Critical evaluation of publications and patents in nanobiotechnology-based research in the last decade

: Nanobiotechnology is a speci ﬁ c ﬁ eld of biotechnology that utilizes nanoscale methods and materials to investigate biological systems and create innovative medical technologies. This review discusses the diverse use of nanobiotechnology in health, focusing on both its superior properties and challenges. The main aims of this report are to present and elaborate on the global market share of this growing ﬁ eld as well as the scienti ﬁ c output, regarding publications and patents in the last decade. Quantitative data is derived from the Statnano database, which includes information related to the articles from the Web of Science (WoS) and approved patents from the European Patent Of-ﬁ ce and the United States Patent and Trademark O ﬃ ce. The ﬁ nal aim of this review is to provide some suggestions based on these data. Government support is the most important driving force in building up research and publications. Support for advancement in nanotechnology to fabricate products for commercial and public bene ﬁ t is the top priority of developed nations. Thus, entrepreneurial training of young researchers, and collaborations between scientists, policymakers, investors, and citizens, should be encouraged. To work together globally and set international standards for the creation of consistent methods in characterizing nanoscale products with biological systems is imperative.


Introduction and basic terminology
The Industrial Revolution which started in the 18th century in Great Britain was the first great move for merging industry and technology.The textile, railroad, auto, and computer industries followed a widespread adoption of novel technologies during the rapid growth phase.These technical innovations brought new tools and machines into these fields affecting labor, production, and resource use.In the late 1990s, the Industrial Revolution was replaced with the Information Revolution due to the advancements in computer-related areas [1].This also paved the way for the emerging field of nanotechnology, a field that has the potential for a more significant revolution than the Information and Industrial Revolutions (Figure 1) [2,3].
Nanotechnology is an interdisciplinary field involving physics, chemistry, biology, and engineering.The intersecting theme is the design and engineering of functional nanostructured materials at the molecular scale.The term is derived from the Greek word 'nano' meaning 'dwarf'.Nanoscience deals with principles of molecules and structures with at least one dimension between 1 and 100 nm (where a nanometer is defined as 1/1,000 of a micrometer or 1/1,000,000,000 of a meter).The aim of the nanoscience discipline is to provide an understanding of these nanostructured materials.Their tiny size and the resultant huge surface-to-volume ratio enable researchers in the field to create devices and systems that exhibit unique physical, chemical, and biological properties and functions.Nanotechnology, by definition, is the numerous applications of these nanostructures in various industrial fields.It covers many nano-related terminologies that are given below [4].
Nanomaterials and nanoparticles are two fundamental terms used in this technology.Nanomaterials are substances with a unit size (in at least one dimension) between 1 and 100 nm [5,6].They exhibit unusual and superior properties that are not present in traditional bulk materials of the same kind.Some nanomaterial applications include energy storage and production, information technology, medical technology, food, and water purification, etc.Based on nanoparticle geometry, nanomaterials may be classified as 1D (examples are graphite, clay, and silicate nanoplatelets), 2D (examples are carbon nanotubes and carbon nanofibers), or 3D (examples are fullerenes, dendrimers, and quantum dots).
Nanoparticles (NPs) are extremely small materials, ranging in size from 1 to 100 nm, and can be as small as atomic and molecular length scales.NPs possess a variety of morphologies such as amorphous, crystalline, spherical, flat, or needle, with surfaces that can transport liquid droplets or gases [6,7].Nanotubes and nanowires are well-known examples of NPs.
The primary distinction between nanomaterials and NPs is that nanomaterials can have any internal or external structure on the nanoscale dimensions, whereas NPs are nano-objects with three external nanoscale dimensions [8].
Nanobiotechnology, which is a hybrid science of biotechnology and nanotechnology, refers to the application of nanotechnology to life sciences.Over the last decades, the multidisciplinary work of basic scientists, engineers, and clinicians on nanoscale materials generated many favorable results which are transferred to science, tissue and implant engineering, and medicine subfields [9].
Nanomedicine is the application of nanotechnology for medical purposes, and it is defined as the use of nanomaterials for the diagnosis, monitoring, control, prevention, and treatment of diseases [10].Recently, important applications in biomedicine paved the way to concomitant promising uses in diagnostics (nano biosensors, nano-based lab-on-chips, nanopore technology, etc.) and therapeutics (nano-based drug delivery systems, magnetothermal therapy, photothermal therapy, gene editing of viruses via CRISPR, etc.) (Figure 2).Biological information can be acquired easily, quickly, and low cost by using nanobiotechnology in this field.Also, the utilization of nanobiotechnology in treatments leads to positive outcomes such as more specific and personalized therapy.Recently, the importance of the field in the prevention of diseases such as COVID-19 (nano-based vaccines, nano-coating of personal protective equipment, antiviral surface coatings based on nanomaterials, etc.) has also been acknowledged widely.
Based on the general introduction above, this review will provide a critical assessment of the tremendous progress of nanobiotechnology and its medical applications over the last decade: (1) The extensive and diverse use of nanobiotechnology in health science will be discussed focusing on both its superior properties and challenges.(2) The share of this growing field in the global market will also be evaluated with future predictions.(3) The scientific output in nanobiotechnology, regarding publications and patents, will be evaluated and discussed.Statnano (a nonprofit organization established in 2012 to provide the latest information and statistics in nano-based science, technology, and industry) database, which includes information related to the articles from the Web of Science (WoS) and information related to the patents from the European Patent Office (EPO) and the United States Patent and Trademark Office (USPTO) will be used for this step.(4) Our final aim is to provide some suggestions on the growth of the field based on these quantitative and qualitative data.

