Visualizing the Knowledge Domain of

applied sciences Review

Visualizing the Knowledge Domain of Nanoparticle Drug Delivery Technologies: A Scientometric Review Yen-Chun Lee 1, *, Chaomei Chen 2 and Xing-Tzu Tsai 3 Received: 19 November 2015; Accepted: 31 December 2015; Published: 7 January 2016 Academic Editor: Philippe Lambin 1 2 3

*

Office of Research and Development, National Chiao Tung University, 1001, Ta-Hsueh Rd., Hsinchu 30010, Taiwan College of Computing and Informatics, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104-2875, USA; [email protected] Department of Foreign Languages and Literatures, National Chiao Tung University, 1001, Ta-Hsueh Rd., Hsinchu 30010, Taiwan; [email protected] Correspondence: [email protected]; Tel.: +886-3-5712121 (ext. 31448)

Abstract: The scientific literature of nanoparticle drug delivery technologies (NDDT) between 2005 and 2014 was reviewed. The visualized co-citation network of its knowledge domain was characterized in terms of thematic concentrations of co-cited references and emerging trends of surging keywords and citations to references through a scientometric review. The combined dataset of 25,171 bibliographic records were constructed through topic search and citation expansion to ensure adequate coverage of the field. While research in gold nanoparticle and magnetic nanoparticle remains the two most prominent knowledge domains in the NDDT field, research related to clinical and therapeutic applications has experienced a considerable growth. In particular, clinical and therapeutic developments in NDDT have demonstrated profound connections with the mesoporous silica nanoparticle research and microcrystal research. A rapid adaptation of mesoporous silica-based nanomaterials and rare earth fluoride nano-/microcrystal in NDDT is evident. Innovative strategies have been employed to exploit the multicomponent, chemical synthesis, surface modification, and controlled release imparting functionalized targeting capabilities. This study not only facilitated the connection of authors and research themes in the NDDT community, but also demonstrated how research interests and trends evolve over time, which greatly contributes to our understanding of the NDDT knowledge domains. Keywords: drug delivery; nanoparticle; knowledge domain; scientometrics

1. Introduction In recent years, increasing attention has paid to the development of novel drug delivery systems (NDDS), because the average cost and time for the development of a new chemical or biochemical entity are much higher than those required to develop a NDDS [1]. Moreover, incorporating an existing medicine into a NDDS can significantly improve its performance in terms of efficacy, safety, and improved patient compliance [2]. Among the various NDDS, a considerable attention has focused on the development of therapeutic nanoparticle technologies, because they have the potential to revolutionize the drug development manner and alter the landscape of the pharmaceutical industry [3]. As nanoparticle drug delivery technologies (NDDT) begin to gain traction over the next several decades, it is important to visualize its knowledge domains. In this context, this paper aimed to explore the knowledge domains associated with NDDT, quantifying research patterns and trends in NDDT. Using CiteSpace as a visualization tool to analyze the scientific literature retrieved from the Web of Science Core Collection (WoSCC) [4], Appl. Sci. 2016, 6, 11; doi:10.3390/app6010011

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this paper reflected a number of remarkable connections and clusters of research in NDDT over the past decade (2005–2014). 2. The Visualization of Scientific Knowledge Domains A knowledge domain is a particular field of study that creates a common ground and a sense of development of a common identity by affirming its purpose and value to members and stakeholders [5]. Moreover, intellectual relationships and collaboration networks are fundamental to a knowledge domain [6]. The visual representation of such “knowledge networks” contributes to the overall understanding of intellectual collaborations in a particular knowledge domain. Scientific knowledge changes all the time. Most of the changes are incremental, but some are revolutionary and fundamental [7]. For example, in the field of NDDT, several subareas have formed through the years, ranging from drug incorporation and release, formulation stability and shelf life, biocompatibility, to biodistribution and targeting, and functionality [8]. With recent advances in computing power, scientific indexes, and bibliographic techniques, progress is being made and researchers are gradually piecing together this dilemma and exploring hidden connections and knowledge domains in the literature. In the next section, the process of exploring the knowledge domains associated with NDDT was described. 3. Method 3.1. Bibliographic Records We collected the bibliographic records from the WoSCC of Thomson Reuters. We determined the time frame of this analysis to the last decade (2005–2014) due to a concerted effort to improve the clarity of derived results. The search consists of two subqueries about NDDT: “nanoparticle* drug delivery” in topic search and “nanoparticle* drug delivery” in title search. Two datasets of bibliographic records on NDDT were retrieved from the WoSCC, including both SSCI and SCI-Expanded subsidiary databases. The topic-search dataset is referred as the core dataset [9]. The query resulted in 1770 bibliographic records which includes 1178 original research articles. The expanded dataset is a superset of the core dataset with extra bibliographic records obtained by association through citation links. Any article citing at least one original article in the core set can be assumed that it may be thematically relevant to the subject matter underlying the core dataset [10]. The resultant expanded dataset consists of 23,993 unique records. Both datasets were merged as a whole for scientometric review. The whole bibliographic records were then exported to CiteSpace [11] for subsequent analysis. 3.2. CiteSpace CiteSpace supports the visualization of a scientific field from bibliographic sources in terms of networks of several types of entities, including cited references, co-authors, and co-occurring keywords [12]. This paper centered on document co-citation networks and networks of co-occurring keywords in an effort to deliver more accurate and complete results for the NDDT knowledge domains. Individual nodes in the network can be aggregated into clusters based on their interconnectivity. Each cluster represents a distinct specialty or a thematic concentration. Other points of interest include highly cited landmark articles, articles with strong citation bursts, and keywords with a strong surge of frequency. The aim of burst detection is to investigate whether the frequency of an entity increases abruptly with reference to its peers. If an article is found to have a steep increase of its citation counts, then the article is regarded as having a citation burst. Similarly, if the number of articles with a term in their titles or abstracts sharply increased at a much faster rate than other terms, then the term is defined as a burst term. For the purposes of this paper, we first identified key articles associated with NDDT. Next, we detected key clusters and emerging topics through citation bursts in the literature for exploring the knowledge domains of NDDT.

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3.3. Network Network Analysis Analysis and and Visualization Visualization 3.3. The data is aiscollection of scientific publications associated with a specific [4]. The datainput inputofofCiteSpace CiteSpace a collection of scientific publications associated with a topic specific Through its network and visualization, we can explore knowledge domains in a specific topic [4]. Through its modeling network modeling and visualization, we canthe explore the knowledge domains in topic. One of the important tools in CiteSpace helps identify betweenness centrality between pivotal a specific topic. One of the important tools in CiteSpace helps identify betweenness centrality between points in the scientific literatureliterature [13]. The [13]. betweenness centrality of a node inofa anetwork as pivotal points in the scientific The betweenness centrality node infunctions a network a measureastoaindicate importance nodes in aofnetwork. functions measurethe to indicate the of importance nodes in a network. Research fronts fronts are are aa collection collection of of articles articles that that are are actively actively cited cited by by researchers researchers and and often often display display Research propertiesofofdomain domain specificity Research generated by CiteSpace capture core properties specificity [14].[14]. Research frontfront termsterms generated by CiteSpace capture core concepts concepts of co-citation anda provide a general of overview of a knowledge domain and its of co-citation clusteringclustering and provide general overview a knowledge domain and its associated associatedFinally, network. time slices are powerful tools for providingperspective a temporaltoperspective to network. timeFinally, slices are powerful tools for providing a temporal the literature the literature and identifying and identifying citation burstscitation [11]. bursts [11].

