Open access peer-reviewed chapter

A Scientometric Study on Graphene and Related Graphene- Based Materials in Medicine

By Nicola Bernabò, Rosa Ciccarelli, Alessandra Ordinelli, Juliana Sofia Somoes Machado, Mauro Mattioli and Barbara Barboni

Submitted: November 28th 2017Reviewed: April 17th 2018Published: July 18th 2018

DOI: 10.5772/intechopen.77288

Downloaded: 133

Abstract

Here we carried out a scientometric analysis of scientific literature published referred to the use of graphene and graphene-based materials. We found that in the last 15 years, more than 1200 issues have been produced, with an H-index of 67 cited 2647 times. The countries that have a larger production, in terms of number of issues published, are China, the United States, South Korea, India, and Iran, and the most relevant subject categories in which they are indexed are materials science, chemistry, science and technology, physics, and engineering, while the biological and medical specialties seem to be actually not deeply involved.

Keywords

  • graphene
  • graphene-based materials
  • graphene oxide
  • nanotubes
  • biomaterials
  • medicine
  • bioengineering
  • scientometrics

1. Introduction

Graphene consists of a single layer of carbon atoms packed into a honeycomb lattice. Its particular atomic organization of the carbon atoms affords graphene a set of very unique characteristics that justify the attention researcher of all fields have given it. The more standing out properties are a high mechanical strength, thermal and electrical conductibility, high surface-to-mas ratio, and relative transparency [1]. Many studies use graphene oxide (GO) or reduced graphene oxide (rGO) instead of pristine graphene, because the oxidized forms are easier to process and can be dispersed in water while at the same time maintaining most of graphene’s properties.

Graphene oxide has shown great potential enhancing differentiation and proliferation of human stem cells in vitro, which tend to adhere to graphene plates. In particular, it favors differentiation of human neuronal stem cells (hNSC) toward neurons rather than glia cells [2]. Combined with its inherent flexibility and strength, the possibility of creating a 3D structure that mimics the original organ, graphene appears to be a great scaffold for stem cell-based therapy [3].

Furthermore, a lot of research has come forward regarding the use of graphene in biosensors. Compared to previously used materials, graphene shows increased resistance and sensitivity. Also, being biocompatible it can be worn, allowing for the possibility of a permanently used sensor. Additionally, graphene can be bound to a wide range of molecules and proteins that allow for better selectivity [4].

Another field to which graphene’s ability to be bound to specific molecules has been applied is drug carrying and delivery. In particular, it has been successfully used for specific anticancer drug delivery [5]. It presents novel perspective in combining site detection and drug delivery. Peptides bound to the GO plates allow for detection by specific cell types, minimizing uptake by other healthy cells [6].

Graphene’s use in the medical field raises a lot of questions regarding its safety and toxicity. In this regard, there are many conflicting studies and opinions. It appears that the matter of toxicity varies greatly depending on the physicochemical characteristics of the administrated graphene, also on the form of administration, and the model, varying between different species and cell types. The characteristics of graphene like concentration, dimensions (lateral and number of layers), surface structure functional groups, and protein corona influence its toxicity in biological systems. Despite its relevance to the effect, some toxicological studies do not give a proper characterization of the form of graphene used. Though most agree on the interaction of graphene with the cellular membrane, the question of its uptake is more controversial [7]. For example, the studies of Yue et al. on the viability of six different cell lines when treated with GO of varying dimensions show that only two phagocytic cell lines were able to internalize both nano- and micro-sized GO sheets. Furthermore, there was no difference in the viability of any of the six cell line studies when the concentration was lower than 20 μg/mL. On the other hand, inhalation of GO particles may lead to an accumulation in the pulmonary surfactant and initiate an inflammatory process [8].

Interestingly, although GO does not show to be absorbed through the gastrointestinal tract, a low dose of GO can cause more damage to the gastrointestinal surface being drank as a suspension than a high dose of GO [9]. Most toxic effects seem to surge from the use of high doses of GO and the sequential aggregation and formation of conglomerates than can block small blood vessels and result in dyspnea [10]. However, recent publications detect no pathological effects in mice exposed to low dosages of GO and functionalized graphene when administrated by intravenous injection [11].

