Dental Implants - NutraPedia

Interleukin-16 rs4072111 Polymorphism is Associated with the Risk of Peri-Implantitis in the Chinese Population

Purpose: Peri-implantitis (PI) is a major contributor to dental implant failure. Genetic predisposition plays an essential role in the development of PI. The purpose of this study was to investigate the correlation of IL-16 gene single nucleotide polymorphisms (SNPs), rs11556218 and rs4072111, with PI at the gene level. Patients and methods: A total of 162 patients with PI and 162 cases with healthy implants were recruited as the case and control groups, respectively. The genotypes were analysed using direct sequencing. The genotype and allele proportion between the case and control groups were compared using the chi-square test. The periodontal status of patients carrying different genotypes was analysed, including gingival index, plaque index, calculus index, peri-implant pocket depth (PPD), and clinical attachment level (CAL). Results: The case and control groups were age- and gender-matched. In the case group, the rs4072111 CT genotype was majorly observed, and the T allele carriers showed a high PI risk. Patients with the rs4072111 CT genotype had worse periodontal status, which was reflected by the higher levels of the gingival index, plaque index, calculus index, PPD and CAL. The distribution of the rs11556218 genotype and T allele showed no significant difference between the case and control groups (P > 0.05). Conclusion: The CT genotype of IL-16 gene rs4072111 SNP can be used as a factor assessing PI risk. Therefore, IL-16 genetic variation may be related to PI susceptibility in the Chinese Han population.

Systematic review on the association between genetic polymorphisms and dental implant-related biological complications

Objectives: The aim of this systematic review was to evaluate the association between specific genetic polymorphisms and dental implant-related biological complications in patients having a follow-up period of at least 12-months post-loading. Material and methods: A sensitive search strategy was developed to identify implant-related genetic-association studies. This was performed by searching five databases. A three-stage screening (titles, abstract, full text) was carried out in duplicate and independently by two reviewers. Assessment was carried out according to the suggested scale for quality assessment of periodontal genetic-association studies and adapted to genetic analyses of implant-related studies leading to an overall final score 0-20 based on the summation of positive answers. Results: The initial search resulted in 1838 articles. Sixty-seven full-text articles were assessed for eligibility and four studies met the defined inclusion criteria. IL-6 G174C, TNF-α -308, IL-1A-889 and IL-1B+3954 and CD14-159 C/T polymorphisms were evaluated. The quality assessment scores ranged from 6 to 11 positive answers from out of a maximum score of 20. The great heterogeneity among the studies did not allow a meta-analysis. Conclusions: The published evidence on genetic predisposition and implant biologic complications is limited. The small number of identified studies evaluating the association between genetic polymorphisms and peri-implant disease presented methodological and reporting inadequacies. Thus, the potential link between genetic polymorphisms and biological complications should be further investigated and clarified through well-designed clinical studies on adequately powered and appropriately included study populations.

An Exploratory Case-Control Study on the Impact of IL-1 Gene Polymorphisms on Early Implant Failure

Background: The association between IL-1 gene polymorphisms and peri-implantitis has been well documented. However, data on the association with early implant failure are scarce. Purpose: The objective of this case-control study was to explore the impact of IL-1A (-889), IL-1B (-511), and IL-1B (+3,954) gene polymorphisms on early implant failure in Caucasians. Materials and methods: Between September 2004 and August 2007, 461 patients were treated with dental implants at the University Hospital in Ghent, Belgium. Fourteen subjects of this patient group who had experienced one or more early implant failures (within 6 months from implant installation) were recruited as "cases." Fourteen "controls," matched in terms of age, gender, and smoking habits, with only surviving implants, were selected from the same patient group. Allele and genotype analysis was performed on the basis of a blood sample by Sanger sequencing of polymerase chain reaction products containing the IL-1A (-889), IL-1B (-511), and IL-1B (+3,954) gene polymorphisms. Results: A significant impact of the IL-1A (-889) T allele (p = .039) and the IL-1B (+3,954) T allele (p = .003) on early implant failure was demonstrated (odds ratios = 3.9 and 15.0, respectively). In addition, the genotypic distribution differed significantly between cases and controls for IL-1B (+3,954) (p = .015). Conclusions: The IL-1B (+3,954) gene polymorphism seems to affect osseointegration. Additional case-control studies in larger patient groups are needed to confirm this observation.

The effect of interleukin-1 allele 2 genotype (IL-1a(-889) and IL-1b(+3954)) on the individual's susceptibility to peri-implantitis: case-control study

Individuals bearing the combination of interleukin (IL)-1 allele 2 at IL-1A(-889) and IL-1B(+3954) are referred to as being genotype positive and are susceptible to increased periodontal tissue destruction. The aim of this study was to assess the possible association of IL-1 allele 2 (IL-1A(-889) and IL-B(+3954)) genotypes with the severity of peri-implantitis progression and the effect of this combination on treatment outcomes. Fifty patients with International Team for Implantology implants were studied; patients ranged in age from 35-55 years, and each patient had 1 implant. According to peri-implant tissue status, patients were divided into 2 groups: group I consisted of 25 patients with peri-implantitis, and group II comprised 25 patients with healthy peri-implant tissue. Clinical parameters were assessed at baseline and after 3 and 6 months. Epithelial cells were collected from the oral mucosa by plastic spatula and were used for IL-1 genotyping by the polymerase chain reaction technique. Group I patients were subjected to a peri-implantitis treatment and maintenance program. In all, 17 patients from group I and 5 patients from group II were genotype positive, with a statistically significant difference noted between the 2 groups. Group I genotype-positive patients presented with higher scores and measurements of clinical parameters with increased suppuration from peri-implant tissues compared with group II; differences were statistically significant (P < .05). In terms of response to treatment, genotype-negative patients demonstrated better response than genotype-positive patients. The combination of IL-1 allele 2 (IL-1A(-889) and IL-1B(+3954)) in patients with inflamed periodontal or peri-implant tissues acts as a risk factor that leads to greater tissue destruction. IL-1 gene polymorphism at IL-1A(-889) and IL-1B(+3954) may affect outcomes of treatment for peri-implantitis in genotype-positive individuals.

A systematic review on the association between genetic predisposition and dental implant biological complications

Objectives: The aim of this systematic review was to evaluate the relationship between genetic polymorphisms and dental implant biological complications. Material and methods: All prospective, cross-sectional and retrospective studies reporting on dental implant loss/peri-implantitis/peri-implant marginal bone loss after loading in association with genetic polymorphism were considered for inclusion. A thorough search of electronic databases, supplemented by checking bibliographies of review articles was performed by two independent reviewers. Quality assessment of the included studies was conducted independently and in duplicate by two reviewers as part of the data extraction process. Results: The search provided 344 related articles. Twenty-two publications were identified for possible inclusion and finally, seven articles met the defined inclusion criteria. Four studies which investigated the potential relationship between early implant loss and IL-1, IL-2, IL-6, TNF-α or TGF-β1 genotype revealed no evidence to support this association. In two of the three studies which evaluated peri-implantitis in relation to IL-1 genotype, the findings indicate that IL-1RN (intron 2), IL-1A (-899), IL-1B (+3954) gene polymorphisms were correlated to increased peri-implant tissue infection and destruction. Conclusions: Methodological and study design issues restricted the possibility to draw robust conclusions. Within the limits of this review, it might be concluded that there is no obvious association between specific genetic polymorphism and dental implant failure in terms of biological complications, although a tendency should be underlined showing the potential link between IL-1 genotype and peri-implantitis. Well designed and adequately powered prospective cohort studies are needed to provide further information.

Associations between peri-implant crevicular fluid volume, concentrations of crevicular inflammatory mediators, and composite IL-1A -889 and IL-1B +3954 genotype. A cross-sectional study on implant recall patients with and without clinical signs of peri-implantitis

Objectives: To assess possible relationships between peri-implant crevicular fluid (PICF) volumes, biochemical markers of the peri-implant immune response, and periodontitis-associated genotype. Material and methods: PICF samples from 29 implant maintenance patients, 24 wearing overdentures, five having single crowns and bridgework (11 patients with peri-implantitis and 18 individuals with healthy peri-implant conditions), were analyzed for per site and per crevicular-fluid-volume concentrations of interleukin-1beta, plasminogen activator inhibitor type 2, and prostaglandin E2 by ELISA. Associations between the three substance concentrations and to crevicular fluid flow rate were analyzed by linear regression analysis. The possible differentiating influence of the composite interleukin-1A and -1B genotype on the patients' peri-implant health and biochemical inflammatory status was checked formally with t-test statistics and the Wilcoxon' test. One implant per patient was chosen for analysis. Results: In patients with healthy peri-implant conditions, genotype-positive individuals showed elevated crevicular fluid flow rates and at the same time reduced mediator concentrations. In patients with an implant affected from peri-implantitis, no statistically significant influence of the periodontitis-associated genotype around the fixture can be stated. There was no statistical difference between per site and per crevicular-fluid-volume concentration analyses. All three mediator concentrations were positively related to each other, while there was a strong negative correlation between crevicular fluid volume and plasminogen activator inhibitor 2 or prostaglandin E2. Conclusions: The Interleukin-1 polymorphism investigated exerted only little influence on the peri-implant crevicular immune response, and this influence appeared to be of limited impact in sites with established peri-implantitis lesions.

IL-1RN gene polymorphism is associated with peri-implantitis

Objectives: Interleukin (IL)-1alpha, IL-1beta and their natural specific inhibitor IL-1 receptor antagonist (IL-1ra) play a key role in the regulation of the inflammatory response in periodontal tissues. Polymorphisms in the IL-1 gene cluster have been associated with severe adult periodontitis. We aimed to investigate the IL-1 gene cluster polymorphisms in patients with peri-implantitis. Material and methods: The study included 120 North Caucasian individuals. A total of 71 patients (mean age 68 years, 76% smokers) demonstrating peri-implantitis at one or more implants as evidenced by bleeding and/or pus on probing and bone loss amounting to >3 threads on Brånemark implants and 49 controls (mean age 66 years, 45% smokers) with clinical healthy mucosa and no bone loss around the implants were recruited for the study. The titanium implants, ad modum Brånemark, had been in function for at least 2 years. Mouthwash samples were collected and used for genotyping of the bi-allelic polymorphisms IL-1A(-889), IL-1B(+3953), IL-1B(-511) and a variable number of tandem repeat IL-1RN gene polymorphisms using PCR technique. Results: Significant differences were found in the carriage rate of allele 2 in the IL-1RN gene between peri-implantitis patients and controls (56.5% vs. 33.3%, respectively; odds ratios (OR) 2.6; 95% confidence interval (CI) 1.2-5.6; P=0.015). Logistic regression analysis taking smoking, gender and age into account confirmed the association between the IL-1RN allele 2 carriers and peri-implantitis (OR 3; 95% CI 1.2-7.6; P=0.02). Conclusions: Our results provide evidence that IL-1RN gene polymorphism is associated with peri-implantitis and may represent a risk factor for this disease.

Association of the composite IL-1 genotype with peri-implantitis: a systematic review

Objective: Cytokine gene polymorphisms may modulate the host response to the bacterial challenge and influence susceptibility to peri-implantitis. Objective: To systematically review the evidence of an association between the interleukin-1 (IL-1) composite genotype, i.e. presence of the allele 2 in the gene clusters IL-1A (-889) and in IL-1B (+3953), and peri-implantitis. Material and methods: An electronic search in the National Library of Medicine-computerized bibliographic database MEDLINE and a manual search were performed. The search was conducted for longitudinal clinical trials comparing progression of peri-implantitis in IL-1 genotype positive (carrying allele 2) with IL-1 genotype negative (not carrying allele 2) subjects. Selection of publications, extraction of data and validity assessment were made independently by two reviewers. Results: The search provided 44 titles of which two longitudinal publications were included. Conclusion: Based on the findings from this study, there is not enough evidence to support or refute an association between the IL-1 genotype status and peri-implantitis. Systematic genetic testing for the assessment of the risk of peri-implantitis cannot be recommended as a standard of care at this time.

Current Molecular, Cellular and Genetic Aspects of Peri-Implantitis Disease: A Narrative Review

(1) Background: Peri-implantitis is a multi-factorial disease with an inflammatory background that occurs in both soft and hard tissues surrounding implants. In recent years, the understanding of the cellular, molecular and genetic background of peri-implantitis has broadened. This study aims to summarize the currently available articles on the subject and highlight the most recent advances over the last 20 years. (2) Methods: For this study, the Embase and PubMed libraries were searched using the keywords: ("peri-implantitis" AND "cytokine" OR "genetics" OR "cellular") and ("peri-implantitis" AND "cytokine" OR "genetics" OR "cellular" AND "risk factors"). The search revealed a total of 3013 articles (992 from PubMed, 2021 from Embase). Following screening of the titles and abstracts and full-text reads, 55 articles were included. (3) Results: In peri-implantitis IL-6, IL-1β, TNF-α, MMP-8 and their genetic variations appear to be the most important cytokines in relation to not only pathogenesis, but also their potential diagnostic capabilities. Epithelial and inflammatory cells, along with those of the bone lineage, are prime cellular elements found in peri-implantitis. (4) Conclusions: A wide array of cells stand behind peri-implantitis, as well as cytokines and their genetic variations that take part in the process. However, the growing interest in this topic has led to the introduction of specific new diagnostic tools to enable a better understanding of patients' responses to treatment and, in turn, to even enable prediction of the risk of developing peri-implant disease.

Association between IL-1A and IL-1B gene polymorphisms with peri-implantitis in a Portuguese population-a pilot study

Background: Scientific evidence indicates that biological complications in dental implants tend to be concentrated in a subset of individuals, which seems to imply that the host response may play a determining role in implant success. Over the last few decades, several polymorphisms have been studied. Polymorphisms in the interleukin (IL) 1 gene cluster have been associated with periodontitis. There are some similar features in the sequence of immunopathological events in peri-implant and periodontal infections. We aimed to investigate if individuals carrying the genetic single nucleotide polymorphism (SNP) in the IL-1A (rs1800587) and IL-1B (rs1143634) genes are more susceptible to develop peri-implantitis. Methods: A cross-sectional analytic pilot study was conducted in 20 Caucasian Portuguese subjects divided into two groups: 10 subjects with peri-implantitis and 10 subjects with peri-implant health (control group). Samples containing cells from the buccal mucosa were stored at -20 °C and later submitted to the DNA extraction process. Genetic analysis was performed using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Data were analyzed by using descriptive and inferential statistical methodologies. Results: For the IL-1A (-889) gene polymorphism, it was observed that the mutated allele was present in a higher percentage in the peri-implantitis group compared to the control group (30% vs 15% respectively, Fisher's exact test, p = 0.45). For the IL-1B (+3954) gene polymorphism, it was also observed that the altered allele was present in a higher percentage in the disease group compared to the control group (35% vs 10% respectively, Fisher's exact test, p = 0.13). The positive genotype (at least one allele with nucleotide sequence changed in both genes) was detected in six patients, five belonging to the disease group and one to the health group. Conclusions: Regarding IL-1 gene polymorphisms, there was no statistically significant difference between the health and disease group, however a trend should be highlighted, showing a potential link between the IL-1 genotype and peri-implantitis. More studies are needed to clarify the role of genetic polymorphisms in the development of peri-implantitis.

Different contribution of BRINP3 gene in chronic periodontitis and peri-implantitis: a cross-sectional study

Background: Peri-implantitis is a chronic inflammation, resulting in loss of supporting bone around implants. Chronic periodontitis is a risk indicator for implant failure. Both diseases have a common etiology regarding inflammatory destructive response. BRINP3 gene is associated with aggressive periodontitis. However, is still unclear if chronic periodontitis and peri-implantitis have the same genetic background. The aim of this work was to investigate the association between BRINP3 genetic variation (rs1342913 and rs1935881) and expression and susceptibility to both diseases. Methods: Periodontal and peri-implant examinations were performed in 215 subjects, divided into: healthy (without chronic periodontitis and peri-implantitis, n = 93); diseased (with chronic periodontitis and peri-implantitis, n = 52); chronic periodontitis only (n = 36), and peri-implantitis only (n = 34). A replication sample of 92 subjects who lost implants and 185 subjects successfully treated with implants were tested. DNA was extracted from buccal cells. Two genetic markers of BRINP3 (rs1342913 and rs1935881) were genotyped using TaqMan chemistry. Chi-square (p < 0.05) compared genotype and allele frequency between groups. A subset of subjects (n = 31) had gingival biopsies harvested. The BRINP3 mRNA levels were studied by CT method (2(ΔΔCT)). Mann-Whitney test correlated the levels of BRINP3 in each group (p < 0.05). Results: Statistically significant association between BRINP3 rs1342913 and peri-implantitis was found in both studied groups (p = 0.04). The levels of BRINP3 mRNA were significantly higher in diseased subjects compared to healthy individuals (p = 0.01). Conclusion: This study provides evidence that the BRINP3 polymorphic variant rs1342913 and low level of BRINP3 expression are associated with peri-implantitis, independently from the presence of chronic periodontitis.

Peri-implant disease and chronic periodontitis: is interleukin-6 gene promoter polymorphism the common risk factor in a Brazilian population?

Purpose: To investigate the association between interleukin-6 (IL-6) G174C polymorphism and susceptibility to peri-implant disease (PID) and/or chronic periodontitis (CP), in Brazilian subjects. Materials and methods: A total of 103 Brazilian patients were submitted to peri-implant and periodontal examination. According to their peri-implant characteristics, patients were divided into: group A (healthy, n = 52), group B (peri-implant mucositis, n = 20), and group C (peri-implantitis, n = 31). All patients (n = 103) were also characterized as healthy periodontium patients without CP (HP, n = 60) or CP patients (CP, n = 43). DNA was extracted from buccal cells, and the IL-6 G174C polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Differences in the prevalence of genotypes and alleles between healthy and ill patients were analyzed by chi-square test (P < .05), considering PID, CP, and PID+CP. Results: Results considered the presence of PID and/or CP in all patients. The CC genotype was the least common in all groups. The chi-square test showed no significant correlation between genotypes. However, the odds ratio showed that individuals with GG genotype and allele G were 1.53 and 1.43 times more susceptible to PID, respectively. The risk of presenting CP was increased in patients with GG genotype and allele G 1.35 and 1.24 times, respectively. When both diseases were evaluated together, patients with GG genotypes and allele G were 1.75 and 1.50 times more likely to present PID and CP together. When PID was evaluated without CP, patients with allele G were 2.08 times more susceptible to PID. Conclusions: The frequency of the genotype IL-6 174GG and allele G was different between healthy and ill groups. Therefore, this genotype may be a common risk factor for both CP and PID in Brazilian populations.

Association Between Tumor Necrosis Factor-α (G-308A) Polymorphism and Chronic Periodontitis, Aggressive Periodontitis, and Peri-implantitis: A Meta-analysis

Objective: Chronic periodontitis (CP), aggressive periodontitis (AP), and peri-implantitis (PI) are chronic inflammatory diseases. Tumor necrosis factor-α (TNF-a) is an effective immune inflammatory mediator. Several studies have been conducted to explore the association between the TNF-α (G-308A) polymorphism and susceptibility to CP, AP, and PI. Our objective was to examine whether the TNF-α (G-308A) polymorphism is related to these diseases. Methods: We conducted a meta-analysis to investigate the association between the TNF-α (G-308A) polymorphism and CP, AP, and PI. The PubMed, Embase, CNKI, and Web of Science electronic databases were searched for studies published from inception to August 11, 2020; the reference lists of included studies were also searched. The included studies were assessed in the following genetic models: dominant model, recessive model, allelic model, heterozygous model, and homozygous model. Results: Forty articles (50 comparisons) with 2243 CP, 824 AP, 615 PI, 795 healthy peri-implant, and 3575 healthy controls were considered for the TNF-α (G-308A) polymorphism in this meta-analysis. Variant A of TNF-α (G-308A) was associated with increased AP risk in the general population, especially in Asians, and this polymorphism was significantly associated with elevated risk of CP in Asians and Caucasians. There was no association between the A allele and PI risk. None of the contrasts of the genetic model yielded a significant finding in Latin Americans. Different genotyping methods may affect the association between the TNF-α (G-308A) polymorphism and these diseases. Conclusion: These findings supported that variant A of the TNF-α (G-308A) polymorphism may contribute to CP and AP susceptibility, particularly in Asians and Caucasians. More efforts and further studies with larger sample sizes will be required to validate the risk of CP, AP, and PI.

