Knowledge Domains and Emerging Trends of Hydrogels in Orthopedic Diseases：A Bibliometric and Visualization Analysis

Knowledge Domains and Emerging Trends of Hydrogels in Orthopedic Diseases：A Bibliometric and Visualization Analysis | 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 Knowledge Domains and Emerging Trends of Hydrogels in Orthopedic Diseases：A Bibliometric and Visualization Analysis Long Xie, Yu qin Peng, Xiang Shen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8008252/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 Hydrogels have emerged as pivotal biomaterials in orthopedic research, attributed to their unique three-dimensional networks, high hydration capacity, and exceptional biocompatibility. Despite extensive exploration of hydrogels in bone repair, cartilage regeneration, and drug delivery, a systematic bibliometric analysis mapping the global research landscape remains absent. Objective This study conducts the first comprehensive bibliometric analysis to delineate research hotspots, evolutionary trends, and collaborative networks in hydrogel applications for orthopedic diseases from 2000 to 2024. Methods A total of 8,685 peer-reviewed articles from the Web of Science Core Collection (WoSCC) were assessed using CiteSpace and VOSviewer. Co-citation networks, keyword clustering, and timeline visualization were employed to identify thematic shifts, interdisciplinary connections, and emerging frontiers. Results Annual publication data demonstrated exponential growth (R² = 0.94), with the United States (36.2%) and China (28.5%) collectively dominating global research output. Established research domains focused on hydrogel-mediated drug delivery systems—particularly for rheumatoid arthritis therapy—alongside tissue-engineered scaffolds and bone regeneration strategies. Concurrently, emerging clusters highlighted transformative innovations, including injectable hydrogels (keyword burst strength: 12.7), antibacterial/antioxidant systems targeting infection and oxidative stress, and 3D-bioprinted constructs for precision orthopedic applications. Furthermore, collaborative networks coalesced into three transnational clusters: (1) mechanoactive hydrogels for load-bearing applications, (2) extracellular vesicle-functionalized systems for enhanced bioactivity, and (3) smart hydrogel-responsive implants integrating real-time diagnostics, collectively driving advancements in personalized orthopedic solutions. Conclusion This analysis reveals a paradigm shift from passive structural hydrogels to multifunctional, stimuli-responsive platforms addressing oxidative stress, microbial resistance, and personalized tissue regeneration. These identified trends provide strategic directions to accelerate clinical translation in the treatment of osteoarthritis, critical-sized bone defects, and inflammatory joint diseases. Cell & Tissue Engineering Hydrogel Orthopedic Diseases Bibliometrics CiteSpace VOSviewer Drug Delivery Tissue Engineering Bone Regeneration Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Orthopedic diseases, including osteoporosis [ 1 ] , osteoarthritis [ 2 ] , and bone cancer, pose significant global health challenges. Conventional treatments often involve surgical interventions, which can be invasive with limited efficacy. Hydrogels, due to their biocompatibility, biodegradability, and ability to mimic the extracellular matrix (ECM), have emerged as promising materials in orthopedic applications [ 3 ] . They are widely exploited for drug delivery, tissue engineering, and as scaffolds for bone regeneration. Despite growing interest in hydrogel-based applications in orthopedics [ 4 , 5 ] , a systematic review mapping the knowledge domains and emerging trends in this field remains lacking. Recent advances in nanotechnology have further expanded the functionality of hydrogels, enabling enhanced mechanical properties, antibacterial activity, and bioactive molecule delivery. For instance, Li et al. developed patterned alginate hydrogels incorporated with CuS nanoparticles, significantly improving antibacterial efficacy and mechanical resilience—key attributes for load-bearing orthopedic applications [ 6 ] . Similarly, Zheng et al. designed polyphenol-mediated electroactive hydrogels for exosome delivery, facilitating targeted bone regeneration through synergistic bioelectrical and biochemical cues [ 7 ] . Bibliometric analysis employs mathematical and statistical methodologies for qualitative and quantitative examination of the distribution, structure, and developmental trajectory of scientific data [ 8 ] . Recent bibliometric studies have highlighted the expanding body of literature on hydrogels, particularly focusing on their biomedical applications [ 9 ] . With the increasing availability of open-source tools such as CiteSpace [ 10 ] , VOSviewer [ 11 ] , the bibliometrix R-package, and HistCite, bibliometric analysis has been extensively applied in numerous biomedical domains. The bibliometric perspective provides insights into the geographical distribution of significant research contributions from countries including China and several European nations. Additionally, such approaches underscore the need for deeper theoretical exploration of hydrogel implications in bone disease management. Overall, bibliometric analysis not only synthesizes existing knowledge but also offers a framework for identifying research gaps and future directions in hydrogel-based orthopedic therapies. Assessment of available trends and literature patterns enables a clearer understanding of the associated complexities. This study primarily explores the following questions: (1) what are the global trends in publication and citation activities? (2) who are the key contributors, including countries/regions, institutions, and funding bodies? (3) which journals are prominent in this field? (4) what is the current research focus and priorities; (5) what emerging topics are likely to become future research hotspots and frontiers? and (6) which are the most extensively studied genes and regulatory pathways? The overarching aim is to identify leading researchers, institutions, and countries along with their collaborative networks, and reveal dynamic research trends in this rapidly advancing field, ultimately underlining both current and future research frontiers. Moreover, our objective is to elucidate the pathway for experts in nanotechnology to translate their foundational discoveries into solutions for enduring clinical challenges in musculoskeletal medicine. By achieving this, we aspire to enhance collaborative dialogue between materials scientists and clinical researchers, thereby expediting the development of next-generation, nano-enabled orthopedic therapies. Materials and Methods 2.1. Data Collection and Statistics The Web of Science Core Collection (WoSCC) by Thomson Reuters, which indexes over 12,000 high-impact academic journals and is widely recognized within the international academic community [ 12 ] , was selected as the target database for this study. For the purpose of this study, 'orthopedic diseases' were operationally defined as pathological conditions affecting the musculoskeletal system, including bones, joints, and associated tissues. This encompasses traumatic, degenerative, inflammatory, and neoplastic conditions. This definition informed the selection of keywords for the second branch of the search strategy, which included terms for anatomical structures (e.g., bone, spine), specific diseases (e.g., osteoporosis, osteoarthritis), and pathological states (e.g., fracture, bone cancer).The following search query was applied to identify relevant literature: ( (TS=(Hydrogels) OR TS=(Hydrogel) ) AND ( (TS=(orthopedic*) OR TS=(fracture*) OR TS=(osteoporosis) OR TS=(spine*) OR TS=("bone tumor") OR TS=(osteoarthritis) OR TS=(Bone*) OR TS=("Bones and Bone Tissue") OR TS=("Bones and Bone") OR TS=("Bone Tissue*") OR TS=("Bony Apophysis") OR TS=(Condyle) OR TS=(Periosteum) OR TS=("Bone Cancer*") OR TS=("Cancer of Bone") OR TS=(osteonecrosis) ) ). The search covered the period from 2000 to 2024, retrieving a total of 8,685 records. These records were downloaded and saved as plain text files in the format "Full Record and Cited References," serving as the sample dataset for analysis and collectively termed as "DATA." Additionally, the raw data collected on the countries/regions, institutions, journals, authors, and article types was organized using Excel (WPS 2019) for statistical description. 2.2. Bibliometric Analysis Tools 2.2.1. CiteSpace Co-occurrence Network Scientific partnerships are defined as the involvement of "multiple authors, institutions, or countries/regions together in a publication." Analyzing such collaborations can reveal the dynamic status of a research field across three dimensions: authors, institutions, and countries. When specific articles are imported into CiteSpace as a dataset, the tool visualizes these collaborative relationships and scientific concepts as a co-occurrence network. CiteSpace uses nodes and edges to differentiate merged networks, color-coded by year. Edge colors indicate the year in which the co-occurrence link was first established. Nodes consist of multi-colored "tree rings", where thickness represents the frequency of co-occurrences in a given year. Red rings correspond to citation bursts in a specific year, while purple rings denote the degree of betweenness centrality. Nodes exhibiting high betweenness centrality are significant, acting as connecting bridges. Burst Detection Castano proposed that document streams, such as emails or articles, have specific themes over time that gradually fade. Specific text data mining algorithms can identify these temporal thematic shifts, represented as "bursts of activity" [ 13 ] . CiteSpace can detect the appearance of citation bursts (which may last several years or occur within a single year), indicating the association of a particular discipline, keyword, or reference with a surge in citations that reflect increasing attention from the scientific community. Cluster Analysis CiteSpace provides three clustering algorithms based on titles, abstracts, and keywords, which categorize publications into clusters with distinct research characteristics. Depending on the time slice settings, cluster maps visualize temporal variations in conceptual clusters. Additionally, timeline maps clearly illustrate the rise and fall of clusters along with their associated nodes. Specific Steps include : Import the "DATA" on hydrogels related to the orthopedic field into CiteSpace (version 6.2.R4). Set the time slice to "2000–2024" with a 1-year interval. Select "Author Keywords" and configure a secondary time slice spanning "2004–2024" with a 1-year interval. Choose the word source as "Title," "Abstract," "Author Keywords," and "Keywords+." Select the appropriate node type, keeping other parameters at default values. Automatically generate knowledge maps of country/region, institution, or author collaboration networks. Manually refine and adjust maps for clarity and aesthetics. For keyword clustering, the node type was set to "Keywords," and the time frame was divided into four distinct periods: 2000–2006, 2007–2012, 2013–2018, and 2019–2024. Reference clustering was visualized using the "Timeline View" to generate citation timeline maps. Furthermore, burst detection maps for keywords, categories, or references were produced using the "Burstness" tab in the control panel. 2.2.2. HistCite Each scientific publication can be viewed as a light in the darkness, and each citation intensifies its brightness, illuminating the academic landscape. HistCite Pro 2.1 software facilitates the visualization of this digital relationship, extracting the most impactful literature based on citation frequency. HistCite scores articles using two metrics, namely Local Citation Score (LCS) and Global Citation Score (GCS). LCS quantifies citation frequency within the dataset, while GCS reflects citation frequency in the WoSCC database. A total of 8,685 articles on hydrogel research in the orthopedic field were imported into HistCite Pro 2.1, setting the threshold to 30 and retaining other default settings. By selecting "Make Graph", a visual research landscape was generated to enable rapid identification of key publications. 2.2.3. The Alluvial Generator Alluvial flow diagrams elucidate temporal patterns in evolving research networks. To construct these diagrams, a series of individual networks for co-occurring keywords were first created using CiteSpace, which were then exported and processed using the Alluvial Generator ( http://www.mapequation.org/apps/AlluvialGenerator.html ). In the resulting diagrams, each keyword was treated as a node clustered by time slices, forming modules. Nodes were split or merged over time, creating new modules that result from the intersection of previous nodes. A donut chart was plotted using R 4.2.2, utilizing the geom_bar function from the ggplot2 package (version 3.4.4). Results 3.1. Historical Features of the Literature on Hydrogels in Bone-Related Applications 3.1.1. Distribution of Publications The volume of scientific publications at specific time points can provide quantitative insights into knowledge accumulation and the developmental trajectory of a research field. This study retrieved 8,685 articles related to hydrogels applicability in orthopedics. These works were authored by 34,906 researchers from 5,937 institutions and published in 759 journals across 93 scientific categories (Table 1 ). Table 1 Summary of Publication Metrics. Categories Publication Articles Review Authors Institutions Journals Subject categories Amount 10145 8685 1460 34906 5937 759 93 As depicted in Fig. 1 A, the annual number of publications remained relatively low from 2000 to 2004, with only 20 articles recorded in the year 2000. However, a steady increase was observed from 2005 to 2017, with a sharper surge in output noted after 2017, reaching a peak in 2024. In terms of journal distribution, Biomaterials ranked first with the largest publication volume (419 articles), closely followed by Acta Biomaterialia (413 articles) and International Journal of Biological Macromolecules (407 articles). Figure 1 B lists the top 20 journals with the highest output, which researchers can refer to when considering manuscript submissions. 3.1.2. The Vein of Research on Hydrogels in Bone-Related Applications Figure 2 presents a co-citation network map illustrating interrelationships among references cited in the field of hydrogels for bone-related applications over the past two decades (Fig. 2 ). The color gradient—from white to red—denotes the publication year of the cited reference, spanning from 2000 to 2024. The network consists of 2,234 nodes and 11,078 links, indicating extensive interconnectivity within the literature. Node size is directly proportional to the citation frequency, and greater node connectivity represents higher betweenness centrality. This network not only visualized the citation structure but also identified influential publications in the field. Metamorphically comparing to a tree, the early literature (2000–2010, gray nodes) forms roots of the field, providing nourishment for sustainable development. The mid-term (2011–2017, blue nodes) dispersing gradually signify the main research branches. In the recent period (2018–2024, red nodes), nodes develop into branches, forming tighter clusters, indicating the concentration and differentiation of the research field, which is further elaborated in the reference timeline maps. Top 10 most co-cited articles These articles exhibiting the highest co-citation frequencies, ranging from 117 to 186, serve as pivotal contributions to the field: Koons GL (2020); Liu M (2017); Sun JY (2012); Bai X (2018); Zhang YS (2017); Kang HW (2016); Hua MT (2021); Chaudhuri O (2016); Murphy SV (2014); Kim J (2021) Additionally, HistCite Pro 2.1 was adopted to plot the citation history of research articles. Table 2 highlights these landmark publications, with the top three being: Double-network hydrogels with extremely high mechanical strength; Why are double network hydrogels so tough?; 3D bioprinting of tissues and organs. Table 2 Summary of Article Information on Hydrogels. This table lists key publications related to hydrogel-based orthopedic applications, including the article title, journal name, local citation score ( LCS ), and global citation score ( GCS ). NO. Article information Journal LCS GCS 79 Double-network hydrogels with extremely high mechanical strength ADV MATER 740 3604 746 Why are double network hydrogels so tough? SOFT MATTER 399 1825 2107 3D bioprinting of tissues and organs NAT BIOTECHNOL 337 4625 2698 Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels BIOMATERIALS 316 1990 1738 Physical hydrogels composed of polyampholytes demonstrate high toughness and viscoelasticity NAT MATER 307 1686 2923 Hydrogels with tunable stress relaxation regulate stem cell fate and activity NAT MATER 238 1688 152 Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering NAT BIOTECHNOL 216 3658 2922 A 3D bioprinting system to produce human-scale tissue constructs with structural integrity NAT BIOTECHNOL 204 1814 4539 Bioactive hydrogels for bone regeneration BIOACT MATER 198 409 839 Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate NAT MATER 191 1255 6058 Materials design for bone-tissue engineering NAT REV MATER 188 1050 330 Large strain hysteresis and mullins effect of tough double-network hydrogels MACROMOLECULES 183 594 3640 Cell-laden hydrogels for osteochondral and cartilage tissue engineering ACTA BIOMATER 169 505 2401 Bioactive Nanoengineered Hydrogels for Bone Tissue Engineering: A Growth-Factor-Free Approach ACS NANO 160 538 3063 3D bioprinting for engineering complex tissues BIOTECHNOL ADV 148 1110 338 A model of the fracture of double network gels MACROMOLECULES 134 277 322 Bone regeneration using hyaluronic acid-based hydrogel with bone morphogenic protein-2 and human mesenchymal stem cells BIOMATERIALS 125 435 334 Multifunctional chondroitin sulphate for cartilage tissue-biomaterial integration NAT MATER 120 921 1332 Functional Human Vascular Network Generated in Photocrosslinkable Gelatin Methacrylate Hydrogels ADV FUNCT MATER 120 573 269 Alginate hydrogels as biomaterials MACROMOL BIOSCI 119 599 185 Determination of fracture energy of high strength double network hydrogels J PHYS CHEM B 118 1407 2545 3D Printing of Highly Stretchable and Tough Hydrogels into Complex, Cellularized Structures ADV MATER 114 266 945 Mineralization of Hydrogels for Bone Regeneration TISSUE ENG PART B-RE 113 763 1096 Biopolymer-Based Hydrogels for Cartilage Tissue Engineering CHEM REV 112 199 1103 Hydrogels for the Repair of Articular Cartilage Defects TISSUE ENG PART B-RE 109 460 2399 Natural-Based Nanocomposites for Bone Tissue Engineering and Regenerative Medicine: A Review ADV MATER 109 359 6773 Advanced hydrogels for the repair of cartilage defects and regeneration BIOACT MATER 108 697 264 Necking phenomenon of double-network gels MACROMOLECULES 107 259 201 The effect of incorporating RGD adhesive peptide in polyethylene glycol diacrylate hydrogel on osteogenesis of bone marrow stromal cells BIOMATERIALS 105 246 3001 Gelatin-Methacryloyl Hydrogels: Towards Biofabrication-Based Tissue Repair TRENDS BIOTECHNOL 103 396 3.1.3. Scientific Cooperation The larger number of nodes and rich connections indicate strong scientific collaboration spanning three dimensions: countries, institutions, and authors (Fig. 3 ). The country collaboration network comprises 108 nodes and 1,005 links; dominant nodes include China, the United States, South Korea, Japan, and Germany (Fig. 3 A). The institution collaboration network consists of 685 nodes and 908 links, with node sizes in the order of the Chinese Academy of Sciences, Sichuan University, Shanghai Jiao Tong University, and Zhejiang University (Fig. 3 B). The author collaboration map showcases top authors (Fig. 3 C), namely Gong Jian Ping, Tabata Yasuhiko, Kurokawa Takayuki, and Reis Rui L., with dense interconnections representing extensive collaborations. Notably, clustering effects were observed among the nodes of Gong Jian Ping, Kurokawa Takayuki, and Nakajima Tasuku, forming one prominent cluster, while Tabata Yasuhiko and Mikos Antonios G. clustered separately (Supplementary Table S1). Country-Level Collaboration : The first graph highlights international collaborations, with "PEOPLES R CHINA" and "USA" serving as the primary central nodes, indicating their dominant roles in the global research landscape. Institutional Collaboration : The second graph visualizes connections among leading universities and research institutions (e.g., Peking University , Harvard University , Chinese Academy of Sciences ), reflecting institutional partnerships. Researcher-Level Collaboration : The third graph displays co-authorship or collaborative ties among influential scholars (e.g., Yasuhiko Tabata , Jian Ping Gong , Byang Taek Lee ), emphasizing strong interdisciplinary linkages. 3.2. Variation of the Most Active Topics 3.2.1. Subject Category Burst From 2000 to 2024, 83 out of 93 subject categories associated with hydrogel-bone research experienced citation bursts. Figure 4 shows the top 50 categories ranked by burst strength over the study period. The blue line represents the time interval, while the red segments indicate the duration of each burst, with labeled start and end years. The subject "ENGINEERING, BIOMEDICAL" demonstrated the highest burst strength (59.9) from 2000 to 2011. Over time, the burst categories diversified into a broader array of disciplines, such as "MICROSCOPY" (2003–2010), "CLINICAL NEUROLOGY" (2006–2014), "COMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS" (2009–2015), "MINERALOGY" (2016–2018), "CHEMISTRY, ANALYTICAL" (2019–2022), and "MATHEMATICAL & COMPUTATIONAL BIOLOGY" (2022–2024). These temporal patterns reflect the multidisciplinary nature of the field. Additionally, 20 burst categories emerged in 2024 alone (Table S2), with the top three being "ENERGY & FUELS" (2023–2024), "ENGINEERING, ENVIRONMENTAL" (2023–2024), and "ELECTROCHEMISTRY" (2023–2024). 3.2.2. Keywords Burst The burst patterns of keywords analyzed at a finer level reveal the dynamic research evolution in the field of hydrogels for bone-related conditions between 2000 and 2024. A total of 990 keywords experienced bursts at different time points, with the top 50 keywords ranked by burst strength delineated in Fig. 5 . The keyword "gene expression" recorded the highest burst strength (29.39) from 2004 to 2014, followed by "high mechanical strength" (22.63; 2011–2018) and "fibroblast growth factor" (22.31; 2007–2017). In particular, 20 keywords whose bursts extended into 2024 may signify potential future research hotspots. Notable examples include "antibacterial" (burst strength: 20.31; 2023–2024), "extracellular vesicles" (18.66; 2021–2024), and "fatigue" (17.02; 2022–2024) (Supplementary Table S2). 