Immune Response to Implants and Biomaterials

Updated: Apr 05, 2022
Author: Steven I Rabin, MD, FAAOS; Chief Editor: Murali Poduval, MBBS, MS, DNB 


Surgically implanted devices, prostheses, grafts, and fixation materials are commonly used for joint replacement, correction of spinal pathology, repair of fractures, treatment of cardiovascular pathology, and control of chronic pain.[1] All implanted materials can be recognized by the patient's immune system as foreign bodies causing cellular and tissue immune responses.[1, 2, 3]

A negative immune response can lead to adverse pathology, including excessive inflammation, interference with healing, fibrous encapsulation, and implant rejection; a positive immune response can lead to successful biointegration of the implant and (for orthopedic implants) bone remodeling. The fate of the implant depends on the immunomodulatory properties of the implant,[2, 3] which include the following:

  • Chemical composition
  • Surface topography
  • Surface wettability
  • Surface charge
  • Release of bioactive molecules

Previous strategies to avoid the negative results of the immune response to implants primarily involved hiding the implant from the immune system by using relatively inert or biocompatible implants to prevent or mitigate the negative aspects of chronic inflammation. These earlier strategies focused almost solely on the osseous cells (osteoblasts and osteoclasts) in preventing implant failure.

Newer strategies recognize the close biologic interactions between the skeletal cells and the immune cells. Such strategies seek to develop new biomaterials that promote the positive aspects of acute inflammation.[2, 3] Future implant design may depend on the relatively new specialty of osteoimmunology, with a shift in emphasis from immune "evasion" to immune "reprogramming."[3, 2]

Although the focus of this review is on orthopedic implants, the immune pathologic response is also relevant for cardiac, vascular, gastric, and other surgical implants.


Immune Response to Metallic Implants

Metal sensitivity is the most common type of immune response to implants.[4] The metals most commonly used in orthopedic and dental implants are stainless steel (with nickel), cobalt, chromium, and titanium.[1, 3] Cardiac stents and patches are made of nitinol (an alloy of titanium and nickel).[1]

The incidence of metal allergies is rising in the general population, probably as a consequence of increased exposure to metal from piercings, jewelry, and internal medical devices or dental restorations. Medical implants are typically made of alloys of metals, including nickel, cobalt, chromium, molybdenum, zirconium, and titanium.[5]

As many as 13% of people are sensitive to nickel, cobalt, or chromium[6, 7, 8, 9, 10, 11, 12, 13, 14] ; 17% of women and 3% of men are allergic to nickel, and 1-2% of people are allergic to cobalt, chromium, or both.[5] It therefore is not surprising that immune response to medical implants is commonly reported in the literature, including hypersensitivity to pacemakers or other cardiovascular devices, endovascular stents and coils, dental implants, and orthopedic hardware (eg, joint replacement prostheses, fracture fixation devices, and pain-relief stimulators).[1, 15, 16]

The development of metal sensitivity after implantation of orthopedic hardware is common.[5, 6, 17, 18, 19]  It is thought that the immune system may become sensitized to the presence of a metal implant with a resultant increase the incidence of positive skin testing, though it is unclear how often this response is pathologic. However, with the large number of joint replacements performed yearly, the largest group of allergic reactions to implants consists of reactions to orthopedic implants.[1]

Metal sensitivity is correlated with osteolysis and aseptic loosening of implanted metal hardware.[10, 17, 19, 20, 21, 22, 23, 24, 6, 25, 26, 27, 28, 29]   However, there is a question as to whether metal sensitivity is the inciting event or whether a failing implant leads to a more robust immune response and possibly increased clinical testing for metal reaction.

When implants degrade or corrode, the immune system also responds to surface changes and degradation products.[2] According to Huber et al, the presence of corrosion products and a hypersensitivity reaction in patients suggests that there is a relation between corrosion and implant-related hypersensitivity. In a study including 11 cases where periprosthetic tissue contained corrosive elements (solid chromium orthophosphate corrosion products) after aseptic loosening of articular implants, immune-response tissue reactions were identified in every case.[24]

The issue of the clinical significance of sensitization to implanted metals has long been debated in the literature. Although some studies have found sensitization to metal implants to be prevalent,[6, 17, 18, 19] others have taken an opposing viewpoint, concluding not only that hypersensitivity fails to develop[30] but also that patients with metal hypersensitivity prior to implantation actually can become desensitized and anergic after implantation.[31]

Whereas some authors have suggested that metal hypersensitivity may be associated with bone loss and aseptic loosening of implanted devices,[10, 18, 21] others have argued that even if a metal allergy exists, no adverse effects occur.[20, 30, 32, 33] Demehri et al reported the rare occurrence of squamous cell skin cancer (specifically, Marjolin ulcer) associated with a contact allergic reaction to superficial metal implants, most likely secondary to chronic inflammation.[34, 35] Metal sensitivity may also be associated with chronic fatigue syndrome, fibromyalgia, and autoimmune syndromes.[4]

In light of these contradicting studies, it is difficult for the orthopedic surgeon to make the diagnosis of symptomatic metal allergy with confidence. The confusion is a result of the presence of different metals in the implants, different manufacturing methods, small numbers of patients in the studies, nonspecific testing modalities, and a lack of definitive clinical guidelines for making the diagnosis. Applying diagnostic criteria may be useful in guiding the decision making process when faced with symptomatic or failing devices.[36]

Although prescreening all patients for metal hypersensitivity may be costly and its clinical relevance dubious, various specific laboratory tests, including the lymphokine migration inhibition factor (MIF) test, appear to be confirmatory. Because this is a diagnosis of exclusion, cases are difficult to identify, given that the signs and symptoms are very similar to those of other, more frequent causes.

