2.1 Data sources and search strategy

The search strategy and screening process are presented in Figure 1. All data were obtained from the Web of Science Core Collection (WoSCC) on May 10, 2024, with all searches conducted concurrently to mitigate potential bias stemming from daily database updates. The search formula is (TS = (stem cell*) OR TS = (SC) OR TS = (SCs) OR TS = (MSC*) OR TS = (Mesenchymal stem cell*)) AND TS = (“extracellular vesicle*” OR “EV” OR “EVs” OR “exosome*” OR “microvesicle*” OR “shed microvesicle*” OR “small microvesicle* ”OR “sMV*”) AND (TS = (skin) OR TS = (Dermatology) OR TS = (Dermatologic Surgical Procedure*) OR TS = (Procedure*, Dermatologic Surgical) OR TS = (Surgical Procedure*,Dermatologic) OR TS = (Cutaneous* Surgical Procedures) OR TS = (Procedure*,Cutaneous Surgical OR TS = (Surgical Procedure*,Cutaneous OR TS = (Skin Surger*) OR TS = (Surger*,Skin) OR TS = (Cutaneous Surger*) OR TS = (Surger*,Cutaneous OR TS = (Dermatologic Surger* OR TS = (Surger*,Dermatologic OR TS = (Surger*, Plastic) OR TS = (Plastic Surger*) OR TS = (Esthetic Surger* OR TS = (Surger*, Esthetic OR TS = (Surger*,Cosmetic) OR TS = (Cosmetic Surger*) OR TS = (Wound Healing*) OR TS = (Healing*, Wound) OR TS = (Re-Epithelialization) OR TS = (Wound Epithelialization) OR TS = (Epithelialization, Wound)) AND (DOP = (2003-01-01/2023-12-31)). Excluded documents included Meeting Abstract, Early Access, Book Chapters, Correction, Editorial Material, Proceeding Paper, Retracted Publication, Data Pape, Letter, and Retraction. And the language of studies was limited to English.

2.2 The bibliometric analysis method

Our study adopted a comprehensive methodology for data extraction from the Web of Science database. To preliminarily analyze the trends of SC-EVs for skin and plastic surgery, Microsoft Excel was used for initial visualization of the data. Then, we conducted a further bibliometric analysis of the aforementioned data from perspectives including the country, institution, journal, author, specific literature, and keywords with the aid of VOSviewer and CiteSpace software, providing a more in-depth understanding of the research landscape and identifying key players and research topics in the field. Additionally, Scimago Graphica was also utilized for data visualization purposes. To ensure the assessment of journal quality and influence, the latest edition (2022) of the Journal Citation Reports (JCR) was also referenced to obtain up-to-date impact factors (IF) for relevant journals.

3.1 Global publishing trends

According to our search strategy, there were a total of 1089 studies on the roles of EVs in skin and plastic surgery in the past two decades. These inclusions of 1089 articles indicate a substantial body of research on this topic. The number of publications from 2003 to 2018 grew slowly and was relatively low (Figure 2A). However, it increased dramatically from 2019 to 2023, highlighting the area's high value and rapid expansion of research.

3.2 Countries distribution analysis

A total of 1089 research articles from 60 countries were analyzed, illustrating the widespread global interest in the research area. Table 1 lists the number of publications, citations, and other relevant data from the top 10 productive countries in this field. China was the most prolific contributor, with 578 publications, which is 53.08% of the total. This significant contribution underscores China's dominant role in propelling research in this field. USA followed with 164 publications, accounting for 15.05% of the total. The substantial input from the USA also highlights its important role in these research endeavors. And South Korea contributed 67 publications (6.15%), Iran and Italy each contributed 48 publications (both 4.41%). These figures point to the active participation of these countries in the research domain. In terms of citation counts, China leads with a significant margin at 20 238 citations, followed by the United States with 7066 citations and Iran with 1895 citations (Table 1). These numbers indicate not only the volume of work produced by these countries but also their influence in the scientific community. From the point of view of the concentrated time of the article, countries in purple (like Germany and France) have a historical depth in publications predating 2020 (Figure 2B). Countries in green (such as China, the USA, and Iran) experienced a surge in publication output from 2020 to 2022. Countries in yellow (including Malaysia, Indonesia, and the Netherlands) showed an increase in publications post-2022. This color-coded mapping helps in understanding the temporal distribution and evolution of research activities across different regions.

In addition to publications, potential collaborations between individual countries are also worth noting; China and the United States have the closest international cooperation on relevant research (Figure 2C and 2D). And some major cooperative groups have been formed in the world (Figure 2E). On the density map, the arresting group of cooperation was the China- focused group, which was formed as a collaboration between many countries, including United States, South Korea, Canada, and Iran, demonstrating a robust network of international research partnerships.

