Abstract
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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.
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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.
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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.
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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.
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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.
Flow diagram of inclusion and analysis process.
Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0083
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.
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.
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.
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).
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).
References
- 1.↑
Sharma J, Hampton JM, Valiente GR, Wada T, Steigelman H, Young MC, Spurbeck RR, Blazek AD, Bösh S & Jarjour WN et al.Therapeutic development of mesenchymal stem cells or their extracellular vesicles to inhibit autoimmune-mediated inflammatory processes in systemic lupus erythematosus. Frontiers in Immunology 2017 8 526. (https://doi.org/10.3389/fimmu.2017.00526)
- 2.↑
Orozco L, Soler R, Morera C, Alberca M, Sanchez A, Garcia-Sancho J. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 2011 92 822–828. (https://doi.org/10.1097/TP.0b013e3182298a15)
- 3.↑
Elabd C, Centeno CJ, Schultz JR, Lutz G, Ichim T, Silva FJ. Intra-discal injection of autologous, hypoxic cultured bone marrow-derived mesenchymal stem cells in five patients with chronic lower back pain: a long-term safety and feasibility study. Journal of Translational Medicine 2016 14 253. (https://doi.org/10.1186/s12967-016-1015-5)
- 4.↑
Kumar H, Ha DH, Lee EJ, Park JH, Shim JH, Ahn TK, Kim KT, Ropper AE, Sohn S & Kim CH et al.Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Research and Therapy 2017 8 262. (https://doi.org/10.1186/s13287-017-0710-3)
- 5.↑
Comella K, Silbert R, Parlo M. Effects of the intradiscal implantation of stromal vascular fraction plus platelet rich plasma in patients with degenerative disc disease. Journal of Translational Medicine 2017 15 12. (https://doi.org/10.1186/s12967-016-1109-0)
- 6.↑
Pang XD, Yang H, Peng BG. Human umbilical cord mesenchymal stem cell transplantation for the treatment of chronic discogenic low back pain. Pain Physician 2014 17 E525–E530.
- 7.↑
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T & Blackstad M et al.Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002 418 41–49. (https://doi.org/10.1038/nature00870)
- 8.↑
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science (New York, NY) 1999 284 143–147. (https://doi.org/10.1126/science.284.5411.143)
- 9.↑
Guadix JA, Zugaza JL, Gálvez-Martín P. Characteristics, applications and prospects of mesenchymal stem cells in cell therapy. Medicina Clinica 2017 148 408–414. (https://doi.org/10.1016/j.medcli.2016.11.033)
- 10.↑
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002 99 3838–3843. (https://doi.org/10.1182/blood.v99.10.3838)
- 11.↑
Anderson P, Gonzalez-Rey E, O'Valle F, Martin F, Oliver FJ, Delgado M. Allogeneic adipose-derived mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by regulating self-reactive T cell responses and dendritic cell function. Stem Cells International 2017 2017 2389753. (https://doi.org/10.1155/2017/2389753)
- 12.↑
Kang Q, Song WX, Luo Q, Tang N, Luo J, Luo X, Chen J, Bi Y, He BC & Park JK et al.A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells. Stem Cells and Development 2009 18 545–559. (https://doi.org/10.1089/scd.2008.0130)
- 13.↑
GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020 396 1204–1222. (https://doi.org/10.1016/S0140-6736(2030925-9)
- 14.↑
Richardson SM, Kalamegam G, Pushparaj PN, Matta C, Memic A, Khademhosseini A, Mobasheri R, Poletti FL, Hoyland JA, Mobasheri A. Mesenchymal stem cells in regenerative medicine: focus on articular cartilage and intervertebral disc regeneration. Methods 2016 99 69–80. (https://doi.org/10.1016/j.ymeth.2015.09.015)
- 15.↑
