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1 e l n i j i O A þ t ý m O i g in h c s Re The Clinicl Effect of Pltelet Rich Plsm Peped Though Diffeent Activtion Methods on Ptients with Knee Osteothitis Fklı Aktivsyon Yöntemleiyle Hzılnn Tombositten Zengin Plzm nın Diz Osteotitli Hstldki Klinik Etkisi l Tombositten Zengin Plzm nın Fklı Aktivsyon Yöntemlei / The Diffeent Activtion Methods of Pltelet Rich Plsm Neves Hüiyet Aydoğn 1, Deniz Gül 2, Sekn İlt 3, Ahmet Özmeiç 3, Tlip K 3, Alpe Öztük 3, Kdi Bhdı Alemdoğlu 3 1 Mugl Sıtkı Kocmn Univesity, Deptment of Othopedics nd Tumtology, Mugl, 2 Tokt Public Hospitl, Deptment of Othopedics nd Tumtology, Tokt, 3 Ank Tining nd Resech Hospitl, Deptment of Othopedics nd Tumtology, Ank, Tukey Özet Amç: Tombositten zengin plzm nın (TZP) eklem içi uygulmsı, diz osteotiti tedvisinde ltentif bi yöntem olbili. Bu çlışmnın mcı, eklem içine uygulnmdn önce tombositten zengin plzmnın ktivsyon yöntemleinin kşılştıılmsıdı. Geeç ve Yöntem: 51 hst (76 diz) stgele iki gub yıldı. 1. gupt TZP ktivsyonu klsiyum kloid (CCl) ekleneek sğlndı. 2. gupt ise TZP ktivsyonu, hzılndıktn son -70 deecede 24 st bekletilip, tmmen çözülmesi için 37 o sud 5 dkik bekletileek eklem içine uygulndı. Hstl VAS ve WOMAC ğı skolı ile bşvuu nınd, ikinci, ltıncı ve onikinci yld değelendiildile. Bulgul: VAS ve WOMAC skolı bşvuu nınd; 2., 6., ve 12. y göe kıyslndığınd isttistiksel olk nlmlı deecede yüksekti (p=0.06). 2., 6., 12. yld gupl sınd isttistiksel nlmlı fk sptnms d 2., 6., ve 12. yld he iki skod kdemeli olk düşme eğilimi olduğu göüldü. Ttışm: Hstl he iki ktivsyon yönteminden de oldukç fzl klinik fyd gödüle. Klinik fydlı çısındn TZP nın CCl vey -70 deecede ktivsyonu sınd nlmlı fk yoktu. Bu nedenle -70 deecede ktivsyon CCl gibi ilve mlzeme ihtiycını otdn kldıcğındn öncelikli tecih edilebili. Anht Kelimele Tombositten Zengin Plzm; Osteotit; Diz Abstct Aim: Int-ticul ppliction of pltelet ich plsm (PRP) cn be n ltentive tetment method fo knee osteothitis. The objective of this study ws to compe the ctivtion methods of pltelet ich plsm befoe intticul ppliction. Mteil nd Method: A totl 51 ptients (76 knees) ws ndomly selected into two goups. In goup 1, ctivtion of PRP ws mnged by dding clcium chloide (CCl). In goup 2, ctivtion of PRP ws mnged by keeping the solution t -70 degees fo 24 hous fte peption nd immesed in wte t 37 o C fo peiod of 5 minutes fo complete dissolution. Then PRP ws pplied. The ptients wee ssessed with VAS nd WOMAC pin scoes both bseline nd fte 2nd, 6th nd 12th months of the tetment. Results: VAS nd WOMAC pin scoes wee significntly highe t bseline comped to the esults obtined t the 2nd, 6th nd 12th months (p=0.06). Following 2nd, 6th nd 12th months gdul downwd tendency ws seen in both scoes, even though no significnt diffeence ws found between the goups fte 2nd, 6th nd 12th months. Discussion: Ptients eceived some clinicl benefits fom both ctivtion methods. Thee is no significnt diffeence between ctivting PRP by CCl o -70 C which comped in tems of clinicl benefits. Theefoe, blood stoge t -70ºC my be pefeed pimy due to no need fo dditionl mteil such s CCl. Keywods Pltelet-Rich Plsm; Osteothitis; Knee DOI: /JCAM.3251 Received: Accepted: Published Online: Coesponding Autho: Ahmet Özmeiç, Deptment of Othopedics nd Tumtology, Ank Tining nd Resech Hospitl, Ank, Tukey. GSM: F.: E-Mil: [email protected] Jounl of Clinicl nd Anlyticl Medicine 1

