Nadim J. Hallab

Metal Sensitivity in Patients with Orthopaedic Implants

All metals in contact with biological systems undergo corrosion. This electrochemical process leads to the formation of metal ions, which may activate the immune system by forming complexes with endogenous proteins. Implant degradation products have been shown to be associated with dermatitis, urticaria, and vasculitis. If cutaneous signs of an allergic response appear after implantation of a metal device, metal sensitivity should be considered. Currently, there is no generally accepted test for the clinical determination of metal hypersensitivity to implanted devices. The prevalence of dermal sensitivity in patients with a joint replacement device, particularly those with a failed implant, is substantially higher than that in the general population. Until the roles of delayed hypersensitivity and humoral immune responses to metallic orthopaedic implants are more clearly defined, the risk to patients may be considered minimal. It is currently unclear whether metal sensitivity is a contributing factor to implant failure.

Early failure of metal-on-metal bearings in hip resurfacing and large-diameter total hip replacement: A CONSEQUENCE OF EXCESS WEAR

Early failure associated with adverse reactions to metal debris is an emerging problem after hip resurfacing but the exact mechanism is unclear. We analysed our entire series of 660 metal-on-metal resurfacings (Articular Surface Replacement (ASR) and Birmingham Hip Resurfacing (BHR)) and large-bearing ASR total hip replacements, to establish associations with metal debris-related failures. Clinical and radiological outcomes, metal ion levels, explant studies and lymphocyte transformation tests were performed. A total of 17 patients (3.4%) were identified (all ASR bearings) with adverse reactions to metal debris, for which revision was required. This group had significantly smaller components, significantly higher acetabular component anteversion, and significantly higher whole concentrations of blood and joint chromium and cobalt ions than asymptomatic patients did (all p < 0.001). Post-revision lymphocyte transformation tests on this group showed no reactivity to chromium or cobalt ions. Explants from these revisions had greater surface wear than retrievals for uncomplicated fractures. The absence of adverse reactions to metal debris in patients with well-positioned implants usually implies high component wear. Surgeons must consider implant design, expected component size and acetabular component positioning in order to reduce early failures when performing large-bearing metal-on-metal hip resurfacing and replacement.

Metal release in patients who have had a primary total hip arthroplasty a prospective, controlled, longitudinal study

There is an increasing recognition that, in the long term, total joint replacement may be associated with adverse local and remote tissue responses that are mediated by the degradation products of prosthetic materials. Particular interest has centered on the metal-degradation products of total joint replacements because of the known toxicities of the metal elements that make up the alloys used in the implants. We measured the concentrations of titanium, aluminum, cobalt, and chromium in the serum and the concentration of chromium in the urine of seventy-five patients during a three-year prospective, longitudinal study. Twenty patients had had a so-called hybrid total hip replacement (insertion of a modular cobalt-alloy femoral stem and head with cement and a titanium acetabular cup without cement), fifteen had had insertion of an extensively porous-coated cobalt-alloy stem with a cobalt-alloy head and a titanium-alloy socket without cement, and twenty had had insertion of a proximally porous-coated titanium-alloy stem with a cobalt-alloy head and a titanium socket without cement. The remaining twenty patients did not have an implant and served as controls. The results of our study showed that, thirty-six months postoperatively, patients who have a well functioning prosthesis with components containing titanium have as much as a threefold increase in the concentration of titanium in the serum and those who have a well functioning prosthesis with cobalt-alloy components have as much as a fivefold and an eightfold increase in the concentrations of chromium in the serum and urine, respectively. The predominant source of the disseminated chromium-degradation products is probably the modular head-neck junction and may be a function of the geometry of the coupling. Passive dissolution of extensively porous-coated cobalt-alloy stems was not found to be a dominant mode of metal release. CLINICAL RELEVANCE: Increased concentrations of circulating metal-degradation products derived from orthopaedic implants may have deleterious biological effects over the long term that warrant investigation. This is a particularly timely concern because of recent clinical trends, including the reintroduction of metal-on-metal bearing surfaces and the increasing popularity of extensively porous-coated devices with large surface areas of exposed metal. Accurate monitoring of the concentrations of metal in the serum and urine after total hip replacement also can provide insights into the mechanisms of metal release. Our findings suggest that fretting corrosion at the head-neck coupling is an important source of metal release that can lead to increased concentrations of chromium in the serum. Determinations of the concentrations of metal in the serum and urine may be useful in the diagnosis of patients who are symptomatic after a total joint replacement as increased levels are indicative of at least one mode of mechanical dysfunction (for example, fretting corrosion) of the device.

