The Web of Science database covers the largest amount of literature in the medical field and is frequently utilized in bibliometric studies (Wang et al., 2022). We collected relevant literature from this database, focusing on the application of bioprinted hydrogels for bone regeneration. To ensure accuracy and consistency, we conducted a systematic search on 27 December 2024, for relevant literature included in the Web of Science database between January 2010 and March 2025. All retrievals were performed on the same day to prevent data bias due to updates in the Web of Science. Based on the previous statistics, we set the search strategy as follows: [(TS=(“print*” OR “bioprint*”) AND TS=(“hydrogel”OR“hydrogels”OR“gel”OR“gels”)) AND TS=(“bone regeneration*” OR “Osteoconduction”OR“bone repair*”OR“bone defect*”)]. Removing conference abstracts, book chapters, and reviews, we retrieved a total of 684 related papers.

684 articles were imported into VOSviewer (1.6.19) and bibliometric analysis was performed using the bibliometrix package (4.1.3) in R (4.3.0). We used tools such as CiteSpace (6.3.1), VOSviewer (1.6.19), the bibliometrix package (4.1.3) in R (4.3.0), and PS (2020) to process, visualize, and analyze the data of the 684 documents collected from the Web of Science database. The counting method used for all analyses was full count. In addition, an online bibliometric analysis platform (https://bibliometric.com) was used to assist in the analysis of the intensity of cooperation between countries.

CiteSpace (6.3.1) is an analytical software program developed for bibliometrics that employs algorithms to automatically extract and analyze key information in a research area. The tool analyzes the scope and hotspots of research in a given field and identifies trends for improvement in related disciplines (Cheng et al., 2022). We used this tool to obtain citation biplot overlays to analyze keywords, references, clusters, and collaborative relationships between countries and institutions. We used the burst detector option to detect the first 30 keywords. VOSviewer (1.6.19) systematically collects and organizes basic information, including countries, institutions, authors, journal publications, and collaborative networks, and visualizes and analyzes the data (van Eck and Waltman, 2010). This software can extract the key information that researchers require from a wide range of literature to create co-citation and co-authorship networks (Chen et al., 2021). We used software to explore the temporal distribution and dynamic variability of keywords in the field and accurately reveal the evolutionary trends of hotspots in the research area. In order to analyze the research hotspots, the type of analysis was selected as co-occurrence, the unit of analysis was selected as keywords, and the analysis was carried out using the full count method.

The bibliometrix package (version 4.1.3) in R is a mapping tool designed for systematic analysis (Aria et al., 2021) that enables the mapping and analysis of country distribution maps, author publications, and keyword development. It also facilitates the identification of trending themes and milestones in the literature for publications in related research areas. The most relevant affiliations should be selected as options during the analysis. Thematic maps and factor analysis are employed to elucidate the components of the constitutional structure.

Keyword analysis can outline the research object, content, and hotspots within a research field by identifying the most frequent words in the field, which are central to academic papers. Supplementary Table S2 lists the top 10 keywords with the highest frequency in this field, and among the extensive literature, “bone regeneration”, “3D printing”, “scaffold” and “hydrogel” are the keywords that appear more frequently (Figure 5), indicating that bioprinted hydrogel scaffolds are the current research hotspot in the field of bone regeneration.

We analyzed the titles, subject headings, and abstracts of 684 papers to identify common phrases and determine their frequency of occurrence. As shown in Figure 6A, “scaffolds” (138) appears most frequently, which is consistent with the results of the word cloud search.

The keywords in the field were categorized into five clusters using VOSviewer, as shown in Figure 6B. Cluster 1 focuses on the development of 3D-printed hydrogel scaffolds in additive manufacturing. Cluster 2 mainly includes the application of cellular scaffolds in bone tissue engineering. Cluster 3 focuses on bio-inks such as hydrogels and the effects of biomaterials on cells in the microenvironment. Cluster 4 investigates the application of growth factors in the field of bone regeneration. Cluster 5 provides an overview of the current state-of-the-art research on 4D printing in the field of biomedical sciences.

