Local Tissue Reaction Research Articles

Metal Articulations as a Source of Total Hip Arthroplasty Pain

The consensus systematic risk stratification algorithm from the American Association of Hip and Knee Surgeons, the American Academy of Orthopaedic Surgeons, and The Hip Society summarizes clinical challenges in evaluation and treatment of metal-on-polyethylene total hip arthroplasty (THA) patients with adverse local tissue reaction (ALTR) due to mechanically assisted crevice corrosion (MACC), reviews up-to-date evidence, and identifies the areas for future research in order to provide a useful resource for orthopedic surgeons providing care to these patients. A painful THA has various intrinsic and extrinsic causes. ALTR is one of the intrinsic causes in patients with painful THA. The occurrence of ALTR due to MACC at modular junctions is likely to be multifactorial, including implant, surgical, and patient factors. Therefore, a systematic evaluation needs to involve a focused clinical history, detailed physical examination, laboratory tests, and imaging in order to identify potential differential diagnoses. There should be a low threshold to perform a systematic evaluation of patients with painful non–metal-on-metal THA, including patients with metal-on-polyethylene THA, and modular dual-mobility THA with the CoCr metal acetabular insert, as early recognition and diagnosis of ALTR due to MACC will facilitate initiation of appropriate treatment prior to significant adverse biological reactions. Specialized tests such as blood metal analysis and metal artifact reduction sequence magnetic resonance imaging are important modalities in evaluation and management of ALTR in patients with painful THA.

Minimal Clinically Important Difference (MCID) at One Year Postoperatively in Aseptic Revision Total Hip Arthroplasty

BackgroundOutcomes after aseptic revision total hip arthroplasty (THA) are variable, and it is unknown whether the indication for aseptic revision THA influences postoperative clinical improvement. The minimal clinically important difference (MCID) assesses if changes in patient-reported outcome measure result in meaningful clinical benefit to patients. The purpose of this study was to quantify the 1-year postoperative MCID for aseptic revision THA and to assess the percentage of patients achieving the MCID for each revision diagnosis. MethodsA prospective, single-institution registry of revision total joint arthroplasties was used. Retrospective review of 413 first-time aseptic revision THAs was performed. Demographics, revision diagnosis, preoperative Hip Disability and Osteoarthritis Outcome Score, Joint Replacement (HOOS Jr.), and 1-year postoperative HOOS Jr. were recorded. The MCID for the HOOS Jr. at one year postoperatively was calculated for each revision diagnosis using a distribution-based method. The percentage of patients exceeding the MCID with each diagnosis was determined. ResultsThere were 9 aseptic revision diagnoses, all with n ≥ 5. The 3 most common revision diagnosis were aseptic loosening (n = 114), dislocation or instability (n = 103), and polyethylene wear or osteolysis (n = 73). The MCID for all the aseptic revision THAs was 10.9. Seven of the nine revision diagnoses achieved the MCID. The highest percentage of patients achieving the MCID was for aseptic loosening (84.2%) and implant fracture (81.3%), whereas lowest was for adverse local tissue reaction (35.3%) and implant recall (20.0%). ConclusionThe one-year revision THA MCID is 10.9 for the HOOS Jr. There is variability in the percentage of patients achieving the MCID based on diagnosis. Our data can be used to counsel patients undergoing revision THA for noninfectious etiologies.

Midterm results of the Birmingham hip resurfacing: a single-surgeon series.