3.2.3. Reference Burst A total of 2,047 articles experienced citation bursts; Table 3 lists the top 30 most-cited references between 2000 and 2024. Among these, the article titled “ Highly stretchable and tough hydrogels ” exhibited the highest citation burst, lasting from 2013 to 2017. This seminal study argued that hydrogels could function as scaffolds for tissue engineering, drug delivery carriers, actuators in optics and fluid mechanics, and ECM mimetics. However, the mechanical properties of hydrogels often limit their broader applications. For instance, most hydrogels (such as alginate) are not highly stretchable and rupture when stretched merely 1.2 times their original length. Although few synthetic elastic hydrogels can elongate 10–20 times, this capacity decrease significantly in notched samples. Typically, hydrogels are brittle, with fracture energies of approximately 10 J m-2, substantially lower than that of cartilage (1,000 J m-2) or natural rubber (10,000 J m-2). Recent advancements aim to synthesize hydrogels with enhanced mechanical properties, yielding synthetic gels with fracture energies ranging from 100-1,000 J m-2 [ 14 ] . Previous study reported polymer-synthesized hydrogels that form ionic and covalent cross-linked networks [ 15 ] . Despite containing 90% water composition, these gels can stretch over 20 times their initial length and achieve fracture energies of 9,000 J m-2; even notched samples exhibit 17-fold stretchability. Hydrogel toughness is attributed to the synergy between two networks: crack bridging through covalent cross-linking and hysteresis through ionic cross-linking. The covalent cross-linked network retains initial state memory, allowing the recovery from large deformations upon unloading. Internal damage from released ionic cross-links heals upon recompression. These hydrogels serve as versatile model systems for exploring deformation and energy dissipation mechanisms, expanding their potential application range. Another article, “ 3D bioprinting of tissues and organs ,” demonstrated a citation burst from 2016 to 2019. Additive manufacturing, also known as 3D printing, is driving significant innovations across engineering, manufacturing, art, education, and medicine. Recent advances have enabled the printing of biocompatible materials, cells, and supporting components into complex, functional 3D living tissues. In regenerative medicine, 3D bioprinting is being applied to address the demand for tissues and organs suitable for transplantation. Unlike non-biological printing, 3D bioprinting faces unique issues, such as precise selection of materials, cell types, growth and differentiation factors, and technical challenges related to the fragility of living cells and tissue construction. Addressing these complexities requires an interdisciplinary approach involving engineering, biomaterials science, cell biology, physics, and medicine. 3D bioprinting has been successfully exploited to generate and transplant various tissues, including multi-layered skin, bone, vascular grafts, tracheal splints, heart tissue, and cartilage structures [ 16 ] . Other applications encompass the development of high-throughput 3D bioprinted tissue models for research, drug discovery, and toxicology purposes.The article “ Multi-scale multi-mechanism design of tough hydrogels: building dissipation into stretchy networks ” recorded the third-highest citation burst, from 2014 to 2019. Hydrogels are usually brittle as water-swollen polymer networks; however, high toughness is essential for diverse plant/animal tissues and engineering applications. This review summarizes the intrinsic mechanisms of various tough hydrogels developed over the past few decades; hydrogels exhibiting enhanced toughness generally integrate mechanisms that dissipate large amounts of mechanical energy while retaining high elasticity during deformation. This review first constructed a matrix framework combining multiple mechanisms to guide the design of next-generation tough hydrogels. It further emphasized that multiscale (nano-, micro-, meso-, and macro-structures) multi-mechanism implementation is a particularly promising design strategy for hydrogels exhibiting toughness and elasticity. From 2024 onwards, 332 articles experienced citation bursts, with the top 20 articles listed by strength index (Table 4 ). These include 13 review articles and 7 original articles, all of which entered the citation burst period immediately upon or within a year after publication. Reviews help establish strategic guidance in hydrogel-based orthopedic research, while original articles provide valuable insights into practical translation. This underscores the need for researchers to closely follow the emerging literature in the field. Table 4 The references with citation bursts from 2019 to 2024 Begin End Strength Year Type Title 2020 2024 37.93 2018 Review Bioactive hydrogels for bone regeneration 2021 2024 35.1 2020 Review Materials design for bone-tissue engineering 2023 2024 34.11 2021 Article Fracture, fatigue, and friction of polymers in which entanglements greatly outnumber cross-links 2022 2024 29.82 2021 Article Strong tough hydrogels via the synergy of freeze-casting and salting out 2023 2024 27.39 2022 Article Fabrication of physical and chemical crosslinked hydrogels for bone tissue engineering 2022 2024 27.15 2021 Review Recent Advances in Design of Functional Biocompatible Hydrogels for Bone Tissue Engineering 2022 2024 24.99 2021 Review Advanced hydrogels for the repair of cartilage defects and regeneration 2022 2024 22.89 2021 Article Tough hydrogels with rapid self-reinforcement 2021 2024 22.44 2018 Review Bone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives 2022 2024 22.33 2021 Review Soft Materials by Design: Unconventional Polymer Networks Give Extreme Properties 2023 2024 22.27 2021 Review Current hydrogel advances in physicochemical and biological response-driven biomedical application diversity 2022 2024 20.63 2020 Review Mechanisms of bone development and repair 2022 2024 20.63 2020 Review Recent trends in the application of widely used natural and synthetic polymer nanocomposites in bone tissue regeneration 2020 2024 19.91 2018 Review Bioinks for 3D bioprinting: an overview 2019 2024 19.88 2018 Review 3D bioactive composite scaffolds for bone tissue engineering 2022 2024 19.62 2019 Review Surgical and tissue engineering strategies for articular cartilage and meniscus repair 2020 2024 19.1 2018 Review Hydrogel ionotronics 2023 2024 18.69 2022 Article Osteoimmunity-Regulating Biomimetically Hierarchical Scaffold for Augmented Bone Regeneration 2022 2024 18.64 2021 Article Injectable Mussel-Inspired highly adhesive hydrogel with exosomes for endogenous cell recruitment and cartilage defect regeneration 2023 2024 18.29 2022 Article A Logic-Based Diagnostic and Therapeutic Hydrogel with Multistimuli Responsiveness to Orchestrate Diabetic Bone Regeneration 3.3. Emerging Trends and New Developments 3.3.1. Temporal Variation of Keyword Clusters Keywords are closely related, and certain keywords can form different clusters based on their affinity. Identifying these clusters can intuitively outline the subfields of hotspots in hydrogel research for bone-related applications. The timeline from 2000 to 2024 was segmented into four stages of 6 years each, with keyword cluster snapshots across these intervals depicted in Fig. 6 . First Stage (2000–2006): Analysis of 299 articles resulted in 7 clusters, including #0 biodegradable polymers, #1 gels, and #2 mesenchymal stem cells (MSCs) (Fig. 6 A). Second Stage (2007–2012): From 1,176 articles analyzed, 9 clusters emerged, such as #0 MSCs, #1 fracture, and #2 bone (Fig. 6 B). Third Stage (2013–2018): This period recorded 3,120 articles, yielding 7 clusters, encompassing #0 hydroxyapatite, #1 MSCs, and #2 double network hydrogels (Fig. 6 C). Fourth Stage (2019–2024): 7,300 articles were analyzed, identifying 8 clusters, including #0 tough, #1 extracellular vesicles, and #2 3D bioprinting (Fig. 6 D). Compared to the preceding 15 years, there is continuous relevance of classical research topics such as hydrogels; however, emerging research clusters—0# tough hydrogels, 1# extracellular vesicles, 2# 3D bioprinting, 3# bone repair, 4# wound healing, 5# bone tissue engineering, 6# cartilage regeneration, and 7# rheumatoid arthritis—have garnered increasing attention from scholars. A deeper literature analysis within these emerging clusters reveals their focus on exploring hydrogel-related orthopedic research hotspots. The 0# tough hydrogels cluster consists of 176 articles addressing their mechanical strength. The 1# extracellular vesicles cluster comprises 146 articles refining studies on the role of extracellular vesicles in bone-related applications. The 2# 3D bioprinting and 5# bone tissue engineering clusters include 129 and 64 articles, respectively, focusing on bone tissue engineering. The 3# bone repair (76 articles) and 6# cartilage regeneration (61 articles) clusters investigate hydrogel applications in bone and cartilage regeneration. The 4# wound healing cluster (66 articles) examines hydrogel use in wound repair, while the 7# rheumatoid arthritis cluster encloses 57 articles on hydrogel-mediated drug delivery for disease treatment. Table S3 (Supplementary Material) represents detailed data for the fourth clustering stage (2019–2024), where "representative keywords within clusters" help identify core research areas in translational applications of hydrogels in orthopedics. 3.3.2. Keyword Alluvial Flow Visualization As shown in Fig. 7 , related keywords form distinct research modules that either diverge or converge over time through recombination to generate new modules. Across the 25 years, certain keywords exhibit enduring relevance, while others emerge as new trends or fade from prominence. Table S4 (Supplementary Material) enlists the top five keyword modules with the highest annual flow. Notably, Module 1 in 2024 (marked in red) emerges as the most persistent module, forming the largest research branch within this flow. Additionally, we visualized the top six modules from 2024 (Fig. 8 ). Module 1, "MSCs," includes 37 keywords (e.g., scaffolds, tissue engineering, and drug delivery) (Fig. 8 A). Module 2, "fracture," contains 23 keywords (e.g., deformation, tough hydrogels, and double network hydrogels) (Fig. 8 B). Module 3, "endothelial cells," encompasses 19 keywords (e.g., blood vessels, coculture, and biomaterial scaffolds) (Fig. 9 C). Module 4, "demineralized bone matrix," lists 17 keywords (e.g., health, periodontal regeneration, and biphasic calcium phosphate) (Fig. 8 D). Module 5, "articular cartilage," comprises 15 keywords (e.g., osteochondral defects and knee osteoarthritis) (Fig. 8 E). Module 6, "DNA," consists of 15 keywords (e.g., calcium carbonate and osteoclastogenesis) (Fig. 8 F). Collectively, these modules likely represent emerging trends for hydrogel-based applications for orthopedics over the coming five years and beyond. A: Mesenchymal stem cells and associated factors. B: Fracture-related cellular and molecular markers. C: Endothelial cells and their functional attributes. D: Polymer networks and mechanical properties (e.g., toughness, hysteresis). E: Articular cartilage and delivery systems. F: DNA mechanics and osteoclastogenesis regulators (e.g., alkaline phosphatase, dexamethasone). 3.3.3. Timeline Visualization of References A timeline visualization based on citation trajectory identifies emerging, classical, and outdated research themes. The timeline map of hydrogel-related studies in orthopedics comprises 17 clusters, ranked by size (Fig. 9 A). Clusters 1 (3D printing), 5 (self-healing), 6 (bone morphogenetic protein), 8 (chondrogenesis), 10 (calcium phosphate cement), 14 (cell viability), and 16 (stiffness) are considered classical topics—not the latest but intricately interconnected with other clusters. Clusters 3 (photopolymerization), 11 (polyion complexation), 12 (biodegradable starch cements), 13 (mannitol porogen), and 15 (tantalum) are indicated as outdated—showing minimal connections and no subsequent development. Clusters 0 (bone regeneration), 2 (bioprinting), 4 (osteoarthritis), 7 (tissue engineering), and 9 (mechanotransduction) are identified as emerging topics—remaining active since their inception and signaling future research directions; Table 5 elaborates on these clusters. Figure 9 B highlights key classical references (large nodes with red circles) that have significantly driven respective subfield development (Fig. 9 B). For example, Koons GL (2020); Materials design for bone-tissue engineering (Cluster 0, co-citation frequency: 186) emphasizes biomimetic material design and scalable fabrication, including 3D printing, for bone regeneration. Kang HW (2016); A 3D bioprinting system to produce human-scale tissue constructs (Cluster 2, co-citation frequency: 135) introduces the Integrated Tissue-Organ Printer (ITOP) for vascularized constructs. Wei W (2021); Advanced hydrogels for cartilage repair (Cluster 4, co-citation frequency: 108) reviews hydrogel innovations in cartilage regeneration targeting osteoarthritis. Huu MT (2021); Strong tough hydrogels via freeze-casting and salting out (Cluster 7) proposes a novel strategy for tendon-like hydrogel synthesis. Turnbull G (2018); 3D bioactive composite scaffolds for bone tissue engineering (Cluster 9) discusses composite materials for bridging bone regeneration challenges. Citation trends for these five articles (Fig. 9 C) suggest their continued relevance in future research. Table 5 Summary of emerging topics ClusterID Size Silhouette Average Year Label (LLR) Representative keywords 0 380 0.802 2019 bone regeneration bone regeneration; hydroxyapatite nanofiber; biomimetic composite hydrogel; adaptable hydrogel; hydroxyapatite nanorods | tissue engineering; growth factors; cells therapies; glioma inhibition; carbon nanotube 2 291 0.943 2016 bioprinting tissue engineering; growth factors; cells therapies; in-situ bioprinting; bioactive ceramics | 3d bioprinting; silk fibroin; 4d bioprinting; cell viability; situ bioprinting 4 152 0.935 2020 osteoarthritis tissue engineering; msk disorders; targeting therapy; ball bearings; cartilage injuries | bone regeneration; bone tissue engineering; schwann cells; bone microenvironment; targeting therapy 7 123 0.934 2018 tissue engineering mechanical properties; double-network hydrogels; soft tissue repair; host-guest interaction; fracture toughness | strain sensor; double-network hydrogel; alpha-thioctic acid; tough adhesive; natural globulin 9 45 0.989 2016 mechanotransduction tissue engineering; extracellular matrix; tumor microenvironment; three-dimensional tumor models; vitro models | bone regeneration; biphasic calcium phosphate; stem cell differentiation; elastomer nanohybrid; stem cell manipulation Discussion The present bibliometric analysis elucidates the dynamic evolution of hydrogel research in orthopedic diseases over the past two decades, revealing a paradigm shift from passive structural scaffolds to multifunctional, stimuli-responsive platforms. By accessing data from 8,685 publications, we identified critical trends, collaborative networks, and emerging frontiers that collectively shape the trajectory of hydrogel-based orthopedic therapies. This review contextualizes these findings within the broader scientific landscape, highlights technological advancements, addresses translational challenges, and outlines strategic directions for future research in the field. 1.Thematic Evolution: From Structural Support to Multifunctional Platforms 1.1 Historical Trajectory and Key Milestones Early research in the 2000s predominantly focused on establishing hydrogels as viable structural substitutes for bone repair. Dominant clusters in this era, such as #0 "biodegradable polymers" and #2 "MSCs" (Fig. 6 A), emphasized hydrogel degradation rates and osteogenic compatibility. A pioneering study by Chen et al introduced double-network hydrogels to address the intrinsic brittleness of conventional materials by combining ionic and covalent crosslinking, achieving fracture energies comparable to natural cartilage [ 17 ] . This innovation enabled mechanoactive hydrogels to withstand mechanical loads in fractures and osteochondral defects. Nonetheless, limitations persisted in replicating bone’s hierarchical architecture and integrating bioactive cues, restricting their clinical adoption. Another noteworthy contribution during this phase included a review by Kaveh Roshanbinfar et al. (2025), which laid the foundation for 3D bioprinting by highlighting hydrogel compatibility with additive manufacturing technologies [ 18 ] . Meanwhile, keyword bursts such as "gene expression" (2004–2014) signaled early attempts at modulating cellular responses via hydrogel-based gene delivery. The mid-2010s witnessed a surge in publications (Fig. 1 A), driven by functionalization strategies to enhance hydrogel bioactivity and adaptability. Burst keywords such as "high mechanical strength" (2011–2018) and "fibroblast growth factor" (2007–2017) underscored concerted efforts to improve mechanical resilience and integrate growth factors for targeted tissue regeneration. Liu et al. (2020) demonstrated that hydrogel stiffness directly regulates MSC differentiation via mechanotransduction, effectively linking material properties with cellular behavior [ 19 ] . Concurrently, Sun et al. (2022) reported that 3D bioprinting enabled the precise fabrication of vascularized bone scaffolds, marking a transition from static implants to spatially organized bioactive matrices [ 20 ] . During this period, "double-network hydrogels" emerged as a prominent cluster (#2 in 2013–2018, Fig. 6 C), with studies further exploring multi-mechanism energy dissipation. These developments positioned hydrogels as dynamic platforms capable of mimicking native tissue mechanics while delivering therapeutic agents [ 21 ] . The post-2018 period entered a phase of exponential growth, characterized by the emergence of clusters such as #0 "tough hydrogels," #1 "extracellular vesicles," and #2 "3D bioprinting" (Fig. 6 D). Citation bursts for "antibacterial" (2023–2024) and "extracellular vesicles" (2021–2024) indicated a paradigm shift toward multifunctionality. For example, Li et al. designed a patterned alginate hydrogel with CuS nanoparticles (NPs), achieving an evaporation rate of 2.42 kg m⁻² h⁻¹ in brine with intrinsic antibacterial activity for solar desalination [ 6 ] . This study influenced 129 articles in cluster #2 "3D bioprinting," accelerating interest in patient-specific implants. Furthermore, Nedorubova et al. demonstrated that BMP2 polyplex-loaded PLA/PRP fibrin hydrogels outperformed chitosan-based matrices in osteoinduction, achieving effective bone regeneration in rat calvarial defect models [ 22 ] . The burst detection maps (Figs. 4 – 5 ) reveal how cross-disciplinary synergy has fueled advancements. Early dominance of bursts in "ENGINEERING, BIOMEDICAL" (2000–2011) has transitioned toward "COMPUTATIONAL BIOLOGY" (2022–2024), reflecting the emergence of AI-assisted hydrogel design. Aghajanpour et al. (2025) documented that machine learning, particularly artificial neural networks, outperforms traditional methods in predicting drug release from polymeric delivery systems, with notable success in 3D-printed formulations [ 23 ] . Moser et al. identified polyurethane (54 MPa) as the optimal material for meniscus implants via finite element analysis (FEA), closely replicating natural biomechanics; conversely, silk fibroin hydrogels showed instability after two weeks [ 24 ] . Emerging clusters such as #4 "wound healing" and #7 "rheumatoid arthritis" (Fig. 6 D) suggest expanding scope of hydrogels beyond orthopedics. The integration of stimuli-responsive hydrogels (e.g., pH- or temperature-sensitive) and smart drug delivery systems (e.g., exosome-loaded matrices) will likely shape the next research frontier in this field [ 25 ] . 1.2 Interdisciplinary Synergy and Technological Convergence The co-authorship networks (Fig. 3 A–C) highlight robust collaborations among countries, institutions, and authors. Notably, China and the United States dominate the country collaboration network (108 nodes, 1,005 links). Institutions (such as the Chinese Academy of Sciences and Harvard University) serve as key hubs bridging gaps between material synthesis and translational medicine. Prominent author clusters led by Gong Jian Ping (materials science) and Tabata Yasuhiko (drug delivery) illustrate how expertise in polymer chemistry, biomechanics, and regenerative medicine synergize to address complex orthopedic challenges. Burst detection analysis of subject categories (Fig. 4 ) further underscores this interdisciplinary shift. Initial dominance of "ENGINEERING, BIOMEDICAL" (2000–2011) gradually shifted toward "COMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS" (2009–2015) and "MATHEMATICAL & COMPUTATIONAL BIOLOGY" (2022–2024), indicating the increasing adoption of computational tools in hydrogel design. Yang et al. developed a linagliptin-loaded dynamic hydrogel (AG-CD@LINA) capable of modulating macrophage polarization via TLR3-NF-κB signaling, thereby promoting osteogenesis and angiogenesis in diabetic bone defects [ 26 ] . Besides, Yu et al. introduced 3D bioprinted GelMA scaffolds embedded with luteolin-loaded ZIF-8 NPs that synergistically enhance osteogenesis and immune regulation for bone regeneration [ 27 ] . The burst keyword "extracellular vesicles" (2021–2024, strength: 18.66) reflects the integration of cell-free regenerative strategies. Li et al. reported an injectable nanofiber-hydrogel composite (NHC) for the delivery of MSC-derived extracellular vesicles, significantly improving healing in Crohn's perianal fistulas by promoting macrophage polarization and angiogenesis. This approach bridges immunology, nanotechnology, and hydrogel design, marking a paradigm shift from cell-based to EV-mediated therapies [ 28 ] . Orthopedic disorders such as osteomyelitis and osteoporotic fractures require solutions that combine structural reinforcement, infection control, and tissue regeneration. This demand has fostered interdisciplinary collaborations among microbiologists (e.g., antibacterial hydrogel design), material scientists (e.g., tough hydrogels), and clinicians (e.g., in vivo validation). Liu et al. developed a piezoelectric hydrogel (Hyd6) that, when combined with ultrasound stimulation, facilitates cartilage regeneration by recruiting stem cells and activating Ca2+/CaM/CaN signaling pathways [ 29 ] . Additionally, Niu et al. engineered a ZIF-8-modified hydrogel (SHPP-ZB) capable of sequentially releasing PDGF-BB and BMP-2 to stimulate vascularized bone regeneration through coordinated MAPK/Wnt signaling [ 30 ] . 