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Metal debris from implants has been shown to alter the function of osteoblasts in cell cultures. Its remains unclear, however, if specific forms of released ionic metals are involved in the pathogenesis of periprosthetic osteolysis. We evaluated the relative effects of ionic forms of implant metals by treating human osteoblast-like MG-63 osteosarcoma cells with eight concentrations (0.001-10.0 mM) of Cr(+3), Mo(+5), Al(+3), Ta(+5), Co(+2), Ni(+2), Fe(+3), Cu(+2), Mn(+2), Mg(+2), Na(+2), and V(+3) chloride solutions. The results demonstrated that the metal ions differentially affected osteoblast proliferation, viability, type-I collagen gene expression, and cytokine release. The metal ions were ranked in order from least to most toxic (based on a 50% reduction in viability) as follows: Na < Cr < Mg < Mo < Al < Ta < Co < Ni < Fe < Cu < Mn < V. Metal-induced decreases in osteoblast proliferation were similar in ranking. Nontoxic concentrations of metals had no effect on procollagen alpha1[I] gene expression; only at toxic concentrations did metals produce a decrease in gene expression. The most toxic metals (V, Mn, Fe, and Ni) were also the only metals found to induce IL-6 secretion on a per cell basis (of the cytokines tested, interleukin 6 (IL-6), interleukin beta 1 (IL-1beta), transforming growth factor beta 1 (TGF-beta1), and tumor necrosis factor alpha (TNF-alpha), only IL-6 was detectable in the culture medium after 48 h for any metal at any concentration). Less toxic metals (e.g., Co and Cr) had little effect on IL-6 release, even at high concentrations. In general, metal ions reduced osteoblast function (i.e., proliferation and collagen gene expression) in proportion to the degree of toxicity. These results support the hypothesis that adverse local cellular responses (particularly necrotic responses) associated with metal debris from implanted metallic devices may be due in part to metal ions released from implants or from particulate debris., (Copyright 2002 Wiley Periodicals, Inc.)

The lymphocyte response to serum protein complexed with metal from implant alloy degradation was investigated in this in vitro study using primary human lymphocytes from healthy volunteers (n = 10). Cobalt chromium molybdenum alloy (Co-Cr-Mo, ASTM F-75) and titanium alloy (Ti-6Al-4V, ASTM F-136) beads (70 microm) were incubated in agitated human serum at 37 degrees C to simulate naturally occurring metal implant alloy degradation processes. Particulate free serum samples that had been incubated with metal were then separated into molecular weight based fractions. The amounts of soluble Cr and Ti within each serum fraction were measured and correlated with lymphocyte proliferation response to the individual serum fractions. Lymphocytes from each subject were cultured with 11 autologous molecular weight based serum fractions either with or without added metal. Two molecular weight ranges of human serum proteins were associated with the binding of Cr and Ti from Co-Cr-Mo and Ti implant alloy degradation (at <30 and 180-250 kDa). High molecular weight serum proteins ( approximately 180 kDa) demonstrated greater lymphocyte reactivity when complexed with Cr alloy and Ti alloy than low (5-30 kDa) and midrange (30-77 kDa) serum proteins. When the amount of lymphocyte stimulation was normalized to both the moles of metal and the moles of protein within each fraction (metal-protein complex reactivity index), Cr from Co-Cr-Mo alloy degradation demonstrated approximately 10-fold greater reactivity than Ti in the higher molecular weight serum proteins ( approximately 180 kDa). This in vitro study demonstrated a lymphocyte proliferative response to both Co-Cr-Mo and Ti alloy metalloprotein degradation products. This response was greatest when the metals were complexed with high molecular weight proteins, and with metal-protein complexes formed from Co-Cr-Mo alloy degradation., (Copyright 2001 John Wiley & Sons, Inc. J Biomed Mater Res 56: 427-436, 2001)

The determination of biocompatibility has been dominated historically by the characterization of candidate materials based upon the observation of adverse host responses. However, some adverse responses are subtle in clinical settings and continue to foster debate and investigation. One of these responses is "metal allergy" or hypersensitivity to metallic biomaterials. Current methods used to diagnose hypersensitivity reactions, such as dermal patch testing and migration inhibition assays, are not well accepted in orthopedic practice as a means for the characterization of hypersensitivity to metallic joint-replacement components. An increasing need to resolve whether metal sensitivity may be a significant and/or predisposing factor for eliciting an over-aggressive immune response in patients with metallic implant components requires improved and standardized widespread study. Here we present three in vitro methodologies: (1) a proliferation assay, (2) cytokine analysis using ELISA, and (3) a migration inhibition assay. When in conjunction with one another, these assays may be used to more comprehensively quantify metal-induced hypersensitivity responses. Therefore, these methodologies are detailed with the intent of facilitating multi-center large-scale studies. In the following cases, a multi-assay approach for measuring the prevalence of delayed-type hypersensitivity in orthopedic patients shows the propensity to yield a more comprehensive and, therefore, more conclusive determination than currently employed patch testing or single assay techniques., (Copyright 2000 John Wiley & Sons, Inc.)

The distribution of titanium [Ti] and chromium [Cr] in serum protein fractions of patients with and without total joint replacements containing Cr and Ti was studied. Three groups were evaluated: 10 patients with cobalt-chromium [CoCr] alloy prostheses and known elevated levels of Cr; 10 patients with Ti containing implants and known elevated levels of Ti; and 10 age matched controls without prostheses. Metal-protein binding was also examined by adding various concentrations of Cr(+3) (CrCl(3)) to control serum. Cr and Ti were bound to serum proteins within specific molecular weight ranges in both patient groups. Two molecular weight ranges were found to bind Cr (at approximately 70 and approximately 180 kDa) in patients with CoCr alloy prostheses, whereas a single molecular weight range (at approximately 70 kDa) was found to bind Ti in patients with Ti alloy implants. This metal-protein binding was reproduced in vitro by adding CrCl(3) at concentrations of approximately 100 and 1000 ppb Cr, which is orders of magnitude higher than that contained in the serum of patients with CoCr alloy implants ( approximately 3 ppb Cr). This suggests that protein binding is initiated in the periprosthetic space where metal concentrations are typically 2-3 orders of magnitude higher than that observed systemically in the serum. In vitro, high molecular weight proteins including immunoglobulins demonstrated the highest affinity to Cr. Determination of specific protein carriers of metal degradation products is an essential component in the assessment of the long-term biological affects of total joint replacement devices., (Copyright 2000 John Wiley & Sons, Inc.)

There is continued interest in the measurement of degradation products of metallic implants in biological tissues and fluids. A study was conducted to compare analytical results obtained by the Zeeman Background Corrected Atomic Absorption Spectrometric and Inductively Coupled Plasma Mass Spectrometric techniques on a uniform set of triple-element (Ti, Al, and V) spiked human serum specimens over concentration ranges up to 20 ppb (20 ng/ml). The results indicate that the two methods are comparable. The positive and negative aspects of each method of instrumental analysis are discussed.

Improved understanding of the clinical outcomes of orthopedic implants requires the study of implants at the end of their service life. Previous studies focused on the retrieval of so-called failed implants during surgical revision. Interest is now moving to the study of successful implants, which are those still in place at the patient's death. A procedure was developed for recruitment of implant patients and their families and for safe and effective device and tissue retrieval after death. More than 50 retrievals were performed to support various research efforts., (Copyright 1999 John Wiley & Sons, Inc.)

The surface characteristics of sixteen "monobloc" titanium-6% aluminum-4% vanadium (Ti6A14V) femoral components (two of the 6-Ti-28 type and 14 of the 6-Ti-32 type) retrieved after periods of 78-131 months following loosening of the femoral component, as well as two unimplanted controls, were studied. The femoral heads were examined by a combination of noncontact light profilometry, scanning electron microscopy, and energy-dispersive X-ray analysis. No consistent correlations were found between classical surface roughness parameters (average, root mean square, peak-to-valley roughness, and radius of curvature) and any clinical parameter studied (patient gender, weight, and height; primary diagnosis; implantation time; or calculated force applied on the hip joint). This extensive quantitative topographic analysis suggests that wear mechanisms in vivo are complex and that wear of titanium alloy femoral heads is partly attributed to a combination of an imperfect nature of the surface before implantation, removal of the oxide layer causing abrasion of the alloy, subsequent deformation of the bearing surface including polishing, and, to a very small degree, patient parameters.

Particulate wear-debris are detected in histiocytes/macrophages of granulomatous tissues adjacent to loose joint prostheses. Such cell-particle interactions have been simulated in vitro by challenging macrophages with particles dosed according to weight percent, volume percent, and number of particles. Each of these dosage methods has inherent shortcomings due to varying size and density of challenging particles of different compositions. In this study we challenged P388D1 macrophages with titania and polystyrene particles (< 2 microns), with dosage based on the ratio of the surface area of the particles to the surface area of the cells. The effect of size and composition on (1) the bone resorbing activity, (2) fibroblast proliferation, and (3) secretion of IL-1 and PGE2 was determined. Macrophage response to particulate debris appears to be dependent on particle size, composition, and dose as given by surface area ratio. P388D1 macrophages challenged with titania particles released IL-1, but did not stimulate fibroblasts. Inhibition of macrophage DNA synthesis at higher surface area ratios suggests cell damage or death. Particle-stimulated cells increased bone resorption up to 125% of controls but released only basal levels of PGE2. Macrophages stimulated by wear particles are expected to synthesize numerous factors affecting events in the bone-implant interface. Using the concept of surface area ratio allows us to study and compare such cellular responses to wear particles in a standardized manner.

One hundred forty-eight retrieved modular hip prostheses of both mixed (Ti-6Al-4V/Co-Cr) and similar (Co-Cr/Co-Cr) metal combinations were examined and positive evidence of corrosive attack was found in the conical taper region between head and stem. Significant corrosion was observed in both mixed and similar metal combinations with 16% of necks and 35% of heads (for mixed-metal cases), and 14% of necks and 23% of heads (for similar-metal cases) showing moderate to severe corrosive attack. There was a significant correlation between the percentage of prostheses with moderate to severe corrosion and the duration of implantation for both mixed and similar metal cases, indicating that this corrosion process is progressive in time. Moderate to severe corrosion was seen as early as 2.5 and 11 months (mixed and similar metals, respectively). Scanning electron microscopy and x-ray analysis identified several forms of corrosive attack in the cobalt-based component of the taper. These included, for both mixed and same metal combinations: preferential dissolution of cobalt, fretting, and pitting; mixed metals only: the formation of a Ti-Cr-Mo interfacial phase and interdendritic corrosion; and for similar metals: intergranular attack adjacent to grain boundaries enriched in molybdenum and silicon. It is hypothesized that the restricted crevice environment, coupled with high cyclic stresses which cause repeated fracture of the passive oxide films in the taper, result in an unstable electrochemical environment within the crevice for both the cobalt alloy and Ti-alloy passive films. The passivity of these alloys is subsequently lost and active attack of the taper results. Also, the repeated fracturing of the passive films will result in large amounts of corrosion products being formed. This corrosion and particulate accumulation could result in loss of mechanical integrity of the implants in vivo, create particles for third body wear, and release particles into the surrounding tissues.

The addition of up to 10 g gentamicin sulfate antibiotic powder to 60 g units of Simplex-P acrylic bone cement caused gradual, proportional decreases in the bulk muchanical properties of compressive and diametral tensile strengths. Water leaching of the antibiotic from the cement did not significnatly decrease these strenghts. Scanning electron microscopy (SEM) and energy-dispersive x-ray spectroscopy (EDS) showed the antibiotic to reside in the acrylic matrix as discrete particles not usually associated with internal porosity. The surface-sensitive flexural strength of a proprietary bone cement was lowered immediately by small quantities of antibiotic powder, and continued to decrease as doses of up to 10 g/unit were admixed. Water leaching caused channeling as the antibiotic was removed from the surface, but it did not create further changes in flexural strength.