Birmingham hip resurfacing (BHR) is readily used as alternative to total hip replacement in younger patients. The current study aims to compare outcomes in terms of adverse local tissue reactions (ALTR), elevated metal ion levels and survival rates between low-risk (femoral component size ≥ 48mm) and high-risk (femoral component size < 48mm) BHR patients at a minimum 5-year follow-up (FU). We report the minimum 5-year, single surgeon outcome results of 183 BHRs, performed between 2007 and 2012. 154 patients, 18 women (20 hips) and 136 men (163 hips) were included in the study. Patients were grouped in 149 low-risk cases (femoral component size ≥ 48mm) and in 34 high-risk cases (18 female/12 male) patients with a femoral head size < 48mm). At a minimum of 5-years FU time, 91% of the patients were available for FU. The overall survival rate was 91.8%. There were five revisions (survival rate 96.6%) in the low-risk group and ten revisions (survival rate 70.6%) in the high-risk group. In the low-risk group, six patients (6.5%) showed elevated metal ion levels (> 7μg/l), compared to five patients (20.8%) in the high risk-group (p = 0.03). Including the surgeon's initial learning curve, the BHR shows very good mid-term survival rates in the low-risk group but should, as previously demonstrated, not be considered for patients with less than 48mm femoral head size. Level III: retrospective cohort study.

Predictors of Adverse Local Tissue Reaction in a High-Risk Population.

BackgroundAdverse local tissue reaction (ALTR) is a recognized complication of total hip arthroplasty (THA) with metal-on-polyethylene (MoP) bearing surface implants. Specific models of THA implants have been identified as having a higher incidence of ALTR. The purpose of this study is to determine if serum metal levels, patient symptoms, implant factors, and imaging findings can be predictive of ALTR within this high-risk population.MethodsWe retrospectively reviewed an observational cohort of 474 patients who underwent MoP THA and were at increased risk of having ALTR. Patients were stratified based on the presence or absence of ALTR. Patient symptoms, serum metal ions, implant head offset, and imaging findings were compared.ResultsPatients with ALTR were more likely to be symptomatic (52.9% vs 9.9%, P < .0001). The presence of ALTR was associated with significantly higher serum cobalt and chromium levels (6.2 ppb vs 3.6 ppb, P < .0001; 2.3 ppb vs 1.2 ppb, P < .0001). Head offsets greater than 4 mm were associated with a higher prevalence of ALTR (53% vs 38%, P = .05). On metal artifact reduction sequence magnetic resonance imaging, patients with ALTR had larger effusions (4.7 cm vs 2.1 cm, P < .001) and a higher incidence of trochanteric bursitis (47% vs 16%, P < .001).ConclusionsIn high-risk MoP implants, serum cobalt and chromium levels are elevated, even in patients without ALTR. A larger femoral head offset is a risk factor for the development of ALTR. Our study suggests that patients presenting with painful THA and elevated metal ions require risk stratification based on patient symptoms, metal artifact reduction sequence magnetic resonance imaging findings, and implant factors.

Morphological evaluation of orbital implants in postenucleation reconstruction (an experimental study)

Comparison of materials biocompatibility, design of different orbital implants and morphological condition of formed postenucleation stumps in an in vivo experiment. In the course of the study 24 rabbits were operated, divided into three comparable groups. Enucleation with primary implantation of an orbital implant was performed in all subjects. The following implants were used: polymeric orbital implant - in the main (experimental) group, polytetrafluorethylene insertion implant - in the control group 1, and silicone endoprosthesis - in the control group 2. We assessed features of the implantation process, implant design, general condition of the operated animals, condition of the postenucleation stumps, passive motility of the stumps, and reaction of the surrounding tissues to the implants. Performed surgeries did not negatively affect the general condition of the rabbits, and there was no significant local tissue reaction to the implants. The structural and design features of the implants used in the main group were found to be more convenient for implantation, ensured stable fixation and position in the orbit. Postenucleation stump motility was comparable in all groups during the early postoperative period. This parameter decreased at later follow-up times mostly in the control group 2. When extracting the implants, it was revealed that in the main group it had secure fixation to the orbital tissues and stable position, did not cause abundant proliferation of connective tissue. Pathomorphological examination revealed that tissue reaction to the implants was less prominent and was reversed soon with fine connective tissue capsule formation in the main group and control group 2. In the control group 1 tissue reaction increased progressively, and capsule formation was delayed. Polymeric implant is the most suitable orbital implant for postenucleation orbital reconstruction.

