Emerging Nanotechnologies for Medical Applications

Emerging Nanotechnologies for Medical Applications focuses on both commercial and premarket tools and their applications in medicine. The book develops the concept of integrating different technologies along a hierarchical structure of biological systems and clarifies biomechanical interactions on different levels for the analysis of multiscale pathophysiological phenomena. With a focus on nano-scale processes and biomedical applications, it demonstrates how knowledge can be utilized in a range of areas, including the diagnosis and treatment of various human diseases, and in alternative energy production.

This book is an important reference source for scientists and researchers involved in micro- and nano-engineering, bio-nanotechnology, biomedical engineering, nanomedicine, and industries involved with optical devices, computer simulation and pharmaceuticals.

• Shows how nanotechnology is being used to improve outcomes in areas of cancer, tissue grafting, and printing drugs
• Explores a variety of nanoengineering techniques used for biomedical applications, including for cardiovascular, renal and dental treatments
• Assesses the major challenges of manufacturing nanomaterials-based medicines on an industrial scale

• Language: English
• Publisher: Elsevier Science
• Release date: Feb 7, 2023
• ISBN: 9780323998307

Book preview

Chapter 1

Introduction to nanoengineering and nanotechnology for biomedical applications

Isha Khuranaa, Prince Allawadhib, Dinesh Neeradic, Anil Kumar Banothuc, Sunitha Thalugulad, Ramavath Redya Naike, Gopinath Packirisamyb, Kala Kumar Bharanif and Amit Khuranac,f,g

aDepartment of Pharmaceutical Chemistry, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, India

bDepartment of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Roorkee, Roorkee, Uttarakhand, India

cDepartment of Veterinary Pharmacology and Toxicology, College of Veterinary Science (CVSc), Rajendranagar, Hyderabad, Telangana, India

dDepartment of Pharmacology, University College of Pharmaceutical Sciences (UCPS), Kakatiya University, Warangal, Telangana, India

eZaney Pharma Innovations, Tarnaka, Hyderabad, Telangana, India

fDepartment of Veterinary Pharmacology and Toxicology, College of Veterinary Science (CVSc), Mamnoor, Warangal, Telangana, India

gCentre for Biomedical Engineering (CBME), Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi, India

1.1 Introduction to nanotechnology

Nanotechnology term can be referred to as the engineering of any functional entity at its molecular scale which includes the alterations made at the range of 1–100 nm. It is understood that a nanometer is one millionth part of a millimeter which is employed in the measurement of atoms as well as molecules. Nanotechnology has various definitions; however, all the definitions highlight the development as well as design of the highly ordered nanostructured materials which give specific responses when it is exposed to a certain stimulus [1]. At nanoscale range, the control over complete fundamental structure of a molecule becomes easy that ultimately permits the manipulation of its physical and chemical properties [2]. These unique properties are because of the increment in the surface area in relation to volume due to the reduction in its size along with the influence of quantum effects at the atomic scale [3]. As the materials at this scale possess a unique chemical, physical as well as biological characteristics which can be different from its behavior in the bulk and hence, these properties are used to address various problems in the field of medicine, physics, energy, mechanics, chemistry, computers, etc. [4]. The actual excitement of nanotechnology is mainly driven by amalgamation of various nanodevices as well as sensors into the biological system for the purpose of drug delivery and diagnostics. As the living organisms are made up of cells which are typically present in the range of 10 µm. On the other hand, the cell parts are relatively much smaller and within the domain of sub-micron size, whereas the proteins are even smaller with a size of approximately 5 nm [1]. This size range is comparable to the dimensions of artificial or synthetic nanoparticles (NPs) produced with the help of nanotechnology. This indicates that the use of NPs as tiny probes would permit the scientists to control the cellular machinery without interfering with its other functions. Hence, the major force behind the development of nanotechnology is the better understanding of various biological processes on nanometric scale. It holds the potential to change our expectations and benefit us with the ability to solve numerous global problems.

Nanotechnology has displayed a wide array of its applications that plays an important role in industrial production to the biomedical applications. This has affected almost every aspect of our lives [5]. In the initial phase, nanotechnology had made its presence in the electronics and computer field for the manufacturing of smart phones, computers, chips, etc. But, with time, it has broadened its horizon to the field of medicine in which nanotechnology has proven to be a boon for the humankind. Important area of medicine in which nanotechnology has made a difference includes imaging and in the therapeutics of various infections and cancers. Nanotechnology has been used to develop various drug delivery systems that allow better precision in the targeting of the drug to a certain receptor and desired site, this results in increased effectiveness of the drug by low doses and decreased toxicity. Moreover, the images of tumors can be improved through the application of iron oxide NPs that can attach to the surface of tumor cells, thereby, resulting into improved images. Currently, therapeutics of cancer is an active area of development which includes various types of chemotherapeutic drugs that are being delivered by the help of nanotechnology. The recent designed systems in the field of cancer therapy are believed to be the active assemblies which hold the potential to enter inside the tumor cell after administration into the body followed by killing the tumor cells after local activation through agents like X-rays as well as infrared rays [6,7].