Sakai D, Mochida J, Iwashina T, Watanabe T, Nakai T, Ando K, Hotta T. Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc model - Potential and limitations for stem cell therapy in disc regeneration. Spine 2005 30 2379–2387. (https://doi.org/10.1097/01.brs.0000184365.28481.e3)
- 16.↑
Risbud MV, Albert TJ, Guttapalli A, Vresilovic EJ, Hillibrand AS, Vaccaro AR, Shapiro IM. Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy. Spine 2004 29 2627–2632. (https://doi.org/10.1097/01.brs.0000146462.92171.7f)
- 17.↑
Clarke LE, McConnell JC, Sherratt MJ, Derby B, Richardson SM, Hoyland JA. Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition, and micromechanical properties of nucleus pulposus constructs. Arthritis Research and Therapy 2014 16 R67. (https://doi.org/10.1186/ar4505)
- 18.↑
Jezierska-Wozniak K, Barczewska M, Habich A, Wojtacha P, Badowska W, Maksymowicz W, Wojtkiewicz J. The feasibility of the CD271+ and CD271- mesenchymal stromal cell enrichment toward nucleus pulposus-like cells. Folia Histochemica et Cytobiologica 2017 55 114–123. (https://doi.org/10.5603/FHC.a2017.0013)
- 19.↑
Shi M, Zhao Y, Sun Y, Xin D, Xu W, Zhou B. Therapeutic effect of co-culture of rat bone marrow mesenchymal stem cells and degenerated nucleus pulposus cells on intervertebral disc degeneration. Spine Journal 2021 21 1567–1579. (https://doi.org/10.1016/j.spinee.2021.05.007)
- 20.↑
Vadalà G, Studer RK, Sowa G, Spiezia F, Iucu C, Denaro V, Gilbertson LG, Kang JD. Coculture of bone marrow mesenchymal stem cells and nucleus pulposus cells modulate gene expression profile without cell fusion. Spine 2008 33 870–876. (https://doi.org/10.1097/BRS.0b013e31816b4619)
- 21.↑
Watanabe T, Sakai D, Yamamoto Y, Iwashina T, Serigano K, Tamura F, Mochida J. Human nucleus pulposus cells significantly enhanced biological properties in a coculture system with direct cell-to-cell contact with autologous mesenchymal stem cells. Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society 2010 28 623–630. (https://doi.org/10.1002/jor.21036)
- 22.↑
Richardson SM, Walker RV, Parker S, Rhodes NP, Hunt JA, Freemont AJ, Hoyland JA. Intervertebral disc cell-mediated mesenchymal stem cell differentiation. Stem Cells 2006 24 707–716. (https://doi.org/10.1634/stemcells.2005-0205)
- 23.↑
Molinos M, Almeida CR, Caldeira J, Cunha C, Goncalves RM, Barbosa MA. Inflammation in intervertebral disc degeneration and regeneration. Journal of the Royal Society, Interface 2015 12 20141191. (https://doi.org/10.1098/rsif.2014.1191)
- 24.↑
Ohtori S, Inoue G, Miyagi M, Takahashi K. Pathomechanisms of discogenic low back pain in humans and animal models. Spine Journal 2015 15 1347–1355. (https://doi.org/10.1016/j.spinee.2013.07.490)
- 25.↑
Monchaux M, Forterre S, Spreng D, Karol A, Forterre F, Wuertz-Kozak K. Inflammatory processes associated with canine intervertebral disc herniation. Frontiers in Immunology 2017 8 1681. (https://doi.org/10.3389/fimmu.2017.01681)
- 26.↑
Teixeira GQ, Pereira CL, Ferreira JR, Maia AF, Gomez-Lazaro M, Barbosa MA, Neidlinger-Wilke C, Goncalves RM. Immunomodulation of human mesenchymal stem/stromal cells in intervertebral disc degeneration insights from a proinflammatory/degenerative ex vivo model. Spine 2018 43 E673–E682. (https://doi.org/10.1097/BRS.0000000000002494)
- 27.↑
Xia C, Zeng ZY, Fang B, Tao M, Gu CH, Zheng L, Wang Y, Shi Y, Fang C & Mei S et al.Mesenchymal stem cell-derived exosomes ameliorate intervertebral disc degeneration via anti-oxidant and anti-inflammatory effects. Free Radical Biology and Medicine 2019 143 1–15. (https://doi.org/10.1016/j.freeradbiomed.2019.07.026)
- 28.↑
Zhao YT, Qin Y, Wu SF, Huang DG, Hu HM, Zhang XL, Hao D. Mesenchymal stem cells regulate inflammatory milieu within degenerative nucleus pulposus cells via p38 MAPK pathway. Experimental and Therapeutic Medicine 2020 20 22. (https://doi.org/10.3892/etm.2020.9150)
- 29.↑
Ekram S, Khalid S, Bashir I, Salim A, Khan I. Human umbilical cord-derived mesenchymal stem cells and their chondroprogenitor derivatives reduced pain and inflammation signaling and promote regeneration in a rat intervertebral disc degeneration model. Molecular and Cellular Biochemistry 2021 476 3191–3205. (https://doi.org/10.1007/s11010-021-04155-9)
- 30.↑
