Bibliometric mapping of mesenchymal stem cell therapy for bone regeneration from 2013 to 2023

Abstract

Mesenchymal stem cells (MSCs) have shown significant potential in bone regeneration and regenerative medicine in recent years. With the advancement of tissue engineering, MSCs have been increasingly applied in bone repair and regeneration, and their clinical application potential has grown through interdisciplinary approaches involving biomaterials and genetic engineering. However, there is a lack of systematic reviews summarizing their applications in bone regeneration. To address this gap, we analyzed the latest research on MSCs for bone regeneration published from 2013 to 2023. Using the Web of Science Core Collection, we conducted a literature search in December 2024 and employed bibliometric tools like CiteSpace and VOSviewer for a comprehensive analysis of the key research trends. Our findings focus on the development of cell engineering, highlighting the advantages, limitations, and future prospects of MSC applications in bone regeneration. These insights aim to enhance understanding of MSC-based bone regeneration, inspire new research directions, and facilitate the clinical translation of MSC research.

1 Introduction

Bones have a unique scarless regenerative capacity, allowing them to completely repair damaged areas and restore their normal shape and function. Unlike most tissues, bone tissue does not form scars after injury but instead undergoes a complete regeneration process through a series of steps (1, 2). This process primarily relies on two pathways: intramembranous ossification and endochondral ossification. These two mechanisms play a crucial role in bone regeneration, jointly facilitating the restoration and repair of bone tissue (3–5).

Mesenchymal stem cells (MSCs) are multipotent stem cells found primarily in bone marrow, periosteum, and endosteum. These cells can differentiate into osteoblasts (bone-forming cells) and chondrocytes (cartilage-forming cells), playing a key role in fracture repair (6–10). MSCs not only promote bone healing by directly forming bone and cartilage but also influence the healing process indirectly through the secretion of cytokines, regulation of angiogenesis, and modulation of inflammatory responses (11, 12). Therefore, MSCs hold great potential in the fields of bone regeneration and tissue engineering.

However, in conventional clinical trials for bone repair, stem cell therapy faces challenges such as significant cell loss post-transplantation, apoptosis, and poor targeting (13, 14). Consequently, it is crucial to target the delivery of MSCs to the site of bone injury or defect to optimize their regenerative effects. Currently, researchers have adopted various strategies to enhance MSC homing and transplantation, including the use of biomaterial scaffolds, growth factors, and cell surface modifications (15–19). These methods aim to improve MSC targeting and survival rates at the target site, thereby promoting tissue regeneration and repair. Despite significant breakthroughs in mesenchymal stem cell therapy for bone regeneration over the past decade, there is still a lack of systematic reviews on its application in this field.

Bibliometric analysis is a method that can quantitatively and qualitatively analyze authors, journals, research teams, sponsoring institutions, or countries, to describe the current state of research and predict trends in related fields (20). Therefore, this paper employs bibliometric analysis to conduct an in-depth examination of the relevant literature, exploring the current status, advantages, limitations, and future prospects of this field. It is anticipated that these insights will positively influence the advancement of stem cell applications in bone regeneration and offer new directions for researchers in this field.

2 Materials and methods

In our study, we conducted a comprehensive literature search on December 2, 2024, utilizing the Web of Science Core Collection as our primary data source. The search terms were as follows: topic = cell delivery OR cell implantation OR cell therapy AND topic = mesenchymal stem cells OR MSCs AND topic = bone regeneration OR osteogenesis AND publishing year = (January 1, 2013, to December 31, 2023). To assess the obtained literature, we employed standard bibliometric indicators commonly used in the scientific community, such as total citations, average citations, and the H-index as proposed by Hirsch (21). We obtained journal impact factors (IF) from Journal Citation Reports 2023 for analysis. We opted to use VOSviewer software to construct and visualize the bibliometric network of publications in our study (22). In our study’s visual depiction using VOSviewer, nodes represent various elements, with their sizes indicating the number of associated publications. The nodes’ colors signify the publication year, while the thickness of the interconnecting lines denotes the strength of collaboration or integration between these elements. CiteSpace (6.3. R1), developed by Professor Chaomei Chen, was used for country and institution collaboration analysis, journal dual-map overlay analysis, author collaboration and cited author analysis, cited literature and keyword cluster detection, and burst citation literature and keyword analysis (23). We conducted analyses using CiteSpace (6.3. R1), incorporating parameters such as the link retention factor (LRF = 2.5), the year of review (LBY = 5), e (N = 1), a time span from 2013 to 2023, 2 years per slice, link strength (cosine, within the slice range), selection criteria based on the g-index (k = 4), and minimum duration for keywords (MD = 2 as a reference).