3.3 Institutional distribution analysis

The top five productive institutions contributing to research on the roles of EVs in skin and plastic surgery are all located in China (Table 2). Leading the pack is Shanghai Jiao Tong University, producing a total of 39 publications, followed closely by Huazhong University of Science and Technology with 34 publications, Fourth Military Medicine University with 31 publications, Sichuan University with 30 publications, and Sun Yat-Sen University with 28 publications. In terms of citations received, Shanghai Jiao Tong University leads with an impressive count of 2472 citations, followed by Fourth Military Medicine University with 1579 citations, and Huazhong University of Science and Technology with 1526 citations (Table 2).

Further analysis utilizing was conducted to explore more potential information. Employing a threshold of 10 documents, the analysis identified the top 32 institutions meeting this criterion, which were then visualized in a time overlay map based on the concentration of their publications by year (Figure 3A). This analysis revealed that Shanghai Jiao Tong University exhibited a concentration of publications in 2020, while Huazhong University of Science and Technology, Fourth Military Medicine University, Sichuan University, and Sun Yat-Sen University predominantly published after 2021. Moreover, cluster density maps based on bibliographic coupling and co-authorship analysis were utilized to demonstrate the thematic relevance and cooperation situation between them, respectively (Figure 3B, C). These visualizations provide insight into the interconnectedness and thematic focus of research efforts across these institutions.

3.4 Journal distribution analysis

Analyzing the distribution of journals provides insight into the prominent publications within the realm of EVs applications for skin and plastic surgery. A radar map was utilized to depict the 10 most prolific journals in terms of publication count and Stem Cell Research & Therapy (Impact Factor [IF] = 7.50, 2023) and the International Journal of Molecular Sciences (IF = 5.60, 2023) stand out with 67 and 64 publications, respectively (Figure 3D).

Subsequently, an examination of journal contributions was undertaken to elucidate the interconnections between these referenced journals. The top 30 referenced journals are depicted in a network, with a units’ density map visualization showcasing all referenced journals (Figure 3E, F). Stem Cell Research & Therapy and the International Journal of Molecular Sciences emerge as primary publishing hubs, characterized by strong links (according to the number of lines between the units, Figure 3E) to other journals and high citations (according to the unit's density, Figure 3F), underscoring their pivotal roles in disseminating research findings and shaping the research agenda in this field. Consequently, these journals are poised to maintain their significance as key outlets for scholarly discourse and dissemination of knowledge in the foreseeable future.

3.5 Analysis of authors contributions

Analyzing the authors of scholarly literature is crucial for identifying prominent scholars and core research contributors within a given field. According to the average citation volume of the top 10 authors (Figure 4A), Zhang Bin leads the pack with an average of 181.5 citations per publication across 11 publications. Following closely behind are Qian Hui with an average of 163.3 citations per publication over 8 publications, and Wang Yang with an average of 144.7 citations per publication across 10 publications. Among highly prolific authors, one stands out with the highest number of publications—Fu Xiaobing. This distinguished scholar, a member of the Chinese Academy of Engineering, has held a longstanding position at the Chinese People's Liberation Army General Hospital. Since 2003, they have contributed to the academic discourse with a total of 12 papers. A comprehensive review of existing literature unmistakably indicates that this scholar's primary research focus revolves around the domain of “trauma and tissue repair and regeneration,” especially diabetic wound.^10-13 Notably, all scholars mentioned above are Chinese, a trend consistent with the dominance of Chinese institutions highlighted in the earlier analysis (Tables 1 and 2). This underscores the significant contributions of Chinese scholars to the advancement of knowledge in this field.

Further analysis, employing a threshold of at least four documents per author, revealed a total of 126 authors making substantial contributions to the field. These highly productive authors have coalesced into several collaborative groups, as depicted in Figure 4B. This collaborative network sheds light on the synergistic efforts of researchers driving advancements in SC-EV research for skin and plastic surgery.

3.6 Analysis of reference contributions

The top 10 most-cited publications in the realm of SC-EVs application for skin and plastic surgery are listed in Table 3. Notably, these publications were predominantly released in 2015 and 2016, indicating a surge of interest and research activity during that period. Among the top 10 publications, “HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing” stands out with the highest citation count (554). This research, published in Stem Cells (IF = 5.2), underscores the importance of exosome-mediated signaling pathways in wound healing processes.¹⁴ Another noteworthy publication among them is the latest study titled “Engineering Bioactive Self-Healing Antibacterial Exosomes Hydrogel for Promoting Chronic Diabetic Wound Healing and Complete Skin Regeneration.” Published in Theranostics (IF = 12.4, the highest one in those journals), this research introduces innovative approaches to chronic wound treatment and skin regeneration using engineered exosome-loaded hydrogels.⁵ Despite the notable advancements, there are still opportunities for further innovation and exploration within the field of SC-EVs application for skin and plastic surgery.

