Nanobionics and nanoengineered prosthetics

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Nanobionics and nanoengineered prosthetics

Hemant K.S. Yadav, Ghufran A. Alsalloum and Noor A. Al Halabi RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates

CHAPTER OUTLINE 14.1 14.2 14.3 14.4

Introduction .................................................................................................514 History ........................................................................................................517 Definition.....................................................................................................520 Types and Classifications .............................................................................523 14.4.1 Orthopedic Prostheses .............................................................. 524 14.4.2 Plastic and Reconstructive Prostheses........................................ 526 14.4.3 Neuroprostheses....................................................................... 526 14.4.4 Cerebrospinal Fluid Drainage Systems........................................ 527 14.4.5 Ophthalmic Prostheses ............................................................. 527 14.4.6 Cardiovascular Prostheses ......................................................... 527 14.4.7 Myoelectric Prostheses ............................................................. 528 14.4.8 Dental Prostheses..................................................................... 528 14.5 Manufacture ................................................................................................529 14.5.1 Lithography.............................................................................. 529 14.5.2 Photolithography ...................................................................... 530 14.5.3 Beam Lithography .................................................................... 530 14.5.4 Micro and Nano Contact Printing ............................................... 530 14.5.5 Jet Printing .............................................................................. 531 14.5.6 Scan Probe Lithography ............................................................ 531 14.5.7 Dip-Pen Nanolithography .......................................................... 532 14.6 Nanobiomaterials .........................................................................................532 14.6.1 Polymeric Materials .................................................................. 533 14.6.2 Nanotitanium (NanoTi).............................................................. 535 14.6.3 Carbon Nanotubes .................................................................... 536 14.6.4 Nanodiamonds ......................................................................... 539 14.6.5 Nanobioceramic ....................................................................... 540 14.6.6 Nanocomposite ........................................................................ 543 14.6.7 Peekpolymer ............................................................................ 549 14.6.8 Hydrogel .................................................................................. 549

Nanostructures for the Engineering of Cells, Tissues and Organs. DOI: http://dx.doi.org/10.1016/B978-0-12-813665-2.00014-4 © 2018 Elsevier Inc. All rights reserved.

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14.7 Applications ................................................................................................550 14.7.1 Orthopedic Prostheses .............................................................. 550 14.7.2 Neuroprostheses....................................................................... 566 14.7.3 Cardiovascular Prostheses ......................................................... 571 14.7.4 Cerebrospinal Fluid Drainage Systems........................................ 572 14.7.5 Plastic and Reconstructive Prostheses........................................ 573 14.8 Ethical Issues ..............................................................................................574 14.8.1 Safe use: benefits Versus Risks.................................................. 575 14.8.2 Justice .................................................................................... 575 14.8.3 Identity, Privacy, and Accountability........................................... 575 14.8.4 Autonomy ................................................................................ 576 14.8.5 Validity of Informed Consent...................................................... 576 14.8.6 Problems of Ambition: Treatment Versus Enhancement................ 577 14.9 Safety Issues Pertinent to Nanobionics and Prosthetics..................................577 14.10 Conclusion ..................................................................................................579 References .............................................................................................................580 Further Reading ......................................................................................................587

14.1 INTRODUCTION Since the beginning of humankind, nature has grabbed the attention of human minds with its intelligent systems and perfect balance. Therefore, scientists have been thoroughly exploring the biosystems of nature and its mechanical and dynamic mechanisms in order to find a way of mimicking those systems. One the most popular examples of a scientist and an artist who tried to mimic nature in his inventions was Leonardo Da Vinci, whose investigations were mainly focused on the mechanism of movement of birds and their way of flying. Even though it is not clear whether those investigations resulted in Da Vinci actually taking flight or not, it is certain that he managed to successfully produce numerous sketches and notes on the anatomy of birds, the biophysics of flying, and the structural design of flying machines. With a lifetime lasting 67 years, starting from 1452 to 1519, Leonardo Da Vinci is considered one of the earliest founders of bionic research (Dickinson, 1999). It can be inferred from this, that the science of bionics is the science of studying the mechanical aspects of biosystems in nature and applying them to many fields of modern technology. In addition, it is considered a combination of biology and electronics that involves engineering devices that mimic the function of biological systems. When speaking of biology, the first structure that comes to mind is the human body, as it is one of the most magnificent creations in nature. Therefore, bionics are regularly linked with artificial organs and engineered body parts. This branch of bionics can be termed as medical bionics. Merging man

14.1 Introduction

with machine has produced stunning outcomes in curing diseases and mending defects. For instance, cochlear implants have been successful in restoring hearing by stimulating the auditory nerve; similarly, the bionic eye can give vision to the blind by stimulating the optic nerve. Furthermore, neuroscientists believe that inserting tiny bionic implants would allow them to detect abnormal neural activity and then correct it by electronic stimulation, thus producing a solution for mental disorders like epilepsy and Parkinson’s disease. Another very popular and outstanding achievement of medical bionic engineering is the manufacture of fully functional artificial limbs (Conroy, 2011). Since ancient times, handicapped soldiers have replaced their amputated extremities with artificial metal ones to help them fight in wars. Artificial extremities have come a long way since then, particularly since nanotechnology has been incorporated into the manufacturing process (Norton, 2007). Nanotechnology, a novel concept originally introduced by Richard Feynman in his lecture There is plenty of room at the bottom in 1959 (Feynman, 1992), is the branch of science that deals with material at the molecular level; or in other words, at the nano scale, which is one billionth of a meter. Nanotechnology has found its way into a variety of sciences such as biophysics, molecular biology, biomedical engineering and, most importantly, medicine. When the dimensions of a specific moiety are reduced to less than a micro, they exhibit exceptional characteristics and properties that facilitate their utilization in a variety of applications. Some of these applications have already reached the market and have achieved huge profit and great benefit for the public (Jain, 2007). Some of the most successful implementations of nanotechnology are: •

• • • • • • •

soft tissue repair and healing using wound dressings that are manufactured from nanofibers, as well as topical skin care products, like sunscreens, that contain lipid nanoparticles implants and prostheses, including plastic surgery procedures tissue engineering nerve and bone regeneration drug delivery cancer treatment (Ver Halen et al., 2014) gene delivery oral vaccine formulations.

Nanotechnology is utilized in the medical and pharmaceutical fields via two basic nanotools: nanodevices and nanomaterials. Nanodevices, including nanoelectromechanical and microelectromechanical systems, microarrays, and microfluidics, are used in biosensors, bioactuators and detectors. Conversely, nanomaterials, which are subclassified into nanocrystalline and nanostructured materials, are employed in tissue engineering, drug encapsulation, bone replacement, implants, and prostheses like neuroprosthetics, artificial organs, and maxillofacial prosthetics (Fig. 14.1; Jain, 2007).

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FIGURE 14.1 Classifications of nanotools and their applications.

The greatest ambition of bionics researchers and scientists is to engineer artificial appendages with the same anthropomorphic and mechanical properties as that of the human body. Even though medical bionic engineering has made tremendous improvement since its wooden peg-leg days, it still endures a lot of obstacles and difficulties. However, with the recent advances in nanotechnology and its application in organ and tissue engineering, as well as orthotics and prosthetics, bionic engineers have found many answers to their queries. Nanobionics is the term used when nanotechnology is utilized in the engineering and the manufacture of bionics. Extensive research is being undertaken to produce prosthetics with human-like performance and good stability by utilizing human-machine neural interfaces, muscle-like actuators, and biomimetic humanoid control schemes (Herr et al., 2003). Aside from mechanical stability, nanotechnology provides fast integration, high fatigue resistance, enhanced durability, great reactivity and optimal design to the prostheses. These beneficial qualities occur due to increased miniaturization of the building components of the prostheses, reduction of limb weight, and improved biocompatibility of implant. Some examples of successful nanobionic products are: • • • •

artificial digestive tract organs including artificial sphincter, artificial esophagus, peristalsis stent, etc. artificial myocardium. control units of central nervous system function. detection of baroreflex reactivity in blood vessels (Yambe, 2009).

Tissue engineering for the purpose of manufacturing prostheses or implants is drawing the attention of scientists and engineers, as it holds endless possibilities. Nanostructures are used to make scaffolds that are structurally similar to living

14.2 History

tissue, which are then used in designing and producing implants or prostheses exhibiting ideal characteristics of the model organ, consequently, allowing the newly implanted organ to function in a safe and natural way inside the body. Different types of nanocomposites are used, depending on the system or the tissue that is to be replaced (SalaheldeenElnashaie et al., 2015). In this chapter, we will focus on various aspects of nanobionics in general, with a focus on nanoengineered prosthetics in particular. These aspects involve manufacture, design, evaluation, safety, and ethical issues as well as many others. Moreover, distinct applications will be discussed including: • • • • • • •

orthopedic prostheses and ligament prostheses cardiovascular implants neural implants and cerebrospinal fluid (CSF) drainage plastic and reconstructive implants dental implants ophthalmic systems in addition, a variety of other modern utilizations.

14.2 HISTORY Many of the most successful human inventions are based on knowledge derived from the natural world. Even nowadays, whenever engineering problems occur, people return to nature for inspiration and guidance. The history of bionics starts with the ancient warriors who used to replace any amputated limbs with artificial ones, made of metal, to help them fight in wars (Kakade, 2006). However, progress in this field has been slow and gradual. Early attempts at bionic engineering started with Leonardo Da Vinci’s sketches and designs of flying machines inspired by the anatomy of birds. Then, almost 300 years later, a German scientist, Otto Lilienthal, managed to fly his gliding machines, which were patterned after birds (Dickinson, 1999). Lilienthal introduced the term biomimetics, which is synonymous with the term bionics, meaning the imitation of natural mechanisms and processes to improve human technology (Schmitt, 1969). Apart from aerodynamics, attempts at creating machines for the medical purposes, that mimic humans instead of animals started as early as the 16th century. When it comes to medical bionics, prosthetic limbs are the earliest attempts to create a biomimetic artefact. Even though hooks and pegs were the only prosthesis used in the Middle Ages, the Renaissance inspired more sophisticated and natural-looking hands, made of wood or metal. In 1504, a German knight called Go¨tz von Berlichingen used a pair of iron prosthetic hands during a battle, which enabled him to continue fighting in wars until he reached the age of 64. What was special about this pair is that it was the first pair of hands to ever have

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flexible finger joints (Frumento et al., 2010). Advancements in medical bionics completely ceased until the 19th century, when contact lenses were first developed for vision correction (Siviglia, 2010). After less than 20 years, early attempts by the French Judet brothers, Robert and Jean, were made to invent a functional artificial hip replacement. However, it failed due to its exceptional susceptibility to corrosion (Gomez and Morcuende, 2005). Fast forward a few years, an artificial iron lung was built for the treatment of polio victims. The iron lung helped in saving thousands of polio sufferers from respiratory paralysis (Emerson, 1958). Later on, in the early 20th century, the first successful kidney dialysis machine was developed for the treatment of renal failure (Blagg, 2007). The years between the 1950s and the 1990s were years of firsts, and years of great importance for medical bionic advancements; a lot of artefacts were created, including the first artificial heart valve, the heart-lung machine, the first cochlear implant, the first auditory brainstem implant, the first successful single channel cochlear implant in a child, the first permanent total artificial heart (Jarvik-7), and the first clinical application of a bioartificial liver device. Moreover, with the start of the 21st century, bionic engineers succeeded in implanting a prototype artificial pancreas, as well as a permanent self-contained total heart replacement (AbioCor) (Historical Highlights in Bionics and Related Medicine, 2002). The science and engineering of prosthetics was, and still is, continuously progressing alongside the aforementioned improvements in medical bionics. An old woman from Cairo was the person that held the first functional prosthesis, which was discovered in a tomb found in the vicinity of the ancient city Thebes, in 2000. The prosthesis was a toe attached to a mummy of a 50
60-year-old woman, having three joints, and displaying signs of damage (Frumento et al., 2010). In addition, an artificial below-knee prosthesis was found in Capua, Italy (Norton, 2007). The artificial leg had a bronze and iron body with a wooden core. The engineering of prosthetics continued to improve using the same basic material, but more evolved springs and releases instead of joints. This advancement is depicted in the iron hands of Go¨tz von Berlichingen. After losing his right arm in the Battle of Landshut, the knight attached an artificial hand that could be moved by a system of releases and springs, and could remain suspended with leather straps. A well-known surgeon, called Ambroise Pare, was capable of creating similarly functional hands. However, lower limb prosthesis was not developed until the end of the 17th century, the year of 1696, when Pieter Verduyn, whose designs became the blueprint for joint and corset devices, made the first nonlocking below-knee prosthesis. No major developments in this field occurred until the late 1800s, when Gustav Hermann used aluminum instead of steel in formulating an artificial limb that was more lightweight and practical (Frumento et al., 2010). Throughout the history of prosthetics, battles have been the major stimulant of progress, with most of the developments occurring at times directly after or during wars. Step after step, a compilation of techniques and principles led to the modern technology we currently have. Thanks to all these advancements in

14.2 History

prosthetics, people can finally have aesthetic-looking artificial limbs that don’t set them apart from others, and give them a sense of fullness and improved their quality of life (Harvey et al., 2012). A popular example of a successful double leg amputee, who has a pair of artificial legs that allowed him to participate in Olympics, is Oscar Pistorius. Known as Blade Runner, Oscar Pistorius is a world record holder in 100, 200, and 400 m Paralympic events and the first amputee to ever participate in nondisabled Olympic games and win. Modern technology has caused great improvement in prosthesis functionality and durability. These technologies include microprocessors, computer chips, robotics, and nanotechnology. Moreover, the materials used in manufacturing artifacts are no longer limited to metals; silicone is now used to provide realistic, natural-looking covers, in addition to various other materials (Norton, 2007). Ceramics are used for manufacturing prostheses for dental, orthopedic, and musculoskeletal applications. Metals are still used to sustain the artifacts with endurance and durability. Metallic-based materials are mainly used for orthopedic prostheses, in order to allow them to endure rigorous activities (SalaheldeenElnashaie et al., 2015). Nanotechnology is a multidisciplinary concept that started less than 60 years ago, but has found its way into every aspect of daily life. Applications of nanotechnology are found in everything, from food industry to medicine, including bionics and biomedical engineering. The early days of nanotechnology involved direct manipulation of atoms and molecules in order to synthesize specific materials. The United States National Nanotechnology Initiative classified nanotechnology into four generations (Fig. 14.2):

FIGURE 14.2 Generations of nanotechnology developments with examples.

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• • • •

First generation (B2000): is the formulation of passive nanostructures that can only perform a single task Second generation (B2005): is the formulation of active nanostructures that can perform multiple functions Third generation (B2010): involves thousands of components that interact together in a network or nanosystem Fourth generation (B2015): involves molecular nanosystems.

Nanotechnology achieved huge advancements in the biomedical field, especially in medical implants and prosthetics, because it utilizes particles having the size of nanometer that are similar to that of living cells. While designing and manufacturing prostheses, the main aim is to create scaffolds identical to natural tissue and to produce prostheses capable of functioning naturally in the body environment (SalaheldeenElnashaie et al., 2015). Apart from artificial limbs, nanotechnology is now being applied in the development of bionic eyes, bionic ears, neuroprosthetics, as well as cardiovascular, dental, and orthopedic prosthetics (Fig. 14.3; Baumann, 2013).

14.3 DEFINITION In order to understand the term prosthetics, we need to elaborate on a broader term: medical devices. A medical device is an article, that could be an instrument, apparatus, material, or an appliance, which is used for the purpose of diagnosis, prevention, treatment, alleviation and/or monitoring of a disease, compensation

FIGURE 14.3 Applications of nanotechnology in prosthetics.

14.3 Definition

for a handicap, control of conception, and modification or replacement of anatomy or physiology. Medical devices, typically, achieve their intended function by physical means, such as mechanical or physical action and replacement of or support to bodily organs or functions. In order to decide whether an implant is considered a medical device or not, different criteria should be explored, such as the time or duration of contact with the patient, the location affected by the use of the device, and the degree of invasiveness. An invasive device is defined as a device that, completely or partially, penetrates the body, either through a natural orifice or through the surface of the body. Implants are considered medical devices because they are surgically invasive, and also because they remain inside the body long term or permanently. Implantable devices must reside in the patient for a specific duration, not less than 30 days, after a procedure. For example, a nontunneled catheter used for temporary vascular access that is intended to be used not more than 7
10 days is not considered a long-term implantable device. Nor is a surgical suture that is taken out before 30 days considered an implant. Implantable devices serve a number of purposes, according to which they can be classified into different groups. Implants are imported into the body for different purposes, to serve as: • • • •

prosthetics, to replace missing body parts orthotics, to support weak or ineffective joints or muscles monitors, to keep track of bodily functions drug delivery systems, to administer medication (European Commission, 2001).

In simple terms, prosthetics is the science of developing artificial body parts and then surgically replacing the amputated body parts with the artificial ones. Prosthesis is the artifact used to replace the missing parts and restore bodily functions. It should be noted that prosthetics is a different field from orthotics, although they are related. Orthotics is a branch of medicine concerned with supporting weak joints and muscles using special artifacts like braces and splints. When an individual is fitted with an artificial prosthesis, he or she is labeled with the name “Cyborg,” meaning part-human part-machine. Since the start of the 21st century, a large number of implants and devices were developed to restore the function of many human biological organs or systems. These prostheses include: • • • • • • •

artificial extremities, both robotic ones and ones with sensory abilities artificial polymer-made muscles artificial skin, with healing promotion abilities artificial hips, joints, and vertebrae artificial bone, intended to help in healing fractures and replacing defects artificial teeth and dental implants cervical implants and bracing systems, intended to provide support to the spine

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• • • • • • •

silicone or plastic implants for cosmetic and maxillofacial reconstruction artificial larynxes for speech restoration and speech processor wired to the nervous system artificial blood vessels retinal implants, intraocular lenses, and artificial cornea for vision restoration cochlear implants neuroprosthetics and spinal-neuro implants many others that will be discussed later on in this chapter (Brey, 2005).

In a broad sense, nanotechnology is a general-purpose technology, based on reducing the particle size of materials to the size of the nano in order to produce new and improved properties and characteristics. The ultimate goal of prostheses is to ensure biocompatibility and functionality, both of which can be enhanced by the utilization of nanostructures and nanodevices in the manufacture of the implant. In addition, multiple benefits can be gained by using nanotechnology in prosthetics, including enhanced mechanical stability and durability, fast integration and low roughness of nanoengineered surfaces, as well as greater strength and high resistance to wear and fatigue (Fig. 14.4). Furthermore, the incorporation of nanotechnology-based tissue engineering techniques can greatly improve the biocompatibility and stability of implantable devices and prostheses (Torrecillas et al., 2009).

FIGURE 14.4 Beneficial effects of nanotechnology on prosthetics.