Diverse uses of nanomaterials in biomedicine
Due to their large surface area and nanoscale size, nanomaterials have unique physical and chemical characteristics.The size influences their optical characteristics and imparts various colors through visible-range absorption [11].The physiological and biological characteristics of nanomaterials depend on their size.The shape and structure along with the size of the nanomaterial influence the reactivity, toughness, and other attributes [8,12].For a variety of biological applications, including enzymatic inhibition, transport, sensing, and transcription regulation, surface recognition by NPs offers a potential tool to control the cellular and extracellular processes.NP cores can vary in size from smaller to bigger sizes depending on the core material, therefore it provides an ideal platform for NP interactions with proteins and other biomolecules [13].

Diagnostic uses
Nanomaterials are very sensitive to minute changes such as electrical variations.This property makes them ideal platforms for diagnostic tools such as biosensors.Thus, higher sensitivities and lower detection limits (by several orders of magnitude) are now possible with the use of nanomaterials as the transducer component of biosensors.High surface-to-volume ratio, chemical activity, mechanical strength, electrocatalytic characteristics, and diffusivity are all boosted in nanostructured materials.In short, the biosensors' performances have greatly improved with the use of nanomaterials.When used as labels, nanomaterials' unique features contribute to signal amplifications or the development of "label-free" transduction systems [14].
The biocompatibility of nanomaterials is a key consideration when constructing a biosensor to examine biomolecules like DNA, bacteria, and viruses, among others.Besides the compatibility with biological molecules, higher electrical conductivity, nanoscale size, and the ability to amplify desired signals are the pros of the designed nanomaterials.Promising applications in tumor or infectious agent detection, and the use in multiplexed diagnostics are emerging [15].
In recent years, advancing point-of-care (POC) devices through integrating innovative nanocomposites led to increased specificity and sensitivity.This is a big step such integration, for example in glucose biosensors may help to revolutionize diagnostics and management during the diabetes pandemic.