Nanomaterials exist in similar size range as that of proteins which makes these materials suitable for the purpose of bio-labeling and bio-tagging. Normal materials when reduced to nanoscale, exhibit certain unique properties which are not present at the micro scale such as chemical reactivity, electrical conductivity, and large surface area. Furthermore, by altering the surface of a nanomaterials in several ways can generate materials with unique biological functions and properties for any specific application along with better solubility under various physiological conditions [8]. In addition, to interact with a specific biological target, a layer of molecular or biological coating should be attached over the surface of NPs that acts as a bioinorganic interface which includes biopolymers, antibodies, or certain monolayers of very small molecules [9]. Fig. 1.1 shows various types of nanocarriers used for biomedical applications.

Figure 1.1 Some of the most commonly used nanocarriers that have been extensively studied and are used for various industrial and biomedical applications. The figure was created with BioRender.com.

Moreover, NPs can be made up of single constituent materials or a composite of various materials. NPs which are found in nature are usually agglomerates of the materials with several compositions [5]. Due to the increasing need of multifunctional NPs, various other complex entities of NPs are being developed. Thereby, the potential developments in the field of nanotechnology are promising. However, there are certain aspects such as the effects of NPs on human as well as on environment along with a proper animal testing for safety studies. No doubt, the ongoing research in the area of nanotechnology is multi-disciplinary.

1.2 Historical evolution of nanotechnology

Nanotechnology is considered as one of the most encouraging technologies of 21st century. Human exposure to the NPs has been present throughout the human history, but it drastically increased at the time of industrial revolution. The use of nanotechnology by humans dates back to 4th century by Romans who represented, the Lycurgus cup, as one of the most fascinating example of nanotechnology [10]. This is the oldest as well as famous type of dichroic glass that changes its color in different lighting conditions. During 1990s, scientists observed this cup with the help of transmission electron microscopy (TEM) to demonstrate the property of dichroism which was because of the existence of NPs within the size range of 50–100 nm [11]. Moreover, X-ray analysis was also performed which indicated that these NPs are alloy of silver and gold which is distributed in a glass matrix within a certain ratio of 7:3 along with some amount of copper [12]. Further, during the 16th century, Italians applied the nanotechnology in the preparation of Renaissance pottery, which were influenced by the techniques of Ottoman [13]. During the period of 13th to 18th century, various nanowires, carbon nanotubes, and Damascus saber blades were produced for the purpose of providing resilience and strength to a material [14]. Moreover, in 1857, Faraday demonstrated the characteristics of colloidal suspension of ruby gold that holds unique optical as well as electronic properties and generates solutions with various colors under the influence of specific light conditions [15].

However, the actual concept of nanotechnology emerged in the year 1959 by the American physicist and Nobel laureate Richard Feynman [10]. During the time of the annual meeting of American Physical Society held at California Institute of Technology, Feynman delivered a lecture with the title There's Plenty of Room at the Bottom and made a hypothesis that Why can't write down the entire 24 volumes of Encyclopedia Britannica on the head of a pin with the vision of constructing the machines at the molecular level [16]. This vision provided by him later was proved and because of which Feynman is considered as the father of nanotechnology. Afterwards, Norio Taniguchi, a Japanese scientist in the year 1974, was the first to employ the term nanotechnology to explain certain mechanisms of semiconductors that take place in the order of nanometers [17]. He defined that nanotechnology is composed of the mechanism of separation, consolidation as well as deformation through one atom or by a molecule. Furthermore, different strategies were discovered and developed for the generation of nanostructures and these strategies were then divided into two main categories which include top-down along with the bottom-up approach [10]. These two approaches differ in the context of their quality, speed of the process as well as the cost involved in a certain method.

