2.1 Study registration

We have registered our systematic review/meta-analysis protocol with PROSPERO, under the identifier CRD42024551651. This registration enhances the transparency, methodological rigor, and credibility of our research, ensuring adherence to established guidelines and facilitating peer review and replication.⁷

2.2 Study design

This systematic review and meta-analysis aimed to evaluate the comparative effectiveness of silver-coated versus titanium-coated implants in preventing periprosthetic infections. We conducted a comprehensive search of the PubMed database up to March 2024.

2.3 Search strategy

Our primary search terms included "Megaprosthesis AND infection" and "Silver-coated AND infection." This approach ensured the inclusion of relevant studies published in English that met our predetermined inclusion and exclusion criteria.

2.4 Inclusion and exclusion criteria

2.5 Search methodology

Initial Search: The PubMed database was systematically searched using the specified search terms.

Search String: "Megaprosthesis AND infection" and "Silver-coated AND infection".

2.6 Screening process

Titles and abstracts of the identified studies were screened to determine their relevance based on the inclusion and exclusion criteria.

Full-text articles of potentially relevant studies were retrieved and reviewed.

2.7 Data extraction

Information was extracted from the selected studies, including study design, sample size, patient demographics, type of prosthesis coating (titanium or silver), follow-up duration, and reported infection rates.

2.8 Quality assessment

The quality of the included studies was assessed using the STROBE standardized criteria to ensure the reliability and validity of the findings.⁸

2.9 PRISMA guidelines

The entire article selection process was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to ensure a systematic and transparent review.⁹

2.10 Data synthesis

Data synthesis was conducted using the JAMOVI software, with the ESCI module employed to determine statistical differences in infection rates between titanium-coated and silver-coated mega prostheses.¹⁰ The I² test was used to assess the heterogeneity of the included studies. This comprehensive approach allowed for a robust analysis of the comparative efficacy of the coatings in preventing periprosthetic infections.

3.1 Literature search and study characteristics

In the initial phase of our systematic review, a total of 1892 records were identified from the MEDLINE database. Following the removal of unrelated article types, specifically 1841 records, the remaining 51 records underwent screening for relevance. From this screening process, 32 records were excluded based on predefined criteria, leaving 19 reports sought for retrieval. Subsequently, all 19 reports were assessed for eligibility, resulting in the exclusion of 8 reports due not including two comparison groups. Ultimately, 11 studies were included in our review for detailed analysis and synthesis of data.^11–21

The all eleven studies were retrospective comparative studies spanning various years from 2010 to 2022. These studies collectively enrolled a total of 1419 patients who underwent mega prosthesis reconstruction. Among these patients, 638 received silver-coated implants, while 781 received titanium-coated implants.^11–21 The incidence of PJI was documented, with a total of 166 recorded cases across the included studies. Each study adhered to a retrospective comparative design, allowing for an examination of the comparative effectiveness of silver-coated versus titanium-coated mega prostheses in preventing PJI (see Fig. 1. and Table 1).

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Fig. 1 Identification of studies via databases and registers.

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3.2 The pooled outcome rates

11 studies comprising a total of 1419 patients were meticulously selected for analysis. Among these patients, 638 individuals were treated with silver-coated implants, while 781 received titanium-coated implants. Across these studies, 61 and 105 infection cases were recorded in silver and titanium groups respectively. Remarkably, the pooled infection rate stood at 9.2 % for the silver-coated group, contrasting with 13.4 % for the titanium-coated group.^11–21

Amputation rates were recorded in eight of the included studies. The pooled amputation rate for patients with silver-coated implants was found to be 18.5 %, with 10 out of 54 patients undergoing amputation. In contrast, patients with titanium-coated implants exhibited a higher pooled amputation rate of 36.6 %, with 33 out of 90 patients undergoing amputation (see Table 2).

3.3 Difference in proportions of infection rates

In the ESCI analysis, our investigation revealed a significant difference in proportions between the groups (P difference = −0.0473, 95 % CI: −0.088 to −0.006). This finding indicates a notable contrast in the incidence of PJI between patients treated with silver-coated implants compared to those receiving titanium-coated implants. The negative value of the difference suggests a lower proportion of PJI cases associated with silver-coated implants, highlighting the potential superiority of this coating in reducing the risk of postoperative infections (Fig. 2).

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Fig. 2 Difference in proportions of infection rates.

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3.4 Silver related adverse events

Silver-related complications were mentioned in only 7 out of the 11 included studies.^11–21 Remarkably, there were no reports of any type of silver-related adverse events across these studies. This finding suggests a favorable safety profile associated with the use of silver-coated implants in mega prosthesis reconstructions. However, it's important to note that some studies did not provide information on silver-related complications, highlighting the need for standardized reporting of adverse events to comprehensively evaluate the safety and efficacy of silver-coated implants (see Table 3).

3.5 Infection origins in the published literature

The results presented in Table 5 summarize the infection origins from various studies, focusing on the presence of Staphylococcus aureus (S. aureus), Methicillin-resistant Staphylococcus aureus (MRSA), Coagulase-negative Staphylococci (CoNS), Staphylococcus epidermidis (S. epidermidis), Enterococci, Pseudomonas, and Escherichia coli (E. coli) in infections associated with silver and titanium materials. Hardes' study reported no S. aureus but found 20 % MRSA in silver and 14.2 % in titanium, with S. epidermidis exclusively in titanium at 57.7 %. Wafa observed 30 % S. aureus in silver and 21 % in titanium, with significant CoNS (40 % in silver, 37 % in titanium) and 30 % Enterococci in silver but none in titanium. Zajons' data indicated higher variability with 40 % S. aureus in silver and 14 % in titanium, MRSA at 25 % in silver and absent in titanium, and notable CoNS (35 % in silver, 28 % in titanium). Enterococci were found in 30 % of silver cases and 21 % of titanium cases, while Pseudomonas and E. coli had variable but present rates in both materials.

3.6 Assessment of heterogeneity

The I² statistic, representing heterogeneity in effect sizes across studies, was calculated at 21.8 % (95 % CI: 0.0–66.9), indicating a modest level of variability among the included studies. This value falls below the conventional threshold of 25 %, suggesting low heterogeneity. The consistency in effect sizes across studies strengthens the reliability of our findings and indicates a coherent pattern in the association between implant coatings and infection rates.

3.7 Bias assessment

Table 4 presents the quality assessment of various studies using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist items. The studies evaluated include those by Hardes, Pala, Streitbuerger, Donati, Piccioli, Sambri, Parry, Wafa, and Zajons. Each study was assessed across several categories: setting, participants, variables, data sources, statistical methods, descriptive data, outcome data, main results, limitations, and inclusion in analysis. Most studies, such as those by Hardes, Sambri, and Parry, were rated as "well" across all categories and were included in the analysis. Some studies, like those by Pala, Streitbuerger, and Donati, showed partial compliance in categories such as outcome data and limitations. Piccioli and Zajons were noted to have partial compliance in several areas, with weaknesses in participant reporting and limitations.

4.1 Importance of the study

Our study's findings underscore the clinical significance of silver-coated mega prostheses in the context of periprosthetic infections. The results indicate that, with low heterogeneity, silver-coated mega prostheses exhibit superior efficacy in preventing periprosthetic infections compared to titanium mega prostheses. This superior performance is particularly relevant for high-risk patient populations, such as those undergoing chemotherapy²² The implications of these findings suggest that the incorporation of silver-coated mega prostheses into clinical practice could enhance patient outcomes by significantly reducing the incidence of periprosthetic infections. This study provides compelling evidence for the preferential use of silver-coated prostheses in surgical settings where infection prevention is paramount.

4.2 Silver-coated superiority in PJIs

In the literature, the superiority of silver-coated implants in preventing periprosthetic joint infections has been demonstrated in comparative studies across ten different investigations, and our meta-analysis confirms these findings with low heterogeneity.^11–21 However, it is crucial to emphasize that the observed superiority of silver-coated implants pertains predominantly to the prevention of "early" postoperative infections.^11–21 Over time, the silver coating tends to degrade, which, although it has not been associated with any toxicity, results in the implants losing their antimicrobial efficacy.²³ Consequently, in the medium to long term, the performance of these implants becomes comparable to that of uncoated implants. This highlights a significant area for future research in metallurgy and prosthetics: the development of more durable silver coatings that maintain their antimicrobial properties over the lifespan of the implant.

4.3 Silver-coated superiority in amputations

This study underscores another compelling attribute of silver-coated prostheses: their notable superiority in reducing amputation rates, a finding previously documented in several articles. Beyond their efficacy in preventing early infections, silver-coated prostheses also demonstrate lower amputation rates in cases where infection does occur. Interestingly, infections associated with silver-coated prostheses often involve more complex and resistant microorganisms, prompting further investigation into their origins.

One potential hypothesis is that infections in silver-coated prostheses exhibit reduced invasiveness and less destructive impact compared to those in titanium-coated prostheses. This suggests that silver-coated prostheses may effectively restrict PJI even in the presence of microbial challenges. Further research is essential to delve deeper into this hypothesis and unravel the underlying mechanisms responsible for these observed clinical outcomes.

4.4 Potential mechanisms of action

Silver is favored for coating large implants because of its broad-spectrum antimicrobial properties, which target bacteria and fungi by binding to their cell membranes, enzymes, and nucleic acids. This rapid binding mechanism prevents the development of microbial resistance to silver. Although randomized controlled trials are lacking, case series suggest that silver-coated prostheses are effective in preventing early-stage infections, particularly benefiting at-risk patients, such as those undergoing chemotherapy^24,25 Despite concerns about skin discoloration (argyria) and elevated serum silver ion levels, these prostheses do not appear to cause significant clinical issues^24,25

The potential mechanism of action for silver in preventing periprosthetic infections involves multiple pathways. Firstly, silver ions (Ag+) are released from the coating and interact with bacterial cell membranes, disrupting their integrity and causing cell lysis. This interaction inhibits the respiratory enzymes, leading to a reduction in adenosine triphosphate (ATP) production and cell death. Secondly, silver ions penetrate the bacterial cell and bind to their DNA and RNA, interfering with replication and transcription processes, thereby preventing bacterial proliferation. Additionally, silver's ability to generate reactive oxygen species (ROS) creates an oxidative environment that further damages cellular components of the bacteria. This multi-faceted attack mechanism not only kills existing bacteria but also prevents the formation of biofilms, a critical factor in the persistence and resistance of bacterial infections on prosthetic surfaces^24,25 The ability of silver to act on multiple bacterial targets simultaneously reduces the likelihood of resistance development, making it an effective agent for long-term infection prevention in prosthetic applications.^24,25

4.5 Silver-related complications

Silver-related adverse events have been a topic of concern in the context of medical applications, particularly with the use of silver-coated materials in prosthetic implants. However, despite the observed degeneration of silver-coated materials over time, the safety profile of silver remains relatively favorable. While localized adverse events such as argyria, characterized by skin discoloration, have been reported in a few studies, there is a lack of robust evidence supporting systemic or general adverse effects related to silver exposure.²⁶ Specifically, there is no strong evidence linking silver exposure to neurological, hepatic, or nephrological complications. This suggests that, overall, silver-coated materials are well-tolerated and pose minimal risk of systemic adverse events, providing reassurance regarding their safety for clinical use. However, continued vigilance and ongoing research are warranted to comprehensively assess the long-term safety profile of silver-coated implants and to monitor for any potential adverse effects that may arise with extended use.