1. Introduction
The field of tissue engineering has an extensive range of potential applications in tissue repair and regeneration [
1]. The role of biomaterials in tissue engineering is to provide support and scaffolding for cell growth, one of the principal factors that determine the success of tissue regeneration [
1,
2,
3]. The utilization of biomaterials as a possible replacement, maintenance, and/or repair for damaged or diseased tissues in a living system is a prime objective in the study of biomaterial research [
4,
5,
6]. The number of publications on tissue engineering using the biomaterial approach continued to increase in recent decades. Tissue engineering is a rapidly advancing field that relies on scaffold biomaterials to provide the appropriate environment to guide the growth of new tissue [
7,
8,
9]. The extracellular matrix (ECM) encompasses the natural surroundings of cells in vivo that not only maintain structure but regulate many aspects of cell behavior, including cell proliferation, growth, and differentiation [
10,
11]. Cellular differentiation is a broad process that aims to specialize a cell in order to perform specific function [
12,
13,
14]. Cell-matrix interactions are pivotal in differentiation regulation and development [
15,
16,
17]. The construction of a template ECM surface with the capability of providing a pertinent, in-vitro environment to regulate cellular behavior is a leading approach in biomaterial publications [
7,
10,
18].
Artificial extracellular matrices (aECMs) are an extension of biomaterials that were developed to provide a model environment for tissue cells in-vitro that mimic the native surroundings of the target tissue in vivo [
10,
18,
19]. The structure of native ECM is contingent upon the developmental stage and type of tissue; therefore the architecture and components of an aECM vary [
10,
18]. The optimal fabrication techniques used to construct aECMs are a focus of many tissue engineering studies and frequently presented in publications. The composition of each aECM is constructed to support the cellular processes for the optimal function of the target tissue [
6,
18,
20]. Artificial ECMs are generally classified as either a natural polymer-based, synthetic polymer-based, or hybrid material, and they differ based on their component materials [
18,
20]. Over the years, the use of aECMs has attained an excellent reputation in the field of tissue engineering due to their exceptional mechanical properties, processability and low cost [
21,
22]. The ideal aECM is physiochemically similar to the target tissues innate ECM, non-toxic, biodegradable, affordable, durable and poorly immunogenic [
23,
24]. Both naturally derived and synthetic materials have been developed to mimic native ECM for the study of regenerative medicine and tissue engineering [
21,
25]. Materials from natural sources such as laminin, fibronectin and vitronectin are beneficial to cell culture because they contain cell recognizable receptors that enhance cell-to-matrix interactions [
26]. However, there are some challenges with natural materials such as the risk of pathogen transmission, purification, immunogenicity and structural complexity [
21,
27]. Advancements in synthetic biomaterials are being developed at a rapid pace for use as 3D extracellular microenvironments to mimic regulatory components and functions of natural ECMs [
21,
28]. Novel designs of aECMs from synthetic materials are a possible alternative due to their minimal risk of pathogen transmission, lack of immune response and the ability for greater control over material properties and tissue responses [
21,
29]. The type of target tissue, accessibility and the biological or therapeutic application of the study are all a few factors to take into consideration when choosing between the various biomaterials available.
The significant attraction in the study of artificial ECMs is largely attributed to their potential applications in the field of regenerative medicine [
26,
30,
31]. There is a considerable amount of studies that focus on the use of aECMs and biomaterials to treat tissue damage and promote tissue regeneration. There has been a recent interest in biomaterial-based approaches to treat the lack of regeneration from spinal cord injuries (SCI) [
32,
33]. A leading factor in the permanence of SCI is the inability of the damaged axons to regenerate, preventing proper function of axonal circuits [
34,
35]. The emergence of biomaterials for regeneration has increased collaborations between engineers, scientist and clinicians to design materials that address the specific criteria for repairing this type of injury [
34,
36]. Tissue damage to skin, bone, liver, lung, heart and the vascular system are among a few targets that also utilize aECM strategies to study potential treatment and repair [
32,
37,
38]. With increasing cases of organ shortages and donor scarcity within the last three decades, the research focus in the field of regenerative medicine and tissue engineering continues to advance toward a potential therapeutic for various types of tissue damage [
39,
40].
Many reviews highlight the current strategies and future prospects of aECMs in tissue engineering; however, there is a lack of bibliometric reviews on the research output of publications. We aimed to evaluate and document how this field is expanding. We assessed the literature on aECMs based on tissue engineering over three decades by performing a bibliometric analysis that highlights (1) the most common terms occurring in related papers and (2) research volume output by authors, institutions, countries, and journals and their impact.
4. Discussion
Bibliometric analysis is a tool used to quantitatively evaluate the output of scholarly journal publications and measure the significance of studies in the scientific community [
44,
45,
46]. This is a very different approach to scientific writing than a review of the literature that summarizes a specific topic from various publications [
47]. Citation data are key to assessing the academic influence of a publication by the number of times it has been cited by other authors [
44,
45]. Results from the bibliometric analysis can also provide information that influences science policymakers and research funders’ decisions [
44,
46]. The analysis can also be a method of ranking journals, institutions, and universities worldwide [
48]. This bibliometric analysis aimed to evaluate the research productivity of aECMs based on tissue engineering technology. The database search was performed through Web of Science citation index on articles published from 1990 through 2019, with titles pertaining to aECM, tissue engineer, biomaterial, and regeneration.
