aseptic loosening in uncemented total hip arthroplasty in a canine model

CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Number 319, pp 106-121 0 1995 Lippincott-Raven Publishers

Aseptic Loosening in Uncemented Total Hip Arthroplasty in a Canine Model J. E. Dowd, MD; L. J. Schwendeman, MD; W. Macaulay, MD;

J. S . Doyle, MD; A. S. Shanbhag, PhD; S . Wilson, MD; J. H. Herndon, MD; and H. E. Rubash, MD

An in vivo canine model was developed to investigate the histologic and biochemical para- meters associated with aseptic loosening. Thirty-eight canines had cementless total hip arthroplasty. Experimental groups were designed specifically to investigate the relative contributions of implant motion and particulate debris (cobalt chrome alloy, titanium aluminum vanadium, and polyethylene) on the resultant periprosthetic tissues. Tissues from a stable, well-ingrown prosthesis provided a control. Importantly, the histologic and biochemical characteristics of the experimentally induced membranes consistently correlated with previous in vitro reports of tissues re- trieved at revision surgery for aseptic loosening. Implant motion and all 3 particulate debris groups resulted in increased numbers of macrophages in the periprosthetic membranes. The histologic findings paralleled the increase in levels of biochemical mediators of bone resorption as measured by collagenase, gelatinase, prostaglandin E,, and interleukin-1 activity. The most striking results were seen in the histology and biochemistry of the particle

Froin Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of Pittsburgh Medical Center. Pittsburgh, PA. Supported by the Veterans Administration Merit Re- view grant 821, University Orthopaedics, Inc, and Zim- mer, Inc. Reprint rcquests to Harry E. Rubash, MD, Kaufmann Building, Suite 1010, 3471 Fifth Ave, Pittsburgh, PA 15213.

groups with highly cellular membranes showing increased biochemical activity when compared with controls. The clinical relevance of this work lies in the description of an in vivo model of aseptic loosening that can be used to investigate the effects of numerous variables implicated in aseptic loosening. Ultimately, the model may serve as a basis for developing ther- aDeutic interventions.

As the segment of the population older than 65 years old steadily increases, the number of total hip arthroplasties done is increasing at a rate of 5% annually. Despite numerous improvements in implant materials, implant designs, and surgical technique, 15% to 20% of all total hip arthroplasties are revisions of failed primary arthroplasties. Of these revision total hip arthroplasties, 3 of 4 are done for aseptic loosening of the prosthesis.” During the past 20 years, aseptic loosening has remained the primary obstacle limiting the longevity of total hip prostheses.

Total hip arthroplasty failure caused by prosthetic loosening in the absence of infec- tion has been well documented in early reports of total hip s~ rge ry .5 .6 .~~) .~~ Gross and histologic examinations of failed total hip prostheses have described the presence of fibrous tissue and wear debris at the cement-bone interface.66 More detailed examination of these tissues found sheets of

106

Number 319 October, 1995 Aseptic Loosening in Total Hip Arthroplasty 107

macrophages in a fibrous tissue stroma with giant cells, polymethylmethacrylate particles, and metal debris in an apparent foreign body- type reaction.43 Initial reports attributed this histologic reaction to the presence of polymethylmethacrylate, leading to the concept of cement disease.3" More recently, however, reports of similar tissue at the bone-implant interface in uncemented total hip arthroplasties have led to the concept of particle disease to describe the foreign body reaction noted in association with metal and polyethylene debris, with or without polymethylmethacrylate debris. Numerous reports also have supported the association between interface membranes and the occurrence of periprosthetic osteoly- ~i~.7.X.1*,3~-3s,44,hs,67 These endosteal erosions have been described around cemented and uncemented implants and loosened and well- fixed implants.39 Cobalt chrome alloy (CoCr), titanium aluminum vanadium (TiAlV), and ultra high molecular weight polyethylene prosthetic materials have been associated with the activation of periprosthetic tissues leading to osteolysis and loosening.

Experimental evidence supporting the association between particulate wear debris and osteolysis has been based on 2 primary observations: (1) Micron-sized metal and polyethylene debris induces a foreign body- type reaction when placed in various animal t i s sues1~~~~~~6~25 ; and (2) these tissues, experimentally induced and human retrieval specimens, produce various enzymes and cytokines capable of stimulating bone resorption. Goldring et a112.13 showed that interface membranes from failed human total hip arthroplasties were capable of producing prostaglandin E, and collagenolytic factors, both of which have been shown to stimulate bone resorption in vitro. The results of similar studies of periprosthetic membranes in tissue cultures have shown the release of collagenase, gelatinase, interleukin-1, interleukin-6, and tumor necrosis factor,7~"]3.23,32-3.5,37 all implicated in the stimulation of bone resorption in vitro. The interface membranes and the conditioned media from tissue explants have

been shown to stimulate bone resorption directly in mice calvaria.13.44 This biochemical link between periprosthetic membranes and subsequent bone resorption is believed to be a result of macrophage activation after the phagocytosis of small wear debris particles present in interface membrane tissue. Murray and Rushton44 showed increased bone resorption in mice calvaria placed in conditioned medium of macrophages cultured in the presence of small particles from joint prostheses. Similarly, the authors have shown the production of interleulun- 1, interleukin-6, and tumor necrosis factor by human macrophages cultured in the presence of various particles from common implant materials,7.*.32~35,5X Recently, advanced techniques such as immunohisto- chemistry and in situ hybridization have strengthened further the association between macrophages in periprosthetic membranes and their production of osteolysis-inducing enzymes and cytokines in response to wear

The current experiment was designed to create an in vivo arthroplasty model of the histology and biochemistry associated with aseptic loosening. Specifically, an attempt was made to investigate the role of implant motion, TiAlV, CoCr, and polyethylene particles to initiate aseptic loosening and to better define the relative contributions of each to the process of osteolysis.

debris.8,29.54

MATERIALS AND METHODS Forty male mongrel canines (weight range, 30-35 kg) had uncemented total hip arthroplasty according to protocol accepted by the authors' institu- tional and animal use review boards. Animals were randomized to either a 12-week control group having total hip arthroplasty, or 1 of 5 experimental 12-week groups having total hip arthroplasties (Fig 1 ) . Ten-millimeter TiAlV femoral prosthesis with proximal anterior, posterior, and medial fiber metal porous pads (Fig 2, far left) and uncemented 29-mm hemispherical acetabular components (with an ultra high molecular weight polyethylene liner; Fig 2, far right) were implanted in the control group (n = 5). A similar prosthesis designed with a mid-shaft ball joint of ultra high molecular weight

108 Dowdetal Clinical Orthopaedics and Related Research

Study Design Flow Chart

Primary Cementless Total Hip Arthroplasty

Group 1 1 1 CoCr (n = 7)

