30.0%)Total 31 (100%) 30 (100%)

*The hypothesis was that the 2 repartitions were identical (types 1 and 2).yThe hypothesis was that the rates of the iterative tears (types 4 and 5) were the same for the 2 groups.zThe hypothesis was that the sizes of the iterative small and large tears (types 4 and 5) were equal for the 2 groups.

432 C. CHAROUSSET ET AL.

showed more patients in the Sugaya type 1 category inthe L-PRP group than in the control group. This ten-dency was not significant when Sugaya type 1 and type2 were taken together (P ¼ .16). The retear rates were35.5% for the L-PRP group and 40% for the controlgroup; this difference was not significant (P ¼ .65).However, the size of retears was significantly smaller inthe L-PRP group (P ¼ .008) (Table 2, Figs 5-7).

Clinical OutcomesClinical outcome measures for both groups were

compared at 2 years’ follow-up. There was no signifi-cant difference between group 1 and group 2 in termsof University of California, Los Angeles score (29.1 and30.1, respectively; P ¼ .90); Simple Shoulder Test score(9.9 and 10.2, respectively; P ¼ .94); Constant score(77.3 and 78.1 respectively; P ¼ .82); or strength (7.5and 7.0 respectively; P ¼ .51) (Table 3).

R

DiscussionThe ultimate goals of tendon reinsertion are (1) to

improve the biological environment around the repairPE

Fig 5. Postoperative MRI scan showing anatomic healing(Sugaya type 1) in L-PRPetreated patient.

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to promote the regeneration of the native insertion siteand (2) to prevent scar tissue formation. A reliablereinsertion technique, faster mobilization of fibroblastsand collagen, and increased local vascularization areessential to optimize healing. For this reason, weassessed whether combining a double-row suture an-chor technique with an L-PRP injection would improveoutcomes. The double-row suture anchor technique forrotator cuff reinsertion, which has been developedto restore the footprint better, resulteddin moststudiesdin a significant improvement in terms ofbiomechanics. Thus, in a cohort study including 78patients, Park et al.20 found that double-row repairresulted in significantly better outcomes than single-row repair for patients with large to massive tears(>3 cm), leading them to recommend double-rowrepair for larger tears. This is why, in this study, wefocused on the treatment of large and massive tearswith a double-row repair technique that led to verysatisfactory biomechanical results.16

The biological study of tendon healing showed thatgrowth factors are 1 of the most important molecular

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Fig 6. Postoperative MRI scan showing small retear (Sugayatype 4) in L-PRPetreated patient.

Fig 7. Postoperative MRI scan showing small retear (Sugayatype 5) in L-PRPetreated patient.

LEUKO-PRP IN ROTATOR CUFF REPAIR 433

families for tissue healing.21 The use of PRP in thetreatment of tendon lesions over several years led to asignificant improvement in healing,7,22-24 thanks to thenumerous growth factors that it releases. Indeed, acti-vated platelets release alpha granules that containgrowth factors and act as messengers by traveling to cellreceptors and promoting cell proliferation (these factorsact as signaling agents to promote and accelerate tissuehealing).8,21

We used L-PRP, which contains a large number ofplatelets (4 to 8 times the circulating levels) and leuko-cytes, in this study. It also contains significant concen-trations of the growth factors (PDGF, basic fibroblastgrowth factor, transforming growth factor b, VEGF, andinsulin-like growth factor 1) that are essential for heal-ing. We noted that the proportion of L-PRP patients inthe type 2 and type 4 categories of the Sugaya classifi-cation decreased in comparison with the repartition ofthe control group, but the tendency was not significant(P ¼ .16). The iterative tears (type 4 and type 5) weresmaller in the L-PRP group than in the control group (P¼.008). However, the overall number of iterative tears(type 4 plus type 5) was 35.5% in the L-PRP group and

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Table 3. SST Score, Pain Rating, Constant Score, UCLA Score,and Strength at Latest Follow-up

Group 1 (L-PRP) Group 2 (Control) PValueMean Range SD Mean Range SD

SST score 9.9 4-12 2.9 10.2 5-12 2 .94Pain rating 1.3 0-4 2.2 1.6 0-4 2.6 .78Constant

score77.3 39-89 9.9 78.1 57-90 7.7 .82

UCLA score 29.1 27.9-35 2.3 30.3 27.2-35 3.2 .90Strength 7.5 kg 0-14 kg 3 kg 7.0 kg 1-15 kg 3.6 kg .51

SST, Simple Shoulder Test; UCLA, University of California, LosAngeles.

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40% in the control group (P ¼ .65), which may explainthe fact that patients in the L-PRP group did not showbetter functional improvement than control patients.A variety of blood sample kits with different types of

centrifugation, in terms of speed and time, are currentlyavailable. The resulting growth factor concentrationobtained is variable, as shown by Castillo et al.25 Wecan especially differentiate PRP (in liquid or gel formafter activation) and platelet-rich fibrin matrix (PRFM),which becomes solid after 2 centrifugations through theformation of a fibrin matrix. Leukocytes may or maynot be present, depending on the kit used. Castillo et al.found significantly higher levels of VEGF and PDGF inL-PRP (Biomet system; Biomet, Warsaw, IN) thanPRFM without leukocytes (Cascade system; MTF SportsMedicine, Edison, NJ). In a prospective randomizedstudy, Randelli et al.11 found that patients treated withL-PRP had accelerated functional recovery and partic-ularly pain reduction, although no difference in tendonhealing could be observed. Barber et al.10 found a sig-nificant improvement in tendon healing for tears ofvarious sizes, but the functional results were identicalin all patients. However, Jo et al.,26 Rodeo et al.,27

Bergeson et al.,28 and Castricini et al.29 could not ob-serve any improvement in terms of function or healing.In fact, Rodeo et al.27 even showed that PRFM couldhave a negative effect on healing by modifying thebiological interface between the tendon and the bone.Gumina et al.,30 who used another form of PRFMthat included leukocytes (L-PRFM), compared 2 groupswith large tears and noted a significant improvement inhealing in patients treated with L-PRP but no differencein functional recovery. These findings are in accordancewith a recent meta-analysis that suggests that the PRPproducts have no benefits on the overall clinical out-comes and retear rates for the arthroscopic repair offull-thickness rotator cuff tears.31 However, a decreaseoccurred in the rate of retears among patients treatedwith PRP for small- and medium-sized rotator cuff tearsbut not for large- and massive-sized tears.31

LimitationsThe main limitation of our study was that the starting

hypothesis could not be confirmed because we werenot able to decrease the rate of iterative tears (types 4and 5) with L-PRP treatment. The a priori analysisshowed that with our statistical choices, a decrease inthe rate of iterative tears of at least 26% was mandatoryto reach a probability of 80% to see a significant dif-ference between the 2 groups. We only observed adecrease of 4.5% (40% for the control group and35.5% for the L-PRP group). If 0.400 and 0.355 werethe proportions of the full populations and not of 2samples, the same power analysis would show that1,434 patients would be required in each group to havea probability of 80% to see a significant difference

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434 C. CHAROUSSET ET AL.

between the 2 groups. This suggests that our study wasunderpowered to detect differences in structuralintegrity. It is generally strongly advised to avoid car-rying out a posteriori power analyses because they canbe very misleading32; hence the previous statementshould be taken as a rough hint, not as a precise figure.Another shortcoming of our study is that the protocol

used, which included only 1 intraoperative injection forlarge or massive tears, may not be very effective. Thus 1or 2 additional injections could be planned within3 weeks of repair, when healing is undergoing its mostsubstantial remodeling. In fact, multiple injectionsproved efficiency for the treatment of Achilles tendinitisand other chronic tendinopathies.22,23

A final limitation of our study is that the number ofplatelets and levels of growth factors injected were notcalculated. McCarrel and Fortier,33 comparing L-PRPwith PRP, showed that the levels of inflammation fac-tors were increased when injecting leukocytes. We doknow the levels in vitro obtained with different tech-niques (PRP/PRFM), but the levels in vivo at the time ofthe injection and a few hours or days later are stillmissing. Further investigations are needed to betterdetermine the amount and the kinetics of the growthfactors released within the cuff tear repair. This wouldcertainly help to develop a postoperative protocolcomprising multiple PRP injections, which may improvetendon healing rates in massive rotator cuff tears.

ConclusionsIn our study the use of autologous L-PRP did not

improve the quality of tendon healing in patients un-dergoing arthroscopic repair of large or massive rotatorcuff tears based on postoperative MRI evaluation. Theonly significant advantage was that the L-PRP patientshad smaller iterative tears. However, the functionaloutcome was similar in the 2 groups of patients.

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