Ferreira JR, Teixeira GQ, Neto E, Ribeiro-Machado C, Silva AM, Caldeira J, Leite Pereira C, Bidarra S, Maia AF & Lamghari M et al.IL-1 beta-pre-conditioned mesenchymal stem/stromal cells' secretome modulates the inflammatory response and aggrecan deposition in the intervertebral disc. European Cells and Materials 2021 41 431–453. (https://doi.org/10.22203/eCM.v041a28)
- 31.↑
Sakai D, Mochida J, Yamamoto Y, Nomura T, Okuma M, Nishimura K, Nakai T, Ando K, Hotta T. Transplantation of mesenchymal stem cells embedded in atelocollagen((R)) gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials 2003 24 3531–3541. (https://doi.org/10.1016/s0142-9612(0300222-9)
- 32.↑
Crevensten G, Walsh AJL, Ananthakrishnan D, Page P, Wahba GM, Lotz JC, Berven S. Intervertebral disc cell therapy for regeneration: mesenchymal stem cell implantation in rat intervertebral discs. Annals of Biomedical Engineering 2004 32 430–434. (https://doi.org/10.1023/b:abme.0000017545.84833.7c)
- 33.↑
Sakai D, Mochida J, Iwashina T, Hiyama A, Omi H, Imai M, Nakai T, Ando K, Hotta T. Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc. Biomaterials 2006 27 335–345. (https://doi.org/10.1016/j.biomaterials.2005.06.038)
- 34.↑
Hiyama A, Mochida J, Iwashina T, Omi H, Watanabe T, Serigano K, Tamura F, Sakai D. Transplantation of mesenchymal stem cells in a canine disc degeneration model. Journal of Orthopaedic Research 2008 26 589–600. (https://doi.org/10.1002/jor.20584)
- 35.↑
Henriksson HB, Svanvik T, Jonsson M, Hagman M, Horn M, Lindahl A, Brisby H. Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model. Spine 2009 34 141–148. (https://doi.org/10.1097/BRS.0b013e31818f8c20)
- 36.↑
Vadala G, Russo F, Ambrosio L, Loppini M, Denaro V. Stem cells sources for intervertebral disc regeneration. World Journal of Stem Cells 2016 8 185–201. (https://doi.org/10.4252/wjsc.v8.i5.185)
- 37.↑
Schol J, Sakai D. Cell therapy for intervertebral disc herniation and degenerative disc disease: clinical trials. International Orthopaedics 2019 43 1011–1025. (https://doi.org/10.1007/s00264-018-4223-1)
- 38.↑
Yoshikawa T, Ueda Y, Miyazaki K, Koizumi M, Takakura Y. Disc regeneration therapy using marrow mesenchymal cell transplantation a report of two case studies. Spine 2010 35 E475–E480. (https://doi.org/10.1097/BRS.0b013e3181cd2cf4)
- 39.↑
Blanco JF, Villaron EM, Pescador D, da Casa C, Gomez V, Redondo AM, López-Villar O, López-Parra M, Muntión S, Sánchez-Guijo F. Autologous mesenchymal stromal cells embedded in tricalcium phosphate for posterolateral spinal fusion: results of a prospective phase I/II clinical trial with long-term follow-up. Stem Cell Research and Therapy 2019 10 63. (https://doi.org/10.1186/s13287-019-1166-4)
- 40.↑
ClinicalTrials.gov. Efficacy of intradiscal Injection of BM-MSC in subjects with chronic low back pain (LBP) due to lumbar degenerative disc disease (DDD) unresponsive (RESPINE). Available at: https://clinicaltrials.gov/ct2/show/NCT03737461
- 41.↑
Amirdelfan K, Bae H, McJunkin T, DePalma M, Kim K, Beckworth WJ, Ghiselli G, Bainbridge JS, Dryer R & Deer TR et al.Allogeneic mesenchymal precursor cells treatment for chronic low back pain associated with degenerative disc disease: a prospective randomized, placebo-controlled 36-month study of safety and efficacy. Spine Journal 2021 21 212–230. (https://doi.org/10.1016/j.spinee.2020.10.004)
- 42.↑
Noriega DC, Ardura F, Hernandez-Ramajo R, Martin-Ferrero MÁ, Sanchez-Lite I, Toribio B, Alberca M, García V, Moraleda JM & González-Vallinas M et al.Treatment of degenerative disc disease with allogeneic mesenchymal stem cells: long-term follow-up results. Transplantation 2021 105 e25–e27. (https://doi.org/10.1097/TP.0000000000003471)
- 43.↑
Noriega DC, Ardura F, Hernandez-Ramajo R, Martin-Ferrero MÁ, Sanchez-Lite I, Toribio B, Alberca M, García V, Moraleda JM & Sánchez A et al.Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial. Transplantation 2017 101 1945–1951. (https://doi.org/10.1097/TP.0000000000001484)
- 44.↑
Tayebi B, Babaahmadi M, Pakzad M, Hajinasrollah M, Mostafaei F, Jahangiri S, Kamali A, Baharvand H, Baghaban Eslaminejad M & Hassani SN et al.Standard toxicity study of clinical-grade allogeneic human bone marrow-derived clonal mesenchymal stromal cells. Stem Cell Research and Therapy 2022 13 213. (https://doi.org/10.1186/s13287-022-02899-9)
