Hydrogel is a three-dimensional (3D) natural or synthetic polymer network composed of crosslinked hydrophilic chains (Gholamali and Yadollahi, 2020). The hydrophilic functional groups constituting the hydrogels make them have the superior ability to absorb and retain a plethora of water, biological fluid and solute molecules, swelling several times to tens of times the dry weight (Rafieian et al., 2019). Due to its swelling/de-swelling behavior, biocompatibility, environmental responsiveness and many other physical, chemical, electrical, and biological characteristics that mimic natural biological tissues, hydrogels have been applied in biomedical fields such as stem cell engineering, cancer research, drug delivery and tissue engineering (Taghizadeh et al., 2019; Liu et al., 2021; Jing et al., 2022). The 3D porous network of hydrogels is often used to retain, capture or release materials, which is particularly beneficial for drug delivery (Gaharwar et al., 2014; Taghizadeh et al., 2019). However, the medium mechanical properties and limited functionality of hydrogels prevent their further application in the biomedical field (Zhao et al., 2020). As a consequence, since nanocomposite hydrogels (NHs) were first demonstrated in 2002 (Haraguchi and Takehisa, 2002), they have captivated extensive attention and study from researchers due to the strategy to improve the performance of hydrogels by integrating the favorable characteristics of nanomaterials with 3D hydrogel networks (Zhao et al., 2020). NHs are 3D molecular networks formed by physically or covalently crosslinking polymer with nanoparticles or nanostructures (Merino et al., 2015; Zhao et al., 2020). A range of nanoparticles or nanostructures, including inorganic nanoparticles (such as clay, hydroxyapatite, carbon nanotubes, graphene, silica, silicates, and metal/metal-oxide nanoparticles) and organic/polymer nanoparticles (such as polymer nanoparticles, dendrimers, hyperbranched polyesters) are crosslinked with polymer networks to produce NHs (Sharma et al., 2017). The drug delivery systems are designed to keep, control and release the therapeutic agent, and their aim is to deliver the drug or any other active agent to the specific parts of the body with a predetermined release curve within a predetermined period of time, while avoiding possible toxicity, minimizing side effects, and increasing patients comfort by reducing the frequency of administration (Sirousazar, 2013; Xiao et al., 2019). NHs are undoubtedly suitable carriers for drug delivery systems. Because by developing nanocomposites with specific mechanical properties and functions, different types of NHs can 1)regulate the release behavior of therapeutic agents through their unique physical properties (e.g., swelling ratio, diffusion coefficient), 2)serve as therapeutic agent molecules library through the interactions between therapeutic agent molecules and nano-partials or hydrogel matrix, 3)be responsible for the multi-stimulus (i.e., external stimuli such as electric field, magnetic field, temperature and pH) response systems of drug delivery, 4)enhance the synergies (e.g., photothermal conversion effect) for disease treatment, achieve targeted drug delivery and so forth (Merino et al., 2015; Song et al., 2015; Li et al., 2021; Zhao et al., 2021).

In recent years, many excellent reviews have been made applications of nanocomposite hydrogels for drug delivery. However, researchers may miss many important facts due to the study of literature from one or several aspects, which is inevitable. For researchers, it is also a great challenge to explore the intrinsic relationship in a large number of literatures in related fields. As an advanced method of paper analysis bibliometrics focuses on bibliometric analysis in terms of countries, institutions, journals, authors, keywords and cited documents to determine the knowledge base, hotspots, frontiers and development trends of relevant scientific research fields (Chen, 2004; Ellegaard and Wallin, 2015; Gonzalez-Alcaide et al., 2017; Chen and Song, 2019). Information visualization based on computer science is one of the significant developments of bibliometrics, researchers can have a concrete and intuitive understanding of specific research fields through information networks and maps (Gonzalez-Alcaide et al., 2017). Bibliometrics has become a powerful tool for people to quickly grasp the scope and theme, history and current situation, frontiers and trends of a certain scientific research field, which has been widely used in many fields and achieved a lot of research results (Qi-Qi et al., 2016; Ke et al., 2020; Liu T. et al., 2021; Dong et al., 2022; Xiong et al., 2022). However, the bibliometric and visualized analysis for NHs is still lacking, especially their applications in drug delivery system.

In this study, we performed bibliometric analysis using bibliometrics software CiteSpace and the R-language package Bibliometrix to analyze the retrieved articles worldwide regarding the applications of NHs for drug delivery. We identified the knowledge domain, research hotspots in this research field, and shed light on the future directions based off our research outcomes.