2. Translational Challenges: Bridging the Lab-to-Clinic Gap 2.1 Standardization and Regulatory Hurdles Hydrogel research is impeded by variability in synthesis methods, mechanical testing protocols, and in vitro/in vivo evaluation criteria. For instance, cluster #0 "tough hydrogels" (2019–2024, 176 articles) encompasses diverse approaches to achieving mechanical resilience—ranging from double-network architectures to nanocomposite reinforcement. However, inconsistencies in reporting parameters, such as fracture energy (varying widely from 100 to 9,000 J m⁻²), complicate direct cross-study comparisons. These challenges largely stem from the lack of standardized evaluation protocols for material performance, discrepancies in regulatory policies across countries, and insufficient guidance on clinical trial design. Wu et al. (2018) emphasized that the absence of unified standards for assessing biocompatibility and mechanical properties undermines the preclinical development of hydrogel-based products [ 31 ] . Moreover, divergent regulatory frameworks across countries further exacerbate the assessment and approval timelines of these products. The United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have established distinct regulatory pathways that reflect their individual legal and safety requirements. Consequently, hydrogel manufacturers must navigate a complex landscape of requirements, increasing compliance burdens with delays in market approval [ 32 , 33 ] . Multicomponent hydrogels have garnered attention owing to their excellent biocompatibility and versatile functionalization capabilities, rendering them suitable for various clinical applications, including bone repair and tissue regeneration [ 34 ] . Nevertheless, the lack of standardized protocols and well-defined regulatory guidelines significantly hampers the clinical transition of injectable hydrogels being extensively explored for tissue regeneration [ 35 , 36 ] . Similarly, 3D bioprinting (cluster #2, 129 articles) faces challenges related to bioink viscosity and printing resolution. One primary obstacle is the optimization of bioink viscosity to ensure both printability and cellular viability. Studies have demonstrated that bioinks exhibiting rapid recovery characteristics post-extrusion can improve shape fidelity during 3D printing processes [ 37 ] . Specific formulations that balance high viscosity for structural integrity while allowing for workable rheological properties are crucial. For instance, the inclusion of nanomaterials such as nanocellulose or Laponite in the bioink composition has been documented to enhance mechanical strength while preserving the desired shear-thinning properties [ 38 , 39 ] . Additionally, the size of printing nozzles significantly impacts the resolution of bioink deposition. Smaller nozzle diameters facilitate higher print resolution but may require corresponding adjustments in bioink viscosity to prevent clogging and ensure smooth flow [ 40 ] . These complex requirements underline the need for bioink formulations that not only support cell viability but also tailor to the specific operational constraints of bioprinting systems [ 41 ] . 2.2 Scalability and Manufacturing Challenges Although 3D bioprinting holds promise for producing patient-specific implants, scalability remains a significant bottleneck. Existing bioprinting technologies struggle to achieve the high resolution (< 50 µm) required for trabecular bone structures. Furthermore, post-printing cell viability often declines below 70%, largely due to shear stress during extrusion. Recent advances in *sacrificial bioinks* and *light-based printing* (e.g., digital light processing; DLP) likely present avenues to address these issues; however, cost-effective production methods are urgently needed for low-resource settings. Bioinks incorporating additives such as methylcellulose for spatially controlled gene delivery have demonstrated improved printability and cell viability [ 42 , 43 ] . DLP-based methods facilitate enhanced printing precision and speed. They employ light to polymerize bioinks with high resolution, thereby augmenting the capability for complex tissue structures [ 44 , 45 ] . These technologies may offer superior control over the printed microstructure while potentially increasing cell viability through reduced mechanical strain during the process [ 46 ] . Current bioprinting systems are often prohibitively expensive, which limits accessibility and widespread adoption, especially in underserved regions. Research efforts focusing on the development of more affordable and versatile bioprinting technologies could bridge this gap. Ongoing studies indicate that automation in bioprinting may enable rapid scaling of production without compromising the quality and fidelity of printed constructs [ 47 , 48 ] . 3. Emerging Frontiers: From Personalized Medicine to Sustainable Solutions 3.1 Smart Hydrogels with Diagnostic Capabilities Recent innovations emphasize the potential of MXene-based hydrogels as intelligent materials for wound healing. Notably, these hydrogels exhibit excellent conductivity and create a moist microenvironment that accelerates the healing process [ 49 ] . The integration of MXenes enables these materials to function effectively as epidermal sensors, facilitating real-time monitoring of wound conditions and thus transforming passive hydrogel systems into active, responsive platforms [ 50 ] . Moreover, the fabrication of multifunctional hydrogels, such as those utilizing agarose sacrificial templates, demonstrates the versatility of these materials. By incorporating pore channels, these hydrogels support controlled drug release and establish responsive therapeutic microenvironments [ 51 ] . Self-healing features represent another significant frontier in the field. Hydrogels with an intrinsic ability to autonomously repair upon damage provide unique advantages in medical applications, particularly for chronic wound management. Injectable formulations of these intelligent hydrogels for direct applications to wounds allow for rapid injury response, aiding healing while addressing challenges concerning accessibility and complexity of larger wound areas [ 52 ] . Furthermore, the integration of smart hydrogels into wearable medical devices has gained traction. These devices are capable of responding to physiological stimuli, offering a non-invasive approach for monitoring diseases such as diabetes or neuromuscular conditions [ 53 , 54 ] . The coupling of biosensing abilities with therapeutic functionalities positions these smart hydrogels at the forefront of personalized medicine, enabling tailored treatment strategies. 3.2 Combatting Oxidative Stress and Microbial Resistance Emerging research demonstrates that hydrogels functionalized with materials such as graphene and cerium oxide NPs (CNPs) effectively combat oxidative stress. For example, Zhou et al. reported that a ROS-scavenging graphene-based hydrogel significantly enhanced vascularized bone regeneration by eliminating ROS, thus promoting an optimal extracellular environment for bone healing [ 55 ] . Likewise, Li et al. explored the use of ursodeoxycholic acid NPs, exerting potent antioxidant and anti-inflammatory activities in MSCs to improve osteogenic differentiation [ 56 ] . In parallel, the incorporation of silver NPs into hydrogel scaffolds serves as another viable antimicrobial therapy. The well-documented effectiveness of silver against a range of bacteria, coupled with its controlled release behavior within hydrogel matrices, facilitates localized infection management in open fractures [ 57 ] . However, balancing antimicrobial efficacy with cytocompatibility remains a critical challenge, as elevated silver concentrations can adversely impair MSC proliferation [ 58 ] . The integration of antioxidant and antibacterial properties in hydrogels presents a dual approach to mitigating oxidative stress and microbial resistance effectively. For instance, Zheng et al. developed a multifunctional polyphenol-containing hydrogel that reduced oxidative stress while concomitantly enhancing cellular responses favorable to bone regeneration [ 7 ] . Furthermore, the combination of polyphenols and CNPs within hydrogels demonstrate synergistic effects, offering simultaneous protection against oxidative stress and microbial invasion [ 59 ] . Innovative hydrogel designs capable of delivering these therapeutics in a site-specific, controlled manner are crucial for localized treatment strategies. Incorporating self-healing functionality and biological activity in these hydrogels could significantly improve the clinical management of bone degeneration and associated infections [ 60 ] . 4. Future Directions: Strategic Priorities for Innovation 4.1 Multi-Omics Integration for Personalized Implants The convergence of genomics, proteomics, and advanced hydrogel designs could open new avenues for *patient-specific therapies*. Artificial intelligence (AI)-driven platforms are poised to be pivotal players in optimizing the design of personalized therapies. AI-assisted examination of bone density scans and other relevant omics data can help predict optimal scaffold porosity and mechanical properties compatible with individual patients. Recent advancements in computational methodologies for multi-omics analysis suggest that AI integration can unravel intricate interactions within metabolic pathways, thereby refining personalized medical strategies [ 61 ] . Additionally, the increasing incorporation of genomic profiling into clinical trials emphasizes the potential of precision medicine to improve patient outcomes significantly [ 62 ] . These innovations align with the recent keyword bursts in *computational biology* (2022–2024) and *precision medicine*. 4.2 Hybrid Systems for Complex Tissue Regeneration To create a hierarchical tissue scaffold, combining biodegradable hydrogels with electrospun fibers can reproduce the intricate architecture of native ECMs [ 63 ] . Electrospun fiber mats can markedly enhance the mechanical integrity of hydrogels, which are otherwise susceptible to mechanical failure under stress [ 64 ] . These composite materials merge the advantageous properties of both hydrogels (hydrophilicity and biocompatibility) and electrospun fibers (tensile strength and structural mimicry of ECM), creating scaffolds conducive to osteochondral tissue engineering [ 65 , 66 ] . Development of vascularization strategies is crucial for scaling these hybrid systems for clinical applications. One innovative solution is the fabrication of microfluidic-channeled hydrogels, designed to mimic the Haversian canal networks of natural bone. These microchannels facilitate nutrient diffusion and cellular migration, essential for tissue integration and vascularization during implantation [ 67 ] . Embedding microchannels within hydrogel-based scaffolds can not only enhance cell infiltration and nutrient supply but also address key challenges in large-scale tissue engineering [ 68 ] . 5. Limitations and Methodological Reflections Despite offering a comprehensive overview of hydrogel research in orthopedic applications, this bibliometric analysis is subject to several limitations that warrant consideration. First, the exclusive reliance on WoSCC introduces language bias, as non-English publications (e.g., Chinese or Japanese studies) are underrepresented. Second, keyword-based clustering may overlook nuanced thematic connections, such as specialized hydrogel applications in rare bone cancers. Future studies would benefit from incorporating semantic analysis tools and multi-lingual databases to enhance inclusivity. Moreover, the rapid evolution in hydrogel technology—evidenced by 332 citation bursts in 2024—necessitates continuous bibliometric updates to capture emerging trends effectively. Collaborative platforms such as *OpenHydrogelDB*, a community-driven repository for hydrogel properties, hold potential to standardize data sharing and accelerate innovation. Conclusion This discussion synthesizes the transformative potential of hydrogels in orthopedic therapy while concurrently acknowledging the multifaceted challenges impeding their clinical translation. By leveraging interdisciplinary collaboration, advancing bio-fabrication technologies, and prioritizing sustainable design, the next decade holds promise for hydrogel-based solutions. These innovations could revolutionize areas, including osteoarthritis management, critical-sized defect repair, and personalized regenerative medicine. Future progress will depend on fostering partnerships across academia, industry, and clinical sectors to overcome translational barriers and accelerate the deployment of hydrogel-based platforms in orthopedic care. Declarations Data Availability Statement The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Author Contributions Long Xie: Writing – original draft, Visualization, Methodology, Investigation, Formal analysis, Data curation. Yuqin Peng: Writing – review & editing, Writing – original draft, Visualization. Xiang Shen: Validation. Investigation. Validation. Methodology. Supervision, Resources. Funding Statement Not applicable Ethics approval and consent to participate Not applicable. Competing interests The authors declare no competing interests. References Xiao PL, Cui AY, Hsu CJ et al (2022) Global, regional prevalence, and risk factors of osteoporosis according to the World Health Organization diagnostic criteria: a systematic review and meta-analysis. Osteoporos Int 33(10):2137–2153 Diseases GBD, Injuries C (2024) Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 403(10440):2133–2161 Sasaki M, Karikkineth BC, Nagamine K et al (2014) Highly conductive stretchable and biocompatible electrode-hydrogel hybrids for advanced tissue engineering. Adv Healthc Mater 3(11):1919–1927 Lin Y, Wu H, Wang J et al (2025) Nicotinamide Adenine Dinucleotide-Loaded Lubricated Hydrogel Microspheres with a Three-Pronged Approach Alleviate Age-Related Osteoarthritis. ACS Nano 19(18):17606–17626 Shan J, Cheng L, Li X et al (2025) End-tail soaking strategy toward robust and biomimetic sandwich-layered hydrogels for full-thickness bone regeneration. Bioact Mater 49:486–501 Li Y, Chen B, Yao D et al (2025) Enhancing salt resistance and all-day efficient solar interfacial evaporation of antibacterial sodium alginate-based porous hydrogels via surface patterning. Carbohydr Polym 359:123588 Zheng J, He J, Wu J et al (2025) Polyphenol-Mediated Electroactive Hydrogel with Armored Exosomes Delivery for Bone Regeneration. ACS Nano 19(18):17796–17812 Gao Y, Liu Y, Hao H (2025) A 10-year knowledge mapping of T cells in rheumatoid arthritis: A bibliometric analysis. Hum Vaccin Immunother 21(1):2450855 Sun W, Wu W, Dong X et al (2024) Frontier and hot topics in the application of hydrogel in the biomedical field: a bibliometric analysis based on CiteSpace. J Biol Eng 18(1):40 Cao S, Wei Y, Yao Z et al (2024) A bibliometric and visualized analysis of nanoparticles in musculoskeletal diseases (from 2013 to 2023). Comput Biol Med 169:107867 Arruda H, Silva ER, Lessa M et al (2022) VOSviewer and Bibliometrix. J Med Libr Assoc 110(3):392–395 Liao G, Wu J, Peng X et al (2020) Visualized analysis of trends and hotspots in global oral microbiome research: A bibliometric study. MedComm 1(3):351 – 61. 2020 Castano S, Ferrara A, Montanelli S (2017) Exploratory analysis of textual data streams. Future Generation Comput Syst 68:391–406 Qin L, Zhu Y, Zhang H et al (2024) Lignin-modified cellulose nanofibers hydrogel under adjustable binary solvent systems with excellent adhesion, self-healing and anti-freeze properties. Int J Biol Macromol 279(Pt 2):135559 Zhan H, Jiang S, Jonker AM et al (2020) Self-recovering dual cross-linked hydrogels based on bioorthogonal click chemistry and ionic interactions. J Mater Chem B 8(27):5912–5920 Lu J, Gao Y, Cao C et al (2025) 3D bioprinted scaffolds for osteochondral regeneration: advancements and applications. Mater Today Bio 32:101834 Chen J, Huang J, Hu Y (2021) 3D Printing of Biocompatible Shape-Memory Double Network Hydrogels. ACS Appl Mater Interfaces 13(11):12726–12734 Roshanbinfar K, Evans AD, Samanta S et al (2025) Enhancing biofabrication: Shrink-resistant collagen-hyaluronan composite hydrogel for tissue engineering and 3D bioprinting applications. Biomaterials 318:123174 Liu Y, Li Z, Li J et al (2020) Stiffness-mediated mesenchymal stem cell fate decision in 3D-bioprinted hydrogels. Burns Trauma 8:tkaa029 Sun X, Jiao X, Yang X et al (2022) 3D bioprinting of osteon-mimetic scaffolds with hierarchical microchannels for vascularized bone tissue regeneration. Biofabrication 14(3) Ma C, Wang J, Li Q et al (2025) Injectable oxidized high-amylose starch hydrogel scaffold for macrophage-mediated glioblastoma therapy. Biomaterials 318:123128 Nedorubova IA, Bukharova TB, Mokrousova VO et al (2022) Comparative Efficiency of Gene-Activated Matrices Based on Chitosan Hydrogel and PRP Impregnated with BMP2 Polyplexes for Bone Regeneration. Int J Mol Sci 23(23) Aghajanpour S, Amiriara H, Esfandyari-Manesh M et al (2025) Utilizing machine learning for predicting drug release from polymeric drug delivery systems. Comput Biol Med 188:109756 Moser AC, Fritz J, Kesselring A et al (2025) Biomechanical testing of virtual meniscus implants made from a bi-phasic silk fibroin-based hydrogel and polyurethane via finite element analysis. J Mech Behav Biomed Mater 162:106830 Ghasemi S, Najafi M, Doroudian M et al (2025) Temperature- and pH-Responsive Poly(NIPAM-co-HEMA-co-AAm) Nanogel as a Smart Vehicle for Doxorubicin Delivery; Combating Colorectal Cancer. Gels 11(4) Yang P, Chen X, Qin Y et al (2025) Regulation of osteoimmune microenvironment via functional dynamic hydrogel for diabetic bone regeneration. Biomaterials 320:123273 Yu SY, Wu T, Xu KH et al (2025) 3D bioprinted biomimetic MOF-functionalized hydrogel scaffolds for bone regeneration: Synergistic osteogenesis and osteoimmunomodulation. Mater Today Bio 32:101740 Li L, Yao Z, Salimian KJ et al (2025) Extracellular Vesicles Delivered by a Nanofiber-Hydrogel Composite Enhance Healing In Vivo in a Model of Crohn's Disease Perianal Fistula. Adv Healthc Mater 14(7):e2402292 Liu YB, Liu X, Li XF et al (2025) Multifunctional piezoelectric hydrogels under ultrasound stimulation boost chondrogenesis by recruiting autologous stem cells and activating the Ca(2+)/CaM/CaN signaling pathway. Bioact Mater 50:344–363 Niu X, Xiao S, Huang R et al (2024) ZIF-8-modified hydrogel sequentially delivers angiogenic and osteogenic growth factors to accelerate vascularized bone regeneration. J Control Release 374:154–170 Wu D, Xu X (2018) Exploring cutting-edge hydrogel technologies and their biomedical applications. Bioact Mater 3(4):446–447 Cruz Rivera S, Torlinska B, Marston E et al (2021) Advancing UK Regulatory Science Strategy in the Context of Global Regulation: a Stakeholder Survey. Ther Innov Regul Sci 55(4):646–655 Ovrebo O, Perale G, Wojciechowski JP et al (2022) Design and clinical application of injectable hydrogels for musculoskeletal therapy. Bioeng Transl Med 7(2):e10295 Huang Y, Yin B, Wong SHD (2023) Multicomponent Hydrogels in Clinical and Pharmaceutical Applications.449–501 Mandal A, Clegg JR, Anselmo AC et al (2020) Hydrogels in the clinic. Bioeng Transl Med 5(2):e10158 Zhang Y, Li Z, Guan J et al (2021) Hydrogel: A potential therapeutic material for bone tissue engineering. AIP Adv. 11(1) Arslan H, Davuluri A, Nguyen HH et al (2024) 3D Bioprinting Using Universal Fugitive Network Bioinks. ACS Appl Bio Mater 7(10):7040–7050 Golebiowska AA, Tan M, Ma AW et al (2025) Decellularized cartilage tissue bioink formulation for osteochondral graft development. Biomed Mater 20(2):025002 Gu Y, Schwarz B, Forget A et al (2020) Advanced Bioink for 3D Bioprinting of Complex Free-Standing Structures with High Stiffness. Bioeng (Basel) 7(4):141 Jeon O, Park H, Lee MS et al (2025) In situ cell-only bioprinting of patterned prevascular tissue into bioprinted high-density stem cell-laden microgel bioinks for vascularized bone tissue regeneration. bioRxiv Kim J, Kong JS, Kim H et al (2021) Maturation and Protection Effect of Retinal Tissue-Derived Bioink for 3D Cell Printing Technology. Pharmaceutics 13(7):934 Gonzalez-Fernandez T, Rathan S, Hobbs C et al (2019) Pore-forming bioinks to enable spatio-temporally defined gene delivery in bioprinted tissues. J Control Release 301:13–27 Aydin L, Kucuk S, Kenar H (2020) A universal self-eroding sacrificial bioink that enables bioprinting at room temperature. Polym Adv Technol 31(7):1634–1647 Light-based vat-polymerization bioprinting (2023) Nat Reviews Methods Primers. 3(1) Tao J, Zhu S, Zhou N et al (2022) Nanoparticle-Stabilized Emulsion Bioink for Digital Light Processing Based 3D Bioprinting of Porous Tissue Constructs. Adv Healthc Mater 11(12):e2102810 Huh J, Moon YW, Park J et al (2021) Combinations of photoinitiator and UV absorber for cell-based digital light processing (DLP) bioprinting. Biofabrication 13(3):034103 Bhusal A, Dogan E, Nieto D et al (2022) 3D Bioprinted Hydrogel Microfluidic Devices for Parallel Drug Screening. ACS Appl Bio Mater 5(9):4480–4492 Bhusal A, Dogan E, Nguyen HA et al (2021) Multi-material digital light processing bioprinting of hydrogel-based microfluidic chips. Biofabrication 14(1):014103 Li M, Zhang Y, Lian L et al (2022) Flexible Accelerated-Wound‐Healing Antibacterial MXene‐Based Epidermic Sensor for Intelligent Wearable Human‐Machine Interaction. Adv Funct Mater. 32(47) Wang W, Zhou H, Xu Z et al (2024) Flexible Conformally Bioadhesive MXene Hydrogel Electronics for Machine Learning-Facilitated Human-Interactive Sensing. Adv Mater 36(31):e2401035 Mao J, Yu QJ, Wang S (2021) Preparation of multifunctional hydrogels with pore channels using agarose sacrificial templates and its applications. Polym Adv Technol 32(4):1752–1762 Huang W, Wang Y, Huang Z et al (2018) On-Demand Dissolvable Self-Healing Hydrogel Based on Carboxymethyl Chitosan and Cellulose Nanocrystal for Deep Partial Thickness Burn Wound Healing. ACS Appl Mater Interfaces 10(48):41076–41088 Fang Y, Han Y, Yang L et al (2025) Conductive hydrogels: intelligent dressings for monitoring and healing chronic wounds. Regen Biomater 12:rbae127 Chen Z, Liu J, Chen Y et al (2021) Multiple-Stimuli-Responsive and Cellulose Conductive Ionic Hydrogel for Smart Wearable Devices and Thermal Actuators. ACS Appl Mater Interfaces 13(1):1353–1366 Zhou J, Li Y, He J et al (2023) ROS Scavenging Graphene-Based Hydrogel Enhances Type H Vessel Formation and Vascularized Bone Regeneration via ZEB1/Notch1 Mediation. Macromol Biosci 23(4):e2200502 Li J, Han F, Ma J et al (2021) Targeting Endogenous Hydrogen Peroxide at Bone Defects Promotes Bone Repair. Adv Funct Mater 32(10) Thakur N, Manna P, Das J (2019) Synthesis and biomedical applications of nanoceria, a redox active nanoparticle. J Nanobiotechnol 17(1):84 Iqbal N, Anastasiou A, Aslam Z et al (2021) Interrelationships between the structural, spectroscopic, and antibacterial properties of nanoscale (< 50 nm) cerium oxides. Sci Rep 11(1):20875 Xv D, Cao Y, Hou Y et al (2025) Polyphenols and Functionalized Hydrogels for Osteoporotic Bone Regeneration. Macromol Rapid Commun 46(2):e2400653 Rizwana N, Maslekar N, Chatterjee K et al (2024) Dual Crosslinked Antioxidant Mixture of Poly(vinyl alcohol) and Cerium Oxide Nanoparticles as a Bioink for 3D Bioprinting. ACS Appl Nano Mater 7(16):18177–18188 Yetgin A (2025) Revolutionizing multi-omics analysis with artificial intelligence and data processing. Quant Biology 13(3) Radigan R, Sangal A, Zhang D et al (2025) Feasibility trial of Darwin OncoTreat and OncoTarget precision medicine testing to improve outcomes for patients with limited metastatic disease that failed first-line systemic therapy. PLoS ONE 20(6):e0325769 Erben J, Jirkovec R, Kalous T et al (2022) The Combination of Hydrogels with 3D Fibrous Scaffolds Based on Electrospinning and Meltblown Technology. Bioeng (Basel) 9(11):660 Yu X, Zou Z, Li Y et al (2025) Fiber-reinforced gelatin-based hydrogel biocomposite tubular scaffolds with programmable mechanical properties. Biomed Mater 20(3):035031 de Souza SOL, de Oliveira SM, Silva LM et al (2022) Biomolecule-based hydrogels containing electrospun fiber mats with enhanced mechanical properties and biological activity. JOURNAL OF APPLIED POLYMER SCIENCE. 