Metal Ion Sensitivity

  • William M. MihalkoEmail author
  • Catherine R. Olinger
Living reference work entry


Metal hypersensitivity to biomaterial alloys have been reported since the 1970s. While most reports have been in the total joint literature, in the last 10 years isolated spinal implant reactions have been reported. Much of this is because spine implants have been developed with bearing surfaces that may be a trigger for sensitizing patient from the local wear debris. Reaction to metal alloys and debris is a type IV hypersensitivity immunologic reaction in that it does not produce anaphylaxis. The adverse local tissue reactions (ALTR) around the implant can be substantial and lead to further surgery. The metal alloys used in spinal implants typically have an oxide passivation layer that can protect the body from these local reactions, but any type of fretting from modular connections of wear from a metal bearing can lead to exposure of the alloy below the passivation layer and be the trigger to the start of a reaction leading to ALTR.

Knowing the frequency of these sensitivities in the general population can help surgeons identify hypersensitive patients and notify them of the possible risk.


Biomaterial Metal alloy Passivation layer Hypersensitivity 


Metal hypersensitivity to biomaterial alloys has been reported since the 1970s. While most reports have been in the total joint literature, there also are case reports of spinal implant reactions in the last 10 years. Reaction to metal alloys and debris is a type IV hypersensitivity immunologic reaction that does not produce anaphylaxis. The adverse local tissue reactions (ALTR) around the implant can be substantial and lead to further surgery or significant morbidity. Knowing how common these sensitivities are in the general population, understanding the physiology of metal hypersensitivity, identifying appropriate testing protocols, and recognizing clinical signs of sensitivity can help surgeons properly diagnose this uncommon complication and notify patients of the possible risk of ALTR.

Metal Hypersensitivity Physiology

The pathophysiology behind metal hypersensitivity is a type IV hypersensitivity or delayed type hypersensitivity reaction. When a hypersensitivity reaction occurs, activated T-lymphocytes react to a foreign antigen presented via co-stimulatory molecules, which play a critical role in sustaining the chronic inflammatory response (Goodman 2007). Through this inflammatory cascade, T-lymphocytes CD4 and CD8 cells are activated and release a multitude of cytokines including IFN-gamma, IL-1, IL-6, and TNF-alpha (Merritt and Brown 1980).

The immune system can mount an adaptive or innate immune response to metal debris. The innate or nonspecific foreign body reaction is composed primarily of macrophages, foreign body giant cells, fibroblasts, and occasional lymphocytes. The aggressive inflammatory granulomatosis found in the monocyte-macrophage mediated clearance of debris is normally followed by the resolution of the reaction via the fibroblast mediated synthesis of remodeling the extracellular matrix. Metal implants may have osteoclasts that line the bone implant interface and in the presence of metallic or bearing debris the tissue may have high levels of proinflammatory cytokines, indicating an immune response that can put the longevity of the implant at risk (Goodman 2007). Animal models of exposed rabbits with implanted nickel demonstrated tissue reaction to screws with inflammatory cells and macrophages in induced sensitivity models (Merritt and Brown 1980). A combination of both innate and acquired immune response has been elucidated in the metal hypersensitivity reaction pathway.

In the case of metal hypersensitivity, the foreign antigen is metal debris from an implanted medical device. Metal wear degradation products combined with serum proteins form haptens. Haptens are then recognized via antigen presenting T-cells and initiate the activated T cell cascade. This activation of T-cells locally produces an inflammatory response and lessens circulating T cells. One study demonstrated that the serum analysis of patients with aseptic loosening showed decreased levels of circulating T-cells indicating an inflammatory consumptive process (Goodman 2007).

Proposed intracellular indigestible particles, via metal implant debris, together with elevated costimulatory molecule expression via antigen presenting cells and macrophages, promote T-cell inflammatory reactions in the surrounding tissues. Cobalt-chromium (Co-Cr) alloys are common metal compounds used in spinal implants. In vitro proliferation of cellular responses to Co-Cr has been found to be significantly higher in patients with revision surgery for aseptic loosening compared to patients with revision for infection. Furthermore, patients demonstrated higher proliferative responses and cytokine production in response to Co-Cr challenge postoperatively after total joint replacement (TJR) than preoperatively (Goodman 2007).

