A microtomographic and histopathological evaluation of dental cements as late-stage peri-implant complication in a rat model.

Cement mediated peri-implantitis accounts for 1.9-75% of dental implant failures associated with peri-implant diseases. This study evaluated the biological impact of dental cements on osseointegrated implants using Lewis rats. Twenty-two rats were distributed into 6 groups: negative control (NC) soft diet (SD), and hard diet (HD); positive control SD and HD (n = 3); Implant + bio-ceramic Cement (BC) SD and HD which included contralateral Sham sites (n = 5). Titanium implants were placed on either side of the maxillae and allowed to heal for 14 days. Later, both sides of experimental groups underwent a re-entry surgery to simulate clinical cementation. The right side received 0.60 mg of BC. At 14 days post cement application, maxillae were harvested for clinical, microtomographic, and histological evaluations. Clinical and microtomographic evaluations indicated evidence of extensive inflammation and circumferential bone resorption around BC implants in comparison to NC. Histology revealed cement particles surrounded by inflammatory infiltrate in the implant area accompanied by biofilm for SD groups. Both sides of BC indicated intensive bone resorption accompanied by signs of osteolysis when compared to NC. Cemented groups depicted significantly lower bone to implant contact when compared to NC. In conclusion, residual cement extravasation negatively impacted osseointegrated implants after re-entry surgeries.

Oral Exposure to Titanium Dioxide E171 and Zinc Oxide Nanoparticles Induces Multi-Organ Damage in Rats: Role of Ceramide.

Food-grade titanium dioxide (E171) and zinc oxide nanoparticles (ZnO NPs) are common food additives for human consumption. We examined multi-organ toxicity of both compounds on Wistar rats orally exposed for 90 days. Rats were divided into three groups: (1) control (saline solution), (2) E171-exposed, and (3) ZnO NPs-exposed. Histological examination was performed with hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). Ceramide (Cer), 3-nitrotyrosine (NT), and lysosome-associated membrane protein 2 (LAMP-2) were detected by immunofluorescence. Relevant histological changes were observed: disorganization, inflammatory cell infiltration, and mitochondrial damage. Increased levels of Cer, NT, and LAMP-2 were observed in the liver, kidney, and brain of E171- and ZnO NPs-exposed rats, and in rat hearts exposed to ZnO NPs. E171 up-regulated Cer and NT levels in the aorta and heart, while ZnO NPs up-regulated them in the aorta. Both NPs increased LAMP-2 expression in the intestine. In conclusion, chronic oral exposure to metallic NPs causes multi-organ injury, reflecting how these food additives pose a threat to human health. Our results suggest how complex interplay between ROS, Cer, LAMP-2, and NT may modulate organ function during NP damage.

Prosthetic Metals: Release, Metabolism and Toxicity.

The development of metallic joint prostheses has been ongoing for more than a century alongside advancements in hip and knee arthroplasty. Among the materials utilized, the Cobalt-Chromium-Molybdenum (Co-Cr-Mo) and Titanium-Aluminum-Vanadium (Ti-Al-V) alloys are predominant in joint prosthesis construction, predominantly due to their commendable biocompatibility, mechanical strength, and corrosion resistance. Nonetheless, over time, the physical wear, electrochemical corrosion, and inflammation induced by these alloys that occur post-implantation can cause the release of various metallic components. The released metals can then flow and metabolize in vivo, subsequently causing potential local or systemic harm. This review first details joint prosthesis development and acknowledges the release of prosthetic metals. Second, we outline the metallic concentration, biodistribution, and elimination pathways of the released prosthetic metals. Lastly, we discuss the possible organ, cellular, critical biomolecules, and significant signaling pathway toxicities and adverse effects that arise from exposure to these metals.

Titanium corrosion products from dental implants and their effect on cells and cytokine release: A review.