14.4 Types and Classifications

The application of nanotechnology in implantable devices is considered a subdivision of Nanomedicine. Nanomedicine is basically the branch of nanoscience concerned with the utilization of nanotechnology in medical devices and for medical purposes (SalaheldeenElnashaie et al., 2015). Relatively, nanobionics is the field that integrates both nanoscience, or more particularly nanomedicine, and biomedical engineering for the purpose of creating fully functional bionic implantable devices. The term bionic comprises bio- from biology and -nic from electronic. Nanobionic devices are electronic artifacts that are manufactured to imitate, mimic, and restore bodily functions (Herr et al., 2003). In summary, this chapter focuses on nanoengineered prosthetics, which are implantable devices that are intended to replace a missing body organ and that utilize nanotools and nanostructures in their constitution to gain exceptional and superior properties.

14.4 TYPES AND CLASSIFICATIONS According to the United States Food, Drug and Cosmetics Act (FD&CA), implantable medical devices are classified into three classes: •

•

•

Class I: General controls must be applied to this class and they state that a medical device from this class cannot be adulterated, misbranded, subject to recall, or a banned device. Moreover, the firm must be registered with the Federal Drug Administration (FDA), must list its devices with the FDA, must maintain the required reports and records, and must apply good manufacturing practices. Class II Special controls, like performance standards, postmarket surveillance, patient registries and guideline, are the control procedures applied when general controls are not sufficient to assure the safety and effectiveness of a device. Class III When neither general controls nor special controls are sufficient to ensure the safety of a medical device, premarket approval is the type of control applied. A premarket approval application must contain information about the safety and effectiveness of the device, information about the components, ingredients, and properties and of the principles of operation, of the device, information about the manufacture, processing, packaging, and installation of the device, and references, labels and clinical trial certification, as well as other relevant information.

According to their purpose, implantable devices are divided into four groups. Some implants are prosthetics, introduced into the body to replace missing body parts, while some are orthotics, intended to support weak or ineffective joints or

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FIGURE 14.5 Types of implantable devices.

muscles. Some implants are inserted into the body to monitor the internal environment and to keep track of bodily functions. One more type of implants is implantable drug delivery systems; these are used to deliver drugs or hormones (Fig. 14.5; European Commission, 2001). Since the start of the cyborg era, many prostheses were invented for cardiac, cosmetic, orthopedic and other applications. However, only some artifacts have implemented nanotechnology into their manufacture and design. There is no specific system that can be followed to classify nanoengineered prostheses, therefore, they are classified according to the organ they replace or support (Fig. 14.6; Baumann, 2013).

14.4.1 ORTHOPEDIC PROSTHESES In the market of prosthetics, orthopedic implants take up the largest segment of market value. This is a reflection of the unhealthy sedentary lifestyle of a large portion of the society and the rapidly growing prevalence of degenerative musculoskeletal disorders. Major disorders of the bones and joints include osteoarthritis and rheumatoid arthritis, both of which can cause considerable damage to the synovial joints like the hips, knees, shoulders, ankles, and elbows. Damage to these joints, especially the weight-bearing ones like the hips and knees, elicits excruciating pain. Accordingly, when the possibility of replacing the damaged joints with prostheses became a reality, it was a relief for patients all over the world. Arthroplasty, the process of inserting an artificial joint for the purpose of treating joint defects, relieving pain, and restoring movement, is a major advancement in the field of orthopedic surgery. It is based on steps like the excision,

14.4 Types and Classifications

FIGURE 14.6 Types of nanoengineered prostheses.

interposition, and the replacement of diseased bone or cartilage. For example, a total knee arthroplasty involves replacing the ailing cartilage of the femur, the tibia, and the patella with a metallic or polymeric prosthesis (Khan et al., 2013). Orthopedic implants have gained huge benefit from nanotechnological advancements. Applications of nanotechnology in this field involve using nanograined materials, including metal alloys, polymers, and nanoceramics like alumina, titania, and hydroxyapatite. Nanoceramics demonstrate better mechanical stability, enhanced osteoblast adhesion, increased calcium deposition, and improved in vitro osteoblast proliferation, when compared to their microsized counterparts (Teoh et al., 2014). In addition, coating the implants with crystalline calcium phosphate nanoparticles exhibited increased contact between bone and implant (Deshmukh et al., 2010). Since most of the cellular activities involved in implanting a prostheses, such as cell attachment, locomotion, growth, gene expression, and stem cell differentiation, occur at the nano scale, incorporating nanodevices and nanotools in the process of implantation will increase the chances of prostheses success. Examples of nanoengineered orthopedic prostheses are knee and hip joint prostheses, spinal implants, bone fixators, and tendon and ligament prostheses.

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14.4.2 PLASTIC AND RECONSTRUCTIVE PROSTHESES Another field that has benefitted greatly from nanotechnological advancements is plastic and reconstructive surgery. It is a very diverse field, involving aesthetic surgery and injectable collagen for soft tissue augmentation, oncologic and congenital reconstruction such as breast augmentation, and craniofacial or maxillofacial reconstruction, burn wounds and trauma care, and various other surgical and nonsurgical procedures. Miscellaneous nanotools are used in the field of plastic surgery, such as nanofibers, nanoparticles, nanocomposites, in addition to other nanostructures. Nanofiber matrices have been successfully used for constructing and repairing a variety of tissues, such as muscle, cartilage, bone, and skin, which are needed for plastic surgery procedures in both in vitro and in vivo conditions. Currently, reconstructive aesthetic surgeons are using nanoengineered cartilage tissue for ear reconstruction or nasal reconstruction, as well as bone and skin tissue for craniofacial reconstruction after congenital defects, trauma, and cancer. Nanofibrous scaffolds, made of polylactic and polyglycolic acid and ingrained with growth factor, are used to formulate artificial skin for the treatment of skin defects by stimulating and enhancing the skin healing process (Ver Halen et al., 2014).

14.4.3 NEUROPROSTHESES Neuroprosthetics is a rapidly expanding field that is greatly dependent on computer technology and consequently, it will surely be broadened with the application of nanotechnology. In simple terms, neural prostheses are artifacts that replace or repair neural function through electronic interfaces such as neuromuscular electrical stimulation for improving strength and fatigue resistance, and functional electrical stimulation for stimulating paralyzed limbs to execute motor functions. In other words, neuroprostheses are electronic devices used for stimulating nerves to do bodily functions lost due to damage or trauma (Prochazka, 2009). With the application of nanotechnology to the cell-electrode interface in implantable devices, human cognitive function can be improved in patients with neurological disease like Parkinson’s and Alzheimer’s disease, both of which are caused by damage to neural and cognitive function. Nanotools also increase the lifetime of the implant, thereby enhancing its quality and avoiding additional surgeries and procedures for replacing it. In addition, restoration of hearing via cochlear implants, and sight via retina implants are huge applications of neuroprosthetics that benefit greatly from nanotechnology (Wolpe and Wu, 2006).

14.4 Types and Classifications

14.4.4 CEREBROSPINAL FLUID DRAINAGE SYSTEMS The CSF flows in the space between the brain and the inner lining of the skull, then it is drained to the blood via sinuses. When the outflow of the CSF is obstructed, often by a tumor, pressure inside the skull increases due to fluid build-up. This is a condition called hydrocephalus, in which the increased pressure leads to compression of brain tissue, resulting in a number of symptoms like headaches, drowsiness, and fainting. The solution to this problem is to implant a CSF drainage system, or shunt. However, conventional shunts have a limitation of being prone to infections and blockages, which will lead to the patient requiring another surgery to replace the dysfunctional shunt. In order to make these shunts more functional, carbon nanotubes (CNTs) can be used in bundles to form a new catheter that acts as filter of the CSF to prevent bacteria and other macromolecules that can cause blockage of the shunt (Spiers et al., 2010).

14.4.5 OPHTHALMIC PROSTHESES Vision impairment due to ocular disease, such as diabetic retinopathy and macular degeneration, are serious problems that permanently damage the photoreceptor cells in the eyes. Retinal implants are a modern approach to fix these problems and restore vision by stimulating the retina to produce visual percepts. Nanophotonic devices are currently being used to provide vision with high resolution, along with improved biocompatibility and reduced power consumption, leading to reduced tissue damage. In addition, utilizing nanowires and nanosized surface modification techniques results in enhanced tissue integration (Hamsika et al., 2016) Another utilization of nanotechnology in ophthalmic devices like intraocular lenses, keratoprostheses, ophthalmic lenses, contact lenses, and drainages for glaucoma, is the manufacture of a special coating made of metabolically active material, such as platinum nanocoating, which aids in bioadhesion as well as providing a variety of unique properties (Babizhayev, 2013).

14.4.6 CARDIOVASCULAR PROSTHESES Various branches of cardiology have benefited from nanotechnology since the manufacture of the first pacemaker. Such applications include intravascular stents, transjugular intrahepatic stents, and portocaval stents, all of which are currently being evaluated for the use of nanobiomaterials to prevent in-stent restenosis, bioincompatibility, and other complications. Stents are used as standard procedure of percutaneous coronary intervention, also known as coronary angioplasty, for the management of atherosclerosis (Kong et al., 2006). Polymeric nanocoatings, absorbable stents, and nanocoated drug-eluting stents are also extensively studied and have been in use for several years (Keyhanvar et al., 2015).

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Another example of a major heart disease is valvular heart disease, in which a heart valve needs to be repaired or, in severe cases completely replaced. The replacement can be a prosthetic heart valve, which is mechanical, made of stainless steel or silicon, and has great durability, lasting a lifetime; or a bioprosthetic heart valve, which is extracted from humans or animals and requires replacement after a certain period. Nanotechnology offers the chance to bioengineer a more compatible and durable heart valve that can be even better than the normal valves. One more brilliant prosthetic device is the pacemaker, which is an electrical device intended to function like the sinoatrial node to control the speed of impulse generation, thereby controlling the rhythm of the heart. Utilizing nanodevices in pacemakers technology can result in more biocompatible devices with less chance of rejection or displacement, allowing the patients more freedom in their daily life and activities. Furthermore, the use of nanowires and nanochips in engineering artificial pacemakers is currently being investigated for better conduction and control of electrical impulses (Iqbal and Mohan, 2010).

14.4.7 MYOELECTRIC PROSTHESES After upper or lower limb amputation, a patient has the opportunity to choose between two types of prosthetic limbs. The first is passive prosthesis, generally used to serve cosmetic purposes, and is usually used for upper limb amputations. The other type is functional prosthesis, which allows the user to perform simple tasks and is divided into two types: body-powered and myoelectric-powered. Body-powered prostheses have limited functionality and are moved by the action of nearby muscles; however, myoelectric prostheses provide a functionality almost identical to that of the real limb. They act by amplifying the electronic signals coming from the muscles of the residual limb (Patel, 2012). The greatest limitation of functional prostheses is that they require a lot of energy to function, specifically, to drive its motor into motion. Chemically fueled prostheses make a better replacement for conventional body-powered ones, as they are capable of imitating the action of the actual muscle fibers. CNTs, when filled with hydrogen sulfate, have the ability to move in a fashion similar to that of muscle tissue. Because of a complicated mechanism of action, the nanotubes require only water and air as fuel for the artificial limb. Moreover, the CNTs provide the limb with a high degree of stress tolerance, even more than that of the normal skeletal muscle, indicating that utilizing nanotechnology in myoelectric prostheses can actually give the user higher strength and better abilities than other people (Ebron, 2006).

14.4.8 DENTAL PROSTHESES When it comes to the dental field, nanotechnology has many applications, including: • •

local nanoanesthesia hypersensitivity cure

14.5 Manufacture

• • • • • • • • •

tooth repositioning nanorobotic dentifrice dental cosmetics nanodiagnostics nanofillers nanoadhesives bone replacement dentition replacement therapy prosthetic implants.

Dental prosthetic implants are used for replacing missing teeth or root systems and for any defective soft or bony structures of the jaw and palate. Dental prosthetics or prosthodontics utilize nanotechniques in the development of unique surface characteristics with a precise topography and chemical structure that mimics the surface topography of the extracellular matrix, improving the chances of successful cell attachment, proliferation, and differentiation. Moreover, special agents like antibiotics and growth factors are incorporated into the implant to reduce the chances of infections or rejection of prostheses (Bhardwaj et al., 2013; Tomsia et al., 2011). Since tissue integration is the primary determinant of implant success, it was essential to develop modern techniques that promote osseointegration, mainly by surface modification and the application of bioactive nanocrystalline coating made of nanomaterials such as calcium phosphate. In addition, nanoceramics such as silicon carbide, alumina, and zirconia, are used in the formulation of dental implants (Pai et al., 2015).

14.5 MANUFACTURE Manufacturing of nanobionics and nanoprosthetics is a process of high precision to serve a specified application and stimulate a very particular area. Fabricating nanoscaled devices and gadgets with electrical circuits needs a flawlessly peculiar technique that can be applicable to wide range of materials; organic, inorganic or biomolecules. Before Dip-Pen nanolithography, many approaches were implemented to construct nanoengineered bionics, including multiple types of lithography and printing, explained as follows:

14.5.1 LITHOGRAPHY Lithography comes from the Greek words (lithos) which means stone and (graphein) which means write. In other words, it means stone-writing which designates the ancient technique of using stones after chemical treatment and modification as stamps. Therefore, we can define it as a method in which a particular pattern is transferred onto a solid surface in a miniaturized manner (Madou, 2012). It can be easily comprehended if we compare it to printing a picture on

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your computer. You design this picture and specify the measurements, dimensions and details, then give the order of printing. Then, an ink jet printer transfers the design and its specifications and copies it on a paper. In that case, the predesigned picture resembles the specific detailed pattern desired, and the technique of transferring the picture from computers to papers is lithography. The ink printed can refer to various means of transfer upon which lithography can be classified into photolithography, scanning beam lithography and other classes.

14.5.2 PHOTOLITHOGRAPHY This class indicates the use of light in lithography. Here, the substrate is covered with a thin layer of light-sensitive liquid, known as photoresist, and a patterned mask is applied. Afterwards, it is exposed to UV light, which alters the solubility of the substrate. When rinsed with a suitable solvent, the exposed area dissolves, the unexposed remains and subsequent chemical treatments and processing follows (Madou, 2012; O’Connell et al., 2015). Much advancement was made to generate specialized photolithographic techniques, like extreme-UV lithography and X-ray lithography, applying limited wavelengths. In spite of the high costs required and the difficulty in tailoring soft organic materials, it was considered the best technique of lithography prior to the invention of dip-pen nanolithography.

14.5.3 BEAM LITHOGRAPHY This type of lithography can be considered as an upgraded extension to photolithography, in which a fixated beam generates the pattern, without a mask or a photoresist film. The beam can exert two actions. It selectively either removes or deposits a material. The beams can be charged or uncharged. More commonly used are electron beams (e-beam) and ion beams (i-beam), which introduce high current density influencing electron-sensitive or ion-sensitive resists (Madou, 2012). The process is very slow and tedious, it take 24 h/cm2 to synthesize 20 nm structures. Yet, the outcomes possess a distinguished resolution and pattern integrity which suitably qualifies it for production of nanowires of neuron interfacing transistors, among other beneficial applications (O’Connell et al., 2015).

14.5.4 MICRO AND NANO CONTACT PRINTING This procedure can be described as an actual chemical stamping. A stamp (conventionally polydimethylsiloxane (PDMS)) is carved with intended pattern, and then an organic dye or metallic ink transfers this pattern on a solid surface, where they form covalent bonding. Generally, it produces microformats but it is

14.5 Manufacture

also able to produce them in nano ranges to a limited extent (around sub100 nm). They feature stamp size-controlled resolution, which means that the size of the stamp influences the resolution of the printing. However, the size is determined by (1) the accuracy of the stamp mold when carved, (2) the nano properties of the stamp material, (3) stamp distortion upon surface contact. Being relatively inexpensive has facilitated its use in much biomedical research (O’Connell et al., 2015).

14.5.5 JET PRINTING The term jet printing is very popular with documentations and publications, but due to its functional flexibility it was endorsed for biofabrication. It has the ability to directly deposit a unique ink convoluting living cells or subcellular components. What makes them flexible and versatile is the fact that the droplet size can range from microns (μL) to picoliters (pL). This contributes to printing of high resolution textures, but the resolution can be still altered by (1) properties of liquid material, (2) wettability of substrates, (3) jet nozzle diameter. It could be used widely if it wasn’t for the specific requirement of conductive substrates (O’Connell et al., 2015).

14.5.6 SCAN PROBE LITHOGRAPHY This is a group of techniques that uses a probe or a small tool that can measure, test, or obtain information, which is the reason why it was considered a good characterization tool. However, when customized for fabricating miniaturized structures, it is adjusted to have a very sharp nanosized tip. It is capable of scanning the surface of the substrate in an alternating manner (forwards and backwards), while printing images of the desired nanostructures. Although scanning probe lithography can be used, atomic force microscope (AFM) is popularly utilized for this purpose. Applying this technique offers unique precision in positioning atoms individually, as well as fabricating larger devices, such as transistors. While depositing the materials, AFM delivers the correct and exact mechanical forces, heat energy, and electrical characteristics of voltage and currents needed. The working principle is that the AFM tip scratches or carves into the substrate, yielding the pattern wanted. If a nanograft is desired, a subsequent step can follow, whereby other materials are adsorbed to fill the voids formed by the AFM nanotip. Applying electrical bias can also be used to guide the deposition of charged particles to the voids and is preferred in the case of synthesizing metal oxide semiconductors. Many applications relied on this innovation, from printing DNA and proteins to fabricating metal electrodes (O’Connell et al., 2015).

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14.5.7 DIP-PEN NANOLITHOGRAPHY If we scrutinize AFM techniques, we can find out that both scanning probe lithography and dip pen nanolithography are actually subtypes of AFM and, accordingly, perceived as characterization methods. The main difference between the two is the working principle, as it no longer uses the sharp tip to shave a substrate surface. In fact, it treats the tip as a quill that is dipped into an inkwell then used to write or draw respective pattern on any surface. Consequently, it offers superb attributes over the aforementioned techniques, such as: 1. Flexibility: the fact that it isn’t a destructive technique (shoveling and cutting through substrates is no longer necessary) opens up a wide range of choices for substrates of various natures (soft and hard); 2. Tremendous resolution: it allows accurate and precise control of the pen movement, position and spacing; 3. Scalability: the ability of scaling up this method from small laboratory scale with a single pen to large production scale with multiple cantilever arrays that can print up to 11 million patterns simultaneously in an area of few cm2; 4. Relatively economical: providing all these merits it’s still considered cost-effective, when compared to other methods (Eby and Leckenby, 2004; O’Connell et al., 2015). There are two main modes to apply dip-pen nanolithography, which are called meniscus transport and liquid ink deposition. Meniscus transports adopt a kind of ink that was formulated by the self-assembly of molecules in monolayers. The AFM tip is dipped into the ink and allowed to dry. Then, it is put in touch with the surface of the substrate, where it forms a meniscus or a crescent of water as the capillary condensation phenomenon takes place. The ink dissolves when in contact with the water meniscus, shifts to the surface and forms covalent bonds, which allow it to stick. Liquid deposition uses capillary action to transfer and deposit the ink with a solvent carrier. Therefore, the solvent carrier permits a large range of choices of ink to include proteins, metal nanoparticles, and conducting polymers. The modes previously mentioned are the most basic and common of approaches. Nonetheless, some ink types or substrates may require some alterations or modifications. There may be similar approaches, but under different names, such as: nanografting, polymer pen nanolithography, electrostatic transport, and electrochemical dip-pen nanotechnology technique (DPN) (O’Connell et al., 2015).