Tissue samples from retrieved failed implants that formed pseudocapsules around metal implants have been analyzed for inflammatory cells. One study examined 123 tissue samples excised from reoperations for loosening, fracture, or mechanical irritation (infections were excluded). The removed pseudocapsule represented a crude joint capsule of scar tissue without defined layers. The inflammatory response to foreign bodies inside the fibrous tissue was characterized pathologically as granulation tissue. This inflammatory tissue was surmised to be from production of continual foreign material from wear particles. Patients with retrieved tissue from loosening had a marked tendency towards fibrosis, which gave rise to numerous lymphoplasmacellular infiltrations surrounding the implants (Willert and Semlitsch 1977). Metal hypersensitivity-induced osteolysis and aseptic loosening have been suggested to represent an underappreciated and ignored subset of failure mechanisms within TJR (Jacobs and Hallab 2006).

Knowing the mechanism behind these reactions in aseptic lymphocytic vasculitis-associated lesion (ALVAL) from metal-on-metal hip prosthesis is important since similar bearings are now being used in spinal implants. Patients deemed to have either a high- or low-wear pattern were identified and during retrieval had tissue analysis regarding the ALVAL score as determined by the histologic scoring of the synovial lining, inflammatory infiltrate, and tissue organization (low, 0–4; moderate, 5–8; high, 9–10). Tissues from patients who had revisions for suspected high wear had a lower ALVAL score, fewer lymphocytes, more macrophages, and more metal particles than tissues from patients who had revisions for pain and suspected metal hypersensitivity (Campbell et al. 2010). The characterization of the type of local tissue response and the patient’s presenting symptoms of pain and dermatitis could help differentiate between metal type IV hypersensitivity reaction and metal-on-metal ion release from failed components (Verma et al. 2006).

Total joint literature has demonstrated periprosthetic pseudocapsule tissues harvested from failed TJR implants containing titanium and Co-Cr alloy to have pathologic demonstration of abundant macrophages containing titanium particles, numerous T-cells, but few B-cells. This pathologic evaluation was further used with tissue marker enzyme-linked immunosorbent assay (ELISA) studies in these samples for T-cell markers Cd11c, CD25, IL-2R, HLA-DR, CD35, CD36, CD2, and CD22. IL-2 was used as the main cell marker for activated T-cells in this population (Goodman 2007). The type IV hypersensitivity response surrounding failed arthroplasties has been supported by the presence of activated T-cells in vivo, and both pathologic and ELISA testing confirms their presence in these tissues.

Osteolysis mechanisms surrounding failed aseptic TJR have been investigated on the cellular levels. Receptor activator of nuclear factor-kappa B (RANK) production, determined by ELISA testing of harvested pseudocapsule tissue in failed implants, has been shown to be increased, as have abnormally high levels of RANK. The RANK-RANKL mediation has been shown to contribute substantially to aseptic implant loosening. Activation of this pathway via the type IV hypersensitivity response has been elucidated. Activated T-cells have been shown to express RANKL activating osteoclastogenesis. TNF-a and IL-1 are pro-inflammatory cytokines present in type IV hypersensitivity reactions that also upregulate the expression of RANK/RANKL (Holt et al. 2007).

Other cytokines have been demonstrated to contribute to bone homeostasis surrounding metal implants. IL-18 is a novel cytokine involved in the role of disturbance in bone homeostasis observed in numerous systemic disorders, specifically inflammatory arthritis. It initially was characterized in properties of acquired immune response via activated T1 and T2 helper cells. After inflammatory responses are initiated, IL-18 is widely distributed, even in pseudocapsules from retrieved failed implants, as identified by PCR/ELISA testing (Goodwin et al. 2018).

The method of reaction to metal hypersensitivity in vivo may be a combination of several factors. Local inflammatory responses to the presence of metal alloys are recognized by the innate immune response, leading to T-cell activation, inflammatory cytokine production, osteolysis, and loosening via RANKL/RANK activation. Loosening of the implant-bone surface can lead to further wear debris and propagation of this cascade.

Implant Sources of Particulate Debris

Mechanisms that produce increased metal hypersensitivity require a nidus for metal debris. Metal implant wear can produce local tissue infiltration of metal ions and particles. Wear involves the loss of the material (mass) as a consequence of relative motion between two surfaces. Gravimetric wear is measured by the weight loss of the individual component after simulator or retrieval in vivo use. The amount of wear depends on two factors: the amount of force pressing the two materials together and the type or amount of lubrication between the two surfaces (Hallab 2009).

Wear is a mechanical or physical degradation of materials characterized as either abrasive or adhesive. The primary sources of articulating wear debris from hard-on-hard material couples, such as metal-on-metal articulations, generally produce less wear (volumetric loss) than metal-on-polymers. Corrosion is a chemical or electrochemical form of degradation of metal implants. Implant corrosion reduces structural integrity and causes release of by-products that interact locally and systemically. Stainless steel alloys generally corrode to a greater extent than cobalt or titanium. Fretting corrosion can take place at mechanical connections between implants. This is a common occurrence in spinal reconstructive surgery. With this kind of fretting in spinal instrumentation, chemical degradation is enhanced by mechanical factors such as a crevice and abrasive wear. Corrosion products typically are oxides, metal phosphates, metal salts, metal-ions bound to proteins, or organometallic complexes (Hallab 2009).