We then further used VOSviewer to color-code all keywords based on the average publication year, revealing trends in the field over time and exploring upcoming innovation directions. By analyzing the keyword sequencing map (Figure 6C), we found that osteogenesis, microenvironment, hydrogel, and 4D printing are relatively novel and promising areas in the field of bone regeneration. Recently, researchers have combined bioprinted hydrogel technology with cell-loaded scaffolds to advance the field of bone regeneration by restoring microenvironmental homeostasis at bone defect sites.

Keyword clustering analysis reveals the main themes and development states of a particular research area (Zhong et al., 2020). CiteSpace was used to divide the keywords into 19 sets and generate a clustering timeline. As shown in Figure 6D, the keywords included “#0 3 d printing”“#1 alginate fiber”“#2 3d bioactive composite scaffold”“#3 3d-printed barium strontium”“#4 stem cell function”“#5 topical review”“#6 inert dental glass-ceramics”“#7 cell-patterned construct”“#8 vivo repair”“#9 enhanced toughness”“#10 organ engineering”“#11 beta tri-calcium phosphate”“#12 bactericidal activity”“#13 bone tissue”“#14 3 d-bioprinted osteoblast-laden nanocomposite hydrogel construct”“#15 injectable bmp2”“#16 nitride-based hybrid aerogel membrane”“#17 dicalcium phosphates bioceramics”and“#18 recent advancement”. That the result shows that “3D printing” is the most important research area for hydrogels in bone tissue engineering. To further confirm the accuracy of our results, we conducted a thematic analysis of keyword trends using R (Figure 6E). Keywords such as “microenvironment” “defect” “biomaterials” “cells” “osteogenesis” “scaffolds” have been emerging in the field recently, indicating their importance. In addition, “scaffolds” “mesenchymal stem-cells” “ vitro” “hyaluronic-acid hydrogels” and “biofabrication” are important parts of bone tissue engineering in long-term studies. The evolutionary trend of these themes is consistent with the results of our analysis above.

Each quadrant on the thematic map has a specific meaning. The horizontal axis (X-axis) indicates centrality, and the vertical axis (Y-axis) indicates density. Regarding the quadrant distribution plotted in this study (Figure 7), the first quadrant (upper right) focuses on the optimization of hydrogel scaffolds, suggesting a promising future for this area. The second quadrant (upper left) shows the preparation of hydroxyapatite, the mechanical properties of biomaterials and the study of composite scaffolds, suggesting that this topic is well-developed but less important in the field of bone regeneration. The third quadrant (lower left) focuses on the imminent rapid surge or imminent slow disappearance of the controlled release of nanoparticles. Finally, the fourth quadrant (lower right) is dedicated to in vitro manufacturing of stem cells for bone regeneration and osteogenic differentiation. While these directions have not yet achieved mature research results, they hold an important position in the field of bone regeneration and may become a hot research area in the future.

The dual-map overlay of journals illustrates the citation relationships between journals and cited journals, with cited journals on the left and cited sources on the right. As shown in Figure 8, two primary and several secondary paths are displayed. Path ① indicates that literature published in CHEMISTRY, MATERIALS, and PHYSICS journals is mainly cited by other literature in PHYSICS, MATERIALS, and CHEMISTRY journals. Path ② indicates that literature published in MOLECULAR, BIOLOGY, and GENETICS journals is primarily cited by papers in PHYSICS, MATERIALS, and CHEMISTRY journals. The top 10 most cited articles in this field are shown in Supplementary Table S3, in which “Three-dimensional (3D) printed scaffold and material selection for bone repair” published by Zhang et al. (2019b) in Acta Biomaterialia in 2019, ranked first with 52 citations.

