Metal Ion Release in Cancer Patients Following Megaprosthesis Salvage Surgery.

BACKGROUND: Megaprostheses contain many more modular components than conventional total hip and knee arthroplasty, which may lead to higher serum levels of metal ions. The aim of this study was to determine serum concentrations of titanium, chromium, and cobalt ions in cancer patients after limb salvage surgery with a megaprosthesis. METHODS: A retrospective, descriptive cohort analysis consisting of patients who underwent cancer-related limb salvage surgery with a megaprosthesis at our hospital between 2010 and 2020 was conducted. Baseline and follow-up data were extracted from clinical and surgical records. Blood samples were prospectively obtained. Descriptive statistics were used for the analysis. RESULTS: A total of 71 patients underwent limb salvage surgery during the study period. Of these, 22 (10 women, 12 men) were included in the study. The mean age was 52 years (range, 21 to 80). Most cases (n = 16; 72.7%) involved the femur. Most patients (n = 14, 63.6%) underwent total knee megaprosthesis surgery. Implant revision surgery was required in 45% of cases (n = 10), with a mean interval of 4.32 years between the initial and revision surgeries. The mean follow-up time after revision surgery was 4.05 years. High levels of chromium were observed in 22.7% of patients (n = 5). High cobalt levels were found in 68.2% (n = 15) of patients, with toxic levels in 9.1% (n = 2). Titanium levels were high in 77.3% (n = 17) of cases and toxic in 22.7% (n = 5). Postoperative chemotherapy was significantly associated with titanium levels (P = .017). No correlation was observed between metal ion levels and time from primary or revision surgery or time from the first to revision surgery. CONCLUSIONS: This study shows that cancer-related limb salvage surgery with megaprosthesis is associated with metal ion levels that exceed established safe thresholds. Compared to conventional hip arthroplasty, a higher proportion of the patients in this cohort presented elevated levels of metal ions. LEVEL OF EVIDENCE: III.

Plasma titanium level is positively associated with metabolic syndrome: A survey in China's heavy metal polluted regions.

OBJECTIVE: Several heavy metals have been reported to be associated with metabolic syndrome(MetS) in general population, while effects of multiple metals exposure on MetS in residents living in heavy metal polluted regions have not been investigated. We aimed to assess the association of 23 metal levels and MetS among population living in China's heavy metal polluted regions. METHODS: From August 2016 to July 2017, a total of 2109 eligible participants were consecutively enrolled in our study in Hunan province, China. The levels of plasma and urine metals were measured by inductively coupled plasma mass spectrometer (ICP-MS). MetS was defined by the criteria of the International Diabetes Federation. Multivariable regression models were applied to analysis the potential relationship. RESULTS: In the overall population, crude model showed positive relationship of plasma titanium (Ti) with MetS and negative association of urine vanadium, iron, and selenium with MetS. After adjusted for potential confounders, only plasma Ti was positive associated with MetS (adjusted OR for Q4 versus Q1: 1.46; 95% CI: 1.06-1.99), and this positive correlation was explained by abdominal obesity (OR = 1.84, 95% CI: 1.41-2.39) and high triglycerides (OR = 2.23, 95% CI: 1.68-2.96). Further linear regression analysis revealed significant association of plasma Ti levels with waist circumference (ß = 0.0056, 95% CI: 0.0004-0.0109, P = 0.036) and triglycerides (ß = 0.0012, 95% CI: 0.0006-0.0019, P < 0.001), respectively. CONCLUSION: High plasma Ti level was associated with increased risk of MetS via increasing waist circumference and triglycerides in people under high metal exposure.

Environmental titanium exposure and reproductive health: Risk of low birth weight associated with maternal titanium exposure from a nested case-control study in northern China.