4. BibliographicLandscape Landscape 4. Bibliographic 4.1. 4.1. Document Document Co-Citation Co-Citation Analysis Analysis The of 25,171 bibliographic records combining both the corethe dataset the expanded The complete completesetset of 25,171 bibliographic records combining both coreand dataset and the dataset were visualized and analyzed using CiteSpace. Next, the bibliographic records were extracted expanded dataset were visualized and analyzed using CiteSpace. Next, the bibliographic records were from the WoSCC their and document co-citation networknetwork was generated as shown in Figure 1. extracted from theand WoSCC their document co-citation was generated as shown in Figure 1.

Figure 1. 1. Key Key articles articles in in nanoparticle nanoparticle drug drug delivery delivery technologies. technologies. Figure

In this network, there are 402 unique nodes and 2974 links for a one-year time slice. These nodes In this network, there are 402 unique nodes and 2974 links for a one-year time slice. These nodes represent cited references from the collected articles, and the links in the network represent co-citation represent cited references from the collected articles, and the links in the network represent co-citation relationships. Each link colors correspond directly to each time slice. For example, blue links describe relationships. Each link colors correspond directly to each time slice. For example, blue links describe articles that were co-cited in 2005, and the most recent co-citation relationships are visualized as articles that were co-cited in 2005, and the most recent co-citation relationships are visualized as orange orange or red links. We can further conclude three focal points from Figure 1. First, larger node sizes or red links. We can further conclude three focal points from Figure 1. First, larger node sizes imply imply that the article is an important one within the knowledge domain. Second, red rings around a that the article is an important one within the knowledge domain. Second, red rings around a node node represent a citation burst. Third, purple rings indicate nodes that have a relatively high represent a citation burst. Third, purple rings indicate nodes that have a relatively high betweenness betweenness centrality in the network. centrality in the network. Table 1 presents the five top-cited articles associated with the term “nanoparticle drug delivery” Table 1 presents the five top-cited articles associated with the term “nanoparticle drug delivery” between 2005 and 2014. between 2005 and 2014.

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Table 1. Five critical articles in nanoparticle drug delivery technologies. Cited Frequency

Title

Author

Year

Betweenness Centrality

Journal

1014

Nanocarriers as an emerging platform for cancer therapy

Peer et al.

2007

0.00

Nature Nanotechnology

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829

Synthesis and surface engineering Gupta and 2005 0.02 of iron oxide nanoparticles for Gupta drug delivery technologies. Table 1.applications Five critical articles in nanoparticle biomedical

Cited Multifunctional inorganic Title nanoparticles 764 Frequency for imaging, targeting, and drug delivery

Author Liong et al.

Year 2008

Betweenness 0.00 Centrality

Biomaterials Journal ACS Nano

Nanocarriers as an emerging Nature 1014 Superparamagnetic nanoparticles for Peer et al. 2007 0.00 Journal of platform for cancer therapy Nanotechnology 755 biomedicalSynthesis applications: possibilities and Neuberger et al. 2005 0.01 Magnetism and and surface engineering Gupta and limitations of new drug delivery system Magnetic Materials 2005 0.02 Biomaterials 829 of airon oxide nanoparticles for Gupta biomedical applications Tumor vascular permeability and the Journal of Multifunctional inorganic nanoparticles 712 EPR effect in macromolecular Maeda et al. al. 2000 764 Liong et 2008 0.00 0.08 ACS Nano Controlled Release fortherapeutics: imaging, targeting, and drug delivery a review Superparamagnetic nanoparticles for Journal of 755 biomedical applications: possibilities and Neuberger et al. 2005 0.01 Magnetism and limitations of a new drug delivery system Magnetic Materials The first is a paper by Peer et al. [15], which examined some of the approved formulations Tumor vascular permeability and the Journal of EPR effect inthe macromolecular Maeda et al. basic 2000 research 0.08 to the clinic. The second clinical 712 use and discussed challenges in translating Controlled Release therapeutics: a review

for is Gupta and Gupta [16] work, which discussed the synthetic chemistry, fluid stabilization and surface modification superparamagnetic iron oxide nanoparticles. The other three papers The first is of a paper by Peer et al. [15], which examined some of the approved formulations for focus on particular application areastheorchallenges techniques. For example, Liongto et [17]The demonstrated the clinical use and discussed in translating basic research theal. clinic. second is multifunctional nanoparticles can the be synthetic monitored insidefluid living cells by both magnetic Gupta and inorganic Gupta [16] work, which discussed chemistry, stabilization and surface modification of superparamagnetic iron oxide Neuberger nanoparticles. otherdiscussed three papers on resonance and fluorescence imaging methods. et The al. [18] the focus characteristics particular application areas or techniques. For example, Liong et al. [17] demonstrated the multifunctional and applications of superparamagnetic nanoparticles based on a core consisting of iron oxides inorganic nanoparticles can be monitored inside living cells by both magnetic resonance and (SPION). Finally, Maeda et al. [19] reviewed the basic characteristics of the enhanced permeability fluorescence imaging methods. Neuberger et al. [18] discussed the characteristics and applications of and retention (EPR) effect. In sum, regardless nanoparticle superparamagnetic nanoparticles based on of a the coresubareas, consistingall of five ironarticles oxides represent (SPION). Finally, drug delivery asal.a [19] keyreviewed enablingthe technology for pursuing substantive researchand questions physical or Maeda et basic characteristics of the enhanced permeability retentionin(EPR) effect. In sum, regardless of the subareas, all five articles represent nanoparticle drug delivery as a key social environments. enabling technology for pursuing substantive research questions in physical or social environments.

4.2. Identification and Interpretation of Clusters

4.2. Identification and Interpretation of Clusters

We used CiteSpace to explore research patterns and emerging trends in the body of knowledge in We used CiteSpace to explore research patterns and emerging trends in the body of knowledge terms ofinkey clusters of articles. Figure 2 shows clusters withtitle title terms. Theofsize of a cluster’s terms of key clusters of articles. Figure 2 shows clusterslabeled labeled with terms. The size a cluster’s label is proportional to thetosize of the cluster. label is proportional the size of the cluster.

Figure 2. Clusters visualization based on a document co-citation network.

Figure 2. Clusters visualization based on a document co-citation network. In this instance, there are total 55 clusters in the network. To characterize the nature of a cluster, CiteSpace can extract phrases from the in titles articles that the clusterthe based on three In this instance, therenoun are total 55 clusters theofnetwork. To cited characterize nature of a cluster, specialized metrics—TF*IDF, log-likelihood tests (LLR) and mutual information tests (MI). LLR usually CiteSpace can extract noun phrases from the titles of articles that cited the cluster based on three 4 of 14

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specialized metrics—TF*IDF, log-likelihood tests (LLR) and mutual information tests (MI). LLR usually gives the best result in terms of the uniqueness and coverage of themes associated with a cluster. Table 2 details the top 11 clusters in rank order. Table 2. Top-ranked clusters in nanoparticle drug delivery technologies. Label (TF*IDF)

Label (LLR)

Label (MI)

Mean (Cited Year)