Implant debris types can be characterized as particles or ions. Particulate wear debris (metal or ceramic) exists from the submicron size up to thousands of microns in size. Soluble debris is limited to metal ions that are bound to plasma proteins. The most numerous particulate debris to measure is typically less than 1 μ in size. Particles generated in simulator studies of articulating spinal implants match the sizes and types of particles produced from hip and knee arthroplasty. Metal-on-metal articulations generally produce smaller-sized (submicron) fairly round debris, whereas traditional metal-on-polymer bearings produce larger (micron) debris that is more elongated in shape (Hallab 2009). Polymeric particles produced from implants generally fall into the range 0.23–1 μ. During articulating implant studies, 70– 90% of recovered particulates were submicron, with the mean size being 0.2–1 μ. Newer polymer implant debris from highly cross-linked polymers have demonstrated the production of smaller, more rounded debris in the submicron range as small as 0.1 μ (Hallab 2009).

Metal-on-metal particles are one to three orders of magnitude in number over those produced by metal-on-polymer articulating surfaces, but with far less volume. Cobalt alloy corrosion mechanisms also produce a chromium phosphate hydrate-rich material termed “orthophosphate,” which ranges in size from submicron to aggregates of particles up to 500 μ. Low-angle laser light scattering (LALLS) can perform particulate characterization and increase the number of counted and sized particles from hundreds to millions. It is important to perform a number-based and volume-based analysis. Ability to accurately and comprehensively characterize implant debris is important where weight loss from the implant after a year of use (<0.2 mm3 volume loss) could be attributed to the loss of a relatively few large particles or hundreds of millions of small particles (Hallab 2009).

For soluble metal ions, metal levels measured in people with disc arthroplasties have comparable levels of circulating metal ions as people with TJR. Normal human serum levels of prominent implants metals are approximately
  1. (a)

    1–10 mg/mL AL

  2. (b)

    0.15 ng/mL Cr

  3. (c)

    <0.01 ng/mLV

  4. (d)

    0.1–0.2 ng/Ml Co

  5. (e)

    <4.1 ng/mL Ti


Recent studies of metal-on-metal total disc arthroplasty found serum levels of Co-Cr to concentrations of 3–4 ng/mL Co, 1–2 ng/mL for Cr (Guyer et al. 2011; Hallab et al. 2003; Seo et al. 2016). The concentrations of circulating Co-Cr metal in serum with total disc arthroplasty are similar to levels measured in well-functioning metal-on-metal THA. This has not been demonstrated in nonarticulating implants, where recent studies have failed to detect elevated amounts of Cr or Ni from stainless steel scoliosis rod fixation (Hallab 2009).

In vitro assessment of ion levels from spinal implants with 20% volumetric wear in comparison between serum and saline testing found 1000-fold more particles in saline testing, demonstrating a protective effect of serum proteins and demonstrating a worst case scenario in saline testing (Hallab et al. 2008).

Implant Debris Physical Attributes and Local Physiological Response

Particle-sizing techniques such as scanning electron microscopy (SEM) or transmission electron microscopy can determine the size of the wear particles ranging from nanometer to submicron range. New low-angle laser light scattering (LALLS) techniques sample millions to billions of particles that determine the significant portion of the total mass loss (the total amount of debris). A volume-based analysis that also can characterize implant debris with a number bases is very important, where different samples of particles look demonstrably very different when viewed as a volume-based distribution compared to number-based distribution. Collected metal particles are characterized for size and number by laser diffraction technology and have a mean diameter of less than 10 μ, usually approximately 1–2 μ with a size range of 1–10 [ (Garcia et al. 2020)].

General particle characteristics on which local inflammation has been shown to depend are particle load (particle size and volume), aspect ratio, and chemical reactivity. (Bio Reactivity index: particle load x aspect ratio x material type x K unknown). Greater particle load can increase inflammation and is directly correlated to the concentration of phagocytosable particles per tissue volume. The degree to which equal numbers (dose) of large versus small particles (10 μ vs. 1 μ) induce an inflammatory response on a per-particle basis in vivo has not been thoroughly investigated. However, some studies have shown that in equal amounts of debris mass, small particles (0.4 μ) produced a greater inflammatory response than larger (7.5 μ) particles (Hallab 2009).

