Trends in photodynamic therapy for dermatology in recent 20 years: A scientometric review based on CiteSpace

Analyze the research state and development trend of photodynamic therapy for dermatology using visual knowledge graphs derived from the Web of Science Core Collection database.


| INTRODUC TI ON
Photodynamic therapy (PDT) is a minimally invasive treatment, which has attracted widespread attention as a new treatment method in recent years.Photosensitiser (PS), light source and oxygen are the three main elements of PDT.Local or intravenous are the two basic methods for administering PS.PS accumulates selectively in the sick tissue during the drug-light interval, followed by exposure to an appropriate wavelength light (often in the red spectrum region, λ ≥ 600 nm).Normally, PS itself does not react with biomolecules.
When illumination transfers energy from light to oxygen molecules, reactive oxygen species (ROS) are produced, such as singlet oxygen (1O 2 ), superoxide radical (•O 2 − ), hydroxyl radical (•HO), and hydrogen peroxide (H 2 O 2 ), etc.[4][5] CiteSpace is a software for tracking and analyzing international cutting edge research.It is used in various research fields to illustrate patterns over time in a discipline or field of knowledge and track the development of research frontiers. 6VOSviewer is a software for constructing and visualizing co-occurrence networks of key terms extracted from a large body of scientific literature.The Web of Science Core Collection database (WoSCC) is of excellent quality, which basically covers high-quality research on PDT treatment of dermatosis.
Articles about PDT for dermatology published at WoSCC between January 1, 2000, and December 31, 2022, were visually analyzed using software such as CiteSpace (5.7.R5) and VOSviewer (1.6.18).The aim is to summarize the scope of application of PDT in dermatology and its indications, explore the hot spots of PDT research in dermatology, predict the hot spots of future research, and develop more effective and efficient therapeutic regimens.

| ME THODS
The source for the study came from WoSCC, and the search strategy is shown in Figure 1A.As the database is updated daily, we repeated the search on different days to eliminate substantive bias.Figure 1B shows the search process.CiteSpace (5.7.R5) was used to perform a bibliometric analysis and generate knowledge maps of countries/ regions, institutions, journals, authors, keywords, references.
CiteSpace: "Time Slicing" was set from January 2000 to December 2022; "Years Per Slice" was set to 1; "Pruning" was set to "Pathfinder"; and other parameters were left at their default settings. 6,7VOSviewer: The threshold was set to maintain 25-50 nodes, depending on the circumstance.

| General analysis
We searched and included 747 studies (including 537 articles and 210 reviews).As shown in Figure 2, the number of articles/reviews has steadily increased over the last 20 years, indicating that PDT remains a major interest topic in the field of dermatology.

| Analysis of institutions, journals, and authors cooperation
A total of 1130 institutions, 229 journals, and 3265 authors made contributions to the field.In terms of major publishing institutions, the University of Copenhagen published the most papers, with 21 articles (Figure 4A).Collaboration between the top 10 institutions is mostly regional, with international collaboration still lacking.Within our observation, publications on PDT for dermatology cover a wide range of fields, including basic medicine, clinical medicine, optics, photoimmunology, and more, of which 34.94% (261 articles) were published in the 10 journals listed in Figure 4B.
Among them, 62 articles were published in photodiagnosis and photodynamic therapy (5-Year IF = 3.577), accounting for 8.30%, which was the magazine with the largest number of publications.
Szeimies, Rolf-Markus (H-index was 62) was the most prolific author with 11 publications.The h-index is an objective criterion for assessing scientific achievement.For example, the H-index of 62 means that Rolf-Markus has published at least 62 papers, each of which has been cited at least 62 times. 8

| Analysis of references cooperation
Generally, in the research field, the more frequently literature is mentioned, the greater its influence and authority in the field, and the greater the reliability of the research results.The higher centrality of the cited literature is, the greater its mediating significance in this field, which is worthy of further study.CiteSpace was used to create the co-occurrence map of references (Figure 5, the co-citation network contained 976 cited references and 3826 links).The top five frequency of cited literature [9][10][11][12][13] in Table 1, and the top five centrality of cited literature [14][15][16][17][18] in Table 2.
"Burstness" was used to detect articles that have attracted a great deal of attention from scientists at various times during the last 20 years.The citation burst analysis (Figure 6) shows that "Morton CA, 2002" 9 earned the highest burst value (16.30)  potentially beneficial are also noted, including viral warts, acne, psoriasis, and cutaneous T-cell lymphoma.