Group II Control

No Particles (n = 5)

I 1 4

I I

Group IV Ti AIV (n = 7 )

Group V High Density Polyethylene

(n = 7)

dogs were randomized to ei- Fig 1. Schematic representation of experimental design. Thirty-eigl ther a control group or 1 of 5 experimental total hip arthroplasty groups.

polyethylene allowing motion between the proxi- ma1 and distal segments about the joint (Figure 2, middle right) was implanted in Group 1 (motion

control with the addition of a 2-mm circuniferen- tial recessed gap in the proximal stem (Fig 2, middle left) was implanted in Group 11 (gap model

model group, n = 7). A prosthesis similar to the group, n = 5 ) . The gap in this prosthesis served as a reservoir for the implantation of either 100 mg of CoCr, 100 mg of TiAlV, or 30 mg of high density polyethylene wear debris (Group 111, n = 7; Group IV, n = 7; Group V, n = 7, respectively). These particles were placed in the gap reservoir within the proximal femoral canal after mixing in 2 in1 of clotted blood. After the 12-week study period, the animals were euthanized humanely, bacterial cultures were obtained to assure asepsis, and the proximal femur with implant was harvested en bloc. The femur was split longitudinally to expose the periimplant tissues. After the prosthesis was re- moved, specimens were taken from the interface membrane and the contralateral hip joint capsule for histologic and biochemical analyses. Tissue harvest, culture, and handling were done under sterile operative conditions.

Synthetic wear particles of CoCr ( 1 00 mg = -0.22 x lo8 particles; density = 8.32 g/cc), TiAlV (100 mg = -14 X lo8 particles; density = 4.40

Fig 2. Left to right: 10-mm porous ingrowth control prosthesis; gap prosthesis with 2-mm proximal reservoir; motion prosthesis with mid- shaft ball joint; 29-mm porous ingrowth acetab- ulum with 26-mm inner diameter ultra high molecular weight polyethylene liner.


gkc) , and polyethylene (30 mg = -8.8 x lo8 particles; density = 0.95 g k c ) were selected for use in the particle model representing commonly used implant materials. The CoCr and TiAlV particles were fabricated in an ultra high molecular weight polyethylene ball mill by Zimmer, Inc (Warsaw, IN). The high density polyethylene particles were obtained from Smith & Nephew Richards, Inc (Memphis, TN). Energy dispersive xray analyses and fourier transform infrared spectroscopy were used to confirm elemental composition and purity of the experimental particles. Particle size analyses were done using an automated 2-dimensional light transmission particle analyzer (k0.2 pm) and confirmed with scanning electron microscopy analyses. Cobalt chrome alloy debris averaged 10.2 k 2 pm; TiAlV debris averaged 3.1 k 1.7 pm; and high density polyethylene averaged 4.1 ? 1.8 pm. Particle size was chosen to represent similar particle size distributions to those previously described in human membrane retrievals and to ensure the greatest number of particles in the size range known to be phagocy- tosed easily by macrophages.23 The weight of particles placed in each joint was chosen to ensure that periarticular tissue was exposed to ade- quate numbers of particles in light of previously reported number of particle wear debris loads expected in human total hip arthroplasty.~7,4l,sY

A representative sample of the interface membrane from each dog was prepared for hematoxylin and eosin staining and histologic grading according to Mirra et al's scale for the density of macrophages.43 Each histologic specimen was graded semiquantitatively for the presence of macrophages per high power field according to a modification of the scale previously described by Mirra et 211.46 Five representative high power fields x400 were reviewed from each specimen, and the number of macrophages were averaged and as- signed a score based on the following scale: Grade 0 (0-4 macrophages per high power field), Grade 1 + (5-9 macrophages per high power field), Grade 2+ (1049 macrophages per high power field), and Grade 3+ (>SO macrophages per high power field). A single observer graded the specimens to eliminate interobserver variability. Histo- logic specimens were reviewed similarly using polarized light microscopy to detect the presence of birefringent polyethylene debris. Two, 50- to 100-mg samples from each of the harvested membranes (interface membrane and contracted joint

capsule) then were cultured sterilely in 2 ml of serumless medium with 1% penicillin and strepto- mycin for 72 hours at 37" C and 5% CO, by a method similar to that of Goodman and Fornasier.16 The tissue was moderately diced to increase surface area. The supernatant was re- moved at 72 hours and assayed for collagenase, gelatinase, prostaglandin E,, and interleukin- 1. Collagenolytic activity was measured using tritiated collagen as substrate. Gelatinase was measured via radioimmunoassay using tritiated gelatin as a substrate. Prostaglandin E, was measured by radioimmunoassay, using a commercially available kit (New England Nuclear, Boston, MA). In- terleukin-1 was measured via bioassay using DIO.G4.1 T helper cell proliferation, as described previously.60 Absolute values of enzyme and cy- tokine activity representing activity per milligram of tissue were normalized with the contralateral control joint capsule assay results to reduce inherent interspecimen variability and therefore are reported as normalized units of activity. Statistical comparisons were done among experimental groups and the control group using an unpaired Student's t-test.

RESULTS

Forty, 30- to 35-kg mongrel canines had right uncemented total hip arthroplasty. There were no deep wound infections. There were intra- operative complications in 2 dogs resulting in fracture of the femoral canal during final seat- ing of the prosthesis. Both of these animals were excluded from the study. There were 2 minor postoperative complications: a superfi- cial hematoma and a postoperative dislocation. The sterile hematoma was drained, and the animal with the dislocation had an open reduction. Both animals had no further prob- lems. Thus, 38 dogs remained in the study. Postoperative activity was limited for 1 week, after which the animals were returned to full activity in a socialized environment. Clini- cally, all animals tolerated the procedure without difficulty, were fully ambulatory at the end of the first postoperative week, and had resumed full weightbearing on the operative hip with clinically normal gait by the end of the second week.


After the harvest of the proximal '/z of the femur with the prosthesis in place, a qualita- tive assessment of implant stability was done by manual application of anteroposterior, mediolateral, and rotational forces. All of 5 control specimens were stable to manual testing, with no obvious motion between the implant and the bone. In general, a thin fibrous-appearing membrane was present distally around the nonporous portion of the implant and extended proximally between the ingrowth pads. Five of 7 motion implants in Group 1 had gross motion of the implant relative to the femoral bone at the time of harvest. The remaining 2 specimens in Group I had some degree of fibrous ingrowth; however, the 2 halves of the femoral bone separated easily from the prosthesis. All of the Group I specimens produced a thick (>I mm) periprosthetic membrane proximally and distally. Group 11 gap specimens also were noted to have had fibrous stabilization, and again all specimens exhibited motion at the implant-bone interface. Separation of Group I1 prostheses from the femoral bone was accomplished without difficulty. The implant bed of these specimens contained a membrane of variable thickness that filled the prosthesis gap. Distally a continuous thin fibrous membrane resembling the control specimens was noted. Groups 111, IV, and V had the greatest degree of movement with manual testing. After splitting of the femoral cortex, these prostheses easily separated from the femoral canal. At the time of harvest of the debris specimens, a thick (range, 2-3 mm) membrane was seen filling the prosthesis gap and extending distally along the implant. Additionally, a thick fibrous pseudocapsule was noted around the hip joint. This reaction was particularly prominent in Groups 111 and IV, with obvious metal staining of the membranes and deeper layers of the pseudocapsule.