0.789

nano

gold nanoparticle

biomaterial-based technologies

2003

53

0.853

ion

magnetic nanoparticle

behavior

2003

51

0.776

nano

oral delivery

general strategy

2001

anticancer drug delivery system

2007

ID

Size

0

55

1 2

Silhouette

3

48

0.933

silica

mesoporous silica nanoparticle

4

46

0.704

nano

nanoparticle

drug discovery

2003

5

42

0.811

nano

polymeric micelle

nanofibrous scaffold

2001

6

23

0.890

nano

mesoporous silica nanoparticle

ouzo region

2002

7

13

0.972

upconversion

microcrystal

drug-delivery system

2010

8

8

1.000

plaque angiogenesis

nanomedicine strategies

mechanism

2002

9

8

0.954

nano

nanotechnology-based drug delivery

drug-delivery system

2000

10

5

0.998

carboxymethyl konjac

glucomannan-chitosan nanoparticle

drug delivery

1994

As shown in Figure 2, gold nanoparticle and magnetic nanoparticle are the two largest clusters. Microcrystal and mesoporous silica nanoparticle are the two youngest clusters, and glucomannan-chitosan nanoparticle is the oldest cluster. The values of the silhouettes for each cluster are greater than 0.5, suggesting robust and meaningful results. The largest cluster, gold nanoparticle (#0), consists of 55 members. The three most active citers in this cluster are Aswathy et al. [20], Alkilany and Murphy [21], and Chithrani [22]. According to the titles of these citers in this cluster, research works related to gold nanoparticle shape a foundation of the knowledge domain. Researchers interested in gold nanoparticle are particularly concerned with near-infrared quantum dot, toxicity, and biomaterial-based technologies. Not surprisingly, this cluster covers a range of interests, reflecting the interdisciplinary nature of NDDT and their use. The second largest cluster (#1) in this knowledge domain, magnetic nanoparticle, has 53 member articles and an average publication year of 2003. The three most active citers to this cluster are Hao et al. [23],Veiseh et al. [24], and Faraji et al. [25] accordingly. Because of their remarkable magnetic properties and biologically comparable sizes, these magnetic nanoparticles are very beneficial for biomedical applications [23]. In addition, these magnetic nanoparticles can also respond resonantly to an alternating magnetic field and function as a heater, offering a promising therapeutic solution by magnetic fluid hyperthermia [25]. In recent years, the synthesis, design, and fabrication of multifunctional magnetic nanoparticles for biomedical applications has become one of the most active research areas in this knowledge domain [24]. As shown in Figures 1 and 2 this cluster has the top ranked burst item—Neuberger et al. [18] among all clusters, with bursts of 61.86. Thus, the magnetic nanoparticle cluster is essential to the literature represented by the datasets. The third largest cluster (#2) is oral delivery which has 51 member articles and an average publication year of 2001. The three most active citers in this cluster are Ratzinger et al. [26], Roger et al. [27], and Patel et al. [28] accordingly. According to the titles of these citers in this cluster,

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nanometric-sized drug delivery systems are being extensively studied and provide promising potential for oral drug delivery. Researchers interested in oral delivery focus particularly on how technological solutions can enhance the bioavailability or the targeting of anticancer drug after oral administration. There Appl. Sci. 2016,are 6, 11other clusters worth mentioning. For example, the cluster (#3) for mesoporous silica nanoparticle consists of 48 member articles and an average publication year of 2007. According to major citing articles [29,30], it is notitsurprising that previous advances advances push mesoporous silica nanoparticle the major citing articles [29,30], is not surprising that previous push mesoporous silica to the research forefront of forefront drug delivery development. nanoparticle to the research of drug delivery development. Another major major cluster cluster corresponds corresponds to to the the terms terms polymeric polymeric micelle. micelle. In In most most instances, instances, polymeric polymeric Another micelles play play aa significant significant role role in in the the advancement advancement of of NDDT NDDT by by providing providing controlled controlled release release of of micelles therapeutic agents therapeutic agents in in constant constant doses doses over over long long periods periods[31,32]. [31,32].Thus, Thus,polymeric polymericmicelle micellehas hasbecome becomea asubstantive substantiveknowledge knowledgedomain domainininNDDT NDDTresearch researchfield. field. Finally,the theterm termmicrocrystal microcrystal also represents a cluster 13 member and an Finally, also represents a cluster whichwhich has 13has member articles articles and an average average publication year of 2010. Thisiscluster is the one newest one inthe which themost three mostciters activeinciters publication year of 2010. This cluster the newest in which three active this in this cluster are Li and LinChen [33],et Chen et al.and [34], and et al.accordingly. [35] accordingly. Dramatic have cluster are Li and Lin [33], al. [34], Liu et Liu al. [35] Dramatic effortsefforts have been been dedicated the chemical synthesis ofearth rare earth fluoride nano-/microcrystals uniform size dedicated to thetochemical synthesis of rare fluoride nano-/microcrystals withwith uniform size and and shapes [33]. Hence, research works related to microcrystal reflect the recent knowledge domain shapes [33]. Hence, research works related to microcrystal reflect the recent knowledge domain in in NDDT research field. NDDT research field. An alternative alternative approach approach for for viewing viewing these these clusters clusters and and their their relationships relationships is is with with timeline timeline An visualization as as shown shown in in Figure Figure 3. 3. visualization

Figure 3. 3. Timeline view for for nanoparticle nanoparticle drug drug delivery delivery technologies: technologies: 2005–2014. 2005–2014. Figure Timeline view

The most obvious trend in Figure 3 is that most of the documents cited were published after The most obvious trend in Figure 3 is that most of the documents cited were published after 1985, roughly corresponding to the rise and deployment of an existing drug molecule from a classic 1985, roughly corresponding to the rise and deployment of an existing drug molecule from a classic type to a novel nanoparticle drug delivery system. Interestingly, the earliest cited document in the type to a novel nanoparticle drug delivery system. Interestingly, the earliest cited document in the derived network was published before 1970 [36] and is found in the cluster of magnetic nanoparticle. derived network was published before 1970 [36] and is found in the cluster of magnetic nanoparticle. Moreover, as shown in Figure 2 and Figure 3, the top ranked item by centrality is Yoon et al. [37] in Moreover, as shown in Figures 2 and 3 the top ranked item by centrality is Yoon et al. [37] in Cluster #1, Cluster #1, with centrality of 0.26. The second one is Giri et al. [38] in Cluster #3, with centrality of with centrality of 0.26. The second one is Giri et al. [38] in Cluster #3, with centrality of 0.22. The third 0.22. The third is Gao et al. [39] in Cluster #0, with centrality of 0.14. These nodes can be considered is Gao et al. [39] in Cluster #0, with centrality of 0.14. These nodes can be considered as pivotal points as pivotal points that provide important bridging connections between two research interests. that provide important bridging connections between two research interests. 4.3. Most Most Active Active Clusters Clusters 4.3. Figure 33 shows and cluster #7, #7, withwith the strongest citation bursts. This Figure shows two twoclusters, clusters,cluster cluster#3#3 and cluster the strongest citation bursts. means that cluster #3 and cluster #7 represent where the major efforts of the research in this field since This means that cluster #3 and cluster #7 represent where the major efforts of the research in this field 2010. 2010. Cluster #3 is labeled as mesoporous silica nanoparticle. TableTable 3 lists3five in cluster #3 with since Cluster #3 is labeled as mesoporous silica nanoparticle. listsarticles five articles in cluster #3 the strongest citation bursts. with the strongest citation bursts.