- 45.↑
Sakai D, Schol J. Cell therapy for intervertebral disc repair: clinical perspective. Journal of Orthopaedic Translation 2017 9 8–18. (https://doi.org/10.1016/j.jot.2017.02.002)
- 46.↑
Smith LJ, Silverman L, Sakai D, Le Maitre CL, Mauck RL, Malhotra NR, Lotz JC, Buckley CT. Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: recommendations of the ORS spine section. JOR Spine 2018 1 e1036. (https://doi.org/10.1002/jsp2.1036)
- 47.↑
Lu K, Li HY, Yang K, Wu JL, Cai XW, Zhou Y, Li C. Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells. Stem Cell Research and Therapy 2017 8. (https://doi.org/10.1186/s13287-017-0563-9)
- 48.↑
Xiang HF, Su WL, Wu XL, Chen WJ, Cong WB, Yang S, Liu C, Qiu C, Yang SY & Wang Y et al.Exosomes derived from human urine-derived stem cells inhibit intervertebral disc degeneration by ameliorating endoplasmic reticulum stress. Oxidative Medicine and Cellular Longevity 2020 2020 6697577. (https://doi.org/10.1155/2020/6697577)
- 49.↑
Zhang JW, Zhang JY, Zhang YL, Liu WJ, Ni WF, Huang XY, Yuan J, Zhao B, Xiao H, Xue F. Mesenchymal stem cells-derived exosomes ameliorate intervertebral disc degeneration through inhibiting pyroptosis. Journal of Cellular and Molecular Medicine 2020 24 11742–11754. (https://doi.org/10.1111/jcmm.15784)
- 50.↑
Zhang Q, Shen YF, Zhao SJ, Jiang YQ, Zhou D, Zhang YK. Exosomes miR-15a promotes nucleus pulposus-mesenchymal stem cells chondrogenic differentiation by targeting MMP-3. Cellular Signalling 2021 86 110083. (https://doi.org/10.1016/j.cellsig.2021.110083)
- 51.↑
Bertram H, Kroeber M, Wang H, Unglaub F, Guehring T, Carstens C, Richter W. Matrix-assisted cell transfer for intervertebral disc cell therapy. Biochemical and Biophysical Research Communications 2005 331 1185–1192. (https://doi.org/10.1016/j.bbrc.2005.04.034)
- 52.↑
Barcellona MN, Speer JE, Jing LF, Patil DS, Gupta MC, Buchowski JM, Setton LA. Bioactive in situ crosslinkable polymer-peptide hydrogel for cell delivery to the intervertebral disc in a rat model. Acta Biomaterialia 2021 131 117–127. (https://doi.org/10.1016/j.actbio.2021.06.045)
- 53.↑
Yao RQ, Ren C, Wang JN, Wu GS, Zhu XM, Xia ZF, Yao YM. Publication trends of research on sepsis and host immune response during 1999–2019: a 20-year bibliometric analysis. International Journal of Biological Sciences 2020 16 27–37. (https://doi.org/10.7150/ijbs.37496)
- 54.↑
Liu F, Wu TT, Lei G, Fadlelseed AFA, Xie N, Wang DY, Guo QY. Worldwide tendency and perspectives in traumatic dental injuries: a bibliometric analysis over two decades (1999–2018). Dental Traumatology: Official Publication of International Association for Dental Traumatology 2020 36 489–497. (https://doi.org/10.1111/edt.12555)
- 55.↑
Small H Visualizing science by citation mapping. Journal of the American Society for Information Science 1999 50 799–813. (https://doi.org/10.1002/(SICI)1097-4571(1999)50:9<799::AID-ASI9>3.0.CO;2-G)
- 56.↑
Wu H, Zhou Y, Xu L, Tong L, Wang Y, Liu B, Yan H, Sun Z. Mapping knowledge structure and research frontiers of ultrasound-induced blood-brain barrier opening: a scientometric study. Frontiers in Neuroscience 2021 15 706105. (https://doi.org/10.3389/fnins.2021.706105)
- 57.↑
Liang M, Meng Y, Zhou S, Tao Z, Tao L. Research hotspots and trends analysis of ankylosing spondylitis: a bibliometric and scientometric analysis from 2009 to 2018. Annals of Translational Medicine 2020 8 1445. (https://doi.org/10.21037/atm-20-1259)
- 58.↑
van Eck NJ, Waltman L. Software survey: VOSviewer, a computer program for bibliometric mapping. Scientometrics 2010 84 523–538. (https://doi.org/10.1007/s11192-009-0146-3)
- 59.↑
Sabe M, Pillinger T, Kaiser S, Chen C, Taipale H, Tanskanen A, Tiihonen J, Leucht S, Correll CU, Solmi M. Half a century of research on antipsychotics and schizophrenia: a scientometric study of hotspots, nodes, bursts, and trends. Neuroscience and Biobehavioral Reviews 2022 136 104608. (https://doi.org/10.1016/j.neubiorev.2022.104608)
- 60.↑
Chen CM CiteSpace II: Detecting and visualizing emerging trends and transient patterns in scientific literature. Journal of the American Society for Information Science and Technology 2006 57 359–377. (https://doi.org/10.1002/asi.20317)
