Insights into the history and trends of nanotechnology for the treatment of hepatocellular carcinoma: a bibliometric-based visual analysis

Abstract

Background

Nanotechnology has great potential and advantages in the treatment of hepatocellular carcinoma (HCC), but the research trends and future directions are not yet clear.

Objectives

Analyze the development trajectory, research hotspots, and future trends of nanotechnology and HCC research globally in the past 20 years, providing a more comprehensive and intuitive reference for researchers in this field.

Methods

Retrieve relevant literature on nanotechnology and HCC research in the Web of Science (WOS) Core Collection database, and conduct bibliometric analysis using software such as CiteSpace, VOSviewer, and SCImago Graphica.

Results

A total of 852 English publications meeting the criteria were retrieved from the WOS database, with an overall increasing trend in the number of publications and citation frequency over the years. China leads in the number of publications and international collaborations, followed by the USA and India. The most influential research institution is the Chinese Academy of Sciences, the most influential scholar/team is the Rahman, Mahfoozur team, and the journal with the most publications is the International Journal of Nanomedicine. A comprehensive analysis reveals that the current main research directions include new types of nanoparticles, targeted drug delivery systems, photothermal/photodynamic therapy, gene delivery systems, diagnostics, and imaging. It is anticipated that further collaboration among scholars, institutions, and countries will accelerate the development of nanotechnology in the field of HCC research.

Conclusion

This study provides an in-depth analysis of the research status and development trends of nanotechnology in treating HCC from a bibliometric perspective, offering possible guidance for researchers to explore hot topics and frontiers, select suitable journals, and partners in this field.

Introduction

Primary liver cancer ranks sixth among the most common cancers globally, with the third highest mortality rate, significantly impacting the health and quality of life of people worldwide [1]. Hepatocellular carcinoma (HCC) is a form of liver cancer, accounting for approximately 90% of primary liver cancer cases, characterized by significant incidence and mortality rates [2, 3]. Currently, there are numerous international treatment methods for HCC (chemotherapy, radiotherapy, etc.), but the treatment outcomes remain suboptimal, leading to poor prognosis. Surveys indicate that the 5-year recurrence rate after liver resection surgery is close to 70%, with around 2/3 of HCC cases experiencing a recurrence within 2 years [4, 5]. There is an urgent need to research new treatment methods to improve the clinical efficacy and prognosis of liver cancer patients.

In recent years, due to the unique properties of nanotechnology and the precise control of material characteristics, it has become an important approach to drive cancer management [6]. Especially in the field of HCC, nanotechnology, with advantages such as targeted therapy, controlled drug release, improved imaging diagnostic capabilities, and overcoming multi-drug resistance, has shown great potential in addressing the limitations of conventional treatment methods and driving innovation in the field of oncology [7, 8]. Many scholars worldwide have delved into research on nanotechnology in the field of HCC, yielding significant results, but also sparking issues such as research fragmentation, repetitive studies, varying quality, and increased difficulty in clinical application translation. For young scholars, the emergence of numerous literature not only burdens them with heavy reading loads but also makes it difficult for them to precisely grasp research hotspots and cutting-edge directions. Under these circumstances, conducting a bibliometric analysis of literature on nanotechnology in the HCC field can not only help scholars quickly grasp research hotspots and trends in a specific area but also assess the distribution of countries, institutions, authors, and journals in this research field, laying a foundation for finding directions and partners for future studies. Furthermore, this analysis helps young scholars adjust their research direction more timely, grasp the development trends of cutting-edge technology, and stand out in a fiercely competitive academic environment.

Methods

Data source and literature inclusion criteria

The Web of Science (WOS) Core Collection database (www.webofscience.com) is an important academic resource platform that covers a wide range of academic journal literature worldwide [9]. We conducted a literature search in WOS with the search framework: [TI = (Hepatocellular Carcinoma*) OR TI = (Adult Liver Cancer*) OR TI = (Liver Cell Carcinoma*)] AND [TI = (nano*)]. The retrieved literature was imported into Zotero software for automatic deduplication. YXM and WXX read the titles and abstracts of the literature to exclude those not relevant to nanotechnology-HCC. In case of disagreements, the corresponding author HBB made the final decision. The search period was limited from the establishment of WOS to November 30, 2023. The article categories were limited to English-language Articles and Review Articles. In the end, 852 eligible literature were included in this study, and the specific screening process is shown in Fig. 1. ZYL exported the titles, authors, institutions, etc., in Refworks and Excel spreadsheet formats, and used bibliometric software such as CiteSpace, VOSviewer, and SCImago Graphica to obtain knowledge information from the nanotechnology-HCC literature. The information was then converted into panoramic data images to visually display the development trajectory, research hotspots, and potential trends of nanotechnology in HCC.

Fig. 1.

Nanotechnology-HCC literature selection flowchart

Visualization and network mapping

Currently, VOSviewer, CiteSpace, and SCImago Graphica are widely used software tools in the field of bibliometrics and scientific visualization. Each of them has unique functions and advantages, suitable for different analysis needs and research purposes [10–12].

VOSviewer software, developed by Waltman and Van Eck, is a tool widely used for bibliometric analysis and scientific visualization. In this study, the “Network Visualization,” “Overlay Visualization,” and “Density Visualization” functions within VOSviewer software were used to evaluate the contributions and collaboration relationships of researchers, journals, institutions, countries, etc., in the field of nanotechnology-HCC. It helps identify core research teams and emerging research forces, providing important references for academic exchange and collaboration.

CiteSpace software is an internationally popular tool for drawing knowledge maps. It visualizes journals, keywords, co-cited literature, and assists researchers in analyzing the basic knowledge contained in the literature to reveal the relational patterns of knowledge. In this study, the “Overlay Maps,” “Burstness,” and “Clusters” functions within CiteSpace software were used to identify research hotspots, thematic trajectories, and frontier trends in the field of nanotechnology-HCC development, especially turning points, key points, and mutations in research.

SCImago Graphica is a lightweight graph plotting software. In this study, a combination of SCImago Graphica and VOSviewer was used to more vividly display cooperation relationships between institutions, countries/regions, helping researchers better understand the structure and characteristics of academic collaboration networks, providing reference for academic exchange and cooperation.

