FormalPara Core Messages
  • Nanotechnology revealed that organic structures have different physical, chemical, and biological features in macroscopic and nanometric forms.

  • “Nanomedicine” emerged as a new scientific area in nanotechnology and makes important conceptual changes in medical methods all over the world due to the different diagnostic and therapeutic alternatives.

  • The use of nanomedicine in otorhinolaryngology is very important to meet the changing and increasing expectations of health.

  • Today, the main three areas of experimental and clinical studies related to nanomedicine concentrates:

    1. (a)

      Nanotechnology-based imaging and diagnostic methods

    2. (b)

      Targeting delivery systems

    3. (c)

      Regenerative nanomedicine

39.1 Introduction

Developments in nanotechnology have revealed that macroscopic and nanometric forms of organic structures possess different features in physical, chemical, and biological aspects. By proving that nanodevices which are produced at the laboratory can interact with biomolecules, both physiological processes in healthy tissues and physiopathologic basis of diseases began to be understood in a more clear way.

Nanomedicine” which appeared as a new scientific interest parallel to the above-mentioned developments in nanotechnology became one of the most studied topics in the world by the reason of the fact that it leads conceptual changes in accepted and applied medical methods up to now and presents different diagnosis-treatment alternatives.

Although nanotechnology is a commonly studied field all around the world, there is still no clear consensus about what nanoscala really is. One nanometer is calculated as one billionth (10−9). It is possible to fit 5 carbon atoms in this scale as in three-dimensional forms. According to BSI (PAS 71) applications, less than 100 nm or even smaller scales are evaluated within the concept of nanotechnology. While at the beginning of 2000s, studies less than 200 nm and in smaller scale were considered as nanomedicine, today this range is accepted between 5 and100 nm.

Otorhinolaryngology is one of the basic disciplines of medicine which closely follows and implements medical innovations and advancements. In this regard, otorhinolaryngology is one of the leading areas which heavily utilizes microscopic and endoscopic treatments. Nowadays, treatment and rehabilitation methodologies like vocal prosthesis, cochlear implant, and brainstem implants are the top and best-known implementations examples of the micro-nanocircuits.

Nanomedicine will offer significant opportunities in meeting the treatment expectations of the otolaryngology patients with the new and advanced nanomedical diagnosis and treatment technologies in coming years. Such treatment solutions with advanced technologies will offer important treatment solutions for many different types of medical problems from hearing loss to facial paralysis, from nasal plastic surgery to early diagnosis and treatment of the head and neck cancers.

39.2 Clinical Nanomedicine Perspectives

Currently the most important aim to approach patients and diseases is to diagnose, if possible, when pathologic change is only at single-cell level and to start treatment. However, this could only be possible by increasing the efficiency of in vivo and in vitro diagnosis methods. Although nanomedicine is a field presenting great opportunities in this regard, it also brings along disadvantages because it is a new developing discipline.

Regarding the literature, it is possible to come across a wide range of research topics from the discovery of new nanobiomaterials to using these materials in clinics. While searching for physical, chemical, and biological principles for nanomaterials on one hand, on the other hand it is attempted to be understood how to use these materials on living creatures and what could be the adverse effects caused by the use of these materials and effects of nanomaterials on human health and environmental health. In addition, possible social and legal problems have been discussed and new ethical rules have been introduced.

A certain part of the studies is more in details, more specific, and more focusing on developing safer diagnosis devices. Also, there are studies for performing different biological measuring methods with one integrated device. By means of very precise biosensors which are tried to be developed with the use of nano-electronic circuits, it is attempted to establish micro-mobile laboratories which can be easily used by patients and, if necessary, can transmit multiple data to external user.

The other research topic in the related literature which requires advanced technology is about the combination of above-mentioned in vitro monitoring techniques and in vivo nanomedical devices. In those studies conducted within this regard, it is basically tried to be developed nanostructures which are able to carry specific contrast substance and be directed from the outside. Thus, it will be possible to take detailed molecular image of target tissues.

In another conducted group study, it is researched how to combine these nanostructures with pharmacological agents. By means of nanostructures which carry therapeutic and diagnostic agents at the same time, especially in cancer cases, it would be possible to administer a treatment on target tissue directly. With this approach defined as theragnostic (therapy + diagnose), again primarily for cancer patients, it is aimed to follow up efficiency of the treatment by taking the images of the target tissue at different times.

Lastly, it has also been conducted intense studies on successful regeneration of diseased or injured tissues by means of nanografts and reproducing needed artificial organs by means of nanoscafolds in in vitro conditions and then replacing diseased or injured organs with the artificial ones.