- 61.↑
Small H. Cocitation in scientific literature - new measure of relationship between 2 documents. Journal of the American Society for Information Science 1973 24 265–269. (https://doi.org/10.1002/asi.4630240406
- 62.↑
Newman ME Fast algorithm for detecting community structure in networks. Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics 2004 69 066133. (https://doi.org/10.1103/PhysRevE.69.066133)
- 63.↑
Rousseeuw PJ Silhouettes - a graphical aid to the interpretation and validation of cluster-analysis. Journal of Computational and Applied Mathematics 1987 20 53–65. (https://doi.org/10.1016/0377-0427(8790125-7)
- 64.↑
Kleinberg J Bursty and hierarchical structure in streams. Data Mining and Knowledge Discovery 2003 7 373–397. (https://doi.org/10.1023/A:1024940629314)
- 65.↑
Horner HA, Urban JP. 2001 Volvo Award Winner in Basic Science Studies: effect of nutrient supply on the viability of cells from the nucleus pulposus of the intervertebral disc. Spine 2001 26 2543–2549. (https://doi.org/10.1097/00007632-200112010-00006)
- 66.↑
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006 8 315–317. (https://doi.org/10.1080/14653240600855905)
- 67.↑
Carragee EJ, Don AS, Hurwitz EL, Cuellar JM, Carrino JA, Herzog R. 2009 ISSLS Prize Winner: does discography cause accelerated progression of degeneration changes in the lumbar disc: a ten-year matched cohort study. Spine 2009 34 2338–2345. (https://doi.org/10.1097/BRS.0b013e3181ab5432)
- 68.↑
Sakai D, Nakamura Y, Nakai T, Mishima T, Kato S, Grad S, Alini M, Risbud MV, Chan D & Cheah KS et al.Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nature Communications 2012 3 1264. (https://doi.org/10.1038/ncomms2226)
- 69.↑
Smith LJ, Nerurkar NL, Choi KS, Harfe BD, Elliott DM. Degeneration and regeneration of the intervertebral disc: lessons from development. Disease Models and Mechanisms 2011 4 31–41. (https://doi.org/10.1242/dmm.006403)
- 70.↑
Risbud MV, Schoepflin ZR, Mwale F, Kandel RA, Grad S, Iatridis JC, Sakai D, Hoyland JA. Defining the phenotype of young healthy nucleus pulposus cells: recommendations of the spine research interest group at the 2014 annual ORS meeting. Journal of Orthopaedic Research 2015 33 283–293. (https://doi.org/10.1002/jor.22789)
- 71.↑
Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nature Reviews. Rheumatology 2014 10 44–56. (https://doi.org/10.1038/nrrheum.2013.160)
- 72.↑
Sakai D, Andersson GB. Stem cell therapy for intervertebral disc regeneration: obstacles and solutions. Nature Reviews. Rheumatology 2015 11 243–256. (https://doi.org/10.1038/nrrheum.2015.13)
- 73.↑
Cheng XF, Zhang GY, Zhang L, Hu Y, Zhang K, Sun XJ, Zhao C, Li H, Li YM, Zhao J. Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration. Journal of Cellular and Molecular Medicine 2018 22 261–276. (https://doi.org/10.1111/jcmm.13316)
- 74.↑
Tang RH, Jing LF, Willard VP, Wu CL, Guilak F, Chen J, Setton LA. Differentiation of human induced pluripotent stem cells into nucleus pulposus-like cells. Stem Cell Research and Therapy 2018 9 61. (https://doi.org/10.1186/s13287-018-0797-1)
- 75.↑
Bowles RD, Setton LA. Biomaterials for intervertebral disc regeneration and repair. Biomaterials 2017 129 54–67. (https://doi.org/10.1016/j.biomaterials.2017.03.013)
- 76.↑
Centeno C, Markle J, Dodson E, Stemper I, Williams CJ, Hyzy M, Ichim T, Freeman M. Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy. Journal of Translational Medicine 2017 15 197. (https://doi.org/10.1186/s12967-017-1300-y)
- 77.↑
Clouet J, Fusellier M, Camus A, Le Visage C, Guicheux J. Intervertebral disc regeneration: from cell therapy to the development of novel bioinspired endogenous repair strategies. Advanced Drug Delivery Reviews 2019 146 306–324. (https://doi.org/10.1016/j.addr.2018.04.017)
- 78.↑
Barakat AH, Elwell VA, Lam KS. Stem cell therapy in discogenic back pain. Journal of Spine Surgery 2019 5 561–583. (https://doi.org/10.21037/jss.2019.09.22)
- 79.↑
Richardson SM, Walker RV, Parker S, Hunt JA, Freemont AJ, Hoyland JA. Differentiation of human mesenchymal stem cells to nucleus pulposus cells using a novel co-culture technique. International Journal of Experimental Pathology 2006 87 A20–A21.