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Table 3. Articles with the strongest citation bursts in cluster #3. Citation

Burst

Author

Year

Title

Source

248

46.48

Tang et al. [40]

2012

Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery

ADV MATER

222

44.12

Yang et al. [41]

2012

Functionalized mesoporous silica materials for controlled drug delivery

CHEM SOC REV

238

41.45

Li et al. [42]

2012

Mesoporous silica nanoparticles in biomedical applications

CHEM SOC REV

127

20.30

Liong et al. [43]

2009

Mesostructured multifunctional nanoparticles for imaging and drug delivery

J MATER CHEM

297

13.07

Trewyn et al. [44]

2007

Mesoporous silica nanoparticle based controlled release, drug delivery, and biosensor systems

CHEM COMMUN

The title terms in Table 3 mainly include mesoporous silica nanoparticle, controlled release, and drug delivery. The highest bursted article in this cluster, Tang et al. [40], discussed the recent progress in the synthesis of mesoporous silica nanoparticles for drug delivery applications. The second highest bursted article in this cluster, Yang et al. [41], reviewed the most recent research progress on silica-based controlled drug delivery systems. The common theme in terms of the bursted articles to this cluster is the design, synthesis and functionalization of mesoporous silica nanoparticles for efficient drug delivery systems. Cluster #7 is labeled as microcrystal. Table 4 lists five articles in cluster #7 with the strongest citation bursts. Table 4. Articles with the strongest citation bursts in cluster #7. Citation

Burst

Author

Year

Title

Source ADV MATER

Mn2+ 200

37.79

Tian et al. [45]

2012

Dopant-Controlled Synthesis of NaYF4 : Yb/Er Upconversion Nanoparticles for in vivo Imaging and Drug Delivery

186

24.91

Zhou et al. [46]

2012

Upconversion nanophosphors for small-animal imaging

CHEM SOC REV

178

19.64

Haase and Schäfer [47]

2011

Upconverting nanoparticles

ANGEW CHEM INT EDIT

233

19.44

Wang and Liu [48]

2009

Recent advances in the chemistry of lanthanide-doped upconversion nanocrystals

CHEM SOC REV

221

13.97

Wang et al. [49]

2010

Simultaneous phase and size control of upconversion nanocrystals through lanthanide doping

NATURE

The title terms in Table 4 mainly include nanocrystals, upconversion, and drug delivery. Tian et al. [45] has the strongest citation burst in the cluster. The work suggested that upconversion nanoparticles (UCNPs) could be used as potential bio-labels for in vivo imaging, and as promising drug carriers for intracellular drug delivery. The second highest bursted article in this cluster, Zhou et al. [46], considered a rational approach to obtain suitable UCNP nanoprobes for small animal bioimaging. A common theme among this group of articles appears to focus on applications of UCNP research for novel imaging agents and therapy.

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4.4. References with Strong Citation Bursts Significant increases of research interests within the NDDT knowledge domain are characterized Appl. Sci. 2016, 6, 11 by publications that experienced citation bursts. This was based on a total of 25,171 bibliographic records which were selected from 555,999 valid references. Figure 4 shows the top 30 references with records which were selected from 555,999 valid references. Figure 4 shows the top 30 references with the strongest citation bursts during 2005and and2014. 2014. the strongest citation bursts duringthe theperiod period between between 2005

Figure 4. Top 30 references with strong citation bursts.

Figure 4. Top 30 references with strong citation bursts. As shown in Figure 4, most of the references started to burst in year 2005, two references started to burst in in year 2006,4, and onereferences reference started started to to burst burst in inyear year2005, 2007.two Table 5 showsstarted the As shown Figure mostonly of the references to representative references for three groups by the beginning time of burst.

burst in year 2006, and only one reference started to burst in year 2007. Table 5 shows the representative references for three groups by the beginning time of burst. Table 5. Representative references with the strongest citation bursts. Citation burst Table 5. Representative References Year references with the strongest citation bursts. Strength Begin End Chaw et al. [50] 2004 19.67 Citation Burst 2005 2007 Feng et al. References [51] 2004 Year 16.47 2005 2006 Strength Begin End Anderson et al. [52] 2000 13.95 2005 2007 19.67 2005 2006 2007 Liu et al.Chaw [53] et al. [50] 2003 2004 15.23 2007 Feng et al. [51] 2004 16.47 2005 2006 Little et al. [54] 2004 6.56 2007 2008 Anderson et al. [52] 2000 13.95 2005 2007 Liu et al. [53] 2003 15.23 2006 2007 In the group of year 2005, the top three references with the strongest citation bursts are Little et al. [54] 2004 6.56 2007 2008 Chaw et al. [50], Feng et al. [51], and Anderson et al. [52] accordingly. Chaw et al. [50] analyzed the drug-loading process for understanding the effect of various fabrication parameters on drug encapsulation efficiency. The burst lasted for three years from 2005 till 2007. Feng et al. [51] article 8 of 14