Titanium (Ti) is commonly used in additives in the form of titanium dioxide (TiO2). However, our understanding of the effect of Ti on reproductive health remains limited. This nested case-control study, performed in a Ti mining exposure field, investigated the association between maternal blood Ti concentration and the risk of low birth weight (LBW), as well as the potential biological mechanism. A total of 45 women who delivered LBW infants (cases) and 352 women with normal birth weight infants (controls) were included. We collected maternal peripheral blood samples in the first or early second trimester to measure Ti concentration in serum (Tisr) and blood cells (Tibc), as well as inflammatory, lipid, and oxidative stress biomarkers thereof. The demographic characteristics of the women included in the study were also obtained. The results showed that the median total blood Ti concentration (Titb) in the case group was significantly higher than that in the control group (134 vs. 129 ng/mL, P = 0.039). A higher Titb level was associated with a greater risk of LBW [odds ratio = 2.62; 95% confidence interval (CI): 1.16-5.90], but no such association was observed for Tisr or Tibc after adjusting for potential confounders. The serum lipid biomarkers TC, TG, and total lipids (TL) were all negatively associated with Tisr and Titb. Serum 8-OHdG was positively associated with Tibc. We concluded that a high Titb during early pregnancy may increase the risk of LBW. Lipid metabolism and oxidative stress may play an important role in the adverse health effects associated with Ti exposure. Thus, our results merit more attention to the probable adverse effects of titanium exposure during pregnancy.

Benefits and Biosafety of Use of 3D-Printing Technology for Titanium Biomedical Implants: A Pilot Study in the Rabbit Model.

BACKGROUND: Titanium has been used in osteosynthesis for decades and its compatibility and safety is unquestioned. Studies have shown that there is release and collection of titanium in the organ systems with little note of toxicity. The gold standard is considered to be titanium osteosynthesis plate produced by milling methods. The use of customized titanium plates produced with 3D printing, specifically direct metal laser sintering, have found increasing use in recent years. It is unknown how much titanium is released in these printed titanium implants, which is known to be potentially porous, depending on the heat settings of the printer. We hypothesize that the amount of titanium released in printed titanium implants may be potentially more or equal compared to the gold standard, which is the implant produced by milling. METHODS: We studied the biosafety of this technology and its products by measuring serum and organ titanium levels after implantation of 3D-printed versus traditionally fabrication titanium plates and screws in a pilot study using the rabbit model. A total of nine rabbits were used, with three each in the control, milled and printed titanium group. The animals were euthanized after six months. Serum and organs of the reticuloendothelial system were harvested, digested and assayed for titanium levels. RESULTS: Organ and serum titanium levels were significantly higher in rabbit subjects implanted with titanium implants (milled and printed) compared to the control group. However, there was no significant difference in organ and serum titanium levels of subjects implanted with milled and traditionally fabricated titanium implants. CONCLUSIONS: The biosafety of use of 3D-printed titanium implants and traditionally fabricated titanium implants are comparable. With this in mind, 3D-printed custom implants can not only replace, but will very possibly surpass traditionally fabricated titanium implants in the mode and extent of use.

Unexpected varus deformity and concomitant metal ion release and MRI findings of modular-neck hip stems: descriptive RSA study in 75 hips with 8 years' follow-up.

Background and purpose - Modular-neck hip stems have been identified with corrosion-related problems from the neck-stem junction. We report an ongoing varus deformity of modular-neck hip stems with simultaneous metal ion release observed during a study comparing the migration of modular vs. standard hip stems.Patients and methods - We followed 50 patients with modular and 25 with standard neck stems using radiostereometry (RSA). At 5-year follow-up, we noted a compromised integrity of the modular stem with varus deformity in the neck-stem interface. Changes in head-tip distance as well as whole-blood ion concentration and MRI findings were analyzed. The modular stems were followed further up to 8 years.Results - The head-tip distance decreased continuously by 0.15 mm per year resulting in 1.2 (95% CI 1.0-1.4) mm at 8 years for modular stems, while for the standard stems at 5 years, the decrease was 0.09 (CI 0.0-0.2) mm or 0.02 mm/year. For the modular stems, the reduction in head-tip distance correlated to the increase in whole-blood cobalt concentration at 8 years but not to the MRI grading of tissue reactions. At 5 years, cobalt levels were 4.9 µg/L for modular stems and at 8 years 4.8 µg/L, whereas for standard stems this was 1.0 µg/L. After 8 years, 9 of 72 stems had been revised for different reasons, but only 1 with obvious adverse local tissue reaction (ALTR).Interpretation - We present a surprisingly large progressive deformation at the modular neck-stem junction, but so far without a definite clinical problem. Even the femoral head seems to show slight compression onto the taper over time. A high rate of revisions for the modular type of this stem has raised general concerns, and it has been recalled from the market.