Association between tumor necrosis factor-alpha G-308A polymorphism and dental peri-implant disease risk: A meta-analysis

Background: Tumor necrosis factor-alpha (TNF-α) is a potent immune-inflammatory mediator involved in the regulation of bone resorption. The single nucleotide polymorphism G-308A in the TNF-α gene increases the level of this cytokine. This phenomenon is also related to several diseases. Although the association between TNF-α (G-308A) polymorphism and dental peri-implant disease has been investigated, results have remained controversial. Hence, we performed this meta-analysis to provide a comprehensive and systematic conclusion on this topic. Methods: We performed a systematic literature search in PubMed, Embase, ISI Web of Science, Cochrane Library, and Chinese National Knowledge Infrastructure until July 2015. A fixed-effect model was established to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). The calculated values were then used to assess the strength of the association between the TNF-α (G-308A) polymorphism and the dental peri-implant disease risk. The heterogeneity between included studies was evaluated with Cochran Q and I statistics. Interstudy publication bias was investigated with a funnel plot. Results: Six eligible studies were included in this meta-analysis. The pooled ORs did not reveal a significant relationship between the TNF-α (G-308A) polymorphism and the disease susceptibility. Subgroup analyses in terms of ethnicity and disease type yielded similar results. Conclusion: Our meta-analysis revealed that TNF-α (G-308A) polymorphism was not significantly associated with the risk of dental peri-implant disease. However, further studies with large sample sizes should be performed to verify these results.

Genetic association of the epidermal growth factor gene polymorphisms with peri-implantitis risk in Chinese population

Peri-implant disease is an inflammatory disease and is related to genetic heterogeneity. Considering the genetic association of epidermal growth factor (EGF) gene polymorphisms with the susceptibility of periodontitis, its genetic association with peri-implantitis risk in a Chinese Han population was explored. Three hundred individuals who underwent dental implants were recruited, and divided into healthy implant group and peri-implantitis group. The genotype and allele distribution of EGF gene rs2237051 and rs4444903 polymorphisms were analyzed via direct sequencing and the frequencies were compared between the two groups using chi-square test. No significant difference was detected for the clinical information between healthy implant group and peri-implantitis group, including lifestyle habits platform type and position, peri-implant phenotype, brushing time, dental floss, and mouth washing frequencies. Individuals with peri-implantitis had poor periodontal status. The GG genotype and G allele of rs2237051 showed significant increasing trend in peri-implantitis group compared with the healthy implant group. Compared with the AA genotype carriers, rs2237051 GG genotype carriers showed lower risk to suffer from peri-implantitis (OR = 0.236, 95%CI = 0.089-0.624), and possessed low values of gingival index, plaque index and calculus index, peri-implant pocket depth (PPD) and clinical attachment level (CAL). But there was no significant difference for the rs4444903 genotype distributions between the case and control groups. In summary, EGF rs2237051 polymorphism showed close association with the genetic background of peri-implantitis. Rs2237051 GG genotype and G allele might be protective factors for the onset of peri-implantitis.

Osteoprotegerin Gene (OPG) Polymorphisms Associated with Peri-implantitis Susceptibility in a Chinese Han Population

BACKGROUND The aim of this study was to investigate the association between T950C (rs2073617) and G1181C (rs2073618) polymorphisms of the osteoprotegerin gene (OPG) and the susceptibility of peri-implantitis in the Chinese Han population. MATERIAL AND METHODS 110 patients with peri-implantitis and 116 healthy persons from the Chinese Han population were included in this study using a case-control design; rs2073617 and rs2073618 in OPG were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The linkage disequilibrium (LD) and haplotype analysis were performed with Haploview software. Hardy-Weinberg equilibrium (HWE) was assessed in the control group based on the genotype distributions of OPG polymorphisms. The genotype, allele, and haplotype distribution differences between the case and control groups were analyzed by chi-square test, and the relative risk of PD was expressed by odds ratio (OR) and 95% confidence interval (CI). RESULTS The study results showed that people carrying the CC genotype of rs2073618 were more likely to have peri-implantitis than GG genotype carriers (OR=2.18, 95% CI=1.03-4.62, p=0.04). In addition, patients with the C allele had 1.47 times the risk of suffering from peri-implantitis (OR=1.47, 95% CI=1.01-2.13, p=0.04), but not rs2073617 polymorphism. The G-C haplotype frequency of rs2073618-rs2073617 in OPG was significantly correlated to the increased susceptibility of peri-implantitis (OR=2.27, 95% CI=1.20-4.30). CONCLUSIONS OPG rs2073618 polymorphism may be related to the risk of peri-implantitis, but not rs2073617. Moreover, haplotype is also a non-ignorable risk factor.

Analysis of osteoprotegerin (OPG) gene polymorphism in Iranian patients with chronic periodontitis and peri-implantitis. A cross-sectional study

Purpose: Receptor activator for nuclear factor kappa B ligand (RANKL)/RANK/OPG pathway plays a redundant role in osteoclastogenesis, osteoclast activation and regulation of bone resorption. Recently, single nucleotide polymorphisms (SNP) have been reported as a co-factor in pathogenesis of inflammatory diseases. The aim of this study was to investigate the relationship between osteoprotegerin (OPG) gene polymorphisms and chronic periodontitis and peri-implantitis in an Iranian population. Materials and methods: 77 patients with chronic periodontitis (CP), 40 patients with peri-implantitis (PI) and 89 periodontally healthy subjects were enrolled in this study. A total of 5 ml of blood was obtained from the arm vein of participants. DNA was extracted based on the salting out method. Two functional SNPs (T950C and G1181C) were analysed by using polymerase chain reaction and restriction fragment length polymorphism (PCR_RFLP). The prevalence differences in three batches were evaluated by chi-square test. Results: An evaluation of the T950C genotype found that there was no statistical difference between groups. A comparison of the G1181C genotype distribution between peri-implantitis and chronic periodontitis groups, and between peri-implantitis and normal groups found that the frequency of the CC genotype was significantly higher in patients with peri-implantitis (P = 0.005). Conclusions: Our results indicate that a SNP at G1181C is associated with the presence of PI.

Comparison of IKKI gene polymorphisms (rs1539243 and rs12728136) between chronic periodontitis and peri-implantitis patients in an Iranian population (a cross-sectional study)

Aim: In the present study, we sought to assess the correlation of IKKi gene polymorphisms (rs1539243 and rs12728136) with chronic periodontitis and peri-implantitis in an Iranian population for the first time in dentistry. Materials and methods: This cross-sectional study was conducted on 75 patients with chronic periodontitis, 38 patients with peri-implantitis, and 84 periodontally healthy subjects. Blood samples were taken from all subjects (5 cc venous) and transferred into Falcon tubes containing EDTA. Extracted DNA samples were evaluated with a spectrophotometer (75 ng), transferred into a 96-well plate, and sent to KBioscience Institute in the United Kingdom for analysis. Assessment of IKKi gene polymorphisms was performed at the KBioscience Institute. Data were analyzed using SPSS v19 software. Differences in genotype frequencies and allele among patients and controls were evaluated using the chi-squared test (P<0.05). Results: A significant difference was detected between the peri-implantitis and chronic periodontitis groups in distribution of CC, TC, and TT genotypes in rs1539243 (P<0.05). Statistically significant differences were detected among the three groups in the frequency of T and C alleles for rs1539243 (P=0.03). Conclusions: Within the limitations of the present study, the results showed a significant difference in IKKi gene polymorphism rs1539243 between the peri-implantitis and chronic periodontitis groups. However, such difference was not observed in rs12728136 between the two groups.

TRAF family member-associated NF-KB activator (TANK) gene polymorphism in chronic periodontitis and peri-implantitis patients

This study sought to determine TANK (rs1921310, rs3820998) gene polymorphism in patients suffering from chronic periodontitis and peri-implantitis among an Iranian population. Materials and methods: In this cross-sectional study, 77 chronic periodontitis and 40 peri-implantitis patients, along with 89 periodontally healthy subjects, were evaluated. A 5 cc venous blood sample was obtained from subjects. DNA was extracted using Miller's salting-out method and polymorphisms were determined by the use of KBioscience's Competitive Allele-Specific PCR (CASP) genotyping system. Data were analyzed using SPSS version 11.5 software. Differences in allele and genotype frequencies among patients and controls were evaluated with Kruskal-Wallis test. P<0.05 was considered statistically significant. Results: No significant differences were detected between understudy groups in distribution of CC and CA genotypes and alleles when evaluating rs3820998 polymorphism or in distribution of GA and AG genotypes and alleles when assessing rs1921310 polymorphism. Conclusions: Within the limitations of this study, it seems that these two polymorphisms do not play a significant role in pathogenesis of chronic periodontitis or peri-implantitis among the Iranian population. However, we recommend performing similar studies with larger sample sizes among the Iranian population and other communities.

Haptoglobin gene polymorphisms in peri-implantitis and chronic periodontitis

Aim: The haptoglobin-hemoglobin (Hp-Hb) complex plays a significant role in regulating immune responses and acts as a bacteriostatic agent. Haptoglobin polymorphisms result in different Hb binding affinities. This study sought to assess whether Hp 2-2 could be a genetic determinant for increasing the risk of peri-implantitis and chronic periodontitis. Methods: Of the Iranian subjects referred to the Department of Periodontics, Shahid Beheshti University, Tehran, 203 were entered into the study, including 117 patients and 86 periodontally healthy individuals. Polymerase chain reaction (PCR) was performed for genotyping. Data were analyzed by Kruskal-Wallis test using the SPSS statistics software package. Results: The prevalence of Hp 2-2, 2-1, and 1-1 did not differ significantly between patients and healthy subjects (P > 0.05). The highest frequencies of Hp 1-1, 2-1, and 2-2 genotypes were seen in the control (7%), peri-implantitis (51%) and periodontitis (64%) groups, respectively. Conclusions: Haptoglobin polymorphisms may not play a role in development of peri-implantitis or chronic periodontitis among Iranians but we strongly suggest researchers to evaluate this polymorphism in further studies on larger sample sizes, different populations, and other types of periodontitis.

BRAF gene polymorphism (rs10487888) assessment in chronic periodontitis and peri-implantitis in an Iranian population

Background: Peri-implantitis (PI) and chronic periodontitis (CP) are multifactorial diseases of implant/tooth supporting tissue that are caused by bacterial infection and increased host immune response. T-cell proliferation plays a pivotal role in the orchestration of host response to bacterial infection. BRAF is a positive regulator of T-cell proliferation. The aim of this study was to evaluate for the first time the role of a functional single nucleotide polymorphism (SNP) of the BRAF gene in association to PI and CP. Methods: A total of 194 individuals referred to the Periodontology Department of Shahid Beheshti Dental School, Tehran, Iran, were divided into three groups: 74 patients in the CP group (39 men and 35 women, with mean age of 48.3 years), 38 patients in the PI group (20 men and 18 women, with mean age of 50.2 years), and 82 patients in the healthy periodontium group (39 men and 43 women, with mean age of 45.4 years). DNA was extracted from fresh blood samples collected from the arm vein of participants and was transferred to KBiosience institute (United Kingdom) for genotyping. χ2 and Kruskal-Wallis tests were conducted using SPSS software v. 19 for statistical analysis (p<0.05). Results: The allele (C/T) and genotype (CC, CT, TT) frequencies had insignificant differences among the three groups; however, the CC genotype was more prevalent in the healthy condition than in the disease conditions. Conclusions: The BRAF gene polymorphism (rs10487888) may not be a genetic determinant for increasing the risk of CP and PI among the Iranian population. More studies with more sample size in different populations are necessary for determining the effect of this SNP.

Investigation of pathogenic genes in peri-implantitis from implant clustering failure patients: a whole-exome sequencing pilot study

Peri-implantitis is a frequently occurring gum disease linked to multi-factorial traits with various environmental and genetic causalities and no known concrete pathogenesis. The varying severity of peri-implantitis among patients with relatively similar environments suggests a genetic aspect which needs to be investigated to understand and regulate the pathogenesis of the disease. Six unrelated individuals with multiple clusterization implant failure due to severe peri-implantitis were chosen for this study. These six individuals had relatively healthy lifestyles, with minimal environmental causalities affecting peri-implantitis. Research was undertaken to investigate pathogenic genes in peri-implantitis albeit with a small number of subjects and incomplete elimination of environmental causalities. Whole-exome sequencing was performed on collected saliva samples via self DNA collection kit. Common variants with minor allele frequencies (MAF) > = 0.05 from all control datasets were eliminated and variants having high and moderate impact and loss of function were used for comparison. Gene set enrichment analysis was performed to reveal functional groups associated with the genetic variants. 2,022 genes were left after filtering against dbSNP, the 1000 Genomes East Asian population, and healthy Korean randomized subsample data (GSK project). 175 (p-value <0.05) out of 927 gene sets were obtained via GSEA (DAVID). The top 10 was chosen (p-value <0.05) from cluster enrichment showing significance of cytoskeleton, cell adhesion, and metal ion binding. Network analysis was applied to find relationships between functional clusters. Among the functional groups, ion metal binding was located in the center of all clusters, indicating dysfunction of regulation in metal ion concentration might affect cell morphology or cell adhesion, resulting in implant failure. This result may demonstrate the feasibility of and provide pilot data for a larger research project aimed at discovering biomarkers for early diagnosis of peri-implantitis.

The impact of genotypes and immune reactivity on peri-implant inflammation: Identification and therapeutic use of anti-inflammatory drugs and immunomodulators

Purpose: Peri-implantitis is a growing problem because of the increasing number of patients rehabilitated with oral implants. Predictors of susceptibility to peri-implantitis and pharmacological agents for the treatment of inflammatory peri-implantitis are of significant interest to the practicing community. The goal of this paper is to review the current literature relating to the impact of genotypes and immune reactivity on peri-implant inflammation and to identify the potential use of anti-inflammatory and immunomodulatory drugs. Materials and methods: A MEDLINE search of the relevant literature was performed and all related articles were evaluated. Results: There was little support in the literature for a specific genotype or phenotype of immune reactivity that could be reliably used as an indicator of susceptibility to peri-implant disease. Furthermore, no currently available anti-inflammatory drugs were identified that could be used long term for the treatment of inflammatory peri-implantitis. New pathways for the control of inflammation have been identified that have the potential for new pharmacologic therapies. The basis for these new discoveries is reviewed in some detail. Conclusions: While there are varying reports of associations of specific genotypes with peri-implantitis, the studies are inconsistent and generally underpowered precluding any interpretable pattern. Inflammatory peri-implantitis is associated with increased local inflammation, but no consistent systemic inflammatory markers have been identified. To date, no safe and effective anti-inflammatory therapy is known for the treatment of peri-implantitis. However, a new class of molecules in development for the active regulation and resolution of inflammation shows theoretical promise for the treatment of inflammatory lesions.

Risk indicators for peri-implantitis. A narrative review

Aim: To examine the existing evidence in identifying risk indicators in the etiology of peri-implantitis. Material and methods: A literature search was performed in MEDLINE via PubMed database of the US National Library of Medicine, for articles published until October 2014 using Medical Subject Heading search terms + free text terms and in different combinations. Results: The microbiota associated with peri-implantitis is complex, demonstrating differences and similarities to the one seen at periodontitis sites. Plaque accumulation at dental implants triggers the inflammatory response leading to peri-implant mucositis/peri-implantitis. Individuals with a history of periodontal disease and smokers have an increased risk of developing peri-implantitis. There is some evidence to support the role of genetic polymorphism, diabetes, and excess cement as risk indicators for the development of peri-implantitis. There is also evidence to support that individuals on regular maintenance are less likely to develop peri-implantitis and that successful treatment of periodontitis prior to implant placement lowers the risk of peri-implantitis. Conclusions: Plaque accumulation at implants will result in the development of an inflammation at implants. A history of periodontal disease, smoking, excess cement, and lack of supportive therapy should be considered as risk indicators for the development of peri-implantitis.

Prevalences of peri-implantitis and peri-implant mucositis: systematic review and meta-analysis

Objectives: Due to the inconsistent definitions, reporting methods and study characteristics, prevalences of peri-implant diseases significantly varied in studies. This study aimed to systematically analyze implant-based and subject-based prevalences of peri-implant diseases and assess clinical variables potentially affecting the prevalence. Sources: Electronic search of studies was conducted using MEDLINE (PubMed), EMBASE and Web of Science. Publication screening, data extraction, and quality assessment were performed. Study selection: Clinical studies having an at least average three-year follow-up period were selected. The numbers of subjects and implants in the studies had to be equal to or more than thirty. Data: Forty seven studies were selected and prevalences of peri-implant diseases were analyzed. Since heterogeneity existed in each outcome (I2=94.7, 95.7, 95.3, and 99.3 for implant-based and subject-based peri-implantitis and peri-implant mucositis, respectively), the random-effects model based on the DerSimonian and Laird method, which incorporate an estimate of heterogeneity in the weighting, was applied to obtain the pooled prevalence. Weighted mean implant-based and subject-based peri-implantitis prevalences were 9.25% (95% Confidence Interval (CI): [7.57, 10.93]) and 19.83% (CI [15.38, 24.27) respectively. Weighted mean implant-based and subject-based peri-implant mucositis prevalences were 29.48% (CI: [22.65, 36.32]) and 46.83% (CI: [38.30, 55.36]) respectively. Functional time and implant to subject ratio were associated with subject-based peri-implantitis prevalence, but not peri-implant mucositis prevalences. Conclusions: Peri-implant diseases were prevalent and prevalence of peri-implantitis increased over time. Prevalences of peri-implantitis and peri-implant mucositis might not be highly associated since the prevalences were influenced by distinct variables. The results should be carefully interpreted because of data heterogeneity. Clinical significance: Peri-implant diseases affect a significant number of dental implants and patients. It is important to understand the difficulties in diagnosis of these diseases and risk factors which may be modified to reduce the potential for disease occurrence or progression.

Association of haptoglobin and natural resistance-associated macrophage protein 1 alleles with heme-consuming periodontal pathogens in chronic periodontitis and peri-implantitis: A pilot study

Background: This study aimed to assess the association of haptoglobin (HP) and natural resistance-associated macrophage protein 1 (NRAMP1) alleles with the presence of heme-consuming periodontal pathogens in a group of Iranian patients with chronic periodontitis and peri-implantitis. Methods: This cross-sectional study evaluated 69 eligible chronic periodontitis and peri-implantitis patients selected from Shahid Beheshti Dental School. The periodontally diseased individuals had at least three teeth with clinical attachment loss of ≥3 mm and a probing pocket depth (PPD) of ≥3 mm in at least two quadrants. Peri-implant PPD of at least one site was ≥5 mm with or without suppuration and bleeding on probing. A plaque index of >20% and a radiographic crestal bone loss was present in at least one site around the implant. The paper point method was used for sampling from the deepest periodontal/peri-implant pocket of each tooth or implant for the DNA checkerboard hybridization technique. Statistical analyses were performed with PASW Statistics 18.0. The variables were presented as absolute and relative frequencies (%). Results: An Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) score of 1-2 was 5.8 times more frequent in HP 2, rs1723540 G, and rs2276631 G alleles. A Porphyromonas gingivalis (P. gingivalis) score of 1-2 was 4.8 times more common in the subjects carrying HP 2, rs1723540 G, and rs2276631 G alleles compared with HP 1, rs1723540 A, and rs2276631 A alleles. Conclusion: Within the limitations of this study, it seems that there was a relationship between HP and NRAMP1 allele frequencies and the presence of heme-consuming periodontal pathogens in the Iranian patients with chronic periodontitis and peri-implantitis evaluated in the present study.

Current understanding of genetic polymorphisms as biomarkers for risk of biological complications in implantology

Background: In the last decade, multiple studies have been published that analyze the relationship between the risk of experiencing biological complications with implants and the presence of certain types of genetic polymorphisms. In the present report, we analyze the controversies that have arisen from this important area of investigation and synthesize the most prominent aspects of knowledge related to this possible etiopathogenic relationship. Material and methods: For this review, the biomedical databases PubMed-Medline, SciELO, and DOAJ were used. Different search strategies were employed, from which 298 articles initially emerged. After refinement of the search, 55 articles published between 2002 and 2018 were finally selected based on relevance. Results: In certain population groups, there is evidence to support that about a dozen polymorphisms could in some way be related to biological complications in implantology. Indeed, the results may vary according to the ethnic origin of the population studied. Most of the published investigations are initial studies reporting small sample sizes and utilizing different study group homogenization methods. We are still at a preliminary stage of our understanding and development with regard to these types of biomarkers. The interesting results identified indicate that new investigations will be necessary to eliminate the biases observed in some studies and to homogenize the research groups. In order to clarify the controversies surrounding the current knowledge in this field, we believe that it will be necessary to employ larger study groups and search for possible synergistic effects between different polymorphisms. Key words:Polymorphism, genetic markers, peri-implantitis, biological complication, dental implant.