Results

Annual publications

The 852 included literature were cited a total of 20232 times. The most cited literature is “Internalization and cytotoxicity of graphene oxide and carboxyl graphene nanoplatelets in the human hepatocellular carcinoma cell line Hep G2” by Lammel, T (326 citations, IF = 10, Q1, 2013) [13]. The following is “The performance of docetaxel-loaded solid lipid nanoparticles targeted to hepatocellular carcinoma” (275 citations, IF = 14, Q1, 2009) [14]. “M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma” (245 citations, IF = 28.5, Q1, 2020) [15]. “Increase of doxorubicin sensitivity by doxorubicin-loading into nanoparticles for hepatocellular carcinoma cells in vitro and in vivo” (205 citations, IF = 25.7, Q1, 2005) [16]. The cited articles above have been cited over 200 times, indicating their high impact and importance in the field of nanotechnology and HCC. Generally, publications are more likely to be cited earlier, but we found that the article “M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma” published in 2020 received widespread citations within 3 years. This literature summarizes the relevance of high expression of LINC00958 in HCC with adverse clinical outcomes and demonstrates that targeting inhibition of LINC00958 can inhibit the growth and metastasis of liver cancer. In addition, the study proposes a novel nano-therapeutic strategy, using PLGA nano platforms to deliver siRNA for targeted treatment of HCC, bringing new hope and possibilities to the field of liver cancer treatment. Therefore, the publication of this article not only contributes to academia but also has potential clinical application prospects. We further analyzed the research conducted by Xueliang Zuo, which focuses on exploring the molecular mechanisms of HCC, particularly focusing on the roles of circular RNA, long non-coding RNA, and microRNA in the development of HCC and their clinical application prospects [15]. Although Xueliang Zuo and their research team have made significant achievements in exploring the molecular mechanisms of HCC and potential therapeutic targets, there are still challenges and limitations to overcome [15, 17–28]. This suggests that emerging scholars can verify the exact roles of these molecules in the development of HCC through further in-depth experimental studies and explore their combination with nanotechnology to improve treatment efficacy.

Year of publication and citation

To better reveal the academic activity, literature influence, and development trends in the field of nanotechnology—HCC, we plotted the graphs of the annual number of published papers, the average number of citations, and the total number of citations (Fig. 2). Based on the annual number of published papers, the development of the nanotechnology—hepatocellular carcinoma field can be divided into the following three stages: ① Initial development stage (2005–2013): The annual number of published papers in this field was less than 20, and the total number of citations was relatively low. Through an analysis of the background and literature of this stage, we believe that the relatively sluggish research on nanotechnology in the HCC field was mainly due to factors such as insufficient technological maturity and awareness, high research thresholds and costs, and strict safety and effectiveness reviews. ② Stable development stage (2014–2020): Starting from 2014, there was a significant increase in both the number of published papers and the total number of citations in the research field. The influx of a large number of researchers greatly improved the technological maturity of this field, promoted the growth of research output and academic influence in the nanotechnology—hepatocellular carcinoma field, and provided a solid foundation for the further development of this field. ③ Rapid development stage (2021–2023): The number of studies in this research field has surged, and research results have been used rapidly and frequently, indicating technological progress, increased awareness, and growing research interest in this field, and revealing that research on nanotechnology in the field of HCC treatment is in an unprecedentedly active period (Table 1).

Fig. 2.

Nanotechnology-HCC literature publication trend chart

Table 1.

Number of publications, citation count, and usage of nanotechnology-HCC literature

Publication year	Average citation	Count	Always cited	Since 2013 usage count	180 day usage count
2005	77.00	3	231	72	2
2006	40.00	1	40	18	2
2007	88.00	2	176	41	4
2008	16.50	2	33	10	1
2009	82.14	7	575	196	4
2010	43.83	6	263	170	5
2011	48.00	7	336	169	8
2012	69.06	16	1105	884	16
2013	56.07	15	841	979	29
2014	45.78	37	1694	2420	47
2015	40.70	40	1628	2844	51
2016	40.83	40	1633	2861	59
2017	36.30	56	2033	3260	97
2018	40.40	70	2828	5916	185
2019	29.20	76	2219	4809	281
2020	22.50	92	2070	5200	355
2021	12.61	125	1576	4957	536
2022	6.25	132	825	3893	812
2023	1.01	125	126	1969	1325

Distribution per journal

We imported 852 included articles into the VOSviewer software, with a total of 290 journals publishing research related to nano-technology and liver cancer. The largest group of related projects consists of 233 journals, indicating extensive collaboration and knowledge exchange in this field (Fig. 3A). To better capture the collaboration network and knowledge exchange pattern within this field, we analyzed journals with publication volumes of ≥ 10 articles (Fig. 3B). The journal with the highest publication volume is “International Journal of Nanomedicine” (N = 46, Q1, IF = 8.0), followed by “ACS Applied Materials and Interfaces” (N = 29, Q1, IF = 9.5), “Journal of Biomedical Nanotechnology” (N = 20, Q3, 2.9), “Biomaterials” (N = 17, Q1, IF = 14), and “Journal of Nanobiotechnology” (N = 17, Q1, IF = 10.2). These journals play significant roles in the field and actively contribute to its development and knowledge dissemination. Among the journals with the highest total citation frequency, “Biomaterials” ranks first (N = 1185, Q1, IF = 14), followed by “International Journal of Nanomedicine” (N = 1181, Q1, IF = 8.0), and “ACS Applied Materials and Interfaces” (N = 1104, Q1, IF = 9.5). This indicates that the research outcomes of these journals have received widespread attention and citation, demonstrating high impact and academic status. On the other hand, “Particle and Fibre Toxicology” receives the highest average number of citations per article (1 article, 315 citations). International Journal of Nanomedicine, Journal of Nanobiotechnology, and Biomaterials are core journals in the field of nano-technology and liver cancer, playing a leading and exemplary role in this field (Fig. 3C). The research of International Journal of Nanomedicine focuses on the development and application of nano-drugs [29–53], targeted drug delivery systems [7, 36, 39, 42, 54–58], modulation of the immune microenvironment [57, 59, 60], as well as the integration of multi-modal imaging and therapeutic techniques [34, 40, 44, 61–63]. The Journal of Nanobiotechnology focuses on aspects such as nano-drug delivery systems, photothermal therapy, immunotherapy, and combination therapy [64–80]. Biomaterials focuses on research in the field of nano-technology and liver cancer, with a focus on drug carriers, molecular imaging, and targeted therapy [14, 81–96]. Pharmaceutics (Q1, IF = 5.4), Journal of Nanobiotechnology (Q1, IF = 10.2), Journal of Drug Delivery Science and Technology (Q1, IF = 5.0), and Frontiers in Bioengineering and Biotechnology (Q1, IF = 5.7) are emerging journals with a relatively high number of publications in recent years (Fig. 3D). Through analysis of emerging journal literature, we believe that the future research hotspots of nanotechnology in the field of HCC treatment may focus on biological targeting and molecular targeted therapy [65, 97, 98], multifunctional and combination therapy strategies on nanoplatforms [68, 72, 74], image-based and efficacy monitoring based on nanotechnology [67, 99, 100], adaptive nanotherapy [73, 80, 101], as well as the intersectional application of immunology and nanotechnology [69, 102, 103]. Q1 journals are those that are ranked highly in specific disciplines, which means they have been recognized by peer review in the same field and have significant contributions and impact in that discipline. The emerging journals are all Q1 journals, indicating that the application of nanotechnology in HCC has been widely recognized and valued by the academic community, making nanotechnology in the field of HCC treatment still an active research direction.

