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//-->Knee Surg Sports Traumatol ArthroscDOI 10.1007/s00167-011-1837-xKNEEPlatelet-rich plasma intra-articular injections for cartilagedegeneration and osteoarthritis: single- versusdouble-spinning approachGiuseppe Filardo•Elizaveta Kon•Maria Teresa Pereira Ruiz•Franca Vaccaro•Rita Guitaldi•Alessandro Di Martino•Annarita Cenacchi•Pier Maria Fornasari•Maurilio MarcacciReceived: 22 April 2011 / Accepted: 13 December 2011ÓSpringer-Verlag 2011AbstractPurposeTo compare the safety and efficacy of two dif-ferent approaches of platelet-rich plasma (PRP) productionmethods as intra-articular injection treatment for kneecartilage degenerative lesions and osteoarthritis (OA).MethodsThe study involved 144 symptomatic patientsaffected by cartilage degenerative lesions and OA. Sev-enty-two patients were treated with 3 injections of plateletconcentrate prepared with a single-spinning procedure(PRGF), the other 72 with 3 injections of PRP obtainedwith a double-spinning approach. The patients were eval-uated prospectively at the enrollment and at 2, 6, and12 months’ follow-up with IKDC, EQ-VAS and Tegnerscores; adverse events and patient satisfaction were alsorecorded.ResultsBoth treatment groups presented a statisticallysignificant improvement in all the scores evaluated at allthe follow-up times. Better results were achieved in bothgroups in younger patients with a lower degree of cartilagedegeneration. The comparative analysis showed similarimprovements with the two procedures: in particular,IKDC subjective evaluation increased from 45.0±10.1 to59.0±16.2, 61.3±16.3, and 61.6±16.2 at 2, 6, and12 months in the PRGF group, and from 42.1±13.5 to60.8±16.6, 62.5±19.9, and 59.9±20.0 at 2, 6, and12 months in the PRP group, respectively. Concerningadverse events, more swelling (P=0.03) and pain reaction(P=0.0005), were found after PRP injections.ConclusionsAlthough PRP injections produced morepain and swelling reaction with respect to that produced byPRGF, similar results were found at the follow-up times,with a significant clinical improvement with respect to thebasal level. Better results were achieved in youngerpatients with a low degree of cartilage degeneration.Level of evidenceII.KeywordsPRPÁCartilageÁOsteoarthritisÁKneeÁIntra-articular injectionIntroductionThe social impact of degenerative diseases such as articularcartilage disease and osteoarthritis (OA) is increasing, dueto the continued rise in the mean age of the population andgreater emphasis on physical activity in all age groups[7,36].Unfortunately, the regeneration ability of cartilageis limited, and trauma, chronic overload, as well as meta-bolic and biological predisposition, may lead to the loss oftissue homeostasis thus resulting in accelerated joint sur-face damage and eventually end-stage arthritis [4], and wedo not have evidence-based methods for the treatment ofcartilage defects in the knee, yet [3].Numerous approaches have been proposed as non-invasive treatment with variable success rates, but none hasclearly shown an ability to alter the natural history of thisG. FilardoÁE. Kon (&)ÁA. Di MartinoÁM. MarcacciBiomechanics Laboratory, III Clinic, Rizzoli OrthopaedicInstitute, Via Di Barbiano 1/10, 40136 Bologna, Italye-mail: e.kon@biomec.ior.itM. T. Pereira RuizÁR. GuitaldiVilla Stuart, Sport Rehabilitation Center, Roma, ItalyF. VaccaroImmunohematology and Transfusion Medicine Service,San Pietro Hospital, Roma, ItalyA. CenacchiÁP. M. FornasariImmunohematology and Transfusion Medicine Service,Rizzoli Orthopaedic Institute, Bologna, Italy123Knee Surg Sports Traumatol Arthroscdisease, and therefore, none can be considered as an idealprocedure for the treatment of chronic severe chondrallesions or OA [15].Recently, platelet-rich plasma (PRP) has been attractingattention as an innovative and promising procedure tostimulate repair or replace damaged cartilage, due to thepools of growth factors (GFs) stored in thea-granulesofplatelets, which have been found to take part in the regu-lation of articular cartilage [34]. Among these, TGF-b hasshown an important role in phenotype