Bioimaging applications
Nanomaterials' structural designs for biomedical imaging are becoming more varied and advanced.The distribution, absorption, and elimination of NPs are typically influenced by their size and surface properties.For usage in molecular imaging applications, NP sizes between 10 and 100 nm or somewhat bigger are desired.Smaller NPs may be eliminated through the kidneys, whereas significantly bigger ones may be eliminated more quickly via the reticuloendothelial system (RES).
The introduction of targeted contrast agents like fluorescent probes has made it possible to selectively view biological events and processes in both living and nonviable systems.Among the most promising materials for fluorescence imaging are quantum dots.The total efficiency of the contrast agent in molecular imaging is influenced by the density and size of the targeting ligands on the NP surface.NPs are preferred for fluorescence imaging by some criteria such as their size, brightness, photostability, toxicity, and surface.Their enhanced targeting, sensitivity, stability, and availability make them great tools for the fluorescent labeling of biomolecules and multimodal imaging [16,17].The disadvantages of fluorescent dyes that are used in bioimaging applications are their weak photochemical stability and a small Stokes shift (where the fluorescence intensity might be reduced by the self-absorption which can decrease the detection sensitivity).This property is also valid for luminescent near-infrared (NIR) dyes.So, NIR and fluorescent dyes are protected by a layer of nanomaterials during encapsulation, which increases dye photostability [18,19].Such particulates are now being developed for NIR absorbance and emission, which will allow for real-time and deeptissue imaging via optical routes.Similar efforts to improve deep tissue imaging resulted in the development of multimodal NPs that are active both optically as well as in their use in magnetic resonance imaging (MRI) [20].
The use of gold NPs in X-ray computer tomography (CT) imaging applications has generated interest due to their rich surface chemistry and absorption capability.New NP-gadolinium conjugates and engineered iron oxide NPs with exquisite control over size and composition are being investigated also as MRI contrast agents.
These promising NP-based molecular imaging applications are emerging but formulation issues including aggregation and storage in clinical settings still need more research and settlement [17,20].

Drug delivery applications
Some insoluble drugs can be modified as NPs since their small size allows diffusion easily through cell membranes.Nanostructures are absorbed by cells at a rate that is substantially higher than that of big particles, which can be between 10 and 1,000 nm in size.Thus, nanostructures can be used as delivery agents to encapsulate or attach therapeutic pharmaceuticals and deliver them to target tissues more accurately with a controlled release.Such formulated agents persist in the blood circulation system for a long time, with fewer plasma fluctuations, and consequently allow the release of combined medications at the prescribed dose with fewer side effects.NPs help to increase permeability and selectivity by overcoming the potential obstacles in therapy like the blood-brain barrier, bone-implant contact, etc.This medication administration is more effective, and the medicine acts where it is intended [21,22].
Targeted drug delivery systems (DDS) have several benefits, including the ability to fight off drug-resistant cancer cells, protect healthy cells from harmful substances, and reduce dose-limiting side effects.NP enables the delivery of sensitive treatments to their targeted lesions in active form, in appropriate concentration, and reduces the amounts that accumulate in unintended organs/tissues due to their unique cell uptake and trafficking mechanisms [23].
Although targeted NPs show promise for disease detection and treatment, toxicitywhether potential or real -remains a major barrier to clinical translation.Especially the diagnostic agents but also the treatment delivery agents introduced into the human body should entirely be cleared within a fair amount of time.However, the renal filtration threshold for metal-based nanometer-sized objects is currently unknown, as are which organic coatings are compatible with renal clearance [24,25].It is a very unusual phenomenon when certain NPs with diameters larger than 8 nm can avoid the glomerular filtration barrier.Some of them can gather in various glomerular regions, while others can escape into the urine.Depending on their diverse physicochemical properties, these NPs can either totally experience renal clearance or accumulate in particular regions of the kidney.It is still unclear how exactly some of these particles can concentrate in the glomerulus or escape into the urine at the cellular and molecular levels [26].
Nanomaterials can be employed as membranes, films, additives, moisturizers, and formulation modifiers depending on their morphology (e.g., size, aspect ratio, geometry, porosity).The testing of effective nanomaterial dosages requires strict regulation because toxicological assessment varies in size and morphologies.The difficulties and opportunities for a nanomaterials industrial breakthrough are connected to the improvement of manufacturing and processing conditions [27].
While tumor detection, targeted drug delivery, and prognostic visual monitoring of therapy, tissue engineering, antimicrobial and antiviral coatings, etc. take advantage of the enhanced strength, durability, flexibility, performance, and unique physical properties associated with these materials [27,28], the increase in usage areas and applications enhances the exposure to NPs.These molecules carry potential toxicity hazards to both humans and the environment and this issue has become an important research topic today [29].Although nanobiotechnology research is growing enormously due to the pros which outweigh the cons for the moment, the drawbacks need to be properly considered (Figure 3).In different organs, NPs can cause oxidative stress and inflammation, which harm the cell's biological molecules (such as proteins, lipids, and DNA).The entrance of the NPs to the body (inhalation, oral route, or imaging, etc.) may vary however the detoxification organs (liver, lungs, spleen, kidneys) are affected the most.The toxicity of NPs depends on the dose and duration of exposure [30].
NPs can cause toxicity with different routes/ways as follows: (1) The direct interaction of NPs with an organism's cell surface can lead to cell membrane deterioration, (2) The dissolution of the substances releases toxic ions that affect the organism via interfering activities of critical enzymes or direct interaction with DNA, (3) The production of reactive oxygen species (ROS) and consequent oxidative stress in an organism, can also harm the genetic formation or vital enzymes of the organism [31].
Traditional toxicity studies are useful for identifying acute immune system toxicity, but they frequently miss immunotoxicity brought on by immune system dysregulation.In comparison to traditional in vivo models, in vitro screening NP formulations enable quick and affordable evaluation.
There are still legitimate worries about in vitro procedures since a variety of factors affect how predictable they are in vivo.These issues mostly revolve around (1) dose selection, (2) dosage metrics, (3) assay format, (4) cell and matrix species, and (5) frequently, the absence of nano-relevant controls [32].Traditional in vivo methods like rodent models have some limitations on nano-bio studies.Although mouse models are a helpful tool for studying NP interactions with vasculature, they can be expensive.Also, their numbers should be minimized.Therefore, 3D cell culture, organ on a chip platform, chick embryo (CE), and its chorioallantoic membrane (CAM) applications were suggested to present a wide range of options for researching nano-bio interactions in vivo with mimicking the living systems in the updated literature [33][34][35][36].