While studying toxicity it is very important to analyze the effect on the reproductive system and development because this can lead to more lasting effects. Graphene plaques seem unable to penetrate the blood-testis barrier in mice, and therefore sperm function and male reproductive activity show no alteration even for high doses of graphene [12]. In the female, there are no alterations if GO is administered before mating or during early gestation, and the female can give birth to healthy litters. However, if administered during late gestation, it leads to abortion and even death of the pregnant mice for high dose [13]. Injection of chicken eggs leads to reduced vascularization of the heart [14]. Despite showing no obvious malformation or mortality in zebrafish embryo, GO aggregates were retained in many organelles leading to hypoxia and ROS generation in these areas [15].

Even though graphene toxicity has drawn a lot of attention from scientists, there is a remarkable lack of understanding of the mechanisms underlying this effect. The use of different models and forms of graphene seem to lead to very dissimilar conclusions. There is a clear need for more systematic and in-depth studies, before graphene can be brought to its full potential use [7].

In this context, it is evident that, in one hand, graphene and graphene-related materials are even more used in medicine and bioengineering; on the other one, the information about their safety, their toxicity, and about the way of their possible interaction with living being (and human body and fluids) are still incomplete.

For this reason, here, we carried out a scientometric study on this very interesting topic, with the aim to study the scientific literature and to identify the most relevant topic and the countries that are more involved in this research activity.

2. Materials and methods

2.1. Data collection and dataset

We accessed the data from Web of Science repository (https://apps.webofknowledge.com/) in December 2017–January 2018. The data have been filtered using the Advanced Search tool with the following syntax:

TS=topic1ANDTS=topic2E1

where TS is the topic; AND is the Boolean operator.

In our queries, we used as topic 1 “graphene” or “graphene oxide” or “graphene-related material,” combined with the following keywords as topic “medicine,” “biomaterials,” “scaffold,” “regenerative medicine,” or “bioengineering.” Then all the data sets obtained were merged with the “Combine Sets” tool. As a result, we obtained a dataset in .txt format containing a list of 1208 articles with their attributes. All the following analyses have been carried out on this data set:

  • Number of citable issues: are considered exclusively articles, reviews, and conference papers.

  • Number of cites per documents: it is the number of citation of documents published in specific years.

  • H index: a topic/journal/author has index h if h of its Np papers has at least h citations each, and the other (Np − h) papers have no more than h citations each.

2.2. Temporal and geospatial analysis

The data were processed for temporal and geospatial analysis by Sci2 Tool (Sci2 Team). We generated temporal visualization of burst detection analysis of ISI keywords used in the papers. The geolocation of author collaboration was realized using Citespace (http://cluster.cis.drexel.edu/~cchen/citespace/) and Google Earth (https://www.google.it/intl/it/earth/).

3. Results and discussion

Overall, we found 1248 issues characterized by the bibliometric parameters shown in Table 1.

ParameterValue
H-index67
Average citation per item17.65
Sum of time cited2647
Citing articles14,055

Table 1.

Bibliometric parameters referred to the studied dataset.

The number of issues published per year is described in Figure 1. As it is evident in the period 2009–2011, the number of papers published per year was very low (<10/year); then it increased with a linear trend, to reach about 350 issues published in 2017.

Figure 1.

Graph showing the time trend of issues published per year.

The time trend of citations (sum of cited per year) has a different pattern, described by more than linear pattern, as reported in Figure 2.

Figure 2.

Graph showing the time trend of sum of cited per year.

Interestingly, the distribution of cites per year, as shown in Figure 3, in keeping with the Bedford’s, follows a power law, with a negative exponent.

Figure 3.

Graph showing the distribution of cites/year.

In addition it has been possible to compute the main parameters of cites/year distribution (see Table 2).

ParameterValue
Max117
95° percentile17.96825
75° percentile6
Median2.25
25° percentile0.666667
5° percentile0
Min0

Table 2.

Citation parameters.

To explore the temporal pattern of the most important themes studied, we analyzed the burst in citations referred to specific keywords (see Table 3 for the list of citation bursts identified).