139(28) Geng X, Xu ZQ, Tu CZ et al (2021) Hydrogel Complex Electrospun Scaffolds and Their Multiple Functions in In Situ Vascular Tissue Engineering. ACS Appl Bio Mater 4(3):2373–2384 Zhu Y, Zhang Q, Shi X et al (2019) Hierarchical Hydrogel Composite Interfaces with Robust Mechanical Properties for Biomedical Applications. Adv Mater 31(45):e1804950 Bandiera A, Passamonti S, Dolci LS et al (2018) Composite of Elastin-Based Matrix and Electrospun Poly(L-Lactic Acid) Fibers: A Potential Smart Drug Delivery System. Front Bioeng Biotechnol 6:127 Table 3 Table 1 is available in the Supplementary Files section. Additional Declarations The authors declare no competing interests. Supplementary Files Table3Referenceswithcitationburstsatdifferenttimeintervals.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8008252","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":538572436,"identity":"c92279bb-795d-442c-b57b-e9e4c9b90dee","order_by":0,"name":"Long Xie","email":"","orcid":"","institution":"Department of Orthopedics, The Fourth Hospital of Changsha (Integrated Traditional Chinese and Western Medicine Hospital of Changsha), Hunan Normal University, Changsha, 410006, Hunan Province, China.","correspondingAuthor":false,"prefix":"","firstName":"Long","middleName":"","lastName":"Xie","suffix":""},{"id":538572437,"identity":"a235f62c-550f-4fc9-84d5-c5550737037d","order_by":1,"name":"Yu qin Peng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYBACNoaDzQ8//vnPwyZ/+ABxWvgYDx8zlmxgluGXYEsgTosc87EECd4GZhvJGTwGRDqM7YyBgeQONh6D2z0fb7xhsJPTbSCkheeMwYPCMzw8BnfObracw5BsbHaAkBYJoC0SbBI8Bgdyt0nzMBxI3EZQi/wbAwkeNgOglpxnRGphAHm/LYFHckYOG7FagIEsceYADz/PMWPLOQZE+EW+ARiVHyoO2LOxNz+88abCTo6gFhQgQWzUIGshVccoGAWjYBSMCAAAfqRBdZLJSAoAAAAASUVORK5CYII=","orcid":"","institution":"Department of ophthalmology, The Fourth Hospital of Changsha (Integrated Traditional Chinese and Western Medicine Hospital of Changsha), Hunan Normal University, Changsha, 410006, Hunan Province, China.","correspondingAuthor":true,"prefix":"","firstName":"Yu","middleName":"qin","lastName":"Peng","suffix":""},{"id":538572438,"identity":"9ba588e4-bbe1-45b1-bcc9-8cdd82abc1ea","order_by":2,"name":"Xiang Shen","email":"","orcid":"","institution":"Department of Orthopedics, The Fourth Hospital of Changsha (Integrated Traditional Chinese and Western Medicine Hospital of Changsha), Hunan Normal University, Changsha, 410006, Hunan Province, China.","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Shen","suffix":""}],"badges":[],"createdAt":"2025-11-02 00:53:41","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-8008252/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8008252/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95225320,"identity":"0525de9c-6373-43e8-a970-8fccba883336","added_by":"auto","created_at":"2025-11-05 16:24:52","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6709953,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/2287fe4f9e4a7564a3508b1d.docx"},{"id":95089226,"identity":"7e583232-b266-46c5-bd82-1c1b09395fef","added_by":"auto","created_at":"2025-11-04 07:56:30","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":342,"visible":true,"origin":"","legend":"","description":"","filename":"rs8008252.json","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/e28c0b3da933f276706736db.json"},{"id":95089246,"identity":"8c12fa20-9cbc-431f-8f81-bb36043c0ca3","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":214204,"visible":true,"origin":"","legend":"","description":"","filename":"rs80082520enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/14698d10d0986298bded8a8f.xml"},{"id":95089233,"identity":"cf25ec20-b87a-4edd-ae3c-44f3e786222b","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"jpeg","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":533482,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/49b86146991889ab8fcf6f62.jpeg"},{"id":95089247,"identity":"49e136c8-db4b-4466-a63c-cab555de5305","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"jpeg","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":499770,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/0ed53f67928af5becfe6a1c1.jpeg"},{"id":95089243,"identity":"7d92db8c-e1c3-4e8e-94b4-741051faccd6","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"jpeg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":916766,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/b86bddfaacc4ed09c5c69981.jpeg"},{"id":95089254,"identity":"3a109b51-52d9-4daa-9277-dcd509754319","added_by":"auto","created_at":"2025-11-04 07:56:32","extension":"jpeg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":956634,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/29542be1b63e34d0afe2eb4b.jpeg"},{"id":95089238,"identity":"d86a2619-d087-4dba-ac7d-721777ce9c21","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"jpeg","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1023372,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/b3a94ecb4d3bb3fdeafa4f65.jpeg"},{"id":95089236,"identity":"5be6b76e-cd37-4770-a1ec-c0e7fa112995","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"jpeg","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":840126,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/b436692942ba3195bad9f2e7.jpeg"},{"id":95089249,"identity":"ef534948-289c-4009-9de3-2ab8ca0d209e","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"jpeg","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":884684,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/11ef35b1bb98c1f042504896.jpeg"},{"id":95089234,"identity":"4ffd6511-0a74-4f98-a26e-18abeffc8fa1","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"jpeg","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":262046,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/5f31f2b8bfe071c9d1524f06.jpeg"},{"id":95089259,"identity":"2c6795e9-730d-4d19-a9f9-3d3a71164e13","added_by":"auto","created_at":"2025-11-04 07:56:32","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":844238,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage9.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/95fe5fd25c96ff7c3401f9f6.jpeg"},{"id":95224782,"identity":"4ffea612-182e-4bf5-aa2c-eaf61fa5c79e","added_by":"auto","created_at":"2025-11-05 16:24:17","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":69931,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/d9e8e383e6318b1e60f6bda4.png"},{"id":95089251,"identity":"4ddbb099-5773-4a7a-96c9-452a643d3abb","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":82769,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/9a66f3f928b5cbab94159474.png"},{"id":95223435,"identity":"525a8c10-9467-4c2a-83af-f03f6109ea4c","added_by":"auto","created_at":"2025-11-05 16:22:16","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":155214,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/fd8367e1ce048e2cb48bb8cf.png"},{"id":95089266,"identity":"4a061c30-7701-437b-b2b9-b387864c7b81","added_by":"auto","created_at":"2025-11-04 07:56:32","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":160271,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/45048b11dd8367eb299d4c47.png"},{"id":95089253,"identity":"3296618e-92ff-487a-8625-0ebd0ada16f6","added_by":"auto","created_at":"2025-11-04 07:56:32","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":161193,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/eef742b352e282abf0250717.png"},{"id":95224682,"identity":"297bbe29-3a45-41c1-a82a-7431bacd5aec","added_by":"auto","created_at":"2025-11-05 16:24:10","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":198036,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/21d48d2e109c78a7f2598d12.png"},{"id":95089263,"identity":"a21da44c-6404-49d0-aa9c-811d5e9fa1be","added_by":"auto","created_at":"2025-11-04 07:56:32","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":150190,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/d7e7746e8e5340243385c528.png"},{"id":95089244,"identity":"bd18d648-0bb6-48bb-b036-4120ed5d4c35","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":43854,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/bce605e12ac61432c465853c.png"},{"id":95089245,"identity":"cd050872-bf1e-41dd-811f-00bfe876b305","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"png","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":132451,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/9c9c80691e315cfe842d4b6f.png"},{"id":95089252,"identity":"81e774df-31b1-4e8c-be9b-74300ae48f1e","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"xml","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":212641,"visible":true,"origin":"","legend":"","description":"","filename":"rs80082520structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/22c667646d38be672490f65e.xml"},{"id":95089248,"identity":"b784f9c4-7d7b-487d-ad5f-c8e7d5037edc","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"html","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":220336,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/276db4074187d06529465394.html"},{"id":95089224,"identity":"5c5aec74-2fbc-446e-b818-38082f0bf6a9","added_by":"auto","created_at":"2025-11-04 07:56:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":317417,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 1A illustrates the annual research output related to hydrogel-based orthopedic applications, while Figure 1B presents the top 20 journals ranked by publication volume, serving as a reference for researchers seeking appropriate journals for manuscript submissions.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/c7d9d094bd00409e7b9d8998.png"},{"id":95089227,"identity":"68849f5e-ee6c-44b9-9dc4-2507f0323672","added_by":"auto","created_at":"2025-11-04 07:56:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":455190,"visible":true,"origin":"","legend":"\u003cp\u003eCo-citation literature map (the color bar from left (white) to right (red) represents the years from 2000 to 2024).\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/5ef8ffb5e9f04c85cdce4c61.png"},{"id":95089231,"identity":"f410818f-dbc7-4cb5-a53c-9f8761162b65","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":893424,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCollaborative Networks in Hydrogel-Related Research for Orthopedic Applications\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/e3bb3f9a7ac9a5fb2e01dfe1.png"},{"id":95224044,"identity":"99213f7b-1fd1-4aee-a47c-c0140f7a9d1f","added_by":"auto","created_at":"2025-11-05 16:23:14","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":706181,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTop 50 subject categories with the highest citation counts from 2000 to 2024.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/51044aa032eb37442be246f8.png"},{"id":95089235,"identity":"2fbf7bed-961b-4d5b-b842-14c36366d4c4","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":726186,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTop 50 keywords with the highest citation counts from 2000 to 2024.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/459c09582a4aeff13ae80807.png"},{"id":95089228,"identity":"eae4859c-cd8a-4048-9584-7db622a9ab8c","added_by":"auto","created_at":"2025-11-04 07:56:30","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":513011,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnalysis of Keyword Clustering Over Time\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst Stage (2000-2006): Analysis of 299 articles resulted in 7 clusters, including #0 biodegradable polymers, #1 gels, and #2 mesenchymal stem cells (MSCs) (Figure 6A). Second Stage (2007-2012): From 1,176 articles analyzed, 9 clusters emerged, such as #0 MSCs, #1 fracture, and #2 bone (Figure 6B). Third Stage (2013-2018): This period recorded 3,120 articles, yielding 7 clusters, encompassing #0 hydroxyapatite, #1 MSCs, and #2 double network hydrogels (Figure 6C). Fourth Stage (2019-2024): 7,300 articles were analyzed, identifying 8 clusters, including #0 tough, #1 extracellular vesicles, and #2 3D bioprinting (Figure 6D).\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/715ea50807c2f24cee67cde4.png"},{"id":95089239,"identity":"b7dbc081-e4f0-4953-a2b4-f5e2ae4b26b3","added_by":"auto","created_at":"2025-11-04 07:56:31","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":485169,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrends in Research Topics Related to Tissue Engineering and Regenerative Medicine (2000–2024).\u003cbr\u003e\n \u003c/strong\u003eThe Sankey diagram illustrates the temporal evolution of key research topics in the domains of tissue engineering and regenerative medicine over the period 2000–2024. The X-axis represents years, while the Y-axis denotes the prevalence of each topic, differentiated with color-coding for clarity. Major topics include \u003cem\u003eangiogenesis in vitro\u003c/em\u003e, \u003cem\u003emesenchymal stem cells\u003c/em\u003e, \u003cem\u003ebiodegradable polymers\u003c/em\u003e, \u003cem\u003edental implants\u003c/em\u003e, and \u003cem\u003earticular cartilage\u003c/em\u003e, among others. The varying stream heights reflect the relative prominence of each topic within the literature during specific years.\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/a7523592e1cdf389e1447039.png"},{"id":95223946,"identity":"a30c0854-eff4-4905-993b-4fac9d18570a","added_by":"auto","created_at":"2025-11-05 16:23:06","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":329120,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCompositional Analysis of Key Cellular and Material Components in Tissue Engineering.\u003cbr\u003e\n \u003c/strong\u003eThe figure presents a series of ring charts (A–F) arranged in a grid layout, each illustrating the proportional distribution of critical components in tissue engineering research.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eA: Mesenchymal stem cells and \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;associated factors.\u003c/li\u003e\n \u003cli\u003eB: Fracture-related cellular and \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;molecular markers.\u003c/li\u003e\n \u003cli\u003eC: Endothelial cells and their \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;functional attributes.\u003c/li\u003e\n \u003cli\u003eD: Polymer networks and mechanical \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;properties (e.g., toughness, hysteresis).\u003c/li\u003e\n \u003cli\u003eE: Articular cartilage and delivery \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;systems.\u003c/li\u003e\n \u003cli\u003eF: DNA mechanics and \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;osteoclastogenesis regulators (e.g., alkaline phosphatase, dexamethasone).\u003c/li\u003e\n\u003c/ul\u003e","description":"","filename":"image8.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/8fef10494959d5f9e370aee3.png"},{"id":95223926,"identity":"5773e141-541e-4c6c-b4f6-69bb1cd726b6","added_by":"auto","created_at":"2025-11-05 16:23:05","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":593010,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCitation Analysis of Seminal Literature in Hydrogel-based Orthopedic Research.\u003c/strong\u003e\u003cbr\u003e\n \u003cstrong\u003e(A)\u003c/strong\u003e Timeline visualization of cited literature, highlighting prominent publications across various themes, including bone regeneration, 3D printing, and bioprinting. The color gradient represents the year of publication, with darker colors indicating more recent publications.\u003cbr\u003e\n \u003cstrong\u003e(B)\u003c/strong\u003e Identification of burst literature among the top-cited articles, specifically references within clusters #0, #2, #4, #7, and #9, which show notable citation bursts indicative of increased research interest.\u003cbr\u003e\n \u003cstrong\u003e(C)\u003c/strong\u003e Citation trends for the five highlighted publications, reflecting the number of citations from 2016 to 2024. Color lines represent individual papers: Koons GL (2020, red), Kang HW (2016, green), Wei W (2021, blue), Huu MT (2021, orange), and Turnbull G (2018, purple), illustrating their citation dynamics within the research community.\u003c/p\u003e","description":"","filename":"image9.png","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/8983d264b89a40063acccddc.png"},{"id":95312086,"identity":"cf2b7fc4-d4d6-44b1-8fb7-ecc2f7f0c37a","added_by":"auto","created_at":"2025-11-06 15:46:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6161338,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/12b8e3e6-21f0-4967-9a16-a27bdfabf7a4.pdf"},{"id":95089225,"identity":"aa5b88df-0322-4700-8cea-9060e1242dbb","added_by":"auto","created_at":"2025-11-04 07:56:30","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20595,"visible":true,"origin":"","legend":"","description":"","filename":"Table3Referenceswithcitationburstsatdifferenttimeintervals.docx","url":"https://assets-eu.researchsquare.com/files/rs-8008252/v1/0f47ea90e6b81924d8df0ef4.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eKnowledge Domains and Emerging Trends of Hydrogels in Orthopedic Diseases：A Bibliometric and Visualization Analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOrthopedic diseases, including osteoporosis\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e, osteoarthritis\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e, and bone cancer, pose significant global health challenges. Conventional treatments often involve surgical interventions, which can be invasive with limited efficacy. Hydrogels, due to their biocompatibility, biodegradability, and ability to mimic the extracellular matrix (ECM), have emerged as promising materials in orthopedic applications\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. They are widely exploited for drug delivery, tissue engineering, and as scaffolds for bone regeneration.\u003c/p\u003e\u003cp\u003eDespite growing interest in hydrogel-based applications in orthopedics\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, a systematic review mapping the knowledge domains and emerging trends in this field remains lacking. Recent advances in nanotechnology have further expanded the functionality of hydrogels, enabling enhanced mechanical properties, antibacterial activity, and bioactive molecule delivery. For instance, Li et al. developed patterned alginate hydrogels incorporated with CuS nanoparticles, significantly improving antibacterial efficacy and mechanical resilience\u0026mdash;key attributes for load-bearing orthopedic applications\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Similarly, Zheng et al. designed polyphenol-mediated electroactive hydrogels for exosome delivery, facilitating targeted bone regeneration through synergistic bioelectrical and biochemical cues\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Bibliometric analysis employs mathematical and statistical methodologies for qualitative and quantitative examination of the distribution, structure, and developmental trajectory of scientific data\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Recent bibliometric studies have highlighted the expanding body of literature on hydrogels, particularly focusing on their biomedical applications\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. With the increasing availability of open-source tools such as CiteSpace\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, VOSviewer\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e, the bibliometrix R-package, and HistCite, bibliometric analysis has been extensively applied in numerous biomedical domains. The bibliometric perspective provides insights into the geographical distribution of significant research contributions from countries including China and several European nations. Additionally, such approaches underscore the need for deeper theoretical exploration of hydrogel implications in bone disease management. Overall, bibliometric analysis not only synthesizes existing knowledge but also offers a framework for identifying research gaps and future directions in hydrogel-based orthopedic therapies. Assessment of available trends and literature patterns enables a clearer understanding of the associated complexities.\u003c/p\u003e\u003cp\u003eThis study primarily explores the following questions: (1) what are the global trends in publication and citation activities? (2) who are the key contributors, including countries/regions, institutions, and funding bodies? (3) which journals are prominent in this field? (4) what is the current research focus and priorities; (5) what emerging topics are likely to become future research hotspots and frontiers? and (6) which are the most extensively studied genes and regulatory pathways? The overarching aim is to identify leading researchers, institutions, and countries along with their collaborative networks, and reveal dynamic research trends in this rapidly advancing field, ultimately underlining both current and future research frontiers. Moreover, our objective is to elucidate the pathway for experts in nanotechnology to translate their foundational discoveries into solutions for enduring clinical challenges in musculoskeletal medicine. By achieving this, we aspire to enhance collaborative dialogue between materials scientists and clinical researchers, thereby expediting the development of next-generation, nano-enabled orthopedic therapies.