Interventions for replacing missing teeth: treatment of peri-implantitis

Background: One of the key factors for the long-term success of oral implants is the maintenance of healthy tissues around them. Bacterial plaque accumulation induces inflammatory changes in the soft tissues surrounding oral implants and it may lead to their progressive destruction (peri-implantitis) and ultimately to implant failure. Different treatment strategies for peri-implantitis have been suggested, however it is unclear which are the most effective. Objectives: To identify the most effective interventions for treating peri-implantitis around osseointegrated dental implants. Search methods: We searched the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE and EMBASE. Handsearching included several dental journals. We checked the bibliographies of the identified randomised controlled trials (RCTs) and relevant review articles for studies outside the handsearched journals. We wrote to authors of all identified RCTs, to more than 55 dental implant manufacturers and an Internet discussion group to find unpublished or ongoing RCTs. No language restrictions were applied. The last electronic search was conducted on 9 June 2011. Selection criteria: All RCTs comparing agents or interventions for treating peri-implantitis around dental implants. Data collection and analysis: Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two review authors. We contacted the authors for missing information. Results were expressed as random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals (CI). Heterogeneity was to be investigated including both clinical and methodological factors. Main results: Fifteen eligible trials were identified, but six were excluded. The following interventions were compared in the nine included studies: different non-surgical interventions (five trials); adjunctive treatments to non-surgical interventions (one trial); different surgical interventions (two trials); adjunctive treatments to surgical interventions (one trial). Follow-up ranged from 3 months to 4 years. No study was judged to be at low risk of bias.Statistically significant differences were observed in two small single trials judged to be at unclear or high risk of bias. After 4 months, adjunctive local antibiotics to manual debridement in patients who lost at least 50% of the bone around implants showed improved mean probing attachment levels (PAL) of 0.61 mm (95% confidence interval (CI) 0.40 to 0.82) and reduced probing pockets depths (PPD) of 0.59 mm (95% CI 0.39 to 0.79). After 4 years, patients with peri-implant infrabony defects > 3 mm treated with Bio-Oss and resorbable barriers gained 1.4 mm more PAL (95% CI 0.24 to 2.56) and 1.4 mm PPD (95% CI 0.81 to 1.99) than patients treated with a nanocrystalline hydroxyapatite. Authors' conclusions: There is no reliable evidence suggesting which could be the most effective interventions for treating peri-implantitis. This is not to say that currently used interventions are not effective.A single small trial at unclear risk of bias showed the use of local antibiotics in addition to manual subgingival debridement was associated with a 0.6 mm additional improvement for PAL and PPD over a 4-month period in patients affected by severe forms of peri-implantitis. Another small single trial at high risk of bias showed that after 4 years, improved PAL and PPD of about 1.4 mm were obtained when using Bio-Oss with resorbable barriers compared to a nanocrystalline hydroxyapatite in peri-implant infrabony defects. There is no evidence from four trials that the more complex and expensive therapies were more beneficial than the control therapies which basically consisted of simple subgingival mechanical debridement. Follow-up longer than 1 year suggested recurrence of peri-implantitis in up to 100% of the treated cases for some of the tested interventions. As this can be a chronic disease, re-treatment may be necessary. Larger well-designed RCTs with follow-up longer than 1 year are needed.

Association between Osteoprotegerin rs2073618 polymorphism and peri-implantitis susceptibility: a meta-analysis

Objectives: Peri-implantitis was an inflammatory progress on the tissue around the implant. The Osteoprotegerin G1181C (rs2073618) polymorphism was reported to be related to the increased risk of the peri-implantitis, whereas another found no relationship. The present study was conducted to research the relationship between Osteoprotegerin rs2073618 polymorphism and peri-implantitis susceptibility. Materials and methods: The meta-analysis was performed according to the Preferred Reporting Items for Systematic reviews. Electronic databases including PubMed, Web of science, Springer Link and Embase (updated to April 15, 2022) were retrieved. The cohort study, case-control study or cross-sectional study focusing on the Osteoprotegerin rs2073618 polymorphism and peri-implantitis were retrieved. The data included basic information of each study and the genotype and allele frequencies of the cases and controls. Results: Three studies were finally included, including 160 cases and 271 controls. Allelic model, homozygote model, recessive model, dominant model, and heterozygous model were established to assess the relationship between OPG rs2073618 polymorphism and peri-implantitis susceptibility. The Osteoprotegerin rs2073618 polymorphism was significantly associated with peri-implantitis in Recessive model and Homozygote model. Conclusion: OPG rs2073618 polymorphism in Recessive model and Homozygote model was highly likely related to the risk of peri-implantitis. PROSPERO registration number: CRD42022320812.

Association between Genetic Polymorphisms in RANK, RANKL and OPG and Peri-Implant Diseases in Patients from the Amazon Region

The present study evaluated polymorphisms in RANK, RANKL and OPG-encoding genes to assess whether they are associated with mucositis and peri-implantitis in a population from the Brazilian Amazon region. One hundred and fourteen patients with dental implants were included in the study. After clinical and radiographic examination, the sample was categorized into 4 groups, according to the peri-implant status: Healthy (n=71), Mucositis (n=30), Peri-implantitis (n=13) and Diseased (Mucositis + Peri-implantitis, n=43). Genomic DNA was extracted from buccal cells from saliva, and the genetic polymorphism in osteoprotegerin (OPG), Kappa nuclear factor activator receptor (RANKL) and nuclear kappa factor activator receptor (RANK) were genotyped by the real time PCR. Univariate and multivariate statistical analyses were performed to compare clinical variables among groups and to evaluate genotypes and alleles distributions and the established alpha was 5%. Age, peri-implant biotype, diabetes and presence of peri-implant biofilm were associated with mucositis (p<0.05) and peri-implantitis (p<0.05). Smoking, alcoholism, and periodontal biofilms were also associated with the presence of peri-implantitis (p<0.05). Univariate and multivariate analysis did not demonstrate an association of peri-implantitis or mucositis with any genetic polymorphism in RANK (rs3826620), RANKL (rs9594738) and OPG (rs2073618) (p>0.05). The studied genetic polymorphism in RANK, RANKL and OPG were not associated with mucositis and peri-implantitis in a Brazilian population from the Amazon region.

Genetic Risk Factors for the Development of Periimplantitis

Introduction: Periimplantitis etiology is multifactorial. The aim of this review is to identify the available data so far concerning the association between genetic polymorphisms and periimplantitis risk. Materials and methods: A literature search was performed in MEDLINE using the PubMed database of the US National Library of Medicine for articles published until March 2018. In addition, a manual search was performed. Our search and application of eligibility criteria provided 23 articles. Genes in these 23 studies could be divided into 3 overlapping categories: genes associated with (a) immune function, (b) bone growth, and (c) regulation of gene expression. Discussion: The pathogenesis of periimplantitis is not currently well understood. There are some polymorphisms, for which different studies state consistent results. However, there are many polymorphisms with conflicting results, which could be attributed to differences in study design. Conclusion: The identification of genetic biomarkers associated with periimplantitis risk could be valuable in daily clinical practice. However, no robust conclusions could be drawn from the current literature. The inequality of these studies' design necessitates the conduction of further studies using larger population samples and from different ethnic groups.

Role of proinflammatory mutations in peri-implantitis: systematic review and meta-analysis

Purpose: To perform a systematic review and meta-analysis on the presence of inflammatory polymorphisms in patients with peri-implantitis (PI). PI is the main complication associated to dental implant therapy. Although its main risk factors are history of periodontitis, poor plaque control and lack of regular maintenance, genetic susceptibility could also be a determinant factor for its appearance. Single nucleotide polymorphisms (SNP) are small mutations of the DNA that alter the osseointegration of implants. Inflammatory proteins participate in both destruction of the extracellular matrix and reabsorption of the alveolar bone. Methods: A bibliographical research was made in PubMed, Scopus and Web of Science (keywords: "single nucleotide polymorphism", "polymorphism", "periimplantitis", "SNP" and "implant failure"). Results: There is a statistically significant association of peri-implant bone loss with the homozygotic model of IL-1β (- 511) (OR: 2.255; IC: 1.040-4.889). Conclusions: Associations between inflammatory polymorphisms and PI must be taken with caution due to the heterogeneous methodological design, sample size and diagnostic criteria of the studies. Thus, more well-designed studies are needed that analyze the relationship between these and more SNP and PI.

A complete physical mapping of the vitamin D receptor gene for dental implant loss: A pilot study

Objectives: The aim of this pilot case-control study was to investigate the association of clinical variables and genetic polymorphisms in the vitamin D receptor gene (VDR) with dental implant loss. Material and methods: This study was carried out with 244 individuals with mean age 51.90 ± 11.28 (81 cases and 163 controls matched by age, sex, and smoking habit). Also, the clusterization phenomenon was investigated stratifying the sample into two groups: (a) 34 patients with multiple losses (presenting two or more lost implants) and (b) 210 without multiple losses (up to one implant loss). Sociodemographic, clinical, and periodontal parameters were analyzed. The tagSNPs in the VDR gene were analyzed by real-time PCR. Univariate and multivariate analyses were performed (p < .05). Results: Edentulism, number of implants installed, and Gingival, Plaque, and Calculus Indexes were associated with implant loss in the univariate analysis. After the multivariate analysis, the allele G of rs3782905 in the recessive model, together with number of installed implants and Gingival Index, was associated with implant failure. Conclusion: It is suggested that the allele G of rs3782905 in the recessive model may be a new genetic risk marker for dental implant loss in patients who lost two or more dental implants. In addition, number of implants installed and Gingival Index were also associated. Replication is mandatory to confirm these findings, due to the modest sample size of this work.

Analysis of the association of IL1B (C+3954T) and IL1RN (intron 2) polymorphisms with dental implant loss in a Brazilian population

Background: Although dental implants have a high success rate, failures occur, in spite of adequate clinical conditions. Together with the observation that multiple implant losses occur in certain groups of individuals (clusterization phenomenon), this suggests that host response may influence implant failure. Little is known about the influence of genetic susceptibility on implant loss. Interleukin (IL)-1 beta and IL-1 ra are believed to play a key role in the immune-inflammatory response, and polymorphisms IL1B (C+3954T) and IL1RN (intron 2) are shown to alter the coding proteins expression. Objectives: The aim of this study was to investigate the association between dental implant loss and polymorphisms IL1B (+3954) and IL1RN (intron 2). Material and methods: The study population (n=266) was divided into Test group (T)- 90 subjects with implant loss, and Control group (C)- 176 subjects without any implant failure. Genotyping was performed by PCR-RFLP. Results: The number of present teeth was observed to influence implant loss. No differences in genotype and allele frequencies between C and T were found for IL1B (+3954) and IL1RN (intron 2) polymorphisms. However, the analysis of the whole study population (control and test groups) showed that genotype 2/2 was significantly more frequent in individuals with multiple implant losses (n=35) than in individuals that lost up to a single implant (n=231) (OR: 3.07, IC: 1.13-8.34, P=0.027). Conclusion: It was observed that number of teeth and edentulism were associated with implant loss. Genotype 2/2 of IL1RN polymorphism was significantly more frequent in patients who presented multiple losses, which suggests that the clusterization phenomenon has a genetic basis.

Analysis of the association of IL1B(C-511T) polymorphism with dental implant loss and the clusterization phenomenon

Objectives: Endosteous dental implants consist in the treatment of choice to replace tooth loss. The knowledge that implant loss tends to cluster in subsets of individuals may indicate that host immune-inflammatory response is influenced by genetic factors. Interleukin-1 (IL-1) is a key mediator of inflammatory processes and functional polymorphisms in IL1 gene could be candidate genetic risk factors to study susceptibility to implant failure. The objective of this study was to investigate the association between IL1B (C-511T) genetic polymorphism and dental implant loss in a Brazilian population and its influence in the clusterization phenomenon. Material and methods: The sample composed of 277 unrelated, both gender, mean age 53.63 ± 11.14 years individuals, divided into test group - 92 subjects with implant loss, and control group - 185 subjects with no implant loss. Patients' socioeconomic profile and clinical variables were investigated. Genomic DNA from oral mucosa was analyzed by polymerase chain reaction-restriction fragment length polymorphism. Results: There was significant difference between the groups in medical treatment (P=0.040), edentulism (P=0.019), and mean number of placed implants (P=0.001). There was difference between groups with and without implant loss neither considering genotypes (P=0.279) nor alleles (P=0.168) for IL1B (C-511T) polymorphism. When individuals showing up to one implant failure (n=254) were investigated vs. patients presenting multiple implant loss (n=23), no difference was either observed between groups for genotype (P=0.083) and allele (P=0.838) frequencies. Conclusions: The borderline association of the study polymorphism with implant loss suggests further IL1 haplotype analysis to elucidate the global involvement of IL-1 proteins in the modulation of the osseointegration process.

A comparative study of the role of cytokine polymorphisms interleukin-10 and tumor necrosis factor alpha in susceptibility to implant failure and chronic periodontitis

Purpose: The presence of pathogenic microorganisms associated with both chronic periodontitis and implant failure can induce a host immune response. The type of response is determined by an individual's genetic makeup. The aim of this study was to investigate the genetic relationship between interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α) polymorphisms and patient susceptibility to chronic periodontitis or implant failure and to compare their immunogenetic functions. Materials and methods: This study recruited subjects according to clinical diagnostic criteria for failing implants, chronic periodontitis, healthy implants, and healthy controls. Human DNA from buccal swabs was analyzed by amplification refractory mutation system-polymerase chain reaction and agarose gel electrophoresis performed for gene polymorphisms of IL-10 (IL-10, IL-1082, IL-819, and IL-592) and TNF-α (TNF-α-308). Differences in the polymorphisms between test groups and healthy controls were assessed by Pearson chi-square test. Results: A total of 95 patients (16 failing implants, 22 chronic periodontitis, 23 healthy implants, and 34 healthy controls) were enrolled in this study. No significant association of IL-10 and TNF-α alleles, genotypes, or haplotypes were observed in chronic periodontitis or failing implant patients (P > .005). However, both patient groups showed highly similar frequencies of alleles, genotypes, and haplotypes (P > .99). Conclusion: This study found no significant association of either IL-10 or TNF-α genes in the susceptibility to the development of chronic periodontitis or implant failure.

Genetic susceptibility to dental implant failure: a critical review

The observation that clinical factors alone do not explain why some patients develop implant loss; the understanding of the osseointegrated implant failure as a complex, multifactorial process; and the observed aggregation of repetitive failure in certain individuals raise interesting questions related to host susceptibility to dental implant failure. Genetic analysis applied to dental implants began in the late 1990s, and since then, increased interest in genetic susceptibility to the phenotype has been demonstrated by several studies. These studies, however, have been based on and limited to candidate gene association analysis and were intended to find associations between specific alleles and/or genotypes of genetic markers and susceptibility to implant failure. The aim of this review is to provide a brief description of the current methodology for genetic analysis of complex traits, followed by a comprehensive review of the literature related to genetic susceptibility to dental implant failure and a discussion of different aspects of the applied methodology. Moreover, a novel approach of genome wide, case-control analysis is discussed as an alternative method to access genetic influence to dental implant failure mechanisms. Advances toward the elucidation of the genetic basis of dental implant loss may contribute to the understanding of why some patients do not respond to currently available treatments while others do and provide potential targets for effective screening, prevention, and treatment. For example, clinicians might be able to estimate, before the elective surgical procedure, the risk of a given patient to develop a negative individual host response.

Osseointegrated implant failure associated with MMP-1 promotor polymorphisms (-1607 and -519)

Purpose: Two polymorphisms in the promoter region of human MMP-1 gene, an insertion of a guanine at position -1607 and A-519G substitution, have been shown to increase the transcriptional activity of these matrix metalloproteinases (MMPs). The objective of this study was to investigate the possible relationship between these polymorphisms and early implant failure. Materials and methods: A sample of 104 nonsmokers was divided into 2 groups: a test group comprising 44 patients with 1 or more early failed implants and a control group consisting of 60 individuals with 1 or more healthy implants. Genomic DNA from oral mucosa was amplified by polymerase chain reaction and analyzed by restriction endonucleases. The significance of the differences in observed frequencies of polymorphisms were assessed by chi2 tests. Results: The G-1607GG polymorphism with the genotype G/G was observed at a frequency of 62% in the control group, while in the test group this genotype was noted in 34% of the individuals (P = .011). The allele G was found at a frequency of 75% in control group and 61.66% in the test group (P = .05). No significant differences were seen in the genotypes and allele frequencies in the A-519G polymorphism among the groups (P = .064 and P = .124, respectively). The distribution of the haplotypes arranged as alleles and genotypes showed a significant difference between control and test groups (P = .031 and P = .002, respectively). Conclusion: On the basis of this study of 60 patients who experienced no implant failure and 44 patients who experienced implant failure, the results suggest that G-1607GG polymorphism in MMP-1 gene is associated with early implant failure, while A-519G polymorphism in MMP-1 gene does not show a significant relationship with implant loss. This study also suggests that haplotypes G-1607GG and A-519G of MMP-1 may be associated with the osseointegration process.

Analysis of MMP-1 and MMP-9 promoter polymorphisms in early osseointegrated implant failure

Purpose: Polymorphisms, such as a guanine inserted at position -1607 in the promoter region of human matrix metalloprotenase 1 (MMP-1) or a C-1562T substitution in the MMP-9 gene, have been shown to increase the transcriptional activity of these MMPs. The objective of this study was to investigate the possible relationship between these polymorphisms and early implant failure. Materials and methods: Genomic DNA from oral mucosa was amplified by polymerase chain reactions (PCRs) and analyzed by restriction endonucleases. The significance of the differences in observed frequencies of polymorphisms was assessed by the chi-square and Fisher exact tests. Results: The test group comprised patients with early failure of osseointegrated oral implants. In the MMP-1 gene, 2G allele was observed in 25% of the control group and in 50% of the test group (P = .013). The genotype 1G/1G was found in 61.5% of the control group, while all patients in the test group had the genotype 1G/2G (P < .001). No differences were seen in the allele and genotype frequencies in the MMP-9 gene among the groups (P = .15 and P = .13, respectively). Discussion and conclusion: These results suggest that polymorphism in the promoter region of the MMP-1 gene may be associated with early implant failure, while polymorphism in the promoter region of the MMP-9 gene may not have a relationship with implant loss.

Influence of Serum Vitamin D Levels on Survival Rate and Marginal Bone Loss in Dental Implants: A Systematic Review

This systematic literature review set out to investigate the relationship between serum vitamin D levels and dental implants in terms of survival rates, marginal bone loss, and associated complications. The review was conducted according to PRISMA guidelines, performing an electronic search in four databases (Pubmed, Web of Science, Cochrane, and Scopus), complemented by a manual search up to April 2022. Four articles were selected for analysis. The Newcastle-Ottawa Quality Assessment Scale tool was used to assess the quality of evidence of cohort studies, and the Cochrane bias assessment tool was used to assess the quality of evidence of randomized clinical trials. The study included 1089 patients restored with 1984 dental implants, with follow-up periods ranging from 20-240 months. Cases presenting lower serum vitamin D levels obtained slightly worse results in terms of marginal bone loss. Longer follow-up periods are needed in order to determine whether serum vitamin D levels affect implant survival rates and osseointegration over time.

Analysis of association of clinical aspects and vitamin D receptor gene polymorphism with dental implant loss

Osseointegration failure is a complex, multifactorial trait shown to concentrate in some treated populations. There has been shown evidence for genetic contribution to dental implant loss. Genetic polymorphisms have been classically considered as genetic risk factors for several diseases and, more recently, for dental implant loss. Objectives: The purpose of this study was to access clinical factors related to failure process, and to investigate the relationship between a vitamin D receptor (VDR) polymorphism (rs731236, TaqI) and dental implant loss. Material and methods: Two hundred and seventeen unrelated patients, mean age 51.7+/-11.3 years, were divided into two groups: (i) control group (C), 137 individuals presenting at least one osseointegrated implant in function for 6 months or more and without any implant loss, and (ii) study group (S), 80 individuals presenting at least one implant loss. After DNA collection and purification, VDR TaqI polymorphism analysis was performed by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). Differences between C and S, and between healthy (H; n=1232) and lost (L; n=135) implants were accessed. Results: Positive evidence of association has been detected between implant loss and the following variables: edentulism, implant position, primary stability, and implant length. Cox's regression model showed that primary stability, surgical technique and bone quantity were related to implant survival over time. No association between genotypes or alleles of VDR TaqI polymorphism and implant loss was found between the groups. Conclusion: It was observed that clinical variables, but not the study polymorphism, were associated with dental implant loss.