Derivation of whole blood biomonitoring equivalents for titanium for the interpretation of biomonitoring data.

Biomonitoring equivalents (BEs) have been increasingly applied for biomonitoring purposes by regulatory bodies worldwide. The present report describes the development of a BE for titanium based on a 4-step process: (i) identification of a critical study/point of departure (PoD) supporting an established oral exposure guidance value (OEGV);, (ii) review the available oral PK data and application of a pharmacokinetic model for titanium; (iii) selection of the most appropriate biomarker of exposure in a specific tissue and calculation of steady-state tissue levels corresponding to the PoD in the critical study; and (iv) derivation of BE value adjusting for the uncertainties considered in the original OEGV assessment. Using the above 4-step approach, a blood BE value of 32.5 µg titanium/L was derived. Key components of the analysis included a pharmacokinetic model developed by investigators at the Netherlands National Institute of Public Health (RIVM) and a two-year rodent bioassay of titanium conducted by the US National Cancer Institute. The most sensitive pharmacokinetic parameter involved in the current BE derivation is the oral absorption factor of 0.02%. The provisional BE proposed in this article may be updated as new information on the pharmacokinetics of titanium becomes available.

Elevated Serum Titanium Levels in Children With Early Onset Scoliosis Treated With Growth-friendly Instrumentation.

BACKGROUND: A previous study showed significantly higher serum titanium levels in patients with early-onset scoliosis (EOS) treated with traditional growing rods (TGR) and magnetically controlled growing rods (MCGR) compared with controls. Children with vertical expandable prosthetic titanium rib (VEPTR) were not assessed. The purpose of this study was to compare serum titanium levels in EOS patients treated with TGR, MCGR, and VEPTR. We hypothesized that EOS patients treated with all forms of growth-friendly instrumentation (GFI) have elevated serum titanium levels. METHODS: This was a prospective cross-sectional case series. Serum titanium levels were collected from patients with GFI who were enrolled in an EOS database. Blood samples were collected at a clinic visit or lengthening/exchange procedure between April and December 2018. The normal range for serum titanium is 0 to 1 ng/mL. Analyses were conducted using analysis of variance and Bonferroni post hoc test. RESULTS: A total of 23 patients (2 TGR, 8 MCGR, 13 VEPTR) were analyzed. There was a significant difference in age at the time of blood sample collection (12.5 vs. 9.8 vs. 7.5 y, P=0.015) and serum titanium level (1.5 vs. 4.5 vs. 7.6 ng/mL, P=0.021) between TGR, MCGR, and VEPTR, respectively. All of the MCGR and VEPTR patients had a serum titanium level ≥2 ng/mL. Binary comparisons showed that VEPTR had a significantly higher serum titanium level than TGR (P=0.046). There was no difference in serum titanium level when MCGR was compared with TGR and VEPTR. Time from implant insertion to blood sample collection, number of rods currently implanted, total number of rods implanted throughout treatment, and number of lengthenings per patient was similar between the groups. CONCLUSIONS: Elevated serum titanium levels may be present in EOS patients treated with all forms of GFI. Although our TGR patients had indwelling implants for the longest period of time, they had the lowest serum titanium level. Repetitive chest wall motion during respiration may lead to continued wear and metal ion release with VEPTR. LEVEL OF EVIDENCE: Level II-therapeutic.

The effect of work environment on the biochemical profile of workers operating at the Ust-Kamenogorsk Titanium and Magnesium Plant.