2 Intoduction Osteothitis (OA) is degenetive chonic joint disese which is genelly pogessive. It is musculoskeletl system poblem seen emkbly widesped in people bove the ge of 50 yes [1]. In pimy OA, the knee joint is one of the most fequently involved joints nd this leds to degenetive lesions in ctilge. Oxidtive stess, lipid peoxidsyon nd poteolytic enzymes my hve ole in ptogenesis of knee osteothitis (gonthosis) [2]. Howeve, thee is limited self heling of ctilge lesions nd tetment pesents chllenge fo othopedic sugeons [3]. As initil tetment, non-steoidl nti-inflmmtoy dugs (NSAIDs) e the fist choice; howeve these dugs hve toxic effects on the cdiovscul system nd gstointestinl system [4]. Topicl gents hve shot tem effect on cses with modete pin. Thee hve lso been studies whee int ticul steoid injection hs been pplied, lthough only shottem benefits hve been detemined [5]. The effectiveness of glucosmine, chondites sulfte, vitmin E, hyluonic cid nd thoscopic debidement on chonic sevee chondopthy o osteothitis is still contovesil [6]. Recently, the efficcy nd sfety of contempoy tetment methods fo the ctilge dmge hve been evluted nd comped in sevel studies. Autologous biologicl thepy fo egenetive puposes, hyluonic cid, mtix metllopoteinse inhibitos, gene thepy, cytokine inhibitos, nd the gowth fctos hve been ssessed [7-8]. Among them, pltelet ich plsm (PRP) is ntul concenttion which contins utologous gowth fctos in noml blood nd contins highe concenttions of ntul pltelet deived gowth fcto, tnsfoming gowth fcto, insulin like gowth fcto, vscul endothelil gowth fcto nd epithelil cell gowth fcto [9]. These gowth fctos e seceted fom the lph gnules fte pltelet ctivtion nd fcilitte tetment by eching the dmged zone [10]. The benefits of int ticul ppliction of PRP in the tetment of degenetive thitis of knee on the clinicl findings hve been shown peviously [11-13]. Routine peption of PRP is consisting of centifugtion of whole blood fom ptient. PRP ws peped by centifugtion vying the eltive centifugl foce, tempetue, nd time. Anothe method consists of ctivtion of PRP with thombin nd clcium chloide fo incesing gowth fcto levels [14]. The influence of ctivtion of PRP using thombin nd clcium chloide on the secetion of gowth fctos nd on the mount of pltelets concentted in plsm ws evluted peviously [14]. The pupose of this study ws to identify if ny diffeences exist cliniclly between the two ctivtion nd peption methods fo int-ticul injection of PRP. Mteil nd Method The study goup consisting of totl of 51 ptients (76 knees) who hd eceived dignosis of osteothitis ws divided into 2 goups, of 38 knees in ech. Int ticul PRP injection ws pplied to ll knees in both goups. In Goup 1, immeditely fte PRP ws peped, 0.22 meqccl ws dded nd pplied s n int-ticul injection. In Goup 2, the peped PRP ws stoed t -70ºC fo 24 hous then econstituted in wte tnk t 37 C fo 5 minutes befoe being pplied s n int-ticul injection. Citei fo dmission of ptients to the study wee the pesence of chonic knee pin fo t lest 4 months o complints of swelling nd degenetive chnges detemined ccoding to the citei defined by Kellgen nd Lwence [15]. Ptients with systemic chonic disese (Dibetes Mellitus, Rheumtoid Athitis), mjo devition ( 5 vus o vlgus), hemtologicl disodes (cogulopthy), sevee cdiovscul disese, dignosed infection, o dignosed immuno deficiency, nd those undegoing nticogulnt/nti-pltelet thepy, using NSAID within the pevious 5 dys, with hemoglobin vlue unde 11 mg/ dl nd pltelet count less thn /ml wee not included in the study. VAS nd WOMAC tests wee used to evlute 76 knees of 51 ptients pe nd post fist injection then t the 2nd, 6th nd 12th month. The ptients wee 6 mles nd 45 femles. Goup 1 consisted of 38 knees of 23 ptients nd Goup 2 of 38 knees of 28 ptients. CCl ws dded to PRP nd dministeed s n int-ticul injection to ll the knees in Goup 1. In Goup 2, the peped PRP ws stoed t -70ºC fo 24 hous then econstituted in wte tnk t 37 C fo 5 minutes, befoe being pplied s n int-ticul injection to ll the knees in Goup 2. PRP peption fo ll ptients used stndd, specilly poduced, steilized, disposble blood tubes nd injecto sets nd specil centifuge pptus comptible with these tubes. 