Elongated fibers are more pro-inflammatory than round particles. Currently, fibers can be categorized as particles with an aspect ratio greater than 3 to be more inflammatory. More chemically reactive particles are more pro-inflammatory. Despite reported differences, there is a growing consensus that metallic particles that are capable of corroding and releasing ions are associated with hypersensitivity responses, cytotoxicity, and DNA damage. Thus, they are more capable of eliciting proinflammatory responses than relatively inert polymers and ceramics (Hallab 2009).

To produce an in vitro inflammatory response, particles need to be less than 10 μ that are within phagocytosable range. Particle mean sizes of 0.2–10 μ are generally the most proinflammatory. The relationship between bacteria and aseptic loosening has been inferred because antibiotic-eluting bone cement and systemically administered antibiotics reportedly reduce the frequency of aseptic loosening (Hallab 2009).

Implant debris from wear causes local inflammation and granulomatous invasion of bone-implant contact that, over time, results in implant loosening and pain, necessitating revision in total joint arthroplasty. Implant debris is known to cause inflammation, osteolysis, and, in some cases, hypersensitivity and concerns persist about implant debris becoming carcinogenic or toxic. Other systemic conditions from implant debris, such as renal failure, have been reported in patients with Co, Cr levels over 100-fold in comparison with individuals with stable prostheses with no aseptic loosening.

Metal debris becomes antigens for T-cell recognition. Once debris is ingested by macrophages and other peri-implant cells, host pro-inflammatory reactions occur, such as activation of metal reactive T-cells. Cobalt-chromium-molybdenum (CoCrMo) alloy debris form metal protein complexes that activate the macrophage inflammasome pathway. CoCrMo alloy debris has been shown to induce macrophage activation, which stimulates secretion of IL-1b TNFa, IL-6, IL-8, and upregulates NFKb and downstream inflammatory cytokines (Mitchelson et al. 2015). Titanium particles induced IL-8, monocyte chemoattractant protein-1 (MCP-1). The study demonstrated that osteoblast chemokine expression with increased NFKB inducing osteoblast activated periprosthetic osteolysis (Fritz et al. 2006).

Biologic reactivity to spinal implant debris has been clinically observed with all the hallmarks of traditional particle-induced osteolysis; granulomatous epithelioid membranes coating the metal implants have been reported, similar to the fibrous membranes associated with loose total hip replacements. Case reports of painful granuloma associated with spinal implant debris demonstrate that spinal implant debris-induced inflammation can result in bone destroying granuloma (Hallab 2009). There are relatively few reports of human retrieval studies of loose spinal implants, but granulomatous epithelioid membranes coating the metal implants, similar to the fibrous membranes associated with loose total hip replacements, have been identified. Metallosis often accompanies metal implant debris-related osteolysis, aseptic fibrosis, local necrosis, or loosening (Hallab 2009).

In a cohort of 12 loosened spinal implants, metallosis of the internal membrane was associated with the outer layer of membrane containing an infiltrate of leukocytes and macrophages and all 12 patients had radiolucency around part of the spinal instrumentation. During the study, 11 of 12 patients demonstrated elevated TNFa levels and an increased osteoclastic response in the vicinity of wear debris caused by dry frictional wear particles of titanium or stainless steel. The focal areas of osteolysis involved loose transverse connectors. Removal of the loose metal implants and tissue surrounding them in the fibro-inflammatory zones resulted in resolution of clinical symptoms in all 12 patients (Hallab 2009).

Particles activate macrophages that secrete TNFa, IL-1b, IL-6, IFNgamma, and PGE2, stimulating differentiation of osteoclast precursors into mature osteoclasts and increasing periprosthetic bone resorption. Wear debris particles also have been shown to compromise mesenchymal stem cell differentiation into functional osteoblasts, and particles can directly inhibit collagen synthesis by mature osteoblasts and induce apoptosis of osteoblasts (Hallab 2009). Protein chip assays of ELISA performed on resected inflammatory tissue surrounding failed arthroplasty demonstrates local increase in IL-6, IL-8 cytokines, driving local osteoclastogenesis and osteolysis (Shanbhag et al. 2007).

The release of IL-1b is a powerful inflammatory cytokine response. Co-Cr-Mo alloy particles were found to activate the inflammatory pathway in part through NADPH-mediated monocyte macrophage production of reactive oxygen species. Activation of the inflammatory pathway leads to cleavage of intracellular pro-IL-1b and pro-IL-18 into their mature forms and ultimately leads to their secretion of pro-inflammatory responses through autocrine and paracrine activation of NFKb, which initiates a powerful pro-inflammatory response. The identification of the inflammatory involvement in particle and metal ion-induced inflammation will likely provide new therapeutic strategies to pharmacologically treat implant debris-induced inflammation and hypersensitivity by specifically interrupting the initiation of the inflammatory response that leads to aseptic osteolysis (Hallab 2009).