- 80.↑
Liao ZW, Luo RJ, Li GC, Song Y, Zhan SF, Zhao KC, Hua W, Zhang Y, Wu X, Yang C. Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo. Theranostics 2019 9 4084–4100. (https://doi.org/10.7150/thno.33638)
- 81.↑
Gruber HE, Hanley EN. Biologic strategies for the therapy of intervertebral disc degeneration. Expert Opinion on Biological Therapy 2003 3 1209–1214. (https://doi.org/10.1517/14712598.3.8.1209)
- 82.↑
Steck E, Bertram H, Abel R, Chen BH, Winter A, Richter W. Induction of intervertebral disc-like cells from adult mesenchymal stem cells. Stem Cells 2005 23 403–411. (https://doi.org/10.1634/stemcells.2004-0107)
- 83.↑
Richardson SM, Hughes N, Hunt JA, Freemont AJ, Hoyland JA. Human mesenchymal stem cell differentiation to NP-like cells in chitosan-glycerophosphate hydrogels. Biomaterials 2008 29 85–93. (https://doi.org/10.1016/j.biomaterials.2007.09.018)
- 84.↑
Stoyanov JV, Gantenbein-Ritter B, Bertolo A, Aebli N, Baur M, Alini M, Grad S. Role of hypoxia and growth and differentiation factor-5 on differentiation of human mesenchymal stem cells towards intervertebral nucleus pulposus-like cells. European Cells and Materials 2011 21 533–547. (https://doi.org/10.22203/ecm.v021a40)
- 85.↑
Ludwinski FE, Gnanalingham K, Richardson SM, Hoyland JA. Understanding the native nucleus pulposus cell phenotype has important implications for intervertebral disc regeneration strategies. Regenerative Medicine 2013 8 75–87. (https://doi.org/10.2217/rme.12.108)
- 86.↑
Serigano K, Sakai D, Hiyama A, Tamura F, Tanaka M, Mochida J. Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. Journal of Orthopaedic Research 2010 28 1267–1275. (https://doi.org/10.1002/jor.21147)
- 87.↑
Miyamoto T, Muneta T, Tabuchi T, Matsumoto K, Saito H, Tsuji K, Sekiya I. Intradiscal transplantation of synovial mesenchymal stem cells prevents intervertebral disc degeneration through suppression of matrix metalloproteinase-related genes in nucleus pulposus cells in rabbits. Arthritis Research and Therapy 2010 12 R206. (https://doi.org/10.1186/ar3182)
- 88.↑
Zhang YG, Guo XO, Xu P, Kang LL, Li J. Bone mesenchymal stem cells transplanted into rabbit intervertebral discs can increase proteoglycans. Clinical Orthopaedics and Related Research 2005 430 219–226. (https://doi.org/10.1097/01.blo.0000146534.31120.cf)
- 89.↑
Zeiter S, van der Werf Mv, Ito K. The fate of bovine bone marrow stromal cells in hydrogels: a comparison to nucleus pulposus cells and articular chondrocytes. Journal of Tissue Engineering and Regenerative Medicine 2009 3 310–320. (https://doi.org/10.1002/term.167)
- 90.↑
Peroglio M, Eglin D, Benneker LM, Alini M, Grad S. Thermoreversible hyaluronan-based hydrogel supports in vitro and ex vivo disc-like differentiation of human mesenchymal stem cells. Spine Journal 2013 13 1627–1639. (https://doi.org/10.1016/j.spinee.2013.05.029)
- 91.↑
Hegewald AA, Ringe J, Sittinger M, Thome C. Regenerative treatment strategies in spinal surgery. Frontiers in Bioscience : a Journal and Virtual Library 2008 13 1507–1525. (https://doi.org/10.2741/2777)
- 92.↑
Blanco JF, Graciani IF, Sanchez-Guijo FM, Muntion S, Hernandez-Campo P, Santamaria C, Carrancio S, Barbado MV, Cruz G & Gutierrez-Cosío S et al.Isolation and characterization of mesenchymal stromal cells from human degenerated nucleus pulposus comparison with bone marrow mesenchymal stromal cells from the same subjects. Spine 2010 35 2259–2265. (https://doi.org/10.1097/BRS.0b013e3181cb8828)
- 93.↑
Atluri S, Murphy MB, Dragella R, Herrera J, Boachie-Adjei K, Bhati S, Manocha V, Boddu N, Yerramsetty P & Syed Z et al.Evaluation of the effectiveness of autologous bone marrow mesenchymal stem cells in the treatment of chronic low back pain due to severe lumbar spinal degeneration: a 12-month, open-label, prospective controlled trial. Pain Physician 2022 25 193–207.