INTRODUCTION: Titanium is considered to be an inert material owing to the ability of the material to form a passive titanium oxide layer. However, once the titanium oxide layer is lost, it can lead to exposure of the underlying titanium substructure and can undergo corrosion. SUMMARY: The article explores the role of titanium ions and particles from dental implants on cells, cytokine release, and on the systemic redistribution of these particles as well as theories proposed to elucidate the effects of these particles on peri-implant inflammation based on evidence from in-vitro, human, and animal studies. Titanium particles and ions have a pro-inflammatory and cytotoxic effect on cells and promote the release of pro-inflammatory mediators like cytokines. Three theories to explain etiopathogenesis have been proposed, one based on microbial dysbiosis, the second based on titanium particles and ions and the third based on a synergistic effect between microbiome and titanium particles on the host. CONCLUSION: There is clear evidence from in-vitro and limited human and animal studies that titanium particles released from dental implants have a detrimental effect on cells directly and through the release of pro-inflammatory cytokines. Future clinical and translational studies are required to clarify the role of titanium particles and ions in peri-implant inflammation and the etiopathogenesis of peri-implantitis.

Inflammatory tissue response in human soft tissue is caused by a higher particle load near carbon fiber-reinforced PEEK compared to titanium plates.

Titanium as the leading implant material in locked plating is challenged by polymers such as carbon fiber-reinforced polyetheretherketone (CFR-PEEK), which became the focus of interest of researchers and manufacturers in recent years. However, data on human tissue response to these new implant materials are rare. Osteosynthesis plates and peri­implant soft tissue samples of 16 healed proximal humerus fractures were examined (n = 8 CFR-PEEK, n = 8 titanium). Soft tissue was analyzed by immunohistochemistry and µCT. The entrapped foreign bodies were further examined for their material composition by FTIR. To gain insight into their origin and formation mechanism, explanted and new plates were evaluated by SEM, EDX, profilometry and HR-CT. In the peri­implant soft tissue of the CFR-PEEK plates, an inflammatory tissue reaction was detected. Tissues contained foreign bodies, which could be identified as tantalum wires, carbon fiber fragments and PEEK particles. Titanium particles were also found in the peri­implant soft tissue of the titanium plates but showed a less intense surrounding tissue inflammation in immunohistochemistry. The surface of explanted CFR-PEEK plates was rougher and showed exposed and broken carbon fibers as well as protruding and deformed tantalum wires, especially in used screw holes, whereas scratches were identified on the titanium plate surfaces. Particles were present in the peri­implant soft tissue neighboring both implant materials and could be clearly assigned to the plate material. Particles from both plate materials caused detectable tissue inflammation, with more inflammatory cells found in soft tissue over CFR-PEEK plates than over titanium plates. STATEMENT OF SIGNIFICANCE: Osteosynthesis plates are ubiquitously used in various medical specialties for the reconstruction of bone fractures and defects and are therefore indispensable for trauma surgeons, ENT specialists and many others. The leading implant material are metals such as titanium, but recently implants made of polymers such as carbon fiber-reinforced polyetheretherketone (CFR-PEEK) have become increasingly popular. However, little is known about human tissue reaction and particle generation related to these new implant types. To clarify this question, 16 osteosynthesis plates (n = 8 titanium and n = 8 CFR-PEEK) and the overlying soft tissue were analyzed regarding particle occurrence and tissue inflammation. Tissue inflammation is clinically relevant for the development of scar tissue, which is discussed to cause movement restrictions and thus contributes significantly to patient outcome.

Inhibitory effects of norcantharidin on titanium particle-induced osteolysis, osteoclast activation and bone resorption via MAPK pathways.

Wear particles generated from the surface of implanted prostheses can lead to peri-implant osteolysis and subsequent aseptic loosening. In the inflammatory environment, extensive formation and activation of osteoclasts are considered the underlying cause of peri-implant osteolysis. Current medications targeting osteoclasts for the treatment of particle-induced bone resorption are not ideal due to significant side effects. Therefore, there is an urgent need to develop more effective drugs with fewer side effects. Norcantharidin (NCTD), a derivative of cantharidin extracted from blister beetles, is currently primarily used for the treatment of solid tumors in clinical settings. However, the potential role of NCTD in treating aseptic loosening of the prosthesis has not been reported. In this study, the in vitro results demonstrated that NCTD could effectively inhibit the formation of osteoclasts and bone resorption induced by the RANKL. Consistently, NCTD strongly inhibited RANKL-induced mRNA and protein levels of c-Fos and NFATc1, concomitant with reduced expression of osteoclast specific genes including TRAP, CTR and CTSK. The in vivo data showed that NCTD exerted significant protective actions against titanium particle-induced inflammation and subsequent osteolysis. The molecular mechanism investigation revealed that NCTD could suppress the activations of RANKL-induced MAPK (p38, ERK). Overall, these findings support the potential use of NCTD for the treatment of aseptic loosening following total joint arthroplasty.

