Sensitivity to Metal as a Possible Cause of

Sterile Loosening after Cobalt-Chromium

Total Hip-Replacement Arthroplasty
BY G. C. BROWN, M.D.*, M. D. LOCKSHIN, M.D.*, E. A. SALVATI, M.D.*,
AND P. G. BULLOUGH, M.D.*, NEW YORK, N.Y.

From the Hospitalfor Special Surgery, Affiliated with The New York Hospital-Cornell Medical Center. New York City

ABSTRACT: We explored the possibility that wear found to contain cobalt in elevated concentrations after all
products of cobalt-chromium alloy might lead to sen- total hip replacements in which metal articulated with
sitivity to metal wear products and in turn to loosening metal, but there was no such increase in the patients whose
of a component of the prosthesis after total joint re- prostheses were metal articulating with polyethylene”.
placement. Twenty patients with sterile, loose In one study positive patch tests for sensitivity to
McKee-Farrar hip replacements had patch tests for cobalt were elicited in nine of fourteen patients with sterile
sensitivity to cobalt, nickel, and chromium. All tests loosening of various prostheses in which metal articulated
were negative in all patients. The histological findings with metal, and it was hypothesized that in those cases
from surrounding tissues in seventeen patients who metal hypersensitivity developed and bed to small-vessel
had reoperation showed no signs of delayed hypersen- occlusion and in turn to osteonecrosis, microfractu.re, and
sitivity. In five patients, lymphokine assays for migra- subsequent loosening of the prosthesis5. In another study,
tion inhibition factor and blastogenic factor were done. seven patients were reported with sterile, loose McKee-
Only one assay was positive. Our findings do not sup- Farrar prostheses, six of them showing positive patch tests
port the suggestion that hypersensitivity to metal is a to cobalt chloride, while thirty patients who had successful
cause of component loosening after McKee-Farrar McKee-Farrar prostheses and were similarly patch-tested
total hip replacement. had negative results’#{176}.
These reports have directed particular attention to the
The encouraging results of total hip-replacement ar- effects of cobalt-chromium articulating directly on
throplasty have stimulated similar applications to other cobalt-chromium (the McKee-Farrar total hip arthro-
joints. In all cases, the materials used and the wear prod- plasty). Although cobalt-chromium alloy has been in
ucts they generate should be well tolerated by the host. widespread use for many years, reports concerning its
Cobalt-chromium-molybdenum alloy, because of its cor- biocompatibility have generally been quite favorable.
rosion resistance, remains one of the most common im- While allergy to cobalt salts has long been recog-
plant materials and has been in use for some forty years. nized, and is indeed not uncommon in Europe, it is dis-
Recent reports, however, raised some questions as to tinctly uncommon in the United States One . group of in-
whether this alloy can in some instances lead to failure vestigators tested 5,000 consecutive patients in five dif-
because of the development in patients of delayed hyper- ferent European clinics and obtained positive cobalt
sensitivity to, or even direct toxicity from, components of patch-test reactions in 7.4 per cent of men and 6.6 per cent
the alloy5-’0. of women ‘ . On the other hand, 2 ,000 consecutive patients
It is known that even the most corrosion-resistant im- were tested for sensitivity to cobalt at the New York Skin
plants ionize locally after implantation6. In 1966, four and Cancer Unit at the New York University Medical Cen-
cases of dermatitis developing after insertion of stainless- ter, and only one patient had a positive result8. Indeed, so
steel implants were described ‘ ‘ In each
. case the der- few positive reactions to cobalt are obtained in this coun-
matitis resolved after removal of the implant. In the first try that the North American Contact Dermatitis Research
reported case of pruritus and urticaria after insertion of a Group does not include cobalt in its battery of patch tests.
cobalt-chromium device (a Smith-Petersen nail) 13, in The reason that many Europeans are sensitive to cobalt is
I 967, patch-testing was positive for nickel sulphate and a not certain, but it may be related to the high concentration
stainless-steel nail taped to the thigh caused local inflam- of cobalt in detergents and cement manufactured in
mation. Europe2.
A considerable quantity of metallic debris usually To explore the possibility that wear products of
surrounds failed cobalt-chromium McKee-Farrar pros- cobalt-chromium alloy might generate hypersensitivity to
theses , even when inflammation is minimum and cultures the metal and that this in turn might lead to loosening of
are sterile. In one study, the hair, blood, and urine were the prosthesis after prosthetic joint replacement, we re-
viewed all of our patients with McKee-Farrar total hip re-
* 535 East 70th Street, New York, N.Y. 10021. placements that became loose and in whom infection as a