Fig. 3.

Visualization map of journal network for nanotechnology-HCC literature (A) Collaborative Network Map of Largest Journals, (B) Collaborative network map of journals with ≥10 publications, (C) Map of core journals in nanotechnology-hepatocellular carcinoma (D) Emerging Journals in Nanotechnology - Hepatocellular Carcinoma

Dual-Map Overlays is a feature in the CiteSpace academic research tool that allows researchers to compare and analyze two distinct knowledge maps [104]. It enables the overlay of two separate knowledge maps and identifies the relationships and differences between them. To further reveal the academic interaction and knowledge dissemination patterns between nanotechnology and HCC journals, we plotted Dual-Map Overlays (Fig. 4, Table 2). The analysis shows that the research field of nanotechnology and HCC exhibits interdisciplinary cross-impact, especially with the fields of physics, materials science, and chemistry having a significant influence on molecular biology and genetics.

Fig. 4.

Overlay map of nanotechnology-HCC literature graphs

Table 2.

Journal flow information of nanotechnology-HCC literature

Cite literature	Cited literature	Z-score	F
PHYSICS, MATERIALS, CHEMISTRY	MOLECULAR, BIOLOGY, GENETICS	3.7249	21320
MOLECULAR BIOLOGY, IMMUNOLOGY	MOLECULAR, BIOLOGY, GENETICS	3.4870	20096
PHYSICS, MATERIALS, CHEMISTRY	CHEMISTRY, MATERIALS, PHYSICS	3.3563	19424
MOLECULAR BIOLOGY, IMMUNOLOGY	CHEMISTRY, MATERIALS, PHYSICS	2.0732	12824

Author and co-author analysis

We conducted an analysis of authors and co-authors using VOSviewer, with a total of 5241 authors participating in research on nanotechnology in HCC. Rahman, Mahfoozur, Yang, Tan, and Beg, Sarwar are the core authors in this field (Fig. 5A). The largest group of connections among authors includes 2226 authors, indicating the level of collaboration and cohesion in this research field (Fig. 5B). In terms of publication output, Liu, Xiaolong has the highest number of publications (N = 13), followed by Tian, Jie (N = 12), Rahman, Mahfoozur (N = 10), and Zheng, Shusen (N = 10). The author with the highest total citation frequency is Liu, Xiaolong (N = 478). To gain a more accurate insight into the influence and research activity of authors, allowing us to focus on authors with significant academic output, we excluded authors with fewer publications and focused on those with a publication count ≥ 5 (Fig. 5C). We found that there are currently five relatively stable teams in the field of nanotechnology-HCC, with limited collaboration between teams. Apart from the team led by Rahman, Mahfoozur, the other teams are mainly composed of Chinese researchers. The team of Tian, Jie and the team of Liu, Xiaolong have initiated cross-collaboration with “Liu, Gang-Tian, Jie” as the core, and the team of Yang, Tan has engaged in international collaboration. Almalki, Waleed H., Hussein, Mohd Zobir, and Li, Dan are emerging scholars who have significantly increased their publications in recent years, with their research teams demonstrating high research activity and output (Fig. 5D). In conclusion, although collaboration has been established in this field, teams with high output still tend to work independently. Therefore, we suggest that governments or relevant institutions promote interdisciplinary collaboration among scholars, actively seek international collaboration opportunities, and strengthen collaboration between teams to drive progress and innovation in the application of nanotechnology in the treatment of HCC.

Fig. 5.

Visualization map of author network for nanotechnology-HCC literature, (A) Core authors in Nanotechnology - Hepatocellular Carcinoma, (B) Collaborative network of largest authors, (C) Collaborative network of authors with ≥ 5 publications (D) Emerging Scholars in Nanotechnology - Hepatocellular Carcinoma

Distribution of countries/regions and institutions

Institutions

We conducted an analysis of publishing institutions using VOSviewer and SCImago Graphica, with a total of 1035 institutions participating in the research. The largest group of connections among institutions includes 778 institutions, indicating the level of collaboration and cohesion in this research field (Fig. 6A). Chinese Acad Sci, Sun Yat Sen University, and Umm Al Qura University are the core institutions in this field (Fig. 6B). Hop Haut Leveque has built the largest collaboration network, with a Total link strength of 36, followed by Cairo Univ and Hop Haut Leveque. Sun Yat Sen Univ has the highest number of publications (N = 46), followed by Zhejiang Univ (N = 45) and Chinese Acad Sci (N = 44). The institution with the highest citation frequency is Chinese Acad Sci (N = 2141), followed by Zhejiang Univ (N = 1235) and Sun Yat Sen Univ (N = 853). Chinese Acad Sci plays an important role in this research field, not only ranking highly in terms of publication quantity but also performing well in citation frequency and average citation count. Chinese Acad Sci has made significant achievements in the research of nanotechnology for HCC, mainly focusing on areas such as targeted drug delivery systems [73, 105–113], multifunctional nanoparticles [57, 83, 114–121], combination therapy of chemotherapy and photothermal therapy [63, 114, 120–124], as well as treatment strategies involving immunity and the tumor microenvironment [57, 83, 122, 125–128]. At the same time, these research directions represent the most promising and active research areas in the field of nanotechnology for HCC treatment, representing the cutting-edge advancements in the field. In order to have a more comprehensive understanding of the research progress of nanotechnology in the HCC field, we will analyze institutions with at least 7 publications (Fig. 6C). There are a total of 60 high-producing institutions, with 59 institutions having connections, indicating that collaborations among high-producing institutions are very common, and they often collaborate with each other to advance scientific research. However, uniquely, Isfahan Univ Med Sci does not show direct connections with other high-producing institutions. This may reflect the institution’s independence in research strategies, collaboration tendencies, or research focus, implying that Isfahan Univ Med Sci has independent research directions and methodologies in its professional field. Its developed diagnostic methods and treatment strategies for HCC are attracting attention from scholars [129, 130]. Time Overlay Visualization can observe and compare data trends in different time periods, revealing patterns, periodicity, or trends over time. We found that Umm Al Qura Univ, Prince Sattam Bin Abdulaziz Univ, and Southern Med Univ are emerging institutions in recent years and are expected to become important research forces in the future (Fig. 6D).