- 94.↑
Oehme D, Goldschlager T, Rosenfeld JV, Ghosh P, Jenkin G. The role of stem cell therapies in degenerative lumbar spine disease: a review. Neurosurgical Review 2015 38 429–445. (https://doi.org/10.1007/s10143-015-0621-7)
- 95.↑
Wang F, Shi R, Cai F, Wang YT, Wu XT. Stem cell approaches to intervertebral disc regeneration: obstacles from the disc microenvironment. Stem Cells and Development 2015 24 2479–2495. (https://doi.org/10.1089/scd.2015.0158)
- 96.↑
Sakai D, Grad S. Advancing the cellular and molecular therapy for intervertebral disc disease. Advanced Drug Delivery Reviews 2015 84 159–171. (https://doi.org/10.1016/j.addr.2014.06.009)
- 97.↑
Krock E, Rosenzweig DH, Haglund L. The inflammatory milieu of the degenerate disc: is mesenchymal stem cell-based therapy for intervertebral disc repair a feasible approach? Current Stem Cell Research and Therapy 2015 10 317–328. (https://doi.org/10.2174/1574888x10666150211161956)
- 98.↑
Velikonja NK, Urban J, Frohlich M, Neidlinger-Wilke C, Kletsas D, Potocar U, Turner S, Roberts S. Cell sources for nucleus pulposus regeneration. European Spine Journal 2014 23(Supplement 3) S364–S374. (https://doi.org/10.1007/s00586-013-3106-9)
- 99.↑
Yim RLH, Lee JTY, Bow CH, Meij B, Leung V, Cheung KMC, Vavken P, Samartzis D. A systematic review of the safety and efficacy of mesenchymal stem cells for disc degeneration: insights and future directions for regenerative therapeutics. Stem Cells and Development 2014 23 2553–2567. (https://doi.org/10.1089/scd.2014.0203)
- 100.↑
Oehme D, Goldschlager T, Ghosh P, Rosenfeld JV, Jenkin G. Cell-based therapies used to treat lumbar degenerative disc disease: a systematic review of animal studies and human clinical trials. Stem Cells International 2015 2015 946031. (https://doi.org/10.1155/2015/946031)
- 101.↑
Frapin L, Clouet J, Delplace V, Fusellier M, Guicheux J, Le Visage C. Lessons learned from intervertebral disc pathophysiology to guide rational design of sequential delivery systems for therapeutic biological factors. Advanced Drug Delivery Reviews 2019 149–150 49–71. (https://doi.org/10.1016/j.addr.2019.08.007)
- 102.↑
Du YX, Wang ZK, Wu YM, Liu CY, Zhang LL. Intervertebral disc stem/progenitor cells: a promising "seed" for intervertebral disc regeneration. Stem Cells International 2021 2021 2130727. (https://doi.org/10.1155/2021/2130727)
- 103.↑
Vadala G, Ambrosio L, Russo F, Papalia R, Denaro V. Interaction between mesenchymal stem cells and intervertebral disc microenvironment: from cell therapy to tissue engineering. Stem Cells International 2019 2019 2376172. (https://doi.org/10.1155/2019/2376172)
- 104.↑
Williams RJ, Tryfonidou MA, Snuggs JW, Le Maitre CL. Cell sources proposed for nucleus pulposus regeneration. JOR Spine 2021 4 e1175. (https://doi.org/10.1002/jsp2.1175)
- 105.↑
Lee CK, Heo DH, Chung H, Roh EJ, Darai A, Kyung JW, Choi H, Kwon SY, Bhujel B, Han I. Advances in tissue engineering for disc repair. Applied Sciences 2021 11 15. (https://doi.org/10.3390/app11041919)
- 106.↑
Ma K, Chen S, Li Z, Deng X, Huang D, Xiong L, Shao Z. Mechanisms of endogenous repair failure during intervertebral disc degeneration. Osteoarthritis and Cartilage 2019 27 41–48. (https://doi.org/10.1016/j.joca.2018.08.021)
- 107.↑
Panebianco CJ, Meyers JH, Gansau J, Hom WW, Iatridis JC. Balancing biological and biomechanical performance in intervertebral disc repair:a systematic review of injectable cell delivery biomaterials. European Cells and Materials 2020 40 239–258. (https://doi.org/10.22203/eCM.v040a15)
- 108.↑
Xie BC, Chen SC, Xu YX, Han WC, Hu RK, Chen MY, He R, Ding S. Clinical efficacy and safety of human mesenchymal stem cell therapy for degenerative disc disease: a systematic review an meta-analysis of randomized controlled trials. Stem Cells International 2021 2021 9. (https://doi.org/10.1155/2021/9149315)
- 109.↑
Navani A, Manchikanti L, Albers SL, Latchaw RE, Sanapati J, Kaye AD, Atluri S, Jordan S, Gupta A & Cedeno D et al.Responsible, safe, and effective use of biologics in the management of low back pain: American Society of Interventional Pain Physicians (ASIPP) guidelines. Pain Physician 2019 22 S1–S74.
- 110.↑
Manchikanti L, Centeno CJ, Atluri S, Albers SL, Shapiro S, Malanga GA, Abd-Elsayed A, Jerome M, Hirsch JA & Kaye AD et al.Bone marrow concentrate (BMC) therapy in musculoskeletal disorders: evidence-based policy position statement of American Society of Interventional Pain Physicians (ASIPP). Pain Physician 2020 23 E85–E131.