Evaluation of metallic and polymeric biomaterial surface energy and surface roughness characteristics for directed cell adhesion.

Directed cell adhesion remains an important goal of implant and tissue engineering technology. In this study, surface energy and surface roughness were investigated to ascertain which of these properties show more overall influence on biomaterial-cell adhesion and colonization. Jet impingement was used to quantify cellular adhesion strength. Cellular proliferation and extracellular matrix secretion were used to characterize colonization of 3T3MC fibroblasts on: HS25 (a cobalt based implant alloy, ASTM F75), 316L stainless steel, Ti-6Al4V (a titanium implant alloy), commercially pure tantalum (Ta), polytetrafluoroethylene (PTFE), silicone rubber (SR), and high-density polyethylene (HDPE). The metals exhibited a nearly five-fold greater adhesion strength than the polymeric materials tested. Generally, surface energy was proportional to cellular adhesion strength. Only polymeric materials demonstrated significant increased adhesion strength associated with increased surface roughness. Cellular adhesion on metals demonstrated a linear correlation with surface energy. Less than half as much cellular proliferation was detected on polymeric materials compared to the metals. However the polymers tested demonstrated greater than twice the amount of secreted extracellular matrix (ECM) proteins on a per cell basis than the metallic materials. Thus, surface energy may be a more important determinant of cell adhesion and proliferation, and may be more useful than surface roughness for directing cell adhesion and cell colonization onto engineered tissue scaffoldings.

Osteolysis: basic science.

Since the recognition of aseptic loosening by Charnley in the early 1960s, much information has been gained on the basic science of periprosthetic bone loss. Initially termed cement disease, it now generally is accepted that, in most instances, osteolysis is a manifestation of an adverse cellular response to phagocytosable particulate wear and corrosion debris, possibly facilitated by local hydrodynamic effects. Tissue explant, animal, and cell culture studies have allowed us to compile an appreciation of the complexity of cellular interactions and chemical mediators involved in osteolysis. Cellular participants have been shown to include the macrophage, osteoblast, fibroblast, and osteoclast. The plethora of chemical mediators that are responsible for the cellular responses and effects on bone include prostaglandin E2, tumor necrosis factor-alpha, interleukin-1, and interleukin 6. However, an increasing number of other proinflammatory and antiinflammatory cytokines, prostenoids, and enzymes have been shown to play important roles in this process. The ultimate goal of basic research is to develop novel strategies for evaluation and treatment of patients with osteolysis. Although initial animal studies are promising for possible pharmacologic treatment and prevention of osteolysis, well-controlled human trials are required before agents such as bisphosphonates can be recommended for general clinical use.

Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans.

Background: The central and peripheral inflammatory response to surgery may influence patient outcomes. This study examines the time course and clinical relevance of changes in prostaglandin E2 and cytokines in cerebrospinal fluid, local tissue (surgical site), and circulating blood during and after total hip replacement. Methods: Thirty osteoarthritis patients undergoing primary total hip arthroplasty with spinal anesthesia were randomly allocated to three groups (n = 10/group): placebo for 4 days before surgery and on the morning of surgery; placebo for 4 days before surgery and oral rofecoxib 50 mg on the morning of surgery; oral rofecoxib 50 mg for 4 days before surgery and the morning of surgery. Cerebrospinal fluid and plasma were collected before surgery and up to 30 h after incision for measurement of prostaglandin E2 and interleukins. When hip replacement was complete, a drain was placed in the hip wound and exudates were collected at 3 to 30 h after incision. Results: Cerebrospinal fluid showed an initial increase in interleukin 6 and a later rise in prostaglandin E2 concentration after surgery; interleukin 1&bgr; and tumor necrosis factor &agr; were undetectable. Hip surgical site fluid evidenced an increase in prostaglandin E2, interleukin 6, interleukin 8, and interleukin 1&bgr;; tumor necrosis factor &agr; decreased at 24 and 30 h. Preoperative administration of the cyclooxygenase 2 inhibitor rofecoxib reduced cerebrospinal fluid and surgical site prostaglandin E2 and cerebrospinal fluid interleukin 6. Cerebrospinal fluid prostaglandin E2 was positively correlated with postoperative pain and cerebrospinal fluid interleukin 6 with sleep disturbance. Poorer functional recovery was positively correlated with increased surgical site prostaglandin E2. Conclusions: These results suggest that upregulation of prostaglandin E2 and interleukin 6 at central sites is an important component of surgery induced inflammatory response in patients and may influence clinical outcome.