Challenges and current status
Nanomaterials are increasingly being used in biological and medical research, especially in fields where conventional methods of diagnosis and therapy have had only patchy success.The success of nanomaterials in the medical field is based on their effective interaction between the extracellular matrix (ECM), cells, and intracellular components.NPs begin to interact with the cellular parts when they come into contact with mammalian cells.This interaction leads to nanoparticle cellular uptake by endocytosis and then internalization and subsequent biological reactions.Mammalian cells' reactions to interactions with NPs, both at the cellular and molecular levels, are primarily influenced by the morphological, chemical, and surface properties of the nanomaterials themselves [37,38].
To specify the appropriate use of NPs in biomedical applications, Minimum Information Reporting in Bio-nano Experimental Literature (MIRIBEL) standards were established in 2018 [39].To enhance reproducibility and quantitative comparisons of bio-nano materials, and facilitate meta-analyses and in silico modeling, MIRIBEL defined a checklist (in 3 categories) of specific components to be mentioned: material characterization, biological characterization, and details of experimental protocols.The bio-nano research community was also called upon action to advance these criteria after the publication of MIRIBEL in Nature Nanotechnology [40].
To utilize nanotechnology in biomedical applications, adequate knowledge of in vivo and in vitro results as well as correlation and consistency between the toxicity testing methodologies are required.Agencies that regulate biopharmaceuticals and toxicology are quickly adopting new criteria to keep up with the paradigm shifts brought forth by nanomedicines [41].This information transfer may enhance the application of nanotoxicology and the efficacy of nanomedicines.From a more philosophical perspective, however, nanotoxicology and nanomedicine are fundamentally two complementary aspects of a single science in nanotechnology that aims to improve and maintain life [42].
Nanobiotechnology is projected to have far-reaching consequences across the economy as well, resulting in new products, businesses, employment, and even industries.Researchers must be aware of the speed and scope of nanotechnology development and the information released across several study disciplines by a variety of laboratories, businesses, industries, and countries [43].The National Institutes of Health (NIH) has indicated nanobiotechnology as an area of concern for medical research in the 21st century [44].
Nanobiotechnology, despite experiencing rapid growth and receiving significant investments from various entities such as start-ups, governments, and universities, faces similar challenges to other applied sciences.While there is an increasing number of promising applied papers, the development and clinical implementation of successful technologies do not always occur simultaneously.As with all applied sciences, it is widely acknowledged that regardless of the rigorous scientific work involved in developing new technologies, equal emphasis must be placed on optimizing and confirming their practical feasibility.Failure to do so often results in the technology fading away and never reaching its potential to provide tangible benefits to society.