Bone is a tissue that can be sustainably regenerated (Dimitriou et al., 2011) and is the hardest organ in the human body. The treatment of both direct and indirect fractures involves bone regeneration. Bone defects not only cause an imbalance in the body, but more importantly, disturb the adaptive system within the bone, limiting its ability to regenerate. The three important processes in bone regeneration are osteoinduction, osteoconduction, and osteointegration (Albrektsson and Johansson, 2001). Osteoinduction refers to the formation of undifferentiated cells for osteogenesis through the aggregation of mesenchymal stem cells (Lewallen et al., 2015), osteoconduction refers to providing an environment for osteoblast growth (Weber, 2019), and osteointegration is the seamless integration of bone tissue with an implant (Morandini Rodrigues et al., 2022). After a patient undergoes trauma and inflammation sets in, mesenchymal stem cells (MSCs) aggregate at the trauma site to form fragile tissue, followed by angiogenesis, which promotes the hardening of soft tissue into hard bone tissue, and finally, osteoclasts and osteoblasts undergo superimposed replacement. Osteoblasts and osteoclasts are key factors involved in the bone regeneration process (Salhotra et al., 2020a). Osteoblasts are mainly derived from stem cells, and MSCs have become common stem cells in the field of bone tissue engineering owing to their proliferative properties (Tsiapalis and O'Driscoll, 2020). Since the internal pore size of the bone varies and is stepped from the inside to the outside, only a suitable pore size can ensure optimal cell adhesion. It has been the most clinically used treatment modality for autologous bone grafting (Dimitriou et al., 2011) because it lacks the risk of immune rejection and retains the same plasticity as living bone (Pereira et al., 2020); however, the limited amount of bone and donor site complications cannot be ignored. Allogeneic grafts have a large numerical advantage but their integration is less efficient (Ehrler and Vaccaro, 2000). Theoretically, allogeneic grafts can achieve the same effects as isografts; however, their use in treatment has not yet been standardized. Artificial bone grafts have become the focus of researchers and are mainly categorized as metals (Lu et al., 2023), bioceramics (Zhao et al., 2022) and polymers (Bharadwaz and Jayasuriya, 2020). However, bone tissue reconstruction with biologically inert metals often leads to secondary surgical repair because of the wear and tear susceptibility of the material (Salhotra et al., 2020b). Compared to other pure bioscaffold materials, hydrogel materials possess unique application potential in the field of bone regeneration.

Hydrogel is a hydrophilic polymer with a three-dimensional network structure, mainly classified as natural (e.g., collagen, hyaluronic acid, chitosan, and alginate) and synthetic (Zhu and Marchant, 2011). The excellent biocompatibility, high mechanical properties, adjustability and cell-carrying properties of hydrogels enable them to better adapt to the geometry and microenvironment of the bone defect sites, while the biodegradable nature of hydrogels avoids the risk of secondary surgeries for patients. Although the excellent biocompatibility of natural hydrogels places them in a high position in the field of regenerative medicine, their potential uncontrollability is an issue that researchers cannot ignore. Synthetic hydrogels lack biological activity, although they exhibit strong mechanical properties. Consequently, researchers are constantly searching for hydrogel materials that can carry cells. Saravanan et al. (Saravanan et al., 2018) indicated that CS/GP/GO hydrogels have better biocompatibility with MSCs and can promote osteogenesis, while Liu et al. (Liu et al., 2020) indicated that CD/HA/PVA hydrogels can support the proliferation and differentiation of MSCs in vivo.