TermSpanWeightBeginEnd
Accelerated-differentiation230.56220132014
Erk1–2246.29920122013
Evidenced-by233.86520152016
Fe3o4-go336.12920112013
Fe3o4-go-nanocomposites327.41120112013
Fe3o4-nanoparticles236.77720102011
Film-is228.36620122013
Films-of531.67420102014
Films-were335.18520112013
Films-with331.61220112013
Functional-theory526.90720062010
G-and239.21420112012
G-and-go241.28220112012
Genotoxicity-of227.53720122013
Graphene-content243.92120142015
Graphene-films45.69220092012
Graphene-nanocomposites433.87620112014
Graphene-nanoflakes432.12820112014
Graphene-nanostructures236.78520132014
Added-to535.57820092013
Graphene-sheets8130.54120062013
Graphene-using227.77920132014
Graphite-oxide343.64220112013
Growth-of348.99620132015
Hectorite-clay229.14420132014
Adhesive-performance238.48720112012
Human-neural441.77720112014
Human-neural-stem440.02820112014
Human-neural-stem-cells433.93820112014
Adsorption-on82.7320062013
Indicates-that226.75620142015
Induction-of232.24620122013
Interaction-between427.17720102013
Investigated-using344.76420122014
Ag-nanoparticles39.1520102012
Mammalian-cells232.25120102011
Medical-research292.30220132014
Metabolic-activity232.63720132014
Mineralization-of230.05620142015
Modified-electrode339.56320102012
Molecular-dynamics838.14220062013
Monitoring-of236.12720122013
Multi-walled234.92220122013
Neural-stem356.25520112013
Neural-stem-cell327.09620112013
Neural-stem-cells433.21820112014
Nitrogen-doped234.02120142015
Oxidation-of32.97920102012
Antibacterial-activity339.68420102012
Peak-current338.87320102012
Porous-scaffolds238.56920152016
Prepared-via329.21220132015
Properties-of-graphene434.08820102013
Protein-corona236.32220142015
Rgo-ppy428.1742016
Schwann-cells238.24720152016
Sheets-in255.56420132014
Sheets-in-the231.92820132014
Sheets-on236.32220142015
Similar-to-123.54220132014
Size-dependent229.38320122013
Stabilizing-agent232.24620122013
Stem-cell-differentiation426.51320102013
Studied-by428.88420122015
Surface-chemistry227.12320132014
Time-dependent226.41320132014
Traditional-Chinese240.82220102011
Translational-medical297.16120132014
Translational-medical-research292.30220132014
Transmission-electron-microscope227.34820122013
Van-der839.86620062013
Van-der-waals839.86620062013
Walled-carbon-nanotubes832.08220062013
Water-molecules252.21420122013
Water-soluble348.75320122014
wt-wt229.57220122013
×-10231.43320102011
Beta-tcp237.85120152016
Bioactivity-of332.75720122014
2015-elsevier-b276.50620152016
bmp-22122.94520132014
Bone-cells429.53620112014
Bone-cement229.57220122013
Cancer-cells-and243.06220132014
Cancer-stem259.11920142015
Cancer-stem-cells255.15320142015
Carbon-nanotubes583.76420062010
Cell-differentiation328.99620122014
Cell-membranes226.42320142015
Cell-to342.16820112013
Cells-on-the229.19720132014
Cellular-uptake227.08820142015
Chemical-inducers227.53720122013
Chitosan-and230.56620102011
Chitosan-composite227.77920132014
Chitosan-film327.41120112013
Collagen-scaffolds243.92120142015
3d-rgo439.7782016
3d-rgo-ppy426.5172016
Composite-film428.75420112014
Composite-films463.61220112014
Concentration-of259.31220112012
Conductivity-of229.08520142015
Cultured-on-the230.05620142015
Cytotoxicity-of348.98520122014
Cytotoxicity-of-the326.63920122014
5-×-10226.52220102011
Delivery-of261.18920132014
Density-functional526.90720062010
Density-functional-theory526.90720062010
Der-waals839.86620062013
Differentiation-of-human327.30520112013
Doped-graphene228.54120132014
Embryonic-stem337.83120122014
Embryonic-stem-cells331.44220122014
Energy427.19920062009

Table 3.

Citation bursts.

Interestingly, we investigated the number of issues published by each country, thus estimating the contribution of different countries in research on graphene application in medicine (Table 4). These data demonstrate that graphene and graphene-based material are used in a wide variety of application in biomedicine such as cell and stem cell culture, translational medicine, bioengineering, toxicology, and development, thus confirming that these materials are becoming to represent a reality in life sciences.

Number of issues% on total issues publishedCountries/territories
55834.0China
23014.0The United States
1549.4South Korea
754.6India
694.2Iran
412.5Spain
392.4Singapore
392.4The United Kingdom
372.3Australia
372.3England
352.1Taiwan
342.1Italy
301.8Japan
281.7Germany
221.3Canada
201.2Saudi Arabia
181.1Brazil
140.9Poland
120.7Romania
110.7Denmark
110.7Sweden
100.6France
100.6Russia
100.6Turkey
90.5Malaysia
90.5Portugal
80.5Egypt
70.4Argentina
70.4Czech Republic
70.4Finland
60.4Belgium
60.4Switzerland
50.3Israel
50.3Thailand
40.2Greece
40.2Mexico
40.2The Netherlands
40.2Serbia
30.2Ireland
30.2Morocco
20.1Pakistan
20.1Scotland
20.1Vietnam

Table 4.

