Does Using Highly Porous Tantalum in Revision Total Hip Arthroplasty Reduce the Rate of Periprosthetic Joint Infection? A Systematic Review and Meta-Analysis

Background Studies suggest tantalum (Ta) implants may have inherent antibacterial properties. However, there is no consensus regarding the effectiveness of Ta in preventing periprosthetic joint infection (PJI) after revision total hip arthroplasty (rTHA). Methods We searched 5 main databases for articles reporting the rate of PJI following rTHA using Ta implants from inception to February 2022. The PJI rates of the Ta group were meta-analyzed, compared with the control group, and represented as relative risks (RRs) in forest plots. Results We identified 67 eligible studies (28,414 joints) for assessing the prevalence of PJI following rTHA using Ta implants. Among these studies, only 9 compared the Ta implant group with a control group. The overall PJI rate following rTHA using Ta implants was 2.9% (95% confidence interval [CI]: 2.2%-3.8%), while it was 5.7% (95% CI = 4.1%-7.8%) if only septic revisions were considered. Comparing the Ta and control groups showed a significantly lower PJI rate following all-cause rTHA with an RR = 0.80 (95% CI = 0.65-0.98, P < .05). There was a trend toward lower reinfection rates in the Ta group after rTHA in septic cases, although the difference was not statistically significant (RR = 0.75, 95% CI = 0.44-1.29, P = .30). Conclusions Ta implants are associated with a lower PJI rate following all-cause rTHA but not after septic causes. Despite positive results, the clinical significance of Ta still remains unclear since the PJI rate was only reduced by 20%. Level of Evidence IV.


Introduction
Periprosthetic joint infection (PJI) is the most unwelcome complication following a total hip arthroplasty (THA) [1,2].It is associated with significant morbidity and mortality and poses a substantial economic burden of as much as $753.4 million on the healthcare system annually [3,4].However, PJI following a revision THA (rTHA) is more frequent and far more burdensome [5].A recent large-sample study in the Medicare population found PJI as the most common complication of rTHA, with an incidence of 17.3% at 1-year follow-up.The rate of new PJI after aseptic rTHA was 8.13% [6].Moreover, the recurrence rate of PJI after a one-stage rTHA was reported to be between 6.5% and 33% [7,8].
The increase in the aging population and hip osteoarthritis prevalence has caused a dramatic rise in THA rates [9].Consequently, the rates of rTHA have been predicted to double from 2005-2026 [10].Moreover, data from UK National Joint Registry has shown a 3-fold increase in re-revision rates due to PJI from 2005-2013 [5].Given the expected surge in rates of rTHA, it is prudent to seek strategies to reduce the rates of post-rTHA PJIs.
Trabecular metal (TM) components with highly porous tantalum (Ta) coatings are one of these strategies.Ta's superior outcomes in rTHA are mainly attributed to its high porosity promoting osteointegration, similar elastic modulus to trabecular bone reducing the stress shielding, and good frictional profile decreasing micromotion [11].It has also been reported to be more resistant to infection than titanium.Tokarski et al found a significantly lower rate of post-rTHA PJI using Ta (3.1%) than titanium (17.5%) [12].Hypothetically, its higher and faster osteointegration leaves less dead space for bacteria to grow, its 3D structure hinders the formation of a biofilm compared with a flat surface, and its chemistry has been proposed to be hostile to bacteria [12,13].Moreover, an in vitro study showed lower S. aureus adhesion to pure Ta than titanium, while another similar study failed to show any difference [14,15].Similarly, the in vivo efficacy and inherent antimicrobial potential of Ta are uncertain [13,15] The 2018 International Consensus Meeting on PJI in Philadelphia (ICM Philly) tried to answer whether Ta can reduce the risk of PJI recurrence in rTHA.Although their answer was positive, especially for the treatment of PJIs, the evidence was limited [16].In addition, they suggested that Ta augments may protect against PJI recurrence following a single-stage revision for PJI [17].Apart from the limited evidence of both statements, it is still unclear whether the potential effects of highly porous Ta differ in rTHAs for septic vs aseptic reasons.Therefore, we performed this systematic review to answer the following questions: 1.What is the rate of PJI after rTHA using Ta implants?2. Is the rate of PJI different after rTHA using Ta vs non-Ta implants?3. Does Ta reduce the risk of PJI following rTHA for septic reasons?

Patients (P), intervention (I), comparison (C), and outcome (O)
This study examined the deep infection (PJI) rate (O) in patients undergoing rTHA (P) using TM implants containing highly porous Ta (I) compared to other materials (C).

Screening and search strategy
We performed this study in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [18] [see Additional file 1].It was registered in the International Prospective Register of Systematic Reviews (PROSPERO, registration ID: CRD42021268518, available at www.crd.york.ac.uk/PROSPERO).
We systematically searched for clinical studies reporting the rate of PJI following rTHA using Ta implants in MEDLINE/PubMed, EMBASE, SCOPUS, Web of Science, and Cochrane Library from inception to February 2022.Our main search strategy was "(Tantalum OR Trabecular metal) AND (Infection OR PJI)".The detailed version of our search strategy in PubMed is presented in (Table 1).Based on the search rules of each database, the search query was modified.We also performed an additional hand search of the related bibliography.The Covidence online systematic review software was used to import all the records (https://www.covidence.org).Two reviewers (A.P. and F.K.) independently reviewed the imported articles for eligibility using the inclusion/ exclusion criteria in 2 steps: title/abstract and full-text screening.Any conflict was resolved by discussion and consultation with a third reviewer (P.M).

Inclusion and exclusion criteria
We included the original studies reporting the rate of PJI following rTHA using Ta implants.The exclusion criteria were: 1) those studies excluding PJIs; 2) non-English studies; 3) nonhuman studies; 4) reviews, congress abstracts, and book chapters; and 5) studies with a follow-up duration of less than 3 months.

Assessment of study quality
Two independent reviewers assessed the quality of the included studies based on the Newcastle-Ottawa Scale (NOS) [19].It has 8 items in 3 categories of selection, comparability of the study groups, and the outcome assessment.Total score can range between 0 and 9.Those studies with 7 or more points were of high, and those with less than 4 points were of low quality.

Data extraction
The study data were extracted and organized into a predesigned Excel sheet (Microsoft Office 2016).The data included demographics, study groups, population, revision indication (septic vs aseptic), re-revision rate, PJI rate in septic and aseptic cases, and implant details.

Statistical analysis and data synthesis
After article selection, a meta-analysis was conducted on the applicable outcome measures using the Comprehensive Metaanalysis software (version 3).We calculated the pooled infection rate following rTHA with Ta implants based on all included studies.From this selection, we specifically chose studies that compared the Ta implant group with a control group to calculate the relative risk (RR).A meta-analysis of the RR of the studies with control groups was done.The funnel plot and Egger's test were used to analyze publication bias.Cochran's Q and I 2 tests were used to identify heterogeneities among the included studies.When the Q and degrees of freedom (Q/df) ratio is less than one, heterogeneity is nonsignificant.I 2 values of 25%, 50%, and 75% revealed low, moderate, and high heterogeneity, respectively [20].When I 2 was greater than 50%, the random-effects model was used.Sensitivity analysis was used to find the sources of heterogeneity.If the same authors reported a newer study from the same population, only the latest study would be included in the analysis.Moreover, studies with fewer than 10 patients as the denominator of prevalence were excluded from the analysis.The P-value < .05 was considered significant.

Included studies and quality assessment
A total of 4151 studies were screened by title and abstract after removing the duplicates (Fig. 1).Finally, 67 articles were selected after full-text evaluation for eligibility.Table 2 provides a summary of the 67 rTHA studies (28,414 hips) showing the studies' characteristics and outcomes [12,21e84].The study quality assessed by NOS was high in 31 (46.3%),medium in 27 (40.3%),and low in 9 (13.4%)studies (Supplementary Table ).The mean (standard deviation) NOS score was 6.3 ± 1.7.Overall, the studies showed medium to high quality.All 9 studies with control groups were of high quality according to the NOS assessment.However, 4 out of 9 (44%) disclosed conflicts of interest, while the same number (44%) revealed funding from companies or institutions.
There was a trend toward lower reinfection rates following rTHA in septic cases in the Ta group than in the control group (4 studies), although the difference was not statistically significant (RR ¼ 0.75, 95% CI ¼ 0.44-1.29,P ¼ .30)(Fig. 6).The studies showed low heterogeneity (I 2 ¼ 32.3, Q/df ¼ 1.5) and no publication bias (Egger's P ¼ .68)(Fig. 3d).NOS assessed all 4 of these studies as of high quality.

Discussion
The main finding of this study was that the rate of PJI following rTHA was about 20% lower in the Ta than non-Ta group (RR ¼ 0.80, P < .05).When considering only the septic rTHAs, the recurrence rate was similar in both groups (RR ¼ 0.75, 95% CI ¼ 0.44-1.29,P ¼ .30).Moreover, the rate of PJI after rTHA using Ta implants was 2.9% overall and 5.7% considering only the septic revisions.In the metaanalysis of the prevalence of PJI after rTHA using Ta (67 studies), significant heterogeneity (I 2 ¼ 58.7, Q/df ¼ 2.4) and publication bias (Egger's P ¼ .02)were observed.However, when conducting a comparative meta-analysis (Ta vs controls, 9 studies), there was no evidence of publication bias (Egger's P ¼ .99),and heterogeneity was low (I 2 ¼ 0.0, Q/df ¼ 0.5).The heterogeneity in this analysis can be attributed to various factors, including differences in revision indications (septic or aseptic), Paprosky bone defect classifications, types of Ta implants (augment or cup), as well as variations in population demographics and surgical settings among the 67 studies included.
Tantalum coatings exhibit similar elastic modulus characteristics to trabecular bone.The result is reduced stress shielding, decreased micromotion, enhanced osteointegration, and the prevention of resorption [17].Studies have reported that Ta augments might possess intrinsic antimicrobial properties and bioactive properties, although there is no consensus [14,17,98,99].
Experimental studies revealed that S. aureus adhesion and proliferation on pure Ta are lower than commonly used orthopaedic implant materials [13,14].Moreover, human leukocytes are more activated and release more cytokines when incubated in Taconditioned media [85].These observations suggest that when leukocytes are activated on the surface of the TM material, a microenvironment is created that may facilitate local host defense [85].However, the inherent antimicrobial potential of Ta in vivo is uncertain [13,15].According to Harrison et al, Ta does not have intrinsic antimicrobial or anti-biofilm properties against S. aureus and S. epidermidis compared to Ti in vitro [15].Therefore, the reduced rate of PJI associated with Ta use in revision procedures [12] could not be explained by its intrinsic antimicrobial properties [15].
In clinical settings, Tokarski et al found an insignificantly lower infection rate in the Ta cup group than Ti in 990 rTHAs (2.9% vs 5%, P ¼ .11)[12].Considering only the septic revisions, the reinfection rate was significantly lower in the Ta group (3.1% vs 17.5%, P ¼ .007)[12].In a study of septic rTHA cases from the National Joint Registry of England and Wales, Matharu et al found no difference between TM and non-TM implants (5.2% vs 5.6%) [31].Additionally, TM did not result in a difference in the rate of infection following all-cause rTHA [35].An earlier study from the same database reported a lower revision rate for infection when TM was used in primary THA (0.5% vs 0.9%, P ¼ .001)[70].A study from Swedish and Australian databases confirms the latter results in all-cause revision [41].Similarly, a matched case-control study by Klatte et al examined the effect of Ta augments on reinfection in patients with septic singlestage rTHA.At early follow-up, both study groups had a similar reinfection rate of 4% [77].Hence, further investigations are warranted to answer whether using TM lowers the incidence of infection following rTHA [17].Some reasons contribute to the possible reduction in infection after rTHA using Ta implants.The literature suggests that Ta may have some antibacterial properties but has not yet reached a clinical consensus [13].First, Ta is mainly used for severe bone loss and complex reconstructions [86].In these situations, the surgeon may do a more extensive debridement with wider margins reducing the risk of infection.Second, Ta has a better chance of osseointegration, even in a septic environment, and consequently eliminating the dead spaces [13,87].The surface morphology of Ta may stimulate host immunity by interacting with leukocytes, releasing specific cytokines, and promoting phagocytosis, thus enhancing the host's natural immunity to infection [85,88].Another possible mechanism is the 3D structure of Ta, which hinders bacteria from entering and proliferating.This meta-analysis showed a slightly lower postoperative rate of PJI for all-cause rTHA using Ta.However, the PJI rate after rTHA in septic cases did not decrease.As mentioned before, the lower adhesion of Ta to bacterial microorganisms can explain a lower postoperative infection rate after rTHA for Ta.Hypothetically, since the microorganism is already colonized during revision for septic reasons, Ta cannot reduce the risk of postoperative infection.
This study faces several serious limitations.As all the included studies were not level I evidence and most were retrospective, biases may threaten the study's conclusion.However, all 9 comparative studies included in the meta-analysis were of high quality, according to the NOS assessment.The other very considerable problem here is that the weight of the studies is basically overpowered by Matharu 2019 [35] and Laaksonen 2017 [41] papers that have considerable weight in all of the analyses.These are both essentially database studies from the English and Swedish/ Australian registries.Although the results showed a significantly lower PJI rate for Ta after all-cause rTHA, the clinical significance is still undecided since the reduction was only 20%.Moreover, the included studies used different criteria to define PJI.Regarding the number of criteria developed in the last decade, inconsistencies   Despite the limitations mentioned, we believe this study is promising and recommend further research.Longitudinal randomized clinical trials evaluating the anti-infection property of Ta in rTHA are recommended.However, the total infection rate is relatively low, and a randomized clinical trials or a cohort study would be challenging.

Conclusions
This meta-analysis indicates that the rate of PJI following allcause rTHA is significantly lower when using Ta implants.However, the PJI rate after rTHA did not decrease in septic revisions.Although the results are in favor of Ta, the clinical significance is still unclear since the PJI rate was only reduced by 20%.

Figure 2 .
Figure 2. Pooled rate of infection after all-cause rTHA with Ta.

Figure 3 .
Figure 3. Publication bias using a funnel plot.(a) Infection rate after rTHA with tantalum, (b) comparing the infection rate between tantalum and the control group after rTHA, (c) re-infection rate after rTHA in septic cases, (d) comparing the re-infection rate between tantalum and the control group after rTHA in septic cases.

Figure 4 .
Figure 4. Comparing the infection rate between the Ta and the control group for all-cause rTHA.

Figure 5 .
Figure 5. Pooled rate of infection after rTHA with Ta in septic revisions (reinfection).

Table 1
PubMed search strategy (using [all fields] and [MeSH]).Related Infections"[MeSH] OR Prosthetic* Infection* OR "Surgical Wound Infection"[MeSH] OR Surgical Wound Infection* OR Surgical Site Infection* OR Periprosthetic joint infection* OR Postoperative Wound Infection* OR PJI OR SSI OR Infect* OR Septic* OR "Sepsis"[MeSH] OR Sepsis* OR "Anti-Infective Agents"[MeSH] OR Anti-Infective OR Anti Infective OR Anti-infective OR "Anti-Bacterial Agents"[MeSH] OR Microbicide* OR Bacteriocide* OR Anti-Microb* OR Anti Microb* OR AntiMicrob* OR AntiBacterial* OR Anti-Bacterial* OR Antibacterial* OR * Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram of the studies' selection process.P. Mirghaderi et al. / Arthroplasty Today 25 (2024) 101293

Table 2
Summary of the rTHA included studies' characteristics and outcomes.

Table 2
TM-coated acetabular components was in company with a low risk of septic rerevision, which was comparable with non-TM components Ta acetabular components (continued on next page) P. Mirghaderi et al. / Arthroplasty Today 25 (2024) 101293

Table 3
Summary of quantitative synthesis.