Global nanobiotechnology market
The nanotechnology market value was approximately $16 billion in 2010 and increased to $27 billion in 2015.The increase from 2015 to 2020 was remarkable, with a 23 % annual growth rate, and the market reached $76 billion by 2020.The global nanotechnology market is predicted to be $170 billion by 2026, growing at a compound annual growth rate (CAGR) of 9.2 % over the analysis period [45].It is predicted that the market value will be almost $288 billion in 2030 [46,47] (Figure 4).The studies on the growth of the market indicate that nanodevices and nanobiotechnology would have the largest shares of around $420 billion and $415 billion, respectively, whereas nanomaterials and nanotools would have a relatively minor influence in the world's economy of nanotechnology.The global nanotechnology market is anticipated to expand as a result of factors including technological advancement, rising government and private sector funding for research and development (R&D) studies, rising need for device miniaturization, and international strategic partnerships [48].Although nanotechnology significantly impacts many areas including the fields of electronics, energy, biomedicine, cosmetics, defense, automotive, and agriculture [49,50], the enormous growth is related to its wide use, especially in electronics, energy, and biomedical research.These fields collectively hold a market share of more than 70 % in nanotechnology applications.
Although the global market value of nanotechnology was growing at an increasing rate in the last decade, the world's biggest public health crisis in history, the COVID-19 pandemic, halted this rate.Strict measures such as partial or complete lockdowns in research labs or industry were the primary reason for this temporary inhibitory effect.However, the pandemic also offered a new area for nanobiotechnology applications: nanocarrier-based strategies to diagnose and treat COVID-19.Nanocarrier-based immunization strategies were the most successful applications in the prevention of the spread of the Coronavirus.In short, this health crisis showed us that the use of nanotechnology can be a great alternative to sanitizing surfaces (nanoproducts efficient as disinfectants and surface sanitizers, and nanosilver-incorporated soaps and dishwashing and laundry detergents), developing drug carriers, diagnosis systems (diagnostic tests using magnetic nanoparticles and nanorods for detecting SARS-Cov-2 RNA and host antibody response), or vaccines against viruses, primarily SARS-CoV-2 [51,52].Two of the vaccines approved for use in humans (Pfizer/BioNTech and Moderna) are based on lipid NPs to cage, stabilize and transport mRNA molecules.The Novavax vaccine, on the other hand, uses a recombinant protein NP technology platform to generate SARS-CoV-2 spike protein antigens.NPs are also showing promise as vehicles for small-molecule antiviral drugs, building on decades of progress with nanoscale drug-delivery systems [53,54].Various additional nanotechnology products are already being employed to offer remedies to combat COVID-19 in a variety of contexts; face masks, gloves, scrubs, sanitizers, and disinfectants [55].Some examples are nanofiber, nanocomposite, and nanoparticle technology incorporated into respiratory masks, providing high breathability and filtration efficacy, washing ability, and antiviral and antibacterial properties; nanofibers and nanoparticles for air filtration systems and air purification devices and medical supplies (scrubs, gloves, wipes, aprons, bandages, etc.) produced based on nanosilver technology.