Systemic Response to Metal Debris and Prevalence in the General Population

Debris-induced systemic effects with implant metals such as Co, Cr, V, and possibly Ni are rare and typically occur with extremely high serum levels of Co. Distant organ levels of cobalt have been found at necropsy with both total hip and knee implants (Arnholt et al. 2020; Urban et al. 2000, 2004). Isolated cases of cardiomyopathy, optic neuritis, and neuropathies from a failing implant have been reported after metal-on metal total hip replacements (Choi et al. 2019; Devendra and Kumar 2017; Garcia et al. 2020; Goodwin et al. 2018; Mikhael et al. 2009; Mosier et al. 2016; Runner et al. 2017; Sabah et al. 2018; Sanz Pérez et al. 2019). A review of the literature, however, does not produce reports of such high levels or systemic symptoms from spinal implants. Neuropathic effects have been reported around both well-functioning and failing articulating implants, but these were generated from a granulomatous response to implant debris and not directly from the implant debris. Inflammation of unknown etiology associated with spinal implants has been shown to resolve after implant removal (Hallab 2009; Zielinski et al. 2014).

Metal hypersensitivity is well documented in case reports and group studies, though overall it remains a relatively unpredictable and poorly understood phenomenon in the context of orthopedic spinal implants. The specific T-cell subpopulations, the cellular mechanism of recognition and activation, and the antigenic metal-protein determinants created by these metals remain incompletely characterized. Nickel is the most common metal sensitizer in humans, followed by Co and Cr. The prevalence of metal sensitivity among the general population is approximately 10–15%, with nickel sensitivity as the highest. Clinical studies of metal implant-related sensitivity link immunogenic reactions with adverse performance of metallic cardiovascular, orthopedic, plastic surgical, and dental implants (Merritt and Brown 1980). Dermatitis, urticaria, and itching, round red wheals, and/or vasculitis have been linked with the relatively more general phenomena of metallosis, excessive periprosthetic fibrosis, and muscular necrosis. Hypersensitivity reactions associated with stainless steel and cobalt alloy implants are more severe than those associated with titanium alloy components (Hallab 2009).

Specific types of implants with a greater propensity to release metal in vivo may be more prone to induce metal sensitivity, as has been shown in metal-on-metal total joint arthroplasty. Spinal implants have been rarely implicated in case reports or group studies of hypersensitivity; thus, metal lymphocyte transformation testing (LTT) prior to receiving an implant may be warranted for people with a history of metal allergy (Hallab 2009).

Toxicity investigations of implant-related metal toxicity include a variety of cell types, including fibroblasts endothelial cells and nonhuman osteoblast like cells, but these generally have been limited to in vitro studies and animal studies. Concentrations at which this will occur are not known and the degree to which soluble metals are able to contribute induced toxic effects will likely be difficult to distinguish from well-established pro-inflammatory effects of metal particles (Hallab 2009).

While reports of titanium hypersensitivity are absent in the total joint literature, there is a case report of one patient with titanium metal hypersensitivity following VEPTR rod insertion for congenital scoliosis confirmed with testing; symptoms improved with removal of the rod (Zielinski et al. 2014). Testing of a carbon coated VEPTR rod was undertaken with rod desensitization under the skin in the forearm for a 3-month trial. The patient tolerated the carbon rod and the metal rod was replaced with a VEPTR carbon-coated implant. No documented hypersensitivity was found following reimplantation with the carbon-coated implants (Zielinski et al. 2014).

Testing for Metal Hypersensitivity

In 2012 the dermatology literature published a report stating that all patients should be patch tested for skin sensitivity before any elective surgery using a metal orthopedic device. A rebuttal of this practice was published soon after, pointing out multiple issues with patch testing as a gold standard for diagnosing metal hypersensitivity. The skin reactions are driven by a dendritic cell called the Langerhans cell. These cells are not what drive the deep tissue reactions that are seen around implants. There have been reports in knee replacement patients showing no correlation to skin patch results and outcomes of patients who test positive for the metal in the alloy of the implant (Bravo et al. 2016). There also are multiple reports of patients changing their skin patch test results from negative to positive after undergoing a total hip or knee replacement. The incidence of sensitization to metals in orthopedic implants by patch testing increased by 6.5% following hip and knee arthroplasty (Mihalko et al. 2012). Sensitivity to Ni, Co, Cr was 25% in well-functioning implants; this is more than twice the rate in the normal population. In patients with a failed or failing hip prosthesis, the rate of metal sensitivity rises dramatically to 60% or six times that of the general population (Hallab et al. 2001). Nickel is the metal that most often leads to hypersensitivity reaction and studies place the prevalence of nickel sensitivity in the general population between 8% and 25% (Mitchelson et al. 2015).