Fig. 6.

Visualization map of institution network for nanotechnology-HCC literature, (A) Diagram of the largest inter-institutional collaboration network, (B) Core Institutions in Nanotechnology - Hepatocellular Carcinoma, (C) Collaboration network of institutions with ≥7 publications (D) Emerging Institutions in Nanotechnology - Hepatocellular Carcinoma

Countries/regions

The functions “Map” and “Circular” in SCImago Graphica software can help researchers quickly understand the number of publications, trends, and impact of each country in a specific field, providing important references and decision support for research direction selection, partner recruitment, and strategic planning. To avoid disputes between countries, we modified the names of participating countries according to the naming conventions of SCImago Graphica software, such as changing “Wales” to “United Kingdom.” Researchers from 48 countries/regions participated in the research of nanotechnology in HCC, forming 8 major clusters (Fig. 7A). China has the closest connection with the USA, and the largest cluster consists of 12 countries including India, Saudi Arabia, Egypt, Iraq, Colombia, Ecuador, Uzbekistan, Sweden, United Arab Emirates, Bangladesh, Yemen, and Algeria (Fig. 7B). Researchers from these countries have close cooperation and communication in the field of nanotechnology in HCC. By sharing experimental data, technical experiences, and research results, they enhance collaboration and understanding, promoting the development of the field. China has established the largest national cooperation network, followed by India, Saudi Arabia, and the USA. The country with the largest number of published articles is China, followed by the USA and India. China has the highest number of citations, closely followed by the USA, India, and Egypt. China, the USA, Saudi Arabia, India, and Egypt are the core in this field (Fig. 7C). These countries have actively explored, innovated, and achieved important breakthroughs in the application of nanotechnology in HCC. Countries such as Austria, Iraq, and Poland have had a relatively high number of citation frequencies in recent years, and their literature may represent the forefront of the discipline. Our analysis of their published papers reveals that the treatment of HCC with nanotechnology is developing towards improving the accuracy of targeted therapy, enhancing treatment effectiveness, and reducing systemic toxicity [63, 131–142]. Researchers by delving into and utilizing the multifunctionality of nanotechnology, future treatment strategies may more seamlessly integrate diagnosis and treatment, providing more personalized and effective cancer treatment options.

Fig. 7.

Visualization map of countries/regions network for nanotechnology-HCC literature, (A) Countries/Regions Collaboration Diagram (B) Countries/Regions Maximum Clustering Collaboration Network Diagram (C) Core Countries in Nanotechnology-Hepatocellular Carcinoma

Keywords co-occurrence, clusters and bursts

We used CiteSpace software to perform keyword co-occurrence analysis on the literature in the field of nanotechnology and HCC, with 101 keywords appearing ≥ 10 times (Table 3, Fig. 8). The most common terms are Hepatocellular carcinoma (N = 413), Nanoparticle (N = 271), and Cancer (N = 212). Common research methods mainly include In vitro (N = 111) and In vivo (N = 54), with in vivo studies often used to evaluate the anti-tumor activity and safety of nanoparticle drugs in animal models, while in vitro studies focus on the initial evaluation of drug release dynamics and anti-cancer effects. In vivo and in vitro studies complement each other to provide a comprehensive understanding of nanoparticle drug delivery systems. The nanoparticles involved include iron oxide nanoparticle (N = 39), mesoporous silica nanoparticle (N = 35), Liposome (N = 34), gold nanoparticle (N = 28), chitosan nanoparticle (N = 23), magnetic nanoparticle (N = 18), and solid lipid nanoparticle (N = 13), each showing specific biological distribution, pharmacokinetics, and therapeutic effects due to their unique physicochemical properties. Chemotherapy drugs encapsulated in nanoparticles mainly include Doxorubicin (N = 87), Sorafenib (N = 108), and Paclitaxel (N = 30). Through in-depth analysis of the current literature, we found that nanogels, liposomes, polymer micelles, and other nano-carriers can be combined with various chemotherapy drugs such as anthracyclines, taxanes, epirubicin, camptothecin, irinotecan, vincristine, vindesine, oxaliplatin, and cisplatin to prepare nano drugs for tumor therapy. The translation of nano drug delivery systems from preclinical research to valuable outcomes faces obstacles such as poor system stability, toxicology, and benefit assessment, leading to only a very small number of drug delivery systems being tested in clinical trials for HCC. Liposome drug delivery systems are currently the first DDS to transition from concept to clinical application, showing the broadest prospects among all nano drug delivery systems [143, 144, 144]. For example, encapsulating Doxorubicin in PEGylated liposomes for HCC treatment is an example [145, 146]. However, it should also be noted that even with successful examples, not all nanomedicine formulations can progress to or pass through the clinical trial stage. Failures in the clinical setting can be attributed to various factors, including but not limited to the complexity of drug design, heterogeneity of patient populations, and cost-effectiveness issues. Additionally, the applicability of existing data may be limited due to the lack of specialized clinical trials targeting HCC. Therefore, future research should focus on designing clinical trials specifically for HCC to comprehensively assess the efficacy and safety of nanomedicine formulations in this field. At the same time, we have identified some new terms (Glycyrrhetinic Acid, Ferroptosis, Asialoglycoprotein, ReceptorSuperparamagnetic Iron Oxide Nanoparticles, Immunotoxin, Chinese Medicine Active Ingredient, Next-Generation Chitosan Nano-Formulation, Theranostic Application, Versatile Bio-Platform, Transarterial Chemoembolization, Ultrahigh Relaxivity, Charge-functionalized Mesoporous Silica Nanoparticle, Dual-Targeted Casein Micelle, etc.), which indicate that future research in the field of nanotechnology and HCC will focus on developing safer and more efficient drug delivery systems, exploring new therapeutic mechanisms, and achieving integrated diagnosis and personalized medicine. These research directions not only herald new opportunities for treating HCC, but also underscore the increasingly important role of nanotechnology in modern medicine.