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In the group of year 2005, the top three references with the strongest citation bursts are Appl. Sci. Sci. 2016, 2016, 6, 6, 11 11 Appl. Appl. Sci. 6, Appl. Sci. 2016, 6, 11 11Feng et al. [51], and Anderson et al. [52] accordingly. Chaw et al. [50] analyzed Chaw et 2016, al. [50], Appl. Sci. Sci. 2016, 6, 11 Appl. 2016, 6, 11 Appl. Sci. Sci. 2016, 2016, 6, 6, 11 11 Appl. Appl. Sci. 2016, 2016, 6, 6, 11 11 process for understanding the effect of various fabrication parameters on drug the drug-loading Appl. Sci. Appl. Sci. 2016, 6, 11 indicated that of polymers can an solution to clinical Appl. 6, 11 indicated that nanoparticles of biodegradable biodegradable polymers can provide provide an ideal ideal solution to article clinical Appl. Sci. Sci. 2016, 2016, 6, efficiency. 11nanoparticles encapsulation Theefficacy burst lasted for side three years from 2005 till 2007. Feng etdemonstrated al. [51] indicated that nanoparticles of biodegradable biodegradable polymers can provide provide an[52] ideal solution to clinical clinicala indicated that nanoparticles of polymers can an ideal solution to administration with better and less effects. Anderson et al. article indicated that that nanoparticles nanoparticles of biodegradable biodegradable polymers can provide provide an[52] ideal solution to clinical clinical administration with better efficacy and less side effects. Anderson et al. article demonstrated aa indicated of polymers can an ideal solution to Appl. Sci. 2016, 6, 11 indicated that nanoparticles of biodegradable polymers can provide an ideal solution to clinical administration with better efficacy and less side effects. Anderson et al. [52] article demonstrated indicated that nanoparticles of biodegradable polymers can provide an ideal solution to clinical indicated that nanoparticles of biodegradable polymers can provide an ideal solution to clinical administration with better efficacy and less side effects. Anderson et al. [52] article demonstrated a v 33 integrin indicated that nanoparticles of biodegradable polymers can provide an ideal solution to clinical new MRI method for visualizing the endothelial α v β 3 in vivo using an antibody-targeted, administration with better efficacy and less side effects. Anderson et al. [52] article demonstrated a v indicated that nanoparticles of biodegradable polymers can provide an ideal solution to clinical v 3 new MRI method for visualizing endothelial α vβ 3 integrin in vivo an antibody-targeted, administration with better efficacythe and less side side effects. effects. Anderson et al.using [52] article demonstrated administration with better efficacy and less side effects. Anderson et al. [52] article demonstrated administration with better efficacy and less Anderson et al. al. [52] article article demonstratedaaaa new MRI MRI method method for visualizing the endothelial αvvβ β33 integrin integrin in vivo vivo using an antibody-targeted, antibody-targeted, administration with better efficacy and less side effects. Anderson et [52] demonstrated new for visualizing the endothelial α in using an administration with better efficacy and less side effects. Anderson et al. [52] article demonstrated site-directed contrast agent. administration with better efficacy and less side effects. Anderson et al. [52] article demonstrated new MRI MRI method method foragent. visualizing the endothelial endothelial αvvvvβ β3 integrin integrin in vivo vivo an using an solution antibody-targeted, site-directed contrast new for visualizing the α in using an antibody-targeted, indicated that nanoparticles of biodegradable polymers can provide ideal to clinicala new MRI method for visualizing the endothelial α v ββ333333of integrin in vivo using an antibody-targeted, anew newIn MRI method foryear visualizing the endothelial endothelial α integrin in vivo using an antibody-targeted, site-directed contrast agent. vβ 3 integrin MRI method for visualizing the α v in vivo using an antibody-targeted, site-directed contrast agent. the group of 2006 by the beginning time burst, Liu et al. [53] reported the synthesis, new MRI method for visualizing the endothelial α v β 3 integrin in vivo using an antibody-targeted, site-directed contrast agent. the new MRI foryear visualizing endothelial αvvβ33ofintegrin in vivo an antibody-targeted, In themethod group of 2006 by the beginning burst, Liu etetal. [53] the synthesis, site-directed contrast agent. administration with better efficacy and less sidetime effects. Anderson al.using [52]reported article demonstrated a the site-directed contrast agent. site-directed contrast agent. In the group of year 2006 by the beginning time of burst, Liu et al. [53] reported the synthesis, site-directed contrast agent. In the group of year 2006 the beginning time of burst, et [53] the site-directed contrast agent. characterization and temperature sensitivity of thermally responsive polymeric micellar In themethod group of year 2006 by by the the beginning time of burst, Liu Liu et al. al.using [53] reported reported the synthesis, synthesis, site-directed contrast agent. characterization and temperature sensitivity of thermally responsive polymeric micellar In the group of year 2006 by beginning time of burst, Liu et al. [53] reported the synthesis, new MRI for visualizing endothelial α v β 3 integrin in vivo an antibody-targeted, the In the group of year 2006 by the beginning time of burst, Liu et al. [53] reported the synthesis, In of year 2006 by burst, Liu reported the synthesis, characterization and temperature sensitivity of of thermally responsive polymeric micellar Inthe thegroup group of year 2006 bythe thebeginning beginning time of burst, Liuet etal. al.[53] [53] reported theThe synthesis, characterization and temperature sensitivity of thermally polymeric micellar nanoparticles that were self-assembled from time cholesteryl end-capped random poly. article In of year 2006 by time burst, Liu et reported the synthesis, characterization and temperature sensitivity of of thermally responsive polymeric micellar In the the group group ofwere year 2006 by the the beginning beginning time of burst, Liuresponsive et al. al. [53] [53] reported theThe synthesis, nanoparticles that self-assembled from cholesteryl end-capped random poly. article characterization and temperature sensitivity of thermally responsive polymeric micellar site-directed contrast agent. characterization and temperature sensitivity of thermally responsive polymeric micellar characterization and temperature sensitivity of thermally responsive polymeric micellar nanoparticles nanoparticles that were self-assembled from cholesteryl end-capped random poly. The article characterization and temperature sensitivity of thermally responsive polymeric micellar nanoparticles that were self-assembled from cholesteryl end-capped random poly. The article published in 2003 has the third strongest citation burst in the entire dataset. The burst lasted for two characterization temperature sensitivity of thermally responsive polymeric micellar nanoparticles thatand were self-assembled from cholesteryl cholesteryl end-capped random poly. The article characterization and temperature sensitivity of of thermally responsive polymeric micellar published in 2003 has the third strongest citation burst in the entire dataset. The burst lasted for two nanoparticles that were self-assembled from end-capped random poly. The article In the group of year 2006 by the beginning time LiuThe et al.article [53] reported the synthesis, published in 2003 has the third strongest citation burst inburst, theend-capped entire dataset. The burst lasted for two nanoparticles that were self-assembled from cholesteryl random poly. The article that were self-assembled from cholesteryl end-capped random poly. published in 2003 has published in 2003 has the third strongest citation burst in the entire dataset. The burst lasted for two nanoparticles that were self-assembled from cholesteryl end-capped random poly. The article published in 2003 has the third strongest citation burst in entire dataset. The burst lasted for two nanoparticles that were self-assembled from cholesteryl end-capped random poly. The article years from 2006 till 2007. Little et al. [54] article in 2004 the strongest citation burst in nanoparticles that were self-assembled from published cholesteryl end-capped random poly. Themicellar article published in 2003 has the third strongest citation burst in the the entirehas dataset. Thepolymeric burst lasted for two years from 2006 till 2007. Little et al. [54] article published in 2004 has the strongest citation burst in published in 2003 has the third strongest citation burst in the entire dataset. The burst lasted for two characterization and temperature sensitivity of thermally responsive published in 2003 has theby third strongest citation burst in They the entire dataset. Theyears burst lasted2006 forDNA two the third strongest citation burst inal. entire dataset. The burst lasted forastrongest two from tillin years from 2006 till 2007. Little et al.the [54] article published in 2004 has the strongest citation burst in published in 2003 has the third strongest citation burst in the entire dataset. The burst lasted for two years from 2006 till 2007. Little et [54] article published in 2004 has the citation burst the group of year 2007 the beginning time of burst. described microparticle-based published in 2003 has the third strongest citation burst in the entire dataset. The burst lasted for two years from 2006 till 2007. Little et al. [54] article published in 2004 has the strongest citation burst in published in 2003 has the third strongest citation burst in the entire dataset. The burst lasted for two the group of year 2007 by the beginning time of burst. They described a microparticle-based DNA years from 2006 till 2007. Little et al. [54] article published in 2004 has the strongest citation burst in nanoparticles that were self-assembled from cholesteryl end-capped random poly. The article years from 2006 till 2007. Little et al. [54] article published in 2004 has the strongest citation burst in the group of year 2007 by the beginning time of burst. They described a microparticle-based DNA 2007. Little et al. [54] article published in 2004 has the strongest citation burst in the group of year 2007 years from 2006 till 2007. Little et al. [54] article published in 2004 has the strongest citation burst in the group of year 2007 by the beginning time of burst. They described a microparticle-based DNA years from 2006 till 2007. Little et al. [54] article published in 2004 has the strongest citation burst in delivery system which is composed of pH-sensitive poly-β amino ester and poly lactic-co-glycolic acid. the group of year 2007 by the beginning time of burst. They described a microparticle-based DNA years from 2006 till 2007. Little et al. [54] article published in 2004 has the strongest citation burst in delivery system which is composed ofdescribed pH-sensitive poly-β esterdataset. and poly lactic-co-glycolic acid. the group of 2003 year 2007 bythird theThey beginning timea microparticle-based ofburst burst. They described a delivery microparticle-based DNA published in has the strongest citation inamino the entire The burst lasted forDNA two the group of year 2007 by the beginning time of burst. They described microparticle-based by the beginning time of burst. system which is delivery system which is composed of pH-sensitive pH-sensitive poly-β amino ester DNA and poly lactic-co-glycolic acid. the of year 2007 by the beginning time of burst. They described aaapoly microparticle-based DNA delivery system which is of ester and lactic-co-glycolic acid. the group of year 2007 by the beginning time of burst. They described microparticle-based DNA the group group of year 2007 by the et beginning time published ofpoly-β burst.amino They described astrongest microparticle-based DNA delivery system which is composed composed of pH-sensitive pH-sensitive poly-β amino ester and poly lactic-co-glycolic acid. delivery system which is composed of poly-β amino ester and poly lactic-co-glycolic acid. years from 2006 till 2007. Little al. [54] article in 2004 has the citation burst in delivery system which is composed of pH-sensitive poly-β amino ester and poly lactic-co-glycolic acid. composed of pH-sensitive poly-β amino ester and poly lactic-co-glycolic acid. delivery system which is composed of pH-sensitive poly-β amino ester and poly lactic-co-glycolic acid. delivery system which is composed of pH-sensitive poly-β amino ester and poly lactic-co-glycolic acid. 4.5. References Bursted Since 2013 4.5. References Bursted Since 2013 delivery system which is composed of pH-sensitive poly-β amino ester and poly lactic-co-glycolic acid. the References group of year 2007 by 2013 the beginning time of burst. They described a microparticle-based DNA 4.5. Bursted Since 4.5. References Bursted Since 2013 4.5. References Bursted Since 2013 of pH-sensitive poly-β amino ester and poly lactic-co-glycolic acid. 4.5. References Bursted Since 2013 4.5. References Bursted Since 2013 delivery system which is composed Table 6 shows the references with 4.5. References Bursted Since 2013 Table 6 shows theSince references with the the recent recent citation citation bursts bursts from from 2010 2010 onward. onward. In In this this subsection, subsection, 4.5. References Bursted 2013 4.5. References Bursted Since 2013 Table 6 shows shows the references with the recent recent citation bursts from 2010 onward. onward. In this this subsection, 4.5. References Bursted Since 2013 Table 6 the references with the citation bursts from 2010 In subsection, we will review key articles with the most recent citation bursts starting from 2013. Citation bursts Table 6 shows the references with the recent citation bursts from 2010 onward. In this subsection, we will review key articles with the most recent citation bursts starting from 2013. Citation bursts Table 6 shows the references with the recent citation bursts from 2010 onward. In this subsection, Table 6 shows the references with the recent citation bursts from 2010 onward. In this subsection, Table 6 shows the references with the recent citation bursts from 2010 onward. In this subsection, we will review key articles with the most recent citation bursts starting from 2013. Citation bursts Table 6 shows the references with the recent citation bursts from 2010 onward. In this subsection, we will review key articles with the most recent citation bursts starting from 2013. Citation bursts 4.5. References Bursted Since 2013 the recent Table 66 shows the references with the citation bursts from 2010 onward. In this subsection, starting from 2013 associated main three 2012 articles. wewill will review keyare articles withthe themost most recent citation bursts starting from2013. 