In this study, we retrieved and performed analysis on 613 articles that scoped on the applications of NHs for drug delivery. With the help of bibliometric and visualized analysis, some milestone literature was also identified (Figure 9; Table 4). Since the publication of the first landmark article reporting the influence of N-isopropylacrylamide (NIPAAm)/organic montmorillonite (MMT) NHs on drug release behavior (Lee and Fu, 2003), the applications of NHs for drug delivery have attracted extensive attention from researchers. Subsequently, magnetic NHs with superparamagnetic Fe₃O₄ particles (Satarkar and Hilt, 2008; Satarkar and Zach Hilt, 2008), poly (ethylene glycol) (PEG)/hydroxyapatite nanoparticles (nHAp) NHs (Gaharwar et al., 2011a), poly (ethylene glycol) (PEG)/silicate nanoparticles NHs (Gaharwar et al., 2011b), injectable hydrogels reinforced with cellulose nanocrystals (CNCs) and aldehyde-functionalized CNCs (Yang et al., 2013), pH sensitive layered double hydroxides (LDH)/CMC NHs (Barkhordari et al., 2014), antibacterial chitosan/silver NHs (Yadollahi et al., 2015a), chitosan/ZnO NHs(Yadollahi et al., 2016), antibacterial chitosan/graphene oxide-Ag NHs (Rasoulzadehzali and Namazi, 2018) and other different types of NHs, were developed and investigated for drug delivery.

In recent years, synthesis and drug delivery application of PVA/CuO NHs (Ahmadian et al., 2018), as well as the nanohybrid (5-fluorouracil loaded in LDH(Zn/Al)) encapsulated with CMC (Pooresmaeil et al., 2019), which was developed for oral delivery of colon cancer drugs, were landmark research results. In general, as a fairly new research field, the research outcome related to the applications of NHs for drug delivery have shown an overall upward trend. Especially in the past 10 years, according to the proportion of publications, we noticed that there has been an explosion of activity in the field.

In terms of the number of publications related to the applications of NHs for drug delivery, China was the country published the most in this area. Tianjin Univ from China was one of the top 10 institutions having the most publications, and Zhang J from this institution ranked third among the most prolific authors. The research team of Tianjin Univ has been committed to the research of NHs applied to drug delivery for a long time. A recent paper of this institution demonstrated the target drug delivery NHs which were selectively delivered to the tumour site (Liu et al., 2021a). In addition, Iran was an important research force in this field, not only because it ranked second in terms of the number of publications, but also because Namazi H, the most prolific author, comes from Iran’s Univ Tabriz. Namazi’s research team recently reported a nanocomposite hydrogel based on hyperbranched polymers for cancer treatment (Aslani and Hassan, 2022). There were four developing countries (China, Iran, India and Egypt) among the top 10 countries with the largest number of publications, which indicates that developing countries contribute in the applications of NHs for drug delivery. Nevertheless, Iran and its research institutions have not cooperated closely with major developed countries in Europe and the United States in this field. From the bibliometric analysis above, we found that academic cooperation is often conducive to the output of research results, whether for countries or institutions and individuals. Therefore, serval research institutions and individuals could further cooperate closely to move the development of this research field forward.

The journal of International Journal of Biological Macromolecules had the most publications in the relevant field so far, indicating the journal made outstanding contributions to the research of NHs applications for drug delivery and was popular with researchers. For example, the journal recently reported a camellia sinensis-loaded nanocomposite hydrogel as a wound dressing (Hezari et al., 2022). Through comprehensive analysis of published and cited journals, we found that the topics in this research field were mainly distributed in chemistry, materials science, physics, and biomedicine, indicating that the applications of NHs for drug delivery is an interdisciplinary research field. This is also supported by the main paths shown on the dual-map.

The keyword with the highest centrality was “polymer,” in fact, hydrogels are polymers in nature. In addition, polymerization or cross-linking between nano-partials and hydrogels, and polymer-based nanoparticles are also important contents of research in this field (Gholamali and Yadollahi, 2020). Some other prominent keywords, such as “carbon nanotubes,” “chitosan,” “clay,” “iron oxide particles,” are also the main sources of nanoparticles and nanostructures constituting NHs (Merino et al., 2015; Song et al., 2015; Gholamali and Yadollahi, 2020). For instance, Jeddi and Mahkam prepared CMC-alginate/chitosan nanocomposite hydrogel magnetized by Fe3O4 nanoparticles for pH sensitive drug release (Karzar Jeddi and Mahkam, 2019). One of the recent keywords with strong citation bursts was “doxorubicin” which is an anti-tumor drug, indicating cancer therapy is a current research hot spot for NHs for drug delivery. This coincided with the result of keywords clustering timeline analysis, which showed that cancer treatment was a rising research topic in recent years. Gholamali et al. (2021) reported CMC/Starch/ZnO NHs used as carriers of doxorubicin for controlled delivery of anticancer drugs (Gholamali and Yadollahi, 2020). Some other NHs for anticancer drug delivery and cancer treatment have also been widely developed (Chen et al., 2012; Li et al., 2016; Taleblou et al., 2020; Gao et al., 2021). Another keyword appeared recently in TOP 16 keywords with the strongest citation bursts was “responsive hydrogels”, which includes “thermosensitive hydrogel” generated by trends of keyword occurrences map, indicating that responsive hydrogels are the current research hotspots and direction. Various stimuli responsive NHs have been investigated for controlled drug delivery, such as pH responsive (Barkhordari et al., 2014), electro-responsive (Yan et al., 2012), thermosensitive (Zhang et al., 2021), magnetic responsive (Satarkar and Hilt, 2008) and light-responsive (Yan et al., 2012) ones. Moreover, targeted drug delivery has received more attention, especially in cancer treatment. Targeting drug delivery requires the ligands recognize and react to specific receptors. The nano-parts of NHs are conducive to the conjugation of active targeting agents, which provides great potential for targeted drug delivery. A paper reported that targeting ligands could easily attach to the active functional groups of CMCs (Upadhyaya et al., 2014), which attracted the attention of researchers. It should be pointed out here that the responsive NHs are not limited to a single response. For example, thermal and pH responsive NHs with surface conjugated nanoparticles have been synthesized, which are further functionalized by tumor targeting peptides (Su al., 2013).

