Corrosion of Metal Hip Arthroplasties and Its Possible Role in Loosening

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1 Cells and Materials Volume 7 Number Artile 997 Corrosion of Metal Hip Arthroplasties and Its Possible Role in Loosening H. K. Koerten Universiteit Leiden J. J. A. M. van Raay Universiteit Leiden J. J. M. Onderwater Universiteit Leiden F. P. Bernoski Leyenburgh Hospital, The Hague P. M. Rozing Universiteit Leiden Follow this and additional works at: Part of the Biomedial Engineering and Bioengineering Commons Reommended Citation Koerten, H. K.; van Raay, J. J. A. M.; Onderwater, J. J. M.; Bernoski, F. P.; and Rozing, P. M. (997) "Corrosion of Metal Hip Arthroplasties and Its Possible Role in Loosening," Cells and Materials: Vol. 7 : No., Artile. Available at: This Artile is brought to you for free and open aess by the Western Dairy Center at DigitalCommons@USU. It has been aepted for inlusion in Cells and Materials by an authorized administrator of DigitalCommons@USU. For more information, please ontat dylan.burns@usu.edu.

2 Cells and Materials Vol. 7, No., 997 (Pages 9-99) 5~79/97$5.+.5 Sanning Mirosopy International, Chiago (AMF O'Hare), IL USA CORROSION OF METAL lllp ARTHROPLASTIES AND ITS POSSffiLE ROLE IN LOOSENING H.K. Koerten, J.J.A.M. van Raay, J.J.M. Onderwater, F.P. Bemoski and P.M. Rozing Laboratory for Eletron Mirosopy, and Department of Orthopaedis, University Medial Center, P.O. Box 95, RA Leiden, The Netherlands; Leyenburgh Hospital, The Hague, The Netherlands (Reeived for publiation May 5, 99 and in revised form Otober 9, 997) Abstrat Tissue removed with human hip arthroplasties during revision surgery of 5 patients was evaluated by transmission eletron mirosopy and X -ray miroanalysis (XRMA). The results show that mirosopi and submirosopi partiles are abundantly present in the tissue at the tissue/implant interfae. XRMA of individual partiles shows that the hemial omposition of a portion of the partiles was in agreement with that of the retrieved implants. Regularly, partiulates with a dissimilar hemial omposition were found. Sometimes, these partiles ould be reognized as filler partiles of the ements used. Other partiles ould partly or ompletely be omposed of the hemial elements that were used to produe the implant, but the mutual proportion of these elements was different from that of the retrieved arthroplasties. It is known that orrosion may provoke the seletive release of metals from metal alloys in an ioni form. The orrosion weakens the implant and wear partiles will easily be detahed from the surfae. These partiles then ontribute to a further abrasion of the implant surfae. In addition, the partiles will ontribute to a foreign body reation that will eventually lead to the asepti loosening of the implant. The results of the present study, using XRMA to evaluate the hemial omposition of many individual partiles, onfirm these assumptions. Key Words: Transmission eletron mirosopy, X-ray miroanalysis, human hip arthroplasties, orrosion, wear partiles. Address for orrespondene: H.K. Koerten, address as above. Telephone number: FAX number: koerten@rullf.medfa.leidenuniv.nl Introdution The evaluation of periprostheti tissue around total hip arthroplasties that are removed during revision surgery, gives important information on the proesses that our at the tissue/implant interfae. In tum, the understanding of these proesses is important for a better knowledge of the onditions that indue loosening of the implant. Thus far the failure of hip arthroplasties has generally been asribed to the release of wear partiles from the ultra high moleular weight polyethylene up (Evans et al., 97; Charnley, 975; Shmalzried et al., 99). Other investigators have reported the presene of metal in tissue at the tissue/implant interfae (Pazzaglia et al., 985; Huo et al., 99; Williams and MQueen, 99). It has already been hypothesized that also the release of metal wear partiles may be an important fator in the failure of human hip arthroplasties (Blak et al., 99; Hirsh et al., 99; Merrit and Brown, 995). The present study was performed to onfirm these observations and to establish the exat nature of the metal wear partiles by transmission eletron mirosopy (TEM) and X-ray miroanalysis (XRMA) so that the mehanism of partile release an be better understood. Materials and Methods Tissue samples from patients undergoing revision of hip arthroplasties were olleted in two orthopaedi departments during a period of two years. Soft tissue biopsies were taken from well defmed plaes around the implant, inluding the superior, lateral, and inferior margins of the aetabulum and the femoral anal in loations orresponding to the middle and distal portions of the femoral omponent (Fig. ). In total, seven different brands of hip arthroplasties were evaluated for this study (Table ). The present paper onerns tissue samples from 5 patients: 9 emented total hip arthroplasties, ementless total hip arthroplasties, seven hybrid total hip arthroplasties (emented femoral and ementless aetabular omponent), and seven ementless bipolar 9