Methods which have been developed by using nanotechnology have potential to be effective on all medical equipments. For example, developing new materials to be used in surgical implants, nanometric systems or minimal invasive sensors which can be used in monitoring metabolic activities can be considered within this regard. Nanopumps, injectable/implantable polymer systems, liposomal drug applications, and cell/gene therapy methods can be considered with regard to developed-controlled drug delivery systems (Wei et al. 2006). Currently half of the improvements related to new molecules all around the world are made by biotechnology companies. Therefore, over 4,000 companies in the world which work related to drug delivery systems, diseased part targeted therapy methods, drug carrying implants- patches and gels (Flynn and Wei 2005).

39.3 Interdisciplinary Frameworks

All those efforts for understanding the development of disease at molecular level and for treatment are very important to spread all the developments in nanomedicine to the society. Since the topic has a wide scale, different disciplines have to work together in nanomedicine area. It can be said that for now, neither any scientific field nor areas of expertise possesses capacity of scientific and technical infrastructure to conduct such a research by itself. To manage scientific research in such a field, it is a must to establish a well-organized “team.” Within such team, conventional disciplines, such as basic-clinic medical scientists, pharmacologists, and physics-chemistry-electric-electronic-biomedical-computer engineers, and new fields, such as genom-proteom science, pharmacokinetic modeling, and microscope designing, should be included.

In addition to the self-disciplinary nature of nanomedicine, the more the number of studies increases in this field, the better new subdisciplines appear. Some of these subdisciplines are mentioned below and many studies have been conducted on each specific topic:

  • Imaging: molecular, vascular, neurological, etc.

  • In vitro diagnosis

  • In vivo diagnosis and biosensors

  • Advanced biomedical materials, including “smart”

  • and functionalized materials and surfaces

  • Regenerative medicine and tissue engineering

  • Infection control

  • Drug design and targeted drug delivery

  • Gene and cell therapy

  • Man–machine interfaces

  • Nanotoxicology

  • Nanomedicine and risk management

  • Nanomedicine and ethics

39.4 Clinical Nanomedicine Applications

Today, big scaled centers which conduct experimental and clinical studies are focused mainly on three fields (Strategic Research Agenda forNanomedicine, ETP-NM 2006).

39.4.1 Regenerative Nanomedicine

Current “traditional treatment” approaches lead to have limited results in many diseases or cause success of training to change from patient to patient. Both for improving the efficiency of the treatment and minimizing the side effects, methods to be used should be patient-specific characteristics.

As a result of “tissue engineering” studies, it has been started to form the basis of patient-specific treatments which can be used in regeneration and reparation of in situ tissues.

Main implementation fields of tissue engineering, which is an interdisciplinary field, are maintaining, improving, and repairing the functions of biological structures through collaboration of engineering and life sciences. By means of tissue engineering, future therapy methods will be more focused on treatment of chronic disorders by the use of self-healing mechanisms of the body than targeting symptoms or reducing the development of diseases.

It is possible to evaluate regenerative nanomedicine studies into two topics as therapy and biomimesis. Therapy

Within the scope of regenerative nanomedicine, studies have been conducted on protecting from such pathologies as diabetes, osteoarthritis, cardiovascular system diseases, and degenerative central neuronal system diseases and therapies for related disorders and functional loss after injuries. Regeneration of cartilage in an articulation with osteoarthritis, production of mechanically stable and elastic scaffolds, vascularization following implantation, and creating a physiologic oscillation in diabetic pancreas islets or starting self-reparation mechanisms in heart and nerve system are the other examples to give.

Both in terms of mortality-morbidity rates and prevalence, there have been more intensified researches on some certain disease groups. This is also the case for clinical studies within the scope of nanomedicine. The most researched diseases are primarily cardiovascular diseases, cancer, musculoskeletal disorders, neurodegenerative diseases, diabetes, and bacterial-viral infectious disease. Cochlear Implants

There are many studies for the utilization of nanosystems in transmission of neural stimulants. Among those, cochlear and brainstem implants are the top areas to be implemented in clinical use. Nanotechnology offers significant alternative treatment opportunities in increasing hearing performances of the patients with sensory-neural hearing losses.

In this context, it is expected to see significant advancements both in increasing the technologic performance of the implants and in improvements in surgical implementations. This way, less invasive and more effective methods could be applied in treatment of patients with hearing loss. For example, using thin-film electrodes that have been manufactured by a study conducted at the University of Michigan, it is now possible to process sound from 128 different channels in comparison to standard 16–22 channel implants (Fig. 39.1). This, as a result, allows transmission of acoustic information with higher-quality frequency, amplitude, and pitch variables to the auditory cortex of the brain. This provides an opportunity in treatment of infants with hearing losses using high-quality acoustic stimulants. Nowadays, this system is in research phase on guinea pigs and cats, and in the coming years, it is expected that production of devices suitable for human use will be possible.