Determination of Incidence of Soft Tissue Reactions after Total Hip Replacement using Elastography and Role of Elastography in Screening of Periprosthetic Soft Tissue: A Prospective Observational Study

Introduction: Adverse local tissue reactions after Total Hip Replacement (THR) have been widely described in literature recently as a course of aseptic loosening. Evaluation for any adverse soft tissue reactions is challenging with traditional imaging techniques like Magnetic Resonance Imaging (MRI), and are limited, due to production of metallic artifact. Ultrasound, specifically its refined form elastography, has emerged recently as a useful tool for assessing the soft tissues. Aim: To determine the incidence of soft tissue reactions in cases of THR and to evaluate role of elastography in assessment of periprosthetic soft tissue. Materials and Methods: This prospective observational study was conducted in the Department of Orthopaedics, Dr. Hardas Singh Orthopaedic Hospital, Amritsar, Punjab, India, from May 2013 to April 2014. Study comprises of consecutively followedup 66 hips which were evaluated and assessed clinically and radiologically using ultrasound elastography for periprosthetic soft tissue and degree of fibrosis. The MRI was done in patients with positive findings only. Diagnosis was then confirmed with biopsy in patients who underwent revision surgery. Incidence of clinical symptoms, implant loosening, stability of implant, various types of soft tissue reactions, pseudotumour formation and synovial hypertrophy were determined and association between clinical and radiological findings was done. Chi-square test was determined to see the statistical significance. Results: Total of 66 hips were studied in 60 patients with mean age of 56.08±16.55 years (26-95 years). The incidence of soft tissue reactions observed in the study was 83.3% (n=55), of all 66 hips 36 were symptomatic, Implant loosening was seen in 29 hips, pseudotumours were detected in 3 (4.5%) hips, cystic nodules in 2 (3.0%) hips, enlarged lymph nodes in one (1.5%) hip, fibrogranuloma in 2 (3%) hips and synovial thickening was seen in 12 hips. Association of Harris Hip Score with capsular thickness, implant stability and acetabular loosening was found to be statistically significant. Conclusion: The study shows a substantially higher incidence of soft tissue reaction and capsular hypertrophy following THR. Ultrasound elastography is a good screening tool to detect early soft tissue changes in periprosthetic tissue.

Biomimetic Ceramic Composite: Characterization, Cell Response, and In Vivo Biocompatibility.

The present study aimed to synthesize biphasic calcium phosphate ceramics (CaPs) composed of β-tricalcium phosphate (β-TCP) and hydroxyapatite (HAp) from the propagated Scleractinian coral and dicalcium phosphate anhydrous using a solid-state reaction followed by heat treatment at a temperature of 1100 °C for 1 h to 7 days. The as-prepared coral and coral-derived biphasic CaPs samples were characterized through scanning electron microscopy, X-ray diffractometry, Fourier transform infrared spectroscopy, and Raman spectroscopy. The cell response of the biphasic CaPs was evaluated by in vitro cytotoxicity assessment using mouse fibroblast (L929) cells. The bilateral femoral defect rabbit model was used to assess the early local reaction of the coral-derived biphasic CaPs bone graft on tissue. The results confirmed that the co-existence of β-TCP and HAp was formed at 1100 °C for 1 h. The ratio of HA/β-TCP increased as the heat-treatment time increased. The coral-derived biphasic CaPs comprising 61% HAp and 39% β-TCP (defined as HT-3) were not cytotoxic. Furthermore, no significant differences in local tissue reaction were observed between the HT-3 sample and autogenous bone. Therefore, the synthesized coral-derived biphasic CaPs is a candidate for bone grafting due to its good biocompatibility.

Adverse local tissue reaction after ceramic-on-ceramic total hip arthroplasty

Outside of cobalt-chromium alloy articulations, the development of adverse local tissue reaction (ALTR) after total hip arthroplasty (THA) is uncommon but remains a significant complication [1]. ALTR is used to describe a granulomatous or destructive cystic lesion that develops around a THA [1,2]. The patient often describes the first sign of the development of ALTR and pseudotumor formation as discomfort and pain. ALTR causes soft tissue mass, osteolysis, bone erosion, and significant damage to periarticular soft tissues, leading to total joint failure and instability [1]. In THA, ALTR may develop around metal-onpolyethylene implants due to taper corrosion and around metal-on-metal (MoM) bearing surfaces [3-6].