3 Result

3.1 Global paper publication trend

A total of 8,243 articles were collected from the Web of Science database. Among them, book chapters (57 articles), proceeding papers (29 articles), early access publications (12 articles), meeting abstracts (9 articles), editorial materials (24 articles), retracted publications (14 articles) and others (2 articles) were excluded. Additionally, 26 non-English studies were excluded. Finally, 8,070 articles met the inclusion criteria for the Web of Science database (Figure 1). We summarized the global literature trends (Figure 2A). From 2013 to 2015, the annual publication counts steadily increased from 496 to 672. After 2016, the annual count fluctuated, peaking at 872 publications in 2020. Despite a slight decline in subsequent years, the overall trend in cumulative publications shows continuous growth, surpassing 8,000 by 2023. The top five countries with the highest number of articles are China (3,006 articles, 37.249%), the USA (1,668 articles, 20.669%), South Korea (545 articles, 6.753%), Germany (462 articles, 5.725%), and Japan (457 articles, 5.663%) (Table 1).

Figure 1

Figure 2

3.2 Author collaboration and co-citation

We collected a total of 8,070 articles involving 38,062 authors and visualized their collaboration networks (Figure 3A), emphasizing the co-authorship connections among the top seven authors (Figure 3B). The collaborative relationships between key authors were further analyzed using CiteSpace (Figure 3C). By examining the co-cited authors, we identified “Caplan A. I.,” “Dominici M.,” “Friedenstein A. J.,” “Liu Y.,” and “Pittenger M. F.” as the top five authors with the highest total connection strength, suggesting they may be central figures in the field (Figure 3D). Citation bursts, which indicate periods of frequent citations, revealed that these authors have experienced significant attention over time, serving as an important metric for their impact. The top 20 most-cited authors demonstrated the strongest citation bursts in publications related to mesenchymal stem cell applications (Figure 3E). “Amini Ami R.” ranked first with a burst strength of 29.34, followed by “Hare J. M.” with a burst strength of 22.25. Notably, “Pittenger M. F.” had the longest duration of citation bursts, spanning over 8 years (2015–2023). Interestingly, our analysis of the top 10 authors with the most publications revealed that nine out of the 10 are based in China (Table 2). Additionally, we summarized the top 10 funding agencies supporting research in this field (Table 3).

Figure 3

3.3 National and institutional cooperation

In the co-authorship countries visualization shown in Figure 4A, it can be observed that the United States (strength = 579) has the highest total connection strength, followed by China (strength = 443), Germany (strength = 175), and Japan (strength = 121). In terms of publication output, China leads with 3,006 articles, followed by the United States (1,668 articles), South Korea (545 articles), Germany (462 articles), and Japan (457 articles) (Table 1). There is a relatively close collaboration among China, the USA, South Korea, Germany, and Japan (Figure 4B). Table 4 lists the top 10 institutions publishing the most related literature, with Shanghai Jiao Tong University ranked first, followed by Sichuan University and the Chinese Academy of Sciences. These results are also reflected in Figure 4C. Among these institutions, there are relatively close connections between the Chinese Academy of Sciences, Shanghai Jiao Tong University, Sun Yat-sen University, Southern Medical University, and Sichuan University (Figure 4D).