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Data Collection and Statistics\u003c/h2\u003e\u003cp\u003eThe Web of Science Core Collection (WoSCC) by Thomson Reuters, which indexes over 12,000 high-impact academic journals and is widely recognized within the international academic community\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, was selected as the target database for this study. For the purpose of this study, 'orthopedic diseases' were operationally defined as pathological conditions affecting the musculoskeletal system, including bones, joints, and associated tissues. This encompasses traumatic, degenerative, inflammatory, and neoplastic conditions. This definition informed the selection of keywords for the second branch of the search strategy, which included terms for anatomical structures (e.g., bone, spine), specific diseases (e.g., osteoporosis, osteoarthritis), and pathological states (e.g., fracture, bone cancer).The following search query was applied to identify relevant literature: ( (TS=(Hydrogels) OR TS=(Hydrogel) ) AND ( (TS=(orthopedic*) OR TS=(fracture*) OR TS=(osteoporosis) OR TS=(spine*) OR TS=(\"bone tumor\") OR TS=(osteoarthritis) OR TS=(Bone*) OR TS=(\"Bones and Bone Tissue\") OR TS=(\"Bones and Bone\") OR TS=(\"Bone Tissue*\") OR TS=(\"Bony Apophysis\") OR TS=(Condyle) OR TS=(Periosteum) OR TS=(\"Bone Cancer*\") OR TS=(\"Cancer of Bone\") OR TS=(osteonecrosis) ) ). The search covered the period from 2000 to 2024, retrieving a total of 8,685 records. These records were downloaded and saved as plain text files in the format \"Full Record and Cited References,\" serving as the sample dataset for analysis and collectively termed as \"DATA.\" Additionally, the raw data collected on the countries/regions, institutions, journals, authors, and article types was organized using Excel (WPS 2019) for statistical description.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Bibliometric Analysis Tools\u003c/h2\u003e\u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\u003ch2\u003e2.2.1. CiteSpace\u003c/h2\u003e\u003cp\u003e\u003cb\u003eCo-occurrence Network\u003c/b\u003e\u003c/p\u003e\u003cp\u003eScientific partnerships are defined as the involvement of \"multiple authors, institutions, or countries/regions together in a publication.\" Analyzing such collaborations can reveal the dynamic status of a research field across three dimensions: authors, institutions, and countries. When specific articles are imported into CiteSpace as a dataset, the tool visualizes these collaborative relationships and scientific concepts as a co-occurrence network. CiteSpace uses nodes and edges to differentiate merged networks, color-coded by year. Edge colors indicate the year in which the co-occurrence link was first established. Nodes consist of multi-colored \"tree rings\", where thickness represents the frequency of co-occurrences in a given year. Red rings correspond to citation bursts in a specific year, while purple rings denote the degree of betweenness centrality. Nodes exhibiting high betweenness centrality are significant, acting as connecting bridges.\u003c/p\u003e\u003cp\u003e\u003cb\u003eBurst Detection\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCastano proposed that document streams, such as emails or articles, have specific themes over time that gradually fade. Specific text data mining algorithms can identify these temporal thematic shifts, represented as \"bursts of activity\"\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. CiteSpace can detect the appearance of citation bursts (which may last several years or occur within a single year), indicating the association of a particular discipline, keyword, or reference with a surge in citations that reflect increasing attention from the scientific community.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCluster Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCiteSpace provides three clustering algorithms based on titles, abstracts, and keywords, which categorize publications into clusters with distinct research characteristics. Depending on the time slice settings, cluster maps visualize temporal variations in conceptual clusters. Additionally, timeline maps clearly illustrate the rise and fall of clusters along with their associated nodes.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSpecific Steps include\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eImport the \"DATA\" on hydrogels related to the orthopedic field into CiteSpace (version 6.2.R4).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eSet the time slice to \"2000\u0026ndash;2024\" with a 1-year interval.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eSelect \"Author Keywords\" and configure a secondary time slice spanning \"2004\u0026ndash;2024\" with a 1-year interval.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eChoose the word source as \"Title,\" \"Abstract,\" \"Author Keywords,\" and \"Keywords+.\"\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eSelect the appropriate node type, keeping other parameters at default values.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eAutomatically generate knowledge maps of country/region, institution, or author collaboration networks.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eManually refine and adjust maps for clarity and aesthetics.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eFor keyword clustering, the node type was set to \"Keywords,\" and the time frame was divided into four distinct periods: 2000\u0026ndash;2006, 2007\u0026ndash;2012, 2013\u0026ndash;2018, and 2019\u0026ndash;2024. Reference clustering was visualized using the \"Timeline View\" to generate citation timeline maps. Furthermore, burst detection maps for keywords, categories, or references were produced using the \"Burstness\" tab in the control panel.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e2.2.2. HistCite\u003c/h2\u003e\u003cp\u003eEach scientific publication can be viewed as a light in the darkness, and each citation intensifies its brightness, illuminating the academic landscape. HistCite Pro 2.1 software facilitates the visualization of this digital relationship, extracting the most impactful literature based on citation frequency. HistCite scores articles using two metrics, namely Local Citation Score (LCS) and Global Citation Score (GCS). LCS quantifies citation frequency within the dataset, while GCS reflects citation frequency in the WoSCC database. A total of 8,685 articles on hydrogel research in the orthopedic field were imported into HistCite Pro 2.1, setting the threshold to 30 and retaining other default settings. By selecting \"Make Graph\", a visual research landscape was generated to enable rapid identification of key publications.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.2.3. The Alluvial Generator\u003c/h2\u003e\u003cp\u003eAlluvial flow diagrams elucidate temporal patterns in evolving research networks. To construct these diagrams, a series of individual networks for co-occurring keywords were first created using CiteSpace, which were then exported and processed using the Alluvial Generator (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.mapequation.org/apps/AlluvialGenerator.html\u003c/span\u003e\u003cspan address=\"http://www.mapequation.org/apps/AlluvialGenerator.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). In the resulting diagrams, each keyword was treated as a node clustered by time slices, forming modules. Nodes were split or merged over time, creating new modules that result from the intersection of previous nodes. A donut chart was plotted using R 4.2.2, utilizing the geom_bar function from the ggplot2 package (version 3.4.4).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Historical Features of the Literature on Hydrogels in Bone-Related Applications\u003c/h2\u003e\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\u003ch2\u003e3.1.1. Distribution of Publications\u003c/h2\u003e\u003cp\u003eThe volume of scientific publications at specific time points can provide quantitative insights into knowledge accumulation and the developmental trajectory of a research field. This study retrieved 8,685 articles related to hydrogels applicability in orthopedics. These works were authored by 34,906 researchers from 5,937 institutions and published in 759 journals across 93 scientific categories (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eSummary of Publication Metrics.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCategories\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePublication\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eArticles\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAuthors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eInstitutions\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eJournals\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSubject categories\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmount\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10145\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8685\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1460\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e34906\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5937\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e759\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e93\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\u003eAs depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, the annual number of publications remained relatively low from 2000 to 2004, with only 20 articles recorded in the year 2000. However, a steady increase was observed from 2005 to 2017, with a sharper surge in output noted after 2017, reaching a peak in 2024. In terms of journal distribution, Biomaterials ranked first with the largest publication volume (419 articles), closely followed by Acta Biomaterialia (413 articles) and International Journal of Biological Macromolecules (407 articles). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB lists the top 20 journals with the highest output, which researchers can refer to when considering manuscript submissions.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\u003ch2\u003e3.1.2. The Vein of Research on Hydrogels in Bone-Related Applications\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents a co-citation network map illustrating interrelationships among references cited in the field of hydrogels for bone-related applications over the past two decades (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The color gradient\u0026mdash;from white to red\u0026mdash;denotes the publication year of the cited reference, spanning from 2000 to 2024. The network consists of 2,234 nodes and 11,078 links, indicating extensive interconnectivity within the literature. Node size is directly proportional to the citation frequency, and greater node connectivity represents higher betweenness centrality. This network not only visualized the citation structure but also identified influential publications in the field. Metamorphically comparing to a tree, the early literature (2000\u0026ndash;2010, gray nodes) forms roots of the field, providing nourishment for sustainable development. The mid-term (2011\u0026ndash;2017, blue nodes) dispersing gradually signify the main research branches. In the recent period (2018\u0026ndash;2024, red nodes), nodes develop into branches, forming tighter clusters, indicating the concentration and differentiation of the research field, which is further elaborated in the reference timeline maps.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTop 10 most co-cited articles\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThese articles exhibiting the highest co-citation frequencies, ranging from 117 to 186, serve as pivotal contributions to the field: Koons GL (2020); Liu M (2017); Sun JY (2012); Bai X (2018); Zhang YS (2017); Kang HW (2016); Hua MT (2021); Chaudhuri O (2016); Murphy SV (2014); Kim J (2021)\u003c/p\u003e\u003cp\u003eAdditionally, HistCite Pro 2.1 was adopted to plot the citation history of research articles. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e highlights these landmark publications, with the top three being: Double-network hydrogels with extremely high mechanical strength; Why are double network hydrogels so tough?; 3D bioprinting of tissues and organs.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eSummary of Article Information on Hydrogels.\u003c/b\u003e This table lists key publications related to hydrogel-based orthopedic applications, including the article title, journal name, local citation score (\u003cb\u003eLCS\u003c/b\u003e), and global citation score (\u003cb\u003eGCS\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNO.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArticle information\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eJournal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLCS\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGCS\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDouble-network hydrogels with extremely high mechanical strength\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eADV MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e740\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3604\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e746\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWhy are double network hydrogels so tough?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSOFT MATTER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e399\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1825\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2107\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3D bioprinting of tissues and organs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNAT BIOTECHNOL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e337\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4625\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2698\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSynthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBIOMATERIALS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e316\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1990\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1738\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhysical hydrogels composed of polyampholytes demonstrate high toughness and viscoelasticity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNAT MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e307\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1686\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2923\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHydrogels with tunable stress relaxation regulate stem cell fate and activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNAT MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e238\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1688\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e152\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSynthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNAT BIOTECHNOL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e216\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3658\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2922\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA 3D bioprinting system to produce human-scale tissue constructs with structural integrity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNAT BIOTECHNOL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e204\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1814\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4539\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBioactive hydrogels for bone regeneration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBIOACT MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e198\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e409\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e839\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHarnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNAT MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1255\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6058\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMaterials design for bone-tissue engineering\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNAT REV MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e188\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1050\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e330\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLarge strain hysteresis and mullins effect of tough double-network hydrogels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMACROMOLECULES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e183\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e594\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3640\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCell-laden hydrogels for osteochondral and cartilage tissue engineering\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eACTA BIOMATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e169\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e505\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBioactive Nanoengineered Hydrogels for Bone Tissue Engineering: A Growth-Factor-Free Approach\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eACS NANO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e160\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e538\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3063\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3D bioprinting for engineering complex tissues\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBIOTECHNOL ADV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e148\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1110\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e338\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA model of the fracture of double network gels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMACROMOLECULES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e134\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e277\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e322\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBone regeneration using hyaluronic acid-based hydrogel with bone morphogenic protein-2 and human mesenchymal stem cells\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBIOMATERIALS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e435\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e334\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMultifunctional chondroitin sulphate for cartilage tissue-biomaterial integration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNAT MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e921\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1332\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFunctional Human Vascular Network Generated in Photocrosslinkable Gelatin Methacrylate Hydrogels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eADV FUNCT MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e573\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e269\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAlginate hydrogels as biomaterials\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMACROMOL BIOSCI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e599\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e185\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDetermination of fracture energy of high strength double network hydrogels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eJ PHYS CHEM B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1407\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2545\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3D Printing of Highly Stretchable and Tough Hydrogels into Complex, Cellularized Structures\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eADV MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e114\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e266\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e945\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMineralization of Hydrogels for Bone Regeneration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTISSUE ENG PART B-RE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e763\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1096\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBiopolymer-Based Hydrogels for Cartilage Tissue Engineering\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCHEM REV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e112\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e199\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1103\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHydrogels for the Repair of Articular Cartilage Defects\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTISSUE ENG PART B-RE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e109\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e460\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2399\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNatural-Based Nanocomposites for Bone Tissue Engineering and Regenerative Medicine: A Review\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eADV MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e109\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e359\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6773\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdvanced hydrogels for the repair of cartilage defects and regeneration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBIOACT MATER\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e108\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e697\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e264\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNecking phenomenon of double-network gels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMACROMOLECULES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e107\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e259\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e201\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThe effect of incorporating RGD adhesive peptide in polyethylene glycol diacrylate hydrogel on osteogenesis of bone marrow stromal cells\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBIOMATERIALS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e105\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e246\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGelatin-Methacryloyl Hydrogels: Towards Biofabrication-Based Tissue Repair\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTRENDS BIOTECHNOL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e103\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e396\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\u003ch2\u003e3.1.3. Scientific Cooperation\u003c/h2\u003e\u003cp\u003eThe larger number of nodes and rich connections indicate strong scientific collaboration spanning three dimensions: countries, institutions, and authors (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The country collaboration network comprises 108 nodes and 1,005 links; dominant nodes include China, the United States, South Korea, Japan, and Germany (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). The institution collaboration network consists of 685 nodes and 908 links, with node sizes in the order of the Chinese Academy of Sciences, Sichuan University, Shanghai Jiao Tong University, and Zhejiang University (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The author collaboration map showcases top authors (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC), namely Gong Jian Ping, Tabata Yasuhiko, Kurokawa Takayuki, and Reis Rui L., with dense interconnections representing extensive collaborations. Notably, clustering effects were observed among the nodes of Gong Jian Ping, Kurokawa Takayuki, and Nakajima Tasuku, forming one prominent cluster, while Tabata Yasuhiko and Mikos Antonios G. clustered separately (Supplementary Table S1).