The well-ingrown, stable specimens in the control group were surrounded by a thin, fibrous, and relatively acellular membrane that was composed largely of linearly

arranged fibroblasts with an abundant, well- organized fibrous stroma and few cells (Fig 3) . Macrophages were rare, and most of the specimens were graded 0 (Table 1). No metal or polyethylene debris was seen.

Motion specimens in experimental Group 1 provided thicker specimens with less-organized fibrous stroma and increased cellularity. Fibroblasts were more numerous in this group than in the control group, and were no longer aligned in parallel (Fig 4). Macrophages also were present in greater numbers in Group I specimens; 9 1 2 of the specimens were graded 2+ (Table 1). Membranes from gap specimens in Group I1 were also more cellular with greater numbers of macrophages than controls (Fig 5 ) . Histologically, Groups I and I1 were similar (Table 1). No metal or polyethylene debris was noted in Group I and I1 specimens, and giant cells were not seen in Group I, 11, or control specimens.

The debris Groups 111, IV, and V were associated with the greatest degree of histologic activation. These membranes as a group contained abundant macrophages and giant cells in a highly disorganized, cellular stroma. Group 111 CoCr specimens seemed to produce the most cellular membranes with abundant giant cells and macrophages, often with large

Fig 3. Photomicrograph of control membrane specimen. Note the relative acellularity of the membranes with few linear-arranged fibroblasts and an abundant fibrous tissue stroma. (Stain, hematoxylin and eosin; original magnification, x400.)

Number 319 October, 1995 Aseptic Loosening in Total Hip Arthroplasty 11 1

TABLE 1. Histologic Grading

Grade (MacrophagedHigh Power Field)

Group 0 (0-4) 1 + (5-9) 2+ (1 0-49) 3+ (>50)

Control (5) 3 2 0 I motion (7) 0 2 5 II gap only (5) 1 1 3 1 1 1 cobalt chromium (7) 0 0 2 IV TiAlV (7 ) 0 0 2 V high density polyethylene 0 0 3

amounts of intracytoplasmic metal debris (Fig 6). Seventy-one percent of these membranes were Grade 3+ for macrophages (Table 1). Membrane cellularity appeared to be propor- tional to the amount of metal debris present. Unique to Group I11 membranes was the iden- tification of areas of cytotoxic changes with nuclear degeneration and cellular swelling. These areas of necrosis were associated with abundant CoCr debris.

The addition of TiAlV debris to Group IV specimens produced membranes qualita- tively similar to those of Group 111. Tita- nium aluminum vanadium debris was present diffusely throughout Group IV membranes proximally and distally. Areas of increased debris concentrations were as-

sociated directly with increased cellularity and large numbers of macrophages; 80% were graded 3+ (Table 1). TiAlV particles frequently were noted within the cytoplasm of macrophages and less commonly in giant cells (Fig 7).

Microscopic examination of the metal debris group membranes (Groups I11 and IV) using polarized light revealed the presence of varying amounts of positive birefringent particles consistent with ultra high molecular weight polyethylene debris from the acetabular component. These particles were unique to the metal debris groups and were not seen in Group I and I1 and control membranes. The ultra high molecular weight polyethylene particles were noted proximally and dis-

Fig 4. Photomicrograph of membrane taken Fig 5. Photomicrograph of membrane from the from around the motion group implant. In- gap group without debris. Their cellularity is increased cellularity is seen with numerous creased with a greater number of macrophages macrophages. No metal or polyethylene debris than controls; however, organized fibrous tissue is present. (Stain, hematoxylin and eosin; origi- remains prominent. (Stain, hernatoxylin and nal magnification, x200.) eosin; original magnification, x200.)


cellularly. No evidence of cytotoxicity or de- generative cell changes were observed in association with the birefringent particles.

The addition of high density polyethylene particles to Group V specimens resulted in a membrane with increased cellularity with numerous macrophages and giant cells (Table 1). As in the other particle groups, high density polyethylene was identified within the cytoplasm of macrophages and giant cells. The presence of high density polyethylene particles within the membrane was assessed Using polarized light miCrOSCOpy Fig 6. Photomicrograph of CoCr debris speci-

men. Abundant CoCr debris is seen within the cytoplasm of macrophages (arrowheads) and areas of increased cellularity. (Stain, hematoxylin and eosin; original magnification, x400.)

tally within the membranes and ranged from 1 pm to larger filaments and shards 20 to 30 ym long. Within the membranes, the ultra high molecular weight polyethylene was associated with an intensely cellular reaction with abundant macrophages and giant cells (Fig 8A-B). Similar to the various implanted particles, ultra high molecular weight polyethylene debris was noted intra- and extra-

Fig 7. Photomicrograph of membrane from TiAlV debris specimen. lntracytoplasmic TiAlV debris is seen in macrophages throughout the specimen (arrowheads) and is associated with a highly cellular macrophage infiltrate. Giant cells were frequently noted in these samples (arrows). (Stain, hematoxylin and eosin; original magnification, x400.)

Fig 8A-B. (A) Specimen from Group IV TiAlV particle membrane with ultra high molecular weight polyethylene debris. A highly cellular reaction is noted with numerous macrophages and giant cells (arrowheads). (B) The same field viewed under polarized light shows abundant birefringent ultra high molecular weight polyethylene debris with highly irregular shapes and borders within macrophages and giant cells (arrowheads). (Stain, hematoxylin and eosin; original magnification, x400.)


(Fig 9A-B). Areas of increased high density polyethylene particle concentrations were accompanied by an increased cellular reaction; however, it was less impressive than the previous metal particle Groups 111 and IV.

Collagenase activity was detected in 84% of all experimental samples (Groups 1-V, collectively), and only 50% of control group membranes showed collagenase activity. All experimental groups produced significantly higher levels of collagenase activity when compared with control activity (Table 2). The greatest activity was seen in CoCr specimens in Group 111, which had an average activity of >15 times that of control specimens.

Fig 9A-B. (A) Specimen from Group V experimental high density polyethylene debris membrane with increased cellularity surrounding particles. (B) The same field viewed under polarized light confirms the presence of regular, spherical-shaped high density polyethylene debris, intra- and extracellularly. (Stain, hematoxylin and eosin; original magnification, x400.)