In the rare case where a patient displays symptoms such as recurrent pain and aseptic loosening related to implanted hardware, the differential diagnosis of metal hypersensitivity should be considered. Skin-patch testing or lymphocyte transformation testing (LTT), when the patch test result is questionable, prior to revision knee or hip replacement has been recommended, despite the limitations[29, 37] and the concern that the immune environment and reactive immune cells are different in the musculoskeletal tissues versus the skin.

More research is clearly needed. In the meantime, the orthopedic surgeon must be aware of the potential problem but should exercise caution in making the diagnosis. Infection, nonunion, aseptic loosening, other inflammatory conditions, mechanical failure of the implant, and malalignment issues must be excluded first before the problem is assumed to be an allergic reaction. Once the more common causes of implant failure have been excluded, the possibility of allergic reaction to the metal must be considered, evaluated, and treated.[38, 5, 39]

Although this article focuses primarily on immune responses in patients with already implanted orthopedic devices, it is also worthwhile to note that efforts to prevent the pathologic reaction to an implant, by choosing alternative prostheses or fracture fixation implants during preoperative planning, should be considered in selected patients with known metal hypersensitivity.

Patients with metal-on-metal bearing surfaces represent special cases, in which corrosion and wear (tribocorrosion) of the implants release metal ions or particles into the joint, stimulating an immune response and giving rise to adverse local tissue reaction, pseudotumor, and possibly prosthetic failure. Severely high serum cobalt or chromium levels can lead to systemic symptoms, cardiotoxicity, neurotoxicity, and may induce chromosomal abnormalities.

Metal artifact reduction sequence (MARS) magnetic resonance imaging (MRI) can be used to visualize local soft-tissue reactions; serum tests are used for screening. Very high ion concentrations (>7 parts per billion [ppb]) are considered an indication for advanced imaging. However, local symptoms, squeaking, or high acetabular version or inclination may also indicate the need for advanced imaging.[4] High chromium ion concentrations may be carcinogenic, and high cobalt ion concentrations may be both cardiotoxic and neurotoxic.[40]  Levels much higher than 7 ppb are typically required to induce systemic symptoms.

Metal ion release may also be due to surgical technique in patients with metal-on-metal prostheses. Koutalos et al found a correlation between patients with adverse reactions to metal debris (ARMD) and prosthesis cup position but no correlation with metal ion levels.[41]

Dobbs et al reported a case where the patient had a metal-on-metal hip prosthesis on one side and a metal-on-plastic prosthesis on the other.[42] The metal ion concentrations (cobalt and chromium) on the metal-on-metal side were 50 times higher than normal both locally and systemically (eg, in the hair, urine, lung, kidney, liver, and spleen), whereas on the metal-on-plastic side, the concentrations were near normal.

Newer implant designs have been developed specifically to minimize the release of metal ions. Measures employed have included minimizing the use of metal-on-metal bearing surfaces, utilizing nickel-free bearing materials (eg, hardened titanium, ceramic, or ceramicized metal), eliminating modular necks in femoral prostheses, and utilizing ceramic rather than metal heads to reduce reactions at the trunnion of a stem.

Markel et al reported the use of a dual-mobility cobalt-chromium hip replacement prosthesis with which metal ion levels were undetectable or minimal after 1-2 years; in addition, percentages of B cells and T cells were normal, with no increase in CD16 inflammatory monocytes, indicating the absence of an immune response to the implant.[43]

For patient education resources, see Total Hip Replacement and Knee Joint Replacement.


Immune Response to Nonmetallic Implants

An immune response can develop against nonmetallic components of implants as well.[4] Nonmetallic materials can be organic or inorganic. Organic biomaterials include natural and synthetic polymers, polysaccharides, and proteins—for example, chitosan, glycosaminoglycans, hyaluronic acid, collagen, and silk. Inorganics include bioactive glass and calcium phosphate.[3] Although technically metals, metal ions are often also included under the immune response to nonmetal implants. Acrylic bone cement and its polymerization additives (benzoyl peroxide and N,N-dimethyl-p-toluidine) can cause severe hypersensitivity reactions in total knee arthroplasty.[44]

Components of bone cement that can be immunogenic include acrylates, benzoyl peroxide, toluidine, and antibiotics.[4]  Bone cement hypersensitivity can be challenging, and revision using cementless procedures does not guarantee relief of presenting symptoms.[44]  

Implanted pulse generators (eg, pacemakers, gastric stimulators, and neurostimulators) are made with stainless steel, titanium alloy, platinum, and iridium but also with epoxy resins, polymethylmethacrylates (PMMAs), and isocyanates, all of which may be immunogenic in some patients.[1]

Recognition of the potentially disastrous consequences of implant-associated infection[45, 46] has prompted the development of multiple types of coatings on implants in order to discourage bacterial adhesion, prevent biofilm formation, or kill bacteria directly. These coating substances can encourage attachment of host cells and a local immune response against the infectious organism[45, 15] but, paradoxically, can also provoke an immune response to the coating substances themselves.[5] Coating substances in use include the following[45, 47] :

  • Antiadhesive polymers
  • Hydrogels
  • Silver ions
  • Titanium dioxide
  • Selenium
  • Copper or zinc ions
  • Antibiotics
  • Chitosan derivatives
  • Cytokines
  • Antimicrobial peptides
  • Silicone
  • Polyurethane

Silver ions are cytotoxic to both bacteria and neutrophils, decreasing the immune response to both the implant and the bacteria.[46] Antimicrobial peptide coatings, besides their direct action against microorganisms, may also exert an immune-regulatory effect by decreasing the immune response to the implant, resulting in osteointegration/bone formation around the implant. These peptides are biocompatible with macrophages and neutrophils.[46]



The immune response to an implant can either be a true systemic hypersensitivity reaction or be caused by local damage from the implant.

In allergic reactions, there is a type IV delayed cell-mediated response. Repeated or prolonged exposure to metals or other substances from jewelry, clothing, or implanted devices sensitizes T cells, which respond to an implanted device[1] with a foreign body reaction.[15] Activated lymphocytes release cytokines (eg, interferon [IFN] gamma[48] , leading to inflammation that activates macrophages as part of the inflammatory cascade. However, some metals (including cobalt) can cause soft-tissue inflammation via direct toxicity of the metal ions without the hypersensitivity response.[5]

An immune response to a surgically implanted medical device begins immediately. Contact with blood activates the coagulation systems, the complement system, platelets, and immune cells, resulting in a thrombus at the interface that is the transient provisional matrix.[2] This matrix is rich in growth factors, cytokines, and matrix metalloproteinases, which promote the immune response and recruit neutrophils.

Activated platelets stimulate migration of monocytes, which differentiate into macrophages.[3] M1 proinflammatory macrophages arrive as part of the initial inflammatory response[49, 50, 2, 3] ; these macrophages release proinflammatory mediators such as interleukin (IL)-1β, IL-6, IL-16, and tumor necrosis factor (TNF)-α[49, 2, 51, 48]  and clear damaged tissues from the area. Persistence of these cytokines leads to excessive inflammation.[3]

Usually, the M1 macrophages transform into M2 macrophages, which help regulate tissue remodeling.[49, 50, 3] Initially, osteoclast activation is important for removal of necrotic tissue and as the first step for bone remodeling around the implant. The immune system modulates the osteoclastogenic process via three main cytokines, as follows:

  • Macrophage colony-stimulating factor (M-CSF)
  • Receptor activator of NF-κB ligand (RANKL)
  • Osteoprotegerin (OPG)

An increased RANKL-to-OPG ratio leads to enhanced osteoclast activity, accelerated bone resorption, and excessive bone loss.[2, 3] A consistently elevated M1 response with a decreased or absent M2 response causes chronic inflammation, delayed tissue healing, and failure of biomaterial integration.[3] In the presence of an implant, a state of "frustrated phagocytosis" may develop, consisting of a mixed pro- and anti-inflammatory state that results in chronic inflammation.[50]

The switch from M1 to M2 is regulated by immune cells, including T cells of various subsets, cytokines, and microRNAs (miRNAs).[3]  IL-10 is an anti-inflammatory cytokine that has a significant role in maintaining immune homeostasis and resolving inflammation.[52]

Dendritic cells sense their local environment via pattern recognition receptors and transfer information on the nature of antigens to T cells in the lymph nodes, thereby regulating the immune response to the foreign body.[52] The strength of this foreign body reaction is variable, and research continues into the question of why some patients have a more excessive response than others. Nevertheless, it is clear that specific osteomodulatory characteristics of the implant contribute.[2]

Metal ions have cytotoxic haptenic potential and have been presumed to induce an adverse reaction to metallic debris and a delayed-type hypersensitivity response.[53]   Mitochondrial stress and cytokine secretion by synovial fibroblasts can be induced by cobalt ions released by failing hip implants.[51]



The clinical presentation of patients with metal implant reactions is often nonspecific. Patients can present with localized dermatitis or rashes but also with systemic eczematous dermatitis. Swelling, pain, draining sinuses, and inflammation at the implant site may mimic infection. The presentation may include dermatitis and skin reactions, joint pain, joint effusions, and decreased wound healing.[5]

The presenting signs and symptoms of a nickel or other metal hypersensitivity to an implanted orthopedic device are variable but usually consist of the expected complaints of a patient with hardware failure. Patients with joint replacement may present with loss of motion.[1] Patients with dermatitis are more likely to have an allergy to nickel allergy than an allergy to a different metal.[5]  It is common for metal hypersensitivity to present as a skin rash at the site of the implant,[19, 4, 5]  especially with superficial implants such as plates at the ankle.

Patients with joint replacements typically have symptoms of loosening, including pain and instability. (For example, with a total hip replacement, the patient often has groin pain radiating to the medial thigh.) Patients with hardware for fractures have symptoms of nonunion, including pain and motion at the fracture site. Local inflammatory symptoms similar to the symptoms of infection are also possible, including warmth, erythema, and swelling over the implant, though systemic complaints (eg, fever) are unlikely. A skin rash may develop over the metal device but is not always present.[54, 55, 56]

Osteolysis and aseptic loosening should always be included in the differential diagnosis. Despite the introduction of highly cross-linked polyethylene in the mid 2000s, decreasing the incidence, these are historically common causes of local reaction, bone resorption, pain, and implant loosening. 

Fujishiro et al identified an association between the extent of inflammation and the amount of visible metal particles and concluded that this relation implied the occurrence of an immune response to the metal.[57] However, the typical morphologic features of an immune inflammatory reaction, including loss of the surface synovial lining, fibrin deposits, and lymphocytes in diffuse and perivascular distributions, were not consistently present. 

More likely, the mechanism of osteolysis is primarily a local reaction to particulate debris,[58, 59] which leads to a cascade of cellular reactions (including activation of monocytes/macrophages, phagocytosis, and release of cytokines) that eventually lead to increased osteoclastic activity around the prosthesis. Whereas the radiographic and clinical symptoms overlap with those of metal immune reaction, osteolysis is a reaction to local irritation from wear debris, not an immune hypersensitivity response.[60]

The causes of these different patterns of inflammation are unknown, but the association between the extent of inflammation and visible metal particles (but not zirconium particles) supports the concept of an immune reaction to metal, and it illustrates that the process is not specific to metal-on-metal constructs.



The increasing frequency of metal allergies in the general population implies the potential need for prescreening of surgical patients to prevent possible allergic reactions to implants.[5] There is no indication for workup of asymptomatic patients with stable implants.[4] Workup may be indicated before surgery for joint replacement patients with a history of skin reactions to metal jewelry, jean snaps, watch bands, metal glass frames, artificial nails, or skin glue.[1]

The American Contact Dermatitis Society has suggested testing before device implantation in patients with a clear history of metal reactions.[5] Testing may also be indicated for patients in whom infection and mechanical factors have been ruled out as the cause of implant failure or for patients with localized rash, pain, swelling, or inflammation near or over the implant or systemic cardiac or neurologic symptoms.[1]

Intraoperative pathology

Biopsy of the synovial membrane at the time of revision surgery is one method for differentiating between infection and hypersensitivity reaction to the implant. Both involve a robust intra-articular immune response; however, metal reaction shows predominance of perivascular lymphocytes, plasma cells, and macrophages, whereas infection is characterized by an abundance of neutrophils on biopsy.[4, 39]  Thomas et al showed that lymphocytic infiltrates and fibrotic (type IV membrane) tissue response were most frequent in metal-sensitive patients, with 81% having positive results on patch testing.[48]

Patients with metal-on-metal implants should be monitored for metal ion levels at intervals of 6-12 months.[4] Preoperative aspiration of synovical fluid for culture, cell count, and neutrophil percentage may also be included in the workup to rule out infection.[39]  However, it is important to note that as many as 20% of periprosthetic joint infections are culture-negative.

Imaging studies

Immune reactivity to metal more commonly leads to pain and local soft-tissue reaction than to loosening. Nonetheless, careful radiographic assessment of the implant is required. Radiolucencies around the hardware, screw migration, and changed position of the implant imply loosening that could be due to hypersensitivity to the metal or could be the catalyst that induces a robust immune response. Cystic changes, such as occur in osteolysis, may be seen (see the image below).

Osteolysis around a total knee implant. Osteolysis around a total knee implant.

Computed tomography (CT) is not sensitive for diagnosing implant loosening but may help characterize the location and extent of the bone resorption when present.

Magnetic resonance imaging (MRI) with metal artifact reduction is recommended for symptomatic patients with metal-on-metal implants or asymptomatic patients with metal-on-metal implants with metal ion levels of 7 ppb or higher to evaluate the status of the implant.

Practitioners should have a low threshold for ordering advanced imaging, in that many of these patients are asymptomatic, and even low metal  ion levels have been associated with local tissue reaction. For example, an MRI study by Galea et al found that cobalt levels in the range of 2.9-3.2 ppb were associated with an increased risk of adverse local tissue reaction in patients who underwent metal-on-metal total hip arthroplasty or hip-resurfacing arthroplasty.[61]

Ultrasonography (US) can also detect fluid around the implant[62] but is also nonspecific.

Skin patch testing

Traditionally, skin patch testing has been the standard screening test for metal hypersensitivity; it is cost-effective and technically simple.[63] The main limitation of this test is that a positive result is not indicative of a true hypersensitivity but must be considered in the context of a patient's medical history and physical findings.[64, 65, 13, 5] A positive result can occur in completely asymptomatic patients.

The prevalence of metal sensitivity on routine skin patch testing is 0.2% for chromium, 1.3% for nickel, and 1.8% for cobalt,[66] though a significantly higher prevalence (10-15%) in the general population has also been reported with nickel.[39] After placement of metal implants, sensitization (ie, a change from a negative result to a positive one) occurs in 2.7% of cases for chromium, 3.8% for nickel, and 3.8% for cobalt. Desensitization (ie, a change from a positive result to a negative one) occurs in 0% of cases for chromium, 2.1% for nickel, and 3.8% for cobalt.[66]

The metals most commonly reported with positive preoperative skin test results before revision knee or hip replacement where metal hypersensitivity is diagnosed are nickel (52%), palladium (32%), gold (23%), and cobalt (19%); patients may be allergic to more than one metal.

The causes of these skin immunologic reactions are unclear.[6, 65] It is thought that antigen-presenting cells that are localized to the skin (dendrite cells) may handle antigens differently from those that are systemic (ie, macrophages and monocytes).[23, 63, 4] The systemic response is cell-mediated and generally involves type IV delayed hypersensitivity with release of inflammatory cytokines and migration of macrophages to the implant.[4, 63] Thus, many people who have skin reactivity to metals may never develop any reactivity at the site of a prosthesis composed of that metal. Skin patch testing may therefore be unreliable.[63]

Additionally, systemic contact dermatitis has been described when a patient becomes sensitized via the cutaneous route and cross-reacts systemically.[4] Screening itself may induce sensitization.[63] Skin test results may not return to normal after metal removal.[23] The systemic response to deep implants can occur acutely or many years later.[63]

Many patients with implanted metal hardware have positive skin test results for those metals but nevertheless are completely asymptomatic.[20, 30] Some 25% of patients with well-functioning prostheses have metal sensitivity.[39] If the skin patch test finding is positive, the patient can be designated as allergic. However, the clinical significance of the allergy is controversial. Most allergy skin patch tests that show skin reactivity have no clinical implications.

In patients with suspected titanium hypersensitivity skin prick testing should be considered to confirm the diagnosis if the patch test to titanium is negative.[67]

Conclusions based on skin patch testing should therefore be made with caution and only assumed to be valid if the whole clinical picture supports the finding of symptoms related to metal allergy. Preoperative skin patch testing is not typically recommended unless there is a strong suggestion of established sensitivity by history, because of the slight chance of sensitization and the high-cost/low-yield results expected. Also, the results depend on the experience of the person visually reading the skin reaction and may be influenced by medications, the quality of the antigens chosen, and the time of reading.[63, 5, 19]

Blood tests

Traditional blood tests are not useful in the work-up of immune response to implants. The white blood cell (WBC) count and other assessments of inflammatory mediators (eg, platelet count, C-reactive protein [CRP] level, and erythrocyte sedimentation rate [ESR]) are not elevated or only minimally elevated, and they are not specific or reliable enough to aid in diagnosis.[39] Nevertheless, they are commonly performed in the workup to rule out infection as the cause of the prosthesis failure.

Concentrations of metal ions increase in the systemic circulation after all metal replacements,[4, 63, 39] most likely secondary to corrosion or bearing wear of the implant. These concentrations increase in loose implants, but the significance of this increase is controversial.[4]

Monitoring chromium and cobalt concentrations has been suggested for all patients with metal-on-metal hip replacement bearing surfaces, but particularly for those who are symptomatic.[40] This serves as a screening test for the possible presence of asymptomatic local soft-tissue reaction. About 90% of patients with these replacements will have loosening at 10-year follow-up.

Blood levels of cobalt and chromium are typically 30 and 45 nmol/L, respectively, in unilateral well-functioning hip prostheses but increase to 6550 and 3400 nmol/L in failed prostheses.[40] At present, the published data are insufficient to determine safe reference ranges for blood levels of cobalt and chromium, but in the unexposed population, normal ranges are below 10 nmol/L and below 5 nmol/L, respectively.[40] In clinical practice, the common cutoff to indicate further testing is 7 ppb.

Researchers at National Jewish Health have developed a nickel lymphocyte proliferation test[62] , but this is not yet commonly available.

The following tests are more difficult to obtain because many clinical laboratories do not run them. In the Chicago area, these tests are available at both Loyola University Medical Center and Rush Presbyterian Mecdical Center.

Lymphocyte transformation test

Tests that may be more specific include the lymphocyte transformation test (LTT) and the lymphokine MIF test (see below), which have been used to help diagnose metal hypersensitivity.[56] Some authors have considered the LTT to be the most reliable test, especially when it is combined with skin patch testing and cytokine detection.[63, 37]

After skin patch testing, in-vitro lymphocyte proliferation testing is perhaps the most prevalent method of assessing hypersensitivities. It involves measuring the proliferative response of T lymphocytes after activation.[63] A radioactive marker (3H-thymidine) is added to lymphocytes along with the desired challenge agent. The incorporation of the radioactive marker into cellular DNA on division facilitates quantification of a proliferation response through measurement of amassed radioactivity after of 3-6 days. At day 6, 3H-thymidine uptake is measured by using liquid scintillation. The proliferation factor or stimulation index is calculated by using measured radiation counts per minute (cpm), as follows:

  • Proliferation factor = (mean cpm with treatment)/(mean cpm without treatment).

The use of proliferation testing in the assessment of metal sensitivity has been well established as a method of testing metal sensitivity in a variety of clinical settings.[68, 69, 70, 71, 72, 73] The technical sophistication and high expense of the LTT for implant-related metal sensitivity has limited its use; therefore, few conclusions can be drawn.[74, 75, 76]

The few investigations using the LTT have reported that increased rates of metal sensitivity can be detected above what can be determined by means of dermal patch testing.[74, 76, 77] Such reports seem to indicate that the LTT, compared with dermal patch testing, may be equally well or better suited for the testing of implant-related sensitivity.[69, 70, 71, 72, 73, 74, 75, 76, 78] The LTT is still not widely available, is not well standardized, is often not covered by insurance, and may yield false-negative results if processing is delayed; accordingly, some authors recommend against its routine use.[4, 5]

Subsequently, with the use of flow cytometry, metal-reactive T helper cells demonstrating high expression of CCD45RO and coexpression of CLA and CCR6 have been shown to improved the LTT in patients with nickel, cobalt, and chromium sensitivity. This approach could be used as an adjunct to routine patch testing.[79]

Lymphokine migration inhibition factor test

Another in-vitro test that has shown promise in diagnosing metal hypersensitivity involves the use of MIF. MIF acts to prevent lymphocytes from leaving a site where foreign antigens are present. This test selectively detects lymphokine MIF, which, when present, does indicate an active immune response and metal sensitivity.[32]

The test is performed by obtaining a blood sample and isolating the lymphocytes. The lymphocytes are then mixed with solutions of specific metal ions, such as nickel, chromium, cobalt, or titanium. The test result is considered positive if the lymphocytes stay in the metal ion solution, indicating a cellular reaction to the metal dissolved in that solution. (In other words, with a positive result, no migration occurs.) The test result is considered negative if the lymphocytes migrate away from the particular metal ion solution, indicating that they are not reacting to the dissolved metal.[6] (See the image below.)

Lymphokine migration test. Lymphokine migration test.

Studies reveal that positive MIF test results to metals implanted in an orthopedic patient are well correlated with pain, swelling, and dermatologic reactions over that area. Furthermore, after the implanted materials are removed, these signs and symptoms improve, and the MIF test result returns to normal.[23]  Hence, the lymphokine MIF may be the most useful clinical test for diagnosis of hypersensitivity reaction to orthopedic implants.[80] Cement wear particles are immunologically inert and have specifically been found not to cause a lymphocyte response in vitro[81] ; thus, the lymphokine MIF result could be negative in osteolysis.

Advances in immune testing

The addition of specific cytokine tests (eg, Luminex cytokine assays) may more accurately reveal the qualitative and quantitive involvement of different cell types. Significantly increased cytokine levels are found in patients with aseptic loosening of implants in comparison with levels at the initial surgical procedure.[63]

Phase-contrast and laser scan confocal microscopy (LSCM) is another method of quantifying the number of positive cells involved in the immune reaction. Titanium, molybdenum, and cobalt have low toxicity as compared with nickel and chromium, which can cause highly toxic intracellular changes.[63]


Metal Alloy Factors

Another important factor to consider in the biologic response to orthopedic implants is metal ion exposure and release. Implants from different manufacturers have varying metal compositions (see the image below). For example, the nickel content in stainless steel may vary in the range of 9-15.5%, whereas in cobalt-base alloys, the nickel content is usually specified to be no greater than 1% (< 0.2% in actual practice), and titanium content is essentially 0%.

Composition of common metal alloys used in orthope Composition of common metal alloys used in orthopedic implants.

In addition to the percentage of a particular metal contained within an alloy, the nature of the alloy and the local exposure of the implant are important. Alloys are graded on a scale that measures their metal ion release rate. For example, implant-grade 316L (low-carbon) stainless steel releases far less nickel than low-grade stainless steel suture. Local exposure of metallic surfaces also affects ion release and can be a factor in the development of hypersensitivity reactions secondary to an implant.

In a prospective cohort study that included 597 patients with metal-on-metal hip resurfacing and total hip prostheses, Hart et al found that elevated blood levels of metal (ie, chromium and cobalt) ions were associated with an increased risk of implant failure.[82]

Implant properties may alter the amount of surface area available for metal ion release. Plasma-spray coatings and grouting agents limit exposure and decrease ion release from the implant. Roughened, grit-blasted, or grooved surfaces increase the surface area available for ion release from the implant and thereby increase the local levels of dissolved metal.[13]

Taking these factors into consideration, many of the manufacturers of these alloys and implants are striving to make them as resistant to breakdown as possible in the hope that by limiting the quantity of ions released, it may be possible to decrease the rate of sensitization.[6, 83]


Clinical Course and Treatment

The usual course of events in patients demonstrating true postimplantation metal hypersensitivity is such that symptoms develop over months to years; this may be long after the device has accomplished the goal of fracture stability.[23] Gradual development of skin changes, pain, tenderness, and swelling over the area of the implanted hardware may be coupled with evidence of loosening of a previously stable implant.[23] Acute symptoms in patients with multipart devices may be associated with periods of increased activity.[84]

No medical treatment is available,[39] though in patients with absolute contraindications for revision surgery, a 21-day course of topical corticosteroids may sometimes control symptoms.[4] Analgesic pain medicines may control symptoms but do not alter the underlying pathology. Nonsteroidal anti-inflammatory drugs (NSAIDs) may worsen the situation by interfering with bone regeneration and incorporation around the implant.[2]

Options for surgical treatment include the following:

  • Joint replacement prosthesis or fracture implant that is still necessary for fracture stability - Revision utilizing a more inert implant with a different metal composition or a coated implant; most commonly, components with titanium alloy or oxidized zirconium coating may be successful [39] ; ceramic implants avoid the effects of all-metal implants [85]  
  • Implant that is no longer necessary - Removal [4]

Revision joint replacement surgery in patients with metal-on-metal prostheses have worse outcomes with more complications when the revision is due to metal reactions[61]  as compared with other modes of failure.


Case Example

A 71-year-old woman had a right intertrochanteric hip fracture and underwent open reduction and internal fixation (ORIF) with the use of a standard stainless steel hip fracture implant (Synthes DHS; Paoli, PA). Postoperatively, the patient did well, with evidence of fracture healing, full weightbearing, and full range of motion by 3 months after surgery.

Approximately 6 months later, the patient began to complain of right hip pain laterally over the area of the implanted hardware. The fracture was radiologically healed, but because of the patient's unbearable pain, technetium bone scanning and tomography of the area were performed. The results demonstrated increased uptake and lucency around the lag screw, indicative of hardware loosening.

The patient underwent debridement, hardware exchange, and an iliac crest bone graft. Intraoperative cultures were obtained that all proved negative for an infectious cause. Again, 4 months postoperatively, the patient began to complain of similar right hip pain, though imaging showed good bone graft incorporation and fracture healing (see the image below).

Case example. Second stainless steel implant in th Case example. Second stainless steel implant in the patient's right hip. Image shows a healed fracture but failing hardware.

A course of anti-inflammatory medicines and steroid injections to the region relieved pain only briefly. Hardware removal was performed 10 months after hardware exchange (see the image below). The patient's symptoms resolved shortly thereafter.

Case example. Image shows the right hip after the Case example. Image shows the right hip after the hardware was removed.

Four years later, the patient had an intertrochanteric fracture of the contralateral left hip and again underwent ORIF with a stainless steel device (Synthes DHS) (see the image below). She was recovering well with signs of fracture healing until 3 months after surgery, when she began to experience pain over the implanted hardware. Over the ensuing 3 months, the patient's pain increased to an unbearable level.

Case example. First stainless steel implant in the Case example. First stainless steel implant in the left hip.

Radiography demonstrated loosening and cutout of the hip lag screw, but the fracture was healing (see the image below). Accordingly, the patient underwent hardware removal 6 months after the initial implantation. At the time of the operation, a collection of serous fluid was noted around the implanted hardware, but no other clinical evidence of infection was observed. The hardware was not loose, and the fracture was stable and clinically healed. Irrigation and debridement were performed, and the patient was treated with intravenous antibiotics until intraoperative cultures proved negative.

Case example. Image shows the failed stainless ste Case example. Image shows the failed stainless steel implant in the patient's left hip.

A short time later, the patient had a fracture of the femoral neck during therapy. Total arthroplasty of the left hip was recommended, but after consideration of her past orthopedic history, the patient was first referred to an allergist for metal allergy patch testing. The results were positive for an allergy to nickel sulfate (with >20 mm of erythema noted) but negative for chromium and cobalt. Given the false-positive results of skin patch testing, blood samples were sent for MIF testing, which later confirmed nickel hypersensitivity (personal communication, Katharine Merritt, PhD, US Food and Drug Administration Office of Science and Technology).

The patient underwent a left THA with the use of a cementless titanium implant with a ceramic head (see the first image below). At 4-year follow-up, she had no further complaints or problems (see the second image below).

Case example. Image shows successful titanium tota Case example. Image shows successful titanium total hip implant in the left hip.
Case example. Final follow-up image after successf Case example. Final follow-up image after successful total hip replacement of the left hip.

This example presents a strong possibility of a true metal hypersensitivity reaction. However, because such a reaction is a diagnosis of exclusion, definitive proof is difficult to achieve.

This patient received three different stainless steel devices at two different sites. At the first site (right hip), complete healing occurred, and the patient remained asymptomatic after the device was removed. At the second (left hip), complete healing again occurred, and the patient remained asymptomatic after a titanium device was implanted. The patient had positive nickel sensitivity, as shown on both skin patch testing and lymphokine MIF testing, and negative culture results with no clinical evidence of infection. It is likely that she did have a true metal sensitivity reaction causing clinical failure of hardware and disabling pain.



Although this article focuses primarily on immune responses in patients with already implanted orthopedic devices, it is also worthwhile to note that prevention of the pathologic reaction to an implant, by choosing alternative prostheses or fracture fixation implants during preoperative planning, should be considered in selected patients with known metal hypersensitivity.

For example, instead of the standard stainless steel fracture fixation devices, the surgeon can substitue titanium plates and screws in patients with known nickel allergy. Before routine total hip or knee replacement in patients suspected of having metal allergies, alternative prostheses may also be indicated, including ceramic implants, implants composed of different alloys, and coated implants[29, 4]

In the view of most authors, routine preoperative screening in patients with no symptoms of metal hypersensitivity is not usually indicated prior to implant placement.[39]  Although Carossino et al recommended routine skin patch testing with confirmatory LTT as a standard procedure for decreasing the potential for allergy-related complications in patients undergoing arthroplasty,[63]  as a rule, testing can be considered in patients with known hypersensitivity reactions.[63]  There is no agreement on which specific patients require testing.

Prospective studies of patients who had positive skin patch test results showed no difference in reoperation rates as compared with patients who had negative skin patch test results. However, patients with known symptomatic metal allergies do have poorer results.[4]  Although skin patch testing does not predict the stability or failure of prostheses, failure rates of joint replacement have been shown to be four times higher in patients with symptomatic metal sensitivity than in those who did not have preoperative symptoms.[4]

Research into the use of anti-immunogenic coatings on implants is promising. These coatings could decrease the immune response to the medical device without compromising its function. Polyelectrolye multilayer films from hyaluronic acid have been developed, with good early experimental results. The film has a strong inhibitory effect on the production of inflammatory cytokines released by macrophages[49, 86] while promoting the release of anti-inflammatory cytokines.[86] These coatings are not yet available for clinical use,[50] but the number of reports in the literature is increasing.

Chae et al reported on a coating designed to prevent bacterial adhesion and biofilm formation that is also "immune evasive."[87] This coating successfully prevented infection without inhibiting bone healing. The authors used a lubricated surface micro/nanostructured implant in a rabbit model.

Another future goal is a more reliable preoperative test. Human primary macrophages exposed to the implantable materials ex vivo might allow prediction of an individual's reactions and in the future allow specific selection of an optimal coating composition for that individual patient to prevent or control the immune response to the implant.[50]

An online study by Mesinkovska showed that preoperative skin patch testing for metal allergy changed treatment in 68% of 31 patients undergoing revision total joint replacement.[88] The presence of known prior metal hypersensitivity was predictive of a good result with the use of an allergen-free implant for the revision surgery. Patients with known nickel allergy who require ORIF of fractures, for example, may be best treated with titanium implants when such devices are available.[4]


Osteoimmunology and Future Implant Design

The field of osteoimmunology focuses on the crucial involvement of both immune cells and bone cells in bone remodeling and the reaction of the host to foreign bodies, including orthopedic and other implants.[2]

Bone marrow provides the same microenvironment for both bone and immune cells, where they share cellular signaling pathways to cooperate tightly in bone metabolism.[3] These two groups of cells communicate via cytokines, signaling molecules, transcription factors, and receptors.[2] For example, osteoblast migration and proliferation are promoted by transforming growth factors (eg, TGF-β) and interleukins (eg, IL-4) but inhibited by tumor necrosis factors (eg, TNF-α) and other interleukins (eg, IL-1β).[2, 49]

After an implant is placed, a complex immune cascade follows that can lead to the following two possible outcomes, depending on the design of the implant[2] :

  • The response to an implant made with good osteoimmunodulatory properties includes the release of inflammatory factors that increase osteogenic cell recruitment and differentiation and therefore results in a stable implant
  • The response to an implant made with poor osteoimmunodulatory properties includes the release of inflammatory factors that promote excessive chronic inflammation with increased osteoclast activity, causing bone destruction, fibrous capsule formation, and implant loosening

An immune response always occurs. The key to success is to design implants with biomaterials that modulate the local immune environment from proinflammatory to healing.[3]  As stated by Alobaid et al, "[t]he ability to suppress adverse immune responses and promote beneficiary regulatory and pro-healing immune responses will improve the clinical outcome for implanted materials whether used as scaffolds for regenerative medicine applications or in medical devices."[52]

Dendritic cells control immune responses against implanted materials. Carbohydrates attached to tumor cells modulate dendritic cell function, switching them from inflammatory to tolerogenic; this hides the tumor from the host immune response. Use of monosaccharides as a surface coating for implants could potentially hide the implant from the host immune response in a similar manner.[52]

The surface of a biomaterial is the interface with the biologic microenvironment and determines the host response to the implant.[2]  Properties of biomaterials that can be manipulated (osteoimmunomodulated) to promote a positive immune response include the following[3] :

  • Surface topography
  • Wettability
  • Surface charge
  • Stimulation of the release of regenerative bioactive molecules and inhibition of the release of proinflammatory molecules

Surface topography

Surface topography can stimulate immune cell functions in such a way as to provide a favorable osteoimmune environment for bone incorporation. Surface roughness promotes positive cytokine secretion and improves immune cell adhesion.[2, 3] Titanium oxide nanotube structures increase surface area, thereby improving macrophage adhesion. Electrospun fibers promote bone regeneration scaffolds by virtue of their similarity to natural collagen fibrils. Pores allow vascularization and provide regulatory cues to the immune system, depending on their size and number.[3] Larger pores decrease inflammation.[2]


Wettability is strongly associated with protein layer absorption, blood clot formation and fibrin formation. Hydrophilic materials are protein-resistant[2, 3]  and decrease macrophage adhesion, thus enhancing osseointegration. When a hydrophilic surface is combined with a rough surface topography, there is a synergistic effect that yields even greater release of anti-inflammatory cytokines.[3] Hydrophobic materials have an intrinsic immunogenicity with increased monocyte adhesion.[2]

Surface charge

Surface charge changes the immune response. Anionic/neutral particles decrease inflammatory reactions, whereas cations increase inflammation.[2, 3] Various antioxidants may modulate a favorable immune response, incuding quercetin, resveratrol, and curcumin.[2]

Stimulation and inhibition of bioactive molecules

Stimulation of T cells to secrete highly immunosuppressive cytokines (eg, IL-17) may promote tolerance of implants.[52] On the other hand, inhibition of inflammatory cytokines is also a powerful method for reducing inflammation, inhibiting osteoclastogenesis, and preventing osteolysis and implant loosening. TNF-α, IL-1, and IL-6 are related to excessive inflammation with higher RANKL/OPG ratios and more active osteoclast functions.

Unfortunately, control of the signaling pathways that regulate immune cytokines is difficult and complex, and further research is required before such control can be brought within reach.[3] Carbohydrates/monosaccharides may have promising potential as materials with high immune compatibility and the ability to positively modify immune responses by stimulating dendritic cells to support T-cell phenotypes that are highly immunosuppressive.[52]