K. Eric Drexler, in 1986 published the very first book on the nanotechnology titled, Engines of Creation: The Coming Era of Nanotechnology that created the theory of molecular engineering very popular [18]. After that, in 1991, Drexler along with Peterson and Pergamit published one more book Unbounding the Future: The Nanotechnology Revolution in which the term of nanobots was included for its role in various nano processes in the field of medicine from which the term nanomedicine came into picture [19]. Till then, experimental nanotechnology was not introduced until the time of 1981 when first scanning tunneling microscope (STM) was built by the IBM scientists in Zurich, Switzerland [20]. This device allowed observing a single atom through the method of scanning a little probe present on the surface of silicone crystal. This microscope was developed to image the surface at atomic level and also employed as a tool by which atoms as well as molecules can be altered to produce unique structures. In this technique, tunneling current was applied to form or break the chemical bonds selectively. Further, in 1990, scientists developed the method of employment of this technique to influence single xenon atoms to move over the surface of nickel to produce the letters of IBM logo [21]. Since then, various techniques have been developed to detect the images at atomic levels which include magnetic resonance imaging (MRI), modified light microscopy and atomic force microscopy (AFM).

This was followed by various other remarkable advancements such as in the year 1985 when chemists, Robert Curl, Richard Smalley, and Harold Kroto developed a method to create molecule in the shape of a soccer ball containing 60 carbon atoms which was named as buckminsterfullerene or buckyballs [22]. Afterwards, in the year 1991, carbon nanotubes were synthesized which were small but super strong rolls of the carbon atoms, almost hundred folds stronger than steel and also six times lighter in weight [23]. These compounds hold a great potential in industrial applications such as nanotubes were converted into composite fibers and long threads which were strong enough to produce computer chips, plastics, detectors and certain other useful materials with improved thermal, mechanical and electrical properties as compared to the bulk product.

A new class of the carbon nanomaterials known as carbon dots was invented accidently by Xu et al. at the time of purification of the single walled carbon nanotubes which contain unique properties such as reduced toxicity, size below 10 nm along with improved biocompatibility [24]. These interesting properties formed carbon dots as the desirable materials for its application in the field of drug delivery, bioimaging as well as biosensors [25,26]. With the discovery of graphene in the year 2004, carbon-based structures became the backbone of science and technology [27]. This field made a great contribution in the area of molecular biology which includes the study of nucleic acids. In addition, Paul Rothemund, in 2006, produced scaffolded DNA origami by increasing the complexity and dimensions of DNA nanostructures in one pot reaction [28]. Hence, remarkable progress has been made during the course of the evolution of nanotechnology.

1.3 Importance of nanotechnology and nanoengineering

Nanotechnology can be defined in many forms and also holds various applications. It is helping us to considerably improve as well as revolutionize various aspects of life. The greatest discoveries through this technology can be seen in the form of several novel devices and process of manufacturing along with new catalysts for the industries and tiny structures for computers. One of the significant and best of its kind we have seen during the coronavirus disease (COVID-19) crisis where nanotechnology-based mRNA vaccines were developed and approved to tackle this deadly virus with an efficacy of around 94% [29–34]. The advantages of nanotechnology are primarily based upon the fact that it is feasible to modify the structures of different materials at a very small scale to attain certain desirable properties as per the need. With the application of nanotechnology, the compounds can be tailored into stronger, durable, lighter, and more reactive species. Various everyday products available in the market widely rely on the use of nanoscale particles in their compositions. The products developed with the help of nanotechnology are extremely useful in the field of biomedicine which resulted into the advancement of a hybrid science, known as nanobiotechnology [35–37].

Faraji et al. stated that nanotechnology holds a great potential in nanomedicine, mainly in the area of diagnosis, prostheses and drug delivery systems. Moreover, nanoscale materials can change their actual size when they come in contact with an aqueous system which indicates that the nanostructures can adapt a unique chemical form by comparatively little interactions. The nanomaterials can integrate with the biomedical devices very easily. Nanotechnology is widening the knowledge as well as treatment options available in the health sector. Nanomedicine, which is an application of nanotechnology, uses a natural scale available in the biological processes to develop precise methods to prevent diseases along with their diagnosis as well as treatment [38]. Various improved diagnostic and imaging tools have been developed that are paving their way for earlier diagnosis with improved therapeutic success rates. Several therapeutic options are available which use NPs that can encapsulate as well as deliver the medicine at the targeted location directly inside the cancer cell which reduces the risk involved to the neighboring healthy cells. This has also helped in lowering down the toxicity caused by various chemotherapeutic drugs due to its potential of targeted drug delivery. Moreover, the process of nanoengineering of the solid nanopore materials has helped in the development of technologies for novel gene sequencing. This process enabled the detection of a single molecule at a relatively high speed and low cost as compared to the conventional methods [39,40].