Groups I1 and IV produced an average of 3 and 7 times the average control collagenase activity, respectively. Although only 30% of Group V polyethylene samples showed collagenase activity, average levels were significantly greater than that of controls.

Gelatinase activity was detected in all control and experimental group membranes. Con- trol specimens produced an average units of activity of 5.83 + 3.70 units (Table 2). Both Groups I and I1 produced significantly higher levels of gelatinase when compared with controls (19.20 k 3.90 and 14.67 & 3.90 units, respectively, p < 0.05). Experimental Groups 111, IV, and V did not produce significantly elevated levels of gelatinase activity when compared with controls (Table 2).

Production of prostaglandin E, by membrane tissue was detected in all control and experimental specimens. Control membranes produced an average of only 0.49 & 0.20 units. Experimental Groups I, 11, 111, and IV produced greater levels of prostaglandin E, than the control specimens (Table 3). Group IV TiAIV debris produced the highest average level of prostaglandin E, (10.88 rl: 9.70 units); however, this was not statistically significant because of a relatively large standard deviation. Similarly motion specimens in Group I produced nearly twice the levels of prostaglandin E, measured in controls; however, this was not statistically significant. High density polyethylene debris specimens in Group V produced prostaglandin E, levels similar to control levels.

Because of the contamination of a group of the interleukin-1 assay specimens at the time of incubation, the interleukin- 1 results are reported as an average of 3 specimens remaining in each experimental group. Com- parison of interleukin- i activity of control specimens with experimental group specimens revealed increased interleukin- 1 activity in all the experimental groups. The highest levels of interleukin-1 activity were shown by debris Groups I11 and V. An average activity of 45.87 & 29.20 units and 46.00 k 35.30 units were recorded respectively


TABLE 2. Collagenase and Gelatinase Membrane Activity

Group Collagenase Gelatinase

Control (n = 5) 0.55 + 0.2 5.83 + 3.7

(mean f standard deviation) (mean I standard deviation)

I. motion (n = 7) 2.36 + 1 .O* 19.2 +- 3.9'* I I : gap only (n = 5) 14.67 + 3.9*'

IV. TiAlV (n = 7) 1.71 + 0.5 V: high density polyethylene (n = 7) 1.6 +05** 4.76 f 1.8

1.91 + 1 .O*

3.96 + 1.6** Ill: cobalt chromium (n = 7) 9.16 + 3.5** 5.9 + 2 0

*Significantly > controls, p < 0.05. '*Significantly > controls, p < 0 01

(Table 3). Group IV titanium alloy specimens produced approximately 15 times the control activity. Nondebris specimens from Groups 1 and 11 also produced elevated levels of interleukin-l activity, though not as elevated as the debris groups.

DISCUSSION

Aseptic loosening remains the primary obstacle in extending the life of total joint arthroplasties. As a result of >3 decades of observations on the loosening of total joint prostheses, it is now evident that the process of aseptic loosening represents more than the simple biomechanical loosening of the prosthesis. The concept of aseptic loosening today incorpo- rates the complex interaction of biomechani-

cal, mechanical, and host-specific biologic factors. The presence of periprosthetic pseudomembranes around aseptically loosened femoral implants is well documented.l?.13 Similarly, these membranes also have been described in association with focal osteolytic lesions around stable and loose implants. Histo- logic studies of these tissues, however, consistently have shown the presence of numerous macrophages and giant cells in a foreign body reaction within the fibrous stroma of the membrane~.5.7.8,32-35,43 Detailed light and electron microscopic studies of these tissues have shown large numbers of micron-sized polymeric and metal wear debris throughout these membranes. The transformation of bulk implanted metal and plastics into these micron-sized particles is thought to lead to the

TABLE 3. Prostaglandin E, and lnterleukin 1 Membrane Activity

Prostaglandin E, lnterleukin 1* Group (mean f standard deviation) (mean I standard deviation)

Control (n = 5) I: motion (n = 7) I I : gap only (n = 5)

IV: TiAlV (n = 7) V: high density polyethylene (n = 7)

0.49 + 0.2 1.36 + 0.8t 4.78 2 2.9**

Ill: cobalt chromium (n = 7) 3.37 i . 5a* * 10.88 * 9.77 0.62 + 0.3t

1.08 2 0.3 6.09 + 3.3 2.41 + 1.4

45.87 + 29.2 15.4 + 7.3 46 * 35.3

*n = 3.

*'Significantly > controls, p < 0 05.

tSignificantly > controls, p < 0.1


migration of macrophages into the periprosthetic tissue and results in the foreign body granulomatous reaction. This hypothesis is supported by several animal modeIs in which the presence of implant debris in various tissues stimulated a similar histologic response to that seen in human periprosthetic membranes. Goodman and Fornasier'6 placed ultra high molecular weight polyethylene particles with average sizes of 16 pm, 26 pm, and 67 ym into a nonarticular site in rabbit tibias and showed particle incorporation into a fibrous tissue stroma with macrophages and giant cells. Howie and Vernon-Roberts'4 showed that intraarticular injection of cobalt alloy produced rapid proliferation of macrophages; in another study, that intraarticular injection of ultra high molecular weight polyethylene particles (mean size, 20-200 pm) induced the formation of a membrane around nonweightbearing cement plugs in rabbit knee joints.'J".'S Paiement et a147 showed a fibrovascular tissue aggregate with numerous histiocytes and giant cells in response to metal and polymeric debris (average size, -30 ym) using a subcutaneous wire mesh chamber in a rabbit model.

In the present study, the authors have developed an uncemented canine total hip arthroplasty model to further the histology and biochemistry of aseptic loosening. There are several advantages of this model to investigate the periprosthetic tissue reactions to wear debris and motion. First, the canine hip is a well-established model for total hip arthroplasty."'63 Second, by incor- porating experimental variables into a fully functioning in vivo total hip prosthesis, normal host biomechanical and biologic processes are present. Local tissues are sub- ject to in vivo mechanical loading, and periprosthetic tissues are presented with debris throughout the confines of the effective joint space56 and are likewise exposed to normal host mechanisms of particle clear- ance. Finally, use of an in vivo model has al- lowed the generation of a stable ingrown control prosthetic membrane to provide an identical site and process-specific control

tissue with which to compare experimental group levels of biochemical and histologic activity. This control tissue source has not been described previously. As a result, previous authors have resorted to comparing biochemical results of periimplant tissues with a variety of nonspecific control tissues.