While a skin patch test may be helpful in the identification of a patient with a metal hypersensitivity, there remains no proof that routine screening will make a difference and may complicate treatment plans for many patients who otherwise will have no reaction to their implants after surgery. There are other options for identifying patients who may be at risk. Testing for hypersensitivity with lymphocyte transformation testing (LTT) in vitro involves measuring the proliferative response of lymphocytes obtained from peripheral blood by routine blood draw (Hallab 2009). Testing for metal sensitivity with metal-LTT testing generally is preferable since there is no subjectivity to the results as in skin patch testing. LTT testing is better suited for the testing of implant-related sensitivity because there is no risk of inducing metal sensitization using skin exposure, thus metal-LTT is highly quantitative (Hallab 2009).

Cutaneous patch testing is considered by some to be the gold standard for in vivo evaluation of delayed hypersensitivity reactions. It can be argued to be invalid because of the differences in antigen presentation between superficial and deep tissue responses in delayed type hypersensitivity reactions (Mitchelson et al. 2015). Some physicians also suggest that it can be subjective as far as grading dermal reactions from 1 to 3 (Merritt and Brown 1980).

One study has demonstrated that despite six positive skin tests before implantation of metal-on-metal (MOM) hip, five patients subsequently lost their sensitivity with repeat skin testing. All patients had good clinical outcomes with no evidence of loosening (Jacobs and Hallab 2006). Another disadvantage of patch testing is that the process of in vivo patch testing could potentially induce sensitization in a previously nonsensitized patient (Mitchelson et al. 2015). Patients’ patch test results will shift from negative to positive after joint replacement surgery, suggesting that in vivo metal exposure can cause sensitization (Merritt and Brown 1980).

Postoperative patch testing has been advocated in patients presenting with suspected metal hypersensitivity implant failure in the absence of infection (Mitchelson et al. 2015). The rate of positive patch test results to metals is highest in patients with MOM implants and in those with failed prosthesis (Ooij et al. 2007). Regular preoperative skin testing is not supported; in patients with 21 positive patch results, hypoallergenic TKA components produced no hypersensitivity reactions (Mitchelson et al. 2015). A correlation has been established between patients who had poor outcomes after TKA and positive skin patch testing that indicated metal sensitivity (Maldonado-Naranjo et al. 2015). Routine screening for metal hypersensitivity prior to TKA is not supported by the literature.

Lymphocyte transformation testing (LTT) involves measuring the proliferative response of lymphocytes, following activation, by using a radioactive marker added to patients spun down lymphocytes along with the desired agent (the metal ions) measured in counts per minute of stimulation (Hallab et al. 2001). LTT can be used as an alternative method to determine metal sensitivity by in vitro testing of sensitivity via venipuncture. It has been found to be more sensitive than patch testing and is highly quantifiable and reproducible. LTT does NOT confer sensitization to the patient as does patch testing, and LTT prior to arthroplasty may be effective as a preoperative screening tool for metal hypersensitivity.

In vitro leukocyte migration testing can be performed by capillary tube testing with leukocyte migration in response to antigen, membrane migration, leukocyte migration agarose technique, and collagen gel electrophoresis (Hallab et al. 2001).

Implantable metal testing for sensitivity has not established guidelines regarding the depth or duration of subcutaneous metal implantation as screening tests for hypersensitivity (Mitchelson et al. 2015). The timing of implantable metal testing is not supported in all TKA/THA patients and has only been found to be indicated in patients with a history of a metal allergy or previous aseptic orthopedic implant failure. Postoperative testing should be limited in patients with allergic contact dermatitis, arthralgia, and radiolucencies surrounding the implant or aseptic loosening without infection (Mitchelson et al. 2015).

Routine use of radiographs is supported for identification of periprosthetic radiolucent lines or aseptic loosening after TKA/THA (Mitchelson et al. 2015). Loosening or fracture of spinal implants has not been routinely documented in metal hypersensitivity reactions in the literature.

Risk Factors for Metal Hypersensitvity

One study of 28 TKA patients determined that those with hypersensitivity were more likely to be female; seven patients had a history of metal hypersensitivity before arthroplasty (Mihalko et al. 2012). Twenty-two patients had self-reported allergies, and skin patch testing was positive in 19 patients. Dermatologic symptoms resolved in patients who had revision with hypoallergenic implants with no further instability. A similar study found positive skin patch results in 68% of patients with reported metal allergy (Mitchelson et al. 2015). Another study found that 32% of patients who had TJR with no known prior history of metal allergies developed a positive leukocyte migration inhibition test of Ti, Co, Cr, or Ni 3 months to 1 year following surgery (Goodman 2007). Implant failure was reported to be up to 4 times greater in patients with a self-reported history of preoperative metal allergy compared with patients who did not have an allergy (Mitchelson et al. 2015).