3 H.K. Koerten et al. Table. Overview of metals deteted in individual wear partiles around 5 human hip arthroplasties. Implant Interval A B D E F Al,Ti Cr,Fe,Mo,Ni,Ti Ti Ti Al,Ti Cr,Fe,Ni,Zr Fe,Pt,Zr Zr Co,Cr.Mo,Zr,Zr Al,Co,Cr,Ti Fe,Mg,Si, Ti,Zr Al,Ti,V Al,Co,Cr,Ti Ti,Ti,Zr Ti Al,Cr,Ti

4 Corrosion of human hip implants Table ontinued. Overview of metals deteted in individual wear partiles around 5 human hip arthroplasties. Implant Interval A B D E F 75 8 Zr 7 7,Zr 7 8 Zr Ti,Zr 7 87 Mo,Zr Ti Co,Cr,Fe,Mo 8 Ca,V 7 9 Al,Fe j Fe 8 Zr 5 95 Interval: Interval (months) between primary operation and first revision or between revision and rerevision. A: = Woman; = Man. B: Type of primary arthroplasty: = Unemented Gerard double-up arthroplasty ( alloy) = Cemented MKee-Arden total hip arthroplasty ( alloy) = Unemented madrepori Lord total hip arthroplasty ( alloy) = Unemented Mering total hip arthroplasty (Ti,Al,V femoral stem and threaded up) ( modular femoral head) 5 = Cemented Muller Geradshaft total hip arthroplasty ( alloy) = Cemented Stanmore total hip arthroplasty ( alloy) 7 =Hybrid total hip arthroplasty (Cemented Stanmore femoral omponent alloy) (Unemented Mering threaded up, Ti,Al, V alloy) C: = First revision; = Seond revision; = Third revision. D: Age at time of revision (years). E: = revision of aetabular omponent; = revision of femoral omponent; = revision of both omponents F: Chemial omposition of intraellular partiles obtained by XRMA. = No elements deteted. 9

5 a b Figure. Shemati representation of the loations where the biopsies were taken. The biopsies examined in the present study derived from loations,, and 7 of the femoral omponent (la) and from the loations and of the aetabular omponent (lb). double-up hip arthroplasties. From the 5 patients under study, were male and 5 female. The mean age at revision was 7 years (range -88 years). The mean interval between the primary operation and revision was 9 months (range - months). There were first revisions, one seond (ase 5), and two third revisions (ases and ). The revision in ases involved both omponents, and in ases only the aetabular omponent was revised. The majority of the aetabular omponents were threaded Mering ups (Meron, Berlin, Germany). In two patients, only the femoral omponent was revised. All biopsies presented in this paper were obtained from the remnant soft tissue overing the femoral omponent at loations,, and 7 in Figure la, and soft tissue from between the aetabular omponent and bone at loations and in Figure lb. Sometimes, the biopsies were visibly dark-olored. In other ases, the presene of wear debris ould not be suspeted from the marosopial appearane of the biopsies. After retrieval, the biopsies were prepared for TEM and XRMA evaluation. Deteted partiles were analysed and the hemial elements were reorded. We did not register the elements per individual partile. Speimen preparation All biologial material was prepared aording to our routine method (Koerten et al., 99b). In short, the biopsies were pre-fixed during hours at C in.5% glutaraldehyde in. M sodium-aodylate buffer (ph 7., 5 mosmol). After pre-fixation, the tissue samples were ut into small bloks of approxi- H.K. Koerten et al. mately mm and post fixed in % osmium tetroxide. After fixation, the speimens were dehydrated in a graded series of ethanol and embedded in epoxy resin (LX, LADD Researh Industries In., Burlington, VT). The plasti was allowed to polymerize during 8 hours at o C. Ultrathin setions were made with a dia- mond knife on a Reihert OM U ultratome (C. Reihert Optishe Werke AG, Wien, Austria). 