Research trends and hotspots of mesenchymal stromal cells in intervertebral disc degeneration: a scientometric analysis

in EFORT Open Reviews
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Minghe YaoWest China School of Medicine, Sichuan University, Chengdu, China

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Tingkui WuDepartment of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China

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Beiyu WangDepartment of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China

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Correspondence should be addressed to B Wang; Email: dove-baker@163.com

*(M Yao and T Wu contributed equally to this work)

Open access

  • Mesenchymal stromal cells (MSCs) are important potential candidates for regenerative therapy for intervertebral disc degeneration (IDD). This scientometric study aimed to summarize the main research trends, identify current research hotspots, and measure the networks of the contributors and their scientific productivity.

  • A total of 1102 publications regarding MSC in IDD were recognized from January 2000 to April 2022. The number of records every year followed an overall uptrend with fluctuations.

  • The main trend of research demonstrated the practice of gradually applying MSC-based therapy to IDD with the assistance of advances in biomaterials and IDD pathology. A recent focus on MSC-derived exosomes and notochordal cells was detected.

  • The basic studies in this field were mainly contributed to by Japan, the USA, and European countries, while China dominated in the number of recent publications. Tokai University with Daisuke Sakai was the most productive contributor.

  • Cell biology, tissue engineering, and biomaterials were the categories with deep engagement in research of this field.

Abstract

  • Mesenchymal stromal cells (MSCs) are important potential candidates for regenerative therapy for intervertebral disc degeneration (IDD). This scientometric study aimed to summarize the main research trends, identify current research hotspots, and measure the networks of the contributors and their scientific productivity.

  • A total of 1102 publications regarding MSC in IDD were recognized from January 2000 to April 2022. The number of records every year followed an overall uptrend with fluctuations.

  • The main trend of research demonstrated the practice of gradually applying MSC-based therapy to IDD with the assistance of advances in biomaterials and IDD pathology. A recent focus on MSC-derived exosomes and notochordal cells was detected.

  • The basic studies in this field were mainly contributed to by Japan, the USA, and European countries, while China dominated in the number of recent publications. Tokai University with Daisuke Sakai was the most productive contributor.

  • Cell biology, tissue engineering, and biomaterials were the categories with deep engagement in research of this field.

Introduction

Mesenchymal stromal cells (MSCs) are easily accessed self-renewing cells with proliferation potential, multilineage differentiation potency, and immunoregulatory functions (1). Various cell sources can be used to isolate MSCs, including bone marrow (2, 3), adipose tissue (4, 5), and umbilical cord tissue (6). MSCs have been proved to be able to differentiate into multiple cells of mesodermal lineage (7, 8) and other embryonic lineages (9), making it possible to substitute for dysfunctional cells and repair damaged tissue. With low immunogenicity (10), MSCs also have immunomodulatory characteristics, which could have interactions with various cells in both innate and adaptive immune systems (11), thus downregulating inflammatory response which holds an important position in the tissue injury process. Due to these special biological properties, MSCs hold promising application prospects for regenerative medicine (12).

With a substantial global burden attributed to musculoskeletal disorders (13), regeneration therapeutics for intervertebral disc degeneration (IDD) promoted an etiological treatment to stop the continuous degradation of intervertebral disc. A restoration of the spinal anatomy and biomechanics may avoid the limitations of surgery like disc degeneration at adjacent levels and further pain (14). Among the available cell types, much attention has been paid to MSCs. This preference could be attributed to MSC’s properties and unique biological behaviors. In the degeneration process, disc dehydration and height loss are usually experienced due to the loss of glycosaminoglycans (GAGs). An increasing number of studies have demonstrated the ability of MSCs to differentiate into a nucleus pulposus (NP)-like phenotype which produces GAGs (15, 16, 17). The habitation of MSCs in degenerated discs had been proved to lead to an increase in GAG production rates (18). MSCs have also been shown to communicate with NP cells and influence their function in the coculture system (19, 20, 21, 22), indicating another possible mechanism of MSC’s therapeutic effect. The relevance between inflammation and disc degeneration was suggested by increasing proof (23, 24, 25), while MSCs were also demonstrated to suppress inflammatory mediators in proinflammatory disc models (26, 27, 28, 29, 30). When MSCs were applied to in vivo models, enhanced matrix production and increased disc height and hydration were observed (31, 32, 33, 34, 35). MSCs were also the most clinically evaluated stem cell type in IDD treatment during the last two decades (36, 37). The results of trials supported the efficacy and safety of MSC therapy in IDD (2, 4, 38, 39). Clinical trials of a larger scale (e.g. the RESPINE clinical trial (40)) were in operation. Due to MSC’s low immunogenicity and the immune escape of intervertebral disc, allogeneic MSC clinical injection was also highly expected and has been primarily confirmed on efficacy and safety (41, 42, 43, 44). Different from traditional autologous cell treatment, allogeneic cell therapies would enable the mass production of therapeutic cells, thus improving the cost and quality control and facilitating the introduction to the actual clinical practice (45, 46). Moreover, recent studies of MSC-derived exosomes (48, 49, 50) suggested a possible alternative cell-free therapeutic strategy that may avoid the difficulty in the survival of implanted cells (47).