Biocompatibility Analyses of HF-Passivated Magnesium Screws for Guided Bone Regeneration (GBR).

Background: Magnesium (Mg) is one of the most promising materials for human use in surgery due to material characteristics such as its elastic modulus as well as its resorbable and regenerative properties. In this study, HF-coated and uncoated novel bioresorbable magnesium fixation screws for maxillofacial and dental surgical applications were investigated in vitro and in vivo to evaluate the biocompatibility of the HF coating. Methods: Mg alloy screws that had either undergone a surface treatment with hydrofluoric-acid (HF) or left untreated were investigated. In vitro investigation included XTT, BrdU and LDH in accordance with the DIN ISO 10993-5/-12. In vivo, the screws were implanted into the tibia of rabbits. After 3 and 6 weeks, degradation, local tissue reactions and bony integration were analyzed histopathologically and histomorphometrically. Additionally, SEM/EDX analysis and synchrotron phase-contrast microtomography (µCT) measurements were conducted. The in vitro analyses revealed that the Mg screws are cytocompatible, with improved results when the surface had been passivated with HF. In vivo, the HF-treated Mg screws implanted showed a reduction in gas formation, slower biodegradation and a better bony integration in comparison to the untreated Mg screws. Histopathologically, the HF-passivated screws induced a layer of macrophages as part of its biodegradation process, whereas the untreated screws caused a slight fibrous tissue reaction. SEM/EDX analysis showed that both screws formed a similar layer of calcium phosphates on their surfaces and were surrounded by bone. Furthermore, the µCT revealed the presence of a metallic core of the screws, a faster absorbing corrosion front and a slow absorbing region of corroded magnesium. Conclusions: Overall, the HF-passivated Mg fixation screws showed significantly better biocompatibility in vitro and in vivo compared to the untreated screws.

High Incidence of Mechanically Assisted Crevice Corrosion at 10 Years in Non-Cemented, Non-Recalled, Contemporary Total Hip Arthroplasties

BackgroundOne percent to 3% of contemporary non-cemented total hip arthroplasties (THAs) present with symptomatic mechanically assisted crevice corrosion (MACC). The incidence of this problem, however, as well as the rate of asymptomatic elevations in serum cobalt, is unknown. MethodsCobalt and chromium levels were obtained in conjunction with radiographs at routine 10-year surveillance follow-up of THAs from a single manufacturer with a titanium stem, cobalt alloy femoral head, and cross-linked polyethylene countersurface. ResultsTen-year follow-up of patients with 162 consecutive THAs revealed that 17 patients with 18 hips had died of unrelated causes prior to metal ion testing. Two hips were revised for other reasons, and of the remaining 142 hips, 33 were in patients who were lost, leaving 109 hips (77% of those in alive patients and unrevised for other reasons and 67% of the entire cohort) for investigation. Sixty-three patients (58%) had a serum cobalt less than 1 ppb, and 35 (32%) a cobalt of ≥1 ppb, a cutoff consistent with MACC. Of the 32 hips with definite MACC, 15 of 32 (47%) patients were symptomatic, 16 of 30 (53%) patients had adverse local tissue reaction on magnetic resonance imaging, and 19 of 32 (59%) patients have undergone revision surgery for MACC to date. ConclusionAt 10-year follow-up, a minimum of 22% (35/162) of hips had a cobalt level more than 1 ppb, consistent with MACC. Symptoms and adverse local tissue reactions are each present about one-half of the time, and 59% of those with documented MACC have undergone revision.