Age, gender, and occupation are all risk factors for developing nickel hypersensitivity. Exposure to costume jewelry may account for the higher rates in women. Nickel sensitization has been reported to be present in 17–32% of women and 3– 10% in men. Cr is more common sensitization in men at 10% compared to 7% in women. Cr is associated with concrete exposure in the construction industry, leatherworking, and occupations involving cleaning. Co sensitization is common in hairdressers and textile industry workers. Nickel sensitization is associated with healthcare, agriculture, mechanics, and metal work.

One study demonstrated acquired hypersensitivity following Ti spinal implants and tattoos. Skin biopsy of reaction and surrounding tissues of TI spinal implants demonstrated high levels of Ni and Cr, Ti, skin testing was negative for Ni and Cr (de Cuyper et al. 2017).

The North American Skin Patch testing group reported 21% sensitivity to Ni 21% and 8% to Co and Cr in 5,000 patients (Merritt and Brown 1980). As more patients are repeatedly exposed to metal variants commonly used in orthopedic implants, the possibility of increased sensitivity reactions to these metals may rise.

Clinical Presentation of Metal Hypersensitivity

Metal hypersensitivity may result in localized or systemic allergic dermatitis, loss of joint function, implant failure, and pain. Pruritic erythematous, eczematous, edematous, and sometimes exudative lesions may present over implant sites (Mitchelson et al. 2015). Symptoms ascribed to metal hypersensitivity include pain, swelling, cutaneous rash, patient dissatisfaction, and loss of function (Merritt and Brown 1980). The degree to which the known condition of metal hypersensitivity induced failure is not well known. No clear association between the prevalence of metal sensitivity and duration of implant in situ has been identified, and no clear objective lines have been found between pain-related failure in metal sensitive and nonsensitive patients undergoing revision (Hallab et al. 2001). This may represent an extreme complication or may be a more subtle contribution to implant failure overall (Hallab et al. 2001).

Metal hypersensitivity-induced allergic dermatitis, pain, and implant failure have clinically relevant laboratory markers associated with the conditions (Mihalko et al. 2012). Elevated levels of IL-6, INFa, and IL-17 are common identifiable markers in implant failure. Increased Ni and Ti have been demonstrated to increase expression of RANKL, macrophage colony stimulating factor, TNFa, and CCR4 receptors. Clinicians should have a high level of suspicion when patients present with arthralgia, periprosthetic radiolucent lines, or aseptic implant loosening. Ordering appropriate inflammatory laboratory markers during a workup for suspected metal hypersenstivity is necessary to determine the extent of the response (Mitchelson et al. 2015).

Metal Sensitivity to Spinal Implants

Spinal Implant Composition

Spinal implant composition is dependent on the implant function and location. Multiple implants ranging from pedicle screw instrumentation, metal on polyethylene disc replacements, and PEEK fusion grafts are implanted in patients undergoing spinal surgery for various reasons. Reports of metal sensitivity in patients with spinal implants are primarily single case reports or very small series (2–4 patients).

Disc Replacements

Disc replacements are metal and polyethylene combination implants used to replace symptomatic disc pathology while preserving the motion segment. In one study of 4 patients who had failed lumbar disc replacements, retrieval showed evidence of wear of the polyethylene cores, but the extent and severity varied among the four patients. Wear and fracture of the core were associated with osteolysis of the underlying sacrum. Histologic examination confirmed the presence of wear debris in inflammatory fibrous tissue. Evidence of failure prior to retrieval included subsidence, migration, undersizing, and reactionary adjacent fusion on radiographic analysis. The mechanism of wear was determined by adhesive wear of the central domed region of the polyethylene core and chronic rim impingement resulting in rim fatigue and fracture (Ooij et al. 2007).

In another report of four patients with TDR who had an uncomplicated initial postoperative course followed by worsening pain months after surgery, retrieval found an avascular soft-tissue mass was found to be causing an epidural mass effect scar and causing symptoms to re-emerge. Laboratory analysis of the tissue found lymphocytic reaction tissue, dominated by a large number of lymphocytes and small number of macrophages (Guyer et al. 2011).

Total Disc Replacement (TDR) Materials

The TDR can be composed of stainless steel alloys which confer greater ductility; Co-Cr alloys which confer increased corrosion resistance, hardest, strongest, and most fatigue resistance; or titanium alloys which good flexural rigidity and toughness and high corrosion resistance compared to stainless steel and Co-Cr (Hallab et al. 2003).