Recently, bioprinting technology, which enables the construction of 3D structures using cells, proteins, and biomaterials, has been applied in the field of bone regeneration (Dimitriou et al., 2011) and offers a possibility for bone regeneration therapy. Multi-layer stacked printing can simulate the internal complexity of natural bone tissue, individualize the geometry of the area to be filled with bone defects, and adjust the hydrogel properties to match the mechanical strength of natural bone. Breakthroughs have been made in 3D bioprinting technology (Daly et al., 2017), and cell-loaded bioprinting has been realized (Yang et al., 2017). Bioprinted structures can change the internal spatial structure at different stimuli, enabling a high degree of control over mesenchymal stem cells. However, owing to the limitations of 3D bioprinting in personalizing the treatment of bone defects, 4D bioprinting was developed. This technology can change over time in response to stimuli such as pH, temperature, and is well adapted to the microenvironmental reconstruction of irregular bone defect sites (Zhang et al., 2019a). It can fulfill the functional transformation between organisms and hydrogel materials. In addition, bioprinted hydrogel scaffolds enable controlled release of bioactive molecules to induce vascularization and nerve regeneration in regenerated bone. Currently, bioprinted hydrogel scaffolds applied in the field of bone regeneration have been able to achieve good physical support from the macroscopic structure, but how to change the bionic properties of the microstructure of the hydrogel material to match different functional characteristics is the current challenge. So bioprinting of in situ-loaded stem cell bone-like organs may be the future development direction.

The results of the Most Relevant Affiliations indicate that research on the application of bioprinted hydrogels in bone regeneration is still in its initial stage, proving the great potential of research in this field. The results of the analysis of cooperation between institutions and countries show that although the cooperation between China and the United States is closer, which provides favorable conditions for technological exchanges between the two countries. However, the cooperation network between China and other countries is relatively weaker. The cross-regional and cross-institutional cooperation needs to be strengthened, therefore, institutions of various countries should quickly establish excellent academic cooperation in order to promote the rapid development of bioprinting hydrogel technology in the field of bone regeneration.

Biomaterials science combined with stem cell therapy and tissue engineering techniques are the basis of regenerative medicine. Bone regenerative medicine is a research area that focuses on bioprinted hydrogels. Compared with traditional techniques, bioprinted hydrogels can maximize the filling of space at the fracture site while simultaneously guaranteeing the stability of their mechanical properties. In recent years, research has shown on the development of cell-loaded hydrogels for the reconstruction of bone tissue for vascularization and nerve regeneration (Ashammakhi et al., 2019). However, the desirable decellularized extracellular matrix (ECM) of bone tissue has special mechanical structure and biochemical signals that can support cell adhesion and proliferation, Therefore, achieving the structural stability and signal maintenance of the ECM during decellularization in bioprinted hydrogels is the direction of scholars’ further research. Additionally, exosome hydrogels should also be capable of promoting new vessel generation and tissue regeneration in vivo, as well as inhibiting local tissue fibrosis.

In addition, 3D bioprinting enables the control of hydrogel structure and function, while 4D bioprinting further alters the morphology of the hydrogel over time. Future research on bioprinting will focus on the spatial equilibrium of MSCs with hydrogel scaffolds and osteogenic transformations (Benning et al., 2017). Bioprinting is a relatively recent technology (Kumar Gupta et al., 2022). Although bioprinting technology has been widely used in the field of biomedical engineering, bioprinted hydrogels have certain limitations in terms of computer program settings, large-scale production, and cell-carrying efficiency. To prevent the reduction of cell viability in printed hydrogels, the release of alkaline ions (Heid and Boccaccini, 2020) to prevent local pH increases or to optimize the thickness of the hydrogel coating (Ringeisen et al., 2004) can be considered. Bioprinting can improve the precision of personalized treatment for bone defects to a certain extent. However, printing standardization needs further exploration. To ensure the sustainable development of this technology in the medical field, future restrictions need to be strengthened in terms of the relevant requirements of regulatory authorities, demonstration of safety and efficacy, and translation of results. The stability and safety of hydrogels for bioprinting have to be demonstrated in a variety of animal models to further characterize their physicochemical properties such as degradability and mechanical properties. Additionally, qualified materials and standardized manufacturing lines during clinical translation are prerequisites for avoiding immune response. There is an immediate demand for further biological optimization of the materials and standard safe operating procedures. Basic research is the cornerstone of the development of bone regeneration technology, and translating the results is the key to clinical treatment. Reducing the cost of bioprinting, improving hydrogel cell-carrying technology, and shortening the time required for bone regeneration will promote the application of alternative hydrogel bone grafts in clinical treatment in the field of bone regeneration in the future.