Utilizing CiteSpace, the top 25 references with the strongest citation bursts offer valuable insights into evolving research trends and hot topics (Figure 4C). By conducting burst analysis on references, researchers can identify emerging areas of interest and innovation within the SC-EVs research landscape for skin and plastic surgery. Then, a co-citation network of references was analyzed, providing insights into the interconnectedness of key research works (Figure 4D). This visualization aids in understanding the foundational literature and influential works shaping the field. The title cluster analysis categorizes references into eight distinct clusters, revealing emerging themes in SC-EVs research, including tissue engineering, angiogenesis, apoptosis, therapeutics, myofibroblast, inflammation, adipose tissue-derived stem cells, identification, and skin rejuvenation (Figure 4E). The clustering display of the timeline further highlights shifts in research focus over time, from earlier emphasis on angiogenesis to recent interests in apoptosis, inflammation, tissue engineering, and skin rejuvenation. Notably, myofibroblast and adipose tissue-derived stem cells have consistently remained research hotspots within the field, indicating their enduring significance in SC-EVs application for skin and plastic surgery. Overall, this comprehensive analysis provides valuable insights into the past, present, and future trajectories of SC-EVs research in the context of skin and plastic surgery, guiding researchers toward areas of critical importance and potential innovation.

3.7 Analysis of keywords

Keywords play a pivotal role in discerning the central themes of publications. Through keyword co-occurrence analysis, a systematic understanding of the current progress and trending topics in the utilization of SC-EVs in skin and plastic surgery, along with their intrinsic interconnections, can be attained. Notably, the prominence and significance of keywords are depicted through their size, color, and density within visual representations (Figure 5A, B). Different colors represent distinct clusters of models related to SC-EVs and the skin and plastic surgery, such as “exosomes” in red, “wound healing” in pink, “extracellular vesicle” and “mesenchymal stem cells” in purple, “angiogenesis” in yellow, “stem cell” in blue, and “therapy” in green, collectively outlining the primary research directions in SC-EV application for skin and plastic surgery (Figure 5A). Among these keywords, “exosomes” stood out with the highest frequency and link strength, underscoring the significance and expansive potential of exosomes in the realm of EVs for skin and plastic surgery. Furthermore, the top 10 keywords exhibiting the strongest citation bursts are highlighted, underscoring evolving areas of focus (Figure 5C). Early burst keywords like “TGF-β,” “microvesicle,” “microRNA,” and “stromal cell” have sustained high attention, while others like “enhance angiogenesis” and “myocardial infarction” suggest expanding applications of SC-EVs beyond traditional boundaries. Additionally, the time overlay map also reveals a gradual shift from fundamental research, such as stromal cells and mesenchymal stem cells, toward clinical applications like wound healing and hydrogel (Figure 5D). Correspondingly, timeline analysis echoes these trends, highlighting research hotspots and directions such as endothelial cells, biomaterials, skin rejuvenation, fibrosis, ASC-exosome, and tumor microenvironment (Figure 5E).

4.1 Would healing

Wound repair constitutes a multifaceted physiological mechanism wherein organisms react to tissue damage.²³ It intricately intertwines with inflammation, cell migration recruitment, angiogenesis, matrix deposition, new tissue generation, and wound closure, orchestrated by a myriad of cell types and molecular cues.²⁴ Dysregulated factors above within this intricate repair process frequently culminate in inadequate healing.²⁵ Annually, millions worldwide suffer from compromised wound healing subsequent to trauma, surgical interventions, acute illnesses, or chronic conditions.²⁶ Due to the biological properties of EVs, particularly exosomes, there is a broad potential for their involvement in angiogenesis and wound healing.^{3, 27} In recent years, there has been a growing volume of research focused on elucidating the mechanisms^{28, 29} by which EVs facilitate wound healing, as well as exploring the application of EVs in conjunction with other biomaterials for targeted clinical interventions.³⁰

4.2 Skin rejuvenation

Skin rejuvenation encompasses various objectives, including scar reduction, anti-aging, and anti-pigmentation strategies. EVs have garnered significant interest within the skin rejuvenation domain due to their nanoscale dimensions and favorable biocompatibility, offering the potential for achieving facial enhancement with minimal tissue disruption.³¹ In recent years, research on EVs, particularly exosomes, has experienced significant advancements in understanding the mechanisms underlying skin rejuvenation, including fibroblasts,³² MMPs,³³ ROS.³⁴ Moreover, there is a burgeoning interest in developing novel applications for EVs in this context.^{35, 36}

While research and applications involving EVs in humans have progressed rapidly, yielding notable achievements, there remains a need for further exploration into the mechanisms governing EVs and their scalability for production, issues surrounding stable storage and so on. In conclusion, the translation of these findings into clinical practice warrants continued investigation.