This study explored biochemical parameters of blood in workers operating in the main workshops at the Ust-Kamenogorsk Titanium and Magnesium Plant: magnesium (Mg) workshop (furnace operator, chlorinator operator, and electrolyzer operator), titanium tetrachloride workshop (mill operator and titanium (Ti) production operator), and Ti sponge workshop (reduction furnace operator, knockout operator, and crushing machine operator). The control group consisted of 112 male workers, whose duties were not related to similar occupational hazards (plumbers, electricians, janitors cleaning the administrative building, security guards, and carpenters). The activity of gamma-glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, lactate dehydrogenase, cholinesterase, alkaline phosphate, and α-amylase and the concentration of serum calcium, Mg, phosphorus, and chloride ion were measured. To clarify the nature of pathological changes that occur in the body of mammals under the influence of toxic gases and dust, this study also included 130 sexually mature, white female rats. Animals and workers were exposed to examination of the same indicators. Changes in test results of enzymes and minerals indicated a negative impact that harmful production factors may have had on the bodies of workers. Findings showed significant fluctuations in enzyme and mineral blood profiles of workers as compared to controls. In the test animals, changes in the enzyme activity and mineral blood composition were as diverse as in the workers. These findings will be useful when identifying markers of a negative impact of harmful substances in an industrial workplace and when developing measures to prevent employees from developing an occupational disease.

In vivo blood metal ion levels in patients after total shoulder arthroplasty.

BACKGROUND: Products from metal wear have been identified as a potential cause of adverse local tissue reactions and implant failure in total hip arthroplasty. However, the role of metal ion exposure in patients after total shoulder replacement is unclear. The objective of the present study was to determine in vivo blood metal ion levels of cobalt, chromium, and titanium in patients after anatomic total shoulder arthroplasty (TSA) or reverse TSA. METHODS: A consecutive series of patients after anatomic TSA or reverse TSA was evaluated retrospectively. After exclusion of patients with additional metal implants, 40 patients with unilateral anatomic TSA (n = 20) or reverse TSA (n = 20) were available for whole-blood metal ion analysis at a mean follow-up of 28 ± 9.6 months. Twenty-three healthy individuals without metal implants served as a control group. RESULTS: Mean cobalt ion concentrations were 0.18 µg/L (range, 0.1-0.66 µg/L), 0.15 µg/L (range, 0.03-0.48 µg/L), and 0.11 µg/L (range, 0.03-0.19 µg/L), mean chromium ion levels were 0.48 µg/L (range, 0.17-2.41 µg/L), 0.31 µg/L (range, 0.09-1.26 µg/L), and 0.14 µg/L (range, 0.04-0.99 µg/L), and mean titanium ion concentrations were 1.31 µg/L (range, 0.75-4.52 µg/L), 0.84 µg/L (range, 0.1-1.64 µg/L), and 0.62 µg/L (range, 0.32-2.14 µg/L) in the reverse TSA group, the anatomic TSA group, and the control group, respectively. CONCLUSIONS: TSA resulted in elevated metal ion levels compared with healthy controls, although overall metal ion concentrations measured in this study were relatively low. The role of local metal ion exposure in patients with total shoulder replacements should be further investigated.

The role of citrate, lactate and transferrin in determining titanium release from surgical devices into human serum.

The presence of ionic titanium in the serum of patients with titanium implants is currently unexplained. This is presumed due to corrosion, and yet the serum titanium concentration measured in patients is far greater than that predicted by its solubility. The binding of titanium ion as Ti(IV) to human transferrin (hTF) in serum indicates that Ti(IV) ions interact with human physiology. This is an intriguing finding since there is currently no known role for titanium ions in human physiology. Thus, understanding the factors that determine in vivo titanium ion release is relevant to further understanding this metal's interactions with human biochemistry. The present study sought to determine the extent of titanium ion release of into human serum in vitro, and the role of citrate, lactate and hTF in this process. It was found that, when surgical devices of commercially pure titanium were placed into human serum, citrate and lactate concentrations were the prime determinants of titanium release. Crystallography revealed Ti(IV) bound to hTF in the presence of citrate alone, signalling that citrate can act as an independent ligand for Ti(IV) binding to hTF. Based on these findings, a two-stage process of titanium ion release into human serum that is dependent upon both citrate and hTF is proposed to explain the ongoing presence of titanium ion in human subjects with implanted titanium devices.

Analysis of soluble or titanium dioxide derived titanium levels in human whole blood: consensus from an inter-laboratory comparison.