Reproducibility of pathologic scoring systems for periprosthetic adverse local tissue reactions: A cross-sectional study

BackgroundSeveral previous studies have described broad histologic classifications of peri-prosthetic reactions that likely reflect the underlying mechanism of arthroplasty failure; however, a consensus has not yet been reached about the relative importance of individual observations. Question/PurposeThe purpose of this study was to evaluate the inter-examiner repeatability of commonly used histopathologic grading methods, and to determine the utility of assigning a more simple, global categorization in patients undergoing revision THA surgery of implants with a variety of bearing combinations. MethodsBetween March 2013 and February 2020, a total of 2131 patients underwent revision hip arthroplasty surgery at a one center, of which 12% (248 of 2131) of patients were enrolled. Two pathologists independently reviewed microscope slides of periprosthetic tissue from these patients, of which 425 slides (229 hips, 222 subjects) were reviewed by both pathologists. Separate slides were used for a priori training of the pathologists. Slides were evaluated with the Campbell Aseptic Lymphocyte-dominant Vasculitis-Associated Lesion (ALVAL) score, the Oxford ALVAL score as modified by Grammatopolous, the Fujishiro and Natu scores, and a proposed simplified pattern classification, similar to that of Krenn et al., that incorporates individual factors of these existing scoring methods and was previously shown to correspond to Magnetic Resonance Imaging findings. Inter-rater agreement was assessed using Gwet’s AC1 and AC2 coefficients and correspondence analysis was used to examine associations between individual factors of prior scoring methods with the proposed major pattern. ResultsAlmost perfect inter-rater repeatability (Gwet’s AC2 > 0.8) was found for 71% (15/21) of the individual factors, and substantial interrater agreement was found for the proposed major overall pattern (Gwet’s AC1: 0.80, 95%CI: 0.72–0.85). Correspondence analysis was able to explain 89–91% of data variability and was able to identify individual features not commonly associated with a major pattern, but discriminatory of the major pattern, such as “Lymph Cuff Thickness 0.25–0.5″ with ALVAL. ConclusionIn contrast to prior examinations, excellent interrater agreement was found that may be attributable to a priori training of raters with a test set of slides or difficulty of interpreting grading criteria. The proposed simplified major pattern classification may facilitate evaluation of histopathologic tissue samples.

An In vivo Experimental Study on Investigation of the Osseointegration of Zeolites A and Silicalite in Rats

Background: Zeolites are naturally occurring and can be artificially synthesized hydrated microporous crystallized aluminosilicates. Thus far, medical materials have comprised polycrystalline materials, glass, glass-ceramics and ceramic-filled composites for bone repair. The study aimed to investigate the potential in vivo osseointegration of two types of zeolites (A and silicalite) in rats by histologically presenting the repair process. Methods: Bone cavities of 1 mm3 were formed in rats and filled either with zeolite A or silicalite to investigate the possibility of using zeolites to repair bone defects. A comparative histological evaluation was performed regarding the interaction of zeolites with bone tissue and their osseointegration capacity for 15, 30 and 45-day intervals. Result: According to the results obtained, the growth of both fibrous and bone tissues took place around the zeolites placed in the live organism. It was observed that the zeolites used in this study did not give rise to necrosis, local tissue reaction, allergic or and any other harmful response. In conclusion, histopathology revealed that zeolites A and silicalite were biocompatible with the bone and could integrate with it at certain time intervals.

Delivery of local anaesthetics by a self-assembled supramolecular system mimicking their interactions with a sodium channel.

Site-1 sodium channel blockers (S1SCBs) act as potent local anaesthetics, but they can cause severe systemic toxicity. Delivery systems can be used to reduce the toxicity, but the hydrophilicity of S1SCBs makes their encapsulation challenging. Here, we report a self-assembling delivery system for S1SCBs whose design is inspired by the specific interactions of S1SCBs with two peptide sequences on the sodium channel. Specifically, the peptides were modified with hydrophobic domains so that they could assemble into nanofibres that facilitated specific binding with the S1SCBs tetrodotoxin, saxitoxin and dicarbamoyl saxitoxin. Injection of S1SCB-carrying nanofibres at the sciatic nerves of rats led to prolonged nerve blockade and to reduced systemic toxicity, with benign local-tissue reaction. The strategy of mimicking a molecular binding site via supramolecular interactions may be applicable more broadly to the design of drug delivery systems for receptor-mediated drugs.