2013. Citation bursts Table shows the references the recent citation bursts from 2010from onward. InCitation this subsection, with starting from 2013 are associated main three 2012 articles. we will review key articles with the most recent citation bursts starting from 2013. Citation bursts with the recent we review key articles with citation bursts starting bursts we will review key articles with the most recent citation bursts starting from 2013. Citation bursts starting from 2013 are associated with the main three 2012 articles. we will review key articles with the most recent citation bursts starting from 2013. Citation bursts starting from 2013 are associated with the main three 2012 articles. we will review key articles with the most recent citation bursts starting from 2013. Citation bursts we will review key articles with the most recent citation bursts starting from 2013. Citation bursts starting from 2013 are associated with the main three 2012 articles. starting from 2013are are associated withthe mainthree three 2012 articles. Table 6 shows theassociated referenceswith the recent citation bursts from 2010 onward. In this subsection, themain starting from 2013 2012 articles. starting from 2013 are associated with the main three 2012 articles. starting from 2013 are associated with the main three 2012 articles. Table 6. References with the most recent citation bursts since 2010. Table 6. References with the most recent citation bursts since 2010. starting from 2013 are associated with the main three 2012 articles. Table 6. with the most recent bursts since 2010. starting 2013 associated the main three 2012citation articles. Table 6. References References with the most recent citation bursts since 2010.2013. Citation bursts we will from review keyare articles with with the most recent citation bursts starting from Table 6. References with the most recent citation bursts since 2010. Table 6. References with the most recent citation bursts since 2010. Table 6. References with the most recent citation bursts since 2010. Table 6. References with the most recent citation bursts since 2010. Citation Burst Table 6.References References with themost most recent citation burstssince since 2010. Table 6.6. with recent citation bursts 2010. starting fromReferences 2013 are associated with the the main three 2012 articles. Citation Burst Table References with the most recent citation bursts since 2010. Citation Burst Table 6. References with the most recent citation bursts since 2010. Citation Burst Year Table with the citation bursts 2010. References Year Citation Burst References Year Table 6. 6. References References with Strength the most most recent recent citation bursts since since 2010.Duration Strength Begin End Duration References Year Citation Burst References Year Citation Burst Strength Begin End Duration Citation Burst Strength Begin Begin End End Duration References Year Citation Burst Strength Begin End Duration Citation Burst References Year References Year Citation Burst Liong et al. [43] 2009 20.3 2010 2011 Strength Begin End Duration References Year Table 6. References with the most recent citation bursts since 2010. Liong et al. [43] 2009 20.3 2010 2011 Citation Burst Strength Begin End Duration References Year Liong et al. [43] 2009 20.3 2010 2011 Citation Burst Strength Begin End Duration References Year Liong et al. al. [43] [43] 2009 20.3 2010 2011 Year References Strength Begin End Duration References Year Strength Begin End Duration Liong et 2009 20.3 2010 2011 References Year References Year Jain etet al. [55] 2008 6.2 Strength Begin End Duration Liong al. [43] 2009 20.3 2010 2011 Jain et al. [55] 2008 6.2 Strength Begin End Duration Liong et al. [43] 2009 20.3 Strength Begin End Duration Jain et al. [55] 2008 6.2 2010 2011 Strength Begin End Duration Liong et al. [43] 2009 20.3 Jain et al. [55] 2008 6.2 2010 2011 Liong et al. [43] 2009 20.3 Citation Burst Jain et al. [55] 2008 6.2 2010 2011 Liong etet al. [43] 2009 20.3 Winter et al. [56] 2003 3.7 Liong et al. [43] 2009 20.3 2010 2011 Jain et al. [55] 2008 6.2 Winter al. [56] 2003 3.7 Liong et al. [43] 2009 20.3 2010 2011 References Year Jain et al. [55] 2008 6.2 Winter et al. [56] 2003 3.7 Liong et al. [43] 2009 20.3 2010 2011 Jain et al. [55] 2008 6.2 Winter et al. [56] 2003 3.7 Liong al. [43] 2009 20.3 2010 2011 Jain etet al. [55] 2008 6.2 Liong et al. [43] 2009 20.3 2010 Strength Begin End Duration Winter et al. [56] 2003 3.7 2010 2011 Jain et al. [55] 2008 6.2 McCarthy and Weissleder [57] 2.8 Jain et al. [55] 2008 6.2 2010 2011 Winter et al. [56] 2003 3.7 McCarthy and Weissleder [57] 2.8 Jain et al. [55] 2008 6.2 2010 2011 Winter et al. [56] 2003 3.7 McCarthy and Weissleder [57] 2.8 Jain et al. [55] 2008 6.2 2010 2011 Winter et al. [56] 2003 3.7 McCarthy and Weissleder [57] 2.8 Jain et al. [55] 2008 6.2 Jain et al. [55] 2008 6.2 2010 2011 2010 2011 Winter et al. [56] 2003 3.7 McCarthy and Weissleder [57] 2008 2.8 2010 2011 Liong et al. [43] 2009 20.3 Winter et al.[58] [56] [57] 2003 3.7 Hood et al. [58] 2002 2.5 Winter et al. [56] 2003 3.7 2010 2011 McCarthy and Weissleder 2008 2.8 Hood et al. 2002 2.5 Winter et al. [56] 2003 3.7 2010 2011 McCarthy and Weissleder [57] 2008 2.8 Hood et al. [58] 2002 2.5 Winter et al.[56] [56] [57] 2003 3.7 2010 2011 McCarthy and Weissleder 2008 2.8 Winter et al. 2003 3.7 2010 Hood et al. [58] 2002 2.5 Winter et al. [56] 2003 3.7 2010 2011 McCarthy and Weissleder [57] 2008 2.8 Hood et al. [58] 2002 2.5 2010 2011 Jain et al. [55] 6.2 McCarthy and Weissleder [57] 2008 2.8 Lu et al. [59] 2010 8.9 2012 2013 McCarthy and Weissleder [57] 2008 2.8 2010 2011 Hood et al. [58] 2002 2.5 Lu et al. [59] 2010 8.9 2012 2013 McCarthy and Weissleder [57] 2008 2.8 2010 2011 Hood et al. [58] 2002 2.5 Lu et al. [59] 2010 8.9 2012 2013 McCarthy and Weissleder [57] 2008 2.8 2010 2011 McCarthy and Weissleder [57] 2008 2.8 2010 2011 Hood et al. [58] 2002 2.5 Lu et al. [59] 2010 8.9 2012 2013 McCarthy and Weissleder [57] 2008 2.8 2010 2011 Hood et al. [58] 2002 2.5 Lu etet al. [59] 2010 8.9 2012 2013 Winter et al. [56] 2003 3.7 Hood et al. [58] 2002 2.5 2010 2011 Ashley et al. [60] 2011 8.5 2015 Hood al. [58] 2002 2.5 2010 2011 Lu et al. [59] 2010 8.9 2012 2013 Ashley et al. [60] 2011 8.5 2015 Hood et al. [58] 2002 2.5 2010 2011 Hood et al. [58] 2002 2.5 2010 2011 Lu et al. [59] 2010 8.9 2013 Ashley et al. [60] 2011 8.5 2012 2015 Hood et al. [58] 2002 2.5 2010 2011 Lu et al. [59] 2010 8.9 2013 Ashley et al. [60] 2011 8.5 2015 Hood al. [58] 2002 2.5 2010 2011 2012 Lu etetal. al. [59] 2010 8.9 2013 Ashley et al. [60] 2011 8.5 2015 McCarthy and Weissleder 2008 2.8 2010 2011 Lu et [59] 2010 8.9 2012 2013 Vivero-Escoto et[60] al. [61] [61][57] 7.7 Lu et al. [59] 2010 8.9 2012 2013 Ashley et al. 2011 8.5 2015 Vivero-Escoto et al. 7.7 Lu et al. [59] 2010 8.9 2012 2013 Lu et al. [59] 2010 8.9 2012 2013 Ashley et al. [60] 2011 8.5 2015 Vivero-Escoto et al. [61] 7.7 Lu et al. [59] 2010 8.9 2012 2013 Ashley et al. [60] 2011 8.5 2015 Vivero-Escoto et al. [61] 7.7 Lu et al. [59] 2010 8.9 2013 2012 Ashley et al. [60] 2011 8.5 2015 Vivero-Escoto et al. [61] 2010 7.7 2013 Hood et al. [58] 2002 2.5 2010 2011 Ashley etal. al.et[60] [60] 2011 8.5 2012 2015 Meng et et al. [62] 2010 3.3 Ashley et al. [60] 2011 8.5 2012 2015 Vivero-Escoto al. [61] 7.7 2013 Ashley 8.5 2012 2015 Meng et [62] 2010 3.3 Ashley et al. [60] 2011 2012 2015 Vivero-Escoto et al. [61] 7.7 2013 Meng et al. [62] 2010 3.3 Ashley etal. al.et [60] 2011 8.5 2012 2015 Vivero-Escoto al. [61] 7.7 2013 Meng et al. [62] 3.3 Ashley et al. [60] 2011 8.5 2015 2010 2012 Vivero-Escoto et al. [61] 7.7 2013 Meng et al. [62] 3.3 2015 Lu etet al.al. [59] 8.9 Vivero-Escoto et[40] al.[61] [61] 2010 7.7 2012 2013 Tang et al. [40] 2012 46.5 2013 2015 Vivero-Escoto et al. 2010 7.7 2012 2013 Vivero-Escoto et al. 2010 7.7 2012 2013 al. et Meng [62] 3.3 Tang 2012 46.5 2013 2015 Vivero-Escoto et al. [61] 2010 7.7 2012 2013 Meng et al. [62] 3.3 Tang et al. [40] 2012 46.5 2013 2015 Vivero-Escoto et al. [61] [61] 2010 7.7 2012 2013 Meng al. [62] 3.3 Tang et al. [40] 2012 46.5 2013 Vivero-Escoto et al. 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Liu [65] 2011 34.2 2013 2015 Albanese etal. al. [66] 2012 29.0 Pan etet al. [63] 36.3 Liu et et al. [65] 2011 34.2 2013 2015 Zhang et [67] 25.8 Liu al. [65] 2011 34.2 2013 2015 Albanese et al. [66] 2012 29.0 Zhang al. [67] 25.8 Albanese et al. [66] 29.0 2013 2015 Liu et al. [65] 2011 34.2 2013 2015 2012 Albanese et al. [66] 29.0 Zhang et al. [67] 25.8 Liu et al. [65] 2011 34.2 Albanese et al. [66] 2012 29.0 2013 2015 Zhang et al. [67] 25.8 Albanese et al. [66] 2012 29.0 2013 2015 Zhang et al. [67] 25.8 Du etet al. [64] 2011 35.1 Albanese et al. [66] 2012 29.0 2013 2015 Zhou et al. [46] 24.9 Albanese et al. [66] 2012 29.0 2013 2015 Zhang al. [67] 2012 25.8 2013 2015 Zhang et al. [67] 25.8 Zhou et al. [46] 24.9 Albanese et al. [66] 2012 29.0 2013 2015 Zhang et al. [67] 25.8 Zhou et al. [46] 24.9 Zhang et al. [67] 2012 25.8 2013 2015 Albanese et al. [66] 29.0 Zhou et al. [46] 24.9 Zhang et al. [67] 2012 25.8 2013 2015 Zhou et al. [46] 24.9 Liu et al. [65] 2011 34.2 Zhang et al. 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[49] 2010 14.0 Auzel [71] 2004 12.1 2013 2015 Luo etetal. al. [70] 2011 12.8 Auzel [71] 2004 12.1 Wang and Liu [48] 2009 19.4 Luo et [70] 2011 12.8 2013 2015 He and Shi [72] 10.6 Luo et al. [70] 2011 12.8 2013 2015 Auzel [71] 2004 12.1 He and Shi [72] 10.6 2011 2013 2015 He and Shi [72] 10.6 2013 Luo et al. [70] 12.8 Auzel [71] 2004 12.1 He and Shi [72] 2011 2013 2015 Auzel [71] 2004 12.1 Luo et al. [70] 12.8 He and Shi [72] 2011 10.6 2013 2015 Auzel [71] 2004 12.1 He andetet Shi [72] 2011 10.6 Wang al. [49] 2010 14.0 Auzel [71] 2004 12.1 2013 2015 Thomas al.[72] [73] 2010 9.9 Auzel [71] 2004 12.1 2013 2015 He and Shi 2011 10.6 Thomas etet al. [73] 2010 9.9 2013 2015 Thomas al. [73] 2010 9.9 Auzel [71] 2004 12.1 2013 2015 He and Shi [72] 2011 10.6 Thomas et al. [73] 2010 9.9 He and Shi [72] 2011 10.6 2013 2015 Auzel [71] 2004 12.1 Thomas et al. [73] 2010 9.9 He and Shi [72] 2011 10.6 2013 2015 Thomas et al. [73] 2010 9.9 Luo et al. [70] 12.8 He and Shi [72] 2011 10.6 2013 2015 He and Shi [72] 2011 10.6 2013 2015 Thomas et al. [73] 2010 9.9 He and Shi [72] 2011 10.6 2013 2015 Thomas et al. [73] 2010 9.9 HeAuzel and et Shi 2011 10.6 Thomas et al. [73] 2010 9.9 2013 2015 Thomas et al.[72] [73] 2010 9.9 2013 2015 [71] 2004 12.1 Thomas al. [73] 2010 9.9 2013 2015 Thomas al. [73] 2010 9.9 Among the et articles with strong strong citation bursts2013 since 2015 2013, Tang Tang et et al. al. [40] [40] article, article, titled titled Thomas et al. [73] 2010 9.9 2013 2015 Among the articles citation since 2013, Thomas et al.[72] [73] with 2010 9.9 bursts 2013 2015 Among the articles with strong citation bursts since 2013, Tang Tang et et al. al. [40] [40] article, article, titled titled He and Shi 2011 10.6 2013 2015 Among the articles with strong citation bursts since 2013, et al. Among the articles with strong citation bursts since 2013, Tang et al. [40] article, titled “Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery”, has the strongest Among the articles with strong citation bursts since 2013, Tang et al. [40] article, titled “Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery”, has the strongest Among the articles with strong citation bursts since 2013, Tang et al. [40] article, titled et al. Thomas etarticles al. [73] with strong 2010 citation 9.9 bursts2013 Among the since 2015 2013, Tang et al. al. [40] [40] article, titled “Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery”, has article, the strongest strongest Among articles with strong citation bursts since 2013, Tang et titled “Mesoporous silica synthesis, biocompatibility delivery”, has the citation burst the with burst strength strength of 46.5. 46.5. This article published indrug Advanced Materials discussed the Among the articles with citation bursts since 2013, Tang et al. article, titled “Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery”, has discussed the strongest strongest Among the articles with strong strong citation burstspublished since and 2013, Tang et Materials al. [40] [40] article, titled citation burst with aananoparticles: burst of This article in Advanced the “Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery”, has the