Soluble and particulate Co-Cr-Mo alloy implant metals activate the inflammasome danger signaling pathway in human macrophages: a novel mechanism for implant debris reactivity.

Immune reactivity to soluble and particulate implant debris remains the primary cause of aseptic inflammation and implant loosening. However, the intracellular mechanisms that trigger immune cells to sense and respond to exogenous nonbiological agents such as metal particles or metal ions released from orthopedic implants remain unknown. Recent studies in immunology have outlined the importance of the intracellular inflammasome complex of proteins in sensing danger/stress signals triggered by nonbiological agents in the cytosol of macrophages. We hypothesized that metal implant debris can activate the inflammasome pathway in macrophages that causes caspase‐1‐induced cleavage of intracellular pro‐IL‐1β into its mature form, resulting in IL‐1β secretion and induction of a broader proinflammatory response. We tested this hypothesis by examining whether soluble cobalt, chromium, molybdenum, and nickel ions and Co‐Cr‐Mo alloy particles induce inflammasome‐ mediated macrophage reactivity. Our results demonstrate that these agents stimulate IL‐1β secretion in human macrophages that is inflammasome mediated (i.e., NADPH‐, caspase‐1‐, Nalp3‐, and ASC‐dependent). Thus, metal ion‐ and particle‐induced activation of the inflammasome in human macrophages provides evidence of a novel pathway of implant debris‐induced inflammation, where contact with implant debris is sensed and transduced by macrophages into a proinflammatory response.

Loosening and Osteolysis Associated with Metal-on-metal Bearings: A Local Effect of Metal Hypersensitivity?

Over the last several years, many orthopaedic surgeons have embraced so-called alternative bearing surfaces in total hip arthroplasty, largely on the basis of the hypothesis that a reduction in the volumetric wear rates afforded by these improved articulating couples will reduce the prevalence of osteolysis and aseptic loosening, which in turn will improve implant survivorship. The articles by Korovessis et al.1 and Milosev et al.2 in this issue of The Journal provide valuable new data on the intermediate-term performance of one metal-on-metal-bearing hip-replacement system. These studies show that this particular metal-on-metal system is not immune to osteolysis and aseptic loosening and further suggest that osteolysis and aseptic loosening may be mediated, at least in part, by an adaptive immune response (metal hypersensitivity) independent of, or in concert with, the relatively well-characterized innate immune response (particle-stimulated macrophage, fibroblast, and osteoblast-mediated inflammatory bone loss) typically associated with periprosthetic osteolysis3. Metal hypersensitivity-induced osteolysis and aseptic loosening represent underappreciated and incompletely understood mechanisms of implant failure. How strong is the evidence that the failures in these two cohorts at the time of intermediate-term follow-up (at a mean of seventy-seven months and eighty-five months) were due to metal hypersensitivity? It should be clearly understood that, at present, the evidence linking osteolysis and aseptic loosening with metal …

Spinal implant debris-induced osteolysis.