The Relationship Between Low Serum Vitamin D Level and Early Dental Implant Failure: A Systematic Review

The variety in shape and type of dental implants in the present time is considered one of the most successful evolutions in dentistry. This facilitates dental treatment options to restore patient function and appearance. However, numerous significant factors influence the predictability of survival or the success rates of dental implants, some of which, such as vitamin D levels, have not been included in many studies. The main purpose of this systematic review was to investigate whether there is a relationship between low serum levels of vitamin D and early dental implant failures (EDIFs). Our literature search involved international databases including PubMed, Directory of Open Access Journals (DOAJ), and Web of Science. Initially, according to our search criteria, 1200 studies were found. After excluding duplicates, incomplete studies, and studies not meeting our inclusion criteria, only six human studies were included in this research and analyzed. Finally, upon meticulous analysis of included studies, this systematic review revealed inconsistent results in articles with respect to the association between vitamin D deficiency and implant failures. Large-scale studies, especially clinically relevant studies, on this subject is recommended.

Low serum vitamin D and early dental implant failure: Is there a connection? A retrospective clinical study on 1740 implants placed in 885 patients

Background. Since osseointegration depends on bone metabolism, low levels of vitamin D in the blood may negatively affect bone formation around dental implants. To date, only a few studies have investigated the possible connection between serum levels of vitamin D and early dental implant failure (EDIF), i.e. failure that occurs within 4 months after placement, before the connection of the prosthetic abutment. The aim of this study was to investigate whether there is a relationship between low serum levels of vitamin D and EDIF. Methods. Data used for this retrospective study were derived from the records of a private dental clinic. Inclusion criteria were patients who had been treated with dental implants, inserted with a submerged technique from January 2003 to December 2017. EDIF was the outcome of this study. Chi-squared test was used to investigate the effect of patient-related variables (age, gender, smoking habit, history of periodontal disease and serum levels of vitamin D) on EDIF. Results. Originally, 885 patients treated with 1,740 fixtures were enrolled in this study. Overall, 35 EDIFs (3.9%) were reported. No correlation was found between EDIF and the patients' gender (P=0.998), age (P=0.832), smoking habit (P=0.473) or history of periodontal disease (P=0.386). Three EDIFs (11.1%) were reported in 27 patients with serum levels of vitamin D <10 ng/mL, 20 EDIFs (4.4%) in 448 patients with levels between 10 and 30 ng/mL, and 12 EDIFs (2.9%) in 410 patients with levels >30 ng/mL. Although there was a clear trend toward an increased incidence of EDIF with lowering of serum vitamin D levels, no statistically significant difference (P=0.105) was found among these three groups. Conclusion. Within its limitations (retrospective design, low number of patients with severe blood levels of vitamin D enrolled), this study failed to demonstrate a significant relationship between low serum levels of vitamin D and increased risk of EDIF. However, since a dramatic increase in EDIFs with lowering of vitamin D levels in the blood has been reported, further clinical studies with appropriate design (prospective or randomized controlled studies on a larger sample of severely deficient patients) are needed to better investigate this topic.

Does vitamin D have an effect on osseointegration of dental implants? A systematic review

Purpose: The aim of this study was to systematically review the available evidence to evaluate the efficacy of vitamin D supplementation or vitamin D depletion on the osseointegration of implants in animals and humans. Methods: The focus questions addressed were "Do vitamin D deficient subjects treated with (dental) implants have an inferior osseointegration than subjects with adequate serum vitamin D level?" and "Do vitamin D supplemented subjects treated with (dental) implants have a superior osseointegration than subjects with adequate serum vitamin D level?" Humans and animals were considered as subjects in this study. Databases were searched from 1969 up to and including March 2021 using different combination of the following terms: "implant", "bone to implant contact", "vitamin D" and "osseointegration". Letters to the editor, historic reviews, commentaries and articles published in languages other than English and German were excluded. The pattern of the present systematic review was customize to primarily summarize the pertinent data. Results: Thirteen experimental studies with animals as subject, two clinical studies and three case reports, with humans as subjects, were included. The amount of inserted titanium implants ranged between 24 and 1740. Results from three animal studies showed that vitamin D deficiency has a negative effect on new bone formation and/or bone to implant contact (BIC). Eight animal studies showed that vitamin D supplementation has a enhancing effect on BIC and/or new bone formation around implants. Furthermore, enhancing the impact of vitamin D supplementation on the osseointegration of implants in subjects with diabetes mellitus, osteoporosis and chronic kidney disease (CKD) were assessed. Studies and case reports involving human subjects showed that patients with a low serum vitamin D level have a higher tendency to exhibit an early dental implant failure. When supplemented with vitamin D the osseointegration was successful in the case reports and a beneficial impact on the changes in the bone level during the osseointegration were determined. Conclusions: Vitamin D deficiency seems to have a negative effect on the osseointegration of implants in animals. The supplementation of vitamin D appears to improve the osseointegration in animals with systemic diseases, such as vitamin D deficiency, diabetes mellitus, osteoporosis, and CKD. Slight evidence supports the hypothesis that humans similarly benefit from vitamin D supplementation in terms of osseointegration. Further investigation is required to maintain these assumptions.

Vitamin D Supplementation for Prevention of Dental Implant Failure: A Systematic Review

Background: Many factors play a significant role in osseointegration and healing after dental implant insertion and restoration. Some factors are related to dental biomaterials, such as the dental implant, prosthesis, and grafting materials. Other factors can be connected to operator skills and accumulated experience. Local and systemic patient-related factors are crucial in determining the success of the dental implant. Thorough examination and analysis of local factors using available examination tools are vital to prepare the implant candidate for such treatment. The patient's systemic condition directly affects the healing of the dental implant. One of the most overlooked systemic factors is the patients' vitamin D level, which influences bone formation around the implant and subsequent osseointegration. The current review examined the available literature regarding the association between vitamin D supplementation and dental implant osseointegration. Methods: Data of this review were derived from recent research available on PubMed, Google Scholar, and Scopus. Inclusion criteria were the relation between the vitamin D serum and dental implant osseointegration or failure. The Systematic Reviews and Meta-Analyses (PRISMA) checklist was followed to perform the review. The study's outcome was the need for vitamin D supplementation to prevent implant failure. Results: Five human studies (including case reports, case series, and retrospective studies) and six animal studies. All included studies discussed the relationship between vitamin D, early dental implant failure, and bone implant contact. Three retrospective studies found no significant relationship between vitamin D supplementation and EDIFs in humans. On the other hand, one retrospective study showed a significant relationship in humans. A case report and case series claimed that the implant was successfully placed after vitamin D supplementation. A total of four animal studies showed a significant relationship between vitamin D supplementation and osseointegration of the dental implant. Two animal studies showed no significant association. Conclusion: To ensure optimal treatment outcomes, it is recommended to supplement the patient with vitamin D if the serum level is not within the normal range. Further clinical studies and case reports are needed to confirm the association between serum vitamin D levels and osseointegration.

Basis of bone metabolism around dental implants during osseointegration and peri-implant bone loss

Despite the growing number of publications in the field of implant dentistry, there are limited studies to date investigating the biology and metabolism of bone healing around dental implants and their implications in peri-implant marginal bone loss. The aim of this review article is to provide a thorough understanding of the biological events taking place during osseointegration and the subsequent early and late phases of bone remodeling around dental implants. An update on the coupling mechanism occurring during bone resorption-bone remodeling is provided, focused on the relevance of the osteocytes, bone lining cells and immune cells during bone maintenance. An electronic and manual literature search was conducted by three independent reviewers in several databases, including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Oral Health Group Trials Register databases for articles up to September 2016 with no language restriction. Local bone metabolism is subject to signals from systemic calcium-phosphate homeostasis and bone remodeling. Three areas of interest were reviewed due to recent reported compromises in bone healing including the putative effects of (1) cholesterol, (2) hyperlipidemia, and (3) low vitamin D intake. Moreover, the prominent influence of osteocytes and immune cells is discussed as being key regulators during dental implant osseointegration and maintenance. These cells are of crucial importance in the presence of biofilm accumulation and their associated byproducts that leads to hard and soft tissue breakdown; the so called peri-implantitis. Factors that could negatively impact osteoclastogenesis or osteal macrophage activation should be monitored in future research including implant placement/torque protocols, bone characteristics, as well as meticulous maintenance programs to favor osseointegration and future long-term stability and success of dental implants. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2075-2089, 2017.

Reasons for marginal bone loss around oral implants

Background: The reasons for long-term marginal bone loss around oral implants are not well understood. Purpose: The aim of this paper is to analyze presented evidence behind anticipated reasons for long-term marginal bone loss around oral implants. Materials and methods: A computerized research was conducted on PubMed in April 2011 with the following keywords: oral implants and marginal bone resorption/crestal bone loss/bone loss/bone resorption. This search resulted in a total of one thousand one hundred ninety-four papers of which seven hundred fifty-three were clinical contributions. Further search and filtering finally resulted in 21 experimental studies and one hundred sixteen clinical studies, which were reviewed. Results: No evidence was found that primary infection caused marginal bone resorption. Clinical papers that have reported high levels of peri-implantitis were not supported by data given. Clinical evidence was presented that the so-called combined factors (implant hardware, clinical handling, and patient characteristics) may lead to marginal bone resorption. However, once tissue damage has been caused by combined factors, inflammation and/or infection may develop secondarily and then result in peri-implantitis that may need particular clinical treatment. Conclusions: As marginal bone loss primarily depends on numerous background factors, it seems logical that, for example, the use of poorly constructed implants placed and handled by untrained clinicians may result in high numbers of patients with secondary problems in form of peri-implantitis; having said this, control of combined factors may likewise lead to very good clinical results where peri-implantitis would represent a very rare disease indeed even at follow-up times of 10 years or more.

Is it possible to decrease the occurrence of dental implant failures through the use of preventative antibiotics?

Design: The research was a randomized placebo-controlled clinical trial evaluating the use of clindamycin as a preoperative medication to prevent the dental implant. Aim: The purpose of the study was to assess if giving a single dose of 600 mg oral clindamycin 1 h before a conventional dental implant procedure could reduce the risk of early implant failure and post-surgical complications in healthy adults. Methods: A clinical trial was conducted with ethical standards, utilizing a randomized, double-blind, placebo-controlled approach. Healthy adults who required a single oral implant and had no previous surgical site infection or need for bone grafting were enrolled. Before surgery, participants were given either oral clindamycin or placebo at random. A single surgeon performed all operations, and patients were observed by a trained professional on multiple postoperative days. The study considered early dental implant failure as the loss or removal of an implant. Clinical, radiological, and surgical data were analyzed statistically to identify group differences. The number of subjects needed to treat, or harm, was calculated. Results: The research involved two groups of 31 patients each: the control group and the clindamycin group. Two patients in the clindamycin group experienced implant failures (NNH = 15, p = 0.246). Three patients in the study had postoperative infections; two of them were from the placebo group, while one from the clindamycin group had an unsuccessful treatment outcome. The relative risk was 0.5, with a CI of 0.05-5.23 and an absolute risk reduction of 0.03. The confidence interval was -0.07-0.13, and the NNT was 31, with a CI of 7.2-∞ and p = 0.5. In addition, only one patient treated with clindamycin reported gastrointestinal disturbances and diarrhea. Conclusions: There is no conclusive evidence to suggest that administering clindamycin prior to oral implant surgery in healthy adults reduces the risk of implant failure or post-surgical complications.

This study aimed to evaluate the clinical effect of leukocyte- and platelet-rich fibrin (L-PRF) to improve epithelialization and decrease postoperative pain in post-extraction sockets. Thirty two participants requiring extractions of posterior teeth were randomized into two groups: 1) extractions and socket filling with L-PRF membrane (test group) and 2) extraction with spontaneous healing (control group). One week after extraction, an assessment of soft tissue healing around the sockets was performed using the healing index. Also, postoperative pain by visual analog scale (VAS) and number of consumed analgesic tablets were recorded. In the first week, the sockets of the test group presented a significantly (mean of 3.81 ± 0.54; p = 0.0138) higher level of healing when compared to the sockets of the control group (mean of 3.18 ± 0.65). The participants of control group reported a significantly (mean of 5.12 ± 1.08; p = 0.0128) higher level of postoperative pain when compared to the test group (mean of 4 ± 1.15). Also, the control group consumed a greater number of analgesics (mean of 1.75 ± 0.85; p = 0.0136) when compared to the test group (mean of 1 ± 1.15). The results of the present study demonstrate that whenever improved healing of the extraction socket is needed, the use of L-PRF should be considered. In addition, the use of L-PRF decreases postoperative pain and discomfort.

The current literature was reviewed to analyze the effects of platelet-rich fibrin (PRF) on postoperative complications after mandibular third molar surgery (pain, alveolar osteitis, swelling, and bone healing). A comprehensive literature search was performed up to 2016 in the PubMed/MEDLINE, Cochrane Library, LILACS, and ScienceDirect databases and the grey literature. Additional records were identified through manual and reference searches. The full-text articles of potentially relevant studies were reviewed; only randomized clinical trials were included. Two review authors assessed the risk of bias independently. A total of 1430 publications were evaluated, of which seven were selected for qualitative analysis and two for quantitative analysis. A meta-analysis was performed only for alveolar osteitis, due to the considerable heterogeneity among studies for the other outcome variables. There were 485 extractions (243 test, 242 control) in 280 patients. PRF appeared to accelerate healing in mandibular third molar surgery, reducing postoperative pain and swelling. Quantitative analysis showed a decrease in prevalence of alveolar osteitis (odds ratio 0.31, 95% confidence interval 0.13–0.77, Z = 2.54, P = 0.01). Although more clinical trials of a better design and with larger samples are necessary to allow definitive conclusions to be drawn, PRF is a potentially useful biomaterial.

Association of interleukin-1 gene polymorphism and early crestal bone loss around submerged dental implants: A systematic review and meta-analysis

Aim: Early crestal bone loss (ECBL) has been observed regardless of the absence of possible etiologic factors for bone loss during the healing phase and before the second-stage implant surgery. The purpose of this systematic review and meta-analysis was to correlate the possible association of interleukin-1 (IL-1) gene polymorphisms and ECBL (bone loss before the second-stage surgery) around dental implants. Settings and design: Systematic review and meta-analysis following PRISMA guidelines. Materials and methods: Considering the inclusion criteria, an electronic search by using specific keywords of three databases PubMed [("Dental" OR "oral") AND ("Implants*") AND ("gene polymorphism" OR "genotype" AND ("IL-1" OR "interleukins")], Cochrane library [implant AND (biomarker or cytokine), interleukin-1 or IL-1 AND implants], and EMBASE [("gene polymorphisms"/de OR "interleukins"/cytokine exp OR "biomarker":ti,ab,kw) AND ("dental implantation"/de OR "oral implant")] and manual search from 1995 till March 2020 was made by 2 independently calibrated reviewers. ACROBAT-NRSI, Version 1.0.0 and Review Manager, Version 5.3, computer software were used for the risk of bias assessment and to conduct the meta-analysis respectively. Statistical analysis used: Cochran's Q test and I2 statistics. Results: Of 38 articles which were found eligible for full-text screening, two articles fulfilled the inclusion criteria and hence were included in the meta-analysis. The I2 statistic and Q-test values of the included studies revealed acceptable homogeneity for studied three IL-1 gene polymorphisms (IL-1A-889: I2 = 0%, IL-1B - 511: I2 = 0%, IL-1B+3954: I2 = 24%). Forest plot of association between IL-1B-511 gene and ECBL revealed a significant association between 2/2 genotype of IL-1B-511 gene and an increased risk of ECBL (OR = 0.23, 95% CI = 0.09-0.58, Pheterogeneity = 0.68, I2 = 0%, and P = 0.002). Results of the IL-1A-889 and IL-1B+3954 gene revealed no significant associations between any genotype of these genes with risk of ECBL. Conclusions: There is an evidence of the association of IL-1B-511 (2/2) genetic polymorphisms and increased ECBL in the individuals of Asian ethnicity (OR = 0.23, P = 0.002).

Genetic polymorphisms of the interleukin-1 gene and early marginal bone loss around endosseous dental implants

Dental implant surgery commonly proceeds in two stages. It is generally accepted that bone loss around implants does not occur at stage-II surgery because implants do not receive mechanical loading. However, early marginal bone loss around implants occasionally does occur during the healing period. Genetic polymorphisms in the interleukin-1 (IL-1) gene have been reported to be important for bone homeostasis and susceptibility to bone disease. We therefore investigated whether the idiopathic early marginal bone loss around implants is related to polymorphisms in the IL-1 gene. We performed a case-control study. Patients demonstrating marginal bone loss around implants at stage-II surgery were designated as the 'marginal bone loss (+)' group and those without bone loss as the 'marginal bone loss (-)' group. Polymorphisms of the IL-1alpha and IL-1beta genes (IL-1A-889, IL-1B-511 and IL-1B+3954) were detected by restriction fragment length polymorphism using NcoI, AvaI and TaqI after polymerase chain reactions. A total of 251 implants were placed in 39 patients. Marginal bone loss was observed in 36 implants. The patients with IL-1B-511 2/2 genotype exhibited a significantly higher occurrence of marginal bone loss than those with IL-1B-511 1/1 or 1/2 genotypes (OR=5.63; 95% CI=1.20-26.42; P=0.033). Multiple logistic regression analyses showed a markedly increased odds ratio (OR=10.86; 95% CI=1.64-71.90) in IL-1B-511 2/2 genotype carriers, while ORs of the other risk factors for bone loss, such as age, smoking status, post-menopausal women and bone quality, remained between 0.44 and 6.20. There was no significant difference in the distributions of the IL-1B+3954 and IL-1 A-889 genotypes between cases and controls. These data suggest that the IL-1B-511 2/2 genotype has a significant association with the incidence of early marginal bone loss around endosseous implants.

A comprehensive and critical review of dental implant prognosis in periodontally compromised partially edentulous patients

Objectives: The outcome of implant treatment in periodontally compromised partially edentulous patients has not been completely clarified. Therefore, the aim of the present study was to perform, applying a systematic methodology, a comprehensive and critical review of the prospective studies published in English up to and including August 2006, regarding the short-term (<5 years) and long-term (>or=5 years) prognosis of osseointegrated implants placed in periodontally compromised partially edentulous patients. Material and methods: Using The National Library Of Medicine and Cochrane Oral Health Group databases, a literature search for articles published up to and including August 2006 was performed. At the first phase of selection the titles and abstracts and at the second phase full papers were screened independently and in duplicate by the three reviewers (I. K. K., S. K., I. F.). Results: The search provided 2987 potentially relevant titles and abstracts. At the first phase of evaluation, 2956 publications were rejected based on title and abstract. At the second phase, the full text of the remaining 31 publications was retrieved for more detailed evaluation. Finally, 15 prospective studies were selected, including seven short-term and eight long-term studies. Because of considerable discrepancies among these studies, meta-analysis was not performed. Conclusions: No statistically significant differences in both short-term and long-term implant survival exist between patients with a history of chronic periodontitis and periodontally healthy individuals. Patients with a history of chronic periodontitis may exhibit significantly greater long-term probing pocket depth, peri-implant marginal bone loss and incidence of peri-implantitis compared with periodontally healthy subjects. Even though the short-term implant prognosis for patients treated for aggressive periodontitis is acceptable, on a long-term basis the matter is open to question. Alterations in clinical parameters around implants and teeth in aggressive periodontitis patients may not follow the same pattern, in contrast to what has been reported for chronic periodontitis patients. However, as only three studies comprising patients treated for aggressive periodontitis were selected, more studies, specially designed, are required to evaluate implant prognosis in this subtype of periodontitis. As the selected publications exhibited considerable discrepancies, more studies, uniformly designed, preferably longitudinal, prospective and controlled, would be important.