Number of issues per country.

As it is evident, the most of issues have been published in China, with a total number of issues that accounts for about a third of worldwide production, followed by the United States and South Korea, India, and Iran. This datum is very interesting, because it demonstrates that Asiatic countries are the most important contributor, at least quantitative point of view, to this such important field of research.

To better explore the context to which the research is referred, we assessed the subject categories, as reported in Table 5.

IssuesSubject category
705Materials science
583Chemistry
423Science and technology, other topics
222Physics
161Engineering
66Electrochemistry
62Polymer science
56Biophysics
43Biochemistry and molecular biology
35Biotechnology and applied microbiology
33Pharmacology and pharmacy
26Environmental sciences and ecology
20Energy and fuels
17Instruments and instrumentation
17Toxicology
14Optics
12Cell biology
9Metallurgy and metallurgical engineering
8Research and experimental medicine
4Computer science
3Crystallography
3Dentistry, oral surgery, and medicine
3Mechanics
3Microscopy
3Oncology
2Food science and technology
2Life sciences and biomedicine, other topics
2Public, environmental, and occupational health
2Spectroscopy
2Water resources
1Acoustics
1Education and educational research
1Endocrinology and metabolism
1General and internal medicine
1Genetics and heredity
1Hematology
1Immunology
1Information science and library science
1Mathematical and computational biology
1Medical informatics
1Microbiology
1Neurosciences and neurology
1Nutrition and dietetics
1Ophthalmology
1Pathology
1Physiology
1Plant sciences
1Radiology, nuclear medicine, and medical imaging
1Telecommunications
1Transplantation

Table 5.

List of subject categories.

As it is evident from the analysis of Table 5, the most of issues are indexed in nonbiological fields (materials science, chemistry, science and technology, physics, and engineering) rather than in biological fields. This seems to indicate that, to date, the research is led and defined by hard science scientist and, possibly, the contribution of researched belonging to biological and medical areas could be markedly increased in next years.

The same trend could be identified looking on the WC, i.e., the classification system adopted by Web of Science (see Figures 4 and 5).

Figure 4.

Classification of subject categories (the diameter is proportion to the number of issues).

Figure 5.

Classification of WoS categories (the diameter is proportion to the number of issues).

From these data, we could infer that we are seeing a first phase of the use of graphene and graphene-based materials, in which the studies on basic issues (synthesis, chemical characterization, description of chemical and physical properties) rather than the application in biology and medicine are predominating. Likely, it is possible to hypothesize that in next years, the contribution of life scientists and researchers and clinicians involved in medical field could acquire higher importance.

4. Conclusion

The use of graphene and graphene-based materials in biomedicine and bioengineering is an emergent technology that promises a wide variety of application in human health, diagnostics, and therapeutics. Here, for the first time, we carried out a scientometric analysis on this topic, finding as a result that the number of published issues and of their citations is quickly and markedly increasing, as proof of the intense activity in this field. The countries that display a more active production (in quantitative term) are from Asia (China, South Korea, India, and Iran) and from North America (the USA). The issues published are mainly referred to hard sciences (materials science, chemistry, science and technology, physics, and engineering) rather than biology or medicine. Despite that these materials are used in a wide variety of biomedical and bioengineering applications (from cell culture to stem cell differentiation, from the realization of scaffolds to toxicological studies), the research activity on these issues seems still in an early stage, characterized by the physical and chemical characterization of materials, rather than the massive application in biomedicine and bioengineering.

Acknowledgments

Juliana Sofia Simoes Machado is granted by Rep-Eat-H2020-MSCA-COFUND-2015 No. 713714.

Conflict of interest

The authors declare that they have no competing interests.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Nicola Bernabò, Rosa Ciccarelli, Alessandra Ordinelli, Juliana Sofia Somoes Machado, Mauro Mattioli and Barbara Barboni (July 18th 2018). A Scientometric Study on Graphene and Related Graphene- Based Materials in Medicine, Scientometrics, Mari Jibu and Yoshiyuki Osabe, IntechOpen, DOI: 10.5772/intechopen.77288. Available from:

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