Exposure to titanium (Ti), via the ingestion of pigment grade Ti dioxide (TiO2), is commonplace for westernised populations. It may also occur as a consequence of metal ion leaching in subjects bearing Ti-containing implants. Accurate exposure analysis requires fit-for-purpose analytical methodology, especially for true measures of baseline levels. Inductively coupled plasma (ICP) techniques are, mainly, now used for bio-analysis of Ti. Since whole blood reference materials, certified for natural low levels of Ti, are not currently available, we undertook an inter-laboratory comparison of pooled human blood from fasted volunteers ±low level (+∼2.5 µg L-1) or high level (+10-20 µg L-1) spikes of soluble Ti or TiO2 particles. Seven established laboratories were enrolled to analyse the samples using ICP based techniques, which included at least one of ICP optical emission spectrometry (ICP-OES), high resolution ICP mass spectrometry (HR-ICP-MS), triple quadrupole ICP-MS (ICP-MS/MS) or single quadrupole ICP-MS (SQ-ICP-MS). Five laboratories diluted the blood for analysis whilst two performed acid digestion. Overall, we showed that the laboratories could, mostly, quantitatively detect modest levels of spiked Ti in blood. Markedly varying levels of Ti, however, were reported for the same baseline pooled sample (0.4-24.6 µg L-1) and, in this study, specificity was poor for SQ-ICP-MS. Digestion of samples caused sample contamination compromising limits of detection and accuracy, whilst simple dilution had no such problem, and remained linear in response for spikes with ionic and TiO2 particles. We conclude that measuring baseline levels of Ti in whole blood is challenging but should be readily achievable down to 0.5-1.5 µg L-1, if sample preparation avoids contamination and instrument techniques are used that negate polyatomic or isobaric interferences from the sample matrix. We also remind those relying upon Ti bio-analytical data for their experimental outcomes that (a) spiking and recovery experiments provide information only on linearity of detection but not at all on accuracy as this will not detect constant positive errors and that (b) biological standard materials for Ti generally contain high levels of the analyte and tend to mask baseline analytical errors. Caution may be required in interpreting the findings of some published Ti/TiO2 bio-exposure studies.

Serum Metal Levels in Maxillofacial Reconstructive Surgery Patients: A Pilot Study.

PURPOSE: The aim of this pilot study was to assay metal concentrations in the serum of patients who had undergone dental implant placement, orthognathic surgery using rigid metal fixation plates and screws, and total temporomandibular joint replacement (TMJ TJR). MATERIALS AND METHODS: Thirty patients were identified and included in this pilot study. Sixteen patients (9 men and 8 women), with an average age of 44 years (range, 19 to 79 yr), provided informed consent to participate and were divided into 3 study groups with 4 patients in each (group 1, orthognathic surgery; group 2, TMJ TJR; and group 3, dental implant placement). A control group consisted of volunteers without any implanted metallic devices. Blood samples for serum metal analysis were obtained and analyzed in accordance with the standardized collection and testing protocols used at the Trace Metal Analysis Laboratory of the Department of Orthopedic Surgery at the Rush University Medical Center (Chicago, IL). RESULTS: All control participants had levels below the normal reference range for all serum markers assessed. In the orthognathic group, 1 patient had an increased serum cobalt level. In the TMJ TJR group, 1 patient had an increased serum cobalt level and another patient had an increased serum chromium level. In the dental implant group, 1 patient had an increased serum titanium level and another had increased serum levels of titanium and chromium. CONCLUSIONS: This is the first study to report on the release of metal into the bloodstream in patients with different maxillofacial implanted metallic objects. The results raise questions regarding the types and magnitude of metal released from maxillofacial reconstruction devices and their potential long-term local and systemic effects. Future large-scale prospective studies involving serial measurements in homogeneous groups of patients could further elucidate the impact of these findings.

Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome.