9 Transmission eletron mirosopy Material, that was fixed, embedded and setioned aording to the method desribed above was examined by TEM. The setions, approximately 7 nm thik, were olleted on opper grids. A portion of the setions was ontrasted with uranyl aetate and lead hydroxide, and used for morphologial evaluation. The setions were examined in a Philips EM T (Philips Eletron Optis, Eindhoven, The Netherlands) transmission eletron mirosope {equipped with a sanning transmission eletron mirosopy (STEM) unit} operated at an aelerating voltage of 8 kv. Another part of the setion was studied without the use of ontrasting agents, to allow an undisturbed establishment of the hemial omposition by XRMA. X-ray miroanalysis XRMA was performed in the same Philips EM T, using a Traor Northern TN X-ray Miroanalysis system (Traor Northern, Middleton, WI). For XRMA measurements, the speimen holder was tilted at an angle of 8 o relative to the eletron beam, to allow optimal olletion of the X-rays. The XRMA measurements were performed at an aelerating voltage of 8 kv and a spot size of nm. Peak identifiation was performed using the ommerially supplied software of the XRMA system. Marosopi observations Results All implants were removed beause of linial and roentgenographi mehanial loosening. Cases of septi loosening were exluded by bateriologial tests. The alloys of the arthroplasties under study ontained one or more of the elements Ti, Al, V, Co, Cr and/or Mo (see Table ). In ase of revision of a resurfaing hip arthroplasty, remnant tissue overing the femoral omponent and tissue from between the aetabular omponent and bone were obtained. Sometimes, the biopsies had a darkstained appearane. In other ases, the presene of wear debris ould not be suspeted from the marosopi appearane of the biopsies.

6 Corrosion of human hip implants Figure (at left). Transmission eletron mirograph of tissue, derived from the interfae of the femoral omponent (loation 7) of implant number. Numerous dark inlusions an be seen in the ytoplasm of the ells. The variation in the size and form of the partiles is lear. Bar = 7 Jtm. Figure (at right). Transmission eletron mirograph of a ell in the same loation as Figure, showing endoytosed partiles, some of whih have been removed during setioning. Nevertheless, the limiting membrane of the inlusion bodies ontaining the remaining partiles is intat (arrow). Bar = Jtm. Transmission eletron mirosopy and X-ray miroanalysis TEM of the interfae tissue showed a typial foreign body reation, haraterized by the massive amount of onnetive tissue. Large areas of ollagen and many fibroblasts were observed in the setions. Marophages and multinuleated giant ells were frequently present. Eletron-dense partiles were found to be endoytosed by marophages and to a lesser extent also by fibroblasts. The size of the deteted partiles varied from <. ~tm to JJ.m (Fig. ). As Figure shows, also the form of the partiles varied. Sometimes sharp-edged partiles were seen, but more frequently suh inlusions were rounded off. Regularly, most probably due to their physial hardness, the partiles were removed from their original position during setioning and had shifted to other plaes in the setions. If this happened, harateristi setioning artifats and learly disloated partiles were visible. At other plaes, however, partiles were still in their original position, i.e., ontained in inlusion bodies with the limiting membrane still intat (Fig. ). Cells harateristi for an aute inflammatory reation, i.e., neutrophil granuloytes and monoytes were not deteted in any of the ases. XRMA was used to determine the hemial omposition of the small eletron-dense inlusions. The results of these measurements, as summarized in Table, showed in general peaks that represent the metals that were used to manufature the implants (Fig. ). It appeared, however, that the spetra were not always in agreement with the hemial ompositions as given in the manufaturers doumentation of the ompounds used to produe the implants. Sometimes, one or two of the omposing elements were absent (Fig. 5) or, in ases that all elements were present, the ratios between the peak heights ould be different from those found generally for implants of that speifi brand. In other ases, elements that were ompletely different from those in the implant alloy were deteted. We ould demonstrate the presene of Ni, Fe, Pt, Mg, Si and Zr. Espeially, the number of partiles that gave spetra with peaks for the latter element was relatively large (Fig. ). For ements applied for implantation of the prostheses that were evaluated in the present study, the radiopaque labelling used onsisted of Zr only. In ases where Ba is used as a radiopaque label, this element an be demonstrated as frequently as Zr (results not inluded). Inidently, relatively large eletron dense strutures ( > ~tm) were seen (Fig. 7). XRMA of these partiles gave spetra without speifi elemental peaks, meaning that the measured strutures were omposed of elements with an atomi number below ; hene the measured strutures were of an organi (polymeri) nature. Suh partiles were found exlusively in biopsies from double-up hiparthroplasties ontaining high moleular weight polyethylene. 95