164 ThE JOURNAL OF BONE AND JOINT SURGERY

 SENSITIVITY TO METAL AS A POSSIBLE CAUSE OF STERILE LOOSENING I 65

cause of loosening had been carefully ruled out. Twenty the amount of metallic debris, the degree of inflammatory
patients were available for review, including follow-up response, the amount of tissue necrosis, and the nature and
and testing for signs of hypersensitivity. degree of any vascular changes.

Materials and Methods Lvmphokine Assays

The twenty patients in our study group had had a total Five of the twenty patients still had their loose
of twenty-three McKee-Farrar arthroplasties, but in no pa- prosthesis in place at the beginning of this study, and from
tient was there bilateral loosening. Sixteen patients were these patients joint fluid was obtained by aspiration. In
women and four were men, and the mean age was sixty- vitro assays were done for migration inhibition factor and
two years (range, twenty-nine to eighty). The underlying blastogenic stimulation factor. These factors are known to
disease process was osteoarthritis in eight patients, be secreted by immunocompetent lymphocytes when they
rheumatoid arthritis in five, idiopathic avascular necrosis are presented with a specific antigen to which they have
in three, sequelae of trauma in three, and ankybosing developed hypersensitivity 12 One would expect these fac-
spondylitis in one. Three of the patients had had previous tors to be present in fluids of tissues when a delayed hyper-
arthroplasty, two with a Vitalbiurn Austin Moore pros- sensitivity reaction is taking place. Migration inhibition
thesis and one with a Vitallium cup. Loosening in all cases factor, one of the better known of the lymphokines, is a
usually was first suspected on clinical and roentgeno- protein whose molecule measures in the 20,000 to
graphic grounds, but in each case the loosening was 40,000-dalton size range. It has the in vitro effect of ren-
confirmed by arthrography, direct visualization at reopera- dering monocytes sticky with respect to the wall of the
tion, or both. Loosening was found in the acetabubar corn- containing vessel, thereby inhibiting their migration. BIas-
ponent alone in fourteen patients, in both components in togenic factor is another mediator of the cellular immune
five, and in the femoral component alone in one. Some de- response and has the effect of causing transformation of
gree of pain on motion and weight-bearing accompanied lymphocytes to bymphoblasts.
the loosening in all patients. The pain began at variable The assay for migration inhibition factor is done
times after arthroplasty (mean, thirty-five months; range, using gui nea- pig peritoneal e xudate cells (macrophages
one to sixty-nine months). Infection was carefully ruled and other mononuclear cells) in capillary tubes. The test
out in each case by aerobic, anaerobic, mycobacterial, and fluid is placed in one tube and a control is placed in the
fungal cultures of specimens obtained at aspiration of the other. Various dilutions of the test material are used and
joint, supplemented in seventeen cases by culture of the experiments are done in duplicate or quadruplicate. If
specimens obtained at reoperation. In three patients the test is positive, the extent of migration of the cells is 80
further surgery was deferred. per cent or less of that found in the control.
To evaluate the role of hypersensitivity as a cause of The assay for blastogenic factor is done by introduc-
sterile loosening, we patch-tested each patient, reviewed ing test and control fluids in various dilutions into a culture
the histological material removed at reoperation, and per- of normal human peripheral lymphocytes. After six days,
formed an in vitro lymphokine assay. a tritiated thymidine pulse is introduced for four hours and
DNA synthesis is assayed by scintillation counting. A pos-
Epu’iitaneous Pau’Ii Tests
itive test consists of a twofold or greater increase in the
Patch tests were performed using cobalt chloride 1 uptake of labeled thymidine. This suggests that the lym-
per cent (as recommended by the International Contact phokine is stimulating blastogenesis. Enough synov ial
Dermatitis Research Group), cobalt sulphate 2 percent, fluid was present in our five patients to perform an assay
nickel sulphate 2 per cent, potassium dichromate 0.5 per for migration inhibition factor on four and an assay for
cent, and methylmethacrylate monomer 10 per cent sus- biastogenic factor on five (Cases 1 6 through 20).
pended in olive oil. The patches used were cellulose discs
Results
fastened on polyethylene-coated aluminum as recom-
mended by the International Contact Dermatitis Research Patch Tests
Group. The inner arm and forearm were the testing sites The epicutaneous patch tests for sensitivity to
and the patches were left in contact with the skin for chromium, nickel, cobalt, and methlymethacrylate
forty-eight hours. They were then removed and the skin monomer were uniformly negative.
was inspected for induration, vesiculation, or erythema,
Pathology
any of which constituted a positive test.
In fifteen of the seventeen patients who underwent
Re tie st of Histological Specimens
reoperation, the surgeon who dictated the operative note
In the seventeen patients who had revisions of their mentioned grayish-black discoloration of the tissue around
arthroplasty, we reviewed the descriptions of the gross the loose implant. In most cases a large amount of necrotic
pathological appearance of the tissues and the histological tissue was noted also. In three patients there was a worn
sections prepared from the tissue removed from around the area in the neck of the femoral prosthesis where the im-
prostheses at the time of revision. We specifically noted plant had been impinging on the rim of the cup.