Titanium Allergy: A Retrospective Review of 166 Patch Tested Patients.

Background: Although most patients do not develop hypersensitivity reactions to metals in implanted devices, when they do occur, significant morbidity can result. Titanium-based systems are often considered as an alternative option in metal-allergic patients; however, there are few studies published on titanium allergy and allergic reactions to titanium in implants may be overlooked in clinical practice. Methods: Our aim was to further characterize a single institution's experience with titanium patch testing and evaluation of titanium allergy. We performed a retrospective medical record review of 166 patients evaluated for titanium contact allergy between January 2018-August 2023. Of the 166 patients in our cohort, 67 were referred for pre-implant patch testing and 64 for post-implant patch testing; 35 were tested for reasons unrelated to an implant. Results: Twenty-six of the 166 patients were PTP to titanium (15.7% positive rate). Titanium PTP rates were higher for post-implant cases (28.1%, 18/64) compared to pre-implant cases (6.0%, 4/67) (χ2 9.97, p = 0.002). Among 18 titanium PTPs identified for the 64 post-implant cases, 8 were likely relevant, 8 possibly relevant, and 2 not likely relevant. Conclusions: Further studies should be performed to evaluate the incidence of allergy to titanium implants and to continue surveillance of changes in sensitization rates.

Confirmation of Safety of Titanium Wire in Sternotomy Closure, A Randomized Prospective Study.

BACKGROUND: There are many factors that are known to increase the risk of sternal wound infection (SWI); some studies have reported that nickel is a risk factor for SWI. Titanium wires have only been used as an alternative to steel wires in patients with known allergy to nickel. However, there is a paucity of literature regarding the safety of using titanium wires compared to that on the safety of steel wires for sternum closure after cardiac surgery. Therefore, this study aimed to demonstrate the noninferiority of titanium wires, even in patients without a known allergy. METHODS: A total of 322 patients who underwent elective full median sternotomy were randomly assigned to sternal closure either by titanium wires (n = 161) or by stainless steel wires. RESULTS: Fourteen patients had sternal instability, six (3.7%) patients in the titanium group and eight (5%) patients in the stainless steel group (p = 0.585). There was no statistically significant difference between both groups in terms of postoperative wound infection (p = 0.147). Patients in the titanium group experienced statistically significant lower postoperative pain than those in the stainless steel group (p = 0.024). The wire type was not an independent risk factor for SI, as shown by univariate and logistic regression analyses. CONCLUSION: Titanium wires are a good alternative and have been proven to be safe and effective for sternal closure. The surgeon should be aware of the possibility of developing an allergic reaction to the wires, especially in patients with previous multiple allergic histories.

Risk Factors for Seizures After Titanium Cranioplasty: Five-Year Experience from a Single Institution.

OBJECTIVE: Seizures are one of the complications that can occur after cranioplasty (CP). In some regions, titanium mesh remains the material of choice for CP. However, risk factors for seizures after titanium CP have been less studied. The purpose of this study was to identify potential risk factors for early seizures (≤7 days) and late seizures (>8 days) after titanium CP in a single institution. METHODS: A retrospective review was conducted of 241 consecutive patients who received titanium CP at the First Affiliated Hospital of Harbin Medical University from January 2016 to December 2020. Univariate and multivariable logistic regression analyses were performed to determine the independent risk factors for new-onset seizures after titanium CP. RESULTS: Fifteen patients (6.22%) experienced early post-CP seizures, and late post-CP seizures were observed in 81 patients (33.61%). A flaccid concave cranial defect (P = 0.042) was associated with early post-CP seizures, whereas hypertension (P < 0.001) was the only significant predictor for late seizures after titanium CP. CONCLUSIONS: Seizure is a common complication after titanium CP, especially in patients who do not receive prophylactic antiepileptic drugs before the procedure. Risk factors for new-onset seizures at different periods after titanium CP were found to be different. In addition, radiologic factors before titanium CP may play a role in early new-onset seizures after titanium CP and should not be ignored.