14.6 NANOBIOMATERIALS With the surge of implantable devices for biomedical applications, plenty of nanobiomaterials have been explored to employ only those with desired and suitable features for nanobionic gadgets. Nanomaterials vary in chemical

14.6 Nanobiomaterials

composition, size, shape, intrinsic properties, and functional groups attached, along with optical and magnetic characteristics, rendering them highly versatile. Therefore, it is necessary to confirm that any material to be implanted possesses biocompatibility, in terms of: (1) safety, that it is nontoxic when interacting with living tissues. It shouldn’t cause any thrombosis in blood vessels or provoke tumor formation; (2) nonimmunogenic, which means it doesn’t trigger immune responses, and has less chance of rejection; (3) chemical inertness, to ensure that it won’t have any side reactions with enzymes or ions available in the surrounding environment (Wang et al., 2015). Biomaterials can be classified into three categories: bioinert, bioresorbable, and bioactive. Bioinert materials are well accepted by biological systems, they don’t cause any interaction or elicit any response. Bioresorbable materials possess only surface activity; they dissolve in the body and are replaced by soft or hard tissues. Bioactive materials make obvious interactions and chemical bonds (Ben-Nissan, 2004). There are various types of nanobiomaterials that can be involved in nanoprostheses, including: polymers, nanotitanium, CNTs, nanodiamonds, nanoceramics and nanocomposites. The classification of these materials is illustrated in Fig. 14.7. Each type of these materials can be generally implanted in human body. Few of which are implanted as prosthetics, and even fewer are involved in nanobionics and nanoprosthetics. The different characteristics each type possesses, qualifies them for a specialized use (Aguilar, 2012).

14.6.1 POLYMERIC MATERIALS Polymers are involved in many industrial fields, and biomedical devices have their share of polymeric materials of various qualities. Despite exploiting about 10
20 types of polymers in nanobionic widgets, the diverse characteristics and traits each polymer provides contribute to the wide applications in which they can be found. Here, we will discuss different types of polymeric materials that have served great purposes in numerous classes of nanoprostheses, e.g., polyimide, silicone, parylene, and liquid crystal polymers (LCPs), which are mainly used in neural prostheses. Other polymers are available, but their use is limited for specialized applications.

FIGURE 14.7 Types of implantable biomaterials.

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14.6.1.1 Polyimide A macromolecule of imide units, or \ monomer that has been mainly and widely used in insulating metal electrodes against many environmental factors such as moisture, ions, corrosion, and physical damage by forming a passivation layer. They display remarkable advantages, such as stability in wide range of temperatures and in the presence of oxidizing agents. They also demonstrate good mechanical strength that qualifies them to act as a buffer for mechanical stress applied on the electrode. Their chemical resistance is admirable and they also feature a unique ability to absorb the α particles that can be emitted by ceramics. In addition to that, they offer a possibility to deposit metals after insulation of the electrode with polyimides. They can be followed with further patterning to form a wafer-shaped device that can be easily removed or peeled off with aid of tweezers. Many neural prostheses were implemented in the peripheral and central nervous systems using a polyimide, the majority of which revealed biosafety, biostability, biocompatibility, and long-term effective functioning. Minor cases reported mild immune response to polyimide-coated electrodes (Hassler et al., 2010).

14.6.1.2 Silicone (PDMS) Silicone is used commercially in abundance. The most suitable silicone for medical applications is silicone rubber, which is referred to as polydimethylsiloxane (PDMS) in chemistry. Ordinarily, it presents a low molecule weight and viscosity, yet, cross-linking can alter the molecular weight, permitting it to have a rubberlike nature. Other ameliorations are made to render a grade of silicone suitable for introduction to biosystems, such as incorporating stannous octate catalyst and base polymer, upon production (Lee et al., 2006). Having exquisite endurance to biodegradation and ageing along, with impressive biocompatibility has resulted in prolonged stability in vivo. It can serve as a highly permeable membrane for gases and vapor which are used as ion barriers. They are mainly used for electronic insulation, semiconductor synthesis, and as sealants or adhesives for construction purposes. A good example is Norplant, which is a popular silicone-based device used to deliver luteinizing hormone-releasing hormone in patients suffering from tumors in the male reproductive system. It can also be involved in pace makers, cochlear implants, as well as electrodes in CNS and PNS (Hassler et al., 2010).

14.6.1.3 Parylene Parylene is the commonly used term referring to polyparaxylylene, which is one among several thermoplastic polymers that have a semicrystalline, noncrosslinked morphology. It was introduced in the mid 20th century and manufactured in different types with few variances in the properties. For biomedical purposes, parylene C was found more convenient, as it offers a pleasant electrical/

14.6 Nanobiomaterials

barrier combination, in addition to its biocompatibility and inertness. Therefore, it played a prominent role in neural prostheses. Another subtype, known as parylene HT, is emerging in this field as it possesses a better tolerance to elevated temperatures. The fragility and lack of robustness in the thin sheets of parylenes compels manufacturers to adopt delicate measures when handling them, and it is the only noteworthy drawback pertaining to their employment in neural implants (Hassler et al., 2010).

14.6.1.4 Liquid crystal polymers This is a distinctive class of thermoplastic polymers, portrayed as linked and aligned molecules of rigid and flexible monomers that gives resemblance to the spatial arrangement within crystals. This class is characterized by a remarkable mechanical strength when under high temperature, drastic resistance to chemical degradation, low hygroscopicity and permeability, and tends to form a barrier for gases with good qualities. These traits qualify LCPs to be used in circuit boards and semiconductors. They aren’t considered of high popularity in biomedical applications; yet, some researchers began to experimentally utilize them in flexible electrode arrays for neural interfaces, with optimistic perspectives regarding their performance (Hassler et al., 2010).

14.6.2 NANOTITANIUM (NANOTI) Titanium alloy is a good example of an allotrope, which means it possesses two structures or forms which are: (α), a closely packed hexagon and (β), with a cubic centered architecture. It can exist, accordingly, as (α), (near- α), (α 1 β), metastable (β), or stable (β), and by modifying the alloy composition and manipulating temperature, the desired structure can be established. The main components of Ti alloys, other than titanium, are aluminum and vanadium; each of them can stabilize one of the allotropic structures by influencing the transformation temperature. For example, the presence of aluminum, oxygen, nitrogen and carbon stabilizes (α) forms. Conversely, molybdenum, vanadium, niobium, and tantalum favor the isomorphous (β) form, and iron, tungsten, chromium, and cobalt yield (β) eutectoids. If neutral alloys are to be obtained, zirconium is the element of choice (Liu et al, 2005). Titanium alloys display outstanding features of lightness, flexibility, admirable tensile strength and resistant to both corrosion and biological fluid interactions. Their corrosion resistance can be attributed to the fact that titanium tends to form a thin layer of titanium oxide upon exposure to air or any oxygen-containing medium. However, this layer deactivates any titanium prosthesis in biological environments. Therefore, many means of surface modification were adopted to improve the bioactivity and biocompatibility, especially with bone tissues where it is are often employed. Initially, scientists explored sand blasting and acid etching. These mechanical and chemical methods enhanced the surface properties and roughness, but failed to control the topography as well as

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residuals remaining with these kinds of treatment. The next candidate they tried was plasma spray-coating with hydroxyapatite and calcium phosphates, since they are an integral component of bones. They showed good outcomes short-term, but weren’t successful in long-term use, due to the formation of weak coating-tometal adhesions and ability to dissolve when implanted. A concept of altering surface to acquire nanometer features emerged to resemble the nanometer characteristics of natural bones. Anodization or anodic oxidation is the electrochemical method used to attain the most suitable surface properties of titanium. This process involves three major events: alkaline cleaning, followed by acid activation to remove the TiO2 layer and other residues, and electrolyte anodization in a threeelectrode setup of electrochemical cells including a Ti anode, Pt cathode and Ag/AgCl reference electrode. The applied voltage leads to deposition of an oxide layer on Ti anode in specified thickness, which controls the morphology and nanoscale roughness of the surface. Anodized titanium alloys showed irregular porous surface structures, with greater resistance to corrosion, due to increased layer thickness of TiO2 and optimistic outcomes in terms of cytocompatibility (Jackson and Ahmed, 2007). Another alloy of Ti, known as titanium-nickel (TiNi) alloy, exhibited extraordinary elastic behavior, referred to as shape memory effect or SME. We can clearly portray it in a manner, where the metal is disfigured and twisted, but soon it rebounds and reverts to the shape previously retained. This superelasticity against stress and strain, which can be attained by temperature rising, along with corrosion resistance, led to its employment as orthodontic dental archwire, catheter guide wires, intracranial aneurysm clip, filters of vena cava, and contractile artificial muscles. Another implantable titanium form are titania nanotubes (TNT), which have successfully replaced stainless steel wires in bone fixation, due to the superior advantages they display in terms of biocompatibility, osseointegration, and mechanical properties. The most prominent innovation here lies in minimizing the incidence of infections that may accompany any bone fixation. Stainless steel wires, also known as Kirschner wires and K-wires, used to introduce a passage for microorganisms as they are inserted transversely through the skin. TNT have an the capacity of drug loading, in which antibiotics can be loaded in the wires and released at the site of implantation to fight the microorganisms imported inside. Beside antibiotics, proteins and growth factors can also be delivered to improve bone healing. Consequently, they ensure long term survival of the implant and decrease the chances of failure of implantation (Gulati et al., 2011).

14.6.3 CARBON NANOTUBES CNTs are one of the novel innovations that acquired a great position in multiple fields of application. Yet, it is the so-called one-dimensional construction that entitles them for employment in the design and manufacture of nanobionic devices. Prior to the discovery of CNT attributes in this field, silicone-based

14.6 Nanobiomaterials

devices were the primary trend. However, some limitations pertaining to scalability, electron tunneling, leakage currents, and other variables related to the device structure and activation, motivated research to find a material that can bypass and overcome these limitations and provide better performance outcomes. Accordingly, CNTs have impressed them with their electron transport properties and motivated them to scrutinize the possibility of utilizing them in nanoelectronic devices (Avouris and Chen, 2006; Abuelma’atti, 2013). In essence, CNTs are hollow nanofibers of carbon. They are assembled as one or more layers of graphite that are folded or wrapped as a pipe, known as SWCNT and MWCNT. SWCNT refers to single-walled carbon nanotube, where only one sheet of graphite is rolled, displaying a diameter ranging from 0.4 to 3 nm. Alternatively, MWCNT refers to multiwalled carbon nanotube, that incorporates multiple concentric layers that present an outer diameter up to 100 nm and an interlayer gap of 0.34 nm (Scarselli et al., 2012; Fukuda et al., 2003). The obtainable length can be in micro-, milli-, and even centimeters. According to the geometries that act as repetitive two-dimensional (2D) building blocks perpendicular to the axis of the nanotube, which are controlled by the equation (C 5 na1 1 na2 5 (n,m)), SWCNTs can be classified into three categories, as mentioned in Table 14.1, and shapes illustrated in Fig. 14.8. CNTs have the ability to behave as metallic and semiconductor materials, as per the diameter and chirality. What determines its behavior is the (n, m) rule, in which n & m represent the atoms that roll together to form the cylindrical shape. Table 14.1 Class, Type and Shapes of Nanotubes Class Type Shape

Armchair Shaped Nanotubes

Zigzag Shaped Nanotubes

Chiral Nanotubes

Type (n, n)

Type (n, 0)


Any other shape

FIGURE 14.8 Carbon nanotubes geometries.

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If (n 5 m), which is the case of an armchair structure, the metallic properties dominate and their electrical conductivity outpaces the metals themselves. For zigzag geometry, (n
m 5 3p) where p is an integer and 6¼ 0, it renders them metallic. If (n
m 5 3p 6 1) an energy leak occurs and it results in semiconducting transduction, but still way better than ordinary semiconductors. Therefore, we can conclude that SWCNTs can be either metallic or semiconducting materials, but MWCNTs always possess metallic conductivity (Avouris and Chen, 2006; Abuelma’atti, 2013; Scarselli et al., 2012). The underlying cause of such behavior can be comprehended when noticing the types of electrons available in nanotubes. All graphite-containing systems consist of a valance system of Sigma (δ) and Pi (π) electrons. (π) Electrons are distinguished by their delocalization and free mobility, which makes them easily polarized and transported. Accordingly, (π) electrons generate sensitive electronic structures. (δ) Electrons are localized and contribute to good mechanical properties, including high tensile strength and elasticity as well as stability, in terms of chemicals and temperature (Rotkin, 2004; Scarselli et al., 2012). The early approaches to fabricating CNTs, by either arc discharge or laser ablation, have impressive significance in formulating good quality SWCNTs and MWCNTs, that resulted in them being adopted for large scale production. The arc discharge method is described as passing a high current through a gaseous nonconductive medium (commonly helium) between carbon anode and cathode to form gas plasma. It helps evaporating carbon, which will be collected separately and deposited on a substrate in a particular pattern, constructing the desired nanodevices. Laser ablation employs a laser beam to scan a composite of graphite and different compositions of metals or metal oxides in a closely planned style. This procedure takes place in temperatures of 1200 C in a tube furnace. Then, the soot formed is transferred by argon gas flow from the hot zone in the furnace to a cooled zone outside, where a copper collector awaits deposition of soot. It is noticed that both techniques result in impure CNTs, either in their main composition or overcoated with byproducts like fullerenes and graphitic polyhedrons. Therefore, subsequent purification is necessary to render the nanodevices safe and effective. However, it is very expensive, in a way that exceeds the costs of the entire manufacturing process. In addition, if purification was performed, confirming purity is difficult, since there are no conventional tests to serve this purpose; many defects in the geometry of the nanotubes arise, rendering them undesirable for human use or requiring further modifications. Therefore, as always, a new approach was developed to overcome these drawbacks, referred to as chemical vapor deposition. Chemical vapor deposition, or CVP, is considered the technique of choice for vast production of CNTs. This approach is based on utilizing a metallic nanoparticle as a catalyst, an inert substrate like quartz, silicon, or alumina, and an exposure to hydrocarbon flow. The metallic catalyst provides a surface to grow CNTs and initially form a hemispherical cap, followed by selfassembled growth. Numerous metals like iron, cobalt, nickel, copper, aluminum,

14.6 Nanobiomaterials

gold and others can be used to serve this purpose. The difference in type, size, and thermodynamic properties in each of them helps building variable structures (amorphous, single-walled or multiwalled). The process describes how each metal provides a special solubility of carbon when under high temperature, and how they segregate as they loom on the surface. In other words, they guide the carbon within the particles to attach and adhere as graphene, then start to coil around the metallic catalyst, to give the final tubular shape. This method offers many advantages in CNT fabrication, such as the ability to fabricate ultralong, superaligned CNTs with uniform electrical characteristics. Developments have been made to offer continuous production. This can be obtained if the substrate is treated to act as a platform to support the CNTs and a catalyst at the same time. A good example of that is stainless steel; it possesses the appropriate nanoscale roughness, as well as the possibility of extracting iron exclusively to be the sole catalyst in the reaction. Moreover, it is a reproducible and reusable substrate for subsequent production, but care should be taken to critically remove all the synthesized CNTs to preserve their reusability (Scarselli et al., 2012).

14.6.4 NANODIAMONDS This type of carbon-based material was discovered in the 1960s but didn’t come under spotlight until the 1990s breakthroughs. They are miniaturized diamond particles with a diameter in the nanometer scale. The persistent research done in this field led to the revelation of outstanding characteristics of nanodiamonds, including exceptional hardness, biocompatibility, electrical resistivity, and chemical stability. What is noteworthy is their relatively lower toxicity, compared to carbon nanoparticles, which makes them safer for biomedical applications. In addition, nanodiamonds display a significant tendency to self-assemble and a capability to bind distinctive molecules on their surface that contributes to the increased attention in their application. It is scientifically acknowledged that diamonds are metastable in nature, due to the sp3 cluster surface which necessitates stabilization prior to any application. This can be achieved by either surface reconstruction into sp2 or functionalization. Controlling the size, morphology, and surface terminations can somewhat guarantee the stability. Plenty of methods were adopted to synthesize nanodiamonds, but the most commercially applicable, producing 2
10 nm diamonds, are detonation, laser ablation, and high-energy ball milling of high-pressure high-temperature (HPHT) diamond microcrystals. Detonation relies on explosive molecules, since they can give a suitable combination of carbon source and conversion energy together. Detonation is carried out in a closed chamber. It can take two courses of synthesis: dry, where an inert gas fills the chamber, or wet, where water coolant or ice is used. In the end, soot is formed, consisting of nanodimonds (4
5 nm) along with some carbon allotropes and impurities. The applied temperature and pressure are adequate to not liquefy the carbon in bulk, but to create a liquefied state at nanoscale. In other words, the

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temperature and pressure causes condensation and crystallization of the liquid carbon by provoking a homogeneous nucleation within a volume of supersaturated carbon vapor. If shock waves were used to initiate the explosion, the synthesized nanodiamonds will have a larger diameter (.10 nm). The impurities within the soot need to be eliminated and a subsequent purification of extracted nanodiamonds is necessary to keep them stable. These impurities can develop as a result of the azides use as igniters, or the steel wall of the chamber, and they have the tendency to be superficially attached or internally trapped. Purification can be conducted by liquid oxidants or any other chemical treatment, but it was found hazardous and expensive. The ecofriendly and economical approach depends on oxidizing the noncarbon impurities with air or ozone-enriched air at high temperatures (Mochalin et al., 2011). Nanodiamonds are one of the recent nanobiomaterials that are used in visual prosthetics. They are used for two purposes: to insulate the conductive channels in the electrode array, and to decrease the space between the artificial stimulation and the target neuron. They were employed in much research as either a capsule covering a compartment or as a complete coating of microdevices. The addition of these synthetic diamonds improved the charge injection limit. Other recent works involved the production of electrodes from nanocrystalline diamonds by codeposition of nitrogen as a dopant, or a substance that produce the desired electrical features. Another modification was then made to alter the charge injection limit in a way to improve the neural stimulation without need for water hydrolysis. It was attained by anodization of the electrode in an electrochemical cell to generate an iridium oxide layer on the surface. Advancements are further explored to enhance and widen their field of application (Ghaffari et al., 2016).