Table 3.

Top 60 keywords in nanotechnology-HCC literature

Keywords	Count	Keywords	Count	Keywords	Count
Hepatocellular carcinoma	413	Co delivery	44	Nanocarrier	29
Nanoparticle	271	Nanomedicine	44	Tumor microenvironment	29
Cancer	212	Mechanism	43	Gold nanoparticle	28
Drug delivery	162	Cytotoxicity	42	Chitosan	27
Delivery	150	Iron oxide nanoparticle	39	Toxicity	27
Cell	117	Oxidative stress	39	Efficacy	26
Therapy	116	System	35	Diagnosis	25
In vitro	111	Mesoporous silica nanoparticle	35	Release	24
Sorafenib	108	Liposm	34	Asialoglycoprotein receptor	23
Apoptosis	104	Photodynamic therapy	34	Chitosan nanoparticle	23
Doxorubicin	87	Drug delivery system	33	Glycyrrhetinic acid	23
Liver cancer	78	Cancer therapy	33	Multidrug resistance	23
Chemotherapy	78	Photothermal therapy	33	Hcc	23
Expression	75	Inhibition	32	Gene delivery	22
Tumor	60	Carrier	31	Immunotherapy	22
In vivo	54	Combination	30	Metastasis	22
Cancer cell	51	Resistance	30	Polymeric nanoparticle	22
Growth	50	Targeted delivery	30	Combination therapy	21
Liver	46	Micelle	30	Contrast agent	21
Drug	45	Paclitaxel	30	Design	21

Fig. 8.

Analysis chart of annual keyword changes in nanotechnology-HCC literature

To gain a more comprehensive understanding of the thematic structure and research hotspots in the field of nanotechnology and HCC research, we employed CiteSpace for keyword clustering, identifying 8 main clusters (Table 4, Fig. 9). Cluster 0 primarily involves keywords such as targeted delivery, nanomedicine, glycyrrhetinic acid, sorafenib, and drug delivery, representing the largest cluster with the longest time span, indicating significant research interest in improving the specificity and efficiency of drug targeting in HCC treatment using nanotechnology. Cluster 1 focuses on treatment methods for HCC, especially emerging photothermal and photodynamic therapies and their relationship to ferroptosis, with keywords including hepatocellular carcinoma, photothermal therapy, photodynamic therapy, ferroptosis, and therapy. Cluster 2 showcases the important role of nanoparticles in cancer diagnostics (imaging, ultrasound, etc.) with keywords such as radiotherapy, ultrasound, expression, nanoparticles, and cancer. Cluster 3 concentrates on technologies and methods for HCC treatment using chitosan-based nanoparticles, with keywords like chitosan, chitosan nanoparticle, asialoglycoprotein receptor, gene expression, and core–shell nanoparticles. Cluster 4 is primarily about the application of silver nanoparticles in HCC treatment, particularly their effects on inducing oxidative stress and cytotoxicity, with keywords like oxidative stress, silver nanoparticles, cytotoxicity, hepatocellular carcinoma, and HepG2. Cluster 5 focuses on the use of iron oxide nanoparticles in HCC diagnosis and treatment, especially their potential as MRI contrast agents, with keywords such as superparamagnetic iron oxide nanoparticles, iron oxide nanoparticle, contrast agent, hepatocellular carcinoma (HCC), and magnetic resonance imaging. Cluster 6 emphasizes exploring advanced delivery systems to overcome tumor multidrug resistance, enhance chemotherapy efficiency, and apply in gene therapy, with keywords including delivery, in vivo, multidrug resistance, gene delivery, and chemotherapy. Cluster 7, highlighting developments in targeted and controlled drug delivery strategies in cancer treatment for better therapeutic effects and lower side effects, involves keywords like targeted drug delivery, controlled drug delivery, immunotoxin, cancer targeting, and microparticle. These research areas are vital for the advancement of personalized and precision medicine, offering hope for more effective and safer treatment options for cancer patients. The cluster map (Fig. 9) reveals that research hotspots in the field of nanotechnology-HCC concentrate on targeted drug delivery, detection techniques, and treatment methods. As the field continues to evolve, scholars are beginning to focus on oxidative stress, cytotoxicity, and propose the concept of “Green Nanomedicine.” Young scholars entering this field should not only pay attention to these hotspots but also closely monitor these emerging issues to keep their knowledge updated and keep pace with the latest developments in the field.

Table 4.

Cluster information of keywords in nanotechnology-HCC literature

Cluster ID	Size	Silhouette	Mean (year)	Cluster name	Label
0	91	0.613	2017	Targeted delivery	Targeted delivery; nanomedicine; glycyrrhetinic acid; sorafenib; drug delivery
1	83	0.57	2017	Hepatocellular carcinoma	Hepatocellular carcinoma; photothermal therapy; photodynamic therapy ferroptosis; therapy
2	81	0.597	2013	Radiotherapy	Radiotherapy; ultrasound; expression; nanoparticles; cancer
3	71	0.573	2013	Chitosan	Chitosan; chitosan nanoparticle; asialoglycoprotein receptor; gene expression; core–shell nanoparticles
4	51	0.69	2017	Oxidative stress	Oxidative stress; silver nanoparticles; cytotoxicity; hepatocellular carcinoma; hepg2
5	51	0.693	2014	Superparamagnetic iron oxide nanoparticles	Superparamagnetic iron oxide nanoparticles, iron oxide nanoparticle, contrast agent, hepatocellular carcinoma (hcc), magnetic resonance imaging
6	50	0.757	2010	Delivery	Delivery; in vivo; multidrug resistance; gene delivery; chemotherapy
7	12	0.923	2010	Targeted drug delivery	Targeted drug delivery; controlled drug delivery; immunotoxin; cancer targeting; microparticle

Fig. 9.