expression, chon-drogenic MSC differentiation, matrix deposition, anddecreasing the suppressive effects of inflammatory medi-ator IL 1 on proteoglycan synthesis in cartilage [12,26].PDGF promotes the maintenance of hyaline-like pheno-type, chondrocyte proliferation and proteoglycan synthesis[32]. IGF stimulates proteoglycan production [21], andmany other bioactive molecules are involved in cartilageregeneration and metabolism independently or with syn-ergistic interaction [25]. PRP is a simple and minimallyinvasive method to obtain a high concentrate of autologousGFs in physiological proportions, which can be easily andsafely placed directly into the lesion site [6]. Moreover, therisk of allergy or infection is negligible, due to the autol-ogous nature of the platelet extract [31].Despite the worldwide clinical application of thisappealing innovative treatment approach and interesting,promising findings [33], research into its clinical efficacy isstill in its infancy, and in most cases, results are still pre-liminary and controversial. The difficulty in this field ofresearch is increased by the numerous products used. PRPis generally defined as a blood derivate, generated by dif-ferential centrifugation of autologous whole blood, with ahigher concentration of platelets compared with baselineblood, but more specific elements have not been uniformlydefined in the literature. PRP concentrations have beenreported to range widely, and the numerous preparationmethods present many other different variables, such as thepresence of other cells, activation and storage modalities,and many other aspects that are not of secondary impor-tance for determining PRP properties and clinical efficacy[19]. In particular, the presence of leukocytes and theirintra-articular injection is controversial, since some authorsattribute better results to leukocyte depletion, because ofthe deleterious effects of proteases and reactive oxygenreleased from white cells; others consider them as a sourceof cytokines and enzymes that may also be important forthe prevention of infections [10].The aim of this study was to explore this novel bio-logical treatment for degenerative lesions of articular car-tilage and OA by comparing two products, already used inclinical practice, which are based on different preparationapproaches: single- versus double-spinning procedures.The hypothesis was that the difference in plateletconcentration, cellularity, and storage modality may lead todifferent clinical results.Materials and methodsClinical experimentation was approved by the HospitalEthics Committee and Internal Review Board, andinformed consent of all patients was obtained.The following diagnostic criteria for patient selectionwere used: patients affected by chronic (at least 4 months)pain or swelling of the knee and imaging findings (radio-graph or MRI) of degenerative changes of the joint.Patients were divided into three categories: degenera-tive chondral lesion (Kellgren-Lawrence 0), early OA(Kellgren-Lawrence I-III), and advanced OA (Kellgren-Lawrence IV). Exclusion criteria included systemic disor-ders such as diabetes, rheumatic diseases, hematologicaldiseases (coagulopathies), severe cardiovascular diseases,infections, immunodepression, patients in therapy withanticoagulants-antiaggregants, use of NSAIDs in the5 days before blood donation, patients with Hb valuesof\11and platelet values of\150.000/mmc.For this study, 144 patients affected by cartilagedegenerative lesions and OA were enrolled and treatedwith intra-articular knee injections. Patients without MRIevidence of cartilage changes were excluded from thestudy. Symptoms were due to the degenerative knee con-dition and not related directly to previous trauma. For thepatients who had undergone previous knee surgery, theoperation was performed at least 1 year before the injectivetreatment. Among these patients, 72 were treated with 3autologous PRGF injections and 72 with 3 PRP intra-articular injections. Each center performed only one treat-ment, and so the patient treatment allocation was due to thecenter the patients attended. Both centers enrolled