The histology of the canine experimental groups parallel the histology described in aseptically loosened human membranes. As expected, stable well-functioning control prostheses produced thin, relatively acellular fibrous membranes present distally around the nonporous portion of the implant and extending proximally between the porous pads. Macrophages were rare in these specimens (60% were Grade 0), and giant cells were ab- sent. However, the addition of implant motion in Group I produced a grossly more prominent membrane with increased cellularity and many more macrophages (66% were Grade 2+). Lennox et a138 reported similar membrane activation using a nonweightbearing, moving polymethylmethacrylate plug in the proximal tibia of canines. The authors showed the formation of a fibrous tissue membrane infiltrated by numerous macrophages similar to that seen in aseptic loosening.16 Similarly, Hedley et al,'o Pilliar et al,@ and others*4,2* have shown the deleterious effects of implant motion on osseous ingrowth and resultant fibrous membrane formation. Histologically, the membrane specimens from Group I1 gap prosthesis were similar to those from Group I. Sandbom et a152 showed that poor surgical fit with gaps of 1 to 2 mm results in fibrous tissue ingrowth and histologic changes consistent with aseptic loosening. Because most of the Group I1 implants were noted to be loose at the time of harvest, this group most likely represented fibrous ingrowth of the prostheses with some degree of membrane activation because of implant motion similar to Group I.

The most significant evidence for the role of wear debris particles in the activation of periimplant tissues is seen in experimental Groups 111, IV, and V. The introduction of micron-sized particles of TiAlV, CoCr, or high

116 Dowdetal Clinical Orthopaedics

and Related Research

density polyethylene into the same in vivo total hip arthroplasty environment resulted in an intense cellular activation when compared with control tissue. Membrane specimens from the particle groups contained far greater numbers of macrophages and varying numbers of giant cells. The implanted particle concentration varied within a specific membrane; however, areas of high debris content exhibited correspondingly higher concentrations of macrophages. As described in clinical revision specimens, particles often were identified within the cytoplasm of macrophages and giant cells. Of special note was the apparent cytotoxicity associated with areas of high CoCr particle concentration within the membrane. These changec were not observed with the other debris groups. This supports the cytotoxicity of CoCr previously reportedl’J4.42,”; however, the significance of this is unclear. Recently, Haynec et a119 showed increased production of pro-inflammatory cytokines by rat peritoneal macrophages cultured in the presence of TiAlV particles compared with those cultured with CoCr particles, The authors deduced that the pro-inflammatory stim- ulus of TiAlV on viable cells would be greater than the release of mediators from toxic cells exposed to CoCr particles.

The detection of positively birefringent material in the membranes from the metal particle Groups 111 and IV is consistent with ultra high molecular weight polyethylene debris produced by third body wear from implanted metal particles on the ultra high molecular weight polyethylene acetabular liner. Micron-sized metal particles acting as grind- stones within the articulating joint produced a small but detectable amount of ultra high molecular weight polyethylene debris in several of the metal group membranes. The ultra high molecular weight polyethylene debris resembled debris described in human interface membranes with a combination of small (range, 1-1 0 ,urn) irregular spheroidlike particles and larger filaments and shards. Of par- ticular importance is that when present the in vivo-generated ultra high molecular weight

polyethylene particles were surrounded by an intense cellular reaction with abundant macrophages and giant cells. Larger particles were surrounded by macrophages or engulfed within giant cells; smaller particles were seen predominantly within the cytoplasm of macrophages.

The intensity of the cellular reaction to the small amount of in vivo-generated ultra high molecular weight polyethylene debris is particularly important when compared with the histology seen in the high density polyethylene particle Group V membranes. In this study, commercially produced high density polyethylene particles appeared to be the best tolerated of the experimental particles tested. Although high density polyethylene particles stimulated a cellular reaction with macrophages and giant cells, the small amounts of in vivo-produced ultra high molecular weight polyethylene wear particles appeared to elicit a more intense biologic response (Fig 8 versus Fig 9). This may be explained by several important factors: Firct, Group V received high density polyethylene particles and not the ultra high molecular weight polyethylene currently used in hip prostheses; the primary difference between the 2 is molecular weight. Polyethylene chains in high density polyethylene consist of 2 x 10’ to 5 x 105 repeating units, whereas ultra high molecular weight polyethylene mole- cules consist of 2 x 106 to 5 x lo6 repeating units. Ultra high molecular weight polyethylene is used clinically because of its much greater resistance to wear and creep as a bulk component. Nevertheless, ultra high molecular weight polyethylene particles in this size range were unavailable for use in this study. After numerous unsuccessful attempts to produce these particles themselves, the authors settled on high density polyethylene. Also, because the high density polyethylene particles were commercially produced (proprietary method), they possessed a more regular, spherical, or disk-like surface than particles produced by in vivo wear. Because cellular response and phagocytosis are dependent on


cell-particle surface interaction, the observed differences of commercially produced polyethylene debris may render them less activat- ing than those particles produced in vivo. Synthetically produced CoCr and TiAlV particles also were used; however, the morpholo- gies of these particles closely resembled those seen in human periimplant membranes with highly irregular, sharp edges. The significance of these material and physical proper- ties is not clear; however, these differences may help to explain why the addition of the high density polyethylene appeared to be better tolerated histologically and biochemically than previously reported.

The link between the histologic activation of periprosthetic membranes and loosening of the implant is believed to be a result of increased bone resorption. The dynamic interface of a well-functioning uncemented implant involves constant bone ingrowth and resorption along with fibrous tissue repair. In the stable implant, these forces may be thought of as in equilibrium. However, in the presence of increased wear debris, bone resorption may occur to a greater degree with ensuing fibrous repair filling the interface. This hypothesis is supported by numerous in- vestigations showing the production of enzymes and cytokines known to stimulate bone resorption by interface membranes. Goldring et a112 were among the first to show the bone resorbing potential of interface membranes. They showed the increased production of prostaglandin E, and collagenolytic factors by interface membranes in culture, and that conditioned media from these cultures stimulated increased bone resorption in mice calvaria. More recently, membranes taken from around failed human total hip arthroplasties have been shown to produce increased collagenase, gelatinase, interleukin- 1, and prostaglandin

Neutral metalloproteinases such as collagenase and gelatinase are capable of degrad- ing the extracellular matrix and exposing bone mineral for osteoclast resorption.64 The proinflammatory eicosinoid prostaglandin

E 7-9,12,32-35,46,57 2'

E2 has been shown to stimulate osteoclastic bone resorptionl6,31,36,44,64 and participate in the local control of bone resorption. Inter- leukin-1 also has been implicated in a number of cellular responses leading directly and indirectly to increased bone resorption. In- terleukin-1 has been shown to stimulate chemotaxis by macrophages and to stimulate further release of interleukin-1 by these macrophages producing a positive feedback loop of activation. Osteoclasts exposed to interleukin- 1 show increased proliferation, increased size of the ruffled border, and increased clear zone, all associated with greater bone resorption a~tivity.26~31 Further- more, interleukin-1 is a potent inducer of further prostaglandin E2 and neutral metallo- proteinase release by various cells present in interface membranes.48

The role of particulate wear debris in ini- tiating the cascade of bone resorption and osteolysis at the implant-bone interface has been supported by a number of in vitro in- vestigations. Murray and R ~ s h t o n ~ ~ reported that macrophages produced increased amounts of prostaglandin E, when cultured with polyethylene, and that conditioned media from these macrophage cultures stimulated increased bone resorption from mice calvaria. Particulate wear debris of CoCr, TiAlV, and polyethylene have been shown to activate macrophages and increase release of potent mediators of bone resorption in vitro.