Over the years, the researches in this field have thrived in number, and the engagement of other disciplines especially materials science has become prevalent and played an important role. In MSC treatment for IDD, biomaterials were applied as carriers from the starting stage of the research field (31). Besides, biomaterials were also considered as a potential method against cell leakage risk and harsh environment in the disc (51). The additional load of bioactive factors on biomaterials may also enhance disc regeneration (52). Such an increase in the literature and cooperation of different categories required new approaches to analyze the trends in the field.

Bibliometric analysis is a quantitative study of scientific publications that aims to reveal the progression of a science field. Bibliometrics selects the bibliographic factors as analysis objects (53), including references, keywords, titles, journals, authors, countries/regions, and affiliations (54), and discloses the historic and ongoing trends as well as the productive and important researchers and groups. Bibliometric analysis can also be enhanced by the science map, a representation of how disciplines, fields, and individual papers or authors are related to one another, as shown by their physical proximity and relative locations (55). The scientometric analysis is a combination of both visualization and statistical bibliometric methods (56). Through the recognition of the occurrence burst of a topic in a period, bibliometric analysis also makes recognition of the newly focused hotspots (57). Our research was based on bibliometric data of the literature in the field of MSCs in IDD. We aimed to provide an overview of the spatial and temporal distribution characteristics, development history, and current hotspots of the researches on MSC in IDD.

Methods

Data acquisition

Science Citation Index Expanded (SCI-Expanded) edition of the Web of Science (WOS) Core Collection was employed for document information extraction. The search strategy was built with terms including ‘intervertebral disc’, ‘intervertebral disc degeneration’, ‘nucleus pulposus’, and ‘mesenchymal stromal cells’ (Supplementary information 1, see section on supplementary materials given at the end of this article). The index date of the literature was set before April 30, 2022, and the lower date limit was set at January 1, 1900. The records search and download were conducted on May 1, 2022, and finished within the day. Additional information of the records was also extracted from WOS, including the number of publications, citation counts, and average citations per item (ACI) for each year, WOS category, author, institution, country/region, and journal.

Scientometric analysis

VOSviewer (version 1.6.17) and CiteSpace (version 5.8.R3) were utilized to analyze the retrieved text files. CiteSpace and VOSviewer parameter settings can be found in Supplementary information 2.

VOSviewer is a program presented by Nees Jan van Eck and Ludo Waltman designed for constructing and visualizing bibliometric networks (58). Science maps were conducted using VOSviewer in the aspects of the author, affiliation, and country/region. For these three units of analysis, co-occurrence networks were generated, which are graphs representing how frequently units appear together (59). In such co-occurrence networks, the relative size of a node represents the number of publications, while the link between nodes is the visualization of co-authorship and the relative thickness of the link represents link strength. The total link strength is the sum of the co-occurrence among the units calculated, representing a relative centrality of these units.

CiteSpace, developed by Chen Chaomei, focuses on analyzing the frontiers of research as well as the key knowledge base (60). CiteSpace was employed for network visualization and burst detection of references and author keywords. The data cleaning and duplicate removal were also performed with CiteSpace before scientometric analysis. For author keywords, co-occurrence networks were drawn and clustered. For references, co-citation networks were generated and clustered. Co-citation means that two papers are cited by the same paper published after them (61). There are two indicators in the clustered network: the modularity (Q score) and the silhouette (S score). The Q score, ranging from 0 to +1, is a measure of the extent to which a network can be divided into clusters. A Q score greater than 0.3 represents a significant cluster structure (62). The S score ranges from –1 to +1 and measures the consistency within the cluster (63). Respectively, an S value of more than 0.3, 0.5, or 0.7 means a network that is considered homogenous, reasonable, or highly credible (59). Burst is a description of the rate of change (64). In this study, we analyzed the burst of frequency to detect the soaring appearance of emergent terms.