VOL. 59-A, NO. 2, MARCH 1977

I 66 G. C. BROWN, M. D. LOCKSHIN, E. A. SALVATI, AND P. G. BULLOUGH

TABLE I

Date of Onset of Loose Date of Date of

Case Sex Age Disease Operation Symptoms Component* Reoperation Patch Test Comment*
( Yrs.)

1 F 72 OA 12/68 6/71 A 12/72 9/75

2 M 63 AVN 5/68 8/70 A,F 1/72 12/75
3 M 69 Tr 10/68 1/69 A,F 1/70 9/75 Failed Thompson
4 F 70 RA 2/70 10/70 A 8/72 10/75
5 F 70 OA 6/68 1/70 A,F 8/70 9/75
() F 57 RA 4/69 3/72 A 12/75
7 i 62 AVN 4/69 12/69 A 12/72 10/75 Bilat. THR
It 1. 66 OA 7/68 10/68 A I 1/70 9/75
9 F 80 1r 7/68 4/73 A 6/73 8/75 Failed Moore
10 M 29 AS 11/68 11/69 A.F 12/70 8/75 Bilat. THR
I I F 54 RA 8/70 9/71 A 2/75 9/75
12 F 78 RA 11/68 11/69 A,F 11/70 12/75
13 F 64 Tr 10/68 1/70 A 8/75 Failed Moore
14 M 45 AVN 4/69 5/72 A 7/72 12/75
15 F 75 OA 1/68 9/72 A 5/73 12/75
16 F 60 OA 5/70 5/72 F I 1/75 Bilat. TI-IR;
? pos. MIF test
7 F 54 RA 2/68 1/74 A 7/75 7/75 Pos. BSF test
18 F 76 OA 3/70 3/71 A 11/75 8/75
19 F 68 OA 7/68 10/74 A 9/75 8/75 MIF test not
done
20 F 67 OA 7/68 10/74 A 7/75 7/75

* ()A = osteoarthrit,s: AVN = avascular necrosis; Tr = trauma; RA = rheumatoid arthritis; AS = ankylosing spondylitis; A = acetabular com-
ponent: F = temoral component: THR = total hip replacement; MIF = miation inhibition factor; and BSF = blastogenic stimulation factor.