Polyetheretherketone (PEEK)

PEEK cages have a high biocompatibility profile and are radiolucent. One case report regarding chronic allergic response to interbody PEEK material reported diffuse erythema and itching, tongue swelling, and erythema in the throat following PEEK implantation. No significant inflammatory tissue or response was found in the retrieval (Maldonado-Naranjo et al. 2015).

Device for Intervertebral Assisted Motion (DIAM)

DIAM is a silicone disc enveloped in a polyethylene terephthalate fiber sack. One case report described granulation tissue 5 years after DIAM. Histology demonstrated wear debris and chronic inflammation with a hypersensitivity reaction and subsequent bone osteolysis surrounding the implant (Seo et al. 2016).

Metal-on-Metal Facet Replacements

Two patients with MOM facet replacements were reported to develop local tissue reactions with pseudotumor formation, characteristic soft yogurt-like chalky white scars surrounding the implants (Goodwin et al. 2018).

Carbon-Coated Implants

Metal hypersensitivity was described in one patient after VEPTR titanium rod insertion for congenital scoliosis. No hypersensitivity was documented after reimplantation with carbon-coated implants (Zielinski et al. 2014).

Zirconium Rods

Plasma sprayed zirconium interface rods cannot be contoured, and significant implant brittleness precludes their use in deformity correction, limiting the use of zirconium for spinal implants (Zielinski et al. 2014).

ACDF Implants

Reported allergic reaction to PEEK implant and Ti ACDF plate and screws include system rash, congestion, dysphasia, and urticaria. Symptoms resolved once implants were removed, with no visible osteolysis (Urban et al. 2000).


Treatment of metal hypersensitivity can range from symptomatic treatment to revision surgery. Reactions around the spine obviously play a different role than those in total joint replacement where symptomatic treatment of the dermatologic symptoms may resolve completely with a use of topical corticosteroid (Mitchelson et al. 2015). In the spine these reactions caused by proximity of vital neurologic structures need a more heightened awareness and investigation of possible deep tissue reactions. Metal artifact reduction sequence (MARS) MRI can help determine if a reaction is occurring and can help grade the reaction if any (Connelly et al. 2018). This can aid in the choice of an approach for treatment, which can be difficult depending on the purpose of the implant in place.

New technologies involving immune modulation have emerged, but are still investigative. The use of Nac, an antioxidant inhibitor of NFkB, can potentially be used to augment the inflammatory response via glutathione (GSH), which inhibits serine phosphorylation of iKB, thereby preventing the dissociation of NFkB induced cellular response to particulate debris. Reduction in the stimulation of NFkB leads to decreased osteolysis surrounding an implant (Willert and Semlitsch 1977).

Further use of disease modifying anti-rheumatic drugs (DMARDs) has expanded the pharmacologic treatment of metal hypersensitivity reactions. Numerous in vivo and in vitro animal model studies suggest that bisphosphonates may be a potential benefit for treatment of particle-induced osteolysis. Antitumor necrosis factor alpha (TNFa) therapy with etanercept has been reported to inhibit osteoclastic bone resorption; however, in an underpowered study it was found to produce no change in volumetric wear osteolysis compared to a placebo (Holt et al. 2007).


Over the last 10 years, metal hypersensitivity has been documented in patients with spinal implants with bearing surfaces that may be a trigger for sensitizing patients due to the local wear debris. Reaction to metal alloys and debris is a type IV hypersensitivity immunologic reaction that does not produce anaphylaxis and has led to increased exposure. Realizing that 10–15% of the population has these sensitivities, identifying who is at risk, and noting clinical and radiographic signs of hypersensitivity can help surgeons notify their patients of the possible risk and determine appropriate treatment if required. Treatment can range from symptomatic treatment of dermatologic conditions to revision surgery and use of hypoallergenic implants.


While most reports of metal hypersensitivity have been in the total joint literature, in the last 10 years there have been a number of case reports of spinal implant reactions. Much of this is because spine implants have been developed with bearing surfaces that may be a trigger for sensitizing patients from the local wear debris. Recognizing the signs of metal hypersensitivity, becoming familiar with testing procedures, and identifying risk factors for hypersensitivity, in addition to knowing the frequency of these sensitivities in the general population, can help surgeons identify these patients and notify them of the possible risk.


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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Campbell Clinic Department of Orthopaedic Surgery and Biomedical EngineeringUniversity of Tennessee Health Science CenterMemphisUSA

Section editors and affiliations

  • Boyle C. Cheng
    • 1
  1. 1.Allegheny Health NetworkDepartment of NeurosurgeryPittsburghUSA

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