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eCountry-Level Collaboration\u003c/b\u003e: The first graph highlights international collaborations, with \"PEOPLES R CHINA\" and \"USA\" serving as the primary central nodes, indicating their dominant roles in the global research landscape.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eInstitutional Collaboration\u003c/b\u003e: The second graph visualizes connections among leading universities and research institutions (e.g., \u003cem\u003ePeking University\u003c/em\u003e, \u003cem\u003eHarvard University\u003c/em\u003e, \u003cem\u003eChinese Academy of Sciences\u003c/em\u003e), reflecting institutional partnerships.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eResearcher-Level Collaboration\u003c/b\u003e: The third graph displays co-authorship or collaborative ties among influential scholars (e.g., \u003cem\u003eYasuhiko Tabata\u003c/em\u003e, \u003cem\u003eJian Ping Gong\u003c/em\u003e, \u003cem\u003eByang Taek Lee\u003c/em\u003e), emphasizing strong interdisciplinary linkages.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Variation of the Most Active Topics\u003c/h2\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003e3.2.1. Subject Category Burst\u003c/h2\u003e\u003cp\u003eFrom 2000 to 2024, 83 out of 93 subject categories associated with hydrogel-bone research experienced citation bursts. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the top 50 categories ranked by burst strength over the study period. The blue line represents the time interval, while the red segments indicate the duration of each burst, with labeled start and end years. The subject \"ENGINEERING, BIOMEDICAL\" demonstrated the highest burst strength (59.9) from 2000 to 2011. Over time, the burst categories diversified into a broader array of disciplines, such as \"MICROSCOPY\" (2003\u0026ndash;2010), \"CLINICAL NEUROLOGY\" (2006\u0026ndash;2014), \"COMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS\" (2009\u0026ndash;2015), \"MINERALOGY\" (2016\u0026ndash;2018), \"CHEMISTRY, ANALYTICAL\" (2019\u0026ndash;2022), and \"MATHEMATICAL \u0026amp; COMPUTATIONAL BIOLOGY\" (2022\u0026ndash;2024). These temporal patterns reflect the multidisciplinary nature of the field. Additionally, 20 burst categories emerged in 2024 alone (Table S2), with the top three being \"ENERGY \u0026amp; FUELS\" (2023\u0026ndash;2024), \"ENGINEERING, ENVIRONMENTAL\" (2023\u0026ndash;2024), and \"ELECTROCHEMISTRY\" (2023\u0026ndash;2024).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003e3.2.2. Keywords Burst\u003c/h2\u003e\u003cp\u003eThe burst patterns of keywords analyzed at a finer level reveal the dynamic research evolution in the field of hydrogels for bone-related conditions between 2000 and 2024. A total of 990 keywords experienced bursts at different time points, with the top 50 keywords ranked by burst strength delineated in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The keyword \"gene expression\" recorded the highest burst strength (29.39) from 2004 to 2014, followed by \"high mechanical strength\" (22.63; 2011\u0026ndash;2018) and \"fibroblast growth factor\" (22.31; 2007\u0026ndash;2017). In particular, 20 keywords whose bursts extended into 2024 may signify potential future research hotspots. Notable examples include \"antibacterial\" (burst strength: 20.31; 2023\u0026ndash;2024), \"extracellular vesicles\" (18.66; 2021\u0026ndash;2024), and \"fatigue\" (17.02; 2022\u0026ndash;2024) (Supplementary Table S2).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\u003ch2\u003e3.2.3. Reference Burst\u003c/h2\u003e\u003cp\u003eA total of 2,047 articles experienced citation bursts; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e lists the top 30 most-cited references between 2000 and 2024. Among these, the article titled \u0026ldquo;\u003cem\u003eHighly stretchable and tough hydrogels\u003c/em\u003e\u0026rdquo; exhibited the highest citation burst, lasting from 2013 to 2017. This seminal study argued that hydrogels could function as scaffolds for tissue engineering, drug delivery carriers, actuators in optics and fluid mechanics, and ECM mimetics. However, the mechanical properties of hydrogels often limit their broader applications. For instance, most hydrogels (such as alginate) are not highly stretchable and rupture when stretched merely 1.2 times their original length. Although few synthetic elastic hydrogels can elongate 10\u0026ndash;20 times, this capacity decrease significantly in notched samples. Typically, hydrogels are brittle, with fracture energies of approximately 10 J m-2, substantially lower than that of cartilage (1,000 J m-2) or natural rubber (10,000 J m-2). Recent advancements aim to synthesize hydrogels with enhanced mechanical properties, yielding synthetic gels with fracture energies ranging from 100-1,000 J m-2\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Previous study reported polymer-synthesized hydrogels that form ionic and covalent cross-linked networks\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Despite containing 90% water composition, these gels can stretch over 20 times their initial length and achieve fracture energies of 9,000 J m-2; even notched samples exhibit 17-fold stretchability. Hydrogel toughness is attributed to the synergy between two networks: crack bridging through covalent cross-linking and hysteresis through ionic cross-linking. The covalent cross-linked network retains initial state memory, allowing the recovery from large deformations upon unloading. Internal damage from released ionic cross-links heals upon recompression. These hydrogels serve as versatile model systems for exploring deformation and energy dissipation mechanisms, expanding their potential application range.\u003c/p\u003e\u003cp\u003eAnother article, \u0026ldquo;\u003cem\u003e3D bioprinting of tissues and organs\u003c/em\u003e,\u0026rdquo; demonstrated a citation burst from 2016 to 2019. Additive manufacturing, also known as 3D printing, is driving significant innovations across engineering, manufacturing, art, education, and medicine. Recent advances have enabled the printing of biocompatible materials, cells, and supporting components into complex, functional 3D living tissues. In regenerative medicine, 3D bioprinting is being applied to address the demand for tissues and organs suitable for transplantation. Unlike non-biological printing, 3D bioprinting faces unique issues, such as precise selection of materials, cell types, growth and differentiation factors, and technical challenges related to the fragility of living cells and tissue construction. Addressing these complexities requires an interdisciplinary approach involving engineering, biomaterials science, cell biology, physics, and medicine. 3D bioprinting has been successfully exploited to generate and transplant various tissues, including multi-layered skin, bone, vascular grafts, tracheal splints, heart tissue, and cartilage structures\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Other applications encompass the development of high-throughput 3D bioprinted tissue models for research, drug discovery, and toxicology purposes.The article \u0026ldquo;\u003cem\u003eMulti-scale multi-mechanism design of tough hydrogels: building dissipation into stretchy networks\u003c/em\u003e\u0026rdquo; recorded the third-highest citation burst, from 2014 to 2019. Hydrogels are usually brittle as water-swollen polymer networks; however, high toughness is essential for diverse plant/animal tissues and engineering applications. This review summarizes the intrinsic mechanisms of various tough hydrogels developed over the past few decades; hydrogels exhibiting enhanced toughness generally integrate mechanisms that dissipate large amounts of mechanical energy while retaining high elasticity during deformation. This review first constructed a matrix framework combining multiple mechanisms to guide the design of next-generation tough hydrogels. It further emphasized that multiscale (nano-, micro-, meso-, and macro-structures) multi-mechanism implementation is a particularly promising design strategy for hydrogels exhibiting toughness and elasticity.\u003c/p\u003e\u003cp\u003eFrom 2024 onwards, 332 articles experienced citation bursts, with the top 20 articles listed by strength index (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). These include 13 review articles and 7 original articles, all of which entered the citation burst period immediately upon or within a year after publication. Reviews help establish strategic guidance in hydrogel-based orthopedic research, while original articles provide valuable insights into practical translation. This underscores the need for researchers to closely follow the emerging literature in the field.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe references with citation bursts from 2019 to 2024\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\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\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBegin\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEnd\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStrength\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYear\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eType\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTitle\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e37.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBioactive hydrogels for bone regeneration\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e35.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMaterials design for bone-tissue engineering\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e34.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eArticle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFracture, fatigue, and friction of polymers in which entanglements greatly outnumber cross-links\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e29.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eArticle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eStrong tough hydrogels via the synergy of freeze-casting and salting out\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eArticle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFabrication of physical and chemical crosslinked hydrogels for bone tissue engineering\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRecent Advances in Design of Functional Biocompatible Hydrogels for Bone Tissue Engineering\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e24.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAdvanced hydrogels for the repair of cartilage defects and regeneration\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eArticle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTough hydrogels with rapid self-reinforcement\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSoft Materials by Design: Unconventional Polymer Networks Give Extreme Properties\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCurrent hydrogel advances in physicochemical and biological response-driven biomedical application diversity\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e20.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMechanisms of bone development and repair\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e20.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRecent trends in the application of widely used natural and synthetic polymer nanocomposites in bone tissue regeneration\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e19.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBioinks for 3D bioprinting: an overview\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e19.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3D bioactive composite scaffolds for bone tissue engineering\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e19.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSurgical and tissue engineering strategies for articular cartilage and meniscus repair\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e19.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHydrogel ionotronics\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eArticle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOsteoimmunity-Regulating Biomimetically Hierarchical Scaffold for Augmented Bone Regeneration\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eArticle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eInjectable Mussel-Inspired highly adhesive hydrogel with exosomes for endogenous cell recruitment and cartilage defect regeneration\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eArticle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eA Logic-Based Diagnostic and Therapeutic Hydrogel with Multistimuli Responsiveness to Orchestrate Diabetic Bone Regeneration\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e3.3. Emerging Trends and New Developments\u003c/h2\u003e\u003cdiv id=\"Sec18\" class=\"Section3\"\u003e\u003ch2\u003e3.3.1. Temporal Variation of Keyword Clusters\u003c/h2\u003e\u003cp\u003eKeywords are closely related, and certain keywords can form different clusters based on their affinity. Identifying these clusters can intuitively outline the subfields of hotspots in hydrogel research for bone-related applications. The timeline from 2000 to 2024 was segmented into four stages of 6 years each, with keyword cluster snapshots across these intervals depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eFirst Stage (2000\u0026ndash;2006): Analysis of 299 articles resulted in 7 clusters, including #0 biodegradable polymers, #1 gels, and #2 mesenchymal stem cells (MSCs) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA). Second Stage (2007\u0026ndash;2012): From 1,176 articles analyzed, 9 clusters emerged, such as #0 MSCs, #1 fracture, and #2 bone (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB). Third Stage (2013\u0026ndash;2018): This period recorded 3,120 articles, yielding 7 clusters, encompassing #0 hydroxyapatite, #1 MSCs, and #2 double network hydrogels (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eC). Fourth Stage (2019\u0026ndash;2024): 7,300 articles were analyzed, identifying 8 clusters, including #0 tough, #1 extracellular vesicles, and #2 3D bioprinting (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eD).\u003c/p\u003e\u003cp\u003eCompared to the preceding 15 years, there is continuous relevance of classical research topics such as hydrogels; however, emerging research clusters\u0026mdash;0# tough hydrogels, 1# extracellular vesicles, 2# 3D bioprinting, 3# bone repair, 4# wound healing, 5# bone tissue engineering, 6# cartilage regeneration, and 7# rheumatoid arthritis\u0026mdash;have garnered increasing attention from scholars.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eA deeper literature analysis within these emerging clusters reveals their focus on exploring hydrogel-related orthopedic research hotspots. The 0# tough hydrogels cluster consists of 176 articles addressing their mechanical strength. The 1# extracellular vesicles cluster comprises 146 articles refining studies on the role of extracellular vesicles in bone-related applications. The 2# 3D bioprinting and 5# bone tissue engineering clusters include 129 and 64 articles, respectively, focusing on bone tissue engineering. The 3# bone repair (76 articles) and 6# cartilage regeneration (61 articles) clusters investigate hydrogel applications in bone and cartilage regeneration. The 4# wound healing cluster (66 articles) examines hydrogel use in wound repair, while the 7# rheumatoid arthritis cluster encloses 57 articles on hydrogel-mediated drug delivery for disease treatment. Table S3 (Supplementary Material) represents detailed data for the fourth clustering stage (2019\u0026ndash;2024), where \"representative keywords within clusters\" help identify core research areas in translational applications of hydrogels in orthopedics.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section3\"\u003e\u003ch2\u003e3.3.2. Keyword Alluvial Flow Visualization\u003c/h2\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e, related keywords form distinct research modules that either diverge or converge over time through recombination to generate new modules. Across the 25 years, certain keywords exhibit enduring relevance, while others emerge as new trends or fade from prominence. Table S4 (Supplementary Material) enlists the top five keyword modules with the highest annual flow.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNotably, Module 1 in 2024 (marked in red) emerges as the most persistent module, forming the largest research branch within this flow. Additionally, we visualized the top six modules from 2024 (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). Module 1, \"MSCs,\" includes 37 keywords (e.g., scaffolds, tissue engineering, and drug delivery) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eA). Module 2, \"fracture,\" contains 23 keywords (e.g., deformation, tough hydrogels, and double network hydrogels) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eB). Module 3, \"endothelial cells,\" encompasses 19 keywords (e.g., blood vessels, coculture, and biomaterial scaffolds) (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eC). Module 4, \"demineralized bone matrix,\" lists 17 keywords (e.g., health, periodontal regeneration, and biphasic calcium phosphate) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eD). Module 5, \"articular cartilage,\" comprises 15 keywords (e.g., osteochondral defects and knee osteoarthritis) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eE). Module 6, \"DNA,\" consists of 15 keywords (e.g., calcium carbonate and osteoclastogenesis) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003eF). Collectively, these modules likely represent emerging trends for hydrogel-based applications for orthopedics over the coming five years and beyond.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eA: Mesenchymal stem cells and associated factors.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eB: Fracture-related cellular and molecular markers.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eC: Endothelial cells and their functional attributes.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eD: Polymer networks and mechanical properties (e.g., toughness, hysteresis).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eE: Articular cartilage and delivery systems.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eF: DNA mechanics and osteoclastogenesis regulators (e.g., alkaline phosphatase, dexamethasone).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section3\"\u003e\u003ch2\u003e3.3.3. Timeline Visualization of References\u003c/h2\u003e\u003cp\u003eA timeline visualization based on citation trajectory identifies emerging, classical, and outdated research themes. The timeline map of hydrogel-related studies in orthopedics comprises 17 clusters, ranked by size (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eA). Clusters 1 (3D printing), 5 (self-healing), 6 (bone morphogenetic protein), 8 (chondrogenesis), 10 (calcium phosphate cement), 14 (cell viability), and 16 (stiffness) are considered classical topics\u0026mdash;not the latest but intricately interconnected with other clusters. Clusters 3 (photopolymerization), 11 (polyion complexation), 12 (biodegradable starch cements), 13 (mannitol porogen), and 15 (tantalum) are indicated as outdated\u0026mdash;showing minimal connections and no subsequent development. Clusters 0 (bone regeneration), 2 (bioprinting), 4 (osteoarthritis), 7 (tissue engineering), and 9 (mechanotransduction) are identified as emerging topics\u0026mdash;remaining active since their inception and signaling future research directions; Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e elaborates on these clusters. Figure\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eB highlights key classical references (large nodes with red circles) that have significantly driven respective subfield development (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eB). For example, Koons GL (2020); \u003cem\u003eMaterials design for bone-tissue engineering\u003c/em\u003e (Cluster 0, co-citation frequency: 186) emphasizes biomimetic material design and scalable fabrication, including 3D printing, for bone regeneration. Kang HW (2016); \u003cem\u003eA 3D bioprinting system to produce human-scale tissue constructs\u003c/em\u003e (Cluster 2, co-citation frequency: 135) introduces the Integrated Tissue-Organ Printer (ITOP) for vascularized constructs. Wei W (2021); \u003cem\u003eAdvanced hydrogels for cartilage repair\u003c/em\u003e (Cluster 4, co-citation frequency: 108) reviews hydrogel innovations in cartilage regeneration targeting osteoarthritis. Huu MT (2021); \u003cem\u003eStrong tough hydrogels via freeze-casting and salting out\u003c/em\u003e (Cluster 7) proposes a novel strategy for tendon-like hydrogel synthesis. Turnbull G (2018); \u003cem\u003e3D bioactive composite scaffolds for bone tissue engineering\u003c/em\u003e (Cluster 9) discusses composite materials for bridging bone regeneration challenges. Citation trends for these five articles (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eC) suggest their continued relevance in future research.