The histological sections in the majority of cases amount (Fig. 1). In no case was there an obvious spatial
showed evidence of tissue necrosis both in soft tissue and relationship between the metallic debris and the chronic
in the bone included in the specimen. In four cases the inflammation (Fig. 2). In a few specimens there was evi-
necrosis was very extensive. As is commonly the case in dence of methylmethacrylate debris with a giant-cell reac-
synovial and capsular tissue, the smaller vessels showed tion.
thickening of the walls and intimal proliferation 16 Fi-
Lvinphokine A ssa’s
brinoid necrosis or vascular occlusion was not particularly
remarked, although in one case vasculitis was noted and in The assay for migration inhibition factor was positive
another there was occlusion of the small vessels. in one patient. However, in this patient further fractiona-
In all patients there were signs of chronic inflamma- tion of the active fluid to separate out the protein group in
tion and in some this was extensive. In about one-half of
‘I,,. -
the cases, plasma cells were seen along with lymphocytes.
, I ,
All specimens showed metallic debris, usually with
1’ , #{149}
histiocytes, and in three cases this was rather marked in
.

. . 1,.
‘

I
“
4*

- , - ‘I I

“I-, :
I-‘ii3.(‘;; , , - ‘ ;c’
,;“ :i
,,: , di., ..
.‘,., , . 7

) # ;‘. .-,.. 4 34 , -

“je

- ‘.d -

FIG. 2
Photomicrograph of tissue from a patient with a failed McKee-Farrar
FIG. 1
prosthesis. In the upper left-hand corner of the field there is intracellular
Photomlcrograph demonstrating intracellular metallic debris in a pa- metallic debris in macrophages. In the lower right-hand corner a lym-
tlent with a failed McKee-Farrar prosthesis (hematoxylin and eosin, phocytic infiltrate is seen. There is no obvious cause-and-effect relation-
x 750). ship (hematoxylin and eosin, x 220).

THE JOURNAL OF BONE AND JOINT SURGERY

 SENSITIVITY TO METAL AS A POSSIBLE CAUSE OF STERILE LOOSENING I 67

the 20,000 to 40,000-dalton size range revealed that the fibrinoid necrosis, and thrombosis of arterioles at the mar-
positive test was not attributabk to migration inhibition gins of infarcted tissues. It is well known that in synovium
factor but to a larger protein contaminant. Thus, we con- where any chronic disease process exists the vessels may
cluded that migration inhibition factor was not present in be thick-walled. Therefore, it would seem misleading to
any of the fluids tested. put too much emphasis on this finding as evidence of a
The assay for blastogenic stimulation factor was pos- hypersensitivity reaction t6#{149}