Cluster map of keywords in nanotechnology-HCC literature

Citation bursts may indicate that the research field represented by a particular keyword is becoming popular. By identifying these keywords, we can understand the focal points and trends of the current research community. We used CiteSpace software to detect bursts in literature keywords, aiming to reveal the hot topics and development trends of nanotechnology in HCC application research (Table 5). Through the analysis of burst keywords, we found that from 2005 to 2013 (identification, hepatocyte, angiogenesis, chitosan), scholars demonstrated an initial research interest in this field. The bursts of keywords from 2008 to 2017 (in vivo, cellular uptake, therapy, gene delivery) reflected scholars’ exploration of the practical application of nanotechnology in treatment during this period, focusing on the development of treatment strategies and carriers. The bursts of keywords from 2015 to 2020 (liver cancer, multidrug resistance, tumor microenvironment) revealed a shift in research focus towards the complex tumor microenvironment and the issue of multidrug resistance in HCC treatment, indicating that scientists are beginning to investigate the internal mechanisms of tumors at a micro level and attempting to understand and overcome the reasons for treatment failure. The bursts of keywords from 2019 to 2023 (proliferation, platform, targeted therapy, inhibition) indicated that research combining nanotechnology with HCC is entering a more mature stage focused on precise treatment. Therefore, we speculate that future research in the field of nanotechnology-HCC will focus on developing precise, personalized, and multimodal treatment strategies, while reducing the toxicity and side effects of nanomaterials is also a key concern for scholars. Emerging scholars can achieve the rapid application of innovative treatment methods through interdisciplinary collaboration.

Table 5.

Top 35 keywords with most explosive citations in nanotechnology-HCC literature

Co-cited articles and co-cited reference cluster analysis

Co-cited articles and co-cited reference cluster analysis are methods used to identify and analyze clusters of articles or references that are frequently cited together in scientific research. It helps to reveal the intellectual structure and thematic patterns within a specific research field. Highly co-cited literature refers to articles that have a broad impact and importance, and the research findings of these articles can provide valuable insights and methods to drive the development of nanotechnology in HCC treatment. Therefore, we have ranked the co-cited literature and selected the top 10 relevant articles on nanotechnology-HCC for analysis (Table 6). Among the top 10 highly cited articles, 5 are review articles on nanotechnology-HCC, reflecting researchers' strong demand for knowledge integration and an overview of the latest developments in this field [2, 6–8, 147]. These articles effectively establish a knowledge framework, guide future research directions, and reflect the maturity of research in nanotechnology for HCC treatment and the academic attention to this topic. Additionally, review articles serve as educational resources for newcomers in research, assisting in raising research funds and allocating resources, demonstrating their key role in scientific development and knowledge dissemination. Next, there are 4 empirical studies on the application of nanotechnology in HCC treatment, such as Tian Q describing the development of chitosan/poly(ethylene glycol)-glycyrrhetinic acid (CTS/PEG-GA) nanoparticles as a targeted drug delivery carrier for the liver [148]. This study has been cited 197 times and continues to be widely cited in the past 5 years. Through citation analysis, we found that CTS/PEG-GA nanoparticles can be applied to targeted delivery in the liver, attracting scholars' attention [7, 149–152]. Ruirui Zhao reported a new strategy to simultaneously inhibit the growth and metastasis of HCC using lactobionic acid-modified pH-sensitive chitosan-coupled mesoporous silica nanoparticles co-delivering ursolic acid and sorafenib [96]. This novel nano-composite enhances the bioavailability of both drugs, exhibits pH-responsive and sustained release characteristics. In vivo studies show that the nano-composite significantly reduces tumor burden in H22 tumor-bearing mice and inhibits lung metastasis. Mahfoozur Rahman evaluated the therapeutic effect of ganoderic acid (GA)-loaded nano-lipid carriers on HCC and studied the interaction between GA and various cancer signaling pathways using molecular docking technology [7]. GA-loaded nano-lipid carriers were prepared and evaluated for drug loading capacity, encapsulation efficiency, particle size and gastric stability, in vitro drug release, cytotoxicity, and cellular uptake. Induced HCC in rats by DEN, the results show that GA and its nano-lipid carriers can significantly alter some parameters related to cancer signaling pathways. Albert Lo et al. used phage display technology to identify a novel peptide (SP94) that specifically binds to HCC cells [153]. Further research indicates that SP94 has the potential to improve systemic therapy for advanced HCC patients. Additionally, Carlee E. Ashley's study proposes protocells with a unique high surface area nano-pore core and lipid bilayer structure, which may make it more unique in drug loading capacity and targeting effect compared to other three articles, marking a new stage in a nano-drug delivery system that integrates multiple therapeutic approaches [154]. Through comprehensive analysis of the top 10 co-cited literature, we found that nanotechnology used for encapsulating chemotherapy drugs can improve drug stability, enhance targeting, and reduce adverse effects on normal cells. Encapsulated drugs show enhanced cytotoxicity against cancer cells, targeted release, and better therapeutic effects compared to non-encapsulated drugs, especially in the treatment of HCC. Encapsulation technology provides an effective means to optimize drug delivery, potentially opening up new pathways for personalized medicine and alleviating the side effects of traditional chemotherapy.

Table 6.

Top 10 references with most citations in nanotechnology-HCC literature

Title	Year	Count	Journals	IF	JCR	H-index
Asialoglycoprotein receptor mediated hepatocyte targeting—strategies and applications	2015	33	Journal of controlled release	10.8	Q1	237
Cancer nanomedicine: progress, challenges and opportunities	2017	20	Nature reviews cancer	78.5	Q1	396
Current status of nanomaterial-based treatment for hepatocellular carcinoma	2019	16	Biomedicine & pharmacotherapy	7.5	Q1	78
Challenges in liver cancer and possible treatment approaches	2020	16	Biochimica et biophysica acta (BBA)—reviews on cancer	11.2	Q1	129
Glycyrrhetinic acid-modified chitosan/poly(ethylene glycol) nanoparticles for liver-targeted delivery	2010	15	Biomaterials	14	Q1	337
Hepatocellular carcinoma cell-specific peptide ligand for targeted drug delivery	2008	15	Molecular cancer therapeutics	5.7	Q2	157
Simultaneous inhibition of growth and metastasis of hepatocellular carcinoma by co-delivery of ursolic acid and sorafenib using lactobionic acid modified and pH-sensitive chitosan-conjugated mesoporous silica nanocomplex	2017	14	Biomaterials	14	Q1	337
The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers	2011	14	Nature materials	41.2	Q1	403
Nanomedicine in management of hepatocellular carcinoma: Challenges and opportunities	2017	14	International journal of cancer	6.4	Q1	212
Ganoderic acid loaded nano-lipidic carriers improvise treatment of hepatocellular carcinoma	2019	12	Drug delivery	6	Q1	52