7 H.K. Koert l zl. b b C H u u H H.."8 8- ::5 VFS 89. Figure (at left). (a). Transmission eletron mirograph of a biopsy from loation 7 in the femoral omponent of implant number. A ell ontaining numerous eletron dense inlusions is learly visible. Bar = p.m. (b). XRMA spetrum of the partile (indiated in Fig. a; arrow) showed the presene of the harateristi elements Co, Cr and Mo. Figure 5 (at right). (a). Transmission eletron mirograph of a biopsy from loation 7 in the femoral omponent of implant number 9. Some small eletron dense inlusions are present. Bar = JLm. (b). XRMA spetrum of the partile (indiated in Fig. Sa; arrow) showed the presene of Mo only. Disussion Thus far, many researhers have investigated the loosening of emented and non-emented total hip arthroplasties in humans, but there is still no onsensus about the linial bakground of asepti loosening. It has been postulated that the ourrene of sterile hroni inflammatory reations at the tissue/material interfae is an important fator in the asepti loosening of implants. Foal osteolysis ours frequently around loose emented omponents (Harris et al., 97; Willard and Semlitsh, 977; Carlsson et al., 98; Lennox et al., 987; Tallroth et al., 989; Maloney et al., 99) and ement- less omponents (Maloney et al., 99; Santavirta et al., 99) of total hip arthroplasties. Suh osteolyti ativity is thought to be indued by fators that are released during inflammatory and foreign body reations. The present study was performed to establish the nature of partiles in tissue around revised hip arthroplasties. For that purpose, individual eletron-dense partiles were deteted with TEM and then evaluated by XRMA. It was found in this part of the study that numerous submiron partiles an be present in the ytoplasm of marophages and giant ells, and even in fibroblasts. XRMA showed that the majority of the partiles derived from bone ements, in whih they are used as 9

8 Corrosion of human hip implants z R b Figure 7. Transmission eletron mirograph of a biopsy from loation in the aetabular omponent of implant number. The large partile gave no detetable signal when measured using XRMA, indiating that elements with an elemental number above were absent. We assume that this partile onerns ultrahigh moleular weight polyethylene. Bar =.5 J.tm..il I. u u z R.8 Figure. (a). Transmission eletron mirograph of a biopsy from loation in the femoral omponent of implant number. (b). Numerous small inlusions an be observed. XRMA of the partiles showed the presene of Zr without exeption. radiopaque filler partiles, and from the artiulating surfaes of the implants. We hypothesize that these partiles are therefore important in the indution of hroni inflammatory effets, whose seriousness is related to size and quantity of the wear debris. Indeed, a relation between the size of these partiulates and their effet on inflammation has been shown in a previous study performed by our group (van der Meulen and Koerten, 99). In that study, it was demonstrated by the introdution of latex spheres into the mouse peritoneal avity that the size of the partiles is inversely proportional to the severeness of the inflammatory reation. On the basis of this previous study, it is hypothesized that espeially the small to very small partiles are responsible for the initiation of inflammatory effets. These partiles may, therefore, play an important role in the loosening of total hip arthroplasties. The fat that suh small partiles were without exeption present in tissue derived from loose implants in the present study is suggestive of a relation between the inflammatory effet and nature of the partiles. Future observations on biopsies from non-failed implants, for instane obtained from amputation surgery or from autopsy material, are required to test this hypothesis. The hemial omposition of a large proportion of the partiles generally related to the omposition of the implants. However, in many ases, this omposition did not math with that from the manufaturers' doumentation. A part of these divergent partiles an be explained: Ba and Zr are known to be used in bone ements as radiopaque markers. Si may be remnant from the polishing proedure of the implant. Fe, although also present in low onentrations in some of the implant types, may also represent the normal iron metabolism of marophages. Indeed, we observed in former studies where marophages dealt with poorly dissolvable material in a mouse peritoneal model that marophages are well apable to aumulate iron as hemosiderin in residual bodies or inlusion bodies (Koerten et al., 99a). The origin of platinum in implant remains unlear. We hypothesize that these partiles may be derived from instruments used during surgery; Ca is an element that is present in bone as the mineral omponent, but Ca an also be present due to pathologial alifiation of onnetive tissue. It is our opinion that the differene in hemial omposition between partiles that are with ertainty 97