Results

Publication characteristic analysis

The search retrieved 1102 records published between 2000 and 2022 that met the inclusion criteria (Fig. 1). The search retrieved no record before 2000. The number of publications followed an overall uptrend with fluctuations during the period from 2000 to 2021 (Fig. 2). The number of records in this field experienced a notable escalation in general but fell in 2007, 2011, and 2016. Publications between 2008 and 2015 were cited more frequently.

Figure 1
Figure 1

Flow diagram of inclusion and analysis process.

Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0083

Figure 2
Figure 2

Trends of the number of publications and citations.

Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0083

No duplicate was detected. In data cleaning, the records were divided into six document types. The most common type of literature was article (819), accounting for 74.3% of the total records, and review (244) ranked second, accounting for 22.1%. The other document types were meeting abstract (29), editorial material (6), letter (3), and correction (1). Meeting abstracts and corrections were filtered to improve the quality of the record dataset, leaving 1072 records for the input of scientometric analysis.

Co-cited reference analysis

References clusters and trend evolution

A network of reference co-citation was generated with labeled clusters and their representative articles (Fig. 3). Seventeen main different clusters in this network were detected with significant modularity and silhouette scores, implying high credibility (Q = 0.6918; S = 0.8438). Of the 17 main clusters, four clusters, #9, #10, #13, and #16, were recognized to be of little relevance to the topic after careful inspection. They were excluded from the analysis and the network. Details of all the 13 left clusters are shown in Supplementary Table 1.

Figure 3
Figure 3

Co-citation reference network (2000–2022) (A) and correspondent clustering analysis (B) obtained with CiteSpace. Note: (A) Cluster number is ranked based on the cluster size. The size of a node (article) is proportional to the number of times the article has been co-cited. The number in the center of a node refers to the cluster that it belongs to. The colors of a node represent the years it was cited, from 2000 (pink) to 2022 (yellow). The width of a link is proportional to the number of times the two linked articles are co-cited. The colors of a link represent the publication year of the first citing paper, from 2000 (pink) to 2022 (yellow). (B) Visualization map of the corresponding clusters.

Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0083

The co-citation evolution process is available in Supplementary Video demonstrating how co-citation between references changed by year. The evolution path showed one major trend started in 2000–2002 with two clusters. The two clusters (indicated as the label, size, the average publication year of the cluster references, silhouette score, and the representative reference) were clusters #8 (‘potential therapeutic model’; 35; 2000; S = 0.977; Horner & Urban (65)) and #12 (‘disc cell biology’; 23; 2000; S = 1; Pittenger et al. (8)). These two clusters formed the knowledge base of the following researches and evolved into cluster #1 (‘spinal surgery’; 167; 2004; S = 0.858; Sakai et al. (33)). Cluster #1 shared hotspots with cluster #11 (‘bovine bone marrow’; 24; 2006; S = 0.956; Dominici et al. (66)), which further developed into cluster #14 (‘degenerative disease’; 20; 2008; S = 0.937; Carragee et al. (67)), #2 (‘regeneration potential’; 129; 2009; S = 0.851; Sakai et al. (68)), and #5 (‘nanofibrous scaffold’; 70; 2008; S = 0.889; Smith et al. (69)). They merged into clusters #0 (‘rabbit model’; 180; 2012; S = 0.671; Risbud et al. (70)) and #7 (‘degenerative nucleus pulposus cell’; 35; 2013; S = 0.954; Risbud & Shapiro (71)). After the period of more recent cluster #4 (‘pulposus-derived mesenchymal stem cell’; 88; 2015; S = 0.879; Sakai & Andersson (72)), the trend came into cluster #3 (‘interventional pain physician’; 126; 2017; S = 0.807; Noriega et al. (43)) while branching into two related clusters: #6 (‘mesenchymal stem’; 49; 2018; S = 0.897; Cheng et al. (73)) and #15 (‘notochordal cell-based treatment strategies’; 18; 2018; S = 0.985; Tang et al. (74)).