Prevotella histicola Prevented Particle-Induced Osteolysis via Gut Microbiota-Dependent Modulation of Inflammation in Ti-Treated Mice.

Wear particles generated from total joint replacements induce chronic osteolysis mediated by inflammatory upregulation, which leads to implant failure. Recent studies have suggested an important role of the gut microbiota in modulating the host's metabolism and immune system, leading to alterations in bone mass. Following gavage with P. histicola, micro-CT and HE staining revealed that osteolysis was significantly reduced in titanium (Ti)-treated mice. Immunofluorescence analysis revealed an increased macrophage (M)1/M2 ratio in the guts of Ti-treated mice, which decreased when P. histicola was added. P. histicola was also found to upregulate the tight junction proteins ZO-1, occludin, claudin-1, and MUC2 in the gut, reduce the levels of inflammatory factors IL-1ß, IL-6, IL-8, and TNF-α, primarily in the ileum and colon, and decrease the expression of IL-1ß and TNF-α and increase the level of IL-10 in the serum and cranium. Furthermore, P. histicola treatment resulted in a significant downregulation of CTX-1, RANKL, and RANKL/OPG. These findings demonstrate that P. histicola significantly mitigates osteolysis in Ti-treated mice by improving intestinal microbiota that repairs intestinal leakage and reduces systemic and local inflammation which in turn inhibits RANKL expression for bone resorption. P. histicola treatment may thus be therapeutically beneficial for particle-induced osteolysis.

The contribution of metal allergy to the failure of metal alloy implants, with special reference to titanium: Current knowledge and controversies.

After almost three-quarters of a century during which contact dermatologists have often struggled to comprehend the relationship between metal allergy and failure of metal-alloy containing implant, it is possible to say that a relationship does exist, particularly for cobalt and chromium, but also for nickel. There is still debate as to whether allergy develops as a consequent of failure but thenceforth contributes to it, or whether sensitisation starts first and induces failure secondarily-opinion probably favours the first. Metal-on-polypropylene articulations were associated with few metal allergic problems but now are less favoured by orthopaedists due to plastic wear products causing osteolysis and pseudotumour formation through local inflammation. New metal alloys are regularly being introduced such that interested dermatologists need to stay on top of the situation. The jury is still out as to whether the recent favouring of titanium-containing alloys will confirm them to be more inert allergenically. Case reports do show some clinical reactions to titanium-containing implants and patch test series have inferred sometimes quite a high background rate of allergy, but interpretation must be tempered by the awareness that titanium salts on patch testing have a tendency to cause irritant reactions. Blood monitoring of metal ion values is now recommended in certain situations after joint replacement and increasing levels may be an indication that allergy with joint failure can develop, in which case patch testing is indicated, and suggested series are available. Predictive patch testing, whilst generally not recommended in the past, has been introduced into some protocols often by non-dermatologists, such that it is now needed for temporo-mandibular joint and Nuss bar insertion, and it can be anticipated that this may become more commonplace in the future. One of the major current deficits for patch testers is standardised guidance on which preparation or preparations to use for suspected titanium allergy. One suggestion is 0.5% titanium sulphate in petrolatum, though experience in at least one centre suggests the use of a battery of titanium salts might be desirable.

[Effects of metal materials for oral fixation and restoration on magnetic resonance imaging artifacts and the health of tissues around dental implants].