Role of proinflammatory mutations in peri-implantitis: systematic review and meta-analysis

Purpose: To perform a systematic review and meta-analysis on the presence of inflammatory polymorphisms in patients with peri-implantitis (PI). PI is the main complication associated to dental implant therapy. Although its main risk factors are history of periodontitis, poor plaque control and lack of regular maintenance, genetic susceptibility could also be a determinant factor for its appearance. Single nucleotide polymorphisms (SNP) are small mutations of the DNA that alter the osseointegration of implants. Inflammatory proteins participate in both destruction of the extracellular matrix and reabsorption of the alveolar bone. Methods: A bibliographical research was made in PubMed, Scopus and Web of Science (keywords: "single nucleotide polymorphism", "polymorphism", "periimplantitis", "SNP" and "implant failure"). Results: There is a statistically significant association of peri-implant bone loss with the homozygotic model of IL-1β (- 511) (OR: 2.255; IC: 1.040-4.889). Conclusions: Associations between inflammatory polymorphisms and PI must be taken with caution due to the heterogeneous methodological design, sample size and diagnostic criteria of the studies. Thus, more well-designed studies are needed that analyze the relationship between these and more SNP and PI.

Association between common polymorphisms in IL-1 and TNFα and risk of peri-implant disease: A meta-analysis

Background: Pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) play important roles in host immune response and bone metabolism during dental implant osseointegration. Whether the functional polymorphisms in IL-1α, IL-1β and TNFα were associated with peri-implant disease was unclear, and we performed the present meta-analysis for this purpose. Methods: Eligible studies investigating IL-1α C-889T, IL-1β C+3954T and C-511T, TNFα G-308A, composite genotype of IL-1α C-889T and IL-1β C+3954T for association with peri-implant disease, including peri-implantitis (PI), marginal bone loss (MBL) and implant failure/loss (IF/IL), were searched on several literature databases prior to April 30, 2021. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated for each polymorphism in different genetic models and for composite genotype comparing carriers to non-carriers. Results: Twenty-seven studies (1324 cases with peri-implant disease and 1808 controls with healthy implants) were included. There was significant correlation between IL-1α C-889T and peri-implant disease in all genetic models. IL-1β C+3954T was associated with peri-implant disease risk in allelic (OR = 1.66, 95%CI 1.17-2.35, p = 0.004) and dominant model (OR = 1.74, 95%CI 1.19-2.53, p = 0.004), and in subgroups of Asians, Caucasians, non-smokers, IF/IL and PI. TT genotype of IL-1β C-511T increased the risk of peri-implant disease (OR = 1.68, 95%CI 1.15-2.43, p = 0.007) and MBL (OR = 4.33, 95%CI 1.72-10.9, p = 0.002) compared to CC+CT genotypes. We did not observed a significant association between TNFα G-308A and peri-implant diseases in overall or subgroups analysis. Carriers of positive composite genotype of IL-1α C-889T and IL-1β C+3954T had 1.95-fold (95%CI 1.35-2.80, p<0.001) risk of peri-implant disease and 1.76-fold (95%CI 1.05-2.95, p = 0.032) risk of IF/IL than non-carriers. Conclusion: Functional polymorphisms of IL-1α (C-889T), IL-1β (C+3954T, C-511T) and composite genotype of IL-1 can be used as predictive markers for peri-implant disease, whereas TNFα G-308A polymorphism was not associated with peri-implant disease.

Association of IL-10 and TNF-α Polymorphisms with Dental Peri-Implant Disease Risk: A Meta-Analysis, Meta-Regression, and Trial Sequential Analysis

Genetic susceptibility has been reported to be an important risk factor for peri-implant disease (PID). The aim of this meta-analysis was to assess the association between TNF-α and IL-10 polymorphisms and PID susceptibility. The Web of Science, Cochrane Library, Scopus, and PubMed/Medline databases were searched for studies published until 12 April 2021. RevMan 5.3, CMA 2.0, SPSS 22.0, and trial sequential analysis software were used. Twelve studies were included in our analysis. The pooled ORs for the association of TNF-α (-308 G > A), IL-10 (-1082 A > G), IL-10 (-819 C > T), and IL-10 (-592 A > C) polymorphisms were 1.12, 0.93, 1.35, and 0.77 for allelic; 1.42, 0.95, 3.41, and 0.34 for homozygous; 1.19, 1.88, 1.23, and 0.49 for heterozygous, 1.53, 1.12, 1.41, and 0.39 for recessive; and 1.16, 1.87, 2.65, and 0.75 for dominant models, respectively, with all the estimates being insignificant. The results showed an association between TNF-α (-308 G > A) polymorphism and the risk of PID in patients of Asian ethnicity (OR = 1.59; p = 0.03). The present meta-analysis illustrated that TNF-α (-308 G > A), IL-10 (-1082 A > G), IL-10 (-819 C > T), and IL-10 (-592 A > C) polymorphisms were not associated with the risk of PID, whereas TNF-α (-308 G > A) polymorphism was associated with an elevated risk of PID in Asian patients.

Assessment of IL-10, IL-1ß and TNF-α gene polymorphisms in patients with peri-implantitis and healthy controls

Peri-implantitis (PI) is a multifactorial condition caused by the interactions of pathogens and the host immune response. Previous studies have demonstrated a relationship between PI and specific gene polymorphisms, particularly cytokine genes involved in the pathogenesis of PI. This study aimed to evaluate the frequency of single nucleotide polymorphisms (SNPs) of interleukin-10 (IL-10), interleukin 1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) genes in PI patients and healthy controls. A total of 50 patients with PI and 89 periodontally healthy controls were recruited for this study. Venous blood samples (5 cc) were collected, and DNA was extracted. After DNA purification, the relevant gene segments were amplified by polymerase chain reaction (PCR). Restriction fragment length polymorphism (RFLP) and electrophoresis were performed to assess the polymorphisms of the related genes. The analysis revealed that allele and genotype frequencies of IL-10 ─ 819 C/T, IL-10 ─ 592 C/A, and IL-1ß + 3954 C/T significantly differed between PI patients and healthy controls. The analysis revealed no significant association between TNF-α ─ 857 G/A and TNF-α ─ 308 G/A polymorphisms and PI. Our results indicated that specific gene polymorphisms of IL-10 ─ 819 C/T, IL-10 ─ 592 C/A, and IL-1ß + 3954 C/T may play a role in the pathogenesis of PI, and increase its risk of occurrence.

Association of interleukin-1 gene polymorphism and early crestal bone loss around submerged dental implants: A systematic review and meta-analysis

Aim: Early crestal bone loss (ECBL) has been observed regardless of the absence of possible etiologic factors for bone loss during the healing phase and before the second-stage implant surgery. The purpose of this systematic review and meta-analysis was to correlate the possible association of interleukin-1 (IL-1) gene polymorphisms and ECBL (bone loss before the second-stage surgery) around dental implants. Settings and design: Systematic review and meta-analysis following PRISMA guidelines. Materials and methods: Considering the inclusion criteria, an electronic search by using specific keywords of three databases PubMed [("Dental" OR "oral") AND ("Implants*") AND ("gene polymorphism" OR "genotype" AND ("IL-1" OR "interleukins")], Cochrane library [implant AND (biomarker or cytokine), interleukin-1 or IL-1 AND implants], and EMBASE [("gene polymorphisms"/de OR "interleukins"/cytokine exp OR "biomarker":ti,ab,kw) AND ("dental implantation"/de OR "oral implant")] and manual search from 1995 till March 2020 was made by 2 independently calibrated reviewers. ACROBAT-NRSI, Version 1.0.0 and Review Manager, Version 5.3, computer software were used for the risk of bias assessment and to conduct the meta-analysis respectively. Statistical analysis used: Cochran's Q test and I2 statistics. Results: Of 38 articles which were found eligible for full-text screening, two articles fulfilled the inclusion criteria and hence were included in the meta-analysis. The I2 statistic and Q-test values of the included studies revealed acceptable homogeneity for studied three IL-1 gene polymorphisms (IL-1A-889: I2 = 0%, IL-1B - 511: I2 = 0%, IL-1B+3954: I2 = 24%). Forest plot of association between IL-1B-511 gene and ECBL revealed a significant association between 2/2 genotype of IL-1B-511 gene and an increased risk of ECBL (OR = 0.23, 95% CI = 0.09-0.58, Pheterogeneity = 0.68, I2 = 0%, and P = 0.002). Results of the IL-1A-889 and IL-1B+3954 gene revealed no significant associations between any genotype of these genes with risk of ECBL. Conclusions: There is an evidence of the association of IL-1B-511 (2/2) genetic polymorphisms and increased ECBL in the individuals of Asian ethnicity (OR = 0.23, P = 0.002).

Genetic Polymorphisms Associated with Early Implant Failure: A Systematic Review

Purpose: Early implant failures have been observed in dental implant treatments even when the procedures are performed under appropriate conditions and in patients without local or systemic contraindications, suggesting that an intrinsic component of the patient could modify the osseointegration process. The objective of this systematic review was to analyze the association between early implant failure and genetic polymorphisms. Materials and methods: A systematic search was performed in the PubMed, ScienceDirect, and Scopus databases using the PRISMA statement as the main guidelines and "Dental implant" AND "Polymorphism" as search terms. The search cutoff date was August 2019. In addition, the risk of bias, methodologic quality, and heterogeneity of the included studies were analyzed. Results: The search strategy yielded 225 articles, and the titles and abstracts were reviewed to evaluate if they were relevant to the subject. Twenty-four articles were selected for a complete reading, of which 10 articles met the inclusion criteria. Finally, five studies citing the association of the following polymorphisms with early implant failure were chosen: G-1607GG of the MMP 1 gene, C-799T of the MMP 8 gene, and -77 A>G of the gene MMP 13. Conclusion: The polymorphisms analyzed are from the promoter region, generating altered cellular transcriptional activity for MMP 1, MMP 8, and MMP 13, the effects of which are observed in inflammation and extracellular matrix degradation. Establishing a relationship between genetic polymorphisms and phenomena such as early implant loss is necessary for the development of precision medicine in the field of dentistry.

The effect of static load on dental implant survival: a systematic review

Purpose: The purpose of this study was to systematically review the current evidence related to the effects of static loading on the long-term stability of the osseointegrated interface. Materials and methods: The literature search was conducted using Medline supplemented by SCOPUS and the Cochrane databases as well as hand searching from references of reviewed papers. Relevant studies were selected according to predetermined inclusion and exclusion criteria. Key words used in the search included: dental implant passive fit, dental implant misfit, dental implant static load, dental implant overload, orthodontic forces, and dental implants. Results: The initial database search yielded 192 relevant titles. After the subsequent filtering process, 36 studies were finally selected. Twenty-eight articles involved animal studies and eight articles involved human studies. Conclusions: The results of this systematic review demonstrate that there is no apparent detrimental effect of static loading on osseointegrated dental implants.

What impact do systemically administrated bisphosphonates have on oral implant therapy? A systematic review

Objectives: The aim of this systematic review is to evaluate, analysing the dental literature, whether: * Patients on intravenous (IV) or oral bisphosphonates (BPs) can receive oral implant therapy and what could be the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ)? * Osseointegrated implants could be affected by BP therapy. Material and methods: A Medline search was conducted and all publications fulfilling the inclusion and exclusion criteria from 1966 until December 2008 were included in the review. Moreover, the Cochrane Data Base of Systematic Reviews, and the Cochrane Central Register of Controlled Trials and EMBASE (from 1980 to December 2008) were searched for English-language articles published between 1966 and 2008. Literature search was completed by a hand research accessing the references cited in all identified publications. Results: The literature search rendered only one prospective and three retrospective studies. The prospective controlled non-randomized clinical study followed patients with and without BP medication up to 36 months after implant therapy. The patients in the experimental group had been on oral BPs before implant therapy for periods ranging between 1 and 4 years. None of the patients developed BRONJ and implant outcome was not affected by the BP medication. The three selected retrospective studies (two case-controls and one case series) yielded very similar results. All have followed patients on oral BPs after implant therapy, with follow-up ranging between 2 and 4 years. BRONJ was never reported and implant survival rates ranged between 95% and 100%. The literature search on BRONJ including guidelines and recommendations found 59 papers, from which six were retrieved. Among the guidelines, there is a consensus on contraindicating implants in cancer patients under IV-BPs and not contraindicating dental implants in patients under oral-BPs for osteoporosis. Conclusions: From the analysis of the one prospective and the three retrospective series (217 patients), the placement of an implant may be considered a safe procedure in patients taking oral BPs for <5 years with regard to the occurrence of BRONJ since in these studies no BRONJ has been reported. Moreover, the intake of oral-BPs did not influence short-term (1-4 years) implant survival rates.

Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases

Purpose: In recent years, numerous cases of bisphosphonate-associated osteonecrosis of the jaw have been reported involving both intravenous and oral therapy regimens. The majority of these cases have involved intravenous bisphosphonates. Subsequently, drug manufacturers and the US Food and Drug Administration issued warnings about possible bisphosphonate-associated osteonecrosis of the jaw. The American Dental Association and the American Association of Oral and Maxillofacial Surgeons assembled expert panels to formulate treatment guidelines. Both panels differentiated between patients receiving bisphosphonates intravenously and those receiving the drugs orally. However, the recommendations were based on limited data, especially with regard to patients taking oral bisphosphonates. We wanted to ascertain the extent to which bisphosphonate-associated necrosis of the jaw has occurred in our dental implant patients. We also wanted to determine whether there was any indication that the bisphosphonate therapy affected the overall success of the implants as defined by Albrektsson and Zarb. Patients and methods: We identified 1,319 female patients over the age of 40 who had received dental implants at Montefiore Medical Center between January 1998 and December 2006. A survey about bisphosphonate therapy was mailed to all 1,319 patients. Responses were received from 458 patients of whom 115 reported that they had taken oral bisphosphonates. None had received intravenous bisphosphonates. All 115 patients were contacted and informed about the risk of bisphosphonate-associated osteonecrosis of the jaw. Seventy-two patients returned to the clinic for follow-up clinical and radiological evaluation. Results: A total of 468 implants were placed in the 115 patients who reported that they had received oral bisphosphonate therapy. There is no evidence of bisphosphonate-associated osteonecrosis of the jaw in any of the patients evaluated in the clinic and those contacted by phone or e-mail reported no symptoms. Of the 468 implants, all but 2 integrated fully and meet criteria for establishing implant success. Implant success rates were comparable for patients receiving oral bisphosphonate therapy and those not receiving oral bisphosphonate therapy. Conclusions: Guidelines for treatment of dental patients receiving intravenous bisphosphonate treatments should be different than for patients taking the oral formulations of these medications. In this study, oral bisphosphonate therapy did not appear to significantly affect implant success. Implant surgery on patients receiving bisphosphonate therapy did not result in bisphosphonate-associated osteonecrosis of the jaw. Nevertheless, sufficient evidence exists to suggest that all patients undergoing implant placement should be questioned about bisphosphonate therapy including the drug taken, the dosage, and length of treatment prior to surgery. For patients having a history of oral bisphosphonate treatment exceeding 3 years and those having concomitant treatment with prednisone, additional testing and alternate treatment options should be considered.

Retrospective cohort study of 4,591 dental implants: Analysis of risk indicators for bone loss and prevalence of peri-implant mucositis and peri-implantitis

Background: Due to the risk of peri-implantitis, following dental implant placement, this study aimed to evaluate risk indicators associated with marginal bone loss from a retrospective open cohort study of 4,591 dental implants, placed in private practice, with 5- to 10-year follow-up. Furthermore, the prevalence of mucositis and peri-implantitis among the study cohort was evaluated, comparing strict versus relaxed criteria for bleeding on probing. Methods: Periapical radiographs were used to evaluate changes in crestal bone level. Peri-implant soft tissue was evaluated using an ordinal mucosal index in comparison with the conventional binary threshold for bleeding (i.e., present or not). Periodontal probing depth was not evaluated. Linear mixed models were used to evaluate bone level over time, and other risk indicators, at the patient and implant level. Results: Risk indicators found to have a significant impact on bone level included: autoimmune disease, heavy smoking, bisphosphonate therapy, implant location, diameter and design, and the presence of a bone defect at site of implantation. The prevalence of mucositis at the implant level was 38.6% versus 14.2% at 6 to 7 years, when using strict versus relaxed criteria, respectively. The prevalence of peri-implantitis after 6 to 7 years was 4.7% and 3.6% when using strict versus relaxed criteria, respectively. Conclusions: The results of this study identify several risk factors associated with bone loss. Furthermore, the prevalence of mucositis and peri-implantitis was shown to be lower at both the implant and the patient when using strict versus relaxed criteria based on the assessment of oral health surrounding dental implants.

Risk of bias assessment of systematic reviews regarding dental implant placement in smokers: An umbrella systematic review

Statement of problem: Although dental implant treatment has a high success rate, patient-related factors may cause implant failure. In this context, smoking is associated with adverse effects on implant osseointegration. In spite of systematic reviews addressing this topic, the risk of bias in these reviews must be assessed to inform readers whether the studies were conducted with methodological rigor and whether their recommendations are viable in daily clinical practice. Purpose: The purpose of this umbrella systematic review was to assess the risk of bias of systematic reviews regarding dental implant placement in smokers. Material and methods: Systematic review articles with meta-analysis regarding dental implant placement in smokers were eligible for this study. The following were excluded: articles in which implant survival or failure rate was not the primary outcome; articles in which implant survival or failure rate was not related to smokers; and duplicated articles. The search was performed by 2 independent reviewers on MEDLINE (PubMed), Scopus, Web of Science, LILACS, DARE-Cochrane, and SIGLE via OpenGrey. Non-peer-reviewed literature was sought on SIGLE via OpenGrey without language restrictions. Reviewers read titles and/or abstracts to select potential eligible studies, and articles initially selected were read fully. A third reviewer was consulted in cases of disagreement. References of the selected articles were also screened to identify articles of potential interest. The last search was performed on April 29, 2017. Risk of bias assessment was performed with the Risk of Bias in Systematic Reviews (ROBIS) tool. Results: Of the initial 2539 results, 6 systematic reviews with meta-analysis were eligible for the umbrella review (kappa=0.90; very good agreement). All studies were published in the last 11 years. One meta-analysis (16.7%) presented low risk of bias, 3 (50.0%) were assessed as of unclear risk of bias, and 2 (33.3%) received a score of high risk of bias according to the assessment with the ROBIS tool, which also indicated that the criteria most commonly not met were study eligibility criteria and identification and selection of studies. Conclusions: Five of the 6 included meta-analyses had a risk of bias (high or unclear). Therefore, their conclusions and recommendations required careful review. Future meta-analyses must focus especially on study eligibility criteria and identification and selection of studies.

RANK/RANKL/OPG gene polymorphisms and loss of orthodontic mini-implants

Objective: To investigate the association of genetic polymorphisms (tagSNPs type) of RANK/RANKL/OPG genes with the loss of orthodontic mini-implants (MIs). Setting and sample population: One hundred and thirty-five patients of both sexes, with mean age of 48.7 ± 10 (20-76 years), were studied. The control group was composed of 104 patients, with no MI lost and functioning for at least 6 months and the case group, of 31 patients with at least one MI lost. Materials and methods: Cells were obtained by mouthwash with 3% glucose solution for 1 minute and scraping the buccal mucosa with sterilized spatula. DNA was extracted from buccal epithelial cells with 10 M ammonium acetate and 1 mM EDTA. Genotyping was performed by the real-time polymerase chain reaction (PCR) technique. Univariate and multivariate analyses were performed (P < .05). Results: No markers were associated with MI loss after Benjamini and Hochberg false discovery rate correction of Univariate tests. In the multivariate analysis, the variables that associated with MI loss were the number of MIs installed (P < .000) and the polymorphism rs8086340 in the RANK gene (P = .018). Conclusion: A higher number of MIs installed (P < .000) and polymorphism rs8086340 in the RANK gene (P = .018) were associated with loss of orthodontic MIs after multivariate analysis.

General genetic and acquired risk factors, and prevalence of peri-implant diseases - Consensus report of working group 1

For decades, oral implants have been used successfully for the replacement of missing teeth. Nevertheless, peri-implant diseases have become an increasingly important issue in daily practice. In this working group, the prevalence of peri-implant mucositis and peri-implantitis, as well as different general risk factors and their impact on the onset and progression of peri-implant diseases, were discussed based on reviews reflecting the current state of evidence. The influence of smoking on the peri-implant bone-healing process and its association with peri-implantitis has been explored in the current literature, demonstrating that smoking is an important risk indicator for the development of peri-implantitis and implant loss. Compared with non-smokers, smokers have a higher potential for pathological peri-implant bone loss, which is also influenced by poor oral hygiene. Despite the fact that a growing number of genetic polymorphisms have been identified and related to periodontal diseases, there are still no genetic patterns that could act as adjuncts to clinical diagnostics in order to identify patients at higher risk of peri-implant diseases. Long-term medications, such as bisphosphonate therapy (> 3 years), may have an impact on implant loss. A higher incidence of implant failure was reported in patients using selective serotonin reuptake inhibitors in anti-depression therapy. Alcoholism (defined as more than 5 units a day) has been associated with implant loss in retrospective and case-control studies, as well as in animal studies.