| Analysis of keywords cooperation
The co-occurrence map of keywords (Figure 7) was created after using CiteSpace to analyze the 747 included documents.Tables 3-5 summarize the top-ranked keywords in terms of overall, indications, and complementary therapies.Where the higher frequency of the keyword indicates the more attention it is getting in the field.Centrality is the pivot between articles.The higher the centrality of a node, the more important it is in the field of study (but some nodes with a centrality of 0 may be a recent hotspot in the field and are not yet well studied.So just because a node has a centrality of 0 does not completely negate the importance of that node).
The cluster graph of keywords (Figure 8, Q = 0.3795 and S = 0.7361) was obtained by the cluster analysis (Log-Likelihood Ratio algorithm, LLR) based on the co-occurrence map of keywords.
In general, Modularity Q (Q) is regarded as a network modularity index for evaluating the effectiveness of the cluster.Q > 0.3 indicates an effective cluster.Weighted Mean Silhouette (S) is used to evaluate cluster homogeneity and is a performance indicator of the map's overall structure.S > 0.5 shows a sufficient degree of clustering.S > 0.7 indicates a reasonable cluster. 6,7Calculate the timeline and average year of each keyword's contribution to each cluster based on the publication date of each keyword (Figure 9).The name of each cluster and the keywords included were sorted by frequency, as shown in Table 6.
Using CiteSpace's "Burstness" function, this period suddenly appeared a lot of keywords can be calculated.It can effectively reflect the period of the primary study contents and themes and reveal the development trend.The top 25 of them are listed in Figure 10, showing the duration time and intensity of bursts.

| DISCUSS ION
Based on keyword analysis, burst analysis and cluster analysis, we have identified the following main research themes of interest.

| PDT combination therapy
Combining PDT with other therapies (such as conventional drug therapy, surgery, and other phototherapy) can compensate for the shortcomings of each treatment modality improve clinical efficiency, and reduce recurrence rates.From Table 5 we can see that the treatment regimens that are often combined with PDT tend to be more invasive operations.Literature report: (1).For cancerous or pre-cancerous lesions such as AK, BBC, etc., the fluorescence property of PS can be utilized to detect early cancerous or pre-cancerous lesions that cannot be observed by the naked eye.
Therefore, surgery, laser, and cryotherapy are often combined with PDT.Surgery, laser, and cryotherapy are used to treat lesions visible to the naked eye, while PDT is used to treat potential lesions.

| Clinical applications
According to the PDT clinical guidelines, it is known that PDT is currently recommended for the treatment of AK, AC, BCC, Bowen's disease, moderate to severe and severe acne, rosacea, and photodamage, 23,[31][32][33] etc.There are also numerous reports in the literature on the efficacy of PDT in some bacterial infections skin diseases, fungal infections skin diseases, viral infectious skin diseases, scar, skin amyloidosis, extramammary Paget Disease ,34-39 etc.In the future, we will try to apply PDT to more refractory diseases and work towards writing more complete clinical guidelines.

| Adverse reactions
During PDT (approximately 3 ~ 4 weeks), common adverse reactions to PDT include erythema, oedema, pruritus, pain, and burning sensation, etc.In severe cases, oozing, pustules and flaking may occur. 23,40Most patients refuse to use PDT because of its adverse effects.Thus, the best time for treatment is missed.The search for more appropriate treatment modalities (such as photosensitizers, light sources) to reduce the adverse effects of PDT will be the next research focus and difficulty.

| CON CLUS ION
This study provides academics with a resource for understanding Over the past 20 years, the included publications have been published in 61 countries.The top five countries/regions by publication volume: the United States (175 articles), Germany (109 articles), China (99 articles, Including 10 articles from Taiwan), the United Kingdom (71 articles), and Italy (66 articles).Countries density graph created by the VOSviewer (Figure 3).With its large number F I G U R E 1 The search strategies and the search process.
of publications and high centrality, the United States dominates the field.Regarding teamwork, countries collaborate with each other.
from 2010 to 2013.This review clearly demonstrates the effectiveness of topical PDT for actinic keratosis (AK), Bowen's disease, and superficial basal cell carcinomas (BCCs) of the face and scalp.Areas where PDT is F I G U R E 2 Chronological distribution of publications from 2000 to 2022.