PURPOSE: To investigate the effects of metal materials for oral fixation and restoration on magnetic resonance imaging artifacts and the health of tissues around dental implants. METHODS: A total of 153 patients undergoing fixed oral restoration were selected from May 2018 to June 2020. They were divided according to the random number table method into group A (cobalt-chromium alloy, n=31), group B (nickel-chromium alloy, n=32), group C (titanium alloy, n=28), group D (pure titanium, n=29) and group E (gold alloy, n=33). The largest area of metal crown artifacts and the number of layers of the 5 groups were compared. The probing depth(PD), modified plaque index(mPLI), modified sulcus bleeding index(mSBI) and papilla index(PI) 6 months after restoration were evaluated.The data were statistically analyzed with SPSS 22.0 software package. RESULTS: One-way ANOVA showed that the largest area of metal crown artifacts and the number of layers involved in the 5 groups had significant differences(P＜0.05). Pairwise comparison showed that the largest area of metal crown artifacts, and the number of involved layers in group E were significantly lower than those in groups A, B, C, and D(P＜0.05). One-way ANOVA showed that there was no significant difference in PD, mPLI, mSBI and PI among 5 groups (P＞0.05). Pairwise comparison showed that there was no significant difference in PD, mPLI, mSBI and PI between group A and group B,C,D and E (P＞0.05). CONCLUSIONS: The artifacts produced by metal materials for oral fixation and restoration are closely related to the types of metal materials. Among them, cobalt-chromium alloys produce the largest artifacts, and gold alloys produce the smallest artifacts. The use of metal materials for oral fixation and restoration will not affect the health of tissues around dental implants.

Britanin inhibits titanium wear particle­induced osteolysis and osteoclastogenesis.

Wear particle­induced osteolysis is a serious complication that occurs in individuals with titanium (Ti)­based implants following long­term usage due to loosening of the implants. The control of excessive osteoclast differentiation and inflammation is essential for protecting against wear particle­induced osteolysis. The present study evaluated the effect of britanin, a pseudoguaianolide sesquiterpene isolated from Inula japonica, on osteoclastogenesis in vitro and Ti particle­induced osteolysis in vivo. The effect of britanin was examined in the osteoclastogenesis of mouse bone marrow­derived macrophages (BMMs) using TRAP staining, RT­PCR, western blotting and immunocytochemistry. The protective effect of britanin was examined in a mouse calvarial osteolysis model and evaluated using micro­CT and histomorphometry. Britanin inhibited osteoclast differentiation and F­actin ring formation in the presence of macrophage colony­stimulating factor and receptor activator of nuclear factor kB ligand in BMMs. The expression of osteoclast­specific marker genes, including tartrate­resistant acid phosphatase, cathepsin K, dendritic cell­specific transmembrane protein, matrix metallopeptidase 9 and nuclear factor of activated T­cells cytoplasmic 1, in the BMMs was significantly reduced by britanin. In addition, britanin reduced the expression of B lymphocyte­induced maturation protein­1, which is a transcriptional repressor of negative osteoclastogenesis regulators, including interferon regulatory factor­8 and B­cell lymphoma 6. Conversely, britanin increased the expression levels of anti­oxidative stress genes, namely nuclear factor erythroid­2­related factor 2, NAD(P)H quinone oxidoreductase 1 and heme oxygenase 1 in the BMMs. Furthermore, the administration of britanin significantly reduced osteolysis in a Ti particle­induced calvarial osteolysis mouse model. Based on these findings, it is suggested that britanin may be a potential therapeutic agent for wear particle­induced osteolysis and osteoclast­associated disease.

Selenomethionine against titanium particle-induced osteolysis by regulating the ROS-dependent NLRP3 inflammasome activation via the ß-catenin signaling pathway.

Wear debris-induced osteolysis, especially titanium (Ti) particles-induced osteolysis, is the most common cause of arthroplasty failure with no effective therapy. Previous studies have suggested that inflammation and impaired osteogenesis are associated with Ti particles -induced osteolysis. Selenium (Se) is an essential trace element in the human body, which forms selenomethionine (Se-Met) in nature, and selenoproteins has strong anti-inflammatory and antioxidant stress effects. In this study, the effects of Se-Met on Ti particles-induced osteolysis were observed and the potential mechanism was explored. We found that exogenous Se-Met relieved osteolysis induced by Ti particles in two animal models and MC3T3-E1 cells. We found that the addition of Se-Met effectively inhibited Ti particle-induced inflammation by regulating reactive oxygen species-dependent (ROS-dependent) NOD-like receptor protein 3 (NLRP3) inflammasome activation. These therapeutic effects were abrogated in MC3T3-E1 cells that had received a ß-catenin antagonist, suggesting that Se-Met alleviates inflammatory osteolysis via the ß-catenin signaling pathway. Collectively, these findings indicated that Se-Met may serve as a potential therapeutic agent for treating Ti particle-induced osteolysis.