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of emerging topics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\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\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClusterID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSize\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSilhouette\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAverage Year\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLabel (LLR)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRepresentative keywords\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e380\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.802\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003ebone regeneration\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ebone regeneration; hydroxyapatite nanofiber; biomimetic composite hydrogel; adaptable hydrogel; hydroxyapatite nanorods | tissue engineering; growth factors; cells therapies; glioma inhibition; carbon nanotube\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e291\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.943\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003ebioprinting\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003etissue engineering; growth factors; cells therapies; in-situ bioprinting; bioactive ceramics | 3d bioprinting; silk fibroin; 4d bioprinting; cell viability; situ bioprinting\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e152\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.935\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eosteoarthritis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003etissue engineering; msk disorders; targeting therapy; ball bearings; cartilage injuries | bone regeneration; bone tissue engineering; schwann cells; bone microenvironment; targeting therapy\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e123\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.934\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003etissue engineering\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003emechanical properties; double-network hydrogels; soft tissue repair; host-guest interaction; fracture toughness | strain sensor; double-network hydrogel; alpha-thioctic acid; tough adhesive; natural globulin\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.989\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003emechanotransduction\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003etissue engineering; extracellular matrix; tumor microenvironment; three-dimensional tumor models; vitro models | bone regeneration; biphasic calcium phosphate; stem cell differentiation; elastomer nanohybrid; stem cell manipulation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present bibliometric analysis elucidates the dynamic evolution of hydrogel research in orthopedic diseases over the past two decades, revealing a paradigm shift from passive structural scaffolds to multifunctional, stimuli-responsive platforms. By accessing data from 8,685 publications, we identified critical trends, collaborative networks, and emerging frontiers that collectively shape the trajectory of hydrogel-based orthopedic therapies. This review contextualizes these findings within the broader scientific landscape, highlights technological advancements, addresses translational challenges, and outlines strategic directions for future research in the field.\u003c/p\u003e\n\u003ch3\u003e1.Thematic Evolution: From Structural Support to Multifunctional Platforms\u003c/h3\u003e\n\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e\u003ch2\u003e1.1 Historical Trajectory and Key Milestones\u003c/h2\u003e\u003cp\u003eEarly research in the 2000s predominantly focused on establishing hydrogels as viable structural substitutes for bone repair. Dominant clusters in this era, such as #0 \"biodegradable polymers\" and #2 \"MSCs\" (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA), emphasized hydrogel degradation rates and osteogenic compatibility. A pioneering study by Chen et al introduced double-network hydrogels to address the intrinsic brittleness of conventional materials by combining ionic and covalent crosslinking, achieving fracture energies comparable to natural cartilage\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. This innovation enabled mechanoactive hydrogels to withstand mechanical loads in fractures and osteochondral defects. Nonetheless, limitations persisted in replicating bone\u0026rsquo;s hierarchical architecture and integrating bioactive cues, restricting their clinical adoption. Another noteworthy contribution during this phase included a review by Kaveh Roshanbinfar et al. (2025), which laid the foundation for 3D bioprinting by highlighting hydrogel compatibility with additive manufacturing technologies\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Meanwhile, keyword bursts such as \"gene expression\" (2004\u0026ndash;2014) signaled early attempts at modulating cellular responses via hydrogel-based gene delivery. The mid-2010s witnessed a surge in publications (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA), driven by functionalization strategies to enhance hydrogel bioactivity and adaptability. Burst keywords such as \"high mechanical strength\" (2011\u0026ndash;2018) and \"fibroblast growth factor\" (2007\u0026ndash;2017) underscored concerted efforts to improve mechanical resilience and integrate growth factors for targeted tissue regeneration. Liu et al. (2020) demonstrated that hydrogel stiffness directly regulates MSC differentiation via mechanotransduction, effectively linking material properties with cellular behavior \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Concurrently, Sun et al. (2022) reported that 3D bioprinting enabled the precise fabrication of vascularized bone scaffolds, marking a transition from static implants to spatially organized bioactive matrices \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. During this period, \"double-network hydrogels\" emerged as a prominent cluster (#2 in 2013\u0026ndash;2018, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eC), with studies further exploring multi-mechanism energy dissipation. These developments positioned hydrogels as dynamic platforms capable of mimicking native tissue mechanics while delivering therapeutic agents\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. The post-2018 period entered a phase of exponential growth, characterized by the emergence of clusters such as #0 \"tough hydrogels,\" #1 \"extracellular vesicles,\" and #2 \"3D bioprinting\" (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eD). Citation bursts for \"antibacterial\" (2023\u0026ndash;2024) and \"extracellular vesicles\" (2021\u0026ndash;2024) indicated a paradigm shift toward multifunctionality. For example, Li et al. designed a patterned alginate hydrogel with CuS nanoparticles (NPs), achieving an evaporation rate of 2.42 kg m⁻\u0026sup2; h⁻\u0026sup1; in brine with intrinsic antibacterial activity for solar desalination\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. This study influenced 129 articles in cluster #2 \"3D bioprinting,\" accelerating interest in patient-specific implants. Furthermore, Nedorubova et al. demonstrated that BMP2 polyplex-loaded PLA/PRP fibrin hydrogels outperformed chitosan-based matrices in osteoinduction, achieving effective bone regeneration in rat calvarial defect models\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. The burst detection maps (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) reveal how cross-disciplinary synergy has fueled advancements. Early dominance of bursts in \"ENGINEERING, BIOMEDICAL\" (2000\u0026ndash;2011) has transitioned toward \"COMPUTATIONAL BIOLOGY\" (2022\u0026ndash;2024), reflecting the emergence of AI-assisted hydrogel design. Aghajanpour et al. (2025) documented that machine learning, particularly artificial neural networks, outperforms traditional methods in predicting drug release from polymeric delivery systems, with notable success in 3D-printed formulations \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Moser et al. identified polyurethane (54 MPa) as the optimal material for meniscus implants via finite element analysis (FEA), closely replicating natural biomechanics; conversely, silk fibroin hydrogels showed instability after two weeks\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Emerging clusters such as #4 \"wound healing\" and #7 \"rheumatoid arthritis\" (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eD) suggest expanding scope of hydrogels beyond orthopedics. The integration of stimuli-responsive hydrogels (e.g., pH- or temperature-sensitive) and smart drug delivery systems (e.g., exosome-loaded matrices) will likely shape the next research frontier in this field\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003e1.2 Interdisciplinary Synergy and Technological Convergence\u003c/h2\u003e\u003cp\u003eThe co-authorship networks (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA\u0026ndash;C) highlight robust collaborations among countries, institutions, and authors. Notably, China and the United States dominate the country collaboration network (108 nodes, 1,005 links). Institutions (such as the Chinese Academy of Sciences and Harvard University) serve as key hubs bridging gaps between material synthesis and translational medicine. Prominent author clusters led by Gong Jian Ping (materials science) and Tabata Yasuhiko (drug delivery) illustrate how expertise in polymer chemistry, biomechanics, and regenerative medicine synergize to address complex orthopedic challenges. Burst detection analysis of subject categories (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) further underscores this interdisciplinary shift. Initial dominance of \"ENGINEERING, BIOMEDICAL\" (2000\u0026ndash;2011) gradually shifted toward \"COMPUTER SCIENCE, INTERDISCIPLINARY APPLICATIONS\" (2009\u0026ndash;2015) and \"MATHEMATICAL \u0026amp; COMPUTATIONAL BIOLOGY\" (2022\u0026ndash;2024), indicating the increasing adoption of computational tools in hydrogel design. Yang et al. developed a linagliptin-loaded dynamic hydrogel (AG-CD@LINA) capable of modulating macrophage polarization via TLR3-NF-κB signaling, thereby promoting osteogenesis and angiogenesis in diabetic bone defects\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Besides, Yu et al. introduced 3D bioprinted GelMA scaffolds embedded with luteolin-loaded ZIF-8 NPs that synergistically enhance osteogenesis and immune regulation for bone regeneration\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. The burst keyword \"extracellular vesicles\" (2021\u0026ndash;2024, strength: 18.66) reflects the integration of cell-free regenerative strategies. Li et al. reported an injectable nanofiber-hydrogel composite (NHC) for the delivery of MSC-derived extracellular vesicles, significantly improving healing in Crohn's perianal fistulas by promoting macrophage polarization and angiogenesis. This approach bridges immunology, nanotechnology, and hydrogel design, marking a paradigm shift from cell-based to EV-mediated therapies\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Orthopedic disorders such as osteomyelitis and osteoporotic fractures require solutions that combine structural reinforcement, infection control, and tissue regeneration. This demand has fostered interdisciplinary collaborations among microbiologists (e.g., antibacterial hydrogel design), material scientists (e.g., tough hydrogels), and clinicians (e.g., \u003cem\u003ein vivo\u003c/em\u003e validation). Liu et al. developed a piezoelectric hydrogel (Hyd6) that, when combined with ultrasound stimulation, facilitates cartilage regeneration by recruiting stem cells and activating Ca2+/CaM/CaN signaling pathways\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Additionally, Niu et al. engineered a ZIF-8-modified hydrogel (SHPP-ZB) capable of sequentially releasing PDGF-BB and BMP-2 to stimulate vascularized bone regeneration through coordinated MAPK/Wnt signaling \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003e2. Translational Challenges: Bridging the Lab-to-Clinic Gap\u003c/h3\u003e\n\u003cdiv id=\"Sec26\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Standardization and Regulatory Hurdles\u003c/h2\u003e\u003cp\u003eHydrogel research is impeded by variability in synthesis methods, mechanical testing protocols, and \u003cem\u003ein vitro/in vivo\u003c/em\u003e evaluation criteria. For instance, cluster #0 \"tough hydrogels\" (2019\u0026ndash;2024, 176 articles) encompasses diverse approaches to achieving mechanical resilience\u0026mdash;ranging from double-network architectures to nanocomposite reinforcement. However, inconsistencies in reporting parameters, such as fracture energy (varying widely from 100 to 9,000 J m⁻\u0026sup2;), complicate direct cross-study comparisons. These challenges largely stem from the lack of standardized evaluation protocols for material performance, discrepancies in regulatory policies across countries, and insufficient guidance on clinical trial design. Wu et al. (2018) emphasized that the absence of unified standards for assessing biocompatibility and mechanical properties undermines the preclinical development of hydrogel-based products\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Moreover, divergent regulatory frameworks across countries further exacerbate the assessment and approval timelines of these products. The United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have established distinct regulatory pathways that reflect their individual legal and safety requirements. Consequently, hydrogel manufacturers must navigate a complex landscape of requirements, increasing compliance burdens with delays in market approval\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Multicomponent hydrogels have garnered attention owing to their excellent biocompatibility and versatile functionalization capabilities, rendering them suitable for various clinical applications, including bone repair and tissue regeneration\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, the lack of standardized protocols and well-defined regulatory guidelines significantly hampers the clinical transition of injectable hydrogels being extensively explored for tissue regeneration \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. Similarly, 3D bioprinting (cluster #2, 129 articles) faces challenges related to bioink viscosity and printing resolution. One primary obstacle is the optimization of bioink viscosity to ensure both printability and cellular viability. Studies have demonstrated that bioinks exhibiting rapid recovery characteristics post-extrusion can improve shape fidelity during 3D printing processes\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. Specific formulations that balance high viscosity for structural integrity while allowing for workable rheological properties are crucial. For instance, the inclusion of nanomaterials such as nanocellulose or Laponite in the bioink composition has been documented to enhance mechanical strength while preserving the desired shear-thinning properties\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e. Additionally, the size of printing nozzles significantly impacts the resolution of bioink deposition. Smaller nozzle diameters facilitate higher print resolution but may require corresponding adjustments in bioink viscosity to prevent clogging and ensure smooth flow\u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. These complex requirements underline the need for bioink formulations that not only support cell viability but also tailor to the specific operational constraints of bioprinting systems\u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec27\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Scalability and Manufacturing Challenges\u003c/h2\u003e\u003cp\u003eAlthough 3D bioprinting holds promise for producing patient-specific implants, scalability remains a significant bottleneck. Existing bioprinting technologies struggle to achieve the high resolution (\u0026lt;\u0026thinsp;50 \u0026micro;m) required for trabecular bone structures. Furthermore, post-printing cell viability often declines below 70%, largely due to shear stress during extrusion. Recent advances in *sacrificial bioinks* and *light-based printing* (e.g., digital light processing; DLP) likely present avenues to address these issues; however, cost-effective production methods are urgently needed for low-resource settings. Bioinks incorporating additives such as methylcellulose for spatially controlled gene delivery have demonstrated improved printability and cell viability\u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e. DLP-based methods facilitate enhanced printing precision and speed. They employ light to polymerize bioinks with high resolution, thereby augmenting the capability for complex tissue structures\u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e. These technologies may offer superior control over the printed microstructure while potentially increasing cell viability through reduced mechanical strain during the process \u003csup\u003e[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e. Current bioprinting systems are often prohibitively expensive, which limits accessibility and widespread adoption, especially in underserved regions. Research efforts focusing on the development of more affordable and versatile bioprinting technologies could bridge this gap. Ongoing studies indicate that automation in bioprinting may enable rapid scaling of production without compromising the quality and fidelity of printed constructs\u003csup\u003e[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003e3. Emerging Frontiers: From Personalized Medicine to Sustainable Solutions\u003c/h3\u003e\n\u003cdiv id=\"Sec29\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Smart Hydrogels with Diagnostic Capabilities\u003c/h2\u003e\u003cp\u003eRecent innovations emphasize the potential of MXene-based hydrogels as intelligent materials for wound healing. Notably, these hydrogels exhibit excellent conductivity and create a moist microenvironment that accelerates the healing process\u003csup\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e. The integration of MXenes enables these materials to function effectively as epidermal sensors, facilitating real-time monitoring of wound conditions and thus transforming passive hydrogel systems into active, responsive platforms\u003csup\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e. Moreover, the fabrication of multifunctional hydrogels, such as those utilizing agarose sacrificial templates, demonstrates the versatility of these materials. By incorporating pore channels, these hydrogels support controlled drug release and establish responsive therapeutic microenvironments\u003csup\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/sup\u003e. Self-healing features represent another significant frontier in the field. Hydrogels with an intrinsic ability to autonomously repair upon damage provide unique advantages in medical applications, particularly for chronic wound management. Injectable formulations of these intelligent hydrogels for direct applications to wounds allow for rapid injury response, aiding healing while addressing challenges concerning accessibility and complexity of larger wound areas\u003csup\u003e[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/sup\u003e. Furthermore, the integration of smart hydrogels into wearable medical devices has gained traction. These devices are capable of responding to physiological stimuli, offering a non-invasive approach for monitoring diseases such as diabetes or neuromuscular conditions\u003csup\u003e[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]\u003c/sup\u003e. The coupling of biosensing abilities with therapeutic functionalities positions these smart hydrogels at the forefront of personalized medicine, enabling tailored treatment strategies.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec30\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Combatting Oxidative Stress and Microbial Resistance\u003c/h2\u003e\u003cp\u003eEmerging research demonstrates that hydrogels functionalized with materials such as graphene and cerium oxide NPs (CNPs) effectively combat oxidative stress. For example, Zhou et al. reported that a ROS-scavenging graphene-based hydrogel significantly enhanced vascularized bone regeneration by eliminating ROS, thus promoting an optimal extracellular environment for bone healing\u003csup\u003e[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]\u003c/sup\u003e. Likewise, Li et al. explored the use of ursodeoxycholic acid NPs, exerting potent antioxidant and anti-inflammatory activities in MSCs to improve osteogenic differentiation \u003csup\u003e[\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]\u003c/sup\u003e. In parallel, the incorporation of silver NPs into hydrogel scaffolds serves as another viable antimicrobial therapy. The well-documented effectiveness of silver against a range of bacteria, coupled with its controlled release behavior within hydrogel matrices, facilitates localized infection management in open fractures\u003csup\u003e[\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]\u003c/sup\u003e. However, balancing antimicrobial efficacy with cytocompatibility remains a critical challenge, as elevated silver concentrations can adversely impair MSC proliferation \u003csup\u003e[\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]\u003c/sup\u003e. The integration of antioxidant and antibacterial properties in hydrogels presents a dual approach to mitigating oxidative stress and microbial resistance effectively. For instance, Zheng et al. developed a multifunctional polyphenol-containing hydrogel that reduced oxidative stress while concomitantly enhancing cellular responses favorable to bone regeneration\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Furthermore, the combination of polyphenols and CNPs within hydrogels demonstrate synergistic effects, offering simultaneous protection against oxidative stress and microbial invasion \u003csup\u003e[\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]\u003c/sup\u003e. Innovative hydrogel designs capable of delivering these therapeutics in a site-specific, controlled manner are crucial for localized treatment strategies. Incorporating self-healing functionality and biological activity in these hydrogels could significantly improve the clinical management of bone degeneration and associated infections\u003csup\u003e[\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003e4. Future Directions: Strategic Priorities for Innovation\u003c/h3\u003e\n\u003cdiv id=\"Sec32\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Multi-Omics Integration for Personalized Implants\u003c/h2\u003e\u003cp\u003eThe convergence of genomics, proteomics, and advanced hydrogel designs could open new avenues for *patient-specific therapies*. Artificial intelligence (AI)-driven platforms are poised to be pivotal players in optimizing the design of personalized therapies. AI-assisted examination of bone density scans and other relevant omics data can help predict optimal scaffold porosity and mechanical properties compatible with individual patients. Recent advancements in computational methodologies for multi-omics analysis suggest that AI integration can unravel intricate interactions within metabolic pathways, thereby refining personalized medical strategies\u003csup\u003e[\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]\u003c/sup\u003e. Additionally, the increasing incorporation of genomic profiling into clinical trials emphasizes the potential of precision medicine to improve patient outcomes significantly\u003csup\u003e[\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]\u003c/sup\u003e. These innovations align with the recent keyword bursts in *computational biology* (2022\u0026ndash;2024) and *precision medicine*.