Figure 4

3.4 Journals and research field

In this study, we identified 10 key research fields related to the topic (Table 5). Among these, Cell Biology had the highest number of publications (2,273 papers, H-index = 111), followed by Materials Science (2,197 papers, H-index = 126) and Engineering (1,762 papers, H-index = 108). The top 10 journals by publication volume were also identified, with Stem Cell Research and Therapy leading with 237 articles (impact factor = 7.1, 2023), followed by the International Journal of Molecular Sciences with 228 articles (impact factor = 4.9, 2023), and Acta Biomaterialia with 195 articles (impact factor = 9.4, 2023). Other notable journals included Biomaterials (192 articles, impact factor = 12.8, 2023) and Stem Cells International (162 articles, impact factor = 3.8, 2023). Interestingly, the publication numbers across these journals were relatively similar (Table 6).

We conducted a visual analysis of reference citations across journals (Figure 5A) and performed co-clustering analysis using CiteSpace (Figure 5B). Key research hotspots identified include “mesenchymal stem cells,” “graphene oxide,” and “bone tissue engineering.” Using VOSviewer, we visualized the citation relationships among journals (Figure 5C), with the top five journals by total link strength being Biomaterials (2,717,148), Acta Biomaterialia (1,173,617), Stem Cells (895,597), PLoS One (841,759), and Tissue Engineering Part A (807,800). Additionally, we highlighted the top 15 journals with the highest citation rates in publications related to mesenchymal stem cell therapy for bone regeneration (Figure 5D).

Figure 5

3.5 Literature citation

Figure 4E shows the citation frequency by different countries and regions, with China leading at 2,432,564 citations, significantly ahead of the USA (2,344,484 citations), South Korea (661,042 citations), Italy (678,669 citations), and Germany (838,267 citations). Among the top 10 countries and regions with the highest average citation frequency (Table 1) (Figure 2B, 2C), the USA has the highest average citation frequency (48.04 citations), followed by England (45.85 citations), Italy (45.35 citations), India (38.38 citations), and South Korea (38.11 citations). We also analyzed the top 10 countries with the highest H-index in related publications (Figure 2D), with China (H-index = 130) and the USA (H-index = 125) leading, followed by South Korea (H-index = 72), Italy (H-index = 68), and Germany (H-index = 65).

3.6 Keyword

We conducted a keyword network visualization of the collected articles (Figure 6A). Among the 19,426 keywords, the top five with the highest total connection strength are “mesenchymal stem cells” (total link strength = 24,809), “differentiation” (total link strength = 16,154), “regeneration” (total link strength = 15,189), “in vitro” (total link strength = 14,407), and “bone-marrow” (total link strength = 12,233). We also visualized these keywords based on their average publication year (Figure 6B). Using CiteSpace, we created a visualization of these keywords (Figure 6C) and performed cluster analysis to establish a visual clustering of keywords (Figure 6D). Finally, we identified the 20 keywords with the most significant citation growth, finding that “extracellular vesicles” had the most significant citation growth strength (strength = 43.93, 2021–2023) (Figure 6E).

Figure 6

3.7 References

A total of 128 out of the 261,144 cited references meet the threshold of being cited at least 80 times (Figure 7A). Among the top 5 most cited review articles (Table 7), “Clinical trials with mesenchymal stem cells: an update” was cited 1,023 times (24), followed by “Materials design for bone-tissue engineering” cited 1,016 times (25) and “Alginate-based biomaterials for regenerative medicine applications” cited 907 times (26). In the top 5 most cited research articles (Table 8), “Bone substitutes in orthopaedic surgery: from basic science to clinical practice” was cited 772 times (27), “Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial” was cited 651 times (28) and “Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression” was cited 577 times (29). We performed co-cited references visualization for this field using CiteSpace (Figure 7B) and conducted a cluster visualization analysis of the references (Figure 7C) and found that “extracellular vesicles,” “cardiac regeneration,” and “bone tissue engineering” are hot topics in the references.