Full-thickness skin regeneration beneath the exposed titanium mesh in cranioplasty: Two cases report.

RATIONALE: Titanium mesh is one of the most widely used implant materials applied in cranioplasty; however, it has been reported to encounter the risk of progressive scalp thinning and implant exposure over time. Here we present 2 cases of exposed titanium mesh (TM) and unusual phenomena of full-thickness skin regeneration beneath the mesh. PATIENT CONCERNS: Two patients, 1 with an 8-year and 1 with a 2-year history of implant exposure after cranial TM implantation. DIAGNOSES: The patients were diagnosed with scalp ulcers and cranial TM exposure. INTERVENTION: The exposed part of the implant was removed, and the full-thickness skin beneath the mesh was directly used as functional soft tissue coverage to repair the scalp defect. OUTCOMES: Full recovery for both patients with cosmetic satisfaction. LESSONS: Though the exact mechanism of this epithelisation phenomenon beneath the TM remains to be elucidated, it provided a feasible choice for clinicians to reconstruct the scalp's integrity without exerting complicated procedures when dealing with similar cases.

Titanium Particles Modulate Lymphocyte and Macrophage Polarization in Peri-Implant Gingival Tissues.

Titanium dental implants are one of the modalities to replace missing teeth. The release of titanium particles from the implant's surface may modulate the immune cells, resulting in implant failure. However, little is known about the immune microenvironment that plays a role in peri-implant inflammation as a consequence of titanium particles. In this study, the peri-implant gingival tissues were collected from patients with failed implants, successful implants and no implants, and then a whole transcriptome analysis was performed. The gene set enrichment analysis confirmed that macrophage M1/M2 polarization and lymphocyte proliferation were differentially expressed between the study groups. The functional clustering and pathway analysis of the differentially expressed genes between the failed implants and successful implants versus no implants revealed that the immune response pathways were the most common in both comparisons, implying the critical role of infiltrating immune cells in the peri-implant tissues. The H&E and IHC staining confirmed the presence of titanium particles and immune cells in the tissue samples, with an increase in the infiltration of lymphocytes and macrophages in the failed implant samples. The in vitro validation showed a significant increase in the level of IL-1ß, IL-8 and IL-18 expression by macrophages. Our findings showed evidence that titanium particles modulate lymphocyte and macrophage polarization in peri-implant gingival tissues, which can help in the understanding of the imbalance in osteoblast-osteoclast activity and failure of dental implant osseointegration.

STING/TBK1 Regulates Inflammation in Macrophages and Titanium Particles-Induced Osteolysis.

Inflammatory response in macrophages on account of prostheses-derived wear particles is the leading cause of artificial joint failure. However, the mechanism by which wear particles initiate macrophage inflammation has not been fully elucidated. Previous research studies have identified TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING) as potential factors in inflammation and autoimmune diseases. Here, we found that both TBK1 and STING were increased in synovium from aseptic loosening (AL) patients and were activated in titanium particles (TiPs)-stimulated macrophages. Lentivirus-mediated knockdown of TBK or STING significantly inhibited the inflammatory effects of macrophages, while overexpression of TBK or STING exerted opposite results. In concrete, STING/TBK1 promoted the activation of NF-κB and IRF3 pathways and macrophage M1 polarization. For further validation, a mice cranial osteolysis model was constructed for in vivo assays, and we found that STING-overexpressed lentivirus injection exacerbated osteolysis and inflammation, which was counteracted by TBK1-knockdown injection. In conclusion, STING/TBK1 enhanced TiP-induced macrophage inflammation and osteolysis via orchestrating the activation of NF-κB and IRF3 pathways and M1 polarization, which suggested STING/TBK1 as potential therapeutic targets for preventing AL of prostheses.