The field of TE-related research is continuously growing, as presented in the rising number of publications and the expansion of research areas involved. TEs’ in-vitro research is gradually being transitioned to being applied to in vivo studies with a more clinical focus. This trend is reflected in the last decade as more terms gradually appear to be related to clinical topics like biocompatibility, grafts, transplantation, wound healing, nerve regeneration and bone regeneration. This is evident in the term maps of the most recent publications that highlight groups of tissue regeneration terms that overlap in several publications (
Figure 3,
Table S9). The current dependence on donated tissue and organs is not the most feasible approach as the population continues to age and as the scarcity of organ donors increases [
49]. TE and regenerative medicine (RM) is a promising method to address the urgent demand for organs and tissues needed for transplantation [
50]. In the 2000s for topic set 1 there were quite a few terms that related to bone and cartilage such as chondrogenic differentiation, bone morphogenetic proteins, chondrogenesis, bone tissue engineering, bone formation, articular-cartilage, bone marrow stromal cells and osteogenic differentiation (
Figure S1, Table S2). For topic set 2, from the 1990s to the 2000s there was a significant increase in publications and studies as indicated by the extensive expansion of key terms from 25 to 102 (
Figure S2, Tables S4 and S5).
Biomaterials are important components of tissue engineering studies as shown in the term maps generated for topic set 1. The appearance of terms such as biodegradable polymer, hydrogels, scaffolds, collagen, alginate and fibrin were shown throughout the time period, with scaffolds appearing consistently (
Figure 2a,b,
Tables S1 and S3). During the early decades of the topic set 3 searches the biomaterial related key words were general and extremely vague (
Figure S3, Tables S7 and S8). Advancements in biocompatible materials into complex 3D tissue models provide considerable opportunities for translational research that is slowly moving toward clinical applicability [
49]. There are a few engineered tissues that are being transitioned toward a pre-clinical phase, with the potential to be implanted into patients, such as bladder, skin, trachea, vascular grafts, cartilage and bone [
49,
51,
52]. There were several terms on the 2010 through 2019 maps that appear in publications that relate to these tissues such as mesenchymal stem cells, vascular grafts, stromal cells, bone marrow, chondrocytes and artificial skin (
Figure S2,
Figure 2b and
Figure 3). 3D scaffolds and matrices arranged to mimic the native micro-environment and biological components within the body are continuing to evolve and advance over time. However, there are still limitations and challenges that need to be settled before they can be considered suitable for clinical application. There are a number of hurdles that raise concerns, such as ensuring that materials are harmless to the host and that they support the composition and function of the cells, immune complications, and spatial constraints [
49,
53]. The ECM and cellular composition of different tissues vary widely between cell types and they each pose their own engineering challenges [
49,
54]. It is vital for biomaterials to not only mimic the structural components of the ECM, but to also have the ability to promote adhesion, differentiation and proliferation of cells [
49,
55,
56]. Over the last three decades, there has been an increase in publications developing various types of biomaterials as shown in the key term maps for topic set 2. Hydroxyapatite, chitosan, hydrogels, nanofibers, keratin and alginate are examples of common occurrences in the 2000s and 2010s (
Figure S2 and Table S6). It is evident that understanding the fundamental biology of tissue formation and morphogenesis is important [
24,
30]. There are also some limitations to using human models when moving towards the clinical application that could cause concern for legal constraints. However, the design of ideal biomaterials that can successfully interact with cells within tissues after implantation is a challenge that continues to be studied in TE technology [
21].
Regarding the global trend for topic set 3, there was a large output of publications from the USA. Japan and Germany also contributed a substantial amount of publications related to topic set 3 throughout the time period. The extensive number of publications from these countries were reflected in the large number of articles that cited these publications. For topic set 2, the USA and China were leading in both publication output and citing articles. However, countries like South Korea and Germany were not consistently the top producers of publications, but they did contribute a considerable number of citing articles. For topic set 1, the USA was again the lead producer of publication output throughout the entire period. In the 1990s, China was not a top publication producer, but that shifted in the 2000s and the 2010s as their publications begin to increase. Both countries also continued to lead in citing articles throughout each decade. Although the USA produced the most research for each topic set, their relative contribution to the percentage of the total global output decreased as the other counties began to maintain a significant contribution to their publication output each decade.
Many of the top authors results for each of the topic sets identified individuals that came from the same lab or collaborating labs. A considerable amount of the top authors also coincided with the top country results. For topic set 3, the primary rank for publication output continued to shift throughout each decade. Yannas and Minuth remained in the top five producing authors until the last decade, when all new authors took the lead. Authors of the top citing articles varied greatly from the authors with the greatest publication output. However, there could be a possibility that some of the top producing authors collaborated on publications with the authors from the top citing articles. This trend continued into publications related to topic set 2, aside from Kaplan, Reis and Mikos, who appeared in the top rank for both the publication output and the citing articles at least once in each decade. For topic set 1, quite a few of the top producing authors concur with the authors from the top citing articles throughout the time period.
The institutional results for topic set 3 correspond with the results from the top producing countries based on the geographical location of the institution. For topic set 3 in the 1990s and the 2000s, the USA was the leading producer and citer of publications. This aligns with the results of American institutions such as MIT, Harvard University and the University of California System leading in publication output and citing articles. In the 2010s, Dresden University of Technology in Germany was the leading institution for publications and the Chinese Academy of Sciences in China was the leading citer of publications. This also coincides with the data from the countries during that time period. For topic set 2, during the entire time period the USA and the China continued to the lead the top charts for both publications and citing articles. For topic set 1, the American institutions dominated the publication output and the citing articles for the first two decades. In the 2010s, Chinese organizations such as Shanghai Jiao Tong University were the top producers and the top citer of publications was the Chinese Academy of Sciences (
Table 4).