To recognize more recent trends, reference co-citation networks of the last 6 years (April 2016–April 2022) and the last 1-year period (April 2021–April 2022) were generated (Supplementary Fig. 1 and Fig. 2). The modularity scores were significant, and the silhouette suggested highly credible clusters in both networks (Q = 0.5898, S = 0.7931; Q = 0.7797, S = 0.9064). The two networks offered a closer look at the current development of the main research trend. Cluster #3 in 2000–2022 network developed into two clusters in the last 6 years: cluster #1 (‘rat model’; 79; 2017; S = 0.713; Bowles & Setton (75)) and #3 (‘systematic review’; 59; 2015; S = 0.858; Kumar et al. (4)) and in the last 12 months became cluster #1 (‘intradiscal injection’; 37; 2018; S = 0.883; Centeno et al. (76)), #2 (‘mesenchymal stromal cell’; 33; 2017; S = 0.801 Kumar et al. (4)), #3 (‘tissue regeneration’; 29; 2018; S = 0.75; Bowles & Setton (75)), and #6 (‘omics method’; 20; 2018; S = 0.989; Clouet et al. (77)). The two branch clusters remained in the last 6 years network as clusters #4 (‘extracellular vesicle’; 48; 2018; S = 0.85; Lu et al. (47)) and #7 (‘notochordal cell-based treatment strategies’; 18; 2018; S = 0.979; Tang et al. (74)). In the past 1 year, they further evolved into clusters #0 (‘cell-derived exosome’; 49; 2018; S = 0.915; Cheng et al. (73)) and #7 (‘self-assembling peptide hydrogel’; 19; 2018; S = 0.949; Barakat et al. (78)).

Most cited references and citation bursts

The top 10 cited references related to MSCs in IDD are listed in Table 1. The article published in 2003 by Sakai et al. (31) had the maximum citation counts of 186 times. They reported the transplantation of autologous MSCs to degenerate disc in a rabbit model with a follow-up of 8 weeks, which was the first application of MSCs in IDD experimental animal models. The second most cited article was published by Sakai et al. in 2006 (33) with 178 citations, in which the authors described an autologous MSC transplantation experiment in a rabbit model with a longer follow-up period of 24 weeks. The third most cited paper was published by Risbud et al. in 2004 (16) with 170 citations. In this article, the authors reported that hypoxia and transforming growth factor-β would drive rat MSC differentiation toward the phenotype which was consistent with that of the NP. The involvement of MAPK signaling pathways was also detected. The top 10 most cited papers in the last 6 years are also listed (Supplementary Table 3E). Orozco et al.’s 2011 pilot study (2) assessing the feasibility and safety of autologous mesenchymal bone marrow cells in patients was the most cited one, followed by Sakai et al.’s review in 2015 (72) summarizing the obstacles and solutions of stem cell therapy for intervertebral disc regeneration and Sakai et al.’s 2012 article (68) which reported the correlation between the exhaustion of NP progenitor cells and IDD, providing insights of IDD pathology.

Table 1

Top 10 cited references in mesenchymal stromal cells in intervertebral disc degeneration research (2000–2022).

Rank Reference Title Citations, n
1 Sakai et al. (31) Transplantation of mesenchymal stem cells embedded in Atelocollagen((R)) gel to the intervertebral disc: a potential therapeutic model for disc degeneration 186
2 Sakai et al. (33) Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc 178
3 Risbud et al. (16) Differentiation of mesenchymal stem cells toward a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy 170
4 Sakai et al. (15) Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc model – Potential and limitations for stem cell therapy in disc regeneration 168
5 Orozco et al. (2) Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study 153
6 Richardson et al. (22) Intervertebral disc cell-mediated mesenchymal stem cell differentiation 138
7 Pittenger et al. (9) Multilineage potential of adult human mesenchymal stem cells 137
8 Crevensten et al. (32) Intervertebral disc cell therapy for regeneration: mesenchymal stem cell implantation in rat intervertebral discs 126
9 Sakai et al. (69) Exhaustion of nucleus pulposus progenitor cells with aging and degeneration of the intervertebral disc 124
10 Hiyama et al. (34) Transplantation of mesenchymal stem cells in a canine disc degeneration model 123