OBJECTIVE: Western lifestyle and diet are major environmental factors playing a role in the development of IBD. Titanium dioxide (TiO2) nanoparticles are widely used as food additives or in pharmaceutical formulations and are consumed by millions of people on a daily basis. We investigated the effects of TiO2 in the development of colitis and the role of the nucleotide-binding oligomerisation domain receptor, pyrin domain containing (NLRP)3 inflammasome. DESIGN: Wild-type and NLRP3-deficient mice with dextran sodium sulfate-induced colitis were orally administered with TiO2 nanoparticles. The proinflammatory effects of TiO2 particles in cultured human intestinal epithelial cells (IECs) and macrophages were also studied, as well as the ability of TiO2 crystals to traverse IEC monolayers and accumulate in the blood of patients with IBD using inductively coupled plasma mass spectrometry. RESULTS: Oral administration of TiO2 nanoparticles worsened acute colitis through a mechanism involving the NLRP3 inflammasome. Importantly, crystals were found to accumulate in spleen of TiO2-administered mice. In vitro, TiO2 particles were taken up by IECs and macrophages and triggered NLRP3-ASC-caspase-1 assembly, caspase-1 cleavage and the release of NLRP3-associated interleukin (IL)-1ß and IL-18. TiO2 also induced reactive oxygen species generation and increased epithelial permeability in IEC monolayers. Increased levels of titanium were found in blood of patients with UC having active disease. CONCLUSION: These findings indicate that individuals with a defective intestinal barrier function and pre-existing inflammatory condition, such as IBD, might be negatively impacted by the use of TiO2 nanoparticles.

Titanium Nanoparticle Size Influences Trace Concentration Levels in Skin Appendages.

As a result of biotribocorrosion, the surface of a titanium (Ti) biomedical device can be a potential source of systemic contamination with Ti nanoparticles (NPs). Although NPs can be chemically similar, differences in particle size may lead to different biological responses. The aim of this experimental study was to determine Ti trace levels in skin appendages and plasma and explore the influence of NP size on trace levels using a murine model. Results showed the presence of Ti traces in the nails, hair, and plasma. The concentration of the smallest NPs (5 Nm) was higher than that of 10 Nm NPs in all the studied samples. Irrespective of NP size, Ti levels were always lower in plasma than in skin appendages. Ti levels were higher in nails than in hair. Ti NPs size influenced trace concentration levels in hair/nails, suggesting that 5 Nm Ti particles are more easily eliminated through these skin appendages. Given that the nails showed the highest levels of Ti, and that these skin appendages are not exposed to agents that can leach out Ti, as occurs with hair, we propose the nails as the most suitable and reliable bioindicator for monitoring systemic contamination with Ti.

What Are Normal Metal Ion Levels After Total Hip Arthroplasty? A Serologic Analysis of Four Bearing Surfaces.

BACKGROUND: The recent experiences with adverse local tissue reactions have highlighted the need to establish what are normal serum levels of cobalt (Co), chromium (Cr), and titanium (Ti) after hip arthroplasty. METHODS: Serum Co, Cr, and Ti levels were measured in 80 nonconsecutive patients with well-functioning unilateral total hip arthroplasty and compared among 4 bearing surfaces: ceramic-on-ceramic (CoC); ceramic-on-polyethylene (CoP); metal-on-polyethylene (MoP), and dual mobility (DM). The preoperative and most recent University of California, Los Angeles (UCLA) and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores were compared among the different bearing surfaces. RESULTS: No significant difference was found among serum Co and Cr levels between the 4 bearing surface groups (P = .0609 and P = .1577). Secondary analysis comparing metal and ceramic femoral heads demonstrated that the metal group (MoP, modular dual mobility (Stryker Orthopedics, Mahwah, NJ) [metal]) had significant higher serum Co levels compared with the ceramic group (CoC, CoP, MDM [ceramic]) (1.05 mg/L ± 1.25 vs 0.59 mg/L ± 0.24; P = .0411). Spearman coefficient identified no correlation between metal ion levels and patient-reported outcome scores. CONCLUSION: No serum metal ion level differences were found among well-functioning total hip arthroplasty with modern bearing couples. Significantly higher serum Co levels were seen when comparing metal vs ceramic femoral heads in this study and warrants further investigation. Metal ion levels did not correlate with patient-reported outcome measures.

Ten-Year Cross-Sectional Study of Mechanically Assisted Crevice Corrosion in 1352 Consecutive Patients With Metal-on-Polyethylene Total Hip Arthroplasty.