We used CiteSpace software to conduct clustering analysis of references (Table 7, Fig. 10). By comparing the contents of keyword clustering and literature co-citation clustering, we have drawn some important conclusions and insights: ① Nanoparticles and drug delivery systems: Both clustering results emphasize the concepts of “chitosan nanoparticle,” “targeted delivery,” and “drug delivery.” This indicates that nanotechnology in the field of drug delivery, especially delivery systems related to chitosan nanoparticles, is a hot topic in HCC treatment research. ② Targeted therapy: The emergence of the concepts of “targeted nanomedicine” and “cd44 antibody-targeted liposomal nanoparticle” indicates that scientists are focusing on improving the specificity of therapy and reducing toxicity to normal cells through specific targets. ③ Anticancer efficacy: The repeated appearance of “anticancer efficacy” and “hepatocellular carcinoma” in clustering results clearly points to the focus on the role of nanoparticles in enhancing anticancer effects and treating HCC. ④ Special treatment modalities: References to “photothermal therapy,” “photodynamic therapy,” and “radiotherapy” indicate that research using nanoparticles for these special treatments is increasing, not limited to traditional chemotherapy drugs. ⑤ Gene therapy: The appearance of “small interfering RNA” in both clustering results suggests that RNA interference as a gene therapy method plays an important role in the research field of nanomedicine.

Table 7.

Cluster information of references in nanotechnology-HCC literature

ID	Cluster name	Size	Mean (year)	Label (LLR)
0	Chitosan nanoparticle	126	2012	Chitosan nanoparticle; chinese medicine; active ingredient; next-generation chitosan nano-formulation; chemotherapy stride
1	Exploiting targeted nanomedicine	107	2018	Exploiting targeted nanomedicine; chitosan-based nanoscale delivery system; theranostic application; versatile bio-platform; chitosan nanoparticle
2	Small interfering rna	103	2008	Small interfering rna; active radar guides missile; receptor-based targeted treatment; nanoparticulate system; microrna-34a expression
3	Mesoporous silica nanoparticle	68	2017	Mesoporous silica nanoparticle); sorafenib nanoparticle delivery system; transarterial chemoembolization; hybrid nanoparticulate system; transcatheter arterial chemoembolization
4	Anticancer efficacy	63	2016	Anticancer efficacy; photodynamic therapy; drug resistance; comprehensive review; novel treatment modality
5	Orthotopic model	53	2008	Orthotopic model; ultrahigh relaxivity; nanosized drug delivery system; new molecular target; personalized therapy
6	Vivo suppression	38	2003	Vivo suppression; hepatocellular carcinoma growth; drug vehicle; charge-functionalized mesoporous silica nanoparticle; breakable cholesteryl pullulan nanoparticle
7	5-fluorouracil nanoparticle	35	2006	5-fluorouracil nanoparticle; p53 pathway; orthotopic transplant mouse model; galactosylated nanostructured lipid carrier; retinoic acid
8	Nanoparticle	30	1997	Nanoparticle; vivo; doxorubicin sensitivity; vitro; increase

Fig. 10.

Cluster map of references in nanotechnology-HCC literature

The burst of co-citation literature indicates that a particular topic or field is generating widespread interest and attention. In this study, we used the "Burstness" function within CiteSpace software to analyze the bursts of references in the included literature, helping to reveal the development trends and research focus of the research field and provide reference for future research directions in the field (Table 8). The start and end times of literature bursts reveal the fluidity of research attention, demonstrating the evolution of nanotechnology in the field of HCC from basic theory to applied technology between 2003 and 2023, as well as the gradual deepening application of nanotechnology in HCC diagnosis and treatment. By examining literature with citation bursts, it can be seen that treatment strategies and nanomedicine delivery systems are the current research hotspots [6, 7, 96, 153, 155–170]. The combination of nanotechnology and HCC research, especially in enhancing treatment efficacy and reducing side effects, highlights the importance of interdisciplinary research [7, 96, 160, 166, 167, 171, 172]. For example, “Surface Engineering of Nanoparticles for Targeted Delivery to Hepatocellular Carcinoma” shows how the fusion of physical sciences and biomedicine drives innovation in treatment strategies [170]. Additionally, the article “Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays,” [171] published in 1983 and receiving a large number of citations after 2020, provides a rapid colorimetric assay for measuring cell growth and survival without the use of radioactive isotopes. This study offers a valuable tool for the safety and efficiency evaluation of nanoparticles in drug delivery and cell therapy. Furthermore, there has been a significant increase in the development of comprehensive treatment strategies and novel nanomaterials, indicating that these areas are at the forefront of nanotechnology applications in HCC treatment. The burst of cited literature is mainly published in high-impact factor and Q1 level journals such as “LANCET,” “CA-CANCER J CLIN,” and “NAT REV CANCER,” suggesting that major research achievements leading the research trends in the field of HCC tend to appear in journals with higher academic influence. By conducting a thorough analysis of these burst-cited literature, researchers and decision-makers can better understand research trends and make wiser choices in scientific research and clinical applications.

Table 8.

Top 31 references with most explosive citations in nanotechnology-HCC literature

Discussion

In the bibliometric analysis conducted in this review, we found a steady increase in the number of publications on the application of nanotechnology in HCC treatment. With the continuous development and application of nanotechnology, more researchers are applying it to the field of HCC treatment and achieving a series of research outcomes. A large number of research outcomes may lead to information overload, redundant research, uneven resource allocation, increased cognitive burden, and difficulty in knowledge dissemination and application. This study, through analyzing different dimensions of a large number of nanotechnology-HCC literature (publication volume, authors, keywords, co-cited literature, etc.), reveals the collaborative network, research hotspots, and future trends in this field.