In burstiness detection, the top three references in the strength of burst of all time were Sakai et al.’s 2015 review (72) and 2006 article (33) and Richardson et al.’s 2006 article (79) which presented that human NP and MSC coculture could initiate the differentiation of human MSC (Supplementary Table 2A and 2B). When we focused on the last 6 years (Supplementary Table 2C and D), the top three recent burst citations all focused on MSC-derived exosomes: Liao et al.’s 2019 article (80) about the modulation of endoplasmic reticulum stress by exosomes, Cheng et al.’s 2018 research (73) on miR-21 in exosomes, and Lu and colleagues’ study published in 2017 (47) revealing the interaction between NP cells and MSC by exosomes as the vehicle, thus underpinning a focused interest in exosomes of MSC-based therapy for IDD in recent years.

Co-occurrence analysis

Author keyword analysis

We analyzed author keywords to verify the research trends and recent hotspots. The co-occurrence keyword networks were extracted and displayed as timeline graphs by CiteSpace (Supplementary Fig. 3). Between 2000 and 2022, 10 clusters were identified. The largest one was labeled as ‘clinical trial’, followed by ‘stem cell’, ‘disc degeneration’, ‘biological activity’, ‘PVA cryogel’, ‘gene therapy’, ‘mesenchymal stem cell’, ‘biologic strategies’, ‘high glucose’, and ‘mesenchymal stem cell line’. Focusing on the last 6 years, the same network was extracted, and the most important cluster with the most keywords was ‘current status’, followed by ‘mesenchymal stem’, ‘adipose stem cell’, ‘systematic review’, ‘disc cell’, ‘biological activity’, ‘clinical trial’, ‘calcium-dependent apoptosis’, and ‘induced stem cell migration’. Both networks presented a silhouette score of significance (S > 0.6) and an acceptable modularity score (Q > 0.3).

In addition, the analysis of the keywords burstiness revealed that the four keywords with the earliest bursts were ‘in vivo’, ‘marrow stromal cell’, ‘human intervertebral disc’, and ‘alginate bead’ (Supplementary Table 2E). In the 2016–2022 period, the keywords with a late beginning of burst were ‘extracellular vesicle’, ‘exosome (exosm)’, ‘autophagy’, ‘oxidative stress’, and ‘hyaluronic acid’ (Supplementary Table 2F). Their bursts also lasted till 2022, revealing an ongoing research trend.

Country/region, institution, and authorship analysis

Co-authorship networks of countries/regions (Fig. 4A), institutions (Fig. 4B), and researchers (Fig. 4C) were mapped.

Figure 4
Figure 4

Network of the co-authors’ countries/regions (A), co-authors’ affiliations (B), and co-authors (C) obtained with VOSviewer. Note:The visualization maps of the collaborative country/region, affiliation (based on co-authors’ countries/regions) and author network revealed the publication of each node. The nodes were limited to the top 15 countries/regions, top 31 institutions, or top 44 authors. The size of a node represents the relative number of publications. The color of a node represents the average publication year. The width of the link represents the number of co-authored publications of the linked two nodes.

Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0083

China ranked first in the number of publications (349), accounting for 31.670% of the total, which was followed by the USA (321) accounting for 29.129% (Supplementary Table 3A). The two countries contributed more than 60% of the total publications, while about 90% of China’s papers were published in the last 10 years. The top three countries or regions with the highest ACI values were Japan (63.11), Canada (46.70), and England (43.90). With a total link strength of 200, the USA took the lead in the worldwide cooperation, followed by Switzerland (111), China (81), and England (81). Publication bursts were detected in two countries, and they both lasted for 5 years: the USA, which started in 2000, and Japan, which started in 2003 (Supplementary Table 2G).

Tokai University ranked first in terms of the number of research publications (41), followed by the University of Hong Kong (39) and the University of Bern (38) (Supplementary Table 3B). Tokai University was also the institution with the highest ACI (74.88), followed by the University of Pittsburgh (64.95) and the University of Manchester (60.03). Recently, during 2016–2022, the Third Military Medical University, the University of Gothenburg, and Sahlgrens University Hospital experienced co-occurrence bursts (Supplementary Table 2I).

Daisuke Sakai from the Tokai University in Japan was the author with the largest number of publications (41), followed by Hoyland JA (38) from the University of Manchester in England and Sibylle Grad (36) from AO Research Institute Davos in Switzerland (Supplementary Table 3C). There were multiple authors with bursts (Supplementary Table 2J and K).