In the present study, micron-sized particles of CoCr, TiAlV, and polyethylene were placed within the proximal femoral canal. The addition of all 3 types of debris produced histologic activation. This increased cellular activation was paralleled by an increase in the biochemical activation of the experimental membranes. The importance of the control group specimens in this comparison is para- mount. Previous reports of biochemical activation have been limited by the lack of an ad- equate control tissue with which to compare results. Previously, authors have compared interface membrane activity with synovium, rheumatoid arthritis synovium, and pseudo-


capsule from revision arthroplasties. These controls, however, represent tissues with inherent biochemical activity and response to a number of uncontrolled variables. The identi- fication of a thin, fibrous, relatively acellular membrane around stable well-functioning ingrowth prostheses provided an ideal control tissue for comparison of experimental variables. As expected, these histologically benign-appearing control membranes produced low levels of neutral metalloproteinases, prostaglandin E,, and interleukin- 1 . The greatest degree of foreign body response was seen with the addition of TiAlV and CoCr debris. These membranes produced the highest levels of collagenase, prostaglandin E,, and interleukin- 1 detected. Intermediate hktologic response was seen in nonparticle Groups I and 11, and similarly these groups produced elevated levels of collagenase, prostaglandin E,, and interleukin- I , though generally lower levels than those produced by the debris groups.

The presence of metal particulate debris of either CoCr or TiAlV in the interface membrane surrounding an uncemented femoral prosthesis resulted in a highly cellular foreign body reaction. Histologic activation of these membrane groups by micron- sized metal debris resulted in significant production of collagenase, prostaglandin E,, and interleukin- 1 activity, all known promot- ers of bone resorption. Both metal groups produced a similar spectrum of histologic and biochemical activation. Cobalt chrome debris produced the highest levels of collagenase activity; TiAlV particles stimulated the greatest levels of prostaglandin E,. The relative contributions of these different metals to membrane activation remains unclear and requires further investigation. Group I11 specimens did contain histologic evidence of cytotoxicity, supporting previous reports of CoCr's toxicity in cell c ~ l t u r e . ' ~ ~ ~ ~ These reports have postulated different levels of cellular activation based on toxicity of the metal; however, because Groups I11 and IV produced similar results, the significance of

this observation to the process of aseptic loosening remains unclear.

Although the experimental particle groups produced increased collagenase and prostaglandin E, activity, the most prominent differences in the biochemistry of these specimens was the increased level of interleukin- 1 activity. The presence of particulate debris within the periprosthetic membranes of Groups 111 and IV resulted in 14 to 42 times the interleukin- I activity measured in control specimens. Because of the contamination of a number of interleukin-] assay specimens, the small sample size and the variability inherent in a bioassay, statistical significance is not assessed with this assay. Ultimately an enzyme-linked immunosorbent assay for the presence of interleukin-1 will be needed; however, at this time there is no commercially available monoclonal anti- body specific for canine interleukin- 1. At- tempts to quantify canine interleukin- 1 with available enzyme linked immunosorbent assay kits failed because of a lack of cross re- activity between human and canine interleukin- I .

The current study demonstrates aseptic loosening in an in vivo model reproducing the histology and biochemistry associated with osteolysis. A stable ingrown prosthesis reliably produced a thin relatively acellular fibrous membrane with low levels of biochemical activity. The addition of implant motion or particulate debris to this tissue resulted in a highly cellular foreign body response similar to that seen in failed total hip arthroplasties. Perhaps most significantly, however, was the fact that these same variables resulted in parallel increases in biochemical activity of collagenase, prostaglandin E2, and interleukin- 1, all associated with osteolysis and aseptic loosening. This model may provide the basis for further in- vestigations to better assess relative contributions of various particulate materials to osteolysis and aseptic loosening, and help to identify possible points of intervention in the process of aseptic loosening.


Acknowledgments

The authors thank the following individuals for their invaluable contributions to this project: Jack E. Pam, PhD, for his expertise, advice, and insight into the development of this project; C. H. Evans, PhD, and the staff of the Ferguson Laboratory for guidance with the biochemical assays; Gary An- derson, MD, and Mariko Horikoshi, MD, for their assistance with the surgery; K. Short for the histology; W. Thompson and Shawn Ward for assistance with numerous aspects of the surgery; Hallum Bailey for the electron microscopy; Dawn Tramaglini for the project flow chart and assistance with histology photos; Robin Evans, RN, for help with the manuscript; James Rudert, PhD, University of Iowa, for design of the motion prosthesis; James Davidson, PhD, of Smith & Nephew Richards, Inc, for providing the high density polyethylene particles; the staff of the University of Pittsburgh Central Animal Facility and the Rangos Animal Care Facility of Chil- dren’s Hospital of Pittsburgh for help with the animal care; and Zimmer, Inc, for their technical support, implant supply, and particle analysis.

References

1. Agins HJ, Alcock NW, Bansal M, et al: Metallic wear in failed titanium-alloy total hip replacements. J Bone Joint Surg 70A:347-356, 1988.

2. Amstutz HC, Campbell P, Kossovsky N, Clarke IC: Mechanism and clinical significance of wear-induced osteolysis. Clin Orthop 276:7-18, 1992.

3. Bobyn JD, Aribindi R, Mortimer E, Tanzer M: The susceptibility of smooth implant surfaces to polyethylene debris migration and peri-implant fibrosis. Trans Orthop Res Soc 192344, 1994.

4. Brown IW, Ring PA: Osteolytic changes in the upper femoral shaft following porous-coated hip replacement. J Bone Joint Surg 67B:218-221, 1985.

5. Charnley J: The histology of loosening between acrylic cement and bone (abstract). J Bone Joint Surg 57B:245, 1975.

6. Charosky CB, Bullough PG, Wilson PD: Total hip replacement failures: A histological evaluation. J Bone Joint Surg. 55A:49-58, 1973.

7. Chiba J, Iwaki Y, Kim KJ, Rubash HE: The role of cytokines in femoral osteolysis after cementless total hip arthroplasty. Trans Orthop Res Soc 17:350, 1992.

8. Chiba J, Rubash HE, Kim KJ, Iwaki Y The characterization of cytokines in the interface tissue obtained from failed cementless total hip arthroplasty with and without femoral osteolysis. Clin Orthop 300:304-312, 1994.