- 111.↑
Vadala G, Sowa G, Hubert M, Gilbertson LG, Denaro V, Kang JD. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. Journal of Tissue Engineering and Regenerative Medicine 2012 6 348–355. (https://doi.org/10.1002/term.433)
- 112.↑
Huang YC, Leung VYL, Lu WW, Luk KDK. The effects of microenvironment in mesenchymal stem cell-based regeneration of intervertebral disc. Spine Journal 2013 13 352–362. (https://doi.org/10.1016/j.spinee.2012.12.005)
- 113.↑
Liang CZ, Li H, Li C, Yang ZR, Zhou XP, Tao YQ, Xiao Y, Li F, Chen Q. Fabrication of a layered microstructured polymeric microspheres as a cell carrier for nucleus pulposus regeneration. Journal of Biomaterials Science. Polymer Edition 2012 23 2287–2302. (https://doi.org/10.1163/156856211X614789)
- 114.↑
Risbud MV, Guttapalli A, Tsai TT, Lee JY, Danielson KG, Vaccaro AR, Albert TJ, Gazit Z, Gazit D, Shapiro IM. Evidence for skeletal progenitor cells in the degenerate human intervertebral disc. Spine 2007 32 2537–2544. (https://doi.org/10.1097/BRS.0b013e318158dea6)
- 115.↑
Hu BW, He RJ, Ma KG, Wang Z, Cui M, Hu HZ, Rai S, Wang B, Shao Z. Intervertebral disc-derived stem/progenitor cells as a promising cell source for intervertebral disc regeneration. Stem Cells International 2018 2018 7412304. (https://doi.org/10.1155/2018/7412304)
- 116.↑
Li WH, Zhang SL, Wang D, Zhang H, Shi Q, Zhang YY, Wang M, Ding Z, Xu S & Gao B et al.Exosomes immunity strategy: a novel approach for ameliorating intervertebral disc degeneration. Frontiers in Cell and Developmental Biology 2022 9 20. (https://doi.org/10.3389/fcell.2021.822149
- 117.↑
Lu L, Xu AS, Gao F, Tian CJ, Wang HL, Zhang JY, Xie Y, Liu P, Liu SX & Yang C et al.Mesenchymal stem cell-derived exosomes as a novel strategy for the treatment of intervertebral disc degeneration. Frontiers in Cell and Developmental Biology 2022 9 22. (https://doi.org/10.3389/fcell.2021.770510
- 118.↑
Liang WS, Han B, Hai Y, Sun D, & Yin P. Mechanism of action of mesenchymal stem cell-derived exosomes in the intervertebral disc degeneration treatment and bone repair and regeneration. Frontiers in Cell and Developmental Biology 2022 9 10. (https://doi.org/10.3389/fcell.2021.833840
- 119.↑
Bach FC, Poramba-Liyanage DW, Riemers FM, Guicheux J, Camus A, Iatridis JC, Chan D, Ito K, Le Maitre CL & & Tryfonidou MA. Notochordal cell-based treatment strategies and their potential in intervertebral disc regeneration. Frontiers in Cell and Developmental Biology 2022 9 23. (https://doi.org/10.3389/fcell.2021.780749
- 120.↑
Matta A, Erwin WM. Current status of the instructional cues provided by notochordal cells in novel disc repair strategies. International Journal of Molecular Sciences 2021 23 9. (https://doi.org/10.3390/ijms23010427)
- 121.↑
O'Leary BC, Woodcock P, Kaiser MJ, Pullin AS. Evidence maps and evidence gaps: evidence review mapping as a method for collating and appraising evidence reviews to inform research and policy. Environmental Evidence 2017 6. (https://doi.org/10.1186/s13750-017-0096-9)
- 122.↑
Xu G, Meng X, Guan J, Xing Y, Feng Z, Hai Y. Systematic review of intervertebral disc repair: a bibliometric analysis of the 100 most-cited articles. Journal of Orthopaedic Surgery and Research 2021 16 207. (https://doi.org/10.1186/s13018-021-02303-x)
- 123.↑
Chen C A glimpse of the first eight months of the Covid-19 literature on Microsoft academic graph: themes, citation contexts, and uncertainties. Frontiers in Research Metrics and Analytics 2020 5 607286. (https://doi.org/10.3389/frma.2020.607286)
- 124.↑
Birkle C, Pendlebury DA, Schnell J, Adams J. Web of Science as a data source for research on scientific and scholarly activity. Quantitative Science Studies 2020 1 363–376. (https://doi.org/10.1162/qss_a_00018)
- 125.↑
Visser M, van Eck NJ, Waltman L. Large-scale comparison of bibliographic data sources: Scopus, Web of Science, Dimensions, Crossref, and Microsoft Academic. Quantitative Science Studies 2021 2 20–41. (https://doi.org/10.1162/qss_a_00112)
