Sensitivity to implant materials in patients with total knee arthroplasties
Introduction
Total knee arthroplasty (TKA) has been a major advance in the treatment of knee disabilities, predictably achieving excellent results at a long-term follow-up with relatively low perioperative morbidity [1], [2]. In over 95% of patients TKA relieves pain, improves functional status, and restores most of their normal activities of daily living. In spite of the excellent outcome, TKA can fail over time, and the revision rate over 5 or more years is 2% of knees and 2.1% of patients [1]. TKA failure is generally multifactorial even though the main reasons may be ascribed to mechanical and biological causes [3], [4]. Chronic inflammation following the generation of wear particles has been recognized as the main biological mechanism leading to implant failure [5]. Moreover, if degradation products are able to interact with the immune system, undesirable immunotoxic effects may be induced, including a delayed-type hypersensitivity reaction (DTH) [6], [7], [8], [9]. Metals and acrylic cements represent the main components of TKA: in contact with biological fluids they undergo corrosion and wear, and metal ions or other molecules may induce a DTH [10]. Nickel, cobalt, and chromium are known to be the most common sensitizers, [9], [11] but also hypersensitivity to titanium and vanadium has been described [12], [13]. Polymeric biomaterials, namely acrylic bone cements, are not easily chemically degraded and immunogenic reactions to poly-methyl-methacrylate or other constituents have been occasionally reported [14]. The possible correlation between hypersensitivity and implant failure has been previously investigated, but the main question about the cause–effect relationship between these events has not yet been solved.
One of the major difficulties in understanding the clinical implications of hypersensitivity to the implant components is the lack of universally accepted testing methods [15]. Several in vitro tests based on the reactivity of immune cells to metal–protein complexes have been proposed in diagnosing a systemic hypersensitivity to the implant components [11], [16], [17], but they have some faults that limit large-scale application, including the high costs and the need to be performed in qualified laboratories. In addition, the number of immune cells recruited from biological samples does not allow an exhaustive assay of all the immunogenic substances contained in metal alloys and bone cements, and the elevated toxicity of some chemicals often hampers their in vitro testing [11], [18]. Alternatively, the in vivo approach, i.e. the epicutaneous skin-testing (patch testing), is cheap and allows to estimate simultaneously several haptens [19]. Although patch testing is the most common method used to diagnose contact allergy to metals, its validity in determining a deep-tissue hypersensitivity lets some doubts [10], [11]. Nevertheless, its usefulness in detecting the sensitization to implant materials may be improved if patients are tested with an appropriate series of haptens according to the prosthesis components [19], [20].
An additional limit in establishing the role of the sensitivity to the implant components is the paucity of clinical studies providing clear data of a connection between metal sensitivity and outcome of the implant [15]. The majority of investigators suggest that hypersensitivity can be a contributing factor to implant failure, because of the high proportion of metal DTH in patients with prosthesis loosening [10], the shorter lifespan of the implant in patients having positive patch testing [19], and the histological findings of hypersensitivity-like reaction in tissue around the artificial joint, especially in metal-on-metal bearings [21], [22], [23], [24], [25]. Most studies have been performed in cohorts of patients undergoing a total hip arthroplasty (THA) [10], while few data are available for patients with TKA [9]. From a theoretical point of view, the proportion of positive skin reactions in patients with TKA could differ from those observed in THA for several reasons, including the biomechanics of the joint influencing the metal ion release.
The main goals of our pilot study were to evaluate (i) the frequency of skin sensitization in patients who had undergone TKA, and (ii) the clinical impact of this event on the outcome of the implant. For this purpose we chose to use patch testing by applying a panel of haptens representative of cobalt-based alloys (CoCrMo), titanium-based alloys (TiAlV), and bone cements.