Figure 7

4 Discussion

4.1 Publication trends of this research

Our team conducted a bibliometric analysis of papers published between 2013 and 2023 to explore the progress and future directions in the field of mesenchymal stem cells for bone regeneration. During this period, the global number of papers on this topic showed a fluctuating upward trend, with a peak of 872 papers published in 2020. Although the number of papers published annually has generally increased, this trend was not statistically significant. On a global scale, China and the United States published far more papers than other countries/regions, together accounting for more than 50% of the total papers published in this field worldwide. Interestingly, we found that nine out of the top 10 authors with the highest citation counts were all from China. Furthermore, not only did China publish more papers than the U.S., but its H-index also surpassed that of the U.S., reflecting the significant contributions made by Chinese researchers in this field. However, in terms of average citation count, China ranked 7th, indicating that while China has a large number of papers, the academic impact of each paper is relatively lower. It is also worth noting that only four Chinese institutions appeared in the top 10 institutions by publication volume. This suggests that to enhance a country’s academic standing, it is not only necessary to establish top-tier research institutions and increase research investment but also to focus on improving research quality and avoiding an overemphasis on quantity.

Among the top 10 journals in this field, the leading ones focus on Cell Biology, Materials Science, Engineering, and Research Experimental Medicine. “Cell Biology” and “Materials Science” not only publish a large number of articles but also have high H-indices. This indicates that in this field, authors are more inclined to focus on cell biology and materials, which are highly relevant to the topic.

4.2 Hotpots and frontiers of this research

Highly explosive keywords can predict emerging directions. The current network reflects all keywords included in publication titles or abstracts, which we divide into two parts: mesenchymal stem cells and bone regeneration by tissue engineering.

4.2.1 Mesenchymal stem cells

Mesenchymal stem cells (MSCs) are multipotent stem cells with unique self-renewal ability, pluripotency, and genomic stability (30–34). They are capable of exhibiting multipotent differentiation, making them promising candidates for cell therapy. MSCs are found not only in fetal tissues but also in many adult tissues, with few exceptions (35). According to the standards set by the International Society for Cell Therapy, the expression of specific cell surface markers is one of the fundamental characteristics of MSCs. Cells expressing CD73, CD90, and CD105 are considered MSCs with positive expression, while those expressing CD14, CD34, CD45, and HLA-DR are considered negative (36). MSCs can be induced to differentiate into adipocytes, chondrocytes, or osteocytes (37). In addition to their differentiation potential, MSCs also exhibit immunomodulatory properties, regulating, immune responses through the secretion of anti-inflammatory cytokines and interactions with immune cells (38–43). They also promote tissue repair and regeneration by secreting trophic factors that facilitate angiogenesis, inhibit cell apoptosis, and modulate the local microenvironment (44–48). Therefore, MSCs have a promising application in the field of bone regeneration and tissue engineering.

4.2.2 Bone regeneration by tissue engineering

Bone regeneration is a highly intricate biological process that involves the regulation of inflammation by immune cells (49), the impact of neurotrophic factors on bone repair, angiogenesis providing nutrients, and the involvement of osteoblasts and mesenchymal stem cells in the formation and remodeling of new bone tissue (50, 51). These processes are finely regulated by a range of biological factors and signaling molecules, including growth factors, cytokines, and neurotrophic factors, whose coordinated actions ultimately determine the speed and quality of bone regeneration (52).

To enhance the regeneration of damaged or deficient bone, several strategies are available, including autologous bone grafts, vascularized fiber grafts, allogeneic grafts, bone tissue engineering, and distraction osteogenesis (53–56). Among these, bone tissue engineering, which combines cells, scaffold materials, and growth factors to repair, replace, or enhance tissue function, has emerged as a highly promising approach for treating bone defects (57, 58). In the field, biomaterials play a crucial role as they can serve as carriers for cells, allowing for targeted implantation at the lesion site, and providing an optimal growth environment for the implanted cells (59, 60).