16 ml blood ws tken fom ech knee nd 2 ml of sodium citte ws dded. Fist, the blood tken ws centifuged t 1800 pm fo 15 minutes nd ws septed fom eythocytes. Then, it ws centifuged t 3500 pm fo 10 min nd 3 ml PRP ws obtined fom the bse of the solution. Fo Goup 1, 0.22 meq- CCl ws dded to the PRP nd the injection ws pplied into the knee. The PRP peped fom Goup 2 ws stoed t -70 C fo 24 hous nd then econstituted completely in wte tnk t tempetue of 37 C nd pplied into the knee. A totl of 3 int-ticul injections wee dministeed within 21 dys. The injection ws pplied fom the ltel of the knee. Following the ppliction, 24 hou est nd cold ppliction wee ecommended. The use of NSAIDs ws pohibited until the completion of the int-ticul injections. Follow-up exmintions using WOMAC nd VAS scoing wee mde in the 2nd, 6th nd 12th months. Since continuous dt obtined fo Goups 1 nd 2 did not confom with noml distibution, non-pmetic tests wee used. The diffeences in ge, osteothitis scoe, VAS nd WOMAC scoes between both goups wee nlyzed with the Mnn-Whitney U test, nd the diffeences between the gendes wee nlyzed using the Chi-sque test. To detemine diffeences between the VAS nd WOMAC scoes fo both ptient goups duing the ensuing months of the follow-up peiod, Fiedmn Vince Anlysis nd Bonfeoni coected Wilcoxon signed nking test wee used. Fiedmn ANOVA nlysis ws used in the compison. Vlues of p<0.05 fo Fiedmn Vince Anlysis, chi-sque test nd the Mnn-Whitney U test nd p<0.01 cut-off vlue fo Bonfeoni coected Wilcoxon signed nking test wee ccepted s significnt. Results The study compised 76 knees of 51 ptients; 6 mles nd 45 2

3 Figue 1. The diffeences in VAS nd WOMAC scoes in Clcium Chloide dded PRP (Goup 1) nd PRP stoed in -70 C (Goup 2) between 0, 2, 6, nd 12 Months. (Fiedmnn Vince Anlysis p<0.05). Tble 1. Sttisticl significnce in VAS nd WOMAC scoes in Clcium Chloide dded PRP (Goup 1) nd PRP stoed in -70 C (Goup 2). (Mnn Whitney U Test p<0.05). VAS SCORES CCl dded PRP -70 C stoed PRP P-vlue* VAS ,441 VAS ,117 VAS ,992 VAS ,718 WOMAC SCORES WOMAC ,5 0,144 WOMAC 2 42,5 46 0,196 WOMAC ,529 WOMAC 12 40,5 44,5 0,747 * No significnt diffeence p> th months. Accoding to the Bonfeoni coected Wilcoxon signed nking test esults, the vlues of the scoes t 0 month wee detemined to be considebly gete thn the vlues of the scoes mesued in the subsequent months. In both ptient goups, the VAS scoes obtined in the 2nd nd 6th months showed tendency to decese gdully. Nevetheless, no significnt diffeence ws detemined between the 6th month scoes nd the 12th month scoes (figue 1). femles with men ge of yes. No diffeence ws detemined between the goups in tems of ge, gende nd osteothitis level. No significnt diffeence ws detemined fom the pespective of VAS nd WOMAC scoes between the two ptient goups (Tble 1). In Goup 1, whee CCl ws dded to PRP, significnt diffeence (p<0.01) ws found by Fiedmn Vince Anlysis between VAS nd WOMAC scoes obtined t 0, 2nd, 6th, nd 12th months. Similly, in the goup ctivted by PRP fte hving been stoed t -70 C, significnt diffeence (p<0.01) ws found by Fiedmn Vince Anlysis between VAS nd WOMAC scoes obtined t 0, 2nd, 6th, nd Discussion Recently, the efficcy nd sfety of contempoy tetment methods fo the ctilge dmge hve been evluted nd comped in sevel studies. In n inteesting study which citei fo dmission of ptients to the