9. Dayer JM, Breard J, Chess L, Crane SM: Participa- tion of monocyte-macrophages and lymphocytes in the production of a factor that stimulates collagenase

and prostaglandin secretion by rheumatoid synovial cells. J Clin Invest 64:1386-1392, 1979.

10. Evans EM, Freeman MAR, Miller AJ, Vernon- Roberts B: Metal sensitivity as a cause of bone necrosis and loosening of the prosthesis in total joint replacement. J Bone Joint Surg 56B:626-642, 1974.

I . Garret R, Wilksch J, Vernon-Roberts B: Effects of cobalt-chrome alloy wear particles on the morphology, viability, and phagocytic activity of murine macrophages in vitro. Aust J Exper Biol Med Sci

2. Goldring SR, Jasty M, Roelke MS, et al: Formation of the synovial-like membrane at the bone-cement interface: Its role in bone resorption and implant loosening after total hip replacement. Arthritis Rheum 29336-842, 1986.

13. Goldring SR, Schiller AL, Roelke M, et al: The synovial-like membrane at the bone-cement interface in loose total hip replacements and its pro- posed role in bone lysis. J Bone Joint Surg 65A:

14. Goodman SB: The effects of micromotion and particulate materials on tissue differentiation: Bone chamber studies in rabbits. Acta Orthop Scand 65: 1-43, 1994.

15. Goodman SB, Chin RC, Chiou SS, et al: AClinical- pathologic-biochemical study of the membranes surrounding loosened and nonloosened total hip arthroplasties. Clin Orthop 244: 182-187, 1989.

16. Goodman SB, Fornasier VL: Clinical and Experi- mental Studies in the Biology of Aseptic Loosen- ing of Joint Arthroplasties and the Role of Polymer Particles. In St. John KR (ed). Particulate Debris From Medical Implants: Mechanisms of Formation and Biological Consequences. Philadelphia, Amer- ican Society of Testing Materials STP 1144 27-37, 1992.

17. Gowen M, Mundy GR: Actions of recombinant IL- 1, IL-2, and INF-g on bone resorption in vitro. J Im- munol 136:2478-2482,1986.

18. Harris WH, Schiller AL, Scholler JM, Frieberg RA, Scott R: Extensive localized bone resorption in the femur following total hip replacement. J Bone Joint Surg 58A:612-618,1976.

19. Haynes DR, Rogers SD, Hay S, Pearcy MJ: The differences in toxicity and release of bone resorbing mediators induced by titanium and cobalt chromium alloy wear particles. J Bone Joint Surg

20. Hedley AK, Gruen TA, Ruoff DP: Revision of failed total hip arthroplasties with uncemented porous- coated anatomic components. Clin Orthop 235:75-90, 1988.

21. Herberts P, Ahnfelt L, Malchau H, Stromberg C, An- dersson GB: Multicenter clinical trials and their value in assessing total joint arthroplasty. Clin Or- thop 249:48-55, 1989.

22. Hollis JM, Hofmann C, Stewart CL, Flahiff CM, Nelson C: Effect of micromotion on ingrowth into porous coated implants using a transcortical model. Trans Orthop Res Soc 17:564, 1992.

23. Horowitz SM, Doty SB, Lane JM, Burstein AH: Studies of the mechanism by which mechanical fail-

61 :355-369, 1983.

575-584, 1983.

75A:825-834,1993.

120 Dowdetal Clinical Orthopaedics

and Related Research

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

~ ~~ ~~

I

Callaghan JJ: Endosteal erosion in association with stable uncemented femoral components. J Bone Joint Surg 72A: 1025-1034, 1990.

bone loss in total kip arthroplasty: Pofyethylene wear debris and the concept of the effective joint space. J Bone Joint Surg 74A:849-863, 1992.

ure of polymethylmethacrylate leads to bone resorption. J Bone Joint Surg 75A:802-8 13, 1993. Howie DW, Vernon-Roberts B: The synovial response to intraarticular cobalt-chrome wear particles. Clin Orthop 232:244-254, 1988. Howie DW. Vernon-Roberts B, Oakeshott R, Man- they B: A rat model of resorption of bone at the cement-bone interface in the presence of polyethylene wear particles. J Bone Joint Surg 70A:257-263, 1988. Ibbotson KJ, D’Souza SM, Kanis JA, Douglas DL, Russell RGG: Physiological and pharmacological regulation of bone resorption. Metab Bone Dis 2: 177, 1980. Jasty MJ, Floyd WE, Schiller AL, Goldring SR, Harris WH: Localized osteolysis in stable non-septic total hip replacement. J Bone Joint Surg 68A: 912-919. 1986. Jasty M, Maloney WJ, Bragdon CR, Haire T, Harris WH: Histomorphological studies of the long-term skcletal responses to well fixed cemented femoral components. J Bone Joint Surg 72A: 1220-1229, 1990. Jiranek WA, Machado M, Jasty M, et al: Production of cytokines around loosened cemented acetabular components: Analysis with immunohistochemical techniques and i n situ hybridization. J Bone Joint Surg 7SA:863-879, 1993. Jones LC, Hungerford DS: Cement disease. Clin Or- thop 225: 192-206, 1987. Kern JA, Lamb RJ, Reed JC, Daniels RP, Nowell PC: Dexamethasone inhibition of interleukin 1 beta production by human macrophages. J Clin Invest

Kim KJ, Chiba J, Rubash HE: In vivo and in vitro analysis of membranes from hip prostheses inserted withoul cement. J Bone Joint Surg 76A: 172-1 80, 1994. Kim KJ. Grcis P, Wilson SC, et al: Histological and biochzniical comparison of membranes from titanium, cobalt-chromium and non polyethylene hip prostheses. Trans Orthop Res Soc 16: 19 I , 199 I . Kim KJ. Hashimoto J, Morita H, Sato K, Kashi- wazaki S: Effects of implant particles on the production of L 1 and IL-6 by bone marrow cells. Trans Orthop Res Soc I7:34 I , 1992. Kim KJ. Rubash HE, Wilson SC, D’Antonio JA, McClain EJ: A histologic and biochemical comparison of interface tissues in cementless and cemented hip prostheses. Clin Orthop 287: 142- 152, 1993. Klein DC, Raisz LG: Prostaglandins: Stimulation of bone resorption in tissue culture. Endocrinol 86:

Lee JM. Salvati EA, Betts F, et al: Size of metallic and polyethylene debris particles in failed cemented total hip replacements. J Bone Joint Surg 74B: 380-384. 1992. Lennox DW, Schofield BH. McDonald DF, Riley LH: A histologic comparison of aseptic loosening of cemented. press-fitted, and biologic ingrowth prostheses. Clin Orthop 225:171-191, 1987. Maloney WJ, Jasty M, Harris WH, Galante JO,

81:237-244, 1988.