Influence of MMP-8 promoter polymorphism in early osseointegrated implant failure

Objective: Dental implants consist in the treatment of choice to replace tooth loss. The knowledge that implant loss tends to cluster in subsets of individuals may indicate that host immuneinflammatory response is influenced by genetic factors. In fact, genetic polymorphisms influence the osseointegration process. The objective of this study was investigate the possible relationship between C-799T polymorphism in matrix metalloproteinase 8 (MMP-8) gene and early implant failure in nonsmoker patients. Methods and materials: Subjects were divided into two groups: control group (100 patients with one or more healthy implants) and test group (80 patients that had suffered one or more early implant failures). Genomic DNA from oral mucosa was amplified by PCR and analyzed by restriction endonucleases. The significance of the differences in observed frequencies of polymorphisms was assessed by Chi-square. Results: Statistical analysis shows that in the MMP-8 gene, the T allele in 76.25% in the test group and the T/T genotype, 63.75% in the same group, may predispose to early loss of implants osseointegrated. Conclusion: These results suggest that polymorphism in the promoter region of MMP-8 gene is associated with early implant failure. This polymorphism can be a genetic marker to risk of implant loss. Clinical relevance: The determination of this genetic pattern in osseointegration would enable the identification of individuals at higher risk to loss implant. Thus, genetic markers will be identified, contributing to an appropriate preoperative selection and preparation of strategies for prevention and therapy individualized to modulate the genetic markers and increase the success rate of treatments.

Evaluation of the relationship between interleukin-1 gene cluster polymorphisms and early implant failure in non-smoking patients

Objective: The aim of the present study was to investigate the relationship between specific polymorphisms of the interleukin-1 gene cluster and the early failure of osseointegrated implants. Material and methods: The subject population was composed by a test group comprising 28 non-smoking patients (mean age 52.7) that had suffered one or more early implant failures and by a control group consisting of 34 individuals (mean age 43.3) with one or more healthy implants. Genomic DNA from buccal mucosa was amplified by the polymerase chain reaction (PCR), followed by restriction fragment length polymorphism (RFLP) and submitted to polyacrylamide gel electrophoresis to distinguish the alleles of the interleukin-1A (-889), interleukin-1B (+3953), interleukin-1B (-511) and interleukin-RN (intron 2) gene polymorphisms. Differences in the allele and genotype frequencies between control and test groups were assessed by chi(2) test or by Monte Carlo simulations (P<0.05). Haplotype frequencies, linkage disequilibrium and Hardy-Weinberg equilibrium were also estimated. Results: No statistically significant differences were found in the genotype distribution or allelic frequencies of the polymorphisms. No differences were observed between control and test groups when different interleukin-1 gene cluster haplotypes were compared. Nevertheless, the interleukin-1A (-889) and interleukin-1B (+3953) polymorphic sites were in strong linkage disequilibrium (P=0.00014 for control group and P=0.0238 for the test group). Conclusion: This study suggests that polymorphisms in the interleukin-1 gene cluster are not associated with early implant failure in a non-smoking Brazilian population.

Can Genetic Factors Compromise the Success of Dental Implants? A Systematic Review and Meta-Analysis

Dental implants provide a predictable treatment option for partial and complete edentulism via the placement of a fixed permanent artificial root to support prosthetic dental crowns. Despite the high survival rates, long-term dental implant failures are still reported, leading to implant removals and additional financial and health burdens. While extrinsic factors that improve the success rate of implants have been well explored, the impact of genetic factors on this matter is poorly understood. A systematic review and meta-analysis study was conducted to determine whether genetic factors contribute to an increased risk of dental implant failures. A comprehensive search for peer-reviewed articles on dental implants and genetic factors was performed using various literature database libraries. The study design was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, and the obtained records were registered in the International Prospective Register of Systematic Reviews (PROSPERO) database. According to the exclusion/inclusion criteria, 13 studies were eligible for this study out of 809 articles. The meta-analysis of the combined association studies of DNA variations and dental implants did not indicate an increased risk for implant failure due to DNA variations in IL-1B, IL-10 and TNF-α. This study emphasizes the need for larger randomized controlled clinical trials to inform clinicians and patients about the role of genetic factors on dental implant survival and the success rate in healthy and compromised patients.

Thirty-three comparative studies were included. Nine articles had a parallel design and 24 had a split-mouth design. Twenty studies were considered to have a low risk of bias and 13 were considered to have a high risk. Overall, 1,193 teeth were extracted from 911 patients. Meta-analysis showed that soft tissue healing, probing depth at 3 months, and bone density at 1, 3, and 6 months were statistically better for the APC group. Qualitative analysis suggested that APCs might be associated with a decrease in swelling and trismus. However, no relevant difference among groups was found for probing depth at 1 month, incidence of alveolar osteitis, acute inflammation or infection, percentage of new bone, and indirect measurement of bone metabolism. APCs should be used in postextraction sites to improve clinical and radiographic outcomes such as bone density and soft tissue healing and postoperative symptoms. The actual benefit of APCs on decreasing pain in extraction sockets is still not quantifiable.

Autologous platelet concentrates (APCs) are a relatively new phenomenon, with initial reports of their regenerative potential published as recently as 1998. Despite their relative infancy, a huge body of evidence exists in support of their capacity to promote osseous and soft tissue regeneration through the physiologic processes of platelet activation and subsequent growth factor release. APCs have transformed many areas of healthcare and are now considered an essential component of the surgical milieu. In this narrative review, we explore the evolution of autologous platelet therapies with a particular emphasis on their contemporary applications in oral surgery, which rather fittingly was the first specialty to report the regenerative potential of APCs.

Vitamin D deficiency in early implant failure: two case reports

An association between vitamin D deficiency and early dental implant failure is not properly verified, but its role in osteoimmunology is discussed. This article illustrates two case reports with vitamin D deficiency and early implant failure. Prior to implant placement, the first patient received crestal bone grafting with autologous material. Both patients received dental implants from different manufacturers in the molar region of the mandible. In the case of bone grafting in the first patient, all implants were placed in a two-stage procedure. All implants had to be removed within 15 days after implant placement. Vitamin D serum levels were measured: Both patients showed a vitamin D deficiency (serum vitamin D level <20 μg/l). After vitamin D supplementation, implant placement was successful in both patients. Prospective, randomized clinical trials must follow to affirm the relationship between vitamin D deficiency, osteoimmunology, and early implant failure.

Immediate restoration of single implants placed immediately after implant removal. A case report

The purpose of this case report is to describe the treatment of implants placed in fresh extraction sockets and immediately restored in cases of failure. A healthy 58-year-old nonsmoking man was referred for an implant that had lost osseointegration because of infection. The prosthesis showed slight mobility. It was therefore decided to remove the implant and replace it with a new one immediately. Since the patient refused to wear a provisional removable prosthesis, the possibility of applying an immediate loading protocol was discussed. The failed implant was removed carefully and the residual extraction socket was thoroughly debrided. Subsequently, the new implant was placed with a sterile surgical technique, as described by the manufacturer. The inserted implant had a titanium plasma-sprayed surface. Immediately following implant placement and with the patient still under local anesthesia, the initial restorative treatment began. The patient was placed on a strict follow-up regimen until soft tissue healing was complete. Subsequent follow-up examinations were performed after 12 months. At each recall, the patient underwent a thorough clinical and radiographic evaluation. The healing period proceeded smoothly. At the end of the follow-up period, the implant was asymptomatic, immobile, and osseointegrated. No peri-implant bony defects were observed on probing. The results of the present case report seem to suggest that implants placed in fresh extraction sockets and restored immediately might provide a valid treatment option for the treatment of failed implants.

A comparative retrospective study of immediately loaded implants in postextraction sites versus healed sites: results after 6 to 7 years in the maxilla

Purpose: Immediate loading has become an emerging technique because it has been shown to be a successful, time-saving procedure. Recently, immediate loading has been performed simultaneously with implant placement into fresh extraction sockets; excellent results have been achieved, but few reports are available with a long-term follow-up. The aim of the present study was to evaluate the difference in success rates in the maxilla between postextraction implants and implants placed in healed sites, both of which were immediately loaded, after a long-term follow-up. Materials and methods: Between October 2001 and February 2003, 239 implants were inserted in 81 consecutively operated patients and immediately loaded; 138 implants were placed in fresh postextraction sites (57.7%) and 101 implants were placed in healed sites (42.3%). Two different implant systems were used in this study. Each implant was loaded within 72 hours of placement (60.3% at the time of surgery, 6.3% after 24 hours, 30.1% after 48 hours, and 3.3% after 72 hours). Preestablished success criteria were used to evaluate the success rate of the implants. Results: The mean follow-up was 6.7 years (range: 6.0 to 7.3 years). Only 8 of the 239 implants failed, for an overall success rate of 96.6%. Six of the failed implants were inserted in postextraction sites, and 2 had been placed in healed sites; the success rates were 95.7% and 98.0%, respectively. Statistical analysis revealed no significant differences between postextraction and healed sites. Conclusions: Immediate loading of immediate postextraction sites results in an implant success rate that is broadly comparable to that seen for implants placed in healed sites. Moreover, this procedure can provide predictable and favorable results in many different clinical conditions and for a long term.

Two neglected biologic risk factors in bone grafting and implantology: high low-density lipoprotein cholesterol and low serum vitamin D

Following a failure of a bone graft or an implant placement, the hypothesis of a biological abnormality is rarely considered as a possible cause. A systematic search of peer-reviewed literature for dyslipidemia or vitamin D deficiency may explain this lack of consideration. Excess low-density lipoprotein cholesterol (dyslipidemia) is responsible for a slower bone metabolism or lower dental implant osseointegration. In addition, vitamin D is a key factor for linking innate and adaptive immunity. Both of these factors are compromised under the conditions of vitamin D deficiency. Therefore, vitamin D deficiency slows implant osseointegration and increases the risk of graft infection. Vitamin D is also involved in immune function and therefore allergic reactions.

New and innovative biomaterials, techniques and therapy concepts: Biologization in maxillofacial surgery, oral surgery and dentistry is in full swing. PRF, PRGF, PRP, blood plasma-stabilized augmentations, supplementation of micronutrients and vitamins - what opportunities do such "biological" approaches actually offer? We introduce them here

Biomaterials of natural origin have recently gained increasing attention in the field of dental implantology. The requirements for such materials, however, are very high. In addition to high clinical efficiency in tissue regeneration, wound healing should be demonstrably positively influenced. The translational division for regenerative orofacial medicine of the Clinic and Polyclinic for Oral and Maxillofacial Surgery of the University Medical Center Hamburg-Eppendorf (UKE) is examining this research topic by investigating which innovative treatment methods for the reconstruction of bone defects or for augmentative procedures can be applied in the future or are already being applied in the field of oral and maxillofacial surgery.

Advanced Biomaterials and Techniques for Oral Tissue Engineering and Regeneration-A Review

The reconstruction or repair of oral and maxillofacial functionalities and aesthetics is a priority for patients affected by tooth loss, congenital defects, trauma deformities, or various dental diseases. Therefore, in dental medicine, tissue reconstruction represents a major interest in oral and maxillofacial surgery, periodontics, orthodontics, endodontics, and even daily clinical practice. The current clinical approaches involve a vast array of techniques ranging from the traditional use of tissue grafts to the most innovative regenerative procedures, such as tissue engineering. In recent decades, a wide range of both artificial and natural biomaterials and scaffolds, genes, stem cells isolated from the mouth area (dental follicle, deciduous teeth, periodontal ligament, dental pulp, salivary glands, and adipose tissue), and various growth factors have been tested in tissue engineering approaches in dentistry, with many being proven successful. However, to fully eliminate the problems of traditional bone and tissue reconstruction in dentistry, continuous research is needed. Based on a recent literature review, this paper creates a picture of current innovative strategies applying dental stem cells for tissue regeneration in different dental fields and maxillofacial surgery, and offers detailed information regarding the available scientific data and practical applications.

Recent advancements in regenerative dentistry: A review

Although human mouth benefits from remarkable mechanical properties, it is very susceptible to traumatic damages, exposure to microbial attacks, and congenital maladies. Since the human dentition plays a crucial role in mastication, phonation and esthetics, finding promising and more efficient strategies to reestablish its functionality in the event of disruption has been important. Dating back to antiquity, conventional dentistry has been offering evacuation, restoration, and replacement of the diseased dental tissue. However, due to the limited ability and short lifespan of traditional restorative solutions, scientists have taken advantage of current advancements in medicine to create better solutions for the oral health field and have coined it "regenerative dentistry." This new field takes advantage of the recent innovations in stem cell research, cellular and molecular biology, tissue engineering, and materials science etc. In this review, the recently known resources and approaches used for regeneration of dental and oral tissues were evaluated using the databases of Scopus and Web of Science. Scientists have used a wide range of biomaterials and scaffolds (artificial and natural), genes (with viral and non-viral vectors), stem cells (isolated from deciduous teeth, dental pulp, periodontal ligament, adipose tissue, salivary glands, and dental follicle) and growth factors (used for stimulating cell differentiation) in order to apply tissue engineering approaches to dentistry. Although they have been successful in preclinical and clinical partial regeneration of dental tissues, whole-tooth engineering still seems to be far-fetched, unless certain shortcomings are addressed.

Is Low Serum Vitamin D Associated with Early Dental Implant Failure? A Retrospective Evaluation on 1625 Implants Placed in 822 Patients

Aim. To investigate whether there is a correlation between early dental implant failure and low serum levels of vitamin D. Methods. All patients treated with dental implants in a single centre, in the period 2003-2015, were considered for enrollment in this study. The main outcome was early implant failure. The influence of patient-related variables on implant survival was calculated using the Chi-square test. Results. 822 patients treated with 1625 implants were selected for this study; 27 early failures (3.2%) were recorded. There was no link between gender, age, smoking, history of periodontitis, and an increased incidence of early failures. Statistical analysis reported 9 early failures (2.2%) in patients with serum levels of vitamin D > 30 ng/mL, 16 early failures (3.9%) in patients with levels between 10 and 30 ng/mL, and 2 early failures (9.0%) in patients with levels <10 ng/mL. Although there was an increasing trend in the incidence of early implant failures with the worsening of vitamin D deficiency, the difference between these 3 groups was not statistically significant (P = 0.15). Conclusions. This study failed in proving an effective link between low serum levels of vitamin D and an increased risk of early implant failure. Further studies are needed to investigate this topic.

Comparative evaluation of crestal bone level in patients having low level of Vitamin D treated with dental implant with or without Vitamin D3 supplements

Introduction: Vitamin D has been shown to play a vital role in bone mineral homeostasis by stimulating the intestinal absorption of calcium and phosphate. The critical role of Vitamin D in bone metabolism triggered the need to evaluate the effect of Vitamin D deficiency and hence replacement of the same on osseointegration of dental implants. This prospective study evaluated the crestal bone level in patients having low level of Vitamin D treated with dental implant with or without Vitamin D3 supplements. Materials and methods: A prospective clinical study was conducted on 32 patients based on the inclusion and exclusion criteria. Patients were divided into two groups on the basis of Vitamin D level < 30 ng/ml (Group I: patients receiving Vitamin D3 supplements, i.e., cholecalciferol 1 g sachet 60,000 IU/month) or <30 ng/ml (Group II: not receiving Vitamin D3 supplements). The crestal bone level measurements were made with the help of Digimizer Image Analysis, MedCalc software. Results: All implants showed clinically acceptable crestal bone level at interval of 1 week (baseline), 3 months, and 6 months. There was a statistically nonsignificant difference seen for the values between the groups (P > 0.05) for all other values at various time intervals. However, there was a statistically significant/highly significant difference seen for the values between the groups (P < 0.01, 0.05) for 3 months distal with higher values for Group I as compared to Group II. Conclusion: From the study, it can be concluded that cholecalciferol has systemic effects on accelerating bone formation around titanium implant.

A systematic review of the incidence of biological and technical complications in implant dentistry reported in prospective longitudinal studies of at least 5 years

Objective: To systematically review the incidence of biological and technical complications in implant therapy reported in prospective longitudinal studies of at least 5 years. Methods: A MEDLINE search was conducted for prospective longitudinal studies with follow-up periods of at least 5 years. Screening and data abstraction were performed independently by multiple reviewers. The types of complications assessed were as follows: implant loss, sensory disturbance, soft tissue complications, peri-implantitis, bone loss >or=2.5 mm, implant fracture and technical complications related to implant components and suprastructures. Results: The search provided 1310 titles and abstracts, out of which 159 were selected for full-text analysis. Finally, 51 studies were included. Meta analysis of these studies indicated that implant loss prior to functional loading is to be expected to occur in about 2.5% of all implants placed in implant therapy including more than one implant and when routine procedures are used. Implant loss during function occurs in about 2-3% of implants supporting fixed reconstructions, while in overdenture therapy >5% of the implants can be expected to be lost during a 5-year period. Few studies (41% of those included) reported data on the incidence of persisting sensory disturbance >1 year following implant surgery. Most of the studies that provided such data reported on the absence or a low incidence (1-2%) of this complication beyond this interval. A higher incidence of soft tissue complications was reported for patients treated with implants supporting overdentures. There is limited information regarding the occurrence of peri-implantitis and implants exhibiting bone loss >or=2.5 mm. Implant fracture is a rare complication and occurs in <1% of all implants during a 5-year period. The incidence of technical complications related to implant components and suprastructures was higher in overdentures than in fixed reconstructions. Conclusion: Implant loss was most frequently described (reported in about 100% of studies), while biological complications were considered in only 40-60% and technical complications in only 60-80% of the studies. This observation indicates that data on the incidence of biological and technical complications may be underestimated and should be interpreted with caution.

Analysis of the association of TNF-α, IL-1A, and IL-1B polymorphisms with peri-implantitis in a Chinese non-smoking population

Objectives: The purpose of this study was to investigate whether the genetic variations which could regulate inflammatory responses were associated with the risk of peri-implantitis. Materials and methods: We evaluated three genetic variants including tumor necrosis factor-alpha (TNF-α) - 308G/A, interleukin-1 alpha (IL-1A) - 889C/T, and IL-1 beta (IL-1B) + 3954C/T, as risk factors for peri-implantitis, in a total of 144 patients with peri-implantitis and 174 healthy controls in a Chinese non-smoking population. Results: Logistic regression analyses revealed that subjects carrying the T allele of IL-1A - 889C/T and IL-1B + 3954C/T had a significant 2.27-2.47-fold (CT, OR [95% CI] = 2.27 [1.12-4.58], p = 0.021; TT, OR [95% CI] = 2.47 [1.32-4.69], p = 0.006) and 1.9-1.99-fold (CT, OR [95% CI] = 1.99 [1-3.93], p = 0.041; TT, OR [95% CI] = 1.9 [1.08-3.43], p = 0.03) increased risk of peri-implantitis, respectively, when using the CC genotype as a reference point. And subjects carrying the TT genotype of IL-1A - 889C/T or IL-1B + 3954C/T also had significantly higher periodontal variables including peri-implant pocket depth (PPD), bleeding on probing (BOP), gingival index (GI), plaque index (PI), calculus index (CI), and clinical attachment level (CAL) (p < 0.05). However, no associations were found between the TNF-α - 308G/A polymorphism and the risk of peri-implantitis. Conclusions: Our results suggest that the IL-1A - 889C/T or IL-1B + 3954C/T genetic polymorphisms were associated with the risk of peri-implantitis and periodontal status. Clinical relevance: Genetic polymorphisms are constant and can be measured before disease onset, thus it could be of great benefit for treatment planning and prognosis in an early stage.

The relationship between single nucleotide polymorphisms and dental implant loss: a scoping review

Objectives: The purpose of this review was to evaluate the relationship between genetic polymorphisms and dental implant loss. Materials and methods: All case-control studies examining single nucleotide polymorphisms (SNPs) and dental implant failure were considered. A Boolean search was conducted on PubMed and Scopus to find eligible studies. Results: The initial search produced 78 results. Twenty-one studies were considered for inclusion after review and 16 were included in the final review. Twenty-two different polymorphisms were analyzed and statistically significant correlation was found for IL-4, IL-1A, IL-1B, MMP-8, and MMP-1 polymorphisms for dental implant failure. Discussion: A limited number of comprehensive studies have been done in this field. Additional studies with larger sample sizes and different ethnic backgrounds need to be done to see if the results can be reproduced. Of the polymorphisms studied, the IL-4 (+33), MMP-8 (-799), MMP-1 (-519), and MMP-1 (-1607) polymorphisms show the greatest association with dental implant loss.