Nanotechnology has extensively helped in the area of environmental remediation through the development of NPs that aid in the cleaning of industrial water pollutants into the ground water with the help of certain chemical reactions with a low cost. It has also benefited with the ways to detect as well as filter the bacteria, organic pollutants, heavy metals, and certain toxic chemicals from the supplies of water. Furthermore, it has also provided catalytic converters that have the capability to detoxify fumes coming out of the vehicular engines. Various carbon nanotubes are being employed in the remediation of various toxic sites with the help of their unique physical as well as chemical properties. Nanodevices and nanoscale sensors are cost effective solution in monitoring the structural integrity of various bridges, rails, and tunnels over the period of time. Biochemists are using nanotechnology to deploy certain viruses as nanocameras to obtain a better and clear image of the processes taking place inside the cells. Moreover, in the field of computing nanoscience, more smaller as well as powerful nanochips are being developed that hold increased capacity [41,42].

Nanotechnology is tremendously contributing to the field of diagnostics by developing new molecular agents and specific methods that enable us for the early as well as accurate detection of the disease along with the monitoring of the treatment simultaneously. In addition, the available imaging techniques can detect cancers accurately which earlier could take many years to identify and at that time millions of cells could have proliferated and metastasized. Similarly, nanoengineering carries out the manipulations in the nanostructures at atomic as well as molecular level to produce certain nanomaterials that are having programmed functions. Moreover, the underlying mechanisms and the properties have been unraveled with the advancements in nanoengineering [43]. Nanoengineering has allowed scientists to focus over the conformational modifications in various material entities along with their reactions to the external stimuli. The development in the area of nanoengineering over several material systems has been progressed at a higher speed in recent times [43]. This has created new possibilities in case of both prevention as well as treatment of the disease. The major spotlight in further developments of nanotechnology is focused to develop NPs that are multifunctional along with controllable to the external signals provided [5].

1.4 Fabrication methods in nanotechnology

In recent times, intensive research has been done in the areas of nanotechnology, which led to the development of various new nano-drug delivery techniques. Several important properties of these NPs have to be taken care of while fabricating them which include their biocompatibility, stabilization, accessibility as well as ease of functionalization [44]. These characteristics of NPs aid in carrying the desirable drugs inside their structures and safely transport it to the targeted site of action. Moreover, specific size, composition and shape of the NPs are the key functional properties while fabricating them [45]. Some conventional methods of synthesis such as emulsification cause several hurdles in their drug release profiles, physicochemical properties and pharmacokinetics. Various strategies have been developed as well as refined to overcome the limitations involved in their synthesis. These advanced strategies have provided unique approaches in synthesizing the NPs for drug delivery by having a well-ordered structure and rational design [46]. In this review, these advanced fabrication methods used in nanotechnology are discussed which are two very different paths. Out of which, one is top-down approach which is used to miniaturize the current strategies, whereas another is bottom-up approach that makes more complex molecular devices.

1.4.1 Top-down approaches

Top-down approach is used in nanotechnology for fabrication of NPs and represents a unique pathway to achieve the nanoscale by initiating with the materials of bulk scale followed by scaling them into the dimensions of nanometer level. This approach includes the physical distortion of the source material via processes of high energy. Some of the most frequently employed pathways for the synthesis of nanomaterials are discussed in this book chapter which are used for industrial purposes as well as by the researchers [47].

1.4.1.1 Lithographic technique

It is the most commonly employed method of fabrication in the top-down approach which uses elevated visual sources with a short wavelength. Major advantage of the top-down strategy in the fabrication of various integrated circuits is that the different parts of the assemblage are well patterned as well as built in place hence, no further steps are required. Moreover, optical lithography is an advanced field as it provides high degree of refinement in the preparation of microelectronic chip where recent short wavelength technique of optical lithography has reached to the dimensions of below 100 nm. However, certain sources with shorter wavelength such as X-ray and intense UV were developed to allow the approach of printing lithography to reach a level in between 10 nm and 100 nm [48].

1.4.1.2 Mechanical milling

This approach is used in the preparation of nanomaterials with high acceptability mainly in industrial field because of its simplicity, scalability, versatility, and cost effectiveness. In this process, the bulk material (in micro dimensions) is initially grounded to the nanometric scale by the application of high mechanical shear forces via milling technique. Planetary ball mill, shaker mill and attrition mill are the three types of attrition devices which are most commonly used in this method. In case of planetary ball mill method, the complete system is rotated at a frequency with thousands of rpm generating strong impact and frictional forces that grinds the material to smaller size. However, in case of shaker milling process, the milling balls collide with each other and also with the walls of vial that produces great impact and shear force which grinds down the material and mixes it evenly. On the other hand, in case of attrition mill, the grinding balls are placed in a horizontal cylinder and vertical drum is connected with the series of impellers which are placed at right angles to each other. It is rotated at high speed with the generation of high shear forces and impact [49].