Categories and journal analysis

The top five categories in publications according to WOS classification were Cell Biology (23.503%), Orthopedics (23.230%), Cell Tissue Engineering (22.414%), Engineering Biomedical (21.416%), and Materials Science Biomaterials (18.058%) (Supplementary Table 3D). The other categories each accounted for less than 15% of the total documents. The distribution pattern demonstrated that wide multidisciplinary cooperation was performed, while the adoption of tissue engineering and biomaterials acted as essential technical supports.

The journals with the largest number of publications were Tissue Engineering Part A (44), followed by Spine (41), Journal of Orthopaedic Research (34), Biomaterials (31), European Cells Materials (31), and Spine Journal (31). The journals that had the highest ACI were Biomaterials (112.03), European Spine Journal (72.45), Spine (60.59), Arthritis Research Therapy (54.78), and Acta Biomaterialia (43.07) (Table 2).

Table 2

Top 15 journals in mesenchymal stromal cells in intervertebral disc degeneration research.

Rank Journal title Quantity ACI
1 Tissue Engineering Part A 44 31.91
2 Spine 41 60.59
3 Journal of Orthopaedic Research 34 38.09
4 Biomaterials 31 112.03
5 European Cells Materials 31 72.45
6 Spine Journal 31 33.52
7 European Spine Journal 29 72.45
8 Acta Biomaterialia 27 43.07
9 International Journal of Molecular Sciences 25 9.56
10 Stem Cells International 24 18.54
11 Journal of Tissue Engineering and Regenerative Medicine 21 36.29
12 Stem Cell Research Therapy 21 26.67
13 Arthritis Research Therapy 18 54.78
14 Plos One 17 39.35
15 Current Stem Cell Research Therapy 16 29.44

ACI, average citations per item.

Discussion

Identification of research trends and hotspots

2000–2007

A major trend was identified, starting from research on disc cell biology (81) and disc degeneration pathology (65). When they were combined with the discovery of the multilineage potential of MSCs (8), a potential therapeutic model for IDD was brought up and tested in an animal model (31). After that, an increasing number of studies about regenerative therapy for IDD were conducted, including differentiation of MSCs to NP-like phenotype (16, 17, 79, 82, 83, 84, 85) and more verification trials on animal models (15, 32, 33, 35, 86, 87, 88), with implications of biomaterials as cell carriers and scaffolds especially hydrogels (15, 32, 33, 89, 90). With promising results, regenerative therapy was considered for clinical application (91).

2008–2014

Further inspection revealed the role of MSC in IDD development (68, 92). Cases (38) and pilot studies (2) on patients confirmed the feasibility, safety, and clinical efficacy of autologous bone marrow mesenchymal stromal cell (BMSC) therapy for intervertebral disc repair and gave permission to the following trials (43, 39, 78, 93). With the evidence of a decade in hand, reviews (94, 95, 96, 97, 98) including systematic reviews (99, 100) were published. The persistence of this trend of reviewing was also identified in the following publications as narrative reviews (77, 101, 102, 103, 104, 105, 106), systematic reviews (107, 108), and guidelines from the physicians’ society (109, 110). The appropriate way of transporting MSCs was strongly focused when potential risk lying in disc injection was proposed (67, 111). Other intense focuses were on the effects of microenvironment (112) and inflammatory cytokines involved in IDD and their interaction with MSC (23, 71, 97). During this period, microstructured biomaterials represented by microspheres were applied to NP tissue regeneration as bioactive scaffolds (113).

2015–2022

The survival and adaption of exogenous transplanted cells in intervertebral disc were questioned (72), which raised interest in endogenous intervertebral disc regeneration and cell-free therapy. With the identification of the natural existence of stem/progenitor cells in degenerate intervertebral disc (114), possible approaches were conceived to overcome the endogenous repair failure in natural IDD process (77, 101, 116, 115). In the most recent papers, therapies based on MSC-derived exosomes (116, 117, 118) or notochordal cells (119, 120) were regarded as novel strategies for ameliorating IDD, with a relative preference for exosomes according to the number of articles.