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec33\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Hybrid Systems for Complex Tissue Regeneration\u003c/h2\u003e\u003cp\u003eTo create a hierarchical tissue scaffold, combining biodegradable hydrogels with electrospun fibers can reproduce the intricate architecture of native ECMs\u003csup\u003e[\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]\u003c/sup\u003e. Electrospun fiber mats can markedly enhance the mechanical integrity of hydrogels, which are otherwise susceptible to mechanical failure under stress \u003csup\u003e[\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]\u003c/sup\u003e. These composite materials merge the advantageous properties of both hydrogels (hydrophilicity and biocompatibility) and electrospun fibers (tensile strength and structural mimicry of ECM), creating scaffolds conducive to osteochondral tissue engineering\u003csup\u003e[\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]\u003c/sup\u003e. Development of vascularization strategies is crucial for scaling these hybrid systems for clinical applications. One innovative solution is the fabrication of microfluidic-channeled hydrogels, designed to mimic the Haversian canal networks of natural bone. These microchannels facilitate nutrient diffusion and cellular migration, essential for tissue integration and vascularization during implantation\u003csup\u003e[\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]\u003c/sup\u003e. Embedding microchannels within hydrogel-based scaffolds can not only enhance cell infiltration and nutrient supply but also address key challenges in large-scale tissue engineering \u003csup\u003e[\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003e5. Limitations and Methodological Reflections\u003c/h3\u003e\n\u003cp\u003eDespite offering a comprehensive overview of hydrogel research in orthopedic applications, this bibliometric analysis is subject to several limitations that warrant consideration. First, the exclusive reliance on WoSCC introduces language bias, as non-English publications (e.g., Chinese or Japanese studies) are underrepresented. Second, keyword-based clustering may overlook nuanced thematic connections, such as specialized hydrogel applications in rare bone cancers. Future studies would benefit from incorporating semantic analysis tools and multi-lingual databases to enhance inclusivity. Moreover, the rapid evolution in hydrogel technology\u0026mdash;evidenced by 332 citation bursts in 2024\u0026mdash;necessitates continuous bibliometric updates to capture emerging trends effectively. Collaborative platforms such as *OpenHydrogelDB*, a community-driven repository for hydrogel properties, hold potential to standardize data sharing and accelerate innovation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis discussion synthesizes the transformative potential of hydrogels in orthopedic therapy while concurrently acknowledging the multifaceted challenges impeding their clinical translation. By leveraging interdisciplinary collaboration, advancing bio-fabrication technologies, and prioritizing sustainable design, the next decade holds promise for hydrogel-based solutions. These innovations could revolutionize areas, including osteoarthritis management, critical-sized defect repair, and personalized regenerative medicine. Future progress will depend on fostering partnerships across academia, industry, and clinical sectors to overcome translational barriers and accelerate the deployment of hydrogel-based platforms in orthopedic care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLong Xie: Writing – original draft, Visualization, Methodology, Investigation, Formal analysis, Data curation.\u003c/p\u003e\n\u003cp\u003eYuqin Peng: Writing – review \u0026amp; editing, Writing – original draft, Visualization.\u003c/p\u003e\n\u003cp\u003eXiang Shen: Validation. Investigation. Validation. Methodology. Supervision, Resources.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eXiao PL, Cui AY, Hsu CJ et al (2022) Global, regional prevalence, and risk factors of osteoporosis according to the World Health Organization diagnostic criteria: a systematic review and meta-analysis. Osteoporos Int 33(10):2137\u0026ndash;2153\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDiseases GBD, Injuries C (2024) Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990\u0026ndash;2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 403(10440):2133\u0026ndash;2161\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSasaki M, Karikkineth BC, Nagamine K et al (2014) Highly conductive stretchable and biocompatible electrode-hydrogel hybrids for advanced tissue engineering. Adv Healthc Mater 3(11):1919\u0026ndash;1927\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLin Y, Wu H, Wang J et al (2025) Nicotinamide Adenine Dinucleotide-Loaded Lubricated Hydrogel Microspheres with a Three-Pronged Approach Alleviate Age-Related Osteoarthritis. ACS Nano 19(18):17606\u0026ndash;17626\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShan J, Cheng L, Li X et al (2025) End-tail soaking strategy toward robust and biomimetic sandwich-layered hydrogels for full-thickness bone regeneration. Bioact Mater 49:486\u0026ndash;501\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi Y, Chen B, Yao D et al (2025) Enhancing salt resistance and all-day efficient solar interfacial evaporation of antibacterial sodium alginate-based porous hydrogels via surface patterning. Carbohydr Polym 359:123588\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZheng J, He J, Wu J et al (2025) Polyphenol-Mediated Electroactive Hydrogel with Armored Exosomes Delivery for Bone Regeneration. ACS Nano 19(18):17796\u0026ndash;17812\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGao Y, Liu Y, Hao H (2025) A 10-year knowledge mapping of T cells in rheumatoid arthritis: A bibliometric analysis. Hum Vaccin Immunother 21(1):2450855\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun W, Wu W, Dong X et al (2024) Frontier and hot topics in the application of hydrogel in the biomedical field: a bibliometric analysis based on CiteSpace. J Biol Eng 18(1):40\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCao S, Wei Y, Yao Z et al (2024) A bibliometric and visualized analysis of nanoparticles in musculoskeletal diseases (from 2013 to 2023). Comput Biol Med 169:107867\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArruda H, Silva ER, Lessa M et al (2022) VOSviewer and Bibliometrix. J Med Libr Assoc 110(3):392\u0026ndash;395\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiao G, Wu J, Peng X et al (2020) Visualized analysis of trends and hotspots in global oral microbiome research: A bibliometric study. MedComm 1(3):351\u0026thinsp;\u0026ndash;\u0026thinsp;61. 2020\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCastano S, Ferrara A, Montanelli S (2017) Exploratory analysis of textual data streams. Future Generation Comput Syst 68:391\u0026ndash;406\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQin L, Zhu Y, Zhang H et al (2024) Lignin-modified cellulose nanofibers hydrogel under adjustable binary solvent systems with excellent adhesion, self-healing and anti-freeze properties. Int J Biol Macromol 279(Pt 2):135559\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhan H, Jiang S, Jonker AM et al (2020) Self-recovering dual cross-linked hydrogels based on bioorthogonal click chemistry and ionic interactions. J Mater Chem B 8(27):5912\u0026ndash;5920\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLu J, Gao Y, Cao C et al (2025) 3D bioprinted scaffolds for osteochondral regeneration: advancements and applications. Mater Today Bio 32:101834\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen J, Huang J, Hu Y (2021) 3D Printing of Biocompatible Shape-Memory Double Network Hydrogels. ACS Appl Mater Interfaces 13(11):12726\u0026ndash;12734\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoshanbinfar K, Evans AD, Samanta S et al (2025) Enhancing biofabrication: Shrink-resistant collagen-hyaluronan composite hydrogel for tissue engineering and 3D bioprinting applications. Biomaterials 318:123174\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu Y, Li Z, Li J et al (2020) Stiffness-mediated mesenchymal stem cell fate decision in 3D-bioprinted hydrogels. Burns Trauma 8:tkaa029\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun X, Jiao X, Yang X et al (2022) 3D bioprinting of osteon-mimetic scaffolds with hierarchical microchannels for vascularized bone tissue regeneration. Biofabrication 14(3)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMa C, Wang J, Li Q et al (2025) Injectable oxidized high-amylose starch hydrogel scaffold for macrophage-mediated glioblastoma therapy. Biomaterials 318:123128\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNedorubova IA, Bukharova TB, Mokrousova VO et al (2022) Comparative Efficiency of Gene-Activated Matrices Based on Chitosan Hydrogel and PRP Impregnated with BMP2 Polyplexes for Bone Regeneration. Int J Mol Sci 23(23)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAghajanpour S, Amiriara H, Esfandyari-Manesh M et al (2025) Utilizing machine learning for predicting drug release from polymeric drug delivery systems. Comput Biol Med 188:109756\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoser AC, Fritz J, Kesselring A et al (2025) Biomechanical testing of virtual meniscus implants made from a bi-phasic silk fibroin-based hydrogel and polyurethane via finite element analysis. J Mech Behav Biomed Mater 162:106830\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGhasemi S, Najafi M, Doroudian M et al (2025) Temperature- and pH-Responsive Poly(NIPAM-co-HEMA-co-AAm) Nanogel as a Smart Vehicle for Doxorubicin Delivery; Combating Colorectal Cancer. Gels 11(4)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang P, Chen X, Qin Y et al (2025) Regulation of osteoimmune microenvironment via functional dynamic hydrogel for diabetic bone regeneration. Biomaterials 320:123273\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYu SY, Wu T, Xu KH et al (2025) 3D bioprinted biomimetic MOF-functionalized hydrogel scaffolds for bone regeneration: Synergistic osteogenesis and osteoimmunomodulation. Mater Today Bio 32:101740\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi L, Yao Z, Salimian KJ et al (2025) Extracellular Vesicles Delivered by a Nanofiber-Hydrogel Composite Enhance Healing In Vivo in a Model of Crohn's Disease Perianal Fistula. Adv Healthc Mater 14(7):e2402292\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu YB, Liu X, Li XF et al (2025) Multifunctional piezoelectric hydrogels under ultrasound stimulation boost chondrogenesis by recruiting autologous stem cells and activating the Ca(2+)/CaM/CaN signaling pathway. Bioact Mater 50:344\u0026ndash;363\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNiu X, Xiao S, Huang R et al (2024) ZIF-8-modified hydrogel sequentially delivers angiogenic and osteogenic growth factors to accelerate vascularized bone regeneration. J Control Release 374:154\u0026ndash;170\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu D, Xu X (2018) Exploring cutting-edge hydrogel technologies and their biomedical applications. Bioact Mater 3(4):446\u0026ndash;447\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCruz Rivera S, Torlinska B, Marston E et al (2021) Advancing UK Regulatory Science Strategy in the Context of Global Regulation: a Stakeholder Survey. Ther Innov Regul Sci 55(4):646\u0026ndash;655\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOvrebo O, Perale G, Wojciechowski JP et al (2022) Design and clinical application of injectable hydrogels for musculoskeletal therapy. Bioeng Transl Med 7(2):e10295\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang Y, Yin B, Wong SHD (2023) Multicomponent Hydrogels in Clinical and Pharmaceutical Applications.449\u0026ndash;501\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMandal A, Clegg JR, Anselmo AC et al (2020) Hydrogels in the clinic. Bioeng Transl Med 5(2):e10158\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang Y, Li Z, Guan J et al (2021) Hydrogel: A potential therapeutic material for bone tissue engineering. AIP Adv. 11(1)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArslan H, Davuluri A, Nguyen HH et al (2024) 3D Bioprinting Using Universal Fugitive Network Bioinks. ACS Appl Bio Mater 7(10):7040\u0026ndash;7050\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGolebiowska AA, Tan M, Ma AW et al (2025) Decellularized cartilage tissue bioink formulation for osteochondral graft development. Biomed Mater 20(2):025002\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGu Y, Schwarz B, Forget A et al (2020) Advanced Bioink for 3D Bioprinting of Complex Free-Standing Structures with High Stiffness. Bioeng (Basel) 7(4):141\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJeon O, Park H, Lee MS et al (2025) In situ cell-only bioprinting of patterned prevascular tissue into bioprinted high-density stem cell-laden microgel bioinks for vascularized bone tissue regeneration. bioRxiv\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim J, Kong JS, Kim H et al (2021) Maturation and Protection Effect of Retinal Tissue-Derived Bioink for 3D Cell Printing Technology. Pharmaceutics 13(7):934\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGonzalez-Fernandez T, Rathan S, Hobbs C et al (2019) Pore-forming bioinks to enable spatio-temporally defined gene delivery in bioprinted tissues. J Control Release 301:13\u0026ndash;27\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAydin L, Kucuk S, Kenar H (2020) A universal self-eroding sacrificial bioink that enables bioprinting at room temperature. Polym Adv Technol 31(7):1634\u0026ndash;1647\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLight-based vat-polymerization bioprinting (2023) Nat Reviews Methods Primers. 3(1)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTao J, Zhu S, Zhou N et al (2022) Nanoparticle-Stabilized Emulsion Bioink for Digital Light Processing Based 3D Bioprinting of Porous Tissue Constructs. Adv Healthc Mater 11(12):e2102810\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuh J, Moon YW, Park J et al (2021) Combinations of photoinitiator and UV absorber for cell-based digital light processing (DLP) bioprinting. Biofabrication 13(3):034103\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBhusal A, Dogan E, Nieto D et al (2022) 3D Bioprinted Hydrogel Microfluidic Devices for Parallel Drug Screening. ACS Appl Bio Mater 5(9):4480\u0026ndash;4492\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBhusal A, Dogan E, Nguyen HA et al (2021) Multi-material digital light processing bioprinting of hydrogel-based microfluidic chips. Biofabrication 14(1):014103\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi M, Zhang Y, Lian L et al (2022) Flexible Accelerated-Wound‐Healing Antibacterial MXene‐Based Epidermic Sensor for Intelligent Wearable Human‐Machine Interaction. Adv Funct Mater. 32(47)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang W, Zhou H, Xu Z et al (2024) Flexible Conformally Bioadhesive MXene Hydrogel Electronics for Machine Learning-Facilitated Human-Interactive Sensing. Adv Mater 36(31):e2401035\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMao J, Yu QJ, Wang S (2021) Preparation of multifunctional hydrogels with pore channels using agarose sacrificial templates and its applications. Polym Adv Technol 32(4):1752\u0026ndash;1762\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang W, Wang Y, Huang Z et al (2018) On-Demand Dissolvable Self-Healing Hydrogel Based on Carboxymethyl Chitosan and Cellulose Nanocrystal for Deep Partial Thickness Burn Wound Healing. ACS Appl Mater Interfaces 10(48):41076\u0026ndash;41088\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFang Y, Han Y, Yang L et al (2025) Conductive hydrogels: intelligent dressings for monitoring and healing chronic wounds. Regen Biomater 12:rbae127\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen Z, Liu J, Chen Y et al (2021) Multiple-Stimuli-Responsive and Cellulose Conductive Ionic Hydrogel for Smart Wearable Devices and Thermal Actuators. ACS Appl Mater Interfaces 13(1):1353\u0026ndash;1366\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhou J, Li Y, He J et al (2023) ROS Scavenging Graphene-Based Hydrogel Enhances Type H Vessel Formation and Vascularized Bone Regeneration via ZEB1/Notch1 Mediation. Macromol Biosci 23(4):e2200502\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi J, Han F, Ma J et al (2021) Targeting Endogenous Hydrogen Peroxide at Bone Defects Promotes Bone Repair. Adv Funct Mater 32(10)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThakur N, Manna P, Das J (2019) Synthesis and biomedical applications of nanoceria, a redox active nanoparticle. J Nanobiotechnol 17(1):84\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIqbal N, Anastasiou A, Aslam Z et al (2021) Interrelationships between the structural, spectroscopic, and antibacterial properties of nanoscale (\u0026lt;\u0026thinsp;50 nm) cerium oxides. Sci Rep 11(1):20875\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eXv D, Cao Y, Hou Y et al (2025) Polyphenols and Functionalized Hydrogels for Osteoporotic Bone Regeneration. Macromol Rapid Commun 46(2):e2400653\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRizwana N, Maslekar N, Chatterjee K et al (2024) Dual Crosslinked Antioxidant Mixture of Poly(vinyl alcohol) and Cerium Oxide Nanoparticles as a Bioink for 3D Bioprinting. ACS Appl Nano Mater 7(16):18177\u0026ndash;18188\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYetgin A (2025) Revolutionizing multi-omics analysis with artificial intelligence and data processing. Quant Biology 13(3)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRadigan R, Sangal A, Zhang D et al (2025) Feasibility trial of Darwin OncoTreat and OncoTarget precision medicine testing to improve outcomes for patients with limited metastatic disease that failed first-line systemic therapy. PLoS ONE 20(6):e0325769\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eErben J, Jirkovec R, Kalous T et al (2022) The Combination of Hydrogels with 3D Fibrous Scaffolds Based on Electrospinning and Meltblown Technology. Bioeng (Basel) 9(11):660\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYu X, Zou Z, Li Y et al (2025) Fiber-reinforced gelatin-based hydrogel biocomposite tubular scaffolds with programmable mechanical properties. Biomed Mater 20(3):035031\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Souza SOL, de Oliveira SM, Silva LM et al (2022) Biomolecule-based hydrogels containing electrospun fiber mats with enhanced mechanical properties and biological activity. JOURNAL OF APPLIED POLYMER SCIENCE. 139(28)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGeng X, Xu ZQ, Tu CZ et al (2021) Hydrogel Complex Electrospun Scaffolds and Their Multiple Functions in In Situ Vascular Tissue Engineering. ACS Appl Bio Mater 4(3):2373\u0026ndash;2384\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhu Y, Zhang Q, Shi X et al (2019) Hierarchical Hydrogel Composite Interfaces with Robust Mechanical Properties for Biomedical Applications. Adv Mater 31(45):e1804950\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBandiera A, Passamonti S, Dolci LS et al (2018) Composite of Elastin-Based Matrix and Electrospun Poly(L-Lactic Acid) Fibers: A Potential Smart Drug Delivery System. Front Bioeng Biotechnol 6:127\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 3","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\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":"Hydrogel, Orthopedic Diseases, Bibliometrics, CiteSpace, VOSviewer, Drug Delivery, Tissue Engineering, Bone Regeneration","lastPublishedDoi":"10.21203/rs.3.rs-8008252/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8008252/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eHydrogels have emerged as pivotal biomaterials in orthopedic research, attributed to their unique three-dimensional networks, high hydration capacity, and exceptional biocompatibility. Despite extensive exploration of hydrogels in bone repair, cartilage regeneration, and drug delivery, a systematic bibliometric analysis mapping the global research landscape remains absent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e This study conducts the first comprehensive bibliometric analysis to delineate research hotspots, evolutionary trends, and collaborative networks in hydrogel applications for orthopedic diseases from 2000 to 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e A total of 8,685 peer-reviewed articles from the Web of Science Core Collection (WoSCC) were assessed using CiteSpace and VOSviewer. Co-citation networks, keyword clustering, and timeline visualization were employed to identify thematic shifts, interdisciplinary connections, and emerging frontiers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e Annual publication data demonstrated exponential growth (R² = 0.94), with the United States (36.2%) and China (28.5%) collectively dominating global research output. Established research domains focused on hydrogel-mediated drug delivery systems—particularly for rheumatoid arthritis therapy—alongside tissue-engineered scaffolds and bone regeneration strategies. Concurrently, emerging clusters highlighted transformative innovations, including injectable hydrogels (keyword burst strength: 12.7), antibacterial/antioxidant systems targeting infection and oxidative stress, and 3D-bioprinted constructs for precision orthopedic applications. Furthermore, collaborative networks coalesced into three transnational clusters: (1) mechanoactive hydrogels for load-bearing applications, (2) extracellular vesicle-functionalized systems for enhanced bioactivity, and (3) smart hydrogel-responsive implants integrating real-time diagnostics, collectively driving advancements in personalized orthopedic solutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e This analysis reveals a paradigm shift from passive structural hydrogels to multifunctional, stimuli-responsive platforms addressing oxidative stress, microbial resistance, and personalized tissue regeneration. These identified trends provide strategic directions to accelerate clinical translation in the treatment of osteoarthritis, critical-sized bone defects, and inflammatory joint diseases.\u003c/p\u003e","manuscriptTitle":"Knowledge Domains and Emerging Trends of Hydrogels in Orthopedic Diseases：A Bibliometric and Visualization Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-04 07:56:25","doi":"10.21203/rs.3.rs-8008252/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":"72944530-30ce-4f26-bb7f-aac92347fe97","owner":[],"postedDate":"November 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57281922,"name":"Cell \u0026 Tissue Engineering"}],"tags":[],"updatedAt":"2025-11-04T07:56:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-04 07:56:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8008252","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8008252","identity":"rs-8008252","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}