study nd the ptients ssessment scoes wee simili to ou study, Ediz et l., [16] emphsized tht the ddition of colchicin to cetminophen poduced significntly gete symptomtic benefit thn cetminophen lone with pimy knee osteothitis. In ctilge lesions of vious etiologies, the benefit of PRP tetment hs been poven by mny studies [11, 12, 17]. This effect of PRP depends on the gowth fctos in the lph gnules [18]. Diffeent methods e used fo the elese of these gowth fctos pio to PRP ppliction [19]. Zimmemnn [20] conducted study to detemine by which ctivtion method the gowth fcto concentte could be obtined t highe te pio to ppliction of the peped PRP substnce. As esult of this in vito study, the gowth fctos in CCl dded mteil wee comped with the gowth fctos in PRP stoed t tempetue of -70 C nd then econstituted nd it ws obseved tht the gowth fctos in the CCl dded substnce ws t highe te. The most significnt finding of the cuent study ws tht PRP peped with two diffeent ctivtion methods ws no diffeent in tems of clinicl benefit. Theefoe, the thn peping moe difficult CCl-dded mteil, the ctivtion method of stoing t tempetue of -70 C might be pefeble s it cn be utilized in ll helth centes with blood cente. The ppliction of utogenous PRP hs stted to be used in mny fields togethe with othopedics nd spots medicine nd diffeent esults hve been epoted in vious diseses [21]. PRP cn be obtined esily nd does not cuse disese tnsmission nd it is n esy though invsive wy of pplying mny 3

4 gowth fctos. In ddition, thee is vey little concen on sfety issues such s immunologicl ections o ccinogenesis [22]. In study by Smpson et l., [23] ptients with pimy nd secondy knee osteothitis epoted no dvese effects fte the injection of PRP. Duing the cuent study, n evlution ws lso mde of potentil side effects ising fom the tetment. No complictions such s infection, muscle tophy, feve, hemohge, tissue hypetophy, o cohesiveness occued. Only mild side effects wee obseved such s slight pin ection nd effusion following the injection, which lsted t most fo 2-3 dys. Toeo et l., [24] epoted significnt impovements in clinicl symptoms in knee chondopthies duing 6-month follow-up peiod following single dose of int-ticul PRP nd it could be consideed n ltentive tetment. The fct tht the follow-up peiods wee longe in the cuent study nd the peption nd ppliction of multiple injections with compison of diffeent PRP peption methods e supeio spects of this study. A sttisticlly significnt impovement ws chieved in both goups in ll the pmetes evluted in the cuent study. No sttisticlly significnt diffeence ws seen between the two goups t the conclusion of the follow-up. In ddition, clinicl impovements wee chieved in the mjoity of ptients fo dily ctivities. In the cuent study, the VAS nd WOMAC scoes of both goups in the 2nd nd 6th months showed tendency to decese gdully nd n incese ws obseved in the WOMAC scoes t 12 months. Howeve, when this incese seen in the 12th month ws comped with the scoes of the 6th month, no significnt diffeence ws detemined. In study by Jng et l.,[25] of 65 ptients suffeing fom knee pin due to osteothitis, it ws detemined tht lthough the clinicl impovement within the fist 6 months of the 1 ye postprp injection follow-up peiod ws pomising, it ws emphsized tht thoughout such 1-ye follow-up, clinicl impovement decesed nd tht the tetment ws effective on ely osteothitis but incesing ge nd degenetion decesed the effectiveness of PRP. Lee et l. [14] ws evluted the quntittive meuement of pltelet counts nd gowth fcto levels in PRP which ws ctivted by thombin nd clcium chloide.they stted tht thee ws no influence of ctivtion of PRP using