Interfacial compliance, energy dissipation, frequency effects, and long-term fretting corrosion performance of Ti-6Al-4V/CoCrMo interfaces.

Fretting corrosion in modular orthopedic implants is a well-documented process that may be associated with adverse local tissue reactions, pain, and revisions. Engineering modular junction interfaces to withstand applied fretting motion without surface abrasion could prevent implant degradation and surface damage. Previous work on geometrically modified Ti-6Al-4V/CoCrMo interfaces with increased compliance showed reduced fretting currents and surface damage during short term, variable-load in vitro testing. This study assesses the same interfaces under long-term conditions using an in vitro pin-on-disk fretting corrosion test apparatus. Preliminary variable-load frequency testing of typical control pin geometries showed a frequency-dependent current response, with underlying contact conditions of metal-metal interfaces that remained unchanged. One-million-cycle testing showed diminished fretting currents in all groups by 5× 105 cycles, but consistently lower currents in the high-compliance group. Corresponding fretting currents and work of fretting measurements of high-compliance pins confirmed that minimal fretting was experienced at the interface, with elastic bending of the pin accounting for almost all applied displacement. Debris generated during testing were composed of titanium and chromium oxides, small amounts of cobalt and molybdenum oxides, and sodium and phosphate originating from the surrounding test solution. Post-test analyses of sample surfaces revealed substantially more surface damage on CoCrMo disks than Ti-6Al-4V pins, thought to be a result of adhesive wear of mixed oxide debris on the pin and abrasion of the disk by the oxide debris layer. Surface damage to high-compliance pins suggests some abrasion is unavoidable with geometric modifications.

Local Inflammatory Response after Intramuscularly Implantation of Anti-Adhesive Plasma-Fluorocarbon-Polymer Coated Ti6AI4V Discs in Rats.

Orthopaedic implants and temporary osteosynthesis devices are commonly based on Titanium (Ti). For short-term devices, cell-material contact should be restricted for easy removal after bone healing. This could be achieved with anti-adhesive plasma-fluorocarbon-polymer (PFP) films created by low-temperature plasma processes. Two different PFP thin film deposition techniques, microwave (MW) and radiofrequency (RF) discharge plasma, were applied to receive smooth, hydrophobic surfaces with octafluoropropane (C3F8) or hexafluorohexane (C6F6) as precursors. This study aimed at examining the immunological local tissue reactions after simultaneous intramuscular implantation of four different Ti samples, designated as MW-C3F8, MW-C6F6, RF-C3F8 and Ti-controls, in rats. A differentiated morphometric evaluation of the inflammatory reaction was conducted by immunohistochemical staining of CD68+ macrophages, CD163+ macrophages, MHC class II-positive cells, T lymphocytes, CD25+ regulatory T lymphocytes, NK cells and nestin-positive cells in cryosections of surrounding peri-implant tissue. Tissue samples were obtained on days 7, 14 and 56 for investigating the acute and chronical inflammation (n = 8 rats/group). Implants with a radiofrequency discharge plasma (RF-C3F8) coating exhibited a favorable short- and long-term immune/inflammatory response comparable to Ti-controls. This was also demonstrated by the significant decrease in pro-inflammatory CD68+ macrophages, possibly downregulated by significantly increasing regulatory T lymphocytes.

CORR Insights®: Adverse Local Tissue Reactions are Common in Asymptomatic Individuals After Hip Resurfacing Arthroplasty: Interim Report from a Prospective Longitudinal Study.

CORR Insights®: Adverse Local Tissue Reactions are Common in Asymptomatic Individuals After Hip Resurfacing Arthroplasty: Interim Report from a Prospective Longitudinal Study.

The 20-year results of the first 400 Conserve Plus hip resurfacing arthroplasties.