Association between Interleukin-1 Polymorphisms and Susceptibility to Dental Peri-Implant Disease: A Meta-Analysis

Background and objective: Interleukins (ILs), as important biochemical mediators, control the host response to inflammation and are associated with bone resorption. In the present meta-analysis, we investigated the association between IL-1 polymorphisms and susceptibility to dental peri-implant disease (PID). Materials and methods: We searched Web of Science, Cochrane Library, Scopus, and PubMed/Medline databases for studies published until 9 September2021, without any restrictions. We calculated the crude OR and 95% confidence intervals (CI) to estimate the associations between IL-1 polymorphisms and PID risk in the five genetic models. We further performed the subgroup analysis, sensitivity analysis, meta-regression, trial sequential analysis, and calculated the publication bias. Results: Out of 212 retrieved records, sixteen articles were used in the meta-analysis. There was no association between IL-1A (-889), IL-1B (-511), IL-1B (+3953), and IL-1RN (VNTR) polymorphisms and the risk of dental PIDs, but there was an increased risk of IL-1B (+3954) in the patients with PIDs. In addition, an association of the composite genotype of IL-1A (-889)/IL-1B (+3953) was observed with the risk of PIDs, but not for the composite genotype of IL-1A (-889)/IL-1B (+3954). The publication year, the ethnicity, sample size, and the outcome were significantly influenced pooled estimates of some genetic models. Trial sequential analysis showed the lack of sufficient sample sizes in the studies. Conclusions: Among IL-1 polymorphisms evaluated in the meta-analysis, the composite genotype of IL-1A (-889)/IL-1B (+3953) and IL-1B (+3954) were the only polymorphisms associated with the risk of PID. The T allele and CT genotype of IL-1B (+3954) polymorphism were also associated with an elevated risk of PID.

Genetic Involvement in Dental Implant Failure: Association With Polymorphisms of Genes Modulating Inflammatory Responses and Bone Metabolism

Implant loss is the most serious complication of dental implants. Although the problems and causes behind the implant failure are clearly defined today, determination of the underlying causes of failure varies by the case. The clusterization phenomenon of implant loss (multiple implant failures) implies the existence of genetic risk factors. Inflammation has a critical effect on osseointegration and implant success. Peri-implantitis is an inflammatory disease of tissue supporting the tooth or implant. Inflammation leads to loss of support tissue, particularly bone, resulting in failure of implants. A single nucleotide polymorphism (SNP) of pro-inflammatory mediator genes may affect their expression levels or amino acid sequence, and, consequently, the host inflammatory response. Since the end of the past century, many studies have been conducted to investigate the association of SNP with implant failure and related conditions. Involvement of several groups of genes-including interleukins, tumor necrosis factor-α, matrix metalloproteinases, and growth factors involved in immune regulation, inflammatory response, and bone metabolism-has been explored. Some have been found to be associated with implant loss and considered potential genetic risk factors for implant failure. In this review, we summarize results of recent studies of impact of genetic factors on dental implant failure.

Meta-analysis of the association between common interleukin-1 polymorphisms and dental implant failure

Interleukin-1 (IL) plays a pivotal role in immune-inflammatory response that maintains periodontal homeostasis. A number of epidemiological studies have been conducted to investigate the associations between common polymorphisms of IL-1 (IL-1A, IL-1B) genes and risk of peri-implant disease, but the findings remain inconclusive. Thirteen studies evaluating the association between IL-1 polymorphisms and risk for peri-implant diseases (implant failure/loss, peri-implantitis) were included. Fixed model or random-effects models were applied to calculate overall and ethnicity-specific summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) as risk estimates for IL-1 polymorphisms individually or in combination. Heterogeneity and publication bias were evaluated by Q-test, I2 statistic, Begg's funnel plot and Egger's test accordingly. The composite genotype of IL-1A (-889) and IL-1B (+3954) was associated with increased risk of implant failure/loss (OR 1.76, 95% CI 1.21-2.57) and peri-implantitis (OR 2.34, 95% CI 1.03-5.33). The significance was borderline in European descents (implant failure/loss: OR 1.48, 95% CI 0.99-2.22; peri-implantitis: OR 1.65, 95% CI 1.00-2.73). T allele of IL-1B (-511) was associated with increased risk of implant failure/loss (OR 1.28, 95% CI 1.01-1.62), while the association was not significant in European descents (OR 1.12, 95% CI 0.85-1.48). These findings support a potential role of IL-1 polymorphisms, particularly the composite genotype of IL-1A (-889) and IL-1B (+3954), in peri-implant disease susceptibility. More studies with large sample size are needed to validate the associations.

Relationship between interleukin-1 genotype and peri-implantitis: a literature review

Endosseous implants present high survival rates within a 10-year observation time; however, implant failure and biologic complications are not completely avoidable. Although specific bacteria, dental plaque, and environmental factors are associated with peri-implant disease, there are currently no reliable predictors of peri-implantitis occurrence and severity. Disagreement about which clinical measures of peri-implant health are of diagnostic value continues because of the complexity of the disease process. Thus, identification of genes that control or modify aspects of the host response may provide a method to identify individuals at an elevated risk for peri-implant infections. Elevated levels of the inflammatory cytokine interleukin-1 (IL-1) in the crevicular fluid around diseased implants seem to play an important role in the pathogenesis and severity of peri-implantitis. The purpose of this review article was to critically address the genetic associations regarding IL-1 genotype claimed for peri-implant disease and to validate the use of IL-1 genetic susceptibility tests. It was revealed that the diagnostic value of both IL-1 genotyping and genetic tests for peri-implantitis should be reconsidered before altering treatment planning, regimens, and maintenance in implant dentistry.

Relationship between Genetic Polymorphisms with Periodontitis and Peri-Implantitis in the Iranian Population: A Literature Review

Periodontitis is an infectious disease of the tooth-supporting tissues. Specific periodontal pathogens trigger inflammatory responses and result in progressive bone loss, which eventually leads to exfoliation of teeth. Periimplantitis is the destructive inflammatory process affecting the soft and hard tissues surrounding dental implants. The periodontal pathogens found around failing implants are very similar to those associated with various forms of periodontal diseases. Genetic susceptibility has been known to be an important risk factor for periodontitis and periimplantitis and there have been numerous studies evaluating this in different populations. Many gene polymorphisms may influence individual susceptibility to periodontitis and peri-implantitis. We conducted a review of the literature for gene polymorphisms associated with periodontitis and peri-implantitis susceptibility in the Iranian population. A comprehensive search of the literature on human studies in English, published from January 2004 to February 2015 in PubMed database and Google scholar was performed using the key words "periodontitis," "peri-implantitis," "gene polymorphisms," and "Iranian population." Sixty-six studies were identified; 33 articles were excluded based on review of titles and abstracts. Thirty articles were eligible and had the full text evaluated. Further studies are needed to get more inclusive perception of the influence of gene polymorphisms in periodontitis and peri-implantitis.

Influence of epigenetics on periodontitis and peri-implantitis pathogenesis

Periodontitis is a disease characterized by tooth-associated microbial biofilms that drive chronic inflammation and destruction of periodontal-supporting tissues. In some individuals, disease progression can lead to tooth loss. A similar condition can occur around dental implants in the form of peri-implantitis. The immune response to bacterial challenges is not only influenced by genetic factors, but also by environmental factors. Epigenetics involves the study of gene function independent of changes to the DNA sequence and its associated proteins, and represents a critical link between genetic and environmental factors. Epigenetic modifications have been shown to contribute to the progression of several diseases, including chronic inflammatory diseases like periodontitis and peri-implantitis. This review aims to present the latest findings on epigenetic influences on periodontitis and to discuss potential mechanisms that may influence peri-implantitis, given the paucity of information currently available.

MiR146a and MiR499 gene polymorphisms in Iranian periodontitis and peri-implantitis patients

Aim: MicroRNAs (MiRs) are small noncoding RNAs that are involved in protein translation, osteoclastogenesis, and immunoregulation. Peri-implantitis and chronic periodontitis are multifactorial diseases. They are the consequence of complex interactions among host response, genetics, and environment. In the present study, we aimed to investigate the possible association between MiR146a/MiR499 gene polymorphisms and periodontitis/peri-implantitis as a first report in oral implantology. Methods: From 197 individuals referred to Periodontology Department of Shahid Beheshti Dental School, three groups were enrolled in the assessment: 75 patients in the chronic periodontitis (CP) group, 38 patients in the peri-implantitis (PI) group, and 84 healthy subjects. DNA was extracted from fresh blood samples from the arm veins of participants and transferred to KBiosience Institute (Hoddesdon, United Kingdom) for genotyping. Chi-squared and Kruskal-Wallis tests were performed using SPSS software v.19 for statistical analyses. P-value < 0.05 was considered significant. Results: The genotype frequencies in MiR 146a and MiR 499 were significantly different among the three groups. Conclusions: MiR146a (rs2910146) and MiR499 (rs3746444) gene polymorphisms may be genetic determinants for increased risk of chronic periodontitis and peri-implantitis in Iranians. More studies with larger sample sizes in different populations are necessary for determining the effect of these SNPs.

Prevalence and Possible Risk Factors of Peri-implantitis: A Concept Review

Aim: The purpose of this review is to estimate the prevalence of peri-implantitis, as well as to determine possible risk factors associated with its development in patients treated with oral implants. Background: Although implant therapy has been identified as a successful and predictable treatment for partially and fully edentulous patients, complications and failures can occur. Peri-implantitis is considered a biologic complication that results in bone loss around implants and may lead to implant treatment failure. Results: A great variation has been observed in the literature regarding the prevalence of peri-implantitis according to the diagnostic criteria used to define peri-implantitis. The prevalence ranges from 4.7 to 43% at implant level, and from 8.9 to > 56% at patient level. Many risk factors that may lead to the establishment and progression of peri-implantitis have been suggested. There is strong evidence that presence and history of periodontitis are potential risk factors for peri-implantitis. Cigarette smoking has not yet been conclusively established as a risk factor for peri-implantitis, although extra care should be taken with dental implant in smokers. Other risk factors, such as diabetes, genetic traits, implant surface roughness and presence of keratinized mucosa still require further investigation. Conclusion: Peri-implantitis is not an uncommon complication following implant therapy. A higher prevalence of peri-implantitis has been identified for patients with presence or history of periodontal disease and for smokers. Until now, a true risk factor for peri-implantitis has not been established. Supportive maintenance program is essential for the long-term success of treatments with oral implants. Clinical significance: The knowledge of the real impact of peri-implantitis on the outcome of treatments with oral implants as well as the identification of risk factors associated to this inflammatory condition are essential for the development of supportive maintenance programs and the establishment of prevention protocols.

Association of Cytokine Gene Polymorphism with Peri-implantitis Risk

Purpose: To investigate whether polymorphisms of cluster of differentiation 14 (CD14), tumor necrosis factor alpha (TNFα), interleukin (IL)6, IL10, and IL1ra genes are associated with the risk of peri-implantitis susceptibility in patients with dental implants in the Serbian population. Materials and methods: Isolated DNA from the blood was used for IL10-1082, TNFα-308, IL6-174, CD14-159, and interleukin 1 receptor antagonist (IL1ra) genotyping using polymerase chain reaction (PCR)-based methodology. Clinical parameters included: peri-implant pocket depth (PPD), Plaque Index (PI), Gingival Index (GI), bleeding on probing (BOP), and radiologic bone loss. Results: The study included 98 patients with dental implants in function for at least 1 year, divided into peri-implantitis (34) and healthy peri-implant tissue (64) groups. The percentage distribution of smokers was significantly different between patients who developed peri-implantitis and patients with healthy peri-implant tissue (71% vs 42%, respectively) and associated with increased peri-implantitis risk (OR: 3.289, 95% CI: 1.352 to 8.001; P = .007). A positive history of periodontitis was more frequent in the peri-implantitis group (62%) than in the healthy peri-implant tissue (20%) group and associated with increased peri-implantitis risk (OR: 6.337, 95% CI: 2.522 to 15.927; P = .0001). Frequencies of CD14-159, TNFα-308, IL10-1082, and IL6-174 genotypes were significantly different between patients with and without peri-implantitis. However, logistic regression revealed only TNFα-308 polymorphic GA/AA genotypes (OR: 8.890, 95% CI: 2.15 to 36.7; P = .003) and smoking (OR: 6.2, 95% CI: 1.44 to 26.7; P = .014) as independent factors associated with increased peri-implantitis risk, while CD14-159 polymorphic CT/TT genotypes were associated with decreased risk for peri-implantitis (OR: 0.059, 95% CI: 0.009 to 0.355; P = .002). Conclusion: The findings suggest that smoking and the presence of TNFα-308 GA/AA genotypes may increase the risk for peri-implantitis, while CD14-159 polymorphic CT/TT genotypes decrease the risk. The results also indicate significant association of CD14-159, TNFα-308, and IL6-174 genotypes and clinical parameters in the Serbian population. However, future studies in larger patient groups are necessary to confirm these observations.

Genetic Risk Factors for the Development of Periimplantitis

Introduction: Periimplantitis etiology is multifactorial. The aim of this review is to identify the available data so far concerning the association between genetic polymorphisms and periimplantitis risk. Materials and methods: A literature search was performed in MEDLINE using the PubMed database of the US National Library of Medicine for articles published until March 2018. In addition, a manual search was performed. Our search and application of eligibility criteria provided 23 articles. Genes in these 23 studies could be divided into 3 overlapping categories: genes associated with (a) immune function, (b) bone growth, and (c) regulation of gene expression. Discussion: The pathogenesis of periimplantitis is not currently well understood. There are some polymorphisms, for which different studies state consistent results. However, there are many polymorphisms with conflicting results, which could be attributed to differences in study design. Conclusion: The identification of genetic biomarkers associated with periimplantitis risk could be valuable in daily clinical practice. However, no robust conclusions could be drawn from the current literature. The inequality of these studies' design necessitates the conduction of further studies using larger population samples and from different ethnic groups.

Chemokine Receptor 2 (CXCR2) Gene Polymorphisms and Their Association with the Risk of Developing Peri-Implantitis in Chinese Han Population

Purpose: This study aimed to investigate the role of chemokine receptor 2 (CXCR2) gene polymorphisms in peri-implantitis susceptibility in a Chinese Han population. Patients and methods: A total of 260 individuals were included in this study, including 127 peri-implantitis patients and 133 healthy implants. CXCR2 gene rs2230054 and rs1126580 polymorphisms in different groups were analyzed by the Chi-square test. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were employed to evaluate the association between CXCR2 polymorphism and peri-implantitis susceptibility. Results: The CT genotype of rs2230054 and the AG genotype and G allele of rs1126580 significantly increased in peri-implantitis patients compared with healthy implants (P < 0.05). The CT genotype of rs2230054 (OR = 1.825, 95% CI = 1.028-3.239) and the AG genotype of rs1126580 (OR = 2.223, 95% CI 1.272-3.885) carriers had a high risk to infect with peri-implantitis. Additionally, these CXCR2 gene polymorphisms have been revealed to be associated with the periodontal status of peri-implantitis patients. Conclusion: The CXCR2 gene rs2230054 and rs1126580 polymorphisms were associated with the peri-implantitis susceptibility in the Chinese Han population. The CT genotype of rs2230054 and the AG genotype and G allele of rs1126580 serve as risk factors for the occurrence of peri-implantitis.

On Peri-Implant Bone Loss Theories: Trying To Piece Together the Jigsaw

This review aims to explore the plausibility of new theories on the etiopathogenesis of marginal bone loss (MBL) and peri-implantitis (PI) and to discuss possible underlying pathogenic mechanisms. The former concept of osteointegration of dental implants can now be conceptualized as a foreign body response histologically characterized by a bony demarcation in combination with chronic inflammation. Different risk factors can provoke additional inflammation and, therefore, pro-inflammatory cytokine release in soft tissues and bone, leading to an overpass of the threshold of peri-implant bone defensive and regenerative capacity. Progressive bone loss observed in MBL and PI is ultimately due to a localized imbalance in the receptor activator of nuclear factor kappaB ligand (RANKL)/Receptor activator of nuclear factor κ B (RANK)/osteoprotegerin (OPG) pathway in favor of increased catabolic activity. The genetic background and the severity and duration of the risk factors could explain differences between individuals in the threshold needed to reach an imbalanced scenario. MBL and PI pathogenesis could be better explained by the "inflammation-immunological balance" theory rather than a solely "infectious disease" conception. The link between the effect of biofilm and other risk factors leading to an imbalanced foreign body response lies in osteoclast differentiation and activation pathways (over)stimulation.

Analysis of RANKL gene polymorphism (rs9533156 and rs2277438) in Iranian patients with chronic periodontitis and periimplantitis

Objective: RANK/OPG/RANKL pathway plays a significant role in osteoclastogenesis, osteoclast activation, and regulation of bone resorption. The aim of this study was to investigate the association of RANKL gene polymorphisms (rs9533156 and rs2277438) with chronic periodontitis and peri-implantitis in an Iranian population. Design: 77 patients with chronic periodontitis, 40 patients with peri-implantitis and 89 periodontally healthy patients were enrolled in this study. 5cc of blood was obtained from the cephalic vein of subjects arms and transferred into tubes containing EDTA. Genomic DNA was extracted using Miller's Salting Out technique. The DNA was transferred into 96 division plates, transported to Kbioscience Institute in United Kingdom and analyzed using the Kbioscience Competitive Allele Specific PCR (KASP) technique. Differences in the frequencies of genotypes and alleles in the disease and control groups were analyzed using Chi-square and Fisher's exact statistical tests. Results: Comparison of frequency of alleles in SNP rs9533156 of RANKL gene between the chronic periodontitis group with the control and peri-implantitis groups revealed statistically significant differences (P=0.024 and P=0.027, respectively). Comparison of genotype expression of SNP rs9533156 on RANKL gene between the peri-implantitis group with chronic periodontitis and control groups revealed statistically significant differences (P=0.001); the prevalence of CT genotype was significantly higher amongst the chronic periodontitis group. Regarding SNP rs2277438 of RANKL gene, comparison of prevalence of genotypes and frequency of alleles did not reveal any significant differences (P=0.641/P=0.537, respectively). Conclusions: The results of this study indicate that CT genotype of rs9533156 RANKL gene polymorphism was significantly associated with peri-implantitis, and may be considered as a genetic determinant for peri-implantitis.

CD14 and TNFα single nucleotide polymorphisms are candidates for genetic biomarkers of peri-implantitis

Objectives: This study aims to investigate whether CD14-159 C/T and TNFα -308 A/G single nucleotide polymorphisms are associated with peri-implantitis and to evaluate their effects on bone resorption by correlating with local levels of receptor activator nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG). Material and methods: Study population included 369 Southeastern Europe Caucasians (180 with peri-implantitis and 189 with healthy peri-implant tissues). Genotyping was performed using polymerase chain reaction from the periphery blood samples, while RANKL and OPG were evaluated in peri-implant crevicular fluid specimens using enzyme-linked immunosorbent assay. Results: Analysis of CD14-159 C/T polymorphism showed that genotype of CC nucleic acid combination was associated with peri-implantitis demonstrating a fivefold increased risk in these carriers. Furthermore, for TNFα -308 A/G polymorphisms, it was evidenced that AG genotype was associated with peri-implantitis and a fivefold increased risk in these carriers. Peri-implantitis patients with CC genotype at CD14-159 exhibited significantly higher concentrations of RANKL and relative ratio RANKL/OPG when compared to patients with CT genotype, while concentration of biomarkers between different genotypes at TNFα -308 remained insignificant. Conclusion: Within the limitations of the study, we can conclude that CD14-159 C/T and TNFα -308 A/G polymorphisms are associated with peri-implantitis and may present biomarkers for peri-implantitis. Clinical relevance: Investigated genetic markers might serve as precious parameters in clinical practice in course of treatment planning and prognosis, since preventive and treatment approach could be positively shifted and adjusted depending on present genotype.