9 H.K. Koerten et al. derived from the implant and the implant itself relates to a proess of seletive orrosion. Indeed, orrosion of metalli implants has been reported (Ferguson et al., 9; Meldrum et al., 99). In their paper, Ferguson et al. (9) reported experimental evidene for the ionization of metals in tissues around implants in rabbits. We believe that seletive orrosion of eletrohemially ative phases or other mirostrutural onstituents will result in slow release from the implant alloy. After suh eletrohemial orrosion, the alloy will have lower resistane to wear, and seondary phase partiulates may be released from the surfae. The presene of impurities in the alloys of whih implants are made, may aelerate this proess, due to the formation of additional seondary mirostrutural phases that are suseptible to orrosion. We have indiations that suh metalli impurities are present in brand new human hip arthroplasties already and further investigations direted towards the ourrene of these impurities have already been started. Referenes Blak J, Sherk H, Bonini J, Rostoker WR, Shajowiz F, Galante JO (99) Metallosis assoiated with a stable titanium-alloy femoral omponent in total hip replaement. J Bone Joint Surg 7A: -. Carlsson A, Gentz CF, Linder L (98) Loalized bone resorption in the femur in mehanial failure of emented total hip arthroplasties. Ata Orthop Sand 5: 9-. Charnley J (975) The histology of loosening between aryli ement and bone. Proeedings andreports of universities, olleges, ounils and assoiates. J Bone Joint Surg 57B: 5. Evans EM, Freeman MAR, Miller A, Vernon Roberts B (97) Metal sensitivity as a ause of bone nerosis and loosening of the prosthesis in total joint replaement. J Bone Joint Surg 5B: -. Ferguson AB, Laing PG, Hodge ES (9) The ionization of metal implants in living tissues. J Bone Joint Surg A: Harris WH, Shiller AL, Sholler JM, Freiberg RA, Sott R (97) Extensive loalized bone resorption in the femur following total hip replaement. J Bone Joint Surg 58A: -8. Hirsh D, Shoen FJ, Levy RJ (99) Effets of metalli ions and diphosphonates on inhibition of periardia! bioprostheti tissue alifiation and assoiated alkaline phosphatase ativity. Biomaterials : Huo MH, Salvati EA, Lieberman JR, Betts F, Bansal M (99) Metalli debris in femoral endosteolysis in failed emented total hip arthroplasties. Clin Orthop 7: Koerten HK, de Bruijn JD, Daems WTh (99a) The formation of asbestos bodies by mouse peritoneal marophages: an in vitro study. Am J Pathol 7: -. Koerten HK, Hazekamp J, Kroon M, Daems WTh (99b) Asbestos body formation and iron aumulation in mouse peritoneal granulomas after the introdution of roidolite asbestos fibers. Am J Pathol: -57. Lennox DW, Shofield BH, MDonald DF, Riley LH (987) A histologi omparison of asepti loosening of emented, press-fit, and biologi ingrowth prostheses. Clin Orthop 5: 7-9. Maloney WJ, Jasty M, Harris WH, Galante JO, Callaghan JJ (99) Endosteal erosion in assoiation with stable unemented femoral omponent. J Bone Joint Surg 7B: 5-. Meldrum RD, Bloebaum RD, Dorr LD (99) Metal ion onentrations in retrieved polyethylene total hip inserts and impliations for artifatually high readings in tissue. J Biomed Mat Res 7: Merrit K, Brown SA (995) Release of hexavalent hromium from orrosion of stainless steel and obalthromium alloys. J Biomed Mat Res 9: 7-. Paz.zaglia UE, Ceiliani L, Wilkinson MJ, Dell'Orbo C (985) Involvement of metal partiles in loosening of metal-plasti total hip prostheses. Arh Orth Traum Surg : -7. Santavirta S, Konttinen YT, Hoikka V, Eskola A (99) Immunopathologial response to loose ementless aetabular omponents. J Bone Joint Surg 7B: 8-. Shmalzried TP, Jasty M, Harris WH (99) Periprostheti bone loss in total hip arthroplasty. J Bone Joint Surg 7A: Tallroth K, Eskola A, Santavirta S, Konttinen YT, Lindholm TS (989) Aggressive granulomatous lesions after hip arthroplasty. J Bone Joint Surg 7B: Vander Meulen J, Koerten HK (99) Inflammatory response and degradation of three types of alium phosphate erami in a non-osseous environment. J Biomed Mat Res 8: 55-. Willard HG, Semlitsh M (977) Reations of the artiular apsule to wear produts of artifiial joint prostheses. J Biomed Mater Res : Williams RP, MQueen DA (99) A histopathologi study of late asepti loosening of emented total hip prostheses. Clin Orthop 75: Disussion with Reviewers Reviewer : Could the authors briefly summarize possible explanations for the disrepanies of elemental omposition between partiles and the manufatured implants? Authors: As mentioned in Disussion, we believe that the formation of a galvani element and the subsequent 98