Adverse local tissue reactions associated with abnormal wear considerably slowed down the general use of metal-on-metal (MoM) hip resurfacing arthroplasty (HRA), now limited to a few specialized centres. In this study, we provide the clinical results of 400 consecutive MoM HRAs implanted more than 20 years ago in one such centre. A total of 355 patients (400 hips) were treated with Conserve Plus HRA between November 1996 and November 2000. There were 96 female (27%) and 259 male patients (73%). Their mean age was 48.2 years (SD 10.9). The University of California, Los Angeles (UCLA) hip scores and 12-item Short Form Survey (SF-12) quality of life scores were reported. Survivorship was assessed using Kaplan-Meier analyses. The mean follow-up was 16.5 years (0.1 to 24.0), including 34 patients (37 hips) who died. The mean UCLA hip scores were 9.3 (2 to 10), 9.1 (3 to 10), 9.0 (3 to 10), and 6.9 (2 to 10) for pain, walking, function, and activity, respectively. The mean SF-12 scores were 48.4 (16.0 to 62.1) for the physical component and 48.5 (10.5 to 66.5) for the mental component, and did not differ from those of the general population of the USA. A total of 60 hips in 55 patients were revised. Using revision for any indication as the endpoint, the Kaplan-Meier survivorship was 83.5% at 20 years. A diagnosis of developmental dysplasia (hazard ratio (HR) 2.199 (95% confidence interval (CI) 1.140 to 4.239); p = 0.019) and a low BMI (HR 0.931 (95% CI 0.873 to 0.994); p = 0.032) were risk factors for revision. Female sex was a risk factor only because of hip dysplasia and small component size. There were no cases of metal sensitivity associated with revision surgery. Radiological analysis showed persistent fixation in all but one hip. The 83.5% 20-year survivorship of this initial series surpasses that of total hip arthroplasties in use 20 years ago in these young patients, suggesting satisfactory lifelong durability of the device for almost all of the remaining patients. Cite this article: Bone Joint J2021;103-B(7 Supple B):25-32.

Cobalt ions induce metabolic stress in synovial fibroblasts and secretion of cytokines/chemokines that may be diagnostic markers for adverse local tissue reactions to hip implants

Adverse local tissue reactions (ALTRs) are a prominent cause of hip implant failure. ALTRs are characterized by aseptic necrosis and leukocyte infiltration of synovial tissue. The prevalence of ALTRs in hips with failing metal implants, with highest rates occurring in patients with metal-on-metal articulations, suggests a role for CoCrMo corrosion in ALTR formation. Although hypersensitivity reactions are the most accepted etiology, the precise cellular mechanism driving ALTR pathogenesis remains enigmatic. Here we show that cobalt ions released by failing hip implants induce mitochondrial stress and cytokine secretion by synovial fibroblasts: the presumptive initiators of ALTR pathogenesis. We found that in-vitro treatment of synovial fibroblasts with cobalt, but not chromium, generated gene expression changes indicative of hypoxia and mitophagy responses also observed in ALTRs biopsies. Inflammatory factors secreted by cobalt-exposed synovial fibroblasts were among those most concentrated in ALTR synovial fluid. Furthermore, both conditioned media from cobalt-exposed synovial fibroblasts, and synovial fluid from ALTRs patients, elicit endothelial activation and monocyte migration. Finally, we identify the IL16/CTACK ratio in synovial fluid as a possible diagnostic marker of ALTRs. Our results provide evidence suggesting that metal ions induce cell stress in synovial fibroblasts that promote an inflammatory response consistent with initiating ALTR formation. Statement of significanceWe demonstrate that the cytotoxic effects of cobalt ions on the synovial cells (fibroblast) is sufficient to trigger inflammation on hip joints with metal implants. Cobalt ions affect mitochondrial function, leading to the auto phagocytosis of mitochondria and trigger a hypoxic response. The cell's hypoxic response includes secretion of cytokines that are capable of trigger inflammation by activating blood vessels and enhancing leukocyte migration. Among the secreted cytokines is IL-16, which is highly concentrated in the synovial fluid of the patients with adverse local tissue reactions and could be use as diagnostic marker. In conclusion we define the cells of the hip joint as key players in triggering the adverse reactions to hip implants and providing biomarkers for early diagnosis of adverse reactions to hip implants.