thombin nd clcium chloide on the secetion of gowth fctos nd on the mount of pltelets concentted in plsm. In ddition to this thombin nd clcium chloide ws not consideed to be necessy fo the effective peption of PRP o the elese of gowth fctos [13].Ou clinicl esults wee in ccodnce with this study. Addition of clcium chloide to PRP did not mke ny diffeence in the VAS nd WOMAC scoes comped to the method which the blood ws stoed in -70 C until the pevious dy of intticul injection pocedue. The methods of the cuent study could be open to discussion due to the bsence of the contol goup. Anothe limittion of ou study ws the citei fo dmission of ptients, which ws defined by Kellgen nd Lwence. The citei hd to be checked lso by MR. In conclusion, when PRP tetment ctivted by two diffeent methods ws pplied to ptients with osteothitis nd those two methods wee comped in tems of clinicl efficcy, high te of benefit ws obseved without ny diffeence between the two goups. Theefoe, the PRP ctivtion method used fom stoge t -70 C my be pefeed by helth institutions which hve blood cente s thee is no need fo dditionl mteil fo PRP peption. Also PRP cn be pplied with confidence due to lowe possibility of side effects. Futhe ndomized, contolled studies e equied with lge numbe of ptients nd longe follow up peiods to estblish potocol fo the int-ticul ppliction of PRP. Competing inteests The uthos decle tht they hve no competing inteests. Refeences 1. Peei D, Peleteio B, Auio J, Bnco J, Sntos RA, Rmos E. The effect of osteothitis definition on pevlence nd incidence estimtes: systemtic eview. Osteoth Ctil 2011;19: Asln A, Aydogn NH, İlhn M, Özedemoğlu RA, Altuntş İ, Yogncıgil H. The effect of diffeent intticul dug pplictions to the ntioxidn system nd lipid peoxidtion in gonthosis. Gzintep Med J 2012;18(1): Bhti D, Bejno T, Novo M. Cuent Inteventions in the mngement of knee osteothitis. J Phm Bio Allied 2013;5: Zhng W, Moskowitz RW, Nuki G, Abmson S, Altmn RD, Aden N, et l. OARSI ecommendtions fo the mngement of hip nd knee osteothitis. Osteoth Ctil 2008;16: Sinuss K. Osteothitis: dignosis nd tetment. Am Fm Physicin 2012;85: Asln A, Kıdemi V, Aty T, Bykl YB, Aytekin Ö, Aydoğn FC. The Efficcy of Int-Aticul Injection of Hyluonic Acid With Supplementl Peol Vitmin E Following Athoscopic Debidement in the Tetment of Knee Osteothitis: A Pospective, Rndomized, Contolled Study. Tük Fiz Tıp Rehb Deg 2012;58(3): Longo UG, Petillo S, Fnceschetti E, Beton A, Mffuli N, Deno V. Stem cells nd gene thepy fo ctilge epi. Stem Cells Int 2012; DOI: /2012/ Chevlie X, Eymd F, Richette P. Biologic gents in osteothitis: hopes nd disppointments. Nt Rev Rheumtol 2013;2: Lopez-Vidieo E, Goulding KA, Simon DA, Snchez M, Johnson DH. The use of pltelet-ich plsm in thoscopy nd spots medicine: optimizing the heling envionment. Athoscopy 2010;26: Anitu E, Andi I, Snchez M, Azof J, del M Zlduendo M, de l Fuente M, et l. Autologous peption sich in gowth fctos pomote polifetion nd induce VEGF nd HGF poduction by humn tendon cells in cultue. J Othop Res 2005;23: Kon E, Bud R, Fildo G, DiMtino A, Timoncini A, Cencchi A, et l. 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5 İnjuy 2009;40: Smpson S, Reed M, Silves H, Meng M, Mndelbum B. Injection of plteletich plsm in ptients with pimy nd secondy knee osteothitis: pilot study. Am J Phys Med Rehbil 2010;89: Toeo JI, Aoles F, Fee D. Tetment of knee chondopthy with pltelet ich plsm. Peliminy esults t 6 months of follow-up with only one injection. J Biol Regul Homeost Agents 2012;26: Jng SJ, Kim JD, Ch SS. Pltelet-ich plsm (PRP) injections s n effective tetment fo ely osteothitis. Eu J Othop Sug Tvmtol 2013;23: