Protein Biomarkers in Periodontal Disease: A Bibliometric Review

Protein Biomarkers in Periodontal Disease: A Bibliometric Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Protein Biomarkers in Periodontal Disease: A Bibliometric Review Patricia Castellanos Berrio, Nathalia María Correa Valencia, Sebastian Cardona Ramírez This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8790610/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background This bibliometric study examines research on protein biomarkers in periodontal disease, a condition requiring early and accurate diagnosis. Despite available diagnostic tools, their limitations highlight protein biomarkers as a promising, yet clinically unvalidated, alternative. Methodology: A bibliometric review was conducted using Web of Science Core Collection, focusing exclusively on human clinical studies and excluding animal, in vitro, and in silico research. Two independent authors evaluated titles, abstracts, and full texts following transparency principles inspired by PRISMA. Tools including bibliometrix/Biblioshiny were used to generate bibliometric indicators, collaboration networks, and thematic structures. Results From 191 records identified between 2006–2025, 112 studies met inclusion criteria, showing sustained growth with marked increase in the last five years. Journal of Clinical Periodontology and Journal of Periodontal Research were the main publishing venues. China, the United States, and Italy led scientific production. The most cited articles were König et al., Miller et al., and Liu et al. Thematic analysis revealed an evolution from inflammatory mediator studies toward advanced proteomic approaches, establishing "proteomics" as the dominant contemporary theme. Conclusions Protein biomarker research in periodontal disease shows sustained growth, led by countries with strong molecular research capacity, highlighting proteomic diagnostics and a consolidated agenda toward clinical translation of salivary and gingival crevicular fluid biomarkers. Clinical relevance: This study summarizes the current state of research on protein biomarkers in periodontal disease, providing useful evidence to inform the development and future validation of diagnostic tools with potential clinical application. Dentistry Molecular Biology Epidemiology (MeSH) Periodontal Diseases Protein Biomarkers Saliva Gingival Crevicular Fluid Proteomics Journal Impact Factor Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Background Periodontal diseases comprise a broad spectrum of chronic inflammatory conditions affecting the gingiva, periodontal ligament, cementum, and alveolar bone, arising from a dynamic interaction between dysbiotic microbial biofilms and host immune responses [ 4 ]. Clinically, these conditions are primarily categorized into gingivitis— a reversible inflammation confined to the gingival tissues— and periodontitis, a destructive form characterized by periodontal attachment loss, alveolar bone resorption, periodontal pocketing, and, in advanced cases, tooth loss [ 5 ]. In 2017, the American Academy of Periodontology and the European Federation of Periodontology updated the classification system, distinguishing periodontal health, gingivitis, periodontitis, other periodontal conditions, and peri-implant diseases [ 6 ]. Globally, periodontal diseases are highly prevalent, affecting between 20 and 50% of the population, with severe forms present in nearly one-fifth of individuals older than 15 years [ 7 , 8 ]. Their multifactorial etiology involves dysbiosis-triggered inflammation modulated by individual susceptibility, genetic background, systemic conditions, age, environment, and behavioral determinants [ 9 ]. Diagnosis traditionally relies on clinical and radiographic parameters—including plaque indices, bleeding on probing, probing depth, gingival recession, mobility, and radiographic evidence of bone loss [ 10 ]. While these methods are essential for evaluating disease history and current inflammatory status, they are inherently limited: periodontal probing is operator-dependent, time-consuming, and unable to detect early disease activity or predict progression with precision [ 11 ]. These constraints have prompted a growing interest in molecular and biochemical complementary approaches capable of identifying underlying biological activity rather than merely reflecting structural damage. Within this context, saliva and gingival crevicular fluid (GCF) have emerged as attractive diagnostic matrices. They are easily obtainable, non-invasive, and capable of reflecting ongoing inflammatory, immune, and microbial processes in the periodontium. Although no single biomarker has proven sufficient for robust diagnostic discrimination, combinations of salivary and GCF biomarkers—particularly those related to inflammation, tissue degradation, or microbial burden—have shown promising diagnostic performance [ 12 , 13 ]. Protein biomarkers are especially relevant because their presence, abundance, and post-translational modifications provide direct insight into disease mechanisms and represent potential therapeutic targets [ 14 , 15 ]. As technological capabilities advance, proteomics has become a central tool for exploring the salivary and GCF proteome, enabling high-resolution identification of protein signatures associated with disease onset, severity, and progression. Mass spectrometry–based approaches, in particular, have catalyzed the discovery of novel biomarkers and broadened understanding of periodontal pathophysiology at a systems level [ 16 ]. Given the rapid expansion and methodological heterogeneity of this research area, bibliometric analysis provides a rigorous and quantitative means of evaluating publication trends, mapping scientific collaboration, identifying influential authors and institutions, and detecting emerging thematic structures [ 17 , 18 ]. Although prior bibliometric studies have addressed broader periodontal topics—including regeneration, implantology, and oral microbiome research [ 19 , 20 , 21 , 22 ]—none have specifically characterized the evolution of research on protein biomarkers in saliva and GCF for periodontal diseases, despite their increasing clinical and translational relevance. Therefore, this study aimed to analyze the global scientific literature on protein biomarkers associated with periodontal diseases, specifically those identified in saliva and GCF from human clinical studies. By characterizing publication trends, diagnostic approaches, frequently investigated proteins, influential contributors, and emerging research fronts, this bibliometric assessment seeks to provide a comprehensive and integrative overview of the field. Ultimately, the findings are intended to serve as a reference framework that supports future research, fosters methodological innovation, and accelerates the development of reliable, non-invasive protein-based diagnostic tools in periodontology. Methods Study design A descriptive bibliometric review was conducted to characterize the global scientific output on protein biomarkers associated with periodontal disease in human subjects. The Web of Science (WoS) platfrom served as the primary data source. The study adhered to methodological recommendations for bibliometric research in health sciences [ 23 , 24 , 25 ]. Data source and search strategy An electronic search was performed on November 9, 2025, using WoS database. No publication year limits were applied to preserve the historical integrity of the dataset. The Topic Search (TS) query was designed for high precision and included periodontal disease terms, protein biomarkers, proteomic approaches, biological matrices of interest (saliva and gingival crevicular fluid), and restrictions to human clinical research, while excluding in vitro, in silico, and animal studies: TS = ((“periodontal disease*” OR periodontitis OR gingivitis) AND (“protein biomarker*” OR proteomic* OR proteome* OR “protein expression”) AND (saliva* OR “gingival crevicular fluid” OR GCF) AND (human* OR patient* OR “clinical stud*”) NOT (“in vitro” OR “animal*” OR “mouse” OR “rat” OR “in silico”)). The search and export of records were completed on the same day to minimize temporal indexing fluctuations. Inclusion and exclusion criteria The inclusion criteria comprised original research articles and review papers indexed in WoS that evaluated proteins or proteomic profiles related to periodontal disease in human participants and used saliva, GCF, or other human oral fluids as biological matrices. Studies were excluded if they involved animal models, in vitro experiments, or in silico simulations; if they focused exclusively on non-protein biomarkers such as genomic, transcriptomic, metabolomic, microbiological, or strictly immunologic markers; or if they used non-qualifying matrices, including blood, serum, plasma, or tissue biopsies. Non-original documents—such as letters, conference abstracts, editorials, and technical notes—were also excluded, as were studies addressing oral diseases unrelated to periodontal pathology, investigations centered on systemic conditions without periodontal endpoints, and publications that did not provide extractable or thematically relevant data. Record screening and selection process Two authors independently screened all records at the title and abstract level. Full texts were consulted when eligibility was unclear. Although PRISMA is not specifically designed for bibliometric studies, the screening process followed PRISMA-inspired transparency principles to ensure rigor and reproducibility. Eligible records were exported in BibTeX (.bib) format, including “Full Record and Cited References.” This curated dataset was used for scientometric analyses. Data extraction, preprocessing, and analytical procedures All bibliographic metadata—including titles, authors, affiliations, abstracts, keywords, journal sources, publication year, citation counts, and DOI—were exported in BibTeX and CSV formats for subsequent analysis. Using RStudio (version 4.3.2) and the bibliometrix package (version 5.1.0), we calculated indicators such as annual scientific production, journal source of publication, global distribution of scientific output, scientific productivity by main author affiliation, overall citation output by main author, country collaboration network, keyword co-occurrence structures, conceptual structure of keywords using factorial analysis through Multiple Correspondence Analysis (MCA), thematic evolution, and three-field plots linking countries, keywords, and sources. Biblioshiny was used as an interactive environment for data exploration and visualization using full counting as the counting method and showing top ten journals, institutions and authors. In the international collaboration network analysis, node size reflected frequency, edges represented co-occurrence links, and node color corresponded to geographical clusters, while synonyms and term variants were manually harmonized. Additional tools included Scimago Journal Rankings for classification based on impact factor. Scientometric workflow and conceptual mapping The analytical workflow encompassed several stages, beginning with the assessment of annual scientific production to identify temporal publication trends, followed by source and affiliation analyses to determine the core journals and institutions contributing to the field. Country-level analyses were then conducted through heatmaps, collaboration networks, and productivity indicators. Citation analyses identified the most globally cited documents and the foundational literature shaping the discipline. To elucidate the conceptual structure of the field, we constructed keyword co-occurrence networks through MCA factorial ampping, examined thematic evolution over time, and generated three-field plots integrating geographic origin, thematic focus, and publishing sources. Prior to these analyses, extensive preprocessing was undertaken to resolve ambiguities in author names, institutional variants, and keyword harmonization, ensuring consistency across the dataset and minimizing analytical noise. Ethical considerations The review relied exclusively on secondary data retrieved from publicly available bibliographic sources; therefore, ethical approval was not required. Results A total of 191 records were retrieved from the WoS database using the predefined search strategy. After removing non-eligible document types (e.g., conference abstracts, letters) and applying the inclusion and exclusion criteria, 112 publications remained for the bibliometric dataset. The full screening and refinement process is presented in Fig. 1 . Temporal trends in scientific production The temporal distribution of publications is shown in Fig. 2 . Output was minimal in the mid-2000s, increased steadily starting in 2010, and reached its highest level in 2023 (12 publications). By November 2025, 9 publications had already been indexed. Sources of publication The top-ten journals with the highest number of publications are summarized in Table 1 . Journal of Clinical Periodontology and Journal of Periodontal Research were the leading sources, each publishing 15 articles, followed by Journal of Proteome Research (6 articles) and a group of journals contributing 5 articles each. Table 1 Most productive journals publishing research on salivary and gingival crevicular fluid protein biomarkers, with impact factor (2025). Journal Total Articles IF JOURNAL OF CLINICAL PERIODONTOLOGY 15 6.7 JOURNAL OF PERIODONTAL RESEARCH 15 3.6 JOURNAL OF PROTEOME RESEARCH 6 4.1 ARCHIVES OF ORAL BIOLOGY 5 2.1 CLINICAL ORAL INVESTIGATIONS 5 3.4 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 5 5.6 FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY 3 5.7 JOURNAL OF PERIODONTOLOGY 3 4.3 JOURNAL OF PROTEOMICS 3 3.3 PROTEOMICS 3 3.5 IF = impact factor of the journal in 2025 according to SCImago journal rank Country-level scientific output Geographical productivity is illustrated in Fig. 3 A, indicating the number of publications attributed to each country. China was the most prolific contributor (66 articles), followed by the United States (56) and Italy (44). Country collaboration network Three primary hubs were identified: The United States cluster, connected with Turkey, India, and Finland; The Sweden-centered European cluster, with links to Chile, Egypt, and Syria; and The China cluster, strongly connected to Singapore illustrated in Fig. 3 b. Institutional productivity The Karolinska Institutet ranked first in the institution with most publications (18), followed by Universidade Federal do Rio de Janeiro (14) and Sichuan University (11) as shown in Fig. 4 a. Most globally cited documents König et al. in 2016 [ 1 ] received the highest number of citations (423), and Miller et al. in 2010 [ 2 ] and Liu and Duan in 2012 [ 3 ] followed with 254 and 216 citations, respectively (Fig. 4 b). Factorial analysis and Keyword co-occurrence structure Three distinct research clusters emerge: a blue cluster focused on osteoimmunology and bone metabolism through terms like "rankl" and "osteoclastogenesis"; a red cluster encompassing broad periodontal disease and diagnostics research including "biomarker," "saliva," and "chair-side diagnostics"; and a green cluster representing analytical techniques such as "LC-MS" and "MALDI-TOF" (Fig. 5 a). Four thematic clusters were identified, including a motor theme centered on saliva, periodontitis, and biomarkers, and additional clusters focusing on proteomics, aggressive periodontitis, and salivary biomarkers (Fig. 5 b). Thematic evolution The thematic evolution diagram shows the longitudinal progression of research topics (Fig. 6 ). The intellectual core has shifted from themes like "aggressive periodontitis" and "cytokines" to the emergence of "biomarker" as a motor theme, which has since evolved into the dominant, well-developed research front of "proteomics." This transition marks a maturation from descriptive studies to the application of advanced techniques like mass spectrometry, enabling a more precise decoding of the proteome for disease classification and mechanistic insight. While foundational concepts such as "periodontitis" and "gingival crevicular fluid" remain central, their investigation is now predominantly framed by these high-resolution analytical frameworks. Three-field plot (countries–keywords–sources) The three-field plot analysis elucidates the geographic, thematic, and publishing structure of periodontitis biomarker research, revealing Italy, the USA, Brazil, and China as the most research-active nations (Fig. 7 ). Thematically, "periodontitis" and "saliva" emerge as the core research foci, with these keywords demonstrating the strongest connections to the leading countries. The primary outlet for this body of work is the Journal of Clinical Periodontology , which serves as a central publication venue, followed by other significant journals such as the Journal of Proteome Research . Discussion This analysis presents all available literature indexed in the WoSCC, without imposing publication year limits, in order to generate a comprehensive and unbiased overview of the thematic development of research on protein biomarkers of periodontal disease. This decision followed established methodological recommendations for bibliometric studies, which emphasize the importance of including the full set of available documents when the aim is to characterize historical trajectories, emerging topics, and research fronts within a specialized field [ 23 ]. The final dataset, refined through rigorous manual screening, allowed us to examine the evolution of scientific production, conceptual structure, and collaborative patterns in this domain. With respect to dataset characteristics, although the final sample comprised 112 publications, a figure that may seem modest compared with broader bibliometric reviews, this number is appropriate given the specificity of the inclusion criteria. By limiting the analysis to human clinical research, restricting biomarkers to the proteomic domain, and focusing exclusively on saliva and GCF, the available literature necessarily becomes narrower but more conceptually coherent. Comparable bibliometric studies in dentistry frequently report similar dataset sizes when they are focused on specialized topics. The rigorous dual screening conducted in this study further ensured thematic alignment and minimized the inclusion of peripheral records, thereby improving internal validity and reinforcing the interpretability of the results. The pronounced increase in publications since 2023 indicates that the field is undergoing an accelerated growth phase. This pattern coincides with the increased recognition of oral fluids as diagnostic media and increasing investment in high-throughput proteomic techniques. These tendencies strongly suggest that the study of salivary and GCF protein biomarkers constitutes a contemporary and rapidly advancing domain within dental and biomedical research. Thus, several studies have reported overall diagnostic utility and accuracy of approximately 86% for periodontitis, in addition to the practical advantages derived from the non-invasive nature of these matrices [ 26 , 27 ]. These findings support the notion that oral fluids represent an increasingly accepted diagnostic platform for periodontal assessment. The patterns observed in the country collaboration network likely reflect complex interactions among geographic proximity, established academic partnerships, funding mechanisms, and shared research priorities. Highly connected countries may function as knowledge brokers, while more isolated research clusters may represent regionally focused agendas or emerging collaborations [ 28 ]. The leadership of China, the United States, and Italy, and the contribution of countries such as Brazil, South Korea, and Egypt, is consistent with global data showing both the widespread burden of periodontal disease and the growing interest in non-invasive diagnostic solutions [ 29 ]. The appearance of smaller clusters suggests opportunities for greater global integration as research capacity expands [ 30 ]. The dissemination of knowledge occurs through a well-structured network of scientific journals. High-impact periodontology journals such as Journal of Clinical Periodontology and Journal of Periodontal Research serve as the central outlets for this research. The prominence of proteomic journals—most notably Journal of Proteome Research —confirms the methodological centrality of mass spectrometry and related techniques in advancing the field [ 31 ]. At the same time, the presence of journals focused on immunology, biosensors, and personalized medicine demonstrates an increasingly interdisciplinary orientation, bridging clinical periodontology with broader biomedical and technological domains. The citation analysis supports this interdisciplinary structure. The seminal work of König et al. (2016) [ 1 ] in Science Translational Medicine , along with frequently cited foundational reviews, exemplifies the intersection between advanced analytic methods and clinically relevant inquiry. The rapid accumulation of citations for recent publications [ 27 ] suggests that this research frontier remains active, dynamic, and deeply interconnected with ongoing technological advancement. The longitudinal analysis confirms the maturation of the field. Early research focused on aggressive periodontitis and classical inflammatory mediators, gradually giving way to more complex methodologies and proteomic-based investigations [ 32 ]. The emergence of proteomics as a central, well-established theme [ 33 ] marks a shift toward more systematic, technology-driven investigations capable of elucidating disease mechanisms, improving classification, and enhancing risk prediction (Hu y Leung 2023) [ 16 ]. Although core concepts such as periodontitis and gingival crevicular fluid remain stable, newer approaches grounded in imaging, biomarkers, and emerging data science techniques have begun to shape the evolving research landscape. The keyword co-occurrence patterns indicate strong thematic consolidation around molecular diagnostics and the exploration of saliva and GCF, while also revealing niche areas that contribute to the overall research ecosystem. Structural mapping from the factorial analysis highlights an intellectual organization spanning molecular pathways, clinical diagnostics, and analytical platforms, although the fact that approximately 64% of variance remains unexplained suggests underlying complexity and the possibility that additional thematic areas will emerge as the field expands [ 34 ]. The prominence of terms related to personalized oral health and precision dentistry [ 35 ] reinforces the notion that proteomic research is increasingly integrated into translational efforts aimed at improving diagnostic accuracy. Visualization of relationships among countries, keywords, and journals provides additional insight into patterns of specialization and the principal pathways through which knowledge circulates globally. This complements the collaboration and citation analyses, forming a comprehensive depiction of how the field is structured and how it continues to advance. Despite notable progress, the field continues to face persistent methodological challenges, including heterogeneity in sampling and analytical protocols, reliance on cross-sectional study designs, and fragmentation in biomarker assessment. These issues highlight the need for methodological standardization, multicenter validation, and the development of integrated biomarker panels capable of capturing the biological complexity of periodontal disease. Nonetheless, the field’s conceptual maturation—combined with expanding international collaboration networks and rapid advances in analytical technologies—indicates a strong trajectory toward clinically meaningful, noninvasive molecular diagnostics. Our analysis has certain methodological limitations. Restricting the search to WoS excludes articles indexed exclusively in other databases, potentially omitting relevant regional or emerging research. Bibliometric analyses can also be affected by incomplete metadata or changes in journal indexing. Nonetheless, this study’s methodological rigor, particularly the strict inclusion criteria, dual screening, and comprehensive use of bibliometric tools, strengthens the reliability of the findings. Importantly, bibliometric approaches differ from traditional reviews in that their core objective is not to synthesize evidence but to map scientific production, impact, and structure, all of which are needed to understand a field’s development and influence. Conclusion This bibliometric analysis provides a comprehensive overview of the scientific development of research on salivary and GCF protein biomarkers in periodontal disease. The findings reveal a field that has expanded steadily over the past two decades and is currently undergoing accelerated growth driven by advances in proteomic technologies. The evolution from early exploratory studies to more systematic, technology-driven approaches reflect increasing methodological sophistication and growing translational relevance. The global distribution of scientific activity and the intellectual structure identified through keyword and thematic analyses demonstrate that this research domain is becoming more coherent, interdisciplinary, and aligned with emerging diagnostic paradigms in precision periodontology. Overall, the results indicate that salivary and GCF protein biomarkers represent a rapidly advancing and clinically promising area of investigation. As analytical platforms continue to improve and collaborative networks expand, these biomarkers are likely to contribute meaningfully to non-invasive diagnostic strategies and personalized management of periodontal disease. Declarations Author contributions Patricia Castellanos Berrio: Contributed to conception, design, data acquisition and interpretation, drafted and critically revised the manuscript. Natalia María Correa Valencia: Contributed to design, data acquisition and interpretation, drafted and critically revised the manuscript. Sebastián Cardona Ramírez: Contributed to design, data acquisition and interpretation, drafted and critically revised the manuscript. All authors gave their final approval and agree to be accountable for all aspects of the work. Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This material did not receive any specific grant from public, commercial, or not-for-profit funding agencies. Ethical approval This work did not involve the use of animals or humans; therefore, ethical approval was not specifically required for publication. Data availability statement All data sets generated for this study are included in the manuscript and the supplementary files. Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this work, the authors used OpenAI ChatGPT (October 2023 version, https://chat.openai.com/) to improve the readability and language of the manuscript. After using this tool, the authors reviewed and edited the content as needed and took full responsibility for the content of the published article. Several Grammarly reviewing sessions were applied before submitting the final version of the manuscript. References Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K, Rosen A, Nigrovic PA, Sokolove J, Giles JT, Moutsopoulos NM, Andrade F (2016) Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8790610","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":585972054,"identity":"6d8d233e-bb8b-47ba-bd12-9ead815d28f6","order_by":0,"name":"Patricia Castellanos Berrio","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYPACCxkQycxQASKZGwhrOMAgwQPRcgZEMpKihbENRBHQYs5++PHnDxUSPPyzmw9/LpxXG83fDtTyo2IbTi2WPWlmEgfOSPBI3DmWJj1z2/HcGYcZGxh7ztzGqcXgBoMZw8E2oMNu5Jgx8247ltsA1AJ0IT4t7J8/HPwnwSN/I8f4M++cY7nzCWvhMZA42CDBY3Ajx0Cat6EmdwMhLZY9OWUSZ45J8BjeSEuTnnHsQO5GoJaD+Pxizn5884eKGhs5uRvJhz8X1NTlzjt/+OCDHxV4HIbGPwwmD+BUj0VLHT7Fo2AUjIJRMEIBAAQ/WyVq2ThqAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-5888-277X","institution":"Universidad de Antioquia","correspondingAuthor":true,"prefix":"","firstName":"Patricia","middleName":"Castellanos","lastName":"Berrio","suffix":""},{"id":585972055,"identity":"30b53347-8f6f-4350-a3cd-9d1b8d36feae","order_by":1,"name":"Nathalia María Correa Valencia","email":"","orcid":"https://orcid.org/0000-0001-8836-8827","institution":"Universidad de Antioquia","correspondingAuthor":false,"prefix":"","firstName":"Nathalia","middleName":"María Correa","lastName":"Valencia","suffix":""},{"id":585972056,"identity":"a4e326fd-c6e6-4429-b5b0-e4356a7afb68","order_by":2,"name":"Sebastian Cardona Ramírez","email":"","orcid":"https://orcid.org/0000-0003-2279-4553","institution":"Universidad de Antioquia","correspondingAuthor":false,"prefix":"","firstName":"Sebastian","middleName":"Cardona","lastName":"Ramírez","suffix":""}],"badges":[],"createdAt":"2026-02-04 22:41:04","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8790610/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8790610/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102062262,"identity":"0f3f326c-9986-4868-bcce-6cea477ba435","added_by":"auto","created_at":"2026-02-06 17:14:12","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82777,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA-style flow diagram illustrating the identification, screening, and selection of studies included in the bibliometric dataset.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8790610/v1/deacfbfd8faaade74aabfca5.jpeg"},{"id":102295731,"identity":"46ab0b06-54d7-448c-bb49-0317ac543deb","added_by":"auto","created_at":"2026-02-10 10:14:27","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":63826,"visible":true,"origin":"","legend":"\u003cp\u003eAnnual scientific production (2006–2025) on protein biomarkers in saliva and gingival crevicular fluid related to periodontal health and disease.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8790610/v1/7fc25225f789c20a2a26d17d.jpeg"},{"id":102062266,"identity":"e07cadce-e88f-4f26-bfd0-6508aeda2e62","added_by":"auto","created_at":"2026-02-06 17:14:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":511049,"visible":true,"origin":"","legend":"\u003cp\u003eGlobal distribution of scientific output. a) heatmap of country productivity in the literature on salivary and GCF protein biomarkers. b) International collaboration network among countries publishing on salivary and GCF protein biomarkers.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8790610/v1/1052952a9c44db8f9b696ae9.png"},{"id":102062264,"identity":"1392db7e-d6e7-4d01-97ca-e79e9bf5f90b","added_by":"auto","created_at":"2026-02-06 17:14:12","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":247664,"visible":true,"origin":"","legend":"\u003cp\u003eAffiliation of authors and documents contributing to research on protein biomarkers in saliva and gingival crevicular fluid. a) Most relevant affiliations. b) Most global cited documents in the field of salivary and GCF protein biomarkers for periodontal disease.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8790610/v1/db4c76064f2000c56bbb587f.png"},{"id":102062268,"identity":"be004f7d-7b6d-45d6-bebf-b87a4c083801","added_by":"auto","created_at":"2026-02-06 17:14:12","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1208288,"visible":true,"origin":"","legend":"\u003cp\u003eConceptual structure and Keyword co-ocurrences. A) Multiple Correspondence Analysis of keywords in the literature. B) Author keyword co-occurrence network showing major thematic clusters in the field.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8790610/v1/c614c7374bd862aba9bf3554.png"},{"id":102062269,"identity":"78f2cc90-161a-4bff-ba79-c6094cc5ca6c","added_by":"auto","created_at":"2026-02-06 17:14:12","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":23517,"visible":true,"origin":"","legend":"\u003cp\u003eThematic evolution of research on salivary and GCF protein biomarkers over time.\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8790610/v1/ee395fa221c5427c34c50d0e.jpeg"},{"id":102062265,"identity":"30d000db-31b3-4bec-a1c9-ee14303332b9","added_by":"auto","created_at":"2026-02-06 17:14:12","extension":"jpeg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":38484,"visible":true,"origin":"","legend":"\u003cp\u003eThree-field plot linking countries, author keywords, and journals publishing on salivary and GCF protein biomarkers.\u003c/p\u003e","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8790610/v1/5513212467650a2e48f5bdd3.jpeg"},{"id":102962109,"identity":"d0d31b9d-7f97-4dec-ba10-a35e6607665e","added_by":"auto","created_at":"2026-02-19 04:02:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3101133,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8790610/v1/02f0624b-0d71-417c-add3-83a7d800c9ba.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eProtein Biomarkers in Periodontal Disease: A Bibliometric Review\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003ePeriodontal diseases comprise a broad spectrum of chronic inflammatory conditions affecting the gingiva, periodontal ligament, cementum, and alveolar bone, arising from a dynamic interaction between dysbiotic microbial biofilms and host immune responses [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Clinically, these conditions are primarily categorized into gingivitis\u0026mdash; a reversible inflammation confined to the gingival tissues\u0026mdash; and periodontitis, a destructive form characterized by periodontal attachment loss, alveolar bone resorption, periodontal pocketing, and, in advanced cases, tooth loss [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In 2017, the American Academy of Periodontology and the European Federation of Periodontology updated the classification system, distinguishing periodontal health, gingivitis, periodontitis, other periodontal conditions, and peri-implant diseases [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGlobally, periodontal diseases are highly prevalent, affecting between 20 and 50% of the population, with severe forms present in nearly one-fifth of individuals older than 15 years [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Their multifactorial etiology involves dysbiosis-triggered inflammation modulated by individual susceptibility, genetic background, systemic conditions, age, environment, and behavioral determinants [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDiagnosis traditionally relies on clinical and radiographic parameters\u0026mdash;including plaque indices, bleeding on probing, probing depth, gingival recession, mobility, and radiographic evidence of bone loss [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. While these methods are essential for evaluating disease history and current inflammatory status, they are inherently limited: periodontal probing is operator-dependent, time-consuming, and unable to detect early disease activity or predict progression with precision [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. These constraints have prompted a growing interest in molecular and biochemical complementary approaches capable of identifying underlying biological activity rather than merely reflecting structural damage.\u003c/p\u003e \u003cp\u003eWithin this context, saliva and gingival crevicular fluid (GCF) have emerged as attractive diagnostic matrices. They are easily obtainable, non-invasive, and capable of reflecting ongoing inflammatory, immune, and microbial processes in the periodontium. Although no single biomarker has proven sufficient for robust diagnostic discrimination, combinations of salivary and GCF biomarkers\u0026mdash;particularly those related to inflammation, tissue degradation, or microbial burden\u0026mdash;have shown promising diagnostic performance [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Protein biomarkers are especially relevant because their presence, abundance, and post-translational modifications provide direct insight into disease mechanisms and represent potential therapeutic targets [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs technological capabilities advance, proteomics has become a central tool for exploring the salivary and GCF proteome, enabling high-resolution identification of protein signatures associated with disease onset, severity, and progression. Mass spectrometry\u0026ndash;based approaches, in particular, have catalyzed the discovery of novel biomarkers and broadened understanding of periodontal pathophysiology at a systems level [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the rapid expansion and methodological heterogeneity of this research area, bibliometric analysis provides a rigorous and quantitative means of evaluating publication trends, mapping scientific collaboration, identifying influential authors and institutions, and detecting emerging thematic structures [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Although prior bibliometric studies have addressed broader periodontal topics\u0026mdash;including regeneration, implantology, and oral microbiome research [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u0026mdash;none have specifically characterized the evolution of research on protein biomarkers in saliva and GCF for periodontal diseases, despite their increasing clinical and translational relevance.\u003c/p\u003e \u003cp\u003eTherefore, this study aimed to analyze the global scientific literature on protein biomarkers associated with periodontal diseases, specifically those identified in saliva and GCF from human clinical studies. By characterizing publication trends, diagnostic approaches, frequently investigated proteins, influential contributors, and emerging research fronts, this bibliometric assessment seeks to provide a comprehensive and integrative overview of the field. Ultimately, the findings are intended to serve as a reference framework that supports future research, fosters methodological innovation, and accelerates the development of reliable, non-invasive protein-based diagnostic tools in periodontology.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eA descriptive bibliometric review was conducted to characterize the global scientific output on protein biomarkers associated with periodontal disease in human subjects. The Web of Science (WoS) platfrom served as the primary data source. The study adhered to methodological recommendations for bibliometric research in health sciences [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData source and search strategy\u003c/h3\u003e\n\u003cp\u003eAn electronic search was performed on November 9, 2025, using WoS database. No publication year limits were applied to preserve the historical integrity of the dataset. The Topic Search (TS) query was designed for high precision and included periodontal disease terms, protein biomarkers, proteomic approaches, biological matrices of interest (saliva and gingival crevicular fluid), and restrictions to human clinical research, while excluding in vitro, in silico, and animal studies: TS = ((\u0026ldquo;periodontal disease*\u0026rdquo; OR periodontitis OR gingivitis) AND (\u0026ldquo;protein biomarker*\u0026rdquo; OR proteomic* OR proteome* OR \u0026ldquo;protein expression\u0026rdquo;) AND (saliva* OR \u0026ldquo;gingival crevicular fluid\u0026rdquo; OR GCF) AND (human* OR patient* OR \u0026ldquo;clinical stud*\u0026rdquo;) NOT (\u0026ldquo;in vitro\u0026rdquo; OR \u0026ldquo;animal*\u0026rdquo; OR \u0026ldquo;mouse\u0026rdquo; OR \u0026ldquo;rat\u0026rdquo; OR \u0026ldquo;in silico\u0026rdquo;)). The search and export of records were completed on the same day to minimize temporal indexing fluctuations.\u003c/p\u003e\n\u003ch3\u003eInclusion and exclusion criteria\u003c/h3\u003e\n\u003cp\u003eThe inclusion criteria comprised original research articles and review papers indexed in WoS that evaluated proteins or proteomic profiles related to periodontal disease in human participants and used saliva, GCF, or other human oral fluids as biological matrices. Studies were excluded if they involved animal models, \u003cem\u003ein vitro\u003c/em\u003e experiments, or in silico simulations; if they focused exclusively on non-protein biomarkers such as genomic, transcriptomic, metabolomic, microbiological, or strictly immunologic markers; or if they used non-qualifying matrices, including blood, serum, plasma, or tissue biopsies. Non-original documents\u0026mdash;such as letters, conference abstracts, editorials, and technical notes\u0026mdash;were also excluded, as were studies addressing oral diseases unrelated to periodontal pathology, investigations centered on systemic conditions without periodontal endpoints, and publications that did not provide extractable or thematically relevant data.\u003c/p\u003e\n\u003ch3\u003eRecord screening and selection process\u003c/h3\u003e\n\u003cp\u003eTwo authors independently screened all records at the title and abstract level. Full texts were consulted when eligibility was unclear. Although PRISMA is not specifically designed for bibliometric studies, the screening process followed PRISMA-inspired transparency principles to ensure rigor and reproducibility. Eligible records were exported in BibTeX (.bib) format, including \u0026ldquo;Full Record and Cited References.\u0026rdquo; This curated dataset was used for scientometric analyses.\u003c/p\u003e\n\u003ch3\u003eData extraction, preprocessing, and analytical procedures\u003c/h3\u003e\n\u003cp\u003eAll bibliographic metadata\u0026mdash;including titles, authors, affiliations, abstracts, keywords, journal sources, publication year, citation counts, and DOI\u0026mdash;were exported in BibTeX and CSV formats for subsequent analysis. Using RStudio (version 4.3.2) and the bibliometrix package (version 5.1.0), we calculated indicators such as annual scientific production, journal source of publication, global distribution of scientific output, scientific productivity by main author affiliation, overall citation output by main author, country collaboration network, keyword co-occurrence structures, conceptual structure of keywords using factorial analysis through Multiple Correspondence Analysis (MCA), thematic evolution, and three-field plots linking countries, keywords, and sources. Biblioshiny was used as an interactive environment for data exploration and visualization using full counting as the counting method and showing top ten journals, institutions and authors. In the international collaboration network analysis, node size reflected frequency, edges represented co-occurrence links, and node color corresponded to geographical clusters, while synonyms and term variants were manually harmonized. Additional tools included Scimago Journal Rankings for classification based on impact factor.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eScientometric workflow and conceptual mapping\u003c/h2\u003e \u003cp\u003eThe analytical workflow encompassed several stages, beginning with the assessment of annual scientific production to identify temporal publication trends, followed by source and affiliation analyses to determine the core journals and institutions contributing to the field. Country-level analyses were then conducted through heatmaps, collaboration networks, and productivity indicators. Citation analyses identified the most globally cited documents and the foundational literature shaping the discipline. To elucidate the conceptual structure of the field, we constructed keyword co-occurrence networks through MCA factorial ampping, examined thematic evolution over time, and generated three-field plots integrating geographic origin, thematic focus, and publishing sources. Prior to these analyses, extensive preprocessing was undertaken to resolve ambiguities in author names, institutional variants, and keyword harmonization, ensuring consistency across the dataset and minimizing analytical noise.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthical considerations\u003c/h3\u003e\n\u003cp\u003eThe review relied exclusively on secondary data retrieved from publicly available bibliographic sources; therefore, ethical approval was not required.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 191 records were retrieved from the WoS database using the predefined search strategy. After removing non-eligible document types (e.g., conference abstracts, letters) and applying the inclusion and exclusion criteria, 112 publications remained for the bibliometric dataset. The full screening and refinement process is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eTemporal trends in scientific production\u003c/h2\u003e \u003cp\u003eThe temporal distribution of publications is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Output was minimal in the mid-2000s, increased steadily starting in 2010, and reached its highest level in 2023 (12 publications). By November 2025, 9 publications had already been indexed.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSources of publication\u003c/h2\u003e \u003cp\u003eThe top-ten journals with the highest number of publications are summarized in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Journal of Clinical Periodontology and Journal of Periodontal Research were the leading sources, each publishing 15 articles, followed by Journal of Proteome Research (6 articles) and a group of journals contributing 5 articles each.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMost productive journals publishing research on salivary and gingival crevicular fluid protein biomarkers, with impact factor (2025).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJournal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal Articles\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIF\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJOURNAL OF CLINICAL PERIODONTOLOGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJOURNAL OF PERIODONTAL RESEARCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJOURNAL OF PROTEOME RESEARCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARCHIVES OF ORAL BIOLOGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCLINICAL ORAL INVESTIGATIONS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINTERNATIONAL JOURNAL OF MOLECULAR SCIENCES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJOURNAL OF PERIODONTOLOGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJOURNAL OF PROTEOMICS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROTEOMICS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIF\u0026thinsp;=\u0026thinsp;impact factor of the journal in 2025 according to SCImago journal rank\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCountry-level scientific output\u003c/h2\u003e \u003cp\u003eGeographical productivity is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, indicating the number of publications attributed to each country. China was the most prolific contributor (66 articles), followed by the United States (56) and Italy (44).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCountry collaboration network\u003c/h2\u003e \u003cp\u003eThree primary hubs were identified: The United States cluster, connected with Turkey, India, and Finland; The Sweden-centered European cluster, with links to Chile, Egypt, and Syria; and The China cluster, strongly connected to Singapore illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eInstitutional productivity\u003c/h2\u003e \u003cp\u003eThe Karolinska Institutet ranked first in the institution with most publications (18), followed by Universidade Federal do Rio de Janeiro (14) and Sichuan University (11) as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eMost globally cited documents\u003c/h2\u003e \u003cp\u003eK\u0026ouml;nig et al. in 2016 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] received the highest number of citations (423), and Miller et al. in 2010 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and Liu and Duan in 2012 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] followed with 254 and 216 citations, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eFactorial analysis and Keyword co-occurrence structure\u003c/h2\u003e \u003cp\u003eThree distinct research clusters emerge: a blue cluster focused on osteoimmunology and bone metabolism through terms like \"rankl\" and \"osteoclastogenesis\"; a red cluster encompassing broad periodontal disease and diagnostics research including \"biomarker,\" \"saliva,\" and \"chair-side diagnostics\"; and a green cluster representing analytical techniques such as \"LC-MS\" and \"MALDI-TOF\" (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea). Four thematic clusters were identified, including a motor theme centered on saliva, periodontitis, and biomarkers, and additional clusters focusing on proteomics, aggressive periodontitis, and salivary biomarkers (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eThematic evolution\u003c/h2\u003e \u003cp\u003eThe thematic evolution diagram shows the longitudinal progression of research topics (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). The intellectual core has shifted from themes like \"aggressive periodontitis\" and \"cytokines\" to the emergence of \"biomarker\" as a motor theme, which has since evolved into the dominant, well-developed research front of \"proteomics.\" This transition marks a maturation from descriptive studies to the application of advanced techniques like mass spectrometry, enabling a more precise decoding of the proteome for disease classification and mechanistic insight. While foundational concepts such as \"periodontitis\" and \"gingival crevicular fluid\" remain central, their investigation is now predominantly framed by these high-resolution analytical frameworks.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eThree-field plot (countries\u0026ndash;keywords\u0026ndash;sources)\u003c/h2\u003e \u003cp\u003eThe three-field plot analysis elucidates the geographic, thematic, and publishing structure of periodontitis biomarker research, revealing Italy, the USA, Brazil, and China as the most research-active nations (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). Thematically, \"periodontitis\" and \"saliva\" emerge as the core research foci, with these keywords demonstrating the strongest connections to the leading countries. The primary outlet for this body of work is the \u003cem\u003eJournal of Clinical Periodontology\u003c/em\u003e, which serves as a central publication venue, followed by other significant journals such as the \u003cem\u003eJournal of Proteome Research\u003c/em\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis analysis presents all available literature indexed in the WoSCC, without imposing publication year limits, in order to generate a comprehensive and unbiased overview of the thematic development of research on protein biomarkers of periodontal disease. This decision followed established methodological recommendations for bibliometric studies, which emphasize the importance of including the full set of available documents when the aim is to characterize historical trajectories, emerging topics, and research fronts within a specialized field [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The final dataset, refined through rigorous manual screening, allowed us to examine the evolution of scientific production, conceptual structure, and collaborative patterns in this domain.\u003c/p\u003e \u003cp\u003eWith respect to dataset characteristics, although the final sample comprised 112 publications, a figure that may seem modest compared with broader bibliometric reviews, this number is appropriate given the specificity of the inclusion criteria. By limiting the analysis to human clinical research, restricting biomarkers to the proteomic domain, and focusing exclusively on saliva and GCF, the available literature necessarily becomes narrower but more conceptually coherent. Comparable bibliometric studies in dentistry frequently report similar dataset sizes when they are focused on specialized topics. The rigorous dual screening conducted in this study further ensured thematic alignment and minimized the inclusion of peripheral records, thereby improving internal validity and reinforcing the interpretability of the results.\u003c/p\u003e \u003cp\u003eThe pronounced increase in publications since 2023 indicates that the field is undergoing an accelerated growth phase. This pattern coincides with the increased recognition of oral fluids as diagnostic media and increasing investment in high-throughput proteomic techniques. These tendencies strongly suggest that the study of salivary and GCF protein biomarkers constitutes a contemporary and rapidly advancing domain within dental and biomedical research. Thus, several studies have reported overall diagnostic utility and accuracy of approximately 86% for periodontitis, in addition to the practical advantages derived from the non-invasive nature of these matrices [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. These findings support the notion that oral fluids represent an increasingly accepted diagnostic platform for periodontal assessment.\u003c/p\u003e \u003cp\u003eThe patterns observed in the country collaboration network likely reflect complex interactions among geographic proximity, established academic partnerships, funding mechanisms, and shared research priorities. Highly connected countries may function as knowledge brokers, while more isolated research clusters may represent regionally focused agendas or emerging collaborations [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The leadership of China, the United States, and Italy, and the contribution of countries such as Brazil, South Korea, and Egypt, is consistent with global data showing both the widespread burden of periodontal disease and the growing interest in non-invasive diagnostic solutions [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The appearance of smaller clusters suggests opportunities for greater global integration as research capacity expands [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe dissemination of knowledge occurs through a well-structured network of scientific journals. High-impact periodontology journals such as \u003cem\u003eJournal of Clinical Periodontology\u003c/em\u003e and \u003cem\u003eJournal of Periodontal Research\u003c/em\u003e serve as the central outlets for this research. The prominence of proteomic journals\u0026mdash;most notably \u003cem\u003eJournal of Proteome Research\u003c/em\u003e\u0026mdash;confirms the methodological centrality of mass spectrometry and related techniques in advancing the field [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. At the same time, the presence of journals focused on immunology, biosensors, and personalized medicine demonstrates an increasingly interdisciplinary orientation, bridging clinical periodontology with broader biomedical and technological domains.\u003c/p\u003e \u003cp\u003eThe citation analysis supports this interdisciplinary structure. The seminal work of K\u0026ouml;nig et al. (2016) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] in \u003cem\u003eScience Translational Medicine\u003c/em\u003e, along with frequently cited foundational reviews, exemplifies the intersection between advanced analytic methods and clinically relevant inquiry. The rapid accumulation of citations for recent publications [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] suggests that this research frontier remains active, dynamic, and deeply interconnected with ongoing technological advancement.\u003c/p\u003e \u003cp\u003eThe longitudinal analysis confirms the maturation of the field. Early research focused on \u003cem\u003eaggressive periodontitis\u003c/em\u003e and classical inflammatory mediators, gradually giving way to more complex methodologies and proteomic-based investigations [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The emergence of proteomics as a central, well-established theme [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] marks a shift toward more systematic, technology-driven investigations capable of elucidating disease mechanisms, improving classification, and enhancing risk prediction (Hu y Leung 2023) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Although core concepts such as \u003cem\u003eperiodontitis\u003c/em\u003e and \u003cem\u003egingival crevicular fluid\u003c/em\u003e remain stable, newer approaches grounded in imaging, biomarkers, and emerging data science techniques have begun to shape the evolving research landscape.\u003c/p\u003e \u003cp\u003eThe keyword co-occurrence patterns indicate strong thematic consolidation around molecular diagnostics and the exploration of saliva and GCF, while also revealing niche areas that contribute to the overall research ecosystem. Structural mapping from the factorial analysis highlights an intellectual organization spanning molecular pathways, clinical diagnostics, and analytical platforms, although the fact that approximately 64% of variance remains unexplained suggests underlying complexity and the possibility that additional thematic areas will emerge as the field expands [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The prominence of terms related to personalized oral health and precision dentistry [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] reinforces the notion that proteomic research is increasingly integrated into translational efforts aimed at improving diagnostic accuracy.\u003c/p\u003e \u003cp\u003eVisualization of relationships among countries, keywords, and journals provides additional insight into patterns of specialization and the principal pathways through which knowledge circulates globally. This complements the collaboration and citation analyses, forming a comprehensive depiction of how the field is structured and how it continues to advance.\u003c/p\u003e \u003cp\u003eDespite notable progress, the field continues to face persistent methodological challenges, including heterogeneity in sampling and analytical protocols, reliance on cross-sectional study designs, and fragmentation in biomarker assessment. These issues highlight the need for methodological standardization, multicenter validation, and the development of integrated biomarker panels capable of capturing the biological complexity of periodontal disease. Nonetheless, the field\u0026rsquo;s conceptual maturation\u0026mdash;combined with expanding international collaboration networks and rapid advances in analytical technologies\u0026mdash;indicates a strong trajectory toward clinically meaningful, noninvasive molecular diagnostics.\u003c/p\u003e \u003cp\u003eOur analysis has certain methodological limitations. Restricting the search to WoS excludes articles indexed exclusively in other databases, potentially omitting relevant regional or emerging research. Bibliometric analyses can also be affected by incomplete metadata or changes in journal indexing. Nonetheless, this study\u0026rsquo;s methodological rigor, particularly the strict inclusion criteria, dual screening, and comprehensive use of bibliometric tools, strengthens the reliability of the findings. Importantly, bibliometric approaches differ from traditional reviews in that their core objective is not to synthesize evidence but to map scientific production, impact, and structure, all of which are needed to understand a field\u0026rsquo;s development and influence.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis bibliometric analysis provides a comprehensive overview of the scientific development of research on salivary and GCF protein biomarkers in periodontal disease. The findings reveal a field that has expanded steadily over the past two decades and is currently undergoing accelerated growth driven by advances in proteomic technologies. The evolution from early exploratory studies to more systematic, technology-driven approaches reflect increasing methodological sophistication and growing translational relevance. The global distribution of scientific activity and the intellectual structure identified through keyword and thematic analyses demonstrate that this research domain is becoming more coherent, interdisciplinary, and aligned with emerging diagnostic paradigms in precision periodontology. Overall, the results indicate that salivary and GCF protein biomarkers represent a rapidly advancing and clinically promising area of investigation. As analytical platforms continue to improve and collaborative networks expand, these biomarkers are likely to contribute meaningfully to non-invasive diagnostic strategies and personalized management of periodontal disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatricia Castellanos Berrio:\u0026nbsp;\u003c/strong\u003eContributed to conception, design, data acquisition and interpretation, drafted and critically revised the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNatalia Mar\u0026iacute;a Correa Valencia:\u0026nbsp;\u003c/strong\u003eContributed to design, data acquisition and interpretation, drafted and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSebasti\u0026aacute;n Cardona Ram\u0026iacute;rez:\u0026nbsp;\u003c/strong\u003eContributed to design, data acquisition and interpretation, drafted and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors gave their final approval and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis material did not receive any specific grant from public, commercial, or not-for-profit funding agencies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work did not involve the use of animals or humans; therefore, ethical approval was not specifically required for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data sets generated for this study are included in the manuscript and the supplementary files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of generative AI and AI-assisted technologies in the writing process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work, the authors used OpenAI ChatGPT (October 2023 version, https://chat.openai.com/) to improve the readability and language of the manuscript. After using this tool, the authors reviewed and edited the content as needed and took full responsibility for the content of the published article. Several Grammarly reviewing sessions were applied before submitting the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKonig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K, Rosen A, Nigrovic PA, Sokolove J, Giles JT, Moutsopoulos NM, Andrade F (2016) Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. 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PMID: 35284954; PMCID: PMC8918420\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"(MeSH), Periodontal Diseases, Protein Biomarkers, Saliva, Gingival Crevicular Fluid, Proteomics, Journal Impact Factor","lastPublishedDoi":"10.21203/rs.3.rs-8790610/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8790610/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis bibliometric study examines research on protein biomarkers in periodontal disease, a condition requiring early and accurate diagnosis. Despite available diagnostic tools, their limitations highlight protein biomarkers as a promising, yet clinically unvalidated, alternative.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethodology:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA bibliometric review was conducted using Web of Science Core Collection, focusing exclusively on human clinical studies and excluding animal, in vitro, and in silico research. Two independent authors evaluated titles, abstracts, and full texts following transparency principles inspired by PRISMA. Tools including bibliometrix/Biblioshiny were used to generate bibliometric indicators, collaboration networks, and thematic structures.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFrom 191 records identified between 2006\u0026ndash;2025, 112 studies met inclusion criteria, showing sustained growth with marked increase in the last five years. Journal of Clinical Periodontology and Journal of Periodontal Research were the main publishing venues. China, the United States, and Italy led scientific production. The most cited articles were K\u0026ouml;nig et al., Miller et al., and Liu et al. Thematic analysis revealed an evolution from inflammatory mediator studies toward advanced proteomic approaches, establishing \"proteomics\" as the dominant contemporary theme.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eProtein biomarker research in periodontal disease shows sustained growth, led by countries with strong molecular research capacity, highlighting proteomic diagnostics and a consolidated agenda toward clinical translation of salivary and gingival crevicular fluid biomarkers.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical relevance:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis study summarizes the current state of research on protein biomarkers in periodontal disease, providing useful evidence to inform the development and future validation of diagnostic tools with potential clinical application.\u003c/p\u003e","manuscriptTitle":"Protein Biomarkers in Periodontal Disease: A Bibliometric Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-06 17:14:07","doi":"10.21203/rs.3.rs-8790610/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1f51bf50-3d17-48fa-be63-74374e919e34","owner":[],"postedDate":"February 6th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":62343352,"name":"Dentistry"},{"id":62343353,"name":"Molecular Biology"},{"id":62343354,"name":"Epidemiology"}],"tags":[],"updatedAt":"2026-02-06T17:14:07+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-06 17:14:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8790610","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8790610","identity":"rs-8790610","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}