BACKGROUND: Mechanically assisted crevice corrosion (MACC) in metal-on-polyethylene total hip arthroplasty (THA) is of concern, but its prevalence, etiology, and natural history are incompletely understood. METHODS: From January 2003 to December 2012, 1352 consecutive THA surgeries using a titanium stem, cobalt-chromium alloy femoral head, and highly cross-linked polyethylene liner from a single manufacturer were performed. Patients were followed at 1-year and 5-year intervals for surveillance, but also seen earlier if they had symptoms. Any patient with osteolysis >1 cm (n = 3) or unexplained pain (n = 85) underwent examination, radiographs, complete blood count, erythrocyte sedimentation rate, and C-reactive protein, as well as tests for serum cobalt and chromium levels. RESULTS: Symptomatic MACC was present in 43 of 1352 patients (3.2%). Prevalence of MACC by year of implant ranged from 0% (0 of 61, 2003; 0 of 138, 2005) to 10.5% (17 of 162; 2009). The M/L Taper stem had a greater prevalence (4.9%) of MACC than all other Zimmer (Zimmer, Inc, Warsaw, IN) 12/14 trunnion stem types combined (1.2%; P < .001). Twenty-seven of 43 (62.8%) patients have undergone revision surgery, and 16 of 43 (37.2%) patients have opted for ongoing surveillance. Comparing symptomatic THA patients with and without MACC, no demographic, clinical, or radiographic differences were found. MACC was significantly more common in 0 length femoral heads (compared with both -3.5 mm and +3.5 mm heads). CONCLUSION: The prevalence of MACC in metal-on-polyethylene hips is higher in this cross-sectional study than previously reported. A significantly higher prevalence was found in patients with M/L Taper style stem and THA performed both in 2009 and also between 2009 and 2012 with this manufacturer.

Metallic ion release after knee prosthesis implantation: a prospective study.

INTRODUCTION: Metal-on-metal (MoM) hip replacement bearings produce metallic ions that can cause health complications. Metallic release also occurs with other materials, but data on metallic ion levels after knee arthroplasty are sparse. We postulate that knee replacement generates elevating metallic ions (chromium (Cr), cobalt (Co) and titanium (Ti)) during the first year after implantation. PATIENTS AND METHODS: This ongoing prospective study included all patients who underwent the same type of knee arthroplasty between May and December 2013. Cr, Co and Ti levels were measured in whole blood at pre-operation and one-year follow-up (6 and 12 months). Clinical and radiographic data (range of motion, Oxford, International Knee Society (IKS) and satisfaction scores) were recorded. RESULTS: In 90 patients, preoperative Cr, Co and Ti metallic ion levels were respectively 0.45 µg/l, 0.22 µg/l, 2.94 µg/l and increased to 1.27 µg/l, 1.41 µg/l, 4.08 µg/l (p < 0.0001) at last one-year follow-up. Mean Oxford and IKS scores rose, respectively, from 45.9 (30-58) and 24.9 (12-52) to 88.3 (0-168) and 160.8 (93-200) (p < 0.001). CONCLUSION: After the implantation of knee arthroplasty, we found significant blood elevation of Cr, Co and Ti levels one year after implantation exceeding the normal values. This metallic ion release could lead to numerous effects: allergy, hypersensitivity, etc.

A multi-functional nanoplatform for tumor synergistic phototherapy.

Phototherapy, which mainly includes photothermal treatment (PTT) and photodynamic treatment (PDT), is a photo-initiated, noninvasive and effective approach for cancer treatment. The high accumulation of photosensitizers (PSs) in a targeted tumor is still a major challenge for efficient light conversion, to generate reactive oxygen species (ROS) and local hyperthermia. In this study, a simple and efficient hyaluronic acid (HA)-modified nanoplatform (HA-TiO2@MWCNTs) with high tumor-targeting ability, excellent phototherapy efficiency, low light-associated side effects and good water solubility was developed. It could be an effective carrier to load hematoporphyrin monomethyl ether (HMME), owing to the tubular conjugate structure. Apart from this, the as-prepared TiO2@MWCNTs nanocomposites could also be used as PSs for tumor PTT and PDT. Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly better than those of single treatment manner. In addition, this drug delivery system could realize high ratio of drug loading, sustained drug release, prolonged circulation in vivo and active targeted accumulation in tumor. These results suggest that HA-TiO2@MWCNTs/HMME has high potential for tumor synergistic phototherapy as a smart theranostic nanoplatform.