Collectively, these approaches promote bone repair and regeneration by providing scaffold support, promoting cell proliferation and differentiation, stimulating angiogenesis, repairing and remodeling bone tissue, and ensuring graft integration and stability. These are widely utilized in the field of bone defects.

4.3 Prospects of this research

Based on the above analysis and illustrations, we can observe that over the past 10 years, mesenchymal stem cell (MSC) therapy in the field of bone regeneration has mainly gone through a process from basic research to applied research, and then to clinical application. Early research by scientists was primarily focused on the basic characteristics and differentiation mechanisms of cells, which laid a solid foundation for future studies. During the mid-term phase, the focus shifted towards exploring methods to optimize differentiation and proliferation conditions. With the continuous advancement of technology, researchers have increasingly concentrated on clinical applications and personalized treatment strategies. For instance, they have utilized various technologies to enhance the targeting of MSCs and have developed personalized stem cell treatments tailored to the individual, aiming to improve therapeutic outcomes.

Despite some progress, several challenges remain in using MSCs for bone regeneration therapy. Firstly, issues related to cellular aging and functional decline during in vitro expansion affect not only MSCs derived from patients but also allogeneic MSCs from healthy donors (61). Secondly, the immune response is another critical issue, as the efficacy of MSC transplantation is significantly influenced by the patient’s immune status, and allogeneic MSC transplantation may trigger immune rejection (62). Additionally, although technical advancements have improved cell viability, the post-implantation survival rate remains a pressing issue.

To overcome these challenges, future research needs to further explore and develop new strategies and methods. This includes improving in vitro expansion techniques to minimize cellular aging, optimizing immunomodulatory strategies to reduce the risk of immune rejection, and enhancing the survival rate and functionality of MSCs in vivo. Through these efforts, MSC targeted therapies are expected to achieve safer and more effective applications in the field of bone regeneration.

4.4 Advances and limitations of this research

This study employed bibliometric and visualization analysis methods to explore the literature on mesenchymal stem cell therapy for bone regeneration over the past 10 years. While our findings are comprehensive and objective, there are inevitable limitations. Firstly, we used only the Web of Science Core Collection (WOSCC) for literature retrieval, excluding other databases such as PubMed, Scopus, Cochrane, and Embase. Although WOSCC is a widely used authoritative comprehensive database, this may have led to the omission of some relevant literature, resulting in potential selection bias. Secondly, we excluded non-English literature and non-research/review articles, which may overlook relevant studies published in other languages. Chinese publications, in particular, have made significant contributions in this field. Review and research articles are valuable publication types, each with its unique role and value. Therefore, we did not separately discuss research and review articles. Furthermore, we did not include articles published after January 2024, which may introduce a degree of predictive bias in the relevance analysis. Lastly, we did not consider the quality of the publications in certain analyses, treating high-quality and low-quality publications equally.

5 Conclusion

We conducted an in-depth study on the application of MSCs in bone regeneration therapy, summarizing the development trends in this field over the past 10 years through comprehensive literature analysis and visualization methods. We systematically analyzed global research dynamics and identified influential authors, institutions, and journals. Through co-occurrence analysis of keywords and research directions, we accurately captured the hotspots and emerging trends of MSCs in bone regeneration therapy. Our study comprehensively summarized the current status of MSCs in bone regeneration therapy, outlined the main focuses of research, and provided a forward-looking analysis of future trends. Our work aims to deepen the understanding of MSCs in bone regeneration therapy, provide insights to researchers, guide future research directions, and promote the translation and application of research outcomes. In the future, we will continue to explore the potential applications and mechanisms of MSCs, optimize treatment regimens, and improve treatment efficacy and biocompatibility. Additionally, we will enhance interdisciplinary collaboration to advance the clinical application of MSCs in bone regeneration therapy, aiming to provide more effective treatment options for patients and improve their quality of life. In summary, our study comprehensively elucidates the current status of MSCs in the field of bone regeneration therapy and provides an outlook on future directions, aiming to drive progress in this field, accelerate the translation of relevant research outcomes into clinical practice, and contribute to the development of bone regeneration therapy.

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