“Mesoporous silicaaananoparticles: nanoparticles: synthesis, biocompatibility andin delivery”, has discussed the strongest strongest citation burst burst with with burst strength strengthsynthesis, of 46.5. This This article published published indrug Advanced Materials discussed the “Mesoporous silica biocompatibility and delivery”, has the citation burst of article Advanced Materials the “Mesoporous silica synthesis, biocompatibility and drug delivery”, has the biological barriers for nano-based targeted cancer therapy and mesoporous silica nanoparticle-based citation burst with ananoparticles: burst strength of 46.5. 46.5. This article published indrug Advanced Materials discussed the “Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery”, has discussed the strongest strongest biological barriers for nano-based targeted cancer therapy and mesoporous silica nanoparticle-based citation burst with a burst strength of 46.5. This article published in Advanced Materials the Among the articles with strong citation bursts since 2013, Tang et al. [40] article, titled citation burst with for burst strengthtargeted of 46.5. 46.5. cancer This article published in Advanced Advanced Materials discussed the the biological barriers for nano-based targeted cancer therapy and mesoporous mesoporous silica nanoparticle-based citation with aaaaThe burst strength of This article published in Materials discussed biological barriers nano-based therapy and silica nanoparticle-based citation burst with burst strength of This article published in Advanced Materials discussed the targeting strategies. second article with the most recent citation burst studies the citation burst burst with burst strength of 46.5. 46.5. This article published indrug Advanced Materials discussed the biological barriers for nano-based targeted cancer therapy and mesoporous silica nanoparticle-based targeting strategies. The second article withcancer the most recent citation burstdelivery”, studies the functionalized biological barriers for nano-based targeted cancer therapy and mesoporous silica nanoparticle-based “Mesoporous silicafor nanoparticles: synthesis, biocompatibility and hasfunctionalized the strongest biological barriers nano-based targeted therapy and mesoporous silica nanoparticle-based targeting strategies. The second article with the most recent citation burst studies the functionalized biological barriers for nano-based targeted cancer therapy and mesoporous silica nanoparticle-based targeting strategies. The second article with the most recent citation burst studies the functionalized mesoporous silica materials [41]. The work reported several exciting achievements on mesoporous biological barriers for nano-based targeted cancer therapy and mesoporous silica nanoparticle-based targetingburst strategies. The second article withcancer the article most recent citation burst studies theon functionalized biological barriers nano-based targeted therapy and mesoporous silica nanoparticle-based mesoporous silica materials [41].article The work reported several exciting achievements mesoporous targeting strategies. The second article with the most recent citation burst studies the functionalized citation with for a The burst strength of 46.5. This published in Advanced Materials discussed the targeting strategies. second with the most recent citation burst studies the functionalized mesoporous silica materials [41].article The work reported several exciting achievements on mesoporous targeting strategies. The with most citation burst studies functionalized mesoporous silica materials [41]. The work reported several exciting achievements mesoporous targeting strategies. The second second article with the the most recent recent citation burst studies the theon functionalized