Fig. 39.1
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Thin-film electrodes process to the sound from 128 different channels in comparison to standard 16–22 channel implants (Source: Design an Artificial Nose (Nanonose)

One of the areas with high-implementation potential for nanosensors is the artificial nose studies. Studies are continuing on systems to capture and process odor molecules (Fig. 39.2). Systems designed for this purpose involve use of receptors, transmitters, receivers, and a processor. Receptors used in these systems are manufactured with nanofabrication or MEMS (micro-electromechanical systems) technology. Nanowire and graphene sensors can also be used to produce nanonose (Figs. 39.3 and 39.4). Multisegmented nanowires via surface functionalization method can be used for detection of biological or odor molecules. P-type multisegmented nanostructures are in a back-to-back Schottky diode configuration. Au-part of the multisegment can be surface functionalized to increase the sensitivity of the nanowire sensor with specific sensing molecules. Attachment of odor molecules on Au-portion of the nanowire can modulate the Fermi level of the heterojunction device which leads to detection of the desired molecules. Such multisegmented nanowire sensors can be fabricated into an array format for detection of different types of odor molecules or biological agents.

Fig. 39.2
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Taxonomy of nose-like sensors (Adapted from The MITRE Corporation, McLean, ©1997–2006)

Fig. 39.3
figure 00393

(a) Schematic of CdTe-Au-CdTe nanowire field-effect transistor. (b) SEM image of CdTe-Au-CdTe nanowire FET (Source: Wang and Ozkan 2008)

Fig. 39.4
figure 00394

Graphene-based electronic sensors are successfully used for chemical, biological, and gas sensing (Source: Guo et al. 2012)

Similarly, graphene field-effect transistors arrays can be used for sensing as well. Using graphene sensors, pH, DNA, and vapor detection have been demonstrated. Stability and reliability of such sensors became questionable due to graphene’s fast response to its environment. For this purpose, extraordinary electrical property of a graphene transistor is combined with a cover of block copolymers where nanometer-scale openings provide access to the graphene surface where sensing can occur (Fig. 39.4). Gas/odor molecules can penetrate through the small holes across the block copolymer layer and reach to the graphene layer underneath. Interaction with these molecules and graphene surface leads to a shift in Dirac point of the transistor. Electrical shift in the signal is basically the senor output.

Arrays of graphene field-effect transistors with block copolymer on the surface can be fabricated and used for detection of different molecules. Block copolymers in appropriate volume fractions and molecular weights can provide control over the morphology and size/separation distance of cylindrical microdomains. These domains can be adjusted based on the size of the molecules or biological agents to be detected. As sensor output, the amount of Dirac point shift for different molecules is expected to be different which is important for the array-formatted sensors.

Today, electro-physiological basis of odor detection process is better understood, and in the upcoming period, the most important goal is to create a different type of nanosensors structure that will bring together an integrated system.

With the successful results obtained from studies based on this type of nanosensor will be able to develop an artificial nose. Cancer

It has not gained enough success at the level of meeting the needs of the society regarding cancer, which has one of the highest mortality rates as a disease group in the world and on which billions of dollars are spent every year all around the world for understanding tumoral pathophysiology, for developing effective treatment agents, and for the treatment of patients. Without having the full understanding of chaotic dynamics of tumor tissue, it is not possible to administer an effective anticancer treatment. Today, it has been commonly discussed about the wrongs known as right on the topics of molecular oncology approaches and cancer pathogenesis; accordingly, a new strategy in cancer therapy should be developed.

39.4.2 Diagnosis and Imaging Methods Based on Nanomedicine

The most important aim in diagnosis of diseases is to diagnose disease when it is at the earliest stage, at one-cell level. To reach this aim, it is required to develop new in vivo and in vitro diagnosis methods based on nanotechnology. Within the scope of in vitro applications, studies have been made on chemo-bio-nanosensors and ultrasensitive biochips (“lab-on-a-chip” and “cells-on-chips” devices) and products for routine medical applications have been prepared.

To-be-produced nano-analyzer devices can be used by patients and at the same time will be able to transmit multiple data to clinicians. More important than that, by means of nanobiosensors it will be possible to increase accuracy of already used test methods (Wang et al. 2010). Biosensors (Photonic Crystal Nanobiosensors, Magneto Nano-immunosensor, Piezoelectric Nanosensors, Resonating Beam Sensors, Ion-channel Biosensors, etc.) harness the immensely powerful molecular recognition properties of living systems and engineer these into electronic devices to provide easy-to-use sensing devices. The most successful biosensor developed to date is the home blood glucose sensor which is now ubiquitous worldwide. Biosensors can be used to measure disease markers, food safety, and environmental quality and to ensure safety and security.