Gene Correlation Network Analysis to Identify Biomarkers of Peri-Implantitis

Background and Objectives: The histopathological and clinical conditions for transforming peri-implant mucositis into peri-implantitis (PI) are not fully clarified. We aim to uncover molecular mechanisms and new potential biomarkers of PI. Materials and Methods: Raw GSE33774 and GSE57631 datasets were obtained from the Gene Expression Omnibus (GEO) database. The linear models for microarray data (LIMMA) package in R software completes differentially expressed genes (DEGs). We conducted a weighted gene co-expression network analysis (WGCNA) on the top 25% of altered genes and identified the key modules associated with the clinical features of PI. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the R software. We constructed a protein-protein interaction (PPI) network through the STRING database. After that we used Cytohubba plug-ins of Cytoscape to screen out the potential hub genes, which were subsequently verified via receiver operating characteristic (ROC) curves in another dataset, GSE178351, and revalidation of genes through the DisGeNET database. Results: We discovered 632 DEGs (570 upregulated genes and 62 downregulated genes). A total of eight modules were screened by WGCNA, among which the turquoise module was most correlated with PI. The Cytohubba plug-ins were used for filtering hub genes, which are highly linked with PI development, from the candidate genes in the protein-protein interaction (PPI) network. Conclusions: We found five key genes from PI using WGCNA. Among them, ICAM1, CXCL1, and JUN are worthy of further study of new target genes, providing the theoretical basis for further exploration of the occurrence and development mechanism of PI.

Identification of Potential Genetic Biomarkers and Target Genes of Peri-Implantitis Using Bioinformatics Tools

Objectives: To investigate potential genetic biomarkers of peri-implantitis and target genes for the therapy of peri-implantitis by bioinformatics analysis of publicly available data. Methods: The GSE33774 microarray dataset was downloaded from the Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) between peri-implantitis and healthy gingival tissues were identified using the GEO2R tool. GO enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the DAVID database and the Metascape tool, and the results were expressed as a bubble diagram. The protein-protein interaction network of DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) and visualized using Cytoscape. The hub genes were screened by the cytoHubba plugin of Cytoscape. The potential target genes associated with peri-implantitis were obtained from the DisGeNET database and the Open Targets Platform. The intersecting genes were identified using the Venn diagram web tool. Results: Between the peri-implantitis group and the healthy group, 205 DEGs were investigated including 140 upregulated genes and 65 downregulated genes. These DEGs were mainly enriched in functions such as the immune response, inflammatory response, cell adhesion, receptor activity, and protease binding. The results of KEGG pathway enrichment analysis revealed that DEGs were mainly involved in the cytokine-cytokine receptor interaction, pathways in cancer, and the PI3K-Akt signaling pathway. The intersecting genes, including IL6, TLR4, FN1, IL1β, CXCL8, MMP9, and SPP1, were revealed as potential genetic biomarkers and target genes of peri-implantitis. Conclusions: This study provides supportive evidence that IL6, TLR4, FN1, IL1β, CXCL8, MMP9, and SPP1 might be used as potential target biomarkers for peri-implantitis which may provide further therapeutic potentials for peri-implantitis.

Identification of key genes and pathways for peri-implantitis through the analysis of gene expression data

The present study attempted to identify potential key genes and pathways of peri-implantitis, and to investigate the possible mechanisms associated with it. An array data of GSE57631 was downloaded, including six samples of peri-implantitis tissue and two samples of normal tissue from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in the peri-implantitis samples compared with normal ones were analyzed with the limma package. Moreover, Gene Ontology annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for DEGs were performed by DAVID. A protein-protein interaction (PPI) network was established using Cytoscape software, and significant modules were analyzed using Molecular Complex Detection. A total of 819 DEGs (759 upregulated and 60 downregulated) were identified in the peri-implantitis samples compared with normal ones. Moreover, the PPI network was constructed with 413 nodes and 1,114 protein pairs. Heat shock protein HSP90AA1 (90 kDa α, member 1), a hub node with higher node degrees in module 4, was significantly enriched in antigen processing, in the presentation pathway and nucleotide-binding oligomerization domain (NOD)-like receptor-signaling pathway. In addition, nuclear factor-κ-B1 (NFKB1) was enriched in the NOD-like receptor-signaling pathway in KEGG pathway enrichment analysis for upregulated genes. The proteasome is the most significant pathway in module 1 with the highest P-value. Therefore, the results of the present study suggested that HSP90AA1 and NFKB1 may be potential key genes, and the NOD-like receptor signaling pathway and proteasome may be potential pathways associated with peri-implantitis development.

MMP-13 Polymorphism as a Risk Factor in Implant Loss

Purpose: To investigate whether MMP-13 g.-77 A > G (rs2252070) gene polymorphism is associated with early implants loss. Materials and methods: Two hundred nonsmoking volunteers in good oral health, > 18 years of age, and found to be periodontally healthy by clinical examination were matched by age, sex, and implant position and separated into two groups: control group (100 patients with one or more healthy implants for a minimum of 1 year) and test group (100 patients who had suffered early implant loss, considered when implants presented mobility and/or pain before or during abutment connection, requiring their removal). Genomic DNA from saliva was genotyped by PCR-RFLP. Statistical analysis of the results was done using Mann-Whitney U and chi-square tests, with a significance level of 5%. Results: A significant difference in the presence of the different alleles and genotype was found between groups for the MMP-13 g.-77 A > G (rs2252070) gene polymorphism (P = .0161, OR 95% = 0.57 [0.37 to 0.89]; P = .007, OR 95% = 0.44 [0.25 to 0.78]). The A allele increased susceptibility to early implant loss and appeared to be a genetic risk factor. Conclusion: The findings suggest that MMP-13 g.-77 A > G (rs2252070) polymorphism may contribute to early implants loss.

Analysis of the association of IL4 polymorphisms with orthodontic mini-implant loss

The aim of this study was to investigate the association of clinical characteristics and IL4 tag single nucleotide polymorphisms (SNPs; rs2227284 and rs2243268) with orthodontic mini-implant (MI) failure. The sample included 135 subjects of both sexes, mean age 48.7±10years (range 20-76years): 104 in the control group (patients without any MI loss) and 31 in the study group (patients presenting ≥1 MI loss). Genotypes were determined by real-time PCR. Bivariate and multivariate analyses were performed (P<0.05). No association was found between the selected tag SNPs and MI loss. The C allele of the IL4 rs2243268 polymorphism in the recessive model was more frequent in patients who had fewer MIs installed (≤2 vs. >2; P=0.043, odds ratio 0.65, 95% confidence interval 0.58-0.74). On multivariate analysis, smoking habit was significantly associated with the group with multiple MIs installed (P=0.036), however the significance of the association with rs2243268 was not maintained. No association was found between the socio-demographic, smoking, or genetic factors studied and MI loss. This study supports the interaction between host and environmental factors and its influence on susceptibility to orthodontic MI failure.

Outcome of orthodontic mini-implant loss in relation to interleukin 6 polymorphisms

Mini-implants (MIs) are used increasingly for orthodontic anchorage and their success may require some osseointegration, which is affected by the underlying host immune-inflammatory response. Interleukin 6 (IL-6) is a cytokine expressed during the host response after a trauma or infection. The aim of this study was to investigate the association of clinical characteristics and IL6 tag single nucleotide polymorphisms (which capture the information of the whole gene in terms of genetic variability) with the loss of MIs for orthodontic anchorage. A total of 487 patients were treated with orthodontic MIs between 2004 and 2010. After the application of inclusion and exclusion criteria, the sample comprised 104 patients with one or more MIs that had been in function for at least 6 months with no loss, and 31 patients who had lost one or more MIs. Allele A of rs2069843 and allele T of rs2069849 were suggestively associated with the loss of MIs for orthodontic anchorage and were in complete linkage disequilibrium, which means that one of them is sufficient to capture the same information. The location of installation (mandible) and the number of MIs installed per patient were also associated with the loss of MIs.

Clinical aspects and polymorphisms in the LTA, TNFA, LTB genes and association with dental implant loss

Background: This study shows the relationship between host factors and environmental factors in the influence of susceptibility to loss of dental implants. Purpose: The aim of this study was to investigate the association of clinical aspects and tag SNPs of the genes LTA, TNFA, and LTB with dental implant loss. Materials and methods: The subjects consisted of 244 patients, divided into two groups: control group (C)-163 individuals who did not lose any implants, being in function for at least 6 months; and study group (S)-81 individuals who had lost at least one implant. DNA was collected from saliva, and the genotypes were determined by real time PCR. Univariate and multivariate analysis were employed p < .05. Results: After multivariate analysis, dental implant loss remained associated with the presence of teeth (p = .011), a larger amount of placed implants (p = .001), and allelle C of rs2009658 of the LTA gene (p = .006). For the other tag SNPs of these studied genes, there was no association between the groups C and S with dental implants loss. Conclusion: Presence of teeth, number of placed implants and allele C of rs2009658 of LTA gene were associated with implant loss.

Matrix metalloproteinases gene polymorphism haplotype is a risk factor to implant loss: A case-control study

Background: Dental implants consist in the treatment of choice to replace tooth loss. The knowledge that implant loss tends to cluster in subsets of individuals may indicate that host response is influenced by genetic factors. Matrix metalloproteinases (MMPs) are enzymes that contribute to degradation and removal of collagen from extracellular matrix. Purpose: This case-control study aimed to investigate the haplotypic combination of MMP polymorphism (rs1144393, rs1799750, rs3025058, and rs11225395) and implant loss. Materials and methods: Two hundred nonsmokers subjects were matched by gender, age, implant number and position and divided in control group, 100 patients with one or more healthy implants, and test group, and 100 patients with one or more implant failures. Genomic DNA was extracted from saliva and genotypes were obtained by PCR-RFLP. Results: A significant association of rs1799750 (MMP-1) and rs11225395 (MMP-8) polymorphism on early implant loss was demonstrated (P ≤ 0.001). Global haplotype analysis indicated a significant difference between both groups (P < 0.0001). Haplotype T-A-GG-5A-C had a statistically significant risk effect, while haplotype C-A-G-6A-C andT-G-2G-5A-C had a protective effect in implant loss. Conclusions: The results of this study showed that MMPs haplotype are a risk factor to early implant loss.

The role of IL-1 gene polymorphisms (IL1A, IL1B, and IL1RN) as a risk factor in unsuccessful implants retaining overdentures

Purpose: Implant-supported overdentures are an alternative predictable rehabilitation method that has a high impact on improving the patient's quality of life. However, some biological complications may interfere with the maintenance and survival of these overdenture implants. The goal of this article was to assess the factors that affect peri-implant success, through a hypothetical prediction model for biological complications of implant overdentures. Methods: A retrospective observational, prevalence study was conducted in 58 edentulous Caucasian patients rehabilitated with implant overdentures. A total of 229 implants were included in the study. Anamnestic, clinical, and implant-related parameters were collected and recorded in a single database. "Patient" was chosen as the unit of analysis, and a complete screening protocol was established. The data analytical study included assessing the odds ratio, concerning the presence or absence of a particular risk factor, by using binary logistic regression modeling. Probability values (p values) inferior to 0.05 were considered as representing statistically significant evidence. Results: The performed prediction model included the following variables: mean probing depth, metal exposure, IL1B_allele2, maxillary edentulousness, and Fusobacterium nucleatum. The F. nucleatum showed significant association with the outcome. Introducing a negative coefficient appeared to prevent complications or even boost the biological defense when associated with other factors. Conclusions: The prediction model developed in this study could serve as a basis for further improved models that would assist clinicians in the daily diagnosis and treatment planning practice of oral rehabilitation with implant overdentures.

Haplotypes in BMP4 and FGF Genes Increase the Risk of Peri-Implantitis

Despite the success of osseointegrated implants, failures have increased significantly, associated with development of peri-implantitis. Multiple factors influence the peri-implant bone loss, including environmental and genetic causes. BMPs (Bone morphogenetic proteins) are growth factors that induce bone formation. FGF (fibroblast growth factors) and their receptors (FGFRs) play important roles by controlling the levels of cell proliferation, differentiation and migration. BMP/FGF relationship is responsible for promoting bone regeneration and bone loss. The aim of this study was to analyze the correlation between BMP4, FGF3, FGF10 and FGFR1 genes and peri-implant bone loss. Two hundred and fifteen volunteers, with 754 dental implants, were submitted to oral examination and divided in healthy group (n=129) and peri-implantitis group (n=86). Thirteen polymorphisms in BMP4, FGF3, FGF10 and FGFR1 genes were analyzed individually and in haplotype. The chi-square test correlated genotypes, allelic and haplotype frequencies. Values of p<0.05 were considered significant. Volunteers with peri-implantitis demonstrated high incidence of total edentulism (p<0.0001) and thin peri-implant phenotype (p<0.04). Higher incidence of spontaneous bleeding, plaque and implant mobility was observed in peri-implantitis group (p<0.0001 for all). The TT polymorphic genotype for BMP4 rs2761884 was associated with healthy peri-implant (p=0.01). FGF3 rs4631909 (TT+CT genotype) also showed association with the control group (p=0.04). The frequency of C allele for FGF3 rs4631909 showed a tendency for association with peri-implantitis (p=0.08). FGF10 CCTG (p=0.03), BMP4 GAAA (p=0.05) and GGGA (p=0.02) haplotypes were associated with peri-implantitis (p=0.03). Therefore, it may be concluded that BMP4 and FGF10 haplotypes are associated with peri-implantitis.

Association of interleukin 4 gene polymorphisms with dental implant loss

Purpose: The purpose of this study was to investigate the association between interleukin 4 (IL4) polymorphisms/haplotypes and dental implant loss. Materials and methods: Two hundred and seventy eight (n = 278) unrelated patients were divided into 2 groups: (1) control group (C) composed of 186 individuals presenting at least 1 osseointegrated implant and (2) study group (S) composed of 94 individuals presenting at least 1 implant loss. After DNA collection, IL4 polymorphisms were investigated by polymerase chain reaction (PCR)-restriction fragment length polymorphism and for the variable number of tandem repeat (VNTR) only by PCR. Results: No association between alleles/genotypes of -590 (C/T) (P = 0.9704/P = 0.5992) and VNTR (P = 0.7155/P = 0.8789) polymorphisms and implant loss were found between the groups. Regarding +33 (C/T) polymorphism, no difference was found in genotype frequency (P = 0.1288), but the C allele was associated with implant loss (P = 0.0236, odds ratio = 1.61, 95% confidence interval = 1.1-2.4). Haplotype analysis showed no statistical differences between the groups. Conclusion: The C allele of the +33 (C/T) polymorphism in the IL4 gene was associated with susceptibility to dental implant loss in Brazilians in the studied population.

Genetic and immunological markers predict titanium implant failure: a retrospective study

This study evaluates diagnostic markers to predict titanium implant failure. Retrospectively, implant outcome was scored in 109 subjects who had undergone titanium implant surgery, IL1A -889 C/T (rs1800587), IL1B +3954 C/T (rs1143634), IL1RN +2018 T/C (rs419598) and TNFA -308 G/A (rs1800629) genotyping, in vitro IL-1β/TNF-α release assays and lymphocyte transformation tests during treatment. TNF-α and IL-1β release on titanium stimulation were significantly higher among patients with implant loss (TNF-α: 256.89 pg/ml vs. 81.4 pg/ml; p<0.0001; IL-1β: 159.96 pg/ml vs. 54.01 pg/ml; p<0.0001). The minor alleles of the studied polymorphisms showed increased prevalence in the implant failure group (IL1A: 61% vs. 42.6% in controls, IL1B: 53.7% vs. 39.7% in controls, TNFA: 46.3% vs. 30.9% in controls, IL1RN: 58.5% vs. 52.9% in controls). Increasing numbers of risk genotypes of the studied polymorphisms were associated with an increasing risk of implant loss, suggesting an additive effect. Multiple logistic regression analysis showed positive IL-1β/TNF-α release assay scores (p<0.0001, OR=12.01) and number of risk genotypes (p<0.046, OR=1.57-6.01) being significantly and independently associated with titanium implant failure. IL-1/IL1RN/TNFA genotyping and cytokine release assay scores provide prognostic markers for titanium implant outcome and may present new tools for individual risk assessment.

IL1 gene polymorphisms and unsuccessful dental implants

Objectives: This study aimed to analyse the association between polymorphisms in the IL1 gene cluster and failure of dental implants in a Portuguese population. Material and methods: A total of 155 Caucasian Portuguese subjects were divided into two groups: 100 with successful dental implants and 55 with unsuccessful dental implants. DNA was obtained through an oral mucosa scraping. PCR was used to identify the polymorphisms: single nucleotide changes in positions -889 of IL1A gene and +3953 of IL1B gene. Results: The prevalence of the polymorphisms -889IL1A gene and +3953IL1B gene, determined by the positive result of TGP (Genetic Test for Periodontitis; CGC, Genetics, Portugal), in the studied population rehabilitated with dental implants was of 33.50%. Allele 1 of the IL1B gene was the most prevalent (62.20%), followed by allele 1 of the IL1A gene (54.80%) and the least frequent was allele 2 of IL1B gene (37.40%). Success of dental implants was mainly associated with a negative TGP result, whereas no success was found to be related to a positive result. There were no statistically significant differences between the alleles 1 and 2 of the genes IL1A and IL1B and the tobacco and alcohol consumption for the success or no success of the dental implants. Conclusions: The alleles 1 and 2 of IL1A gene and the alleles 1 and 2 of IL1B gene were statistically associated with the success or no success of the dental implants. Tobacco habit and alcohol consumption showed no statistically significant association with success or no success of the dental implants.

Clinical consequences of IL-1 genotype on early implant failures in patients under periodontal maintenance

Background: Implant failure and biologic complications such as periimplantitis are not completely avoidable. Are there any genetic and microbiologic parameters that could be used to identify patients at risk for implant failure, preferably prior to treatment? This would result in improvement of the diagnostics, treatment decision, and risk assessment. Purpose: The aims of this retrospective study were to describe (1) the absolute failure rate of Brånemark System implants (Nobel Biocare AB, Göteborg, Sweden) consecutively installed over a 10-year period in partially edentulous patients treated for periodontal disease prior to implant treatment and under regular professional maintenance, (2) the rate of interleukin-1 (IL-1) polymorphism in those patients who experienced at least one implant failure during the first year of function, and (3) the prevalence of periodontal pathogens in dental and periimplant sites with and without signs of inflammation. Material and methods: Of 766 patients, 81 encountered at least one implant failure; 22 patients were clinically examined and were tested genetically for IL-1 genotypes. The presence of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella nigrescens was analyzed. Results: The absolute implant survival rate for the whole population was 95.32%; 10.57% of the patients encountered an implant loss. Implant loss in the examined group (n = 22) was 32 of 106 (30.1%); 10 (45%) of the 22 patients were smokers, and 6 (27%) of the 22 patients were IL-1 genotype positive. Patients positive for IL-1 genotype were not more prone to implant loss; however, a significant synergistic effect with smoking was demonstrated. Between patients who were IL-1 genotype positive and those who were IL-1 genotype negative, the differences in regard to bleeding on probing or periodontal pathogens did not reach statistical significance. Conclusion: The overall implant failure rate in a population treated and maintained for periodontal disease is similar to that of healthy subjects. A synergistic effect found between smoking and a positive IL-1 genotype resulted in a significantly higher implant loss. This indicates that further research with a larger patient group should focus on multifactorial analysis for adequate risk assessment.

Impact of IL-1 genotype and smoking status on the prognosis of osseointegrated implants

Aim: This study evaluated the impact of the IL-1 genotype and smoking status on the prognosis and development of complications of osseointegrated implants. Material and methods: The clinical charts of 180 consecutively admitted patients were analyzed with respect to the occurrence of biological complications in conjunction with oral implants. Biologic complications were defined as clinical conditions with suppuration from the peri-implant sulcus, development of a fistula or peri-implantitis with radiologic bone loss. All patients had received one or more ITI dental implants, which had been in function for at least 8 (range: 8-15) years. This patient population had received 292 implants. From these, 51 implants in 34 patients showed late (infectious) biologic complications, and 241 implants had survived without any biologic complications at all. Results: Of the 180 patients, 53 were smokers, who were subdivided in a series of classes according to their intensity of smoking and 127 were never smokers. Sixty-four of 180 (36%) patients tested positive for the IL-1 genotype polymorphism. This prevalence corresponds to previous reports for the prevalence of European descent populations. The results for the non-smoking group indicated no significant correlation between implant complications and a positive IL-1 genotype. However, there was a clear association for heavy smokers between a positive IL-1 genotype and implant complications. 6 of 12 or half of the heavy smokers and IL-1 genotype-positive patients had either an implant failure, i.e. loss of implant, or a biologic complication during the follow-up period. Conclusions: These findings have led to the conclusion that there is a synergistic effect between a positive IL-1 genotype and smoking that puts dental implants at a significantly higher risk of developing biologic complications during function.

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