14.6.5 NANOBIOCERAMIC Ceramic, in essence, is comprised of polycrystalline compounds that generally include silicates, metallic oxides, carbides and numerous refractory hydrides, sulfides, and selenides. Some special types of ceramics may have covalent bonds to diamonds and other carbon-based compounds (Lee et al., 2006). They were found very beneficial due to their exquisite. Bioceramics refers to the class of ceramics that is suitable for biomedical purposes, especially in replacing diseased or damaged bones. They are most commonly exploited in dental and orthopedic implants, due to their low thermal and electrical conductivity and the satisfactory color and translucency, as well as their hardness, rigidity, resistance to abrasion, and low density (Wang et al., 2015; Khalil, 2012). They can be classified into crystalline, bioglass, alumina, and zirconia ceramics, as described in Fig. 14.9.

14.6.5.1 Crystalline ceramics These are structurally and chemically analogous to human bone mineral component, which is displayed as hexagonal symmetry. To achieve such morphology in

14.6 Nanobiomaterials

FIGURE 14.9 Classes of bioceramics.

submicrometric level, several methods of production are employed, such as precipitation of aqueous solutions, liquid mix technique, and aerosol synthetic technique. Being analogous to bone tissues doesn’t mean they are exactly the same. Crystalline ceramics show a deficiency in incorporating carbonate ions to the same extent as bone tissues. Conversely, they are capable of substituting other ions such as Na1, K1, Mg21, Sr21, Cl2, F2, and [HPO4]22 which augment the growth of tissue in a faster manner. Biphasic mixtures are synthesized to generate some of the mineral bone material. It has two phases: stable hydroxyapatite, and resorbable beta tricalcium phosphate (β-TCP), that can form carbonate hydroxyapatite and facilitate the regrowth of bones. Cements are also included in this category; they contain mostly calcium, phosphate, sulfate, or carbonate salts that are biocompatible and excellent for bone repair. Cements acquire a powder phase (of Ca or PO4 or both) with an aqueous medium that crystallize in room or body temperature to form calcium-phosphate crystals that can be directly deposited into bones and hasten repair (Tiwari and Tiwari, 2014).

14.6.5.2 Bioglass ceramics Bioactive glass is a polycrystalline ceramic made by controlled crystallization and is composed of SiO2, Na2O, CaO, and P2O5. It used to be produced through UV irradiation-driven precipitation of metals, which induced nucleation and crystallization of glass into fine grains with thermal and mechanical properties (Lee et al., 2006). Currently, a sol-gel process is adopted to control the necessary composition and architecture. They can exist in binary state of CaO-SiO2, or ternary state of CaO-P2O5-SiO2. Both systems form a Si-OH bond that hinders the formation of calcium-phosphate in amorphous forms and delays the crystallization, but ternary systems takes longer delays in comparison. Generally, this type is used as an

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aid or assistance for regeneration and growth of bones, since they have the power to accelerate mineral apatite action (Tiwari and Tiwari, 2014).

14.6.5.3 Alumina and zirconia ceramics Alumina or aluminum oxide (Al2O3) is mainly available in bauxite and corundum and can be synthetically prepared by calcination of aluminum trihydrate. Synthetic alumina (α) exists as a single crystal or polycrystalline with a rhombohedral shape. Alumina for implantation is required to be constituted of 99.5% pure alumina and 0.1% or less of silicon and alkali oxides. Zirconia, in its pure form, can be acquired from zircon (ZrSiO4). It undergoes phase transition in high temperatures, which is why a dopant oxide is always required to stabilize the cubic phase; Y2O3 is usually used for this purpose (Lee et al., 2006). Both alumina and zirconia are used in dental dentures and ceramic crowns. Alumina is distinguished by its aesthetic suitability, admirable hardness, bioinertness, chemical stability, and abstinence from stimulating any allergic response. The only demerit pertaining to its use is brittleness and possibility of cracking. Zirconia is well-known for its appropriate resistance to abrasion and physiological corrosion, high modulus of elasticity, flexural strength, and hardness. However, it is still considered to be inferior to that of alumina (Wang et al., 2015).

14.6.5.4 Nano versus traditional ceramics Nanoceramics are ceramic structures at the nano scale. They preview outstanding and very distinct properties, compared to traditional ceramics, that can solve problems of low ductility and brittleness. Table 14.2 shows the differences and the changes that occur when handling both traditional and nanoceramics. Atoms in nanoceramics can easily migrate by application of any force of deformation, which can explain the ductility they exhibit. The mechanical strength and hardness of nanocermics is more than traditional ceramics by four- to fivefold. Reinforcement of nanoceramic with CNTs in the form of composites, which will be further discussed in the following section, showed enhanced electrical and mechanical features (Wang et al., 2015). Table 14.2 Comparison Between Traditional and Nanoceramics Plasticity Brittleness Ductility Atom arrangement Mechanical properties

Traditional Ceramic

Nanoceramic

Nonplastic Brittle Poor Fixed in crystals Good

Superplastic Tough Good Loose and indefinite Superior

14.6 Nanobiomaterials

14.6.6 NANOCOMPOSITE Composites are heterogeneous, engineered materials that are assembled in two distinctive phases, which are physically and chemically different. Each phase preserve its own properties and forms an interface between the two phases. Two phases or more can be involved in composites; what is essential for composite fabrication is the existence of a matrix phase and a dispersed phase. Generally, engineering such material is recommended to establish a particular or a synergetic property that cannot be achieved or attained by any phase on its own. This can be explained by understanding the function of each phase. The matrix phase transfers the stress and distributes it between phases, provides a protection from the environment, and supports the dispersed phase. The dispersed phase enhances the matrix characteristics like tensile strength, fracture toughness, and creep resistance; this is usually referred to as reinforcement. There are a variety of factors that can influence the composite features, including properties, volume fracture, and the homogeneity and orientation of the dispersed phase. Classification of composites can be done on three bases, as summarized in Fig. 14.10. Simple composites are the outcome of dispersing a single homogenous dispersion through the matrix phase. If more than one homogenous dispersion is used, it will be called a complex composite. When one or more dispersions are intentionally kept inhomogeneous and dispersed through the matrix, it joins the graded composite family. Hierarchal composites are considered to be of higher level, since they initially form a simple or complex composite with fine entities, agglomerate it to increase the particle size, then disperse it in another matrix material in a hierarchal manner. Particulate composites are those containing particles or flakes, fibrous ones enclose fibers, and laminar incorporates phases as

FIGURE 14.10 Classification of composites.

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laminates or panels within the matrix. A hybrid composite represents a combination of any of the previous three types. Designing a composite requires taking three determinants into consideration: (1) proper selection of both matrix and dispersed phase, (2) the methods of preparation and processing, and (3) the internal and external structural design of the composite (Dorozhkin, 2015). Composites have been very advantageous and involved in variety of fields, but scientists always look for more and for better. They have questioned whether miniaturizing composites to nanoscale can have any impact on their properties, or if it can yield better outcomes in biomedical applications. Nanocomposites can be properly defined as a material of multiple phases, where at least one of which displays a component in 100 nm or less. The first nanocomposite produced was a polyamide nanocomposite in 1950, but the first one to be applied was a polymer/ layered silicate clay mineral composite by Toyota researchers in 1976. Since then, more work was done across many fields. Ordinarily, they are nanoparticle building blocks of clay, polymer, carbon or a combination thereof. When comparing composites to nanocomposites, significant changes are noticed in terms of properties. Their properties don’t merely rely on the properties of the parent material, they also depend on the morphology and surface characteristics (Okpala, 2013). Many alterations can be obtained when the matrix phase is in nanometer scale. The loading, degree of dispersion, size, shape, and orientation of the nanoscale second phase, and interactions between the matrix and the second phase, are determined as per the dimensions of the matrix. Other changes can be attributed to the increased surface-to-volume ratio of the reinforcing material, which is responsible for the improvements in mechanical strength, toughness, and electrical and thermal conductivity of the matrix material. In special materials, it can enhance the chemical resistance, flame retardancy, and decrease the permeability to gases, water, and hydrocarbon (Okpala, 2014). Nanocomposites shouldn’t be confused with composites containing nanoparticles. The former describes when the system of two phases is nanodimensional in total, whereas the latter carries at least one nanoparticulate phase. They share some of the properties related to the surface. However, the difference should be established since their mechanical and optical properties are unalike (Dorozhkin, 2015). Nanocomposites are categorized into two main types: inorganic/organic nanocomposites and lamellar nanocomposites. The lamellar class can be further subdivided into intercalated and exfoliated. Intercalated subtype is when alternating layers of inorganic material and polymer exist in a restricted composition and a limited number of layers and interlamellar spaces. They demonstrate good charge transport, which makes them favorable for use in electronics. Exfoliated possess a ˚ variable number of polymer chains between layers that are separated by .100 A space and are known to have better mechanical properties (Okpala, 2013). Fabrication and processing of nanocomposites is carried out by numerous techniques. Choice of suitable technique depends on the type of materials to be incorporated, the desired properties, and the purpose of their manufacture. Polymeric

14.6 Nanobiomaterials

nanocomposites are very popular for production of nanoprostheses, and they are commonly synthesized by one of these methods: In situ polymerization: In situ is the Latin phrase for in position. Accordingly, in situ polymerization means the polymerization that takes place within the reaction mixture and cannot be carried out separately. Here, the nanoparticles of the dispersed phase are dispersed in the matrix material, which can be composed of liquid monomers or of low molecular weight precursor in its solution form. A homogeneous mixture is formed, and an initiator is added. Initiators can be free radicals that break the double bonds. Eventually, the mixture is subjected to heat or light to yield the nanocomposites in their final form. Polymers can be thermoset and thermoplastic in nature. Thermoset polymers are synthesized by this method; they are covalently cross-linked which means they lack the elasticity to reshape like nylon-6 and phenolic polymers. A good example of utilizing this method is the fabrication of CNT- PMMA nanocomposites (Lee et al., 2006). Solvent casting: It is a simple approach that doesn’t require expensive equipment or high temperature for processing. In addition, it offers the merit of drugloading, which can be very beneficial for specific applications. The process starts as the polymer is dissolved in a solvent and cast on a smooth surface such as a Petri dish. Then, it is exposed to air to evaporate in room temperatures or to heat in hot ovens. At the end, films or membranes are formed and detached from the casting surface, as illustrated in Fig. 14.11 (Moura et al., 2016). Layer-by-Layer (LbL) assembly: Layer-by-Layer assembly is known to be a method of surface modification, but it also fabricates layered and ordered nanocomposites in an efficient manner. It is frequently described as simple, reproducible, and flexible. The procedure starts with adsorption of different macromolecules in a sequential fashion to create layered forms. As layers are formed, various intermolecular forces are created, such as electrostatic interactions, van der Waals forces, and hydrogen bonding. The deposition of layers can be made through three modes; dip, spin, and spray-coating. Layer-by-Layer assembly can control the size, geometry, and chemical composition of the layers,

FIGURE 14.11 Solvent casting to synthesize nanocomposites.

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which can make this method quiet versatile and feasible in many applications. It can organize the building blocks into flat templates that can produce multilayered films and free standing membranes. It can also arrange them into threedimensional (3D) templates to form capsules, tubular, and porous structures, and hierarchical reactors (Moura et al., 2016). Sol-Gel method: Sol-gel is a solution that converts slowly and evenly to a gel-like diphasic system. The end product is diphasic, which suits the concept of nanocomposite matrix and dispersed phases. This process takes three main steps, as follows: •

•

•

Phase separation: This step is necessary when the particle density is low; the solution can be left for some time until sedimentation takes place and then the liquid will be poured off. If waiting cannot be afforded, centrifugation can be used. Drying: The remaining liquid is removed by any appropriate approach. The system starts to shrink and densify. The drying rate is highly influenced by the porosity and its distribution. Firing: This refers to thermal treatment, which is crucial for condensation and mechanical property enhancement. It is followed by sintering, to cause further densification and grain growth, without need of application of higher temperatures (Hench and West, 1990).

At the end of this process, a matrix and dispersed system is formed that can be further processed to construct nanodevices. Electrospinning: It is one of the impressive techniques exploited in synthesizing nanostructures, due to the high control of composition, morphology, and porosity it provides. The working principle can be explained as: the polymer mixture is injected from a syringe towards a collecting area in the presence of an electrical field. The applied electrical field provokes internal electrical repulsion that induces and maintains a fibrous texture. There are three modes that can be pursued to form nanocomposites through this technique: (1) wet-dry electrospinning, which utilizes a volatile solvent that evaporates as the fibers are formed, (2) wet-wet electrospinning, where the formed fibers are nonvolatile solvents spun with other solvents, and (3) coaxial electrospinning, which allows simultaneous spinning of two components in a core-sheath fibrous style (Moura et al., 2016). Many examples of nanocomposites are available for biomedical applications, some of which are extensively employed in nanobionics and nanoprosthetics.

14.6.6.1 Cellulose nanocomposite Cellulose ranks first of most abundant polymers in the biosphere. It is composed of β 1-4 glycosidic linked glucose units in a crystalline form. It can be obtained by extraction from natural sources or prepared by means of biotechnology. Nanocellulose has captured attention lately; it was manufactured by different methods to suit particular applications. Mechanical treatment can yield nanofibrous

14.6 Nanobiomaterials

cellulose, where acid hydrolysis can generate nancrystalline or “nanowhiskers” forms. The other type of cellulose is bacterial cellulose (BC) that is synthesized by bacteria at the nano scale. Nanocellulose proved to be great as a reinforcement in nanocomposites; it increases the strength, flexibility, and biocompatibility. However, some drawbacks are reported pertaining to hygroscopicity, inconsistent thermal stability, and high hydrophilicity that render dispersions in polymer matrix poor. Functionalization becomes a necessity in such conditions to attain better homogeneity in cellulose-polymer nanocomposites. It is accomplished in two ways: (1) a blending process, where nanocellulose plays the part of either a matrix or a nanofiller, or (2) chemical modification of superficial hydroxyl groups via esterification, etherification, or oxidation. BC is considered to be the purest form of nanocellulose and it has been an active topic of recent research. This goes back to the biocompatibility and biodegradability, fine fibrous network, good water-holding capacity, as well as a remarkable strength-to-weight ratio. Many nanocomposites containing BC are prepared and continuously explored for various medical purposes, such as wound healing, bone tissue engineering. A few were efficient enough to synthesize nanobionics that replace damaged organs, such as synthetic blood vessels, and even the replacement of dura mater, which is the tissue surrounding the brain. A few examples of cellulose-containing nanocomposites are: BC-hydroxyapatite nanocomposites, aliphatic polysters
BC nanocomposites, poly(lactic acid)-BC nanocomposite, and many more. Recent work on shape memory polymers pointed out the poor mechanical properties of such polymers, which results in low recovery stress as well as slow recovery speeds that limit their application. Therefore, nanocellulose is incorporated to improve the mechanical strength and widen the range of applications (Olalla et al., 2016; Panaitescu et al., 2016).

14.6.6.2 Chitin Chitin is the second most available polymer in nature. It is a polysaccharide which is biocompatible, bioabsorbable, nontoxic, and nonantigenic. It can be found in many organisms like insects, fungi, and mollusks. It has a strong crystalline structure, with an acetamide group and two hydroxyl groups, which can form strong hydrogen bonds. It is an anisotropic material, which means it has variable magnitudes, depending on the direction of measurement. For example, strength and Young’s modulus are high when measured on the axes, but differ when measured in another direction. In biosystems, it can be found in three semicrystalline structures: α, β, and γ. When it undergoes acid hydrolysis, it becomes highly crystalline and forms chitin whiskers, nanocrystals, or nanofibrils. It also possesses characteristics of self- assembly when present in suspension form. So, nanofibrils start clustering into fiber bundles and then start to self-assemble into tissues. The tissues are cross-linked and calcified, increasing their rigidity. Owing to the resemblance in structure between chitin and cellulose, they are prepared or produced in similar methods. Chitin nanostructures are mainly utilized in

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nanocomposites as reinforcing nanofiller to induce positive impact on the overall features and performance (Joa˜o et al., 2016).

14.6.6.3 Chitosan Chitosan is a polysaccharide derived from chitin by alkaline or enzymatic deacetylation, or just deacetylated chitin. They almost have the same properties and methods of production. It is an excellent candidate for nanocomposite fabrication. It is occasionally prepared in two classes: chitosan-inorganic material and chitosan-polyanion complex nanocomposites. There are plenty of materials that are compatible with chitosan to form very effective nanoengineered composites. Layered silicate, metallic and ceramic nanoparticles, CNTs, and graphene-based materials are used to reinforce chitosan (Cui et al., 2014). Clay refers to hydrous silicates or aluminosilicates; their main structure consists of Si, Al or Mg, O, and (
OH), accompanied by diverse cations. They are available in three types: kaolins, smectites, and layered silicate acids. The reason why they need reinforcement is hydrophilicity. To synthesize proper nanocomposite, homogeneity between silicates and chitosan should be confirmed. Accordingly, there are three possible dispersions conformations: (1) tactoid structure characterized by nonexpendable interlayer space, which results in polymer intercalation failure. This makes this conformation undesirable; (2) intercalated structure where the layers are well-maintained but the space between them can be manipulated to permit polymer penetration through layers; and (3) exfoliated structures that contain well-separated clay layers, which allows efficient mixing of both phases that yields appropriate dispersion. Aluminosilicates, known as montmorillonite, present admirable characteristics such as appearance of negative charge, that give them a weak acid behavior. They also attract cations and forms electrostatic or hydrogen bonding with chitosan, forming very popularly used nanocomposites. Nanoparticles are also other nanofillers that can be used. Their properties should be highly controlled, to tune the overall qualities and behavior of nanocomposites. This includes: particle size, shape, crystallinity, and chemical composition. There are three basic categories of nanoparticle that are extensively utilized, especially in biosensors, e.g.: metallic nanoparticles of silver, gold or zinc oxide. Also, bioactive glass has been intercalated in various polymeric matrixes, due to its surface activity and ability to attach to bones and other physiological structures. Another type is used is ceramic nanoparticles, and the most famous in this category is hydroxyapatite nanoparticles which are known for its osteoconductivity, osteoinductivity, biodegradability and mechanical strength. CNTs and graphene based material are also involved. They increase the elastic modulus and improve thermal and electrical conductivity. However, the surface chemical inertia stands as an obstacle in the way of forming appropriately blended nanocomposites (Moura et al., 2016).