itive in only one patient (not the same one who had the In the experience of most investigators reporting on
false-positive assay for migration inhibition factor). In this avascular necrosis of bone, it has proved very difficult to
patient the test was positive in middle dilutions only, and correlate the site of the necrosis with occlusion of any
total stimulated counts were barely above the normal specific large blood vessels and it is not surprising that
range. We did not have enough material to further analyze small, occluded arterioles should be found in the margins
or purify the sample. of infarcts. However, it seems to us unwarranted to postu-
late a causal relationship between the occlusion and the
Discussion
necrosis.
None of the methods of investigation that we used Ifthe metal was causing hypersensitivity, it would be
supports the contention that delayed hypersensitivity to reasonable to expect that the inflammatory reaction might
metal is associated with or causes sterile loosening after be seen in proximity to the metal, but this was not noted in
McKee-Farrar total hip replacement. While patch-testing our patients.
is an accepted method for demonstrating delayed We think that our failure to demonstrate lymphokines
hypersensitivity and false-positive tests are not uncommon in the synovial fluid is further evidence that delayed hyper-
(the most common cause of error probably being a direct sensitivity was not present. The one positive assay out of
irritant effect of the tested substance), in no case did we nine tests in our study was obtained in a patient with
see erythema, induration, or vesiculation. Faulty reagents rheumatoid arthritis. The other four patients subjected to
and improper test application can result in false-negative lymphokine assay had osteoarthritis. It was recently re-
tests, and for this reason we cross checked our methods by ported that assays for migration inhibition factor and bIas-
applying the reagents in the same manner to patients with togenic factor are frequently positive in fluid from in-
known hypersensitivity - non-orthopaedic dermatology flamed rheumatoid joints 18#{149}Whether one would expect
patients - and those patients had positive test results. It the assays to remain positive after joint replacement is
was because of our early uniformly negative results that conjectural, but to attribute the one positive test to hyper-
we decided to use two different cobalt preparations, sensitivity is not justifiable, in our view.
although this meant calling many of the patients back for a Ifthe sterile loosening in these patients was not due to
second test. Cobalt chloride was the preparation used in hypersensitivity to metal, what could have caused it? 5ev-
two recent British reports5-’#{176}. In six of our patients the eral investigators reported that there are design weakness-
patch tests were applied after the cobalt-chromium es in the McKee-Farrar prosthesis 19.20_ specifically high
McKee-Farrar prostheses had been removed and implants frictional torque, especially when associated with equato-
of stainless steel had been inserted to replace them. How- nab contact, lack of force-damping, and metal-on-metal
ever, this should not negate the importance of our negative impingement at the extremes of motion.
patch tests, because an acquired hypersensitivity should Recently, Rae reported that particulate cobalt-metal
persist throughout life. It is also noteworthy that of the or cobalt-chromium alloy, when taken in by macrophages,
original twenty patients, eleven had replacement of damages the cells, allowing the release of lactic-acid de-
prostheses by models made of cobalt-chromium alloy hydrogenase. He also found that the concentration of in-
(nine Charnley-Mueller, one Aufranc-Turner, and one a tracellular glucose 6-phosphate dehydrogenase was de-
replacement only of the acetabular component with the creased in macrophages with ingested particles. Because
addition of a Vitallium-mesh cement restrictor). Of these this substance is a marker for the capacity of phagocytic
eleven patients, none had recurrence of loosening up to the activity of the cell, ingested particulate metal or alloy
time of writing, and this is further evidence that hypersen- could allow a large volume of debris to remain un-
sitivity to metal was not the cause of the loosening initial- phagocytized, and this might increase the possibility of
by. If it were, one would expect the rejection phenomenon late infection.
to be repeated. However, such a mechanism for an adverse effect
In this series, fourteen of the twenty loose prostheses in tissue of metal debris would not be attributable to de-
were loose on the acetabular side only. One would expect layed hypersensitivity.
loosening to occur on both sides if hypersensitivity was It should be emphasized that metallic wear products -

indeed the mechanism in effect. both those in the region of the implant itself and those car-
Evans and associates commented that the necrosis of ned elsewhere in cells of the reticuboendothelial system -

soft tissue and bone appears to be directly related to the present an enormous total surface area to surrounding
extent of obliterative changes in the vessels supplying body fluids. It is known that solid metals and alloys are in
those tissues. They observed fibrous intimal proliferation, equilibrium with surrounding fluids, with at least trace

VOL. 59-A, NO. 2, MARCH 1977

168 G. C. BROWN, M. D. LOCKSHIN, E. A. SALVATI, AND P. G. BULLOUGH

ionic concentrations of metals in the environment sur- concentration to penetrate the cutis and gain exposure to
rounding the implant The antigenic
6#{149} stimulus to the im- lymphoid cells in the dermis 8 Dermatobogical patch tests
munobogical system is not to any specific salt of the metal are designed so that the concentrations of the metal salts
but to the metal ion, which attaches to a large chemical being tested are safely beyond the threshold concentration
compound or protein and thus acts as a hapten. Similarly, for that particular salt, so that false-negative tests will not
in testing patients for metal sensitivity, the specific salt be obtained.
used is not important as long as that salt will be in a sol-
. . . . NOTE: The aulhcws are graleful Io Dr. A. A. Fisher. Clinical Professor ot Dermalology *1
uble form on the skln surface and will be in a high enough New York Lni%ersity. (or his helpful criocism.

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THE JOURNAL OF BONE AND JOINT SURGERY