Revealing Inflammatory Indications Induced by Titanium Alloy Wear Debris in Periprosthetic Tissue by Label-Free Correlative High-Resolution Ion, Electron and Optical Microspectroscopy.

The metallic-associated adverse local tissue reactions (ALTR) and events accompanying worn-broken implant materials are still poorly understood on the subcellular and molecular level. Current immunohistochemical techniques lack spatial resolution and chemical sensitivity to investigate causal relations between material and biological response on submicron and even nanoscale. In our study, new insights of titanium alloy debris-tissue interaction were revealed by the implementation of label-free high-resolution correlative microscopy approaches. We have successfully characterized its chemical and biological impact on the periprosthetic tissue obtained at revision surgery of a fractured titanium-alloy modular neck of a patient with hip osteoarthritis. We applied a combination of photon, electron and ion beam micro-spectroscopy techniques, including hybrid optical fluorescence and reflectance micro-spectroscopy, scanning electron microscopy (SEM), Energy-dispersive X-ray Spectroscopy (EDS), helium ion microscopy (HIM) and micro-particle-induced X-ray emission (micro-PIXE). Micron-sized wear debris were found as the main cause of the tissue oxidative stress exhibited through lipopigments accumulation in the nearby lysosome. This may explain the indications of chronic inflammation from prior histologic examination. Furthermore, insights on extensive fretting and corrosion of the debris on nm scale and a quantitative measure of significant Al and V release into the tissue together with hydroxyapatite-like layer formation particularly bound to the regions with the highest Al content were revealed. The functional and structural information obtained at molecular and subcellular level contributes to a better understanding of the macroscopic inflammatory processes observed in the tissue level. The established label-free correlative microscopy approach can efficiently be adopted to study any other clinical cases related to ALTR.

The contribution of the histopathological examination to the diagnosis of adverse local tissue reactions in arthroplasty.

The histopathological examination of the periprosthetic soft tissue and bone has contributed to the identification and description of the morphological features of adverse local tissue reactions (ALTR)/adverse reactions to metallic debris (ARMD). The need of a uniform vocabulary for all disciplines involved in the diagnosis and management of ALTR/ARMD and of clarification of the parameters used in the semi-quantitative scoring systems for their classification has been considered a pre-requisite for a meaningful interdisciplinary evaluation.This review of key terms used for ALTR/ARMD has resulted in the following outcomes: (a) pseudotumor is a descriptive term for ALTR/ARMD, classifiable in two main types according to its cellular composition defining its clinical course; (b) the substitution of the term metallosis with presence of metallic wear debris, since it cannot be used as a category of implant failure or histological diagnosis; (c) the term aseptic lymphocytic-dominated vasculitis- associated lesion (ALVAL) should be replaced due to the absence of a vasculitis with ALLTR/ALRMD for lymphocytic-predominant and AMLTR/AMRMD for macrophage-predominant reaction.This review of the histopathological classifications of ALTR/ARMD has resulted in the following outcomes: (a) distinction between cell death and tissue necrosis; (b) the association of corrosion metallic debris with adverse local lymphocytic reaction and tissue necrosis; (c) the importance of cell and particle debris for the viscosity and density of the lubricating synovial fluid; (d) a consensus classification of lymphocytic infiltrate in soft tissue and bone marrow; (e) evaluation of the macrophage infiltrate in soft tissues and bone marrow; (f) classification of macrophage induced osteolysis/aseptic loosening as a delayed type of ALTR/ARMD; (g) macrophage motility and migration as possible driving factor for osteolysis; (h) usefulness of the histopathological examination for the natural history of the adverse reactions, radiological correlation, post-marketing surveillance, and implant registries.The review of key terms used for the description and histopathological classification of ALTR/ARMD has resulted in a comprehensive, new standard for all disciplines involved in their diagnosis, clinical management, and long-term clinical follow-up.Cite this article: EFORT Open Rev 2021;6:399-419. DOI: 10.1302/2058-5241.6.210013