10 Corrosion of human hip implants galvani orrosion may indue the seletive release of ions fnom the implant surfae. In addition impurities in the ompounds have been reported. Wear partiles derived from orroded or impure areas in the surfae will have a deviating hemial omposition. Furthermore, it annot be exluded that partiles are derived from other soures, i.e., instruments used during surgery. Reviewer : Have the authors found any relationships betweejn the type of prothesis and their findings? What is the role of implantation period for the observed findings? Authon: During the ourse of the experiments performed for this paper, we had no indiations that the ourrene of partiles with a deviating hemial omposition ould espeially be asribed to a ertain implant brand. However, impurities were already seen in the surfae of new implants (see last paragraph of Disussion). In evaluations that we are performing presently, observations have been made that point to type related imperfetions. The number of released partiles in relation to implantation time was not evaluated in the present study. We assume, however, that the amount of wear will inrease with the duration of implantation. W.A. Brantley: Could the authors provide referenes to information about the omposition of implant alloys and bone ements? Authors: It is very diffiult to obtain information from implant manufaturers about the aurate omposition of their produts. We did not sueed to get this information from them. To the best of our knowledge there is also not something like a report that gives this information. The data given in Table, olumn B are obtained from the surgeons that performed the revision operations. From XRMA measurements in SEMon the surfae of intat implants, we know that ertain other elements an be present. G.M. Roomans: The authors have found that there were differenes between the manufaturers' data on the alloys used in the implant and the omposition of metal partiles as seen by X-ray miroanalysis. The authors suggest that this is due to (a) leakage of elements by orrosion, (b) the presene of metal impurities. On the basis of their data, an the authors indiate whih ele.ments appeared to have leaked out most frequently, and whih elements ould be onsidered as impurities? Authors: We did not investigate the "leaking" of elements within the sope of the present paper. It was found that, in areas of orrosion on the implants itself, the signal for Co is low, relative to the surrounding nonaffeted areas when X -ray maps are reorded. Cr and Mo are in the same maps present in muh higher on- entrations as was dedued from the intensity of the signal in these maps. The results of this latter study are in relation to one speifi type of implant and urrently being prepared for publiation. G.M. Roomans: Was the dark olor of the biopsies onneted with a higher metal ontent or the presene of speifi elements? Could it be due to hemorrhaging? Authors: The dark olor of the biologial tissue is defmitely derived from the presene of metal residue from the implants. As shown in Figure, for instane, the onentration of partiles in the biopsies an be very high. It an indeed not be exluded that Fe originating from hemorrhage will be present in the ells surrounding the implants. P. Thomsen: Could the authors omment on the spatial distribution of partiles and elements (possible differenes between loations and possible gradients in relation to the surfae of the prosthesis? Authors: As we took the tissue biopsies from the implant after revision, and beause we used remnant tissue at the interfae only, it is not possible to give information on the distane where partiles ould still be found or about the possibility that a gradient in partile onentration is present. We know, however, from the marosopial observations by the surgeons, that tissue next to the implant ould sometimes have a blak appearane, suggestive for large amounts of partiles millimeters distant from the implant surfae. P. Thomsen: Could authors omment on the possible role of impurities for the pathophysiology of inflammation, fibrous repair and loosening? Authors: Referring to our paper (van der Meulen and Koerten, 99), we know that the presene of partiles will indue an inflammatory effet. The smaller the partiles, the stronger the inflammation. The fat that ells in inflamed areas an release osteolyti fators is well known (see referenes indiated in Disussion). Therefore, it an be expeted that the persistent presene of inflammatory agents will maintain the osteolyti effet and ultimately result in the loosening of the implant. 99