In vivo micronucleus studies with 6 titanium dioxide materials (3 pigment-grade & 3 nanoscale) in orally-exposed rats.

Six pigment-grade (pg) or ultrafine (uf)/nanoscale (anatase and/or rutile) titanium dioxide (TiO2) particulates were evaluated for in vivo genotoxicity (OECD 474 Guidelines) in male and female rats by two different laboratories. All test materials were robustly characterized. The BET surface areas of the pg and uf samples ranged from 7 to 17 m(2)/g and 50 to 82 m(2)/g respectively. The materials were assessed for induction of micronuclei and toxicity in bone marrow by analyzing peripheral blood reticulocytes (RETs) by flow cytometry. Single oral gavage doses of 500, 1000 or 2000 mg/kg body weight (bw) of each material were implemented with concurrent negative (water) and positive controls (cyclophosphamide). Approximately 48 and 72 h after exposure, blood samples were collected and 20,000 RETs per animal were analyzed. For each of the six tests, there were no biologically or toxicologically relevant increases in the micronucleated RET frequency in any TiO2 exposed group at either time point at any dose level. In addition, there were a lack of biologically relevant decreases in %RETs among total erythrocytes. All six TiO2 test substances were negative for in vivo genotoxicity effects; however, it is noted that the exposure to target tissues was likely negligible. One pigment grade and one ultrafine material each were evaluated for potential systemic exposure/uptake from the gastrointestinal tract by analysis of TiO2 into blood and liver. No significant increases in TiO2 over controls were measured in blood (48 or 72 h) or liver (72 h) following exposures to 2000 mg/kg bw TiO2. These data indicate that there was no absorption of the test material from the gastrointestinal tract into the blood circulation and the lack of genotoxic effects is therefore attributed to a lack of exposure due to the inability of the test material to migrate from the gastrointestinal tract into the blood and then into target tissues.

Clinical Results and Metal Ion Levels After Ceramic-on-Metal Total Hip Arthroplasty: A Mean 50-Month Prospective Single-Center Study.

BACKGROUND: The aim of our study was to investigate the clinical results and serum metal ion levels in a cohort of patients who received total hip arthroplasty (THA) with ceramic-on-metal (CoM) bearings. METHODS: From September 2009 to December 2011, 78 patients (89 hips) who underwent THA with CoM bearings were involved in this study. Harris Hip Score, Short-Form 12, and Western Ontario and McMaster Universities Osteoarthritis Index scores were measured and radiographs were taken for radiographic analysis. Serum metal ion levels of cobalt (Co), chromium (Cr), molybdenum (Mo), and titanium (Ti) were measured using high-resolution inductively coupled plasma-mass spectrometry. RESULTS: Severy-four patients (85 hips) were followed up at a mean of 50 months. At the end of follow-up, HSS, Short-Form 12, and Western Ontario and McMaster Universities Osteoarthritis Index scores were improved significantly compared with preoperative values. No intraoperative and postoperative complications occurred, and no radiolucency, osteolysis, and loosening was found from radiographic examination. Metal ion analysis showed that serum metal ions levels were significantly elevated compared with normal values. Spearman correlation analysis revealed that there was a correlation between 3 metal ion levels and body mass index(Co: r = 0.49, P < .01; Cr: r = 0.47, P < .01; Mo: r = 0.36, P = .04). No correlation was found between metal ion levels and age, cup abduction angle, cup anteversion angle, acetabular version, bilateral arthroplasty, cup screw used, hip stem implant type, or femoral head size. CONCLUSION: Our study concluded that the use of a CoM THA is effective clinically, but the systemic metal ion levels are significantly elevated at midterm follow-up. Whether the elevated metal ion levels will induce an adverse reaction is unknown and long-term follow-up is need.