Study Design. Generally, implant-induced osteolysis is a manifestation of an adverse cellular response to phagocytosable particulate wear and corrosion debris. Initially termed “cement disease,” particle-induced loosening was recognized by Charnley in the early 1960s. Despite the plethora of information gained over the last 40 years on the basic science of periprosthetic bone loss, much remains unanswered. The effect of unintended debris resulting from wear and corrosion (e.g., micromotion between the interconnection mechanisms in spinal implants) remains a clinical concern. The current study highlights what is known of particle-induced osteolysis and how the presence of spinal implant particulate debris deleteriously influences osseointegration of posterolateral bone graft or disrupts an established posterolateral fusion mass. Tissue explant, animal, and cell culture studies have revealed the complexity of cellular reactivity involved in aseptic particle-induced osteolysis. Objectives. The objectives of this study are twofold: 1) to highlight the dominant cellular participants in total joint arthroplasty particle induced osteolysis, which are purportedly the macrophage, osteoblast, fibroblast, and osteoclast and several of the dominant chemical mediators have been identified as well, which include prostaglandin E2, tumor necrosis factor-alpha, interleukin-1, and interleukin-6; and 2) to demonstrate the potential deleterious effects of spinal implant debris using animal models and analysis of soft tissue surrounding spinal implants in symptomatic patients. Methods. There are a growing number of proinflammatory and anti-inflammatory cytokines, prostenoids, and enzymes that have been shown to play important roles in the pathology of particle-induced osteolysis. Reports that aseptic granulomatous inflammation typical of that associated with corrosion debris appear to correlate with the complexity of the implant. Titanium particulate material was used to induce effects in 34 New Zealand White rabbits where analysis included serological quantification of systemic cytokines. Postmortem microradiographic, immunocytochemical, and histopathologic assessment of the intertransverse fusion mass quantified the extent of osteolysis, local proinflammatory cytokines, osteoclasts and inflammatory infiltrates. Clinical analysis of 12 patients more than 0.4 years after spinal implants (mean 4.03, range 0.4 to 11 years) presented with late operative site pain. Results. Currently the etiology of this inflammation around spinal implants resembles particle-induced osteolysis around joint arthroplasties where there typically is a self-perpetuating fibroinflammatory zone adjacent to the implant, where macrophage exhaustion, reactive oxygen intermediates, and pro-inflammatory cytokines affect a host of local cell types and induce a widening zoneof soft tissue damage and inflammation. Animal model analysis indicated increased levels of local inflammatory cytokines typically associated with osteolysis—tumor necrosis factor-alpha. Osteoclast cell counts and regions of osteolytic resorption lacunas were higher in the titanium-treated versus autograft-alone groups (P < 0.05), and the extent of cellular apoptosis was markedly higher in the titanium-treated sites at both time intervals. Electron microscopy indicated definitive evidence of phagocytized titanium particles and foci of local, chronic inflammatory changes in the titanium-treated sites. Clinical cases: 11 of 12 clinical cases demonstrated elevated tumor necrosis factor-alpha levels and an increased osteoclastic response in the vicinity of wear debris caused by dry frictional wear particles of titanium or stainless steel. Resection of the wear debris and surrounding fibroinflammatory zone resolved clinical symptoms in all 12 cases. Conclusions. More basic science and clinical research is needed to develop novel strategies for gaining knowledge, and developing effective evaluation and treatment of patients with implant debris related osteolysis. Titanium debris simulating that produced by spinal implants introduced at the level of a spinal arthrodesis elicits an inflammatory cytokine mediated particulate-induced response through increased expression of intracellular TNF-&agr;, increased osteoclastic activity and cellular apoptosis. This study highlighted the association between spinal implants particulate wear debris and increased potential for osteolysis. Aseptic osteolysis is among the primary reasons for failure of orthopedic implants. Increased awareness of this destructive process is becoming more important with the growing popularity of total disc arthroplasty and highly modular spinal implants.

Differences in the fretting corrosion of metal–metal and ceramic–metal modular junctions of total hip replacements

The use of modular interlocking components is a central design feature of total joint replacements. In this investigation we hypothesized that clinically available ceramic–metal modular connections used in total hip arthroplasty release more metal through fretting corrosion than traditional metal–metal modular connections. This was investigated using an in vitro comparison of ceramic (zirconia, ZrO2) and metal (Co‐alloy) femoral‐head fretting upon Co‐alloy stem components. In vitro fretting corrosion testing consisted of potentiodynamic monitoring and analysis of metal release from zirconia and Co‐alloy 28 mm femoral heads with similar surface roughnesses (Ra = 0.46 μm) on identical Co‐alloy stems at 2.2 kN for 1 × 106 cycles at 2 Hz. In contrast to our original hypothesis, we found greater metal release (approximately 11‐fold increase in Co and 3‐fold increase in Cr) and potentiodynamic fretting of metal–metal modular junctions when compared to ceramic–metal. Potentiodynamic testing demonstrated that lower initial voltages (−266 < 153 mV), greater maximum voltage changes (116 > 56 mV, p < 0.05, t‐test) and voltage variability (3 > 0.5 mV, p < 0.05, t‐test) were associated with the open circuit potentials of Co‐alloy on Co‐alloy junctions when compared to zirconia on Co‐alloy junctions. In this study of a single total hip replacement stem and head design, zirconia heads mated with Co‐alloy stems produced less fretting than Co‐alloy heads mated with Co‐alloy stems. Although further studies are necessary with a variety of implant designs and under different experimental conditions, the evidence presented here should, in part, alleviate concerns of increases in fretting corrosion at modular junctions of ceramic–metal coupled components.