14.6 Nanobiomaterials

14.6.7 PEEKPOLYMER PEEK is an acronym for a polymer called polyetheretherketone. It is employed in polymer-engineered spinal cages, usually referred to as a Brantigan cage. This is attributed to its biocompatibility and elastic modulus close to that of cortical bones. The small differences in elastic modulus can be compensated via carbon fiber reinforcements. Determining the required fiber amounts and orientation is essential to render the nanocomposites of desired features. PEEK can be involved in two types of nanocomposites and coatings: HA-PEEK and TI-PEEK combinations. HA-PEEK nanocomposites: Hydroxyapatite (HA) was initially added as an attempt to make this combination resemble natural bone, which is a collagenreinforced HA composite. This exploratory move led to the discovery of an impressive alternative for osseointegration. Many approaches were followed to establish this result. For instance, one of the researchers created a strontiumcontaining HA-PEEK composite that mimicked the elasticity of cortical bones and had better bioactivity, as per in vitro testing. Other than HA, some ceramics were experimented like calcium silicates, bioglass and β-TCP. Ti-PEEK nanocomposites: Titanium was used alone instead of PEEK prior to its discovery. It had its merits and demerits comparatively and so does PEEK. A brilliant idea came into light by combining both Ti and PEEK in one nanocomposite, where they can have a positive synergistic effect in some areas and can cover some of the drawbacks that appeared when used separately. Many researchers noted the impact as improved cell attachment, elevated levels of growth factors vital for osteogenesis and maturation, and augmented bone-implant fusion. They are very promising but still not clinically ready to be adopted within therapeutic options (Rao et al., 2014).

14.6.8 HYDROGEL Hydrogels are one of the most vast and versatile biomaterials, they can be manipulated to possess specified qualities physically, chemically, electrically, and biologically. They can be formulated using a wide range of precursors and materials that have even wider spectrum of features. Therefore, we can find hydrogel composites containing carbon-based materials, polymeric, inorganic, and metallic nanoparticles. Hydrogel nanocomposites are utilized in biosensors and biomedical devices. They offer many superior qualities physically, chemically, and biologically, based on altered nanoparticle-polymer chain interactions. Newer generations are being developed to synthesize multicomponent networks that can incorporate many functional groups that help tailor nanocomposites to fit the purpose (Gaharwar et al., 2013).

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14.7 APPLICATIONS Since the manufacture of the very first prosthesis, scientists and engineers have been trying to produce artificial replacements with better functionality, durability, and appearance to suit the demands and needs of users all over the world. Engineering a prosthetic device that is identical to the organ it is trying to replace is the primary goal of all efforts made in this field. In order to produce artifacts that closely mimic the function of living organs of the body, the mechanisms of these organs must be understood thoroughly and perfectly. In addition to the mechanisms of action of both living and prosthetic organs, the utilization of nanotechnology in different types of prosthetic devices is also discussed herein.

14.7.1 ORTHOPEDIC PROSTHESES 14.7.1.1 Artificial joints Arthroplasty, one of the major advancements of the 20th century in the field of orthopedic surgery, is the process of resurfacing or completely replacing a damaged joint with an artificial one made of low friction metal or other material. Damage of joints can be caused by a number of conditions such as inflammatory arthritis, osteoarthritis, avascular necrosis, rheumatoid arthritis, fractures, developmental dysplasia, tumors, road accidents, or soldier’s injuries; all of which lead to pain, stiffness, and deformity, resulting in deteriorated joint movement and stability. As a solution to these problems, total joint replacement procedures were introduced to improve the quality of life for all patients suffering from joint disease (Pramanik et al., 2005). Arthroplasty is classified, according to the location of the joint, into three major types: total hip replacement, total knee replacement, and total shoulder replacement. In addition, other joints that may undergo arthroplasty include ankle, elbow, wrist, foot, and hand joints. In order to understand how any joint replacement prostheses works, the mechanism of action of the normal joint should be completely understood (Janeway and Janeway, 2007). The hip joint is a ball-and-socket joint that allows the leg to move in many directions. The ball of the joint is the femoral head that fits into the acetabulum, which is the socket of the pelvis. A smooth layer of cartilage is pressed between the ends of the acetabulum and the femoral head to prevent friction and provide cushion for constrained motion. Hip joint disease occurs when the cartilage wears away and the bones rub against each other, which results in inflammation and pain (Pramanik et al., 2005; Understanding Total Joint Replacement Surgery, 2016). The operation of total hip arthroplasty is a major surgical procedure that involves distinct risks, as well as hospital admission, anesthesia, and rehabilitation (Neil, 2010). It involves replacing both the acetabulum cup and femoral head

14.7 Applications

with a smooth, freely moving prosthesis that resembles the shape of the actual joint. It consists of two compartments: at the head of the thighbone, a metal or ceramic ball with a long stem is inserted into the thighbone to anchor the prosthetic joint in place. On the other side, a socket that is made of press-fit titanium or cemented plastic is implanted into the pelvic bone (Pramanik et al., 2005; Neil, 2010). According to the materials used, the bearing surfaces of artificial hip joints are either ceramic on plastic, ceramic on ceramic, metal on plastic, or metal on metal, all of which have been approved by the US FDA. They can be cemented or pressfit (Janeway and Janeway, 2007). Although cemented prostheses have been clinically used for a long time as the most common choice of surgeons, noncemented prostheses exhibit better biological compatibility and enhanced osseointegration, due to their rough surfaces (Understanding Total Joint Replacement Surgery, 2016). The choice of prosthesis depends on the patient’s age, their degree of activity, and the quality of the bone (Foran, 2016; Neil, 2010). The knee joint, the largest joint in the body, is made up of three parts: the lower end of the femur, the upper end of the tibia, and the patella. The surfaces of the knee joint are covered with articular cartilage where the three bones come in contact, which allows them to move smoothly. Synovial fluid covers the rest of the knee and produces a lubricating fluid the keeps the friction of the bones to a minimum. Pain, stiffness and muscle weakness result when the cartilage or the bone is damaged, which leads to deformity and the development of a limp. This happens in a number of diseases like osteoarthritis, osteonecrosis, and rheumatoid arthritis, all of which necessitate the performance of total knee replacement surgery. Total knee arthroplasty is contraindicated in tuberculosis and purulent arthritis. During a total knee arthroplasty, the orthopedic surgeon removes the rundown cartilage and bone, then inserts the artificial knee prostheses in position to recover the function and the alignment of the knee. The artificial knee joint consists of four components: a femoral component, made of polished metal that wraps around the lower end of the thighbone; a tibial component, made of either metal or plastic, and used to cover the surface of the upper end of the tibia; a patellar component, made of plastic and used for resurfacing the underside of the patella; and a spacer component, made of plastic and placed on top of the tibial component to form a plastic liner to aid in the smooth movement of the artificial joint (Tateishi, 2001; Understanding Total Joint Replacement Surgery, 2016). There are three major types of knee prostheses: the constrained, the semicostrained, and the unconstrained type. However, only the constrained type is used for total knee arthroplasty. Also termed hinged prostheses, the early constrained prostheses consisted of a tibial and femoral component, connected together with a hinged mechanism and hence exhibited limited freedom of movement. These did not allow for any rotational movement of the joint, therefore extra pressure was applied on the prosthesis when the knee was in motion, which often led to

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destruction of the bone in that area and the wear of the implant. As a result, this type of prosthesis is not commonly used and, in its place, there is a new design of hinged prosthesis called the rotatory prosthesis, reported to exhibit less complication (Tateishi, 2001). The rotatory platform design displays a reduction in the contact stress, shear force, and fatigue, due to a large contact area between separate articulations and separated rotational movements (Haider and Garvin, 2008; Ranawat et al., 2004). One method to fix the knee prosthesis in place is to use methyl methacrylate bone cement, resulting in what are termed cemented prostheses, which are needed for patients with fragile bones, to ensure the stability of the joint and prevent its loosening. The other method, mainly performed in young patients with strong bone, is to use screws, metal beads, and/or hydroxyapatite granules for an uncemented prosthesis. Another method is to mix both these techniques to perform a hybrid fixation of the prosthesis in which one of the femoral or tibial components, usually the tibial, is fixed in a cemented fashion while the other one, usually the femoral, is left uncemented (Tateishi, 2001). The third main type of arthroplasty is total shoulder replacement. The shoulder, much like the hip joint, is a ball-and-socket joint. The upper end of the humerus form has the shape of a ball that allows it to glide against the glenoid that forms a socket in the scapula. The surfaces of theses bones are covered with smooth cartilage that ensures the effortless movement of the joint (Elbaz). A total shoulder arthroplasty involves the replacement of the damaged head of the humerus with a metal ball, which is attached to a stem inserted into the humerus to secure the ball in place. On the other side of the joint, the damaged glenoid must be replaced with a smooth polyethylene socket, which is fixed in place using bone cement. Another technique, which can be completely cementless, involves attaching the metal ball to the socket and the plastic socket to the upper head of the humerus, this is termed a reverse shoulder arthroplasty (Craig, 2013). Hip, knee, and shoulder are the main, and most common, joints that may undergo arthroplasty procedures. However, other joints such as ankle, elbow, wrist, and finger joints may undergo total replacement, when required. Arthritis and degeneration of cartilage in ankle joints causes severe pain as well as limited range of motion. Therefore, artificial ankle joints become an excellent solution that returns the ankle to its normal movement and reduces pain without placing pressure on the other joints of the limb. The early designs of ankle prostheses contained a tibial component and a talar component; however, these joints were constrained and did not allow a wide range of motion. Unconstrained, mobile bearing, three-component artificial ankles were developed later on and had an additional polyethylene meniscus component, along with the metal tibial and talar components (Wang and Brown, 2016). Much like the knee joint, the elbow is a hinge joint. A prosthetic elbow has two components, a humerus component and an ulnar component. In addition,

14.7 Applications

some designs of a prosthetic elbow have a pivot or hinge, while other designs rely on ligamentous and muscular power to hold the joint together. The linked prostheses have an advantage of having a better range of motion and better joint stability, while the unlinked type has a lower risk of wear and less body invasion (Sanchez-Sotelo, 2011). The wrist is a very complicated and flexible joint, constituting carpal bones, radius, ulna, and articular cartilage. A prosthetic wrist helps in rebuilding balance and providing motion (Ma and Xu, 2016). The most common design of wrist implant has two components: the first part is inserted into the radius and has a curved end where it faces the wrist joint. The carpal component is inserted into the hand bone and has a flat surface facing the first component. A polyethylene spacer is fitted between the two metal components. The spacer is flat on the side of the carpal component and round on the side of the radial component to ensure a perfect fit and to enable a natural wrist motion (Carlson and Simmons, 1998). Hands have a number of joints functioning together to achieve a desired motion. Among these joints, the metacarpophalangeal joint (MCPJ), the proximal interphalangeal joint (PIPJ), and the first carpometacarpal joint (CMCJ) undergo total replacement procedures if damaged. The trapeziometacarpal joint, in particular, has a unique anatomic structure that grants it a special range of motion over three different planes, which makes a total arthroplasty procedure quite difficult (Watts and Trail, 2011) Early finger implants were of the constrained hinge type, however, they faced a lot of complications and problems including loosening and fractures. Conversely, the unconstrained prostheses exhibited more favorable outcomes. Silicone and pyrocarbon, among other materials, are used in the manufacture of finger implants (Badia and Sambandam, 2006). In any total arthroplasty procedure, there are a number of complications and problems that need to be overcome in order for the patient to have a completely functional prosthetic joint. These complications include infection, nerve injury, venous thrombosis, as well as loosening, dislocation, and rejection of the prosthesis. Scientists have experimented with many potential solutions, such as the use of new materials in the manufacture of a prosthetic implant for better biocompatibility, or new structural designs for better movement. The utilization of nanotechnology in total joint replacement prostheses is a major approach to improve the outcome of an arthroplasty procedure for many reasons. Nanotechnology provides a solution for plenty of the problems that occur with the use of an artificial joint. Conventional artificial joints are made of titanium, having microsurface features. This results in the body recognizing the artifact as foreign material and immediately initiating a rejection response. Even the smallest rejection response can lead to painful loosening or weakening of the implant. Since osteoblasts function at the nanoscopic scale, it would be easier for the implant to merge with the bone at the prosthesis-bone interface, if it can interact at the same basic level as the osteoblasts. With this idea in mind, scientists utilized nanotechnology in manufacturing artificial joints. The application of nanomaterials in a prosthetic

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implant can greatly reduce the chances of implant loosening by improving the osseointegration (Sullivan et al., 2014). For the purpose of ensuring implant success, a number of issues must be addressed, including the fixation of the implant at the interface between prosthesis and bone. Modification of implant surface properties is essential for improved osteoblast response and osseointegration. This is achieved by designing the surface in a fashion that mimics the natural environment of biological tissue and also incorporating adhesive factors into the interface, thus boosting osteoblast-implant integration. Since all these interactions occur at the nanoscale, it is befitting to use nanotechniques to control the surface topography of the prosthesis, by forming a nanotextured surface pattern that allows easy and efficient osseointegration (Torrecillas et al., 2009). The increased activity of osteoblasts leads to increased bone growth on the nanotextured surface of the prostheses, especially the nanoroughened hydroxyapatite-coated ones (McHale et al., 2013). Therefore, nanotubes became of great benefit in the field of prosthetics. These nanotubes are usually made of metals, metal oxides, metallic alloys, polymers, and ceramics (Ganguly et al., 2014). Titanium prostheses coated with nanotubes have shown better osteoblast attachment. This is because nanotubes have the same chemistry as DNA, which makes it easy for protein components to attach to the surface of these nanotubes, thereby reducing the rejection response or even completely preventing it. Even though the conventional artificial joints served well, they had a short lifetime (of under 20 years) as well as high wear rates. Self-assembling CNTs were introduced into the implant design, resulting in high quality implants that last longer and are better accepted by the body (Chun et al., 2004). The basic concept of self-assembling nanotubes is that they have the same chemistry as DNA which allows them to assemble themselves in the form of tiny rosette-shaped rings, made of base pairs of guanine and cytosine on the surface of the prostheses, which promotes the adhesion of osteoblasts to the titanium joint. Many rings then join together to create rod-like nanotubes having the width of only 3.5 nm. It was found that not only bone cells but also cells from other parts of the body adhere better to foreign bodies exhibiting surface bumps as wide as 100 nm. These bumps mimic the surface features of natural tissue, which promotes cell adhesion as well as cell growth, leading to the development of longlasting natural implants. In addition to their potential in future material design and drug delivery systems, nanotubes can be tailord to suit specific body parts by adding special amino acid sequences or growth factors that signal the surrounding cells to attach to the implant. This is of crucial importance in transplantation of artificial body parts like blood vessels or even the brain (Chun et al., 2004). Furthermore, incorporating nanotubes into the implant is effective and also very economical, as researchers have found that even low concentrations of nanotubes can provide the same results as high concentrations. In other words, you can achieve high osteoblast attachment using a very little amount of nanotubes.

14.7 Applications

Another useful characteristic of these rosette nanotubes is that they automatically arrange themselves into a web on the surface of the implant, which bears a perfect resemblance to the pattern of natural collagen fibers in bones (Chun et al., 2004). After implanting a prosthetic joint, the body reacts to the synthetic material with an inflammatory rejection response that limits the biological integration and activity of the prosthesis, leading to dislocation, loosening, and failure of the implant. Protective nanotextured coating of the prosthesis protects it from this reaction and ensures better mechanical stability and improved long-term results (Torrecillas et al., 2009). Some materials used for coating prosthetic joints are nanoceramics, polymer nanocomposites and nanocrystalline diamonds (McHale et al., 2013). A number of useful properties can be added to the prostheses by coating their surfaces with nanostructured materials such as nanoengineered hydroxyapatite, titanium, and cobalt-chromium-molybdenum, all of which have shown better adhesion of osteoblasts to the implant when compared to their microscopic or macroscopic counterparts. Hydroxyapatite, in particular, has been widely used in its nanophase for orthopedic purposes. A paste made of nanocrystalline hydroxyapatite showed incredible results in healing bone defects and fractures. The paste is used as a filler in between bone cracks and as a substitute to bone grafts for treatment of bone defects (Sullivan et al., 2014). Additionally, nanotextured hydroxyapatite is used in conjugation with type 1 collagen to produce nanocomposite scaffolds, which are arranged in layers to form prosthetic implants that are intended for fixing osteochondral defects. These implants are made of specific and accurate ratios of collagen and nanohydroxyapatite. For instance, the layer of the implant that is inserted into the cartilage region is made of 100% type 1 collagen, whereas a 70% nanohydroxyapatite and 30% type 1 collagen ratio is for the layer to be inserted into the bone region. This results in less morbid and more compatible prostheses (Sullivan et al., 2014). To avoid malignant growth of osteoblasts around the implant, nanoengineered selenium is applied to titanium prostheses to inhibit tumor growth at the interface between implant and tissue. Nanoengineered silver, however, is effective in preventing wound infections and stimulating healing. Therefore, when applied to titanium prostheses, nanoscopic silver prevents acute infections after a total joint replacement surgery, due to its bactericidal and antiadhesive properties (Sullivan et al., 2014). A modern modification to total joint prostheses is the incorporation of nanophase drug delivery systems, by coating the artificial joint with a biodegradable polypeptide nanostructured film of a particular drug, usually antibacterial. For example, when a cefazolin nanofilm was applied to total joint replacement prosthesis, a reduction of bacterial load was observed, as well as an improvement in osteoblast integration. Moreover, the nanofilm resulted in enhanced osteoblast adherence and proliferation, even without the incorporation of cefazolin into the film (Sullivan et al., 2014).

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Nanosized crystallites in diamond coatings are a new trend in the manufacture of artificial joints. Nanocrystalline diamond has great potential in medical implants, as it combines surface smoothness with high corrosion resistance, resulting in reduced amounts of wear debris and prolonged lifetime of prostheses. The coating exhibited the typical morphological patterns of bone cell growth, indicating a lack of cytotoxicity. In fact, most of the wear debris of this type of coating is made up of completely harmless and inert diamond particles that elicit no or little allergic reactions. The very low roughness of the nanocrystalline diamond surface contributes to the biotribological and biomechanical behavior at the sliding contact surface of the prosthesis at the bone-prosthesis interface. In addition to antioxidant and anticancer properties, nanocrystalline diamond also has protective properties that allow it to form a selective protective barrier between the implant and the biological environment. Moreover, it exhibits the highest resistance to bacteria in comparison to steel or titanium (Amaral et al., 2008). The function of nanocrystalline diamond can be improved further by implementing a number of modifications. One example is linking human immunoglobulin G antibody to the surface of nanocrystalline diamonds, consequently providing it with the capability of biomolecular recognition. Another example is functionalizing nanocrystalline diamond coating with bone morphogenetic protein-2, making it more biomimetic and improving its osseointegration (Amaral et al., 2008).