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Among the articles with strong citation bursts since 2013, Tang et al. [40] article, titled “Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery”, has the strongest citation burst with a burst strength of 46.5. This article published in Advanced Materials discussed the biological barriers for nano-based targeted cancer therapy and mesoporous silica nanoparticle-based targeting strategies. The second article with the most recent citation burst studies the functionalized mesoporous silica materials [41]. The work reported several exciting achievements on mesoporous silica-based materials as sustained-release systems and stimuli-responsive controlled release systems. The third article that has drawn much attention is a 2012 article studied by Li et al. [42]. The authors described that the functionalization of mesoporous silica nanoparticles with molecular, supramolecular or polymer moieties provides the material with great versatility and makes the delivery operation highly controllable. 5. Conclusions According to the network visualization and the document co-citation analysis supported by CiteSpace, we explored the key clusters of articles and identified research patterns and emerging trends in the literature. The top two clusters were labeled as gold nanoparticle and magnetic nanoparticle, suggesting that they are foundational to the knowledge domain. Not surprisingly, the two largest clusters cover a range of interests, reflecting the interdisciplinary nature of NDDT and their use. While research in gold nanoparticle and magnetic nanoparticle remains the two most prominent knowledge domains in the NDDT field, research related to clinical and therapeutic applications in NDDT has experienced a considerable growth. The detected surge of the two keywords—“mesoporous silica” and “microcrystal” in the literature of NDDT led us to investigate the nature and context of its use in NDDT. The investigation revealed a rapidly increasing number of studies that specifically used mesoporous silica-based nanomaterials and rare earth fluoride nano-/microcrystal in NDDT research. Similarly, a detected burst of citations underscores a fast-moving knowledge domain. For example, knowing exactly when citations to Chaw et al. [50] had surged (2005–2007) can improve our understanding of the complex adaptive behavior of the field. Knowing that Tang et al. [40] has been attracting much attention since 2012 can help us capitalize on the collective intelligence of the multidisciplinary scientific communities. The emergence of a new cluster indicates the beginning of a trend, for example, in microcrystal. A persistent cluster represents a continuation of an existing trend, for example, in mesoporous silica nanoparticle. In addition, the two most active clusters with the strongest citation since 2010 appear to mesoporous silica nanoparticle (cluster #3) and microcrystal (cluster #7). This means that both mesoporous silica nanoparticle and microcrystal represent where the major efforts of the research in this field. Finally, considering the interdisciplinary characteristic of NDDT, it is not easy to obtain an overall picture of the research field. Hence, the contribution of this work was to explore an efficient and quantitative way of understanding the NDDT knowledge domain. Author Contributions: Yen-Chun Lee designed and proposed the concept of this research. Both Yen-Chun Lee and Xing-Tzu Tsai wrote the paper. Chaomei Chen contributed in terms of guiding the use of CiteSpace and revising the final draft of the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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