Publications
Nanotechnology-related scientific articles indexed in the WOS have doubled over the last 10 years (Figure 5A) and China, India, the USA, Iran, and South Korea are the top five countries (Figure 5B) [56].Interestingly, Santos et al. reported that nanotechnology research during this period in the two world power countries, China and the USA, has primarily focused on health, although Chinese research is more diverse: nanomedicine, triboelectricity, materials for electronic devices, and material characterization for environmental recovery [57].Government support is the most important driving force in building up research and publications in a specific field, and this is apparent in the China example.China is known to invest the most financial budget in the field of nanotechnology between 2006 and 2020.The government also initiated the Strategic Pioneering Programme on nanotechnology with a budget of one billion yuan ($152 million) [58].These initiatives have carried China to the top of the list of countries in nanotechnology publications.
Another example is India; both the funding for India's national nanotechnology development plan and the consequent worldwide peak trend in nanotechnology explain the country's growth ability.The national nanotechnology development plan which operates on a five-year cycle, has established a direction for applying investments in crucial areas to ensure competitiveness against important technology actors like the USA and China.The Indian government also launched a plan to attract young talent to begin research in nanotechnology and other related disciplines.Various schemes are administered by the government not only to develop basic and advanced infrastructure but also to establish manpower, provide fellowships, and raise awareness among Indian researchers [59,60].
The USA has also a national nanotechnology initiative strategic plan to ensure that it remains a world leader in nanotechnology research and development.This strategy provides many benefits to researchers in targeted collaborations and international communications [61].
Similarly, all other countries in Figure 5B have nanotechnology-related action plans, and/or development programs with funding support for the implementation of research projects and promotion of the scientists in the nanotechnology field [62].The leadership of nanotechnology in this field is not a coincidence, it depends on the supporting and strategic planning of governments, agencies, and research institutes.
In the review of Ezema et al., the authors call the African and least-developed countries to make an effort to take advantage of the current aspect of cooperation and collaboration with industrialized nations like the USA, China, and Japan to innovatively employ nanotechnology to enhance the quality of life of their population, allowing local firms and industries to strive for sustainability and competitiveness in the recent global business environment [63].
The total number of nanotechnology-related articles indexed in the WoS in the years between 2012 and 2021 is exhibited in Figure 6.
In the case of Türkiye, a similar increasing trend in terms of publications and patents is apparent.The Statnano research site data indicates that while there were 1,055 nanotechnology articles with an ISI index from Türkiye in 2012, this number reached 5,012 in 2022.Only in the first 6 months of 2023 (up to July 2023) already 2,850 nanotechnology articles with ISI index were published.One of the most important factors triggering this increase is the newly established nanotechnology research centers; i.e. 8 university and college research labs, and 6 companies with a specific nanotechnology focus.Turkish Government Development Plans encourage the establishment of nanotechnology/nanobiotechnology facilities and support existing centers [66].
Regarding the nanomaterials investigated in these articles (Figure 6), the most used are carbon-based materials (although these have limitations because of their potential toxicity on humans) [64] graphenes, nanocrystals, and nanosheets.
Graphene, the thin-layer carbon material, has gained significant attention in research over the past 10 years, due to its exceptional thermal conductivity, mechanical strength, current density, electron mobility, and surface area [65].Because of these unique qualities, graphene has received significantly more attention than carbon nanotubes [66] and researchers often focus on developing graphene-based electrical gadgets.
Nanotubes are known as cylindrical structures with diameters ranging from 1 to 100 nm.They consist of rolledup sheets of graphene in which a single layer of carbon atoms is arranged in a hexagonal lattice.The only difference between nanotubes and nanofibers is that nanotubes are unique hollow tubular structures (cylindrical) while nanofibers are like rods and there is no inner space within them [67,68].Carbon nanotubes (CNTs) are carbon allotropes that are built in the form of cylindrical nanometer-diameter tubes that are several millimeters long and made of graphite.Its compact size and mass, strong mechanical potency, and high electrical and thermal conductivity are the causes of its amazing structural, mechanical, and electronic qualities.Due to their large surface area and ability to adsorb or conjugate with a range of medicinal and diagnostic substances, CNTs have been successfully used in pharmacy and medicine (drugs, genes, vaccines, antibodies, biosensors, etc.).They are also a great means of delivering drugs straight into cells without the body's metabolism [69][70][71].The current centers of CNT manufacture are in Asia and Europe, with the Asia Pacific region dominating.CNT had a $670.6 million global market in 2019 and experienced a 33.4 % CAGR between 2014 and 2019.The CNT market is expected to increase at a rate between 11.53 and 33.4 %.New factories are opening in China, Russia, and India because of the rising demand for CNTs [72].
Nanocrystals are carrier-free submicron colloidal drugcarrying platforms with a mean particle size in the nm range, typically between 10 and 800 nm.They are made of pure drugs and a minimum dose of surface active agents is required for stabilization [73].Its distinctiveness derives from the fact that nanocrystals are 100 % made up of the medication or payload, eliminating the auxiliary function of a carrier [74].
Nanocrystal technology enhances the bioavailability of medications that are not well-soluble in water.Thus, nanocrystal medication products are anticipated to make up 60 % of the market for NP-based drug delivery by 2021.The estimated worth of this is $82 billion.The ease of formulation, homogenous composition, and appealing pharmacoeconomic benefits of nanocrystal technology make it very appealing when compared to alternative nanocarrier drug delivery technologies.
A nanosheet can be defined as a sheet of a material with a thickness between 1 and 100 nm.It can be graphene oxide, molybdenum disulfide, polylactic acid, etc.It has many properties, such as facilities of modification and flexibility which makes it a great candidate to be used in new cell/ protein sensing/imaging techniques.The surface-modified nanosheets demonstrate good drug-or DNA-binding characteristics, and they offer versatile platforms for cell culture.Nanosheets are therefore naturally employed as tools for the transport of genes, cell monolayers, and medications [75,76].Research has demonstrated that nanosheet technology can solve problems and challenges in a variety of biomedical areas, such as drug delivery, wound treatment, and biodevice.With a better understanding of the cell-material interface, nanosheet-based tissue engineering in living organisms is expected to be developed in the future [77].
All other nanomaterials displayed in Figure 6 have unique superior properties and are therefore preferred in various biomedical studies.In addition to the use of individual materials, a widely used method to combine the properties of nanomaterials is by making them composite.Figure 6 also shows the high number of publications in which nanocomposites were used.As a result, many review articles emphasize applications of composite nanomaterials in biomedical engineering in particular [78][79][80][81].