14.7.1.2 Bone fixators Artificial joints are not the only orthopedic prostheses utilized in our current time; bone fixation devices have also become commonly used tools in medical orthopedic procedures. Bone fixators are the medical tools used for osteofixation of bones in the case of orthopedic trauma therapies (Giannoudis et al., 2007). Bone is one of the biological tissues that retains the capability to regenerate throughout a person’s life. The process of bone regeneration is a complicated and well-orchestrated formation process that takes place in normal fracture repair. Although bone tissue has a large capacity for self-healing, intervention is required in many clinical conditions. Such conditions include cases that require a large quantity of bone regeneration, like large-scale skeleton reconstruction in cases of trauma, tumors, and skeleton abnormalities, or in other conditions where the regeneration is hindered by a number of factors like osteoporosis, atrophic nonunions, and avascular necrosis (Dimitriou et al., 2011). Various techniques were developed in an effort to accelerate or compensate for insufficient regeneration and to produce substitutes that are identical to natural bone. These intervention methods include the use of autologous bone grafts, which is considered the so-called “gold standard” for fracture repair; use of osteoconductive scaffolds; and allograft implantation. In addition to the methods that promote the regenerative process, there are other techniques that mainly enhance the mechanical stability and mechanical stimulation of the fractured bone, thereby

14.7 Applications

ensuring optimal bone healing, including the use of bone fixation devices (Dimitriou et al., 2011). Bone fixation devices are systems of internal or external stabilization designed to enhance the mechanical stability and the bone repair process with the help of surgical intervention. Mechanical properties of bones vary according to the interaction of bone with the applied stress, which is described by Wolff’s law. Scientists are attempting to decipher the phenomena of bone fracture repair by applying Wolff’s law, along with variations in other parameters such as implant rigidity, fracture stability, fracture gap size, and interfragmentary strain (Giannoudis et al., 2007). Treatment of fractures mainly aims to restore the anatomical alignment of broken bone fragments in order to allow the bones to heal in the correct position, and to relieve pain. For inherently stable fractures, a minimal amount of effort, using casts or braces, is needed to minimize the interfragmentary movement, as these fractures selfheal by intramembranous and endochondral ossification. When it comes to complex fractures, with severe soft tissue damage or with infections, fixation systems and implants are utilized. The purpose of any fixation system is to provide the stability by reducing external loading and muscle activity to an extent that brings the interfragmentary movement to a minimum. Interfragmentary compression is achieved through devices like compression plates and tension bands, which bring the fracture fragments together via an external application of compression force. Bridging plates are fixation devices that bridge the fracture fragments with a number of screws anchored to the intact parts of the fractured bone, thus decreasing the stress load and increasing vascular supply. Accordingly, bone fixators can be classified into two broad groups (Fig. 14.12; Krishnakanth, 2012).

FIGURE 14.12 Classifications of bone fixation devices.

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External bone fixators are indicated in cases of open fractures having substantial soft tissue injuries that need vascular procedures, fasciotomy, polytrauma, fractures in children to avoid fixation of pins or screws through the growth plate, temporary joint bridging before later open reduction internal fixation (ORIF), and arthrodesis of the ankle, elbow, or knee. Other conditions include corrective osteotomies and limb-lengthening procedures (Taljanovic et al., 2003). Healing of fractures under external fixation is dependent on factors that include the rigidity of the fixator, the configuration of the fracture, the accuracy of fracture reduction, and the amount of physiologic stresses (Aro and Chao, 1993). External fixators have a number of advantages over ORIF and intramedullary nailing, such as the adjustable construction, the simple application, and the increased accessibility for wound care (Moss and Tejwani, 2007). External fixation devices are composed of pins and wires such as Schanz screws, Steinman pins, and Kirschner wires. They are positioned percutaneously on both sides of a fracture. Various clamps connect the pins and wires to external fixation rods made of stainless steel or carbon fibers. Krischner wires, having the widest indications and easiest method of application, have been the most commonly used fixators due to their simplicity, versatility, and economy (Egger, 1992). External fixators are classified into three basic types: standard pin fixator, ring fixator, and hybrid fixator. As the name indicates, a standard pin fixator consists of pins, percutaneously placed into the bone, and externally connected to a rod. Pin fixators are also termed as standard uniplanar fixators. They are indicated in cases of long bone fractures, except those of the proximal femur or humerus, or in cases of complex distal radius fractures. The second type of external fixators is called a ring fixator. Ring fixators, frequently termed Ilizarov fixators, consist of thin wires that are attached to external rings or frames. They were first applied in limb-lengthening procedures by Russian surgeon Ilizarov but are currently used in other applications. Hybrid fixators combine both standard pin fixators and ring fixators together by attaching Krischner wires to a proximal ring that is connected to a unilateral external rod, which is, in turn, connected to the distal bone shaft via Schanz screws. This set up is most commonly used for the mending of proximal and distal tibial fractures that are close to the joint. Some external fixation devices are pinless fixators, in which the clamps are anchored onto the cortex without penetrating the medullary canal. These fixators are commonly used for tibial fractures. Although they are not highly stable, they allow later safe intramedullary nailing (Taljanovic et al., 2003). One of the earliest methods to treat fractures without completely immobilizing the limb with a cast or skeletal traction is ORIF. Internal fixation allows prompt function of the injured bone while it heals. Internal fixators, usually made of stainless steel or titanium, are classified into wires, plates, pins, and screws, and intramedullary nails or rods. Staples and clamps are also used along with plates and wires. Wires, used alone or in conjugation with other fixators, are commonly utilized to reattach osteotomized bone fragments. Used together with pins and

14.7 Applications

screws, wires can create a compression band on the fractured bone. Wires of various diameters are braided together to suture bone and soft tissue (Taljanovic et al., 2003). Another internal fixation device is the compression plate or neutralization plate, which is a stainless steel or titanium plate with screw holes on its length. Compression plates apply pressure at the fracture ends; however, in cases of severe fractures or bone loss where compression is not possible, the plate is applied as neutralizing plating to keep the bone fragments in place as the fracture heals. Therefore, plates are usually used for spinal and long bone fractures. Bone fixation plates are divided into a number of types: dynamic compression plate (DCP), lowcontact DCP, tubular plates, blade plates, reconstruction plates, bridge plates, as well as newer types like point-contact fixator, and less invasive stabilization system plate. Some plates are designed to fit a specific anatomical position such as condylar plate, angled blade plate, condylar buttress plate, T-plate, cobra head, obliqueangled T-plate, and spider plate. Other than compression plating and neutralization plating, percutaneous plating is a new technique for internal fixation and is considered an evolution of plating techniques (Taljanovic et al., 2003). Pins and screws are manufactured in a large variety of sizes and are frequently used in orthopedic practice. They serve a number of purposes, including temporary fixation of fracture fragments, accurate placement of larger screws, and attachment of skeletal traction devices. Krischner wires and Steinman pins are among the most regularly used pins. Screws, usually used with plates, nails or rods, are divided into two classes, according to the Association for the Study of Internal Fixation: cortical screws, which are usually threaded and used in the diaphysis, and cancellous screws, which are designed to cross long portions of cancellous bone. Cortical screws often have smaller thread diameter and less pitch than cancellous screws. According to function, screws are divided into: interfragmentary screws, crossing the fracture line and providing compression between fragments; cannulated screws, having a hollow shank and used for fixation of subcapital hip fractures; syndesmotic screws, used to stabilize distal tibiofibular syndesmosis; and dynamic compression screws, used in the treatment of intertrochanteric proximal femur fractures. One more type is the Herbert screw, which is used for fixation of scaphoid fractures. Anchor screws are used for capsular, tendinous, and ligamentous repairs. Another type is the Kurosaka screw that is an interface screw. Interface screws can be metallic, or bioabsorbable and radiolucent, and are used as fixation devices to anchor bone grafts (Taljanovic et al., 2003). Intramedullary nails and rods are mainly used for the treatment of femoral and tibial diaphyseal fractures, as well as humeral shaft fractures. They have the advantages of allowing early weight bearing, providing optimal biomechanical positioning, resisting torsion and bending, as well as minimizing soft tissue exposure. Various designs of intramedullary nails and rods are available. For example, femoral nails are anteriorly bowed to fit the anatomical shape and position of

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the bone, and reconstruction nails have proximal locking holes designed to accommodate screw insertion into the femoral head and neck. In addition, flexible intramedullary rods, like the Ender nail, Lottes nail, and Rush pin, have small diameters and great flexibility to accommodate long bone anatomy (Taljanovic et al., 2003). Bone fixation devices can be incorporated with an antibacterial property through the utilization of nanoadditives. Metal-based nanoparticles are added to the outer surface of the fixators, inhibiting the growth of a number of pathogens that are present on human skin, thereby decreasing the incidence of infections. This antibacterial protection against bacteria, mold, and mildew, along with regular cleaning of fixation devices prevents cross contamination and prolongs the product life (Frydry´sˇek et al., 2011). Another method to prevent infections of osteofixators is surface modification of titanium devices. Certain nanosized topographies of titanium and its alloys have been proven to greatly reduce the bacterial adhesion to the fixator, while simultaneously enhancing bone repair. Nanoroughened titanium surfaces displayed reduced adhesion of the bacteria that are commonly associated with orthopedic implants infection: Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa (Yang et al., 2015). Another useful application of nanoadditives is the incorporation of bionanocomposites on CNT. Bionanocomposites are nanocomposites of natural organic or inorganic polymer matrices, having remarkable properties of biocompatibility, biodegradability, and stability. CNTs exhibit unique characteristics that make them ideal for the use in fixation devices. In addition to their ability to align themselves naturally into ropes, they display great strength, special electrical properties and high thermal conductivity (Frydry´sˇek et al., 2011). While using conventional metallic fixators, the surgeon must repeat X-ray diagnostics a number of times from different angles to visualize bone fractures properly during a bone fixation operation. Consequently, the need for X-ray invisible fixators has arisen, in order to make the operation easier and shorter, and to reduce the radiation exposure of both the patient and the surgeon (Frydry´sˇek et al., 2012). Incorporation of polyurethanes into the nanotubes have proven to significantly enhance the mechanical properties and reduce X-ray absorption. A great advantage of using CNTs in the manufacture of bone fixation devices is their high X-ray invisibility. This is important as it helps in the clear visualizing of the bone fractures (Frydry´sˇek et al., 2011). Nanotechnology has also aided in improving the fixation efficacy of different internal fixators. Different techniques involve the adjustment of thread design and shape of screws, as well as surface modifications. Surface modifications include nanostructured topographies and nanomaterial coating. Nanostructured topography of titanium enhances the osseointegration of internal fixation devices. Coating internal bone fixators with nanosized HA coating enhances their fixation efficacy, biodegradability, stability, and osseointegration (Yang et al., 2015).

14.7 Applications

Another method to improve osseointegration of titanium implants is anodization. Studies have proven that vitronectin and fibronectin, proteins known to promote cell adhesion, are highly adsorbed on the surface of anodized nanotubular titanium, thus promoting the adhesion and proliferation of osteoblasts. In addition, anodized titanium screws and pins have displayed better skin growth and resistance to infections, when compared to conventional titanium implants. Moreover, it was reported that bone cells deposited high levels of calcium on anodized titanium, resulting in enhanced osteocalcin synthesis, which is important for bone synthesis (Yang et al., 2015). TNTs, in conjugation with titanium wires are currently being used to design new bone fixation tools with drug delivery properties. Electrochemical anodization is used to produce TNT arrays on the surface of titanium implants for the purpose of carrying growth factors, proteins or drugs, including antibiotics and lipophilic drugs. Drug release from antibiotic-loaded TNTs is controlled by a number of factors such as the structure of the nanotubes, their surface topography, and polymeric coating. Poly(lactic-co-glycolytic acid) and chitosan coatings provide extended release of lipophilic drugs, as well as drug-loading nanocarriers like polymeric micelles. Incorporating the antibiotic into the osteofixation device provides the advantage of directly releasing the drug from the implant into the infected area around it, which enhances the antibacterial action and reduces the incidence of infections. In addition to their ability to resist microbial infections, TNTs have the merit of excellent biomechanical compatibility with natural bone, as they have matching elastic modulus. This also results in an even distribution of skeletal load over both the bone and the implant, thereby shielding the bone from stress-induced bone degradation (Gulati et al., 2011).

14.7.1.3 Bone grafts Since the start of this century, orthopedic surgeons have been trying to utilize bone grafts for treatment of fractures as an alternative to internal and external bone fixators. The difference lies in that bone grafts are used to fill in the bone defect, whereas bone fixators just stabilize it mechanically in order to allow it to properly selfheal. There are a number of ways to classify bone grafts: autografts and allografts, or cancellous and cortical bone grafts. The gold standard of bone grafts is autografts. An autograft or autologous bone graft is a specific portion of osseous matter that is extracted from an anatomical site then transplanted into another site in the same person. It has the advantage of complete histocompatibility, along with osteogenic healing properties. Donor site pain, excessive blood loss, infections, and long operation time are the major limitations of autografts. In addition, there is a very limited supply of grafts in the case of pediatric patients, which creates a big obstacle in the application of autologous bone-grafting procedures (Roberts and Rosenbaum, 2012). Another limitation is the inability to customize the graft tissue into the required form (Taljanovic et al., 2003). Allopathic bone grafts, i.e., allografts, are osseous

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matter that is extracted from a different genotype from the same species, sterilized, and then transplanted to the recipient. Allografts have the merits of short surgical time and lack of donor site morbidity. However, they have the limitations of high costs and risk of viral transmission (Roberts and Rosenbaum, 2012). Other disadvantages include loss of biologic and mechanical properties secondary to its processing, as well as immunogenicity (Taljanovic et al., 2003). Bone grafts have various forms, such as osteochondral, cancellous, and cortical grafts, as well as demineralized bone matrix. A cancellous bone graft is the most common form of autograft. It possesses a high concentration of osteoblasts and osteocytes, providing it with great osteogenic property. It also has a large trabecular surface area, which encourages the revascularization at the recipient site and leading to ease of incorporation of the bone graft into the natural bone. Contrary to cancellous bone grafts, cortical bone grafts have great structural integrity, which provides excellent mechanical support to the bone. Conversely, cortical bone has a comparatively small supply of osteocytes and osteoblasts; therefore, its osteogenic properties are very limited. Moreover, most osteocytes in cortical bone grafts perish after transplantation, further deteriorating the osteogenic function and hindering the incorporation process (Roberts and Rosenbaum, 2012). The various complications of allografts and autografts have encouraged scientists to search for alternative bone graft substitutes; accordingly, synthetic bone grafts came into application. Bone graft substitutes are indicated for vertebroplasty, osteomyelitis, fracture augmentation, fracture nonunion, and augmentation of defects occurring due to benign bone lesions. Many materials are commercially available for the fabrication of bone graft substitutes. For instance, ceramics and ceramic composites, collagen and mineral composites, demineralized allograft bone matrix, coralline hydroxyapatite, calcium sulfate and calcium phosphate cement, in addition to bioactive glass (Taljanovic et al., 2003). Bone substitutes have numerous forms such as powder, putty, pellets, and coatings on implants (Harvey et al., 2010). Bone graft substitutes are also engineered in the form of synthetic scaffolds that provide optimal conditions for cell adhesion, proliferation, and growth. They can incorporate diverse polymers, like hydroxyapatite, calcium phosphate, bioactive glasses, and glass-ceramics in various combinations and designs. New methods of manufacture have succeeded in the fabrication of nanostructured bone scaffolds that display excellent biomechanical and biocompatible properties, along with unique characteristics that allow for bone ingrowth, cell migration, vascularization, and extensive fluid transport. CNTs, helical rosette nanotubes, silver nanoparticles, as well as other nanotechnologies have been incorporated into nanocomposite scaffolds in pursuit of optimal bone graft substitution (Harvey et al., 2010). The promising aspects of bionanocomposites include the resemblance between their structure and natural bone geometry, as well as the incorporation of new

14.7 Applications

artificial materials that combine bone minerals with biocompatible materials. In addition, the nanoscale dimensions grant the biocomposites a high surface reactivity, strong interfacial bonds, large surface area, flexibility of design, and good mechanical properties. Integrating bionanocomposites with tissue engineering techniques involving cells and scaffolds, provides the potential of creating authentic bone grafts (Zhao et al., 2010). For a scaffold to be considered successful, it should be osteoconductive with a porous 3D structure that supports formation of new bone, diffusion of nutrients, and neovascularization (Patrascu et al., 2015). Nanocomposite scaffolds can incorporate single-walled CNTs to enhance the mechanical properties (Harvey et al., 2010). CNTs display exceptional toughness and flexural strength, hence their use as reinforcement material. They are also excellent for proliferation of cells (Ravichandran and Rajendiran, 2015). Helical rosette nanotubes (HRN) also have the potential to be used for manufacturing scaffolds and coating implants. They display a self-assembly that can modulate direct bone growth and prevent osteomyelitis. Helical rosette nanotubes are made of DNA base pairs that assemble themselves into stable nanotubes of 3.5 nm diameter in biological solutions. They are linked by hydrogen bonds, hydrophobic interactions, and base-stacking interactions. Helical rosette nanotubes have an helical geometry that mimics the structure of collagen in bone tissue. Incorporating different peptides, such as arginine-glycine-aspartic acid (RGD) and lysine, into the HRNs improves the function of osteoblasts. For instance, HRN coating on titanium implants enhanced the adhesion of osteoblast into the implant surface (Webster, 2008). In addition, the characteristics of the graft-bone contact surface have a crucial role in determining the success of graft-bone integration. The surface topography of the bone graft should be of similar roughness to the fracture surface in order to promote bone growth. Nanotextured surfaces have been proven to improve adhesion, induce metabolism, and release osteoinductive factors like growth factors and matrix proteins (Harvey et al., 2010). Another surface modification technique that improves graft-bone integration is the functionalizing of graft surface through the covalent immobilization of bioactive agents. A special coating, called biocatalytic latex, is 50% by volume microorganisms that form a film on graft surface. The latex emulsion preserves the cell by partial desiccation and forms pores as it dries. As a result, the living cell is entrapped and encircled by nanopores. These latex coatings have shown a great potential in osseous stimulation and antimicrobial action (Harvey et al., 2010). Other nanomaterial used to improve bone graft scaffolds includes silver nanoparticles as antimicrobial agents. Conventional implants exhibit a high risk of infections, which eventually leads to implant failure, even mortality. Therefore, it would be of great benefit if the scaffold biomaterial had an antimicrobial action. Chitosan, a polymer often used in bone grafts, has wound-healing and antimicrobial properties, as well as high metal-binding efficacy, especially to zinc, copper, and silver. Nanosilver has great antibacterial action against harmful pathogenic

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microorganisms. However, metallic copper has a better antimicrobial action than silver. Copper kills bacteria rapidly by severely damaging the bacterial cell membrane. Silver nanoparticles have a wide spectrum action against both grampositive and gram-negative bacteria. The actual mechanism of action is still unclear but the accumulation of silver in the tissues is known to cause disruption of bacterial cells. Silver can kill bacteria through a number of mechanisms; one is through the binding of silver ions to bacterial DNA preventing their replication, or to the sulfhydryl groups of their enzymes disabling cell respiration and the transport if vital nutrients. This usually produces reactive oxygen species that damage the cell structure (Saravanan et al., 2011). Other than nanosilver, nanoparticles incorporated in bone graft scaffolds include biologics and genes. Polymeric spheres are used to entrap growth factors that are released after the degradation of the polymer. In addition to polymers, hydroxyapatite, carbonate apatite, collagen, chitosan, alginate, and hyaluronic acid are used for encapsulation of biologics. The advantage of nanoparticles over microparticles is their ability to penetrate the tissues and cells in order to achieve accurate targeted delivery. This might aid the bone healing process (Harvey et al., 2010).