1436-1440. 1970.

40. Maloney WJ, Jasty M, Rosenberg A, Harris WH: Bone lysis in well fixcd cemented femoral components. J Bone Joint Surg. 72B:966-970, 1990.

41. Maloney WJ, Schmalzried TP, Smith RL, et al: Iso- lation and characterization of wear particles generated in failed uncemented hip arthroplasty. J Bone Joint Surg 77A, 1995.

42. Maloney WJ, Smith RL, Castro F, Schurman DJ: Fi- broblast response to metallic debris in vitro. J Bone Joint Surg 7SA:835-844, 1993.

43. Mirra JM, Amstutz HC, Matos M, Gold R: The pathology of the joint tissues and its clinical relevance in prosthesis failure. Clin Orthop 117:

44. Murray DW, Rushton N: Macrophages stimulate bone resorption when they phagocytose particles. J Bone Joint Surg 72B:988-992, 1990.

45. Nasser S, Campbell PA, Kilgus D, Kossovsky N, Amstutz HC: Cementless total joint arthroplasty prostheses with titanium-alloy articular surfaces: A human retrieval analysis. Clin Orthop 261: 17 1-1 85, 1990.

46. Ohlin A, Johnell 0, Lerner UH: The pathogenesis of loosening of total hip arthroplasties: the production of factors by periprosthetic tissues that stimulate in vitro bone resorption. Clin Orthop 253:287-296, 1990.

47. Paiement G, Jasty M, Goldring SR, et al: Difference in tissue response to metallic biomaterials (metals vs. polymers) in a rabbit wound chamber model. Trans Orthop Res Soc 1 I : I 15, 1986.

48. Pettipher ER, Higgs GA, Henderson B: Interleukin- I induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Nat Acad Sci 83:8749-8753, 1986.

49. Pilliar RM, Lee JM, Maniatopoulos C: Observations on the effect of movement on bone ingrowth into porous coated surfaced implants. Ciin Orthop 208:

50. Rae T: The biologic response to titanium and titanium-aluminum-vanadium alloy particles. I. Tissue culture studies. Biomaterials 7:30-36, 1986.

51. Revell PA, Weightman B, Freeman MAR, Vernon- Roberts B: The production and biology of polyethylene wear debris. Arch Orthop Trauma Surg 91: 167-181, 1978.

52. Sandborn PM, Cook SD, Anderson RE, Spires WP, Kester MA: The effect of surgical fit on bone ingrowth into porous coated implants. Trans Orthop Res Soc 12217, 1987.

53. Santavirta S, Hoikka V, Eskola A, et al: Aggressive granulomatous lesions in cementless total hip arthroplasty: J Bone Joint Surg 72B:980-984, 1990.

54. Santavirta S, Sorsa T, Konttinen YT, et al: Role of mesenchymal collagenase in the loosening of total hip prosthesis. Clin Orthop 290:206-2 IS, 1993.

55. Schindler R, Ghezzi P, Dinarello CA: Interferons as inhibitors of interleukin-1 induced interleukin-l synthesis. Lymphokine Res 8:275-280, 1989.

56. Schmalzried TP. Jastv M. Harris WH: Periorosthetic

221-240, 1976.

108-1 13, 1986.

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57. Sedel L, Simeon J, Villette JM, Launay JM: PGE2 level in the tissue surrounding failed total hip arthroplasty: Effect of materials. Trans Orthop Res Soc 17:351, 1992.

58. Shanbhag AS, Jacobs JJ, Black J, Galante JO, Glant T T Macrophagefparticle interactions: Effect of size, composition and surface area. J Biomed Materials Res 28: 8 1-90, 1994.

59. Shanbhag AS, Jacobs JJ, Glant TT. et al: Composi- tion and morphology of wear debris in failed uncemented total hip arthroplasty. J Bone Joint Surg 76B:6(3-67, 1994.

60. Simon PL, Laydon JT, Lee JC: A modified assay for interleukin-I (IL-I). J Immunol Methods 84: 85-94, 1985.

6 I . Spector M, Shortkroff S, Hsu HP, et al: Synovium- like tissue from loose joint replacement prostheses: Comparison of human material with a canine model. Semin Arthritis Rheum 21 :335-344, 1992.

62. Tanzer M, Maloney WJ, Jasty M, Harris WH: The progression of femoral cortical osteolysis in association with a cementless total hip arthroplasty. J Bone Joint Surg 74A:404-410, 1992.

63. Thornhill TS, Shortkroff S, Hsn HP, et aI: Acanine model for the study of the interface pseudomem-

64

65.

66

67

68

69

brane in loose cemented femoral stems. Trans Or- thop Res Soc 232, 1990. Vaes G: Cellular biology and biochemical mechanism of bone resorption. A review of recent devel- opments on the formation, activation, and mode of action of osteoclasts. Clin Orthop 231 :239-271, 1988. Willert HG, Bertram H, Buchhorn GH: Osteolysis in alloarthroplasty of the hip. The role of ultra-high molecular weight polyethylene particles. Clin Or-

Willert HG, Ludwig J, Semlitsch M: Reaction of bone to methylmethacrylate after hip arthroplasty. A long-term gross, light, and electron microscopic study. J Bone Joint Surg 56A: 1368-1382, 1974. Willert HG, Semlitsch M: Reactions of the articular capsule to wear products of artificial joint prostheses. J Biomed Mater Res 11: 157-164, 1977. Wilson JN, Scales JT: Loosening of total hip replacements with cement fixation: Clinical findings and lab studies. Clin Orthop 72:145-160, 1970. Witt JD, Swann M: Metal wear and tissue response in failed titanium alloy total hip replacements. J Bone Joint Surg 73B:559-563, 1991.

thop 258:95-107, 1990.

https://www.researchgate.net/publication/21607994_The_progression_of_femoral_cortical_osteolysis_in_association_with_total_hip_arthroplasty_without_cement?el=1_x_8&enrichId=rgreq-1ef7d5dd-b805-4811-9c25-fbadd54f8f36&enrichSource=Y292ZXJQYWdlOzE1NjQzNzM3O0FTOjEwMjUyMDkzMjI3NDE4MUAxNDAxNDU0MzAzNjQ0




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https://www.researchgate.net/publication/19228227_A_modified_assay_for_interleukin-1_IL-1?el=1_x_8&enrichId=rgreq-1ef7d5dd-b805-4811-9c25-fbadd54f8f36&enrichSource=Y292ZXJQYWdlOzE1NjQzNzM3O0FTOjEwMjUyMDkzMjI3NDE4MUAxNDAxNDU0MzAzNjQ0



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aseptic loosening in uncemented total hip arthroplasty in a canine model

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