Patents and products
The multidisciplinary nature of nanotechnology creates new technical and legal issues for patent systems all around the world in terms of examination, categorization, and analysis.Inventors and researchers are required to follow the current rules of the patent system in their own country and others as well, to ensure that their ideas are properly protected [82].In the past decade, while the numbers of researchers working in the field, scientific papers, products, and global investments have all enhanced by an average annual rate of 25 %, the number of global patent applications grew with an average annual increase rate of about 35 % [83].
The evaluation of granted patents from EPO and USPTO indicates that the USA, South Korea, Japan, China, and Germany are the top countries granted patents in the field of nanotechnology (Figure 7).This result is consistent with the report of Dang et al. who analyzed the period between 1991 and 2008.One interesting finding of this period was the specific increase in patents in "composite materials", "metal nanoparticles", "gate electrodes" and "quantum dots" [84].This finding is also similar to the study of Chen et al. who analyzed the period between 1976 and 2006 [85].
According to the findings of Wu et al., the USA market attracts more international collaborations and has a higher level of knowledge exchange and resource sharing than the Chinese market.Companies play an important role in the development of nanotechnology in the USA, resulting in more intra-industry collaborations.Universities and research institutes, on the other hand, are the primary contributors to China's nanotechnology development, resulting in more academia-industry collaborations in the Chinese market [86].
Figure 8 indicates that trends of patents granted from USPTO between 2012 and 2021 in terms of nanomaterial types are consistent and almost similar to trends in publications regarding nanomaterial types (Figure 6).The most granted patents were related to nanotubes, graphene, and nanocomposites.Different from the papers, nanowires, and quantum dots are also popular materials in patents.The patent trend on nanowires may be related to their significant properties, especially in the electronic industry.The main attraction of organic molecule nanostructures is their potential low cost as well as the great freedom that the device engineer has in selecting a material whose properties have been specially designed to match the requirements of a given application.The components and circuits for existing photonic systems can now have additional functionality thanks to the materials' simple integration with traditional semiconductor devices.Nanowires are competing with carbon nanotube patents because carbon nanotubes can be produced in different forms [87].The other important nanomaterials in patent search are quantum dots.Nanometer-sized crystals called quantum dots (QDs) feature stronger but narrower emission spectra, tunable fluorescence signatures, and good photostability.QDs can be used as effective inorganic  fluorescent probes for biological applications such as imaging (in vitro and in vivo), biosensing, biolabeling, gene expression research, protein investigations, or medical diagnostics depending on their characteristics.The wide usage area of QDs explains the increase in the number of patents [88].
Nanobiotechnology products are summarized in Figure 9 according to the data from the Statnano database in terms of sub-industrial sectors in medicine.The biggest share is medical supplies and pharmaceuticals.These products are introduced into the market by almost ∼540 companies which are located in 47 different countries.As might be expected, the USA, China, and Germany are the leaders.According to the reports, the most used materials are listed as silver, polymeric NPs, liposomes, and metal dioxides [89].Therapeutic nanomaterials are generally being approached cautiously by pharma and biotech companies, because of the concerns regarding the bioaccumulation of NPs and possible long-term negative impacts.However, recent developments involving lipid NPs in mRNA vaccines demonstrate unequivocally that nanomaterials can be effective in combating viruses.The wide variety of methods used in in vivo research on these materials presents a challenge in comparing them [90].
The data about nanobiotechnology patents and products indicate that this field is currently still in the basic stage of research and is gradually progressing toward the applied research field.Many NP-based product manufacturing companies have already taken place in the market, and the next generation of nanotechnology-enabled products will involve a convergence of technologies, such as nanotechnology combined with modern molecular techniques, microfluidics, chip technologies, as well as 3D-4D printing of nanomaterialcontaining devices.This new field has the potential to transform a wide range of research fields and industries, including important applications such as diagnosis and treatment of diseases.