Section snippets
Study design
Ninety-four Caucasian individuals were enrolled in this retrospective case–control study. The study design was approved by the institutional ethical committee on human research and signed informed consent was obtained from the patients. The sample size was calculated on the basis of the literature data considering the prevalence of sensitization in general population and the mean value of the sensitization frequency recorded in patients undergoing total joint replacement [10], [11], [19]. A
Sensitization and status of the implant
The frequency of skin positive reaction was not influenced by age or presence of other implants, but in all groups females showed a higher percentage of positive patch testing (data not shown). The frequency of positive skin reactions to at least one hapten (metal or cement) was significantly higher in group of patients tested after TKA (No Implant 20%, TKA 55.4%; Chi square 7.9, p = 0.005), and no differences were observed between stable and loosened implants (Stable TKA 48.1%, Loosened TKA
Discussion
In this study, we evaluated the frequency of sensitization in patients undergoing TKA. In absence of universally accepted tests to diagnose hypersensitivity to the implant components [15] we chose the in vivo approach by using patch testing, which presents some evident benefits, i.e. no specific facilities are necessary to perform the analysis, it is suitable for large-scale screening, and it allows the simultaneous evaluation of all the immunogenic substances which may be contained in the
Conclusions
Materials used for TKA are well known for their good biocompatibility, but the corrosion of the implant components and metal ion release may elicit an immune response in patients undergoing TKA. The frequency of positive skin reactions increased significantly after TKA, but the clinical impact of this event on the implant failure has not been proved, because no significant differences were found between stable and loosened prostheses. The only risk factor in our analysis was the presence of a
Acknowledgments
Funded by grants from Italian Ministry of the Health for the National Hospitals and Research Institutes (Ricerca Corrente). The study is part of the activities of the European Cooperation in the field of Scientific and Technical Research (COST), Action 537 “Core laboratories for the improvement of Medical Devices in Clinical Practice from the Failure of the Explanted Prostheses Analyses (FEPA)”.
References (38)
- et al.
Why knees fail: lessons learned
J Arthroplasty
(2004) Importance of immunotoxicity in safety assessment: a medical toxicologist's perspective
Toxicol Lett
(2004)- et al.
Screening for sintomatic metal sensitivity: a prospective study of 92 patients undergoing total knee arthroplasty
Biomaterials
(2005) - et al.
Lymphocyte responses in patients with total hip arthroplasty
J Orthop Res
(2005) - et al.
Expression of the CD69 activation antigen on lymphocytes of patients with hip prosthesis
Biomaterials
(2000) - et al.
Granulomatous reaction to titanium alloy: an unusual reaction to ear piercing
J Am Acad Dermatol
(2006) - et al.
Total knee replacement
Evid Rep Technol Assess
(2003) NIH consensus statement on total knee replacement December 8–10, 2003
J Bone Joint Surg Am
(2004)- et al.
Aseptic loosening, not only a question of wear: a review of different theories
Acta Orthopaedica
(2006) - et al.
Inflammatory response to metals and ceramics
Guidance for industry and FDA reviewers – immunotoxicity testing guidance
Immunological changes in patients with primary osteoarthritis of the hip after total joint replacement
J Bone Joint Surg Br
Metal sensitivity in patients with orthopaedic implants
J Bone Joint Surg Am
Sensitivity to titanium. A cause of implant failure?
J Bone Joint Surg Br
Allergy to components of total hip arthroplasty before and after surgery
Ital J Orthop Traumatol
Hypersensitivity in aseptic loosening of total hip replacements. The role of constituents of bone cement
J Bone Joint Surg Br
Loosening and osteolysis associated with metal-on-metal bearings: a local effect of metal hypersensitivity?
J Bone Joint Surg Am
Validity of MELISA for metal sensitivity testing
Neuroendocrinol Lett
Assessment of metal extract toxicity on human lymphocytes cultured in vitro
J Biomed Mater Res
Cited by (159)
The influence of cross shear and contact pressure on the wear of UHMWPE-on-PEEK-OPTIMA™ for use in total knee replacement
2023, Journal of the Mechanical Behavior of Biomedical MaterialsAdvancement in oral pharmacokinetics of an antibiotic Cefixime using amphiphilic 4-armed macrocyclic surfactant based niosomes
2023, Arabian Journal of ChemistryInfluence of surface finishing and heat treatments on the corrosion resistance of LPBF-produced Ti-6Al-4V alloy for biomedical applications
2022, Journal of Materials Processing TechnologyClinical Results of Revision TKA in Patients With Presumed Metal and Cement Allergy
2022, Journal of Arthroplasty