By analyzing the collaborative networks of authors and institutions, we can see that while a general cooperation network has been formed in this field, highly productive authors and institutions still engage in relatively fixed cooperation relationships. This suggests that the cooperation network in this field may continue to expand, but caution should be taken regarding the relatively fixed cooperation relationships between high-producing authors and institutions in order to promote broader collaboration and knowledge exchange. Currently, universities remain the mainstay in the field of nanotechnology in HCC treatment, although they often face challenges such as insufficient project funding, inadequate industry-academia-research collaboration, and difficulties in technology transfer. This indicates that the clinical translation of nanotechnology in the field of HCC is still in its early stages. Scholars can establish collaborations with clinical doctors or medical institutions, participate in multidisciplinary teams, and enhance the clinical relevance and translational potential of their research. By implementing these strategies, emerging scholars can not only overcome existing challenges but also significantly increase the social and economic impact of their research results, thereby more effectively promoting the application and development of nanotechnology in the field of HCC treatment. International journals such as "International Journal of Nanomedicine," "ACS Applied Materials and Interfaces," and "Biomaterials" play an important role in publishing high-quality research results and serve as important platforms for academic dissemination in this field. Emerging scholars can utilize these international journals to stay informed of the latest developments and trends in the field, and adjust their research directions and strategies accordingly. Countries such as China, the United States, Saudi Arabia, and India lead in terms of publication volume and citation frequency in the field of nanotechnology in HCC treatment, reflecting not only the abundant research resources and high research level in these countries but also the importance and enthusiasm for collaboration at a global scale.

Keywords and co-cited literature analysis play an indispensable role in advancing scientific research, optimizing resource allocation, and promoting innovation. They are important tools in modern research management and knowledge exploration. In this study, the keyword and co-cited literature of nanotechnology in HCC were analyzed using CiteSpace software. Combined with the key research areas of core authors, institutions, journals, and countries, the research hotspots in this field are mainly focused on the following aspects: ① Novel nano particles: Researchers focus on innovative designs and function regulation to improve the efficacy and safety of nano particles in liver cancer treatment. ② Targeted drug delivery systems: Researchers actively use nanotechnology to enhance the specificity and efficiency of drug delivery in HCC treatment. ③ Photothermal/photodynamic therapy: Using the properties of nano materials to generate heat or activate specific drugs after exposure to specific wavelength light, targeting tumor cells through local heat effects or generating reactive oxygen species. These methods are of interest due to their non-invasiveness and high selectivity. ④ Gene delivery systems: Nano carriers play a crucial role in gene therapy, effectively protecting gene materials from enzymatic degradation and facilitating their entry into cells. This is particularly significant for gene therapy for HCC, especially gene editing techniques targeting specific tumor markers. ⑤ Diagnosis and imaging: Nano particles can be designed to carry imaging agents to improve sensitivity and specificity in diagnostics through MRI, CT, PET imaging technologies, showing great potential in early diagnosis and real-time monitoring of HCC. Additionally, nano sensors for detecting liver cancer markers are also a research hotspot. ⑥ Immunotherapy: Nano particles can carry and deliver immunostimulants such as antibodies, cytokines, or directly serve as antigen delivery systems, enhancing the body's immune response against tumor cells. They show potential in activating and guiding the immune system to attack HCC.

Through a comprehensive analysis of the highly focused keywords, highly cited literature, co-cited literature, and the research areas of emerging authors in recent years, we speculate that the development of novel nano materials, targeted drug delivery systems, photothermal/photodynamic therapy, gene delivery systems, diagnosis, and imaging will continue to maintain high research enthusiasm. However, in the future, scholars will pay more attention to the development of biodegradable and eco-friendly nano materials [173, 174], integration of multimodal imaging and therapy, clinical translation, and commercial applications, in order to achieve precise localization and personalized treatment in the clinical diagnosis and treatment of HCC. Interdisciplinary research and collaboration, through the integration of knowledge and technologies from different disciplines, hold promise for providing more effective and safe treatment options for HCC patients. Therefore, young researchers entering this field should actively participate in and drive these emerging research topics, continuously exploring and harnessing innovative research methods and therapeutic strategies. Through interdisciplinary learning and international collaboration, they can adapt quickly and drive innovation and progress in this field.

Conclusion

This study comprehensively and scientifically analyzed the literature in the field of nanotechnology related to HCC, systematically summarized the global publication trends, and identified the main authors, organizations, journals, and countries in this field. Through keyword and co-citation clustering analysis, the study deeply explored the role and prospects of nanotechnology in the occurrence and development of HCC, providing important references for the academic and industrial sectors. New nanoparticles, targeted drug delivery systems, photothermal/photodynamic therapy, gene delivery systems, diagnostics, and imaging are the current main research directions. It can be anticipated that further collaboration among scholars, institutions, and countries will accelerate the development of nanotechnology in the field related to HCC. However, there are certain limitations: (1) In the bibliometric literature search, we used the MeSH vocabulary of the U.S. National Library of Medicine and referred to search formulas of high-impact factor journals. However, we also acknowledge that this search method may exclude some papers that do not explicitly mention nanotechnology in the title. (2) This study only searched English literature and did not include Chinese, Japanese, or Korean literature, which may have a certain impact on the research results. (3) Bias in interpretation: Due to the backgrounds and preferences of the researchers, there may be a certain level of bias in the interpretation of the literature. However, overall, while these limitations exist, they do not detract from the importance and contribution of the study.In future studies, these limitations can be addressed by using more diverse literature search methods, expanding the language scope, and enhancing the objectivity of data analysis to obtain more comprehensive and reliable research results.

Abbreviations

TS

Topic

PD

Parkinson’s disease

MRI

Magnetic resonance imaging

PET

Positron emission tomography

WOS

Web of Science

CTS/PEG-GA

Chitosan/poly(ethylene glycol)-glycyrrhetinic acid

GA

Ganoderic acid

DEN

Diethyl-nitrosamine

Author contributions

ZYL conducted the study, produced the first draft, and updated it. The literature search, retrieval, and data collection were carried out by WXX,LJH and YXM. The data visualization and graphical interpretation were carried out by WXX and ZYL. YXM and HBB were instrumental in providing vital support or finance. Before submission, all authors contributed to and approved the final document of the paper.

Funding

Academic Subjects for College Students in Shandong Province Youth Education Science Planning Project (24BSH478).

Data availability

Data will be made available on request.

Declarations

Ethics approval and consent to participate

Not applicable.

Institutional review board statement

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential Competing interests.