Conclusions
The field of nanobiotechnology is concerned with the development of nanoscale tools that can be used to address medical issues in diagnosis, imaging, and treatments to advance the field of medicine.The potential of this technology is evolving very fast in the last couple of decades and it is challenging to evaluate the growth in the field.Nevertheless, the most critical factors to consider are the global market share, the volume of scientific articles, and patents that have been recently published in these areas.Scientific articles serve as a reliable gauge of scientific activity, while the number of patents signifies the conversion of scientific findings into various technologies, applications, and markets.The rapid and interesting growth in all these three indicators is elaborated on in this critical review.
As in every rapidly growing biotechnology area, side effects related to accumulation in the body, public safety and risk assessment issues in mass production of the technology are continuing to be the main concerns.Along with the efforts to overcome these challenges, there is strong government backing in leading countries, on both basic research in the field and the technology transfer process to commercialize innovative products from the laboratories to the market.Developed countries prioritize this field by providing support and funding, thereby increasing the number of scientific studies that are translated into products through publication and patenting.Support for infrastructure and tools for advancement in nanotechnology to fabricate products for commercial and public benefit are the top priorities of developed nations.Thus, actors like researchers, policymakers, investors, citizens, etc. are encouraged to collaborate during the research and commercialization stages [91,92] as well as the entrepreneurial education and training of young researchers.
At another point, to bridge the gap between developing and developed nations, there is a need for global collaboration to establish and maintain international standards and nomenclature, as well as conduct toxicity testing, risk assessment, and mitigation.This will enable the development of characterization techniques for nanoscale objects and products that are standardized and can be used with biological systems.

Figure 1 :
Figure 1: The schematic representation of the economist Norman Poire's prediction about nanotechnology development.The massive changing landscape of the industry comes about twice a century based on the basic advancements in science and technology.Poire predicts that developments in nanotechnology will be dominating the 21st century.

Figure 2 :
Figure 2: Nanotechnology-based approaches for healthcare systems (scheme was created with Biorender.com).

Figure 3 :
Figure 3: Advantages and disadvantages of nanomaterials (scheme was created with Biorender.com).

Figure 5 :
Figure 5: Nanobiotechnology related articles indexed in ISI.(A) The number of nanotechnology-related articles indexed in ISI is trending between 2012 and 2022.Over the last 10 years, the number of publications has doubled.(B) Top countries based on ISI-indexed nanotechnology-related articles published between 2012 and 2022 (data derived from [56]).

Figure 6 :
Figure 6: The total number of nanotechnology-related articles indexed in the Web of Science (WoS) in terms of nanomaterials types (2012-2021) [93].

Figure 8 :
Figure 8: Number of patents granted in 2012-2021 from USPTO in terms of different nanomaterials [96].