Strengths and limitations

To the best of our knowledge, this is the first scientometric analysis on MSC in IDD. Scientometric analysis can help the practitioner of a science field to better understand how it developed into the current status, guiding their choice of next-stage research targets, especially for the beginners. The identification of important and active contributors can also help researchers seeking academic cooperation. Additionally, this work can help inform stakeholders, policy-makers, and funding agencies and provide references for their decisions (121). We find that our analysis results echoed conclusions of others. In Xu et al.’s 2021 bibliometric analysis of the 100 most cited articles about intervertebral disc repair (122), regenerative medicine and the application of stem cells was the most popular topic with a total of 34 works dedicated to it. Of the 34 articles, 22 papers focused on MSC application. The second most popular topic was biomaterials and cellular scaffolds, especially hydrogel. The authors believed that the regenerative repair of the intervertebral disc will be achieved through the breakthroughs, including simulation of the microenvironment for the regeneration of intervertebral disc cells with growth factors, combination of mechanical simulation with material engineering, and preparation of cellular scaffolds conforming to the natural mechanical properties.

In this study, we conducted the removal of duplicates, corrections, and conference records to obtain a dataset of high quality. We repeated the analysis of clusters in three different time periods, and all these clusters were considered significant and acceptably credible. According to these evidences, we have belief in the overall solidity of our analysis.

Based on the citation data, the results of scientometric studies can be confounded by citation bias. For example, pioneer studies were frequently cited out of reverence but not of close relevance. Such citations could interfere clustering and complicate the network. To diminish this effect, we set the Look Back Year value as 5 years, which meant in the calculated citation, the publication time lag between citing paper and cited paper was no more than 5 years. Therefore, the co-citation change paths over time could reveal the change of research focus better.

There are several other limitations that should be noted in this study. First, the database analyzed in the research was limited to the SCI-Expanded edition of the WOS Core Collection. Lacking reference information as metadata, sources like PubMed, Embase, and Cochrane database are not applicable to bibliometric review (123). WOS and Scopus have long been the options for bibliometric analysis. By comparison, WOS emphasizes more on the selectivity of its content and the completeness of reference lists (124) and is regarded as the most suitable database for scientometric analysis (59), while Scopus has better comprehensiveness (125). Though it was possible to merge the data from the two databases, the different label custom of them would make enormous duplicates in the merged dataset that is hard to eliminate. Therefore, only the SCI-Expanded edition of the WOS Core Collection was chosen.

Conclusion

The publication number of MSC in IDD showed a fluctuating upward tendency and was expected to continue growing. MSC-derived exosomes and notochordal cells gained gradually greater focus recently and would be further studied. The basic studies of the field were mainly contributed by Japan, the USA, and European countries, while Chinese scholars contributed much in recent studies. Tokai University with the researcher Daisuke Sakai was the most productive contributors. Cell biology, Tissue Engineering, and Biomaterials were closely involved categories in the development of the field. These insights into trends of the research and contributors could provide reference for researchers and their academic cooperation.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EOR-22-0083.

ICMJE Conflict of interest statement

The authors declare no conflict of interest relevant to this work.

Funding

This study was funded by Science and Technology Department of Sichuan Province (23NSFSC4423).

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    Figure 1

    Flow diagram of inclusion and analysis process.

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    Figure 2

    Trends of the number of publications and citations.

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    Figure 3

    Co-citation reference network (2000–2022) (A) and correspondent clustering analysis (B) obtained with CiteSpace. Note: (A) Cluster number is ranked based on the cluster size. The size of a node (article) is proportional to the number of times the article has been co-cited. The number in the center of a node refers to the cluster that it belongs to. The colors of a node represent the years it was cited, from 2000 (pink) to 2022 (yellow). The width of a link is proportional to the number of times the two linked articles are co-cited. The colors of a link represent the publication year of the first citing paper, from 2000 (pink) to 2022 (yellow). (B) Visualization map of the corresponding clusters.

  • View in gallery
    Figure 4

    Network of the co-authors’ countries/regions (A), co-authors’ affiliations (B), and co-authors (C) obtained with VOSviewer. Note:The visualization maps of the collaborative country/region, affiliation (based on co-authors’ countries/regions) and author network revealed the publication of each node. The nodes were limited to the top 15 countries/regions, top 31 institutions, or top 44 authors. The size of a node represents the relative number of publications. The color of a node represents the average publication year. The width of the link represents the number of co-authored publications of the linked two nodes.

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