Developments in microscopic scanning-imaging methods (quantitative PET, MRS, d-MRI, f-MRI, etc.) and spectroscopic techniques provide ultrahigh spatial resolutions and give detailed information about the complex “functionality” of cells (Zhang et al. 2012). Data acquired by use of quantum dots and fluorescent nanoparticles will lead to developments of more innovative and stronger in vivo diagnosis devices. Nanodevices produced as accompanying this functional molecular imaging will be more effective and much safer.

39.4.3 Targeting Delivery and Releasing

Long-term aims of controlled drug delivery systems are to develop diagnostic agents with high level of efficiency and safety and to perform treatment, application, and follow-up with the same nanosystem. “Find, fight, and follow,” as is the concept determined, includes early diagnosis, treatment, and monitoring of the results, and also is stated as “theragnostic” (therapy+diagnose).

Drug delivery techniques suitable for theragnostic definition are prepared in accordance with two needs. First, one is drugs targeting more effectively where the disease is located, with high patient tolerance and cost effective, and the other is to detect new methods for distribution of new types of pharmacologic agents which cannot be distributed effectively by conventional methods.

The main aim of pharmaceutic studies in this regard is to address any medication to specific target tissue at the right time, in convenient amount and with safe-repeatable-controllable method. Today 13 % of products on the pharmaceutic market are related to controlled drug distribution systems. Nanoparticle formulations are still used to increase activity without increasing surface/volume proportion. In addition, nanoparticles act as drug carriers to effectively transmit therapeutics which have weak liquidity. If a therapeutic active substance is suitably encapsulated in a nanoparticle, carrying this drug anywhere requested, controlled oscillation of the drug, and protection from early stage activity decreases can be managed. These results will both increase the efficiency of drugs and decrease side effects dramatically. These types of nanoparticle delivery systems can be used for the treatment of cancer and many other diseases (Zhang et al. 2008).

Controlled drug delivery is based on the principle of turning pathophysiological changes, which appear basically in diseased tissue, into advantage for treatment. Because in tissues in which pathological process has already started, all physiological functionality disorders related to cell homeostasis are observed, accumulation of carriers which distribute drugs in a controlled manner will be easier. Anatomic barrier between normal and pathologic tissues and vascularization differences will make it easier to reach of nanocarriers to diseased tissue. Thus, nanocarriers which carry therapeutic agents will reach much higher concentration in target tissue comparing to doses applied with normal drug treatment.

As a result of decrease in vascular permeability and lymphatic drainage appeared especially in tissue which developed tumor and inflammatory diseases, on one hand, reach of nanostructures to target tissue will be facilitated, on the other hand, it will be more difficult to withdraw. By means of the opportunity created by this pathophysiological change, nanostructures can easily be accumulated in extravasations and target tissue.

By means of localization tendency of nanocarrying systems, especially in RES, will be considered as a huge advantage in terms of both controlled and passive distribution of drugs. This natural distribution method managed by macrophages can be used for intracellular infections of liver and spleen.

Patient-specific therapies have a critical role on nanosystems performing controlled distributions to reach the target. It is possible to find many nanocarrying systems having such an aim in the literature (liposomes, micellar and microemulsion systems, liquid crystal-based formulations, nanocrystals, antibodies and conjugates, naturally occurring proteins as delivery systems, polymer conjugates and bio-conjugates, biodegradable nanoparticles/nanocapsules, virus-like particles for gene delivery, delivery of small nucleic acids or mimetics, delivery of vaccines, synthetic biomimetics, dendrimers, carbon nanotubes, etc.) (Fig. 39.5).

Fig. 39.5
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Virus-like particles: AFM and MFM imaging of single CPMV-IO hybrids. (a) AFM topography showing single hybrids (whites squares). AFM/MFM schematic of dynamic lift-mode operation (inset), (b) AFM topography, (c) AFM phase detection, and (d) MFM phase detection of two adjacent CPMV-IO hybrids and their corresponding cross sections (Source: Martinez-Morales et al. 2008)

Although there have been many successful experimental studies on the topic existing today, strategies for developing new drug-carrying systems are not completely accepted yet. Efforts on this topic have been proceeding slowly because of the uncertainties about regulation and toxic side effects. It should be accepted that drug safety has to be attached as much importance as drug efficiency considering all nanoparticles.

39.5 Conclusions

As in all areas related to medicine, nanomedicine applications have many technological, legal, administrative, environmental, toxicological, social, and economic problems. However, in human health-related preventive and curative health services in achieving the objectives and the high-tech solutions on the whole of society through dissemination, nanomedicine will be one of the sciences to shape the world in the near future.