14.7.1.4 Spinal implants The purpose of a spinal prosthesis is to stabilize and treat an ailing spine. The success of the implant is greatly dependent on the material and, to a lesser extent, the mechanics. Osteoconductive properties are necessary to ensure proper fusion of an implant, which is crucial to achieve the needed clinical outcome of a spinal fusion (Martz et al., 1997). Titanium is used to manufacture most spinal implants like PEEK cages, orthopedic screws, and plates. PEEK devices have also been used during the last two decades; however, much like titanium, PEEK had low bioactivity. PEEK is a polymer of high mechanical strength, excellent imaging compatibility, good biological compatibility, chemical inertness, low toxicity, and stiffness closely matching natural bone. To overcome the problem of inadequate osseointegration and achieve high rates of bioactivity and bone infusion, osteoinductive and osteoconductive agents can be incorporated (Yang et al., 2015). Surface modification of spinal prostheses improves implant stability and osseointegration by interacting with the body to generate a bioactive layer at the implant-bone interface (Yang et al., 2015). For instance, surface modification of titanium implants increases both the on-growth and in-growth of bone. Initially, cells attach to the implant, adhere, and then spread through the material. Cell attachment can be improved by manipulating the surface roughness. Nanoscale surface modification increases the porosity and produces surface patterns that resemble natural bone, thus increasing the cell adhesion and differentiation. Increasing the porosity highly enhances the in-growth of cells (Rao et al., 2014). As mentioned earlier, the incorporation of bioactive agents like bioceramics can improve the chances of implant success. Hydroxyapatite is the most commonly

14.7 Applications

used bioceramic in orthopedic implants as it is very similar to natural bone. However, the mechanical properties of hydroxyapatite are not ideal for spinal prosthesis. This problem can be overcome by coating titanium implants with hydroxyapatite, thereby achieving high strength due to the titanium body, and good osseointegration, due to the hydroxyapatite layer on the surface. To achieve ideal results, hydroxyapatite nanoparticles are used in these coatings (Rao et al., 2014). Hydroxyapatite nanoparticles are also incorporated into PEEK implants to improve their biomechanical behavior, as well as their bioadhesion. In addition, nanophase titanium oxide can be added to PEEK implants to achieve enhanced osteoblast attachment and spreading (Yang et al., 2015).

14.7.1.5 Tendon and ligament prostheses Tendons and ligaments play a crucial role in joint stability and movement; therefore, any damage to them can affect the function of the joint and lead to degenerative disease. Tendon and ligament tissue is a dense, fibrous connective tissue connecting muscles to bones and bones to bones. There are two approaches for the management of tendon and ligament injury, be it chronic or acute. The first is a conservative approach. It provides pain relief through rest, injection of antiinflammatory agents, and orthotics. The surgical approach is based on surgically repairing damaged tissue or excision of inflamed areas. Tissue grafts are currently being used to restore the function of damaged tendons and ligaments; however, they may lead to mechanical mismatch, insufficient tissue integration, and laxity, along with the risk of rejection in the case of allografts (Rodrigues et al., 2012). The physiological environment of tendons and ligaments make it hard for a prosthetic device to fit in their position and mimic their action. Nevertheless, a number of prosthetic devices and tissue substitutes have been intended for use as replacement of damaged tendons and ligaments. For example, polytetrafluoroethylene (Gore-TexW), terephthalic polyethylene polyester (LarsW ligament), and polyester ethylene terephthalate (Leeds-KeioW). These products have displayed good results over short-term use, but the results of using them for a long period are still unclear and ambiguous, exhibiting a variety of complications. Although ligament prostheses displayed mechanical characteristics similar to those of natural human tissue, they were not adequate, as they exhibited complications of wear and degeneration. The mechanical properties of tendon and ligament prostheses are highly dependent on the mechanism of surgical fixation. Surgical fixation devices like sutures, staples, screws, and washers can decrease the stiffness and modulus of prosthetic devices. To date, no prosthesis has shown satisfactory results; therefore, autografts remain the first choice for primary tendon and ligament reconstruction (Rodrigues et al., 2012). Currently, the applications of nanotechnology in this field are limited to tissue engineering of biomimetic scaffolds (Chen et al., 2009). Some studies propose the use of polylactide/glycolidenanofiberous scaffolds to engineer tendon and

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ligament prostheses, with an improved collagen deposition and increased tenogenesis (Yang et al., 2013).

14.7.1.6 Dental prostheses In the dental field, prosthetic devices are used to replace missing teeth. The main requirements in dental prostheses are osseointegration and integrity of epithelial junction. Osseointegration is influenced by the surface characteristics of the implant, along with its chemical composition, and wettability. Nanotechnology has opened the chance to modify the surface features to control biological interactions and tissue integration (Y Pai et al., 2016). Nanoscale surface modification and calcium phosphate coating are applied to dental implants to improve their biocompatibility and stability. Like orthopedic prostheses, nanohydroxyappatite coatings were used to provide titanium implants with osteoconductive surfaces. Calcium phosphate coating was used to precipitate biological apatite nanocrystals, which promoted the incorporation of proteins and the bioadhesion of osteoprogenitor cells. This led to the production of the extracellular matrix of bones (Y Pai et al., 2016). Nanoroughness of the implant surface enhances the bone-to-implant contact and improves the healing of bone around the implant, leading to better osseointegration. In addition, titanium oxide nanotubes improved the production of alkaline phosphatase by osteoblastic cells on the surface of titanium implants. This led to better osteogenic differentiation and bone tissue integration (Y Pai et al., 2016). Prosthodontics, the branch of dentistry concerned with implantable prostheses, utilizes various types of nanomaterials to improve the properties of implant material, such as ceramics and cements, and enhance their durability and efficiency. For example, silver and platinum nanoparticles are added to polymethyl methacrylate as antimicrobial agents. Moreover, the addition of metal nanoparticles, such as titanium oxide and ferric oxide to PMMA materials increases the hydrophobicity and decreases bimolecular adherence (Y Pai et al., 2016). Nanoceramics have been used to revolutionize dental crowns. Conventional dental crowns are often made of alumina ceramic and zirconia ceramic. Traditionally, ceramics were made of clay and natural materials, whereas modern ceramics are made of silicon carbide, alumina, and zirconia. Nanoceramics made the dental crown tougher and more ductile than conventional materials. They also have excellent mechanical properties (Y Pai et al., 2016).

14.7.2 NEUROPROSTHESES Neuroprostheses are based on the principle of brain and machine communication, termed brain
machine interface (BMI). It involves processes like signal recording, interpretation, sensory feedback, and adaptation (Greevenbroek, 2011). Currently, only a limited number of neuroprosthetic devices are being commercially used, such as cochlear implants (Chhatbar, 2009).

14.7 Applications

Learning the mechanisms of the brain is crucial for the engineering of intelligent neuroprosthetic devices. However, even after all the research done on the functioning of brain, it still holds so many mysteries that scientists could not decipher to date. Another cause of difficulty in understanding this magnificent creation is the great variations between individuals, which is to be expected when observing how personalities and convictions differ from one person to another. These variations include structural differences in the sizes and connections of the different regions of the brain. Conversely, scientists have discovered that single neurons exchange information via electrical discharges that travel between neurons and accumulate, creating an action potential that leads to the firing of more signals (Greevenbroek, 2011). A BMI functions as a technological replacement of a biological signal modality. For instance, if there is a failure in communication between the brain and an extremity, a BMI neuroprostheses can connect them by reading the signals from the motor cortex, using them to control a robotic limb, then providing feedback to the sensory cortex in a closed-loop control system. Theoretically, this method allows thoughts to be converted into actions seamlessly and subconsciously, which indicates that any activity of the nervous system can be implemented by neuroprostheses. With this idea in mind, scientists have managed to apply this concept to cochlear implants, for the treatment of deafness; and retinal implants, for the treatment of blindness (Greevenbroek, 2011).

14.7.2.1 Cochlear prostheses Cochlear stimulation was first discovered by Allesandro Volta, who also invented the electric battery. The first cochlear implant that succeeded in electrical stimulation of the auditory nerve was created by Djourno and Eyrie´s. A modern cochlear implant is composed of a microphone, a speech processor, and a battery pack fitted in the ear shell. The sound is recorded, processed, and then communicated to an external transmitter, which, in turn, sends the signals into a receiver implanted in the skull. The receiver generates a current between the intracochlear electrodes and the reference electrode (Greevenbroek, 2011). Nanofibers and nanowires have been successfully used to improve the stimulation of auditory nerves in a cochlear implant. Creating electrodes that are made of nanofibers and nanowires provides the implant with an elasticity that allows it to take a curving shape. Moreover, nanofibrous electrodes exhibit an increased number of nanoelectrode brush-ends, thereby increasing the number of stimulating sites. Consequently, the electrode brush-ends are placed closer to their target nerve endings; this solves any problems that may arise from an electrode-nerve gap. In addition, CNTs and polymer composites are used to coat the electrode at the nerve ending
electrode interface to improve the conductivity (Aurora et al., 2010).

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14.7.2.2 Retinal prostheses A fully functional retina consists of photoreceptors that detect the light via photosensitive molecules at their outer segments. When subjected to light, the photosensitive molecules trigger a series of neurochemical events that stimulate ganglion cells to send signals to the visual centers of the brain. An inactive photoreceptor can cause the retina to lose its sensitivity to light; however, the remaining neurons can still be electrically stimulated (Weiland and Humayun, 2014). A basic retinal prosthesis is composed of a number of functional compartments, including an imager that converts light to electrical impulse, an electronic unit that processes the image and generates stimulating signals, and an array of microelectrodes that excite the retina. Wireless data and power transmission are also included in some retinal implants. Retinal prostheses are divided into three classes, according to the location of the functional electrode-nerve interface (Weiland and Humayun, 2014). Epiretinal prostheses, placed on the upper surface of the retina, include Argus I, GmbH (IMI) and the Epi-Ret Consortium (Epi-Ret). All these have wireless data and power transmission to avoid transcutaneous wires (Weiland and Humayun, 2014). Since the prosthesis is implanted on top of the ganglion cells, direct electrical stimulation is possible. An external camera is mounted on glasses to transfer image information wirelessly to an intraocular electrode (Lin et al., 2015). Subretinal prostheses are placed under the retina in the vacancy of degenerated photoreceptors. They can be either passive or active implants. An active system has an external power supply and has a subretinal chip that combines the photoreceptor and electrode array together. It is mainly driven by the surrounding light of the actual image. The incident light is communicated as an electrical impulse by an amplifier, which creates an electronic picture transmitted to an electronic cell that perceives the image in shades of gray (Lin et al., 2015). In a passive system, a subretinal prosthesis is activated by the incident light activating the photodiode arrays on a silicon disk, resulting in an electrical impulse that excites the retina (Weiland and Humayun, 2014). Passive implants are not currently used, as they do not provide a meaningful perception. Generally, a subretinal implant processes information in the inner retina; this allows a natural feel to the perception experience. In addition, they allow natural eye movement, unlike the systems that need a camera, where head movement is required to look at objects. So far, Alpha-IMS is the only subretinal prosthesis that has managed to reach human clinical trials (Lin et al., 2015). The third type of retinal implant is suprachoroidal prosthesis. These are placed between the sclera and choroid, by making an incision in the sclera, and placing an electrode in a position that keeps the exposed electrode contacts directed towards the retina. Another electrode is situated in the vitreous cavity. However, this type of prosthesis requires the aid of a camera to guide the patients (Lin et al., 2015).

14.7 Applications

Many nanostructures are used for the improvement of retinal prostheses. Generally, they showed good cell-implant interaction, improved structural integrity, and high biocompatibility and stability. Decreasing the size of prosthesis by using nanoscale materials will improve the biological compatibility of the implant; reducing tissue injury and inflammatory reaction. Nanoscale resolution can be guaranteed by the application of nanostructures including nanoflakes, nanocrystals, nanoparticles, and nanowires. Good communication between electrode and neuron is crucial for high-resolution perception. Neural electrodes are usually made of gold, platinum, and titanium compounds. Nanoporous electrodes, made by electrochemical methods to form a porous platinum film, displayed an increased specific surface area and lower impedance. Moreover, nanopores increase the mechanical stability for long-term implants. Gold nanostructured electrodes have also shown better neural signaling and electrical performance. In addition, microelectrodes can be modified to design a flake nanopattern on the surface of gold electrodes in order to increase the effective surface area, decrease electrode-electrolyte interface impedance, and improve clarity of vision (Ghaffari et al., 2016). Nanoparticles, both semiconductors and metals, showed good optical sensitivity, a broad-spectrum absorption, and narrow excitation spectra. Optically excited nanoparticles can influence voltage-gated ion channels in neurons; this leads to either the initiation or the suppression of an action potential. Cadmium sulfide quantum dots produced an electrical field of sufficient strength to excite ion channels (Ghaffari et al., 2016). Nanowires have proven to be useful for neural stimulation purposes. Using nanowire microelectrodes in retinal implants enables precise control over the nature of stimulation as they provide high aspect ratio as well as high surface area. They also integrate well with biological tissue, as their dimensions are similar to those of natural nanostructures (Ghaffari et al., 2016). Coating metal electrodes with nanomaterials such as CNTs, polymers, and hydrogels, greatly improves biocompatibility and reduces electrode impedance. Polymers exhibiting loose structure provide high mechanical modulus match, thereby decreasing tissue injury and inflammation. Examples of these polymers are: polypyrroles, poly(ethylenedioxythiophene), and parylene. These are often made of nanoparticles, nanowires, nanotubes, and nanofibers (Ghaffari et al., 2016). Nanostructures having a carbon base, such as CNTs and graphene, have the potential to improve neural electrodes. They display a large surface area, excellent conductance, and the ability to decrease electrode impedance. They also have a flexibility that can aid in engineering a seamless integration circuit. Furthermore, nanocrystalline diamonds, as well as ultra nanocrystalline diamonds, were used as an electrically insulating sheath over the electrode to keep it close to the retina. The space between electrode and neuron should be kept to a minimum, in order to achieve sufficient electrical stimulation of ganglion cells (Ghaffari et al., 2016).

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14.7.2.3 Motor neuroprostheses The purpose of motor neuroprostheses is to achieve cognitive control over an artificial limb. The purpose of a motor neuroprosthetic device is quite different from neuromuscular stimulation device, as the latter stimulates actual muscle while the former links the brain to an external prosthetic device (Turner, et al., 2005). This can only be achieved by creating a connection between the central nervous system and the prostheses, and effectively integrating sensory and motor impulses. This concept was practically realized through brain
machine interfaces (Carmena, 2013). Brain
machine interface neuroprosthetic devices function through a series of steps, starting with real time signal detection via a sensor, then signal transmission to an actuator that will perform the task intended by the first signal. The sensor detects the signal by measuring a certain physiological variable, e.g., the electrical signals and action potential of neurons. It could be achieved through signal detection of individual neurons, known as single-unit recording; or multiple neurons, known as multiunit recording; local field potentials; or several square centimeters of cortex, as in electrocorticography and electroencephalography. Signal detection on both low and high levels is necessary for the construction of a clear, well-detailed control signal. After the sensor detects the signal, it interprets it according to the nature of the signal, its location, and the time of recording, relative to the action time. The next step is to send command signals to nerves, muscles, or even a computer interface of a robotic extremity. A feedback signal is then sent to the brain to fine-tune the action and compensate for any errors that may occur during the execution of the command (Greevenbroek, 2011). To understand the flow of electrical signals, principles of neural decoding and interfacing must be explained. Decoding is a crucial step for a prosthetic device in order to understand and translate a brain signal. A decoder is a device that records neural signals via electrodes and recognizes signal patterns that are then interpreted using multiple mathematical functions. Decoding of neural signals gives rise to cognitive control over paralyzed limbs or prosthetic devices, although gaining control over paralyzed limbs is still far from reality (Vidal et al., 2016; Pedreira et al., 2009). Many upper limb prostheses have been successfully manufactured and utilized, including Luke-Arm, developed by Deka; Modular Prosthetic Limb, developed by John Hopkins Applied Physics Laboratory; and the German Prosthetic Arm, developed by Otto Brock Healthcare. However, lower limb prostheses still do not have adequate evidence of their safety and effectiveness. Examples of lower limb prostheses include Power Knee and Foothill Ranch (Greevenbroek, 2011). To achieve a seamless integration of prostheses and the human nervous system, nanoscale techniques must be applied. For example, since neurons function at the nano level, the application of nanomaterials is essential to enable the

14.7 Applications

designing of a fully functional brain
machine interface. Nanotechnology is incorporated into neuroprosthetic devices through various nanostructures such as nanoparticles, nanowires, CNTs, nanobiomaterial coatings, and nanodevices (Kotov et al., 2009).

14.7.3 CARDIOVASCULAR PROSTHESES 14.7.3.1 Artificial heart valves Prosthetic heart valves are of two types: mechanical and biological. Both types function passively, opening and closing in response to pressure difference and flow changes in the heart chambers. The general appearance and action of prosthetic heart valves is quite similar to natural heart valves. Mechanical heart valves are engineered from rigid nonphysiological material, whereas biological heart valves are made of flexible tissue and synthetic material. Currently, biological heart valves can be made of porcine aortic valves or bovine pericardium (Butany, 2005). Many types of cardiac valvular replacement devices are used currently, including caged-ball devices like Starr-Edwards ball-in-cage prosthesis, caged disc prosthesis (Beall valve), tilting disc valves (Bjork-Shiley valves), and bileaflet tilting disc valves (St Jude Medical valves). Other types include tissue valves (Medtronic or Hancock porcine valves), porcine, or pericardial valves (Carpentier-Edwards valves) and many other devices (Butany, 2005). Mechanical heart valves are made of synthetic material, which tends to be highly thrombogenic. Pure titanium, chromium cobalt, and graphite are used for the manufacture of mechanical heart valves. They are composed of three major compartments. The first is the occluder, which could be a ball or a disc. The second part is the superstructure that keeps the occluder in position. The valve base is the third part and it has a fabric-sewing ring, used to hold the valve in place (Butany, 2005). Biological heart valves, also termed bioprosthetic heart valves, tissue valves, or xenografts, have a structure and shape similar to that of a native aortic valve. The only difference lies in that a biological heart valve is attached to a prosthetic frame. Bioprosthetic heart valves are divided into two classes: heterografts or xenografts, such as porcine aortic valves or bovine pericardial valves. The second class is homografts or allografts, e.g., the aortic or pulmonic valves extracted from human cadavers. Autografts are a new alternative to these options, whereby the patient’s own pulmonary valve is used. The process involves excising the pulmonary valve then grafting it into the aortic root, and then placing a homograft in the pulmonary site (Butany, 2005). When a heart valve becomes too rigid, it becomes difficult for the heart to pump blood sufficiently, thus leading to high blood pressure and possible myocardial infarction. Utilizing nanorods to alter the structure of a valve has proven to

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be useful to solve this problem, as well as many complications of prosthetic heart valves (Duckworth and Kirkham, 2010).