4. 1 |
Selection of photosensitizersPDT induces necrosis and/or apoptosis of diseased tissue (tumor cells or other target cells) by generating ROS with photoactivated PS1,19,20 : The diseased tissue selectively absorbs the applied PS.Visible light to PS absorption bands is then irradiated to diseased tissue.The phototoxicity is initiated by the absorption of photons by PS, which is then followed by the transfer of energy and/or electrons to F I G U R E 3 Countries density graph.F I G U R E 4 Publishing institutions and journals analysis.(A) Top 10 institutions related to PDT in dermatology research.(B) The number of publications and 5-year impact factor of the top 10 scholarly journal.triplet oxygen (primarily), resulting in the production of 1 O 2 , O 2 ( 1 Δg), and/or other ROS, and the subsequent oxidation and degradation of vital biomolecules.Especially short-living O 2 ( 1 Δg) plays a crucial role in propagation the initial damage to biomolecules that results in tissue destruction, vascular collapse, and cell death.Nonetheless, PDT is constrained by the properties of PS, particularly the low quantum yields of ROS in the target environment.A crucial limiting element is also the low selectivity of PS, which causes photodynamic damage to surrounding normal tissues and secondary damage owing to inflammation.Evidently, the choice of PS is crucial to the effectiveness of PDT.Hundreds of PS with tetrapyrrole structures have been used clinically for PDT, including porphyrin, chlorin, and phthalocyanine derivatives.Furthermore, methylene blue, Rose Bengal, and hypericin have been exploited in therapeutic applications or trials as photodynamic agents. 21PDT is often carried out by topically applying PS, particularly 5-aminolevulinic acid (5-ALA) or its ester methyl aminolevulinate (MAL), in dermatological indications.In Europe, three topical photosensitizers are now approved 1 : MAL Metvix®, 5-ALA Ameluz®, and 5-ALA AlaCare®.

4. 2 | 2005 J
Selection of light sourcesThe conventional light sources for PDT are red light (wavelength 630 ~ 635 nm) and blue light (wavelength approx.410 nm).The red light is mostly used as a light source in Chinese dermatology.Commonly used emitters include semiconductor lasers, neon-helium lasers, lightemitting diodes (LED), etc.In addition, daylight, as a compound light, F I G U R E 5 The co-occurrence map of references.TA B L E 1 The top five references with cited frequency.use of photodynamic therapy for nonmelanoma skin cancer: an international consensus.International Society for Photodynamic Therapy in Dermatology, management of actinic keratoses -Developed by the Guideline Subcommittee of the European Dermatology Forum EUR J DERMATOL can also be used as a light source for PDT. 22,23PDT with daylight as the excitation light source is called daylight photodynamic therapy (DL-PDT) and is mainly used for the treatment of facial dermatosis such as Grade I ~ II AK, moderate to severe and severe acne, etc. DL-PDT can be a less painful, more convenient and effective option.

TA B L E 2 | 20 F I G U R E 6 30 F I G U R E 7
The top five references with the centrality.BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observerblind phase III study in comparison with a registered methyl-5split-face study of photodynamic therapy with indocyanine green and indole-3-acetic acid for the treatment of acne consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis -International League of Dermatological Societies in cooperation with the European Dermatology Forumacid photodynamic therapy treatment for tinea cruris caused by Trichophyton rubrum: report of 10 cases acid-photodynamic treatment for dermatophytic tinea pedis of interdigital type: a small clinical study J EUR ACAD DERMATOL 0.Detection of top 25 references with the strongest citation bursts.other inflammatory diseases, PDT can be used to eliminate deep inflammatory cells by reaching the dermis.Therefore, conventional treatment is often combined with PDT.Conventional treatment is used to control secretion and reduce new occurrences, and PDT is used to treat deep inflammation to reduce the formation of acne pits and acne marks.(3).For viral, fungal, and bacterial infections, PDT can be used to eliminate potential viruses, fungi, and bacteria by taking advantage of its wide scope of application and repeatability.Therefore, surgery, laser, cryotherapy, etc. are often combined with PDT.Surgery, laser, and freezing eliminate macroscopic local lesions, while PDT eliminates extensive, occult lesions. 24-The co-occurrence map of keywords.TA B L E 3 High frequency keywords of PDT for dermatology.
High frequency keywords of PDT for dermatology (Indications).