1.4.1.3 Laser ablation

This method involves the use of strong laser beam to produce NPs where a laser of high energy is focused on the target material within a specific solvent. Short pulses of energy from the laser falls on the small spots of targeted metal that condenses it as a NP within the solvent. NPs from several metals as well as metal alloys can be widely generated via this method. Moreover, highly pure NPs can be prepared through this approach where no residual chemicals or any byproducts are produced [49].

1.4.1.4 Evaporation method

This method includes the heating of a metal which results into the evaporation followed by condensation of the vapors to finally obtain nanopowders. The process of vaporization of the metal creates a certain pressure depending upon its chemical strength. Further, the powders are influenced by the cooling effect of released vapor that leads to the production of a large number of NPs. This process is highly used in the generation of ceramic as well as metal nanopowders [50].

1.4.1.5 Arc-discharge method

In this method, the NPs are generated because of the arc associated breaking of the bulk material. Two different electrodes are placed closely inside a solution where high amount of voltage is passed through and an electrical breakdown happens due to the high potential difference that results in the production of arc discharge followed by the generation of thermal plasma discharge. The high temperature of plasma vaporizes the surface of electrodes inside the liquid medium which further condenses at the bottom and results in the final production of NPs. Carbon nanotubes are mainly produced through this method [51].

1.4.2 Bottom-up approach

Bottom-up technique which is also called as self-assembly approach is used in the nanofabrication of nanomaterials by employing physical forces or chemical reactions at the nanoscale which leads to the assemblage of fundamental units into a larger structure. This is also considered as an alternative approach that creates reduced quantity of waste which makes this process more economical. This approach was originally inspired from the natural biological systems of human body wherein nature has associated all the required chemical forces that are essential to form the structures important for life. Scientists tried to replicate the capability of nature to generate clusters that were small in size and made from specific atoms. These clusters can then self-integrate in the forms of even more elaborated structures. This process is widely used in the generation of NPs through the process of condensation of the atomic vapors over the surfaces to coalescence atoms inside the liquids [52]. This approach includes various chemical methods for the production of nanomaterials as mentioned in the following subheadings.

1.4.2.1 Sol–gel process

This technique is an example of long-established processes used in industries for the production of colloidal NPs from liquid phase. This is mainly employed for various oxide NPs and several nanopowders synthesis. Moreover, it mainly focuses on the growth of chemical compounds inside the liquid solution. Major benefit of this method is the fabrication of nanomaterials at very low temperatures and its ability of flexible rheology as well as versatility allows easy embedding and shaping of the materials. Most widely used materials for oxides are alkoxides as they are available commercially [53].

1.4.2.2 Chemical vapor deposition

It involves a chemical reaction in between the surface of substrate with a gaseous precursor. In this process, chemical reaction is activated with the help of temperature which is known as thermal CVD or with the application of plasma that is called as plasma enhanced chemical vapor deposition (PECVD). Carbon nanotubes are widely produced by this method [54].

1.4.2.3 Aerosol-based process

It is a common technique used in the industrial synthesis of NPs. It involves the application of aerosols which are solid or liquid particles present in gaseous phase that ranges up to 100 µm in size. Development of various novel as well as scalable aerosol-based techniques has enabled the process of generation of several new functional NPs such as biomaterials, electroceramics and also nanodevices like gas sensors. The main advantages include the easier and cheaper processes for the collection of particles, high purity, absence of the generation of any liquid by-products and involves few steps to collect the final products [55].

1.4.2.4 Atomic condensation

This process involves the heating of bulk material in vacuum to generate a stream of atomized as well as vaporized matter followed by transferring of the material into a chamber having inert gas atmosphere. Collision between the metal atoms and gaseous molecules results into the rapid cooling which leads to its condensation and ultimately fabrication of the NPs [56].

1.4.2.5 Supercritical fluid process

It includes the application of a supercritical fluid which is employed to significantly improve the physical as well as chemical processes of the earlier employed methods by altering their temperature and pressure. This results into a better and easy control over the chemical reaction. Certain nanomaterials of inorganic nature can be produced by this technique like oxide metals as well as nitrate