14.7.3.2 Artificial myocardium A new application of nanotechnology is the manufacture of a nanosized artificial myocardium. An artificial myocardium is used to assist the pulsation of the heart and is placed on its external surface. It involve the use of nanosized sensor, control chip and an actuator. A nanofilm sensor that utilizes diamond-like carbon was successfully developed. In addition, another nanosensor that uses optical fibers was designed and passed the animal experiment. A nanosensor controls the hemodynamics of an artificial heart, thereby increasing the life expectancy of patients. Nano actuators are not yet successfully developed but once they are, they can be applied to many organs (Yambe, 2008).

14.7.4 CEREBROSPINAL FLUID DRAINAGE SYSTEMS CSF, having a volume of 150 mL, is encompassed in the brain ventricles (25 mL) and subarachnoid spaces (125 mL). The CSF circulates from its secretion sites to its absorption sites under the influence of arterial pulse waves, respiratory waves, posture, and jugular venous pressure. The drainage of CSF is mainly achieved through the arachnoid villi, cranial, and spinal nerve sheaths, the cribriform plate, as well as cerebral arteries adventitia. Normally, the CSF is renewed about four times in a day, however, the rate of turnover decreases as the person ages, leading to an increase in the levels of catabolites and waste products in the brain. This is usually the basis of a number of neurodegenerative diseases. The CSF serves as the hydromechanical protection of the brain and spinal cord. It also influences the development and regulation of the central nervous system and the activity of neurons, as well as the homeostasis of brain interstitial fluid (Sakka et al., 2011). The circulation of CSF is based on the balance between secretion and absorption. The choroid plexus is mainly responsible for the secretion of the CSF. The two major routes for drainage of the CSF are the arachnoid villi route, taking place in the wall of venous sinuses; and the lymphatic drainage route, mediated by olfactory mucosa and cranial nerve sheaths, including optic, trigeminal, facial, and vestibulocochlear nerves. The epidural venous plexus and spinal nerve sheaths mediate the drainage of the CSF into the lymphatic system in the spinal subarachnoid space (Sakka et al., 2011; Pollay, 2010). Any disturbance in the balance between secretion and drainage results in disturbances in the cerebral physiology and disorders of CSF hydrodynamics, resulting in dementia and hydrocephalus. Hydrocephalus is a condition of high intracranial fluid volume, caused by obstruction of drainage system (Sakka et al., 2011). The treatment of hydrocephalus involves the implantation of prosthetic shunt systems. A simple shunt system, like the ventriculoperitoneal shunt, consists of

14.7 Applications

three compartments: a ventricular catheter, made of silicon rubber and placed into the ventricle; a valve, placed between the skull and scalp and used to regulate the CSF flow and pressure; and a peritoneal catheter, used to transport the CSF into the abdominal cavity where it is reabsorbed. A prosthetic shunt remains inside the body of the patient for a lifetime. This gives rise to a variety of complications like blockade and infection (Spiers et al., 2010). The more modern form of a prosthetic shunt is the Programmable Automatic Shunt System. This shunt system is made of a valve, a number of microelectromechanical system (MEMS) sensors, and a microelectronic signal-processing unit. The structural design consists of an implanted coil antenna that transmits information about pressure and flow to a unit that, in turn, adjusts the CSF drainage valve. Control of the valve can be via the input of a neurosurgeon or the internal feedback of a smart system, which is the case in smart shunts (Ferrari et al., 2007). Nanotechnology is involved in the improvement of all compartments of a shunt system. The catheter can be improved by the incorporation of nanotube bundles. The CNTs will work as a filter for the CSF as it enters the shunt through an adjustable valve, keeping out any bacteria or proteins that might block the catheter. This will prevent the complications of infections and blockade; therefore, the risk of shunt malfunction is reduced and the need for additional surgery to replace a faulty shunt is avoided. The overall shunt system would still be the same; therefore, the surgeons will not need additional training (Spiers et al., 2010). Another possible modification to the shunt system is designing an entire catheter made of nanotubes. The downside of this approach is that each nanotube will need a valve of its own to control the drainage of CSF. This problem can be overcome by the manufacture of novel nanovalve systems. However, nanovalves operate by responding to alteration in the pH of the surrounding medium. Since the local pH of the CSF remains constant, nanovalves are not effective in shunt systems at the current time (Spiers et al., 2010). A Programmable Automatic Shunt System can be modified by utilizing (bioNEMS) nanoelectromechanical system instead of its MEMS sensors. Nanoelectromechanical system sensors have demonstrated single molecule sensitivity in biomedical studies. BioNEMS are capable of interacting with an extremely low portion of analyte and generating a response in a short time. Given their nanoscale size, bioNEMS can perform force measurements locally and with very small samples (Roukes, 2000).

14.7.5 PLASTIC AND RECONSTRUCTIVE PROSTHESES 14.7.5.1 Breast augmentation The treatment of breast cancer usually involves partial or complete removal of the breast. This exerts harmful physical and psychological effects on the patient.

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Therefore, reconstructive breast augmentation has become a common procedure to improve the aesthetic and emotional condition of patients. This is usually done through implantation of a synthetic prosthesis, because it requires less recovery time. Breast implants are of three types: silicone gel-filled, inflatable saline-filled, and dual lumen gel/saline-filled, all of which have been approved by the FDA. The implant is often covered by a polyurethane coating layer to improve its appearance and anchor it in place (Gurgacz et al., 2013). Studies have proved that designing nanotopographical features on the surface of the implant improves the biointegration by suppressing the immune response towards a prosthetic breast implant. Furthermore, surface nanotopography helps in anchoring the implant to its place (Salehahmadi and Hajiliasgari, 2013). Artificial skin is also used to enhance the appearance of the breast prosthesis. Nanofibrous scaffolds are used in the engineering of artificial skin, to provide an aesthetic appearance after breast augmentation (Ver Halen et al., 2014). In addition, a common problem that occurred with conventional breast implants is leakage and rupture, which can be overcome by incorporating nanocomposite polymers that will improve the mechanical stability and biocompatibility of implants (Tan et al., 2016).

14.7.5.2 Craniofacial reconstruction Prosthetic facial rehabilitation is usually required after tumor ablative surgery for craniofacial cancers. In ancient times, wax was used in designing artificial facial prostheses. Currently, craniofacial prosthetic devices are often made from polymethyl methacrylate and urethane-backed medical-grade silicone and backed up with skin adhesives, skin loops, or even glasses and magnets (Lemon et al., 2005; Dostalova et al., 2011). Nanomaterials are used in engineering craniofacial replacement grafts. In addition to nanomaterials, nanorobots are used during craniofacial surgery to perform precise processes at the nanoscale and aid in maxillofacial hard tissue repositioning. Furthermore, quantum dots are used for imaging of tumors (Ver Halen et al., 2014).

14.8 ETHICAL ISSUES Since the beginning of civilizations, laws and regulations were made to govern most aspects of life, but there are always few foggy areas of ethical dilemma, which cannot be covered by these rules. Accordingly, moral and ethical obligations surfaced to guarantee the welfare of people, and where would it be most needed, if not in patient healthcare. With the high hopes and prospects for reinforcing the involvement of nanotechnology in bionics and prosthetics for a wide range of biomedical applications,

14.8 Ethical Issues

comes many ifs. Questions such as, the potential to extend their use beyond patients of neural dysfunctions and amputees; or, are there any enfolded facts about these devices that are unethically withheld from the free willing, fully informed, consenting patients? Or the question of would it be morally unacceptable to deprive the patient his right to choose the course of treatment he finds suitable if clinical judgment of the physician declare them undesirable? (Gilbert, 2013). Additionally, since cost and accessibility influence the chances of receiving these implants and prosthetics, can we ensure justice and equal opportunities? (Brey, 2005; Frumento et al., 2010). In order to explore this further, we need to address the following concerns.

14.8.1 SAFE USE: BENEFITS VERSUS RISKS Since safety is a prerequisite in any healthcare services, considering safe implantation and use of nanobionics and prosthetics becomes ethically essential. In spite of all the in vitro, animal tests, and clinical trials conducted and confirming safe use, the risk accompanied with it remains real and individual. There is a constant possibility of them being unsuitable, causing side-effects, or even complete rejection of implantation (Brey, 2005). With that being so, how do we proceed from here? Should we ignore those revolutionary advancements out of fear, or do we go ahead regardless of risk?

14.8.2 JUSTICE There are plenty of legislations and guidelines constituting the criteria for a candidate to receive an implant or a prosthetic. Most of which are medically based on the condition of the patient, which sounds fair. This criteria neglects important factors that establish a barrier to patient care, such as cost, accessibility, adaptability, and training (Frumento et al., 2010). Is it equitable that only few can get the best quality devices and services just because they are financially able or have direct and easy access to centers that sell, set up, and provides training? Should patients pay more in case of immune system reactions against the implantable device, and more for higher quality ones that don’t generate such reactions? And are manufacturers supposed to produce devices for individualized specifications? (Brey, 2005).

14.8.3 IDENTITY, PRIVACY, AND ACCOUNTABILITY When prosthetics are introduced to people’s life, everybody is concerned with the amelioration they provide and overlook the part where people need to accept that prosthetic as a new piece of them. They must live with the fact that they depend on an artificial technology for the rest of their life. This is most likely to be noticed with neural prosthetics, due to the cognitive function and personality

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changes it can produce (Gilbert, 2013). Some neural implants can improve memory and others may control mood; they might change the identity of the patient. This raises important questions: Is it tolerable to have access to one’s memories and emotions? Is it alright to share data obtained from your body with other third parties? Does such access violate people’s right to privacy? Under these circumstances, if a patient with cognitive prostheses committed a crime or felony, will he/she be accountable before the law? (Brey, 2005; Erden, 2016).

14.8.4 AUTONOMY Self-government, or the freedom to one’s own actions, is how the dictionaries define autonomy. Yet, being autonomous among the norms implies being able to take care of oneself; nanobionics and prosthetics offer great promise in this area. When deaf people use cochlear implants, they restore the sense of hearing, thus becoming capable of taking care of themselves. The same goes with amputees that utilize a prosthetic limb, but with neural implants comes the concern. If thoughts and perception are affected by the employment of such devices, can a person still be considered autonomous? Which is more ethically valuable, the person’s autonomy or human race transformation? (Brey, 2005; Erden, 2016).

14.8.5 VALIDITY OF INFORMED CONSENT Technically, there are pillars of informed consent that must be available prior to any experiment or clinical trial to legally approve utilization of data obtained. They include being a noncoerced volunteer with physical, mental, and emotional competency to evaluate merits and demerits of the given procedure. Yet, are these pillars sufficient to accept the informed consent? Let us observe the following scenarios: (1) Many people went through plastic surgeries that enhanced their appearance using what is known as Botox, consciously disregarding the fact that this material is a bacterial toxin that may result in several side effects and dangers when injected into human body; (2) Large groups of people are also encouraged, through media and advertisements, to favor special techniques over others. Directing the conception of an audience toward an area of interest is something that isn’t new to media, but at the same time it can’t be taken as irrefutable evidence. These kind of behaviors in which people are running after quick positive effects, regardless of the long-term consequences; or being already preconditioned to endorse a procedure under influence of media, makes us question the validity and legality of a given informed consent and the need of expanding the borders of approval in this field (Gilbert, 2013).

14.9 Safety Issues Pertinent to Nanobionics and Prosthetics

14.8.6 PROBLEMS OF AMBITION: TREATMENT VERSUS ENHANCEMENT Are nanobionics a course of treatment or a form of enhancement? Answering this question determines the need for employment and development of this new technique, but it also requires an insightful moral reasoning. We can begin with differentiating between both concepts. Treatment merely describes the actions taken to recover health and prevent illness, or any anticipated complication. Defining enhancement, on the other hand, is a bit more complicated, as it can be viewed in both philosophical, ethics-oriented terms and scientific outcomesoriented terms, which discard ethical values (Gilbert, 2013). Estimating the requirement of upgrades in nanobionic devices might become confusing when we differentiate between treatment and enhancement; this confusion ends by asking the right question. We cannot deny the fact that any kind of treatment always strives to enhance a certain circumstance. The real question lies in: Can we consider all enhancements as a form of treatment? In cases of amputees using prosthetic limbs or deaf people using cochlear implants, it is an enhancement of patient’s quality of life which clearly complies with treatment goals. Whilst in other cases, like using neural implants to alter cognitive and physical functions without being therapeutically indicated, they do not constitute a form of treatment. A good example addressing this issue is the military programs for human augmentation. The idea of creating super invincible soldiers with implants, drugs, genetically designed muscles, and generating cyborgs is brilliant, but it isn’t treatment, which reveals that all treatment portrays enhancement but not necessarily vice versa (Brey, 2005; Gilbert, 2013). Another problematic issue linked to neural implants is the optimistic speculations neuroscientists have in this regard. With the rise of attention on the modifications of brain functionality, neuroscientists become more fascinated with idea of developing cognitive traits rather than understanding the brain in essence. Their area of interest is drawn away from changing the brain from an unwanted state and more towards creating a supernatural ideal brain. Do they have the right to be ambitious in changing the human limited potentials and transforming us into more capable, superior organisms in this way? Do such enhancements comply with rules of nature? And are there any consequences to these advancements? (Gilbert, 2013).

14.9 SAFETY ISSUES PERTINENT TO NANOBIONICS AND PROSTHETICS Generally, medical devices should be designed and manufactured in ways that ensure patient safety and well-maintained clinical condition, when operating

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normally for their intended purposes. However, safety is such a relative term. Every device contains a percentage of risk that ought to be assessed in preliminary stages. Devices on nanoscale are the novel technology in focus, promising great advancement in the treatment of sensitive cases and replacement of function losses. Regardless, the risks that can be associated with these tiny structures cannot be controverted. In general terms, risks can be categorized into four classes of risks (Renn and Roco, 2006): 1. Simple risks: characterized by direct, obvious, causal relationship between cause and effect. In other words, the effect is merely attributed to the suspected cause. 2. Complex risks: in this situation, the cause-effect relevance is present, yet, it is difficult to measure and quantify. The difficulty can refer to a host of reasons, like interactive impacts, long lag time between cause and effect, interpersonal variations, or foreign variables. 3. Uncertain risks: uncertainty of the risk points to the involvement of human knowledge, which is always limited and picky, and leans towards predictions and assumptions. If any cause-effect connection is established, the human knowledge intervention will only weaken the confidence initially demonstrated. 4. Ambiguous risks: risks under this category are vague and doubtful, due to two reasons: either there are numerous rational interpretations based on observation and results; or there are variable standards of evaluation to take effects into account, and those are based on the investigator’s opinion. Therefore, when we look into sources of risks using nanobased implantable medical devices, we can find several safety-compromising factors at levels of development, manufacture, packaging and labeling, advertisement, sale, use, and disposal (WHO, 2003). Here, we are more concerned with the risk corresponding to the actual application of the nanobionic device in the human body, which can be traced to either the device itself, or the device as a nanosized entity. The device is constructed from electrodes, a circuit, and other electrically wired components. Unlike large prosthetics, these nanodevices don’t possess external control. Ventimiglia mentioned in his report that one of the design requirements is to ensure safety during conditions of working and failure of the device. He stated that the movement of actuators must be paused in case of control signal loss; that when a battery’s power is low, an LED light notifies the consumer; and, finally, that there must be software and mechanical limits preventing undesired joint movement (Ventimiglia, 2012). In Weir’s chapter on Design of Artificial Arms And Hands for Prosthetic Applications, he highlighted the vital role of manual or current sensing switches, supported with mechanical stops to protect from any unintended motion or any drive burns following (Weir, 2004). This privilege isn’t granted in nanodevices, since they are implanted inside, with no chance of external manual control.

14.10 Conclusion

Consequentially, they become prone to software and hardware malfunction, technical deficiency in cases of battery power exhaustion, and therapeutic misconfiguration (Gupta). During clinical trials for cochlear implants, it was reported that deep insertion of the electrodes can raise complications of destroying the remaining hair cells. It was salvaged later when combined with drugs as a vigilant measure, but that still leaves significant concerns regarding the implantation of other nanobionics and prosthetics to take place in the future (Liu et al., 2013). Another problem acknowledged is the threat to unsecured privacy of related data. In neural cognitive implants, there are considerable data actions that must remain within control of two parties: the patient and the healthcare professional. Data access, accuracy, update, and device identification and settings must be controlled by the aforementioned parties if not by the monitoring healthcare professional alone. Any leakage of data jeopardizes the safety of the patient (Halperin et al., 2008). As a nano entity, the major peril lies within their capability to penetrate biological membranes and interactions with subcellular moieties. Multiple studies confirmed a link between nanosystems and DNA impairment, with further aggravations in embryos that were frequently fatal (Castan˜o et al., 2014). Eventually, the question of whether nanobionics and nanoprosthetics are safely used for their intended purposes is merely relative when employing such delicate technologies for replacement or enhancement of a body function. Weighing the risks and balance becomes essential in these cases. To fully depend on them, such judgments should be made by higher authorities and regulations should be clearly stated once they are officially approved.

14.10 CONCLUSION Through the mid-20th century, nanotechnology built a bridge towards the world of prosthetics to synthesize nanoengineered prosthetics, which revolutionized the way prosthetics can compensate for lost body functions or damaged organs. It is remarkable how marvelous advancements can be made by few manipulations at nanoscale. Nanoprostheses have proven to offer better biocompatibility, durability, strength, integration, wear resistance, and other outstanding qualities. The broad spectrum of nanobiomaterials with their diverse natures, chemical compositions, morphology, thermal, and electrical conductivity can be invested to serve multiple purposes. Various biomedical applications require various types of nanobionics and prostheses. They are readily available in the market as orthopedic, dental, cardiovascular, neural, ophthalmic, and cochlear implants. Continuous and persistent efforts are maintained to keep exploring modern and advanced techniques, and materials that can help reach the ultimate goal of human wellness.

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Further Reading

World Health Organization, 2003. Medical Device Regulations: Global Overview and Guiding Principles. WHO Library Cataloguing-in-Publication Data, Geneva, pp. 3
8. Yambe, T., 2008. Artificial organs with nanotechnology and development of the new diagnosis tool. Annals NanoBME 2, 167
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385. Yang, G., Rothrauff, B., Tuan, R., 2013. Tendon and ligament regeneration and repair: clinical relevance and developmental paradigm. Birth Defects Res. Part C: Embryo Today: Rev. 99, 203
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FURTHER READING Good Samaritan Hospital orthopaedic center of excellence, 2009. Guidelines For Total Joint Replacement Patients. Gupta, S. Implantable Medical Devices
Cyber Risks and Mitigation Approaches. http://csrc.nist.gov/news_events/cps-workshop/cps-workshop_abstract-1_gupta.pdf (accessed 15.07.16.).

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