Notably, two of the top three most local cited references were reviews, which focused on the key issues in the clinical applications of NHs regarding drug delivery, and the application potential of NHs for biomedical field (Hoare and Kohane, 2008; Gaharwar et al., 2014). Another article in the top three groundbreaking reported the synthesis and characterization of NHs, laying a foundation for their applications in biomedical field (Haraguchi and Takehisa, 2002). The local cited references reflect the domain of knowledge in this research field to a great extent. One of the top three references most co-cited reported the synthesis and characterization of an antibacterial nanocomposite hydrogel (Yadollahi et al., 2015b). “Antibacterial” happened to be a recent keyword with strong citation bursts, which also indicates to a certain extent that the study of antibacterial NHs is one of the current focuses in this field. For example, a recent paper demonstrated a nanocomposite hydrogel with antibacterial properties used for bone defect repair (Li et al., 2022).

We noticed that from the timeline of references clustering that, “therapeutics” is a Frontier in the research field we analysed in recent years, which also corresponds to the fact that the “cancer therapy” we identified above is a current research hot spot in this field. Similarly, “bioadhesive” is another research Frontier in this field. Bioadhesive NHs can adhere to biological tissues for an extended time, which is very important for prolonging drug delivery and effective dosage applications, such as oral, rectal, nasal, and vaginal administration. Tan et al. (2019) reported a bioadhesive nanocomposite hydrogel functionalized by (3aminomethylphenyl) boronic acid-conjugated chondroitin sulfate (APBA-CHS), which can improve the delivery of drugs and has a good prospect for the treatment of eye diseases such as dry eye syndrome. One of publications recently appeared in top 16 references with the strongest citation bursts was an article stating nanocomposite hydrogels for cancer treatment (Javanbakht and Namazi, 2018), which is consistent with the research hotspot and Frontier of NHs for drug delivery that we have previously identified. Another paper with high citation bursts recently appeared was a review discussing Raman spectroscopy enhanced by nanostructure-based plasmon (Ding et al., 2016). Enhanced Raman spectroscopy can analyse the composition of nanoscale mixtures (Ding et al., 2016), which can be used to identify the structural compositions and nanoparticle distribution of NHs (M.Kurdtabar et al., 2021). Meanwhile, metal nanoparticles-based NHs can also be used as substrates for surface enhanced Raman spectroscopy (Alvarez-Puebla et al., 2009; Vianna et al., 2016). More importantly, methods based on surface enhanced Raman spectroscopy have been widely used in the detection of biomarkers, especially for the detection of precancerous and malignant tissues (Allayla et al., 2021). Given that cancer treatment is a hot spot and Frontier in the field of NHs applications for drug delivery, the citation of this review increased within a short time period.

The limitations of this study exist as follows: First, we retrieved the articles reporting the applications of NHs for drug delivery merely from the database WoSCC. Second, even for articles included in the WoSCC database, our search excluded the new publications after 1 September 2022 (the search end date). Besides, machine algorithms were utilized for analysis in this study, which would inevitably lead to insufficient human intervention.

This bibliometric analysis identifies the investigative studies that are associated with the applications of NHs for drug delivery 2003–2022, using the bibliometric analysis tools CiteSpace and R-bibliometrix. NHs for drug delivery have been widely studied as a booming interdisciplinary research field. Based off our analyses, we found that developing countries, including China and Iran, contribute the most in this field, and International Journal of Biological Macromolecules published the most in this field. Namazi H, Bardajee G and Zhang J had published a lot of papers in this research area. Academic collaboration among countries, institutions and individuals promotes the rapid development of the field. Cancer therapy, responsive hydrogels and antibacterial NHs are currently research hotspots, and the study of anticancer drug delivery and bioadhesive NHs is at the forefront of this field. In addition, thermosensitive hydrogel, as a kind of responsive hydrogels, represents a potential research direction at present. In a word, this paper will provide researchers in related fields with profound insights and a novel method of literature analysis.