con-secutive patients following the same inclusion criteria. Allthe patients were prospectively evaluated at 2, 6, and12 months’ follow-up. When lesions were bilateral, theworse knee was chosen for the clinical evaluation, beingthe one that determined the level achieved in the subjectivescores used.No statistically significant differences were foundbetween the PRP and the PRGF groups regarding age, sex,number of bilateral lesions, BMI, degeneration level andprevious surgery (Table1).Platelet concentrate preparation and injectionPRGF: The procedure consisted of a 36-ml venous bloodsample for every knee treated for every injection. Fourtubes of 9 ml of blood were centrifuged at 580 g for8 min, obtaining a concentration suspended in plasma123Knee Surg Sports Traumatol ArthroscTable 1Comparison of the patient characteristics of the two treat-ment groups: the groups were homogeneous for age, sex, number ofbilateral lesions, BMI, pathology, and previous surgeryPRGFPatientsAgeSexBilateralBMIPathology7253.8±14.952 M, 20 F1625.1±3.031 Cart degeneration30 Early OA11 Advanced OAPrevioussurgery23 (17 Meniscectomy,8 ACL and 1 PCL,2 tibial plateau osteosynthesis,2 femoral osteosynthesis,2 shaving)PRP7250.3±14.443 M, 29 F1525.4±3.532 Cart degeneration24 Early OA16 Advanced OA33 (19 Meniscectomy,9 ACL, 1 PCL,1 MCL, 6 shaving,6 microfractures,2 ACI, 1 mosaicplasty,2 tibial osteotomy,1 patellar realignment)N.S.N.S.N.S.N.S.N.SN.S.performed in an A-class sterile hood. One unit was sent tothe laboratory for a quality test (platelet count and bacte-riological test), 1 unit was used for the first injection within2 h, and the other two units were stored at-30°C.Injec-tions were administered every 21 days; for the second andthird treatments, the samples were thawed in a dry ther-mostat at 37°C for 30just before application. Before theinjection, 10% of Ca-chloride was added to the PRP unit toactivate platelets.In both procedures, injections were administered every21 days. The skin was sterilely dressed, and the injectionwas performed through a classic lateral approach using a22-g needle. At the end of the procedure, the patient wasencouraged to bend and extend the knee a few times toallow the PRP to spread throughout the joint beforebecoming a gel (Fig.1).Platelet and cell countTo analyze the differences in concentrates obtained withthe two procedures, 7 volunteers underwent blood har-vesting, and both PRGF and PRP were prepared from thesame blood. The mean final quantity of platelet concen-trated was 315,000/ll in the PRGF group and 949,000/ll inthe PRP group, with a concentration factor of 1.59 with thesingle-spinning procedure and 4.79 with the double-spin-ning procedure. The mean final number of leukocytes was8,300/ll in the PRP group and none in the PRGF group,with a concentration factor of 0.09 with the single-spin-ning procedure and 1.49 with the double-spinningprocedure.that was extracted by pipetting carefully to avoid leu-kocyte aspiration. All the open procedures were per-formed in a laminar flow chamber. Before the injection,10% of Ca-chloride was added to the 5 ml PRGF unit toactivate platelets. The procedure was repeated for everyinjection [38].PRP: The procedure consisted of a 150-ml venous bloodsample for every knee treated. Two centrifugations (thefirst at 1,800 rpm for 15 min to separate erythrocytes, and asecond at 3,500 rpm for 10 min to concentrate platelets)produced 20 ml of PRP. The unit of PRP was divided into4 small units of 5 ml each. All the open procedures wereFig. 1PRP and PRGF preparation procedures123Knee Surg Sports Traumatol ArthroscPost-procedure protocol and follow-up evaluationThe patients were sent home after the injection withinstructions to restrict the use of the leg and not to use non-steroidal or steroidal medication but cold therapy for painfor at least 24 h. During the cycle of injections rest or mildactivities were indicated. Subsequently, a gradual resump-tion of normal sport or recreational activities was allowed astolerated in both the treatment groups.Patients were evaluated prospectively before thetreatment, at 2, 6, and 12 months’ follow-up. SubjectiveIKDC, EQ-VAS (as recommended by ICRS evaluationpackage), and Tegner scores were used for clinicalevaluation. Adverse events and patient satisfaction werealso recorded.Statistical analysisAll continuous data were expressed in terms of the meanand the standard deviation of the mean. One-way ANOVAwas performed to assess differences between groups whenthe Levene test for homogeneity of variances was notsignificant (P\0.05); otherwise, the Mann–Whitney test(2 groups) or the Kruskal–Wallis test (more than 2 groups)was used. The least significant difference test was per-formed as post hoc pair-wise analysis of the Kruskal–Wallis test. Generalized linear model for repeated mea-sures with Bonferroni’s correction for multiple compari-sons was performed to test differences of the scores atdifferent follow-up times. The influence of grouping vari-ables on scores at different follow-up times was investi-gated by the generalized linear model for repeatedmeasures with the grouping variable as a fixed effect.Pearson’s nonparametric chi-square test evaluated by theExact method was performed to investigate the relation-ships between grouping variables. Spearman’s rankFig. 2Health status evaluatedwith the IKDC score (0–100) inthe two treatment groupscorrelation was used to assess the correlation betweencontinuous variables.A power analysis was performed for the primary end-point of IKDC-S at the 6-month follow-up for PRP andPRGF. From a pilot study, a standard deviation of 15.8points was found. With an alpha error of 0.05, a beta errorof 0.2 and a minimal clinically significant difference of 7.4points corresponding at 1/3 of the documented meanimprovement, the minimum sample size was 72 for eachgroup. For all tests,P\0.05 was considered significant.Statistical analysis was carried out by using the Statis-tical Package for the Social Sciences (SPSS) softwareversion 15.0 (SPSS Inc., Chicago, USA).ResultsNo severe adverse events were observed during the treat-ment and follow-up periods. Both groups showed a statis-tically significant improvement of all clinical scores frompreoperative to final follow-up.PRGF group: the IKDC subjective score showed astatistically significant improvement (P\0.0005) at2 months, which was maintained at 6 and 12 months(P\0.0005) (Fig.2).Analogously, EQ-VAS improvedsignificantly (P\0.0005) at 2, 6, and 12 months’ follow-up with respect to the basal level (Fig.3).The Tegner scoreimproved at 2 months (P\0.0005); a further improve-ment was seen at 6 months, then results remained stable at12 months (Fig.4).PRP group: the IKDC subjective score showed astatistically significant improvement (P\0.0005) at2 months, which was maintained at 6 and 12 months(P\0.0005). Analogously, EQ-VAS improved signifi-cantly (P\0.0005) at 2, 6, and 12 months’ follow-up withrespect to the basal level (Fig.3).The Tegner score123Knee Surg Sports Traumatol ArthroscFig. 3Health status evaluatedwith the EQ-VAS score (0–100)in the two treatment groupsFig. 4Activity level evaluatedwith the Tegner score (0–10) inthe two treatment groupsimproved at 2 months (P\0.0005); a further improve-ment was seen at 6 months, then results remained stable at12 months (Fig.4).When comparing the two groups, no differences werefound in the subjective IKDC, EQ VAS, or Tegner scores at2, 6, and 12 months’ follow-up. The satisfaction level wassimilar, too: 76.4% in the PRGF group and 80.6% in the PRPgroup. Moreover, there was also no difference in the level ofimprovement: 59 patients reported an improvement at12 months (18 mild improvement, 36 marked improvement,5 complete recovery) in the PRGF group and 56 in the PRPgroup (19 mild improvement, 32 marked improvement, 5complete recovery) (Fig.5).Conversely, the two procedures showed a statisticallysignificant difference in the number of minor adverseevents observed after the injections: both pain and swellingreaction were more frequent in the PRP group (P=0.0005andP=0.03, respectively